BRCA-mutant prostate cancer is a molecularly-defined subset of prostate adenocarcinoma harboring germline or somatic mutations in BRCA1 or BRCA2 genes, which encode critical homologous recombination repair (HRR) proteins. BRCA2 mutations occur in approximately 5-7% of metastatic castration-resistant prostate cancer (mCRPC) and are associated with more aggressive disease, earlier onset, and increased metastatic potential. The identification of HRR deficiency as an actionable target led to approval of PARP inhibitors olaparib and rucaparib for BRCA-mutated mCRPC, representing a paradigm shift in precision oncology for prostate cancer.
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name: BRCA-Mutant Prostate Cancer
creation_date: '2026-01-26T02:55:13Z'
updated_date: '2026-05-06T00:21:04Z'
description: >-
BRCA-mutant prostate cancer is a molecularly-defined subset of prostate adenocarcinoma
harboring germline or somatic mutations in BRCA1 or BRCA2 genes, which encode critical
homologous recombination repair (HRR) proteins. BRCA2 mutations occur in approximately
5-7% of metastatic castration-resistant prostate cancer (mCRPC) and are associated
with more aggressive disease, earlier onset, and increased metastatic potential.
The identification of HRR deficiency as an actionable target led to approval of
PARP inhibitors olaparib and rucaparib for BRCA-mutated mCRPC, representing a
paradigm shift in precision oncology for prostate cancer.
categories:
- Genitourinary Cancer
- Molecularly-Defined Cancer
- DNA Repair Deficiency Syndrome
parents:
- prostate cancer
has_subtypes:
- name: BRCA2-Mutant Prostate Cancer
description: >-
More common than BRCA1 mutations, occurring in approximately 5% of mCRPC.
BRCA2 mutations confer higher sensitivity to PARP inhibitors and platinum
chemotherapy.
- name: BRCA1-Mutant Prostate Cancer
description: >-
Less common than BRCA2 mutations in prostate cancer. Also predicts response
to PARP inhibition and platinum chemotherapy.
pathophysiology:
- name: Homologous Recombination Repair Deficiency
description: >-
Loss of functional BRCA1 or BRCA2 impairs homologous recombination repair (HRR),
the high-fidelity pathway for repairing DNA double-strand breaks. This leads to
accumulation of genomic instability and reliance on error-prone repair pathways.
cell_types:
- preferred_term: prostate gland cell
term:
id: CL:0002231
label: epithelial cell of prostate
biological_processes:
- preferred_term: double-strand break repair via homologous recombination
modifier: DECREASED
term:
id: GO:0000724
label: double-strand break repair via homologous recombination
locations:
- preferred_term: prostate gland
term:
id: UBERON:0002367
label: prostate gland
downstream:
- target: Genomic Instability
description: HRR deficiency leads to accumulation of chromosomal aberrations
- target: Synthetic Lethality with PARP Inhibition
description: HRR-deficient cells are exquisitely sensitive to PARP inhibition
- name: Genomic Instability
description: >-
HRR deficiency leads to genomic instability characterized by chromosomal
rearrangements, copy number alterations, and mutational signatures typical
of BRCA deficiency. This drives aggressive tumor behavior but also creates
therapeutic vulnerabilities.
biological_processes:
- preferred_term: DNA repair
modifier: DECREASED
term:
id: GO:0006281
label: DNA repair
- name: Synthetic Lethality with PARP Inhibition
description: >-
PARP enzymes are essential for single-strand break repair. In HRR-deficient
cells, PARP inhibition causes accumulation of double-strand breaks that cannot
be repaired, leading to synthetic lethality and selective tumor cell death.
biological_processes:
- preferred_term: single-strand break repair
modifier: DECREASED
term:
id: GO:0000012
label: single-strand break repair
downstream:
- target: BRCA Reversion-Mediated PARP Resistance
description: >-
Therapeutic pressure from PARP inhibition can select resistant clones with
BRCA reversion mutations that restore homologous recombination repair.
- name: PARP-Androgen Receptor Co-Dependency
description: >-
BRCA-mutant metastatic castration-resistant prostate cancer remains driven
by androgen receptor biology while also depending on PARP-mediated DNA
damage response. This provides the mechanistic rationale for combining PARP
inhibition with androgen receptor pathway inhibition in HRR-deficient
disease.
genes:
- preferred_term: AR
term:
id: hgnc:644
label: AR
biological_processes:
- preferred_term: androgen receptor signaling pathway
modifier: INCREASED
term:
id: GO:0030521
label: androgen receptor signaling pathway
evidence:
- reference: DOI:10.1038/s41591-023-02704-x
reference_title: "First-line talazoparib with enzalutamide in HRR-deficient metastatic castration-resistant prostate cancer: the phase 3 TALAPRO-2 trial"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Preclinical evidence has suggested an interplay between the androgen
receptor, which largely drives the growth of prostate cancer cells, and
poly(ADP-ribose) polymerase.
explanation: >-
TALAPRO-2 states the PARP-androgen receptor crosstalk rationale for
first-line PARP inhibitor plus AR pathway inhibitor therapy.
- name: BRCA Reversion-Mediated PARP Resistance
description: >-
Acquired BRCA1 or BRCA2 reversion mutations can restore homologous
recombination repair in resistant tumor subclones after PARP inhibitor or
platinum exposure, reducing the synthetic-lethality vulnerability that
defines BRCA-mutant prostate cancer treatment sensitivity.
genes:
- preferred_term: BRCA1
term:
id: hgnc:1100
label: BRCA1
- preferred_term: BRCA2
term:
id: hgnc:1101
label: BRCA2
biological_processes:
- preferred_term: double-strand break repair via homologous recombination
modifier: INCREASED
term:
id: GO:0000724
label: double-strand break repair via homologous recombination
evidence:
- reference: PMID:36243543
reference_title: "Emergence of BRCA Reversion Mutations in Patients with Metastatic Castration-resistant Prostate Cancer After Treatment with Rucaparib."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
No baseline BRCA reversion mutations were observed in 100 BRCA+ patients.
NGS identified somatic BRCA reversion mutations in 39% (39/100) of
patients after progression.
explanation: >-
TRITON2 post-progression cfDNA analysis documents acquired BRCA reversion
mutations after rucaparib treatment in BRCA-mutant mCRPC.
- reference: PMID:39577422
reference_title: Elucidating acquired PARP inhibitor resistance in advanced prostate cancer.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Evaluating samples from patients with metastatic CRPC treated in the
TOPARP-B trial, we identify reversion mutations in most
BRCA2/PALB2-mutated tumors (79%) by end of treatment.
explanation: >-
TOPARP-B resistance analysis supports reversion-mediated restoration of
HRR as a common acquired PARP inhibitor resistance mechanism.
histopathology:
- name: Acinar Adenocarcinoma
finding_term:
preferred_term: Prostate Acinar Adenocarcinoma
term:
id: NCIT:C5596
label: Prostate Acinar Adenocarcinoma
frequency: VERY_FREQUENT
description: The most common prostatic cancers are acinary adenocarcinomas.
evidence:
- reference: PMID:36081403
reference_title: "Histological patterns, subtypes and aspects of prostate cancer: different aspects, different outcomes."
supports: SUPPORT
snippet: "The most common prostatic cancers (PCa) are acinary \nadenocarcinomas."
explanation: Abstract notes that acinary adenocarcinomas are the most common prostatic cancers.
phenotypes:
- category: Genitourinary
name: Lower Urinary Tract Symptoms
frequency: FREQUENT
description: >-
Urinary frequency, urgency, hesitancy, and weak stream due to prostate
enlargement from tumor growth.
phenotype_term:
preferred_term: Abnormality of the urinary system
term:
id: HP:0000079
label: Abnormality of the urinary system
- category: Musculoskeletal
name: Bone Pain
frequency: FREQUENT
description: >-
Bone metastases are common in advanced prostate cancer and may present
earlier in BRCA-mutant disease. Osteoblastic lesions are typical.
phenotype_term:
preferred_term: Bone pain
term:
id: HP:0002653
label: Bone pain
- category: Constitutional
name: Fatigue
frequency: FREQUENT
description: >-
Constitutional symptoms are common in metastatic disease and may be
exacerbated by androgen deprivation therapy.
phenotype_term:
preferred_term: Fatigue
term:
id: HP:0012378
label: Fatigue
biochemical:
- name: PSA (Prostate-Specific Antigen)
notes: >-
PSA is the primary biomarker for prostate cancer detection and monitoring.
BRCA-mutant tumors may have higher PSA levels at diagnosis reflecting
more aggressive biology.
genetic:
- name: BRCA2
gene_term:
preferred_term: BRCA2
term:
id: hgnc:1101
label: BRCA2
association: Germline and Somatic Loss-of-Function Mutations
inheritance:
- name: Autosomal Dominant
notes: >-
BRCA2 is the most commonly mutated HRR gene in prostate cancer, occurring
in approximately 5-7% of mCRPC. Both germline and somatic mutations are
actionable. Associated with earlier onset and more aggressive disease.
evidence:
- reference: PMID:36434163
reference_title: "Germline mutations in prostate cancer: a systematic review of the evidence for personalized medicine."
supports: PARTIAL
snippet: "Emerging data show that germline mutations in homologous recombination genes (BRCA1/2, ATM, CHECK2), in mismatch repair genes (MLH1, MLH2, MSH6), and other additional genes are associated with the development and aggressiveness of PCa."
explanation: "Supports BRCA1/2 mutations contributing to prostate cancer development and aggressiveness."
- name: BRCA1
gene_term:
preferred_term: BRCA1
term:
id: hgnc:1100
label: BRCA1
association: Germline and Somatic Loss-of-Function Mutations
inheritance:
- name: Autosomal Dominant
notes: >-
BRCA1 mutations are less common than BRCA2 in prostate cancer but also
confer HRR deficiency and PARP inhibitor sensitivity.
treatments:
- name: Olaparib
description: >-
PARP inhibitor approved for mCRPC with BRCA1/2 mutations (or other HRR gene
alterations) after progression on enzalutamide or abiraterone. Exploits
synthetic lethality in HRR-deficient tumors.
treatment_term:
preferred_term: targeted therapy
term:
id: NCIT:C93352
label: Targeted Therapy
therapeutic_agent:
- preferred_term: olaparib
term:
id: CHEBI:83766
label: olaparib
- name: Rucaparib
description: >-
PARP inhibitor approved for BRCA1/2-mutated mCRPC after progression on
androgen receptor-directed therapy and taxane-based chemotherapy.
treatment_term:
preferred_term: targeted therapy
term:
id: NCIT:C93352
label: Targeted Therapy
therapeutic_agent:
- preferred_term: rucaparib
term:
id: CHEBI:134689
label: rucaparib
- name: PARP Inhibitor-AR Pathway Inhibitor Combination Therapy
description: >-
First-line combinations pair a PARP inhibitor with an androgen receptor
pathway inhibitor, such as talazoparib plus enzalutamide or niraparib plus
abiraterone acetate, to exploit both HRR deficiency and AR-PARP crosstalk in
HRR-mutated or BRCA-mutated mCRPC.
evidence:
- reference: DOI:10.1200/jco.23.02182
reference_title: "US Food and Drug Administration Approval Summary: Talazoparib in Combination With Enzalutamide for Treatment of Patients With Homologous Recombination Repair Gene-Mutated Metastatic Castration-Resistant Prostate Cancer"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The US Food and Drug Administration (FDA) approved talazoparib with
enzalutamide for first-line treatment of patients with homologous
recombination repair (HRR) gene-mutated metastatic castration-resistant
prostate cancer (mCRPC).
explanation: >-
FDA approval summary supports talazoparib plus enzalutamide as a
first-line HRR-mutated mCRPC regimen.
- reference: DOI:10.1200/jco.22.01649
reference_title: Niraparib and Abiraterone Acetate for Metastatic Castration-Resistant Prostate Cancer
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Median rPFS in the BRCA1/2 subgroup was significantly longer in the
niraparib + AAP group compared with the placebo + AAP group (16.6 v 10.9
months; hazard ratio [HR], 0.53; 95% CI, 0.36 to 0.79; P = .001).
explanation: >-
MAGNITUDE supports niraparib plus abiraterone acetate and prednisone in
the BRCA1/2-mutated subgroup.
treatment_term:
preferred_term: targeted therapy
term:
id: NCIT:C93352
label: Targeted Therapy
therapeutic_agent:
- preferred_term: talazoparib
term:
id: CHEBI:231344
label: talazoparib
- preferred_term: enzalutamide
term:
id: CHEBI:68534
label: enzalutamide
- preferred_term: niraparib
term:
id: CHEBI:176844
label: niraparib
- preferred_term: abiraterone
term:
id: CHEBI:68642
label: abiraterone
target_mechanisms:
- target: PARP-Androgen Receptor Co-Dependency
treatment_effect: INHIBITS
description: >-
Combined PARP and AR pathway inhibition targets the co-dependency between
androgen receptor signaling and PARP-mediated DNA damage response.
evidence:
- reference: DOI:10.1038/s41591-023-02704-x
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This association provides a rationale for their co-inhibition for the
treatment of metastatic castration-resistant prostate cancer (mCRPC), an
area of unmet medical need.
explanation: >-
TALAPRO-2 describes the mechanistic rationale for co-inhibiting AR and
PARP in mCRPC.
- name: Platinum Chemotherapy
description: >-
HRR-deficient tumors show increased sensitivity to platinum agents due to
inability to repair platinum-induced DNA crosslinks. Carboplatin-based
regimens may be considered.
treatment_term:
preferred_term: chemotherapy
term:
id: MAXO:0000647
label: chemotherapy
- name: Androgen Deprivation Therapy
description: >-
Standard treatment for advanced prostate cancer regardless of HRR status.
May be combined with novel hormonal agents like enzalutamide or abiraterone.
treatment_term:
preferred_term: androgen deprivation therapy
term:
id: MAXO:0000283
label: hormone modifying therapy
disease_term:
preferred_term: prostate cancer
term:
id: MONDO:0008315
label: prostate cancer
classifications:
icdo_morphology:
classification_value: Adenocarcinoma
harrisons_chapter:
- classification_value: cancer
- classification_value: solid tumor
references:
- reference: DOI:10.1001/jamaoncol.2024.0734
title: Magnetic Resonance Imaging in Prostate Cancer Screening
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-falcon.md
findings:
- statement: Magnetic Resonance Imaging in Prostate Cancer Screening
supporting_text: ImportanceProstate magnetic resonance imaging (MRI) is increasingly integrated within the prostate cancer (PCa) early detection pathway.ObjectiveTo systematically evaluate the existing evidence regarding screening pathways incorporating MRI with targeted biopsy and assess their diagnostic value compared with prostate-specific antigen (PSA)–based screening with systematic biopsy strategies.Data SourcesPubMed/MEDLINE, Embase, Cochrane/Central, Scopus, and Web of Science (through May 2023).Study SelectionRandomized clinical trials and prospective cohort studies were eligible if they reported data on the diagnostic utility of prostate MRI in the setting of PCa screening.Data ExtractionNumber of screened individuals, biopsy indications, biopsies performed, clinically significant PCa (csPCa) defined as International Society of Urological Pathology (ISUP) grade 2 or higher, and insignificant (ISUP1) PCas detected were extracted.Main Outcomes and MeasuresThe primary outcome was csPCa detection rate.
evidence:
- reference: DOI:10.1001/jamaoncol.2024.0734
reference_title: Magnetic Resonance Imaging in Prostate Cancer Screening
supports: SUPPORT
evidence_source: OTHER
snippet: ImportanceProstate magnetic resonance imaging (MRI) is increasingly integrated within the prostate cancer (PCa) early detection pathway.ObjectiveTo systematically evaluate the existing evidence regarding screening pathways incorporating MRI with targeted biopsy and assess their diagnostic value compared with prostate-specific antigen (PSA)–based screening with systematic biopsy strategies.Data SourcesPubMed/MEDLINE, Embase, Cochrane/Central, Scopus, and Web of Science (through May 2023).Study SelectionRandomized clinical trials and prospective cohort studies were eligible if they reported data on the diagnostic utility of prostate MRI in the setting of PCa screening.Data ExtractionNumber of screened individuals, biopsy indications, biopsies performed, clinically significant PCa (csPCa) defined as International Society of Urological Pathology (ISUP) grade 2 or higher, and insignificant (ISUP1) PCas detected were extracted.Main Outcomes and MeasuresThe primary outcome was csPCa detection rate.
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: DOI:10.1001/jamaoncol.2024.2185
title: <i>BRCA1, BRCA2</i>, and Associated Cancer Risks and Management for Male Patients
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-falcon.md
findings:
- statement: ImportanceHalf of all carriers of inherited cancer-predisposing variants in BRCA1 and BRCA2 are male, but the implications for their health are underrecognized compared to female individuals.
supporting_text: ImportanceHalf of all carriers of inherited cancer-predisposing variants in BRCA1 and BRCA2 are male, but the implications for their health are underrecognized compared to female individuals.
evidence:
- reference: DOI:10.1001/jamaoncol.2024.2185
reference_title: <i>BRCA1, BRCA2</i>, and Associated Cancer Risks and Management for Male Patients
supports: SUPPORT
evidence_source: OTHER
snippet: ImportanceHalf of all carriers of inherited cancer-predisposing variants in BRCA1 and BRCA2 are male, but the implications for their health are underrecognized compared to female individuals.
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: DOI:10.1016/j.ebiom.2023.104738
title: BRCA-deficient metastatic prostate cancer has an adverse prognosis and distinct genomic phenotype
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-falcon.md
findings:
- statement: BRCA-deficient metastatic prostate cancer has an adverse prognosis and distinct genomic phenotype
supporting_text: BRCA-deficient metastatic prostate cancer has an adverse prognosis and distinct genomic phenotype
- reference: DOI:10.1038/s41591-023-02704-x
title: 'First-line talazoparib with enzalutamide in HRR-deficient metastatic castration-resistant prostate cancer: the phase 3 TALAPRO-2 trial'
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-falcon.md
findings:
- statement: Preclinical evidence has suggested an interplay between the androgen receptor, which largely drives the growth of prostate cancer cells, and poly(ADP-ribose) polymerase.
supporting_text: Preclinical evidence has suggested an interplay between the androgen receptor, which largely drives the growth of prostate cancer cells, and poly(ADP-ribose) polymerase.
evidence:
- reference: DOI:10.1038/s41591-023-02704-x
reference_title: 'First-line talazoparib with enzalutamide in HRR-deficient metastatic castration-resistant prostate cancer: the phase 3 TALAPRO-2 trial'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Preclinical evidence has suggested an interplay between the androgen receptor, which largely drives the growth of prostate cancer cells, and poly(ADP-ribose) polymerase.
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: DOI:10.1158/1078-0432.ccr-21-3577
title: Olaparib Efficacy in Patients with Metastatic Castration-resistant Prostate Cancer and <i>BRCA1, BRCA2</i> , or <i>ATM</i> Alterations Identified by Testing Circulating Tumor DNA
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-falcon.md
findings:
- statement: The phase III PROfound study (NCT02987543) evaluated olaparib versus abiraterone or enzalutamide (control) in metastatic castration-resistant prostate cancer (mCRPC) with tumor homologous recombination repair (HRR) gene alterations.
supporting_text: 'The phase III PROfound study (NCT02987543) evaluated olaparib versus abiraterone or enzalutamide (control) in metastatic castration-resistant prostate cancer (mCRPC) with tumor homologous recombination repair (HRR) gene alterations.'
evidence:
- reference: DOI:10.1158/1078-0432.ccr-21-3577
reference_title: Olaparib Efficacy in Patients with Metastatic Castration-resistant Prostate Cancer and <i>BRCA1, BRCA2</i> , or <i>ATM</i> Alterations Identified by Testing Circulating Tumor DNA
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 'The phase III PROfound study (NCT02987543) evaluated olaparib versus abiraterone or enzalutamide (control) in metastatic castration-resistant prostate cancer (mCRPC) with tumor homologous recombination repair (HRR) gene alterations.'
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: DOI:10.1158/1078-0432.ccr-22-0931
title: Detection of <i>BRCA1</i> , <i>BRCA2</i> , and <i>ATM</i> Alterations in Matched Tumor Tissue and Circulating Tumor DNA in Patients with Prostate Cancer Screened in PROfound
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-falcon.md
findings:
- statement: 'Not all patients with metastatic castration-resistant prostate cancer (mCRPC) have sufficient tumor tissue available for multigene molecular testing.'
supporting_text: 'Not all patients with metastatic castration-resistant prostate cancer (mCRPC) have sufficient tumor tissue available for multigene molecular testing.'
evidence:
- reference: DOI:10.1158/1078-0432.ccr-22-0931
reference_title: Detection of <i>BRCA1</i> , <i>BRCA2</i> , and <i>ATM</i> Alterations in Matched Tumor Tissue and Circulating Tumor DNA in Patients with Prostate Cancer Screened in PROfound
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 'Not all patients with metastatic castration-resistant prostate cancer (mCRPC) have sufficient tumor tissue available for multigene molecular testing.'
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: DOI:10.1158/2767-9764.crc-23-0554
title: LP-184, a Novel Acylfulvene Molecule, Exhibits Anticancer Activity against Diverse Solid Tumors with Homologous Recombination Deficiency
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-falcon.md
findings:
- statement: Homologous recombination (HR)-related gene alterations are present in a significant subset of prostate, breast, ovarian, pancreatic, lung, and colon cancers rendering these tumors as potential responders to specific DNA damaging agents.
supporting_text: Homologous recombination (HR)-related gene alterations are present in a significant subset of prostate, breast, ovarian, pancreatic, lung, and colon cancers rendering these tumors as potential responders to specific DNA damaging agents.
evidence:
- reference: DOI:10.1158/2767-9764.crc-23-0554
reference_title: LP-184, a Novel Acylfulvene Molecule, Exhibits Anticancer Activity against Diverse Solid Tumors with Homologous Recombination Deficiency
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Homologous recombination (HR)-related gene alterations are present in a significant subset of prostate, breast, ovarian, pancreatic, lung, and colon cancers rendering these tumors as potential responders to specific DNA damaging agents.
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: DOI:10.1200/jco.22.01649
title: Niraparib and Abiraterone Acetate for Metastatic Castration-Resistant Prostate Cancer
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-falcon.md
findings:
- statement: Metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease with current standard-of-care therapies.
supporting_text: Metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease with current standard-of-care therapies.
evidence:
- reference: DOI:10.1200/jco.22.01649
reference_title: Niraparib and Abiraterone Acetate for Metastatic Castration-Resistant Prostate Cancer
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease with current standard-of-care therapies.
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: DOI:10.1200/jco.23.00339
title: Olaparib for the Treatment of Patients With Metastatic Castration-Resistant Prostate Cancer and Alterations in <i>BRCA1</i> and/or <i>BRCA2</i> in the PROfound Trial
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-falcon.md
findings:
- statement: 'Olaparib improved PFS and OS across subgroups of BRCA1/2mut #prostatecancer patients in the PROFOUND phase III trial.'
supporting_text: 'Olaparib improved PFS and OS across subgroups of BRCA1/2mut #prostatecancer patients in the PROFOUND phase III trial.'
evidence:
- reference: DOI:10.1200/jco.23.00339
reference_title: Olaparib for the Treatment of Patients With Metastatic Castration-Resistant Prostate Cancer and Alterations in <i>BRCA1</i> and/or <i>BRCA2</i> in the PROfound Trial
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 'Olaparib improved PFS and OS across subgroups of BRCA1/2mut #prostatecancer patients in the PROFOUND phase III trial.'
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: DOI:10.1200/jco.23.02182
title: 'US Food and Drug Administration Approval Summary: Talazoparib in Combination With Enzalutamide for Treatment of Patients With Homologous Recombination Repair Gene-Mutated Metastatic Castration-Resistant Prostate Cancer'
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-falcon.md
findings:
- statement: The US Food and Drug Administration (FDA) approved talazoparib with enzalutamide for first-line treatment of patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC).
supporting_text: The US Food and Drug Administration (FDA) approved talazoparib with enzalutamide for first-line treatment of patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC).
evidence:
- reference: DOI:10.1200/jco.23.02182
reference_title: 'US Food and Drug Administration Approval Summary: Talazoparib in Combination With Enzalutamide for Treatment of Patients With Homologous Recombination Repair Gene-Mutated Metastatic Castration-Resistant Prostate Cancer'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The US Food and Drug Administration (FDA) approved talazoparib with enzalutamide for first-line treatment of patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC).
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: DOI:10.1200/po.21.00070
title: Differential Activity of PARP Inhibitors in<i>BRCA1</i>- Versus<i>BRCA2</i>-Altered Metastatic Castration-Resistant Prostate Cancer
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-falcon.md
findings:
- statement: Differential Activity of PARP Inhibitors in<i>BRCA1</i>- Versus<i>BRCA2</i>-Altered Metastatic Castration-Resistant Prostate Cancer
supporting_text: Two poly (ADP-ribose) polymerase (PARP) inhibitors (olaparib and rucaparib) are US Food and Drug Administration–approved for patients with metastatic castration-resistant prostate cancer (mCRPC) harboring BRCA1/ 2 mutations, but the relative efficacy of PARP inhibition in BRCA1- versus BRCA2-altered mCRPC is understudied.METHODSWe conducted a multicenter retrospective analysis involving 12 sites.
evidence:
- reference: DOI:10.1200/po.21.00070
reference_title: Differential Activity of PARP Inhibitors in<i>BRCA1</i>- Versus<i>BRCA2</i>-Altered Metastatic Castration-Resistant Prostate Cancer
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Two poly (ADP-ribose) polymerase (PARP) inhibitors (olaparib and rucaparib) are US Food and Drug Administration–approved for patients with metastatic castration-resistant prostate cancer (mCRPC) harboring BRCA1/ 2 mutations, but the relative efficacy of PARP inhibition in BRCA1- versus BRCA2-altered mCRPC is understudied.METHODSWe conducted a multicenter retrospective analysis involving 12 sites.
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: DOI:10.3390/cancers15061849
title: Advances in PARP Inhibitors for Prostate Cancer
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-falcon.md
findings:
- statement: Poly-adenosine diphosphate-ribose polymerase plays an essential role in cell function by regulating apoptosis, genomic stability and DNA repair.
supporting_text: Poly-adenosine diphosphate-ribose polymerase plays an essential role in cell function by regulating apoptosis, genomic stability and DNA repair.
evidence:
- reference: DOI:10.3390/cancers15061849
reference_title: Advances in PARP Inhibitors for Prostate Cancer
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Poly-adenosine diphosphate-ribose polymerase plays an essential role in cell function by regulating apoptosis, genomic stability and DNA repair.
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: DOI:10.3390/cancers15092435
title: 'Frequency of Germline and Somatic BRCA1 and BRCA2 Mutations in Prostate Cancer: An Updated Systematic Review and Meta-Analysis'
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-falcon.md
findings:
- statement: In prostate cancer (PC), the presence of BRCA somatic and/or germline mutation provides prognostic and predictive information.
supporting_text: In prostate cancer (PC), the presence of BRCA somatic and/or germline mutation provides prognostic and predictive information.
evidence:
- reference: DOI:10.3390/cancers15092435
reference_title: 'Frequency of Germline and Somatic BRCA1 and BRCA2 Mutations in Prostate Cancer: An Updated Systematic Review and Meta-Analysis'
supports: SUPPORT
evidence_source: OTHER
snippet: In prostate cancer (PC), the presence of BRCA somatic and/or germline mutation provides prognostic and predictive information.
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: DOI:10.3390/cancers15092662
title: 'Roles of the PARP Inhibitor in BRCA1 and BRCA2 Pathogenic Mutated Metastatic Prostate Cancer: Direct Functions and Modification of the Tumor Microenvironment'
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-falcon.md
findings:
- statement: Cancer cells frequently exhibit defects in DNA damage repair (DDR), leading to genomic instability.
supporting_text: Cancer cells frequently exhibit defects in DNA damage repair (DDR), leading to genomic instability.
evidence:
- reference: DOI:10.3390/cancers15092662
reference_title: 'Roles of the PARP Inhibitor in BRCA1 and BRCA2 Pathogenic Mutated Metastatic Prostate Cancer: Direct Functions and Modification of the Tumor Microenvironment'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Cancer cells frequently exhibit defects in DNA damage repair (DDR), leading to genomic instability.
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: DOI:10.3390/cancers15153998
title: Circulating Tumor DNA Analysis on Metastatic Prostate Cancer with Disease Progression
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-falcon.md
findings:
- statement: The positivity rate of circulating tumor DNA (ctDNA) next-generation sequencing (NGS) varies among patients with metastatic prostate cancer (mPC), complicating its incorporation into regular practice.
supporting_text: The positivity rate of circulating tumor DNA (ctDNA) next-generation sequencing (NGS) varies among patients with metastatic prostate cancer (mPC), complicating its incorporation into regular practice.
evidence:
- reference: DOI:10.3390/cancers15153998
reference_title: Circulating Tumor DNA Analysis on Metastatic Prostate Cancer with Disease Progression
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The positivity rate of circulating tumor DNA (ctDNA) next-generation sequencing (NGS) varies among patients with metastatic prostate cancer (mPC), complicating its incorporation into regular practice.
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: DOI:10.3390/cells13080673
title: Development and Characterisation of a New Patient-Derived Xenograft Model of AR-Negative Metastatic Castration-Resistant Prostate Cancer
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-falcon.md
findings:
- statement: Development and Characterisation of a New Patient-Derived Xenograft Model of AR-Negative Metastatic Castration-Resistant Prostate Cancer
supporting_text: As the treatment landscape for prostate cancer gradually evolves, the frequency of treatment-induced neuroendocrine prostate cancer (NEPC) and double-negative prostate cancer (DNPC) that is deficient for androgen receptor (AR) and neuroendocrine (NE) markers has increased.
evidence:
- reference: DOI:10.3390/cells13080673
reference_title: Development and Characterisation of a New Patient-Derived Xenograft Model of AR-Negative Metastatic Castration-Resistant Prostate Cancer
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: As the treatment landscape for prostate cancer gradually evolves, the frequency of treatment-induced neuroendocrine prostate cancer (NEPC) and double-negative prostate cancer (DNPC) that is deficient for androgen receptor (AR) and neuroendocrine (NE) markers has increased.
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: DOI:10.3390/life14020198
title: 'PARP Inhibitors in Metastatic Castration-Resistant Prostate Cancer: Unraveling the Therapeutic Landscape'
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-falcon.md
findings:
- statement: 'PARP Inhibitors in Metastatic Castration-Resistant Prostate Cancer: Unraveling the Therapeutic Landscape'
supporting_text: The treatment landscape of metastatic prostate cancer (mPCa) is rapidly evolving with the recent approvals of poly-ADP ribose polymerase inhibitors (PARPis) as monotherapy or as part of combination therapy with androgen receptor pathway inhibitors in patients with metastatic castration-resistant prostate cancer (mCRPC).
evidence:
- reference: DOI:10.3390/life14020198
reference_title: 'PARP Inhibitors in Metastatic Castration-Resistant Prostate Cancer: Unraveling the Therapeutic Landscape'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The treatment landscape of metastatic prostate cancer (mPCa) is rapidly evolving with the recent approvals of poly-ADP ribose polymerase inhibitors (PARPis) as monotherapy or as part of combination therapy with androgen receptor pathway inhibitors in patients with metastatic castration-resistant prostate cancer (mCRPC).
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:10945492
title: The rate of the founder Jewish mutations in BRCA1 and BRCA2 in prostate cancer patients in Israel.
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: '2000 Aug;83(4):463-6. doi: 10.1054/bjoc.2000.1249.'
supporting_text: '2000 Aug;83(4):463-6. doi: 10.1054/bjoc.2000.1249.'
evidence:
- reference: PMID:10945492
reference_title: The rate of the founder Jewish mutations in BRCA1 and BRCA2 in prostate cancer patients in Israel.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2000 Aug;83(4):463-6. doi: 10.1054/bjoc.2000.1249.'
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:15131399
title: Cancer variation associated with the position of the mutation in the BRCA2 gene.
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: '2004;3(1):1-10. doi: 10.1023/B:FAME.0000026816.32400.45.'
supporting_text: '2004;3(1):1-10. doi: 10.1023/B:FAME.0000026816.32400.45.'
evidence:
- reference: PMID:15131399
reference_title: Cancer variation associated with the position of the mutation in the BRCA2 gene.
supports: SUPPORT
evidence_source: OTHER
snippet: '2004;3(1):1-10. doi: 10.1023/B:FAME.0000026816.32400.45.'
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:16964288
title: Characterizing a rat Brca2 knockout model.
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: '2007 Mar 8;26(11):1626-35. doi: 10.1038/sj.onc.1209960.'
supporting_text: '2007 Mar 8;26(11):1626-35. doi: 10.1038/sj.onc.1209960.'
evidence:
- reference: PMID:16964288
reference_title: Characterizing a rat Brca2 knockout model.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: '2007 Mar 8;26(11):1626-35. doi: 10.1038/sj.onc.1209960.'
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:19064968
title: BRCA germline mutations in Jewish patients with pancreatic adenocarcinoma.
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: '2009 Jan 20;27(3):433-8. doi: 10.1200/JCO.2008.18.5546.'
supporting_text: '2009 Jan 20;27(3):433-8. doi: 10.1200/JCO.2008.18.5546.'
evidence:
- reference: PMID:19064968
reference_title: BRCA germline mutations in Jewish patients with pancreatic adenocarcinoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2009 Jan 20;27(3):433-8. doi: 10.1200/JCO.2008.18.5546.'
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:19188187
title: Associations of high-grade prostate cancer with BRCA1 and BRCA2 founder mutations.
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: '2009 Feb 1;15(3):1112-20. doi: 10.1158/1078-0432.CCR-08-1822.'
supporting_text: '2009 Feb 1;15(3):1112-20. doi: 10.1158/1078-0432.CCR-08-1822.'
evidence:
- reference: PMID:19188187
reference_title: Associations of high-grade prostate cancer with BRCA1 and BRCA2 founder mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2009 Feb 1;15(3):1112-20. doi: 10.1158/1078-0432.CCR-08-1822.'
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:20585617
title: Brca2 and Trp53 deficiency cooperate in the progression of mouse prostate tumourigenesis.
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: '2010 Jun 24;6(6):e1000995. doi: 10.1371/journal.pgen.1000995.'
supporting_text: '2010 Jun 24;6(6):e1000995. doi: 10.1371/journal.pgen.1000995.'
evidence:
- reference: PMID:20585617
reference_title: Brca2 and Trp53 deficiency cooperate in the progression of mouse prostate tumourigenesis.
supports: SUPPORT
evidence_source: OTHER
snippet: '2010 Jun 24;6(6):e1000995. doi: 10.1371/journal.pgen.1000995.'
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:20840664
title: 'Targeted prostate cancer screening in men with mutations in BRCA1 and BRCA2 detects aggressive prostate cancer: preliminary analysis of the results of the IMPACT study.'
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: '2011 Jan;107(1):28-39. doi: 10.1111/j.1464-410X.2010.09648.x.'
supporting_text: '2011 Jan;107(1):28-39. doi: 10.1111/j.1464-410X.2010.09648.x.'
evidence:
- reference: PMID:20840664
reference_title: 'Targeted prostate cancer screening in men with mutations in BRCA1 and BRCA2 detects aggressive prostate cancer: preliminary analysis of the results of the IMPACT study.'
supports: SUPPORT
evidence_source: OTHER
snippet: '2011 Jan;107(1):28-39. doi: 10.1111/j.1464-410X.2010.09648.x.'
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:24389137
title: Clinical features and management of BRCA1 and BRCA2-associated prostate cancer.
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: '2014 Jan 1;6(1):15-30. doi: 10.2741/e686.'
supporting_text: '2014 Jan 1;6(1):15-30. doi: 10.2741/e686.'
evidence:
- reference: PMID:24389137
reference_title: Clinical features and management of BRCA1 and BRCA2-associated prostate cancer.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2014 Jan 1;6(1):15-30. doi: 10.2741/e686.'
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:24484606
title: 'Targeted prostate cancer screening in BRCA1 and BRCA2 mutation carriers: results from the initial screening round of the IMPACT study.'
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: Men with germline breast cancer 1, early onset (BRCA1) or breast cancer 2, early onset (BRCA2) gene mutations have a higher risk of developing prostate cancer (PCa) than noncarriers.
supporting_text: Men with germline breast cancer 1, early onset (BRCA1) or breast cancer 2, early onset (BRCA2) gene mutations have a higher risk of developing prostate cancer (PCa) than noncarriers.
evidence:
- reference: PMID:24484606
reference_title: 'Targeted prostate cancer screening in BRCA1 and BRCA2 mutation carriers: results from the initial screening round of the IMPACT study.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Men with germline breast cancer 1, early onset (BRCA1) or breast cancer 2, early onset (BRCA2) gene mutations have a higher risk of developing prostate cancer (PCa) than noncarriers.
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:25454609
title: Effect of BRCA Mutations on Metastatic Relapse and Cause-specific Survival After Radical Treatment for Localised Prostate Cancer.
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: Germline BRCA mutations are associated with worse prostate cancer (PCa) outcomes; however, the most appropriate management for mutation carriers has not yet been investigated.
supporting_text: Germline BRCA mutations are associated with worse prostate cancer (PCa) outcomes; however, the most appropriate management for mutation carriers has not yet been investigated.
evidence:
- reference: PMID:25454609
reference_title: Effect of BRCA Mutations on Metastatic Relapse and Cause-specific Survival After Radical Treatment for Localised Prostate Cancer.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Germline BRCA mutations are associated with worse prostate cancer (PCa) outcomes; however, the most appropriate management for mutation carriers has not yet been investigated.
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:28342640
title: Systematic Review Links the Prevalence of Intraductal Carcinoma of the Prostate to Prostate Cancer Risk Categories.
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: '2017 Oct;72(4):492-495. doi: 10.1016/j.eururo.2017.03.013.'
supporting_text: '2017 Oct;72(4):492-495. doi: 10.1016/j.eururo.2017.03.013.'
evidence:
- reference: PMID:28342640
reference_title: Systematic Review Links the Prevalence of Intraductal Carcinoma of the Prostate to Prostate Cancer Risk Categories.
supports: SUPPORT
evidence_source: OTHER
snippet: '2017 Oct;72(4):492-495. doi: 10.1016/j.eururo.2017.03.013.'
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:28835508
title: 'Thwarting endogenous stress: BRCA protects against aldehyde toxicity.'
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: '2017 Oct;9(10):1331-1333. doi: 10.15252/emmm.201708194.'
supporting_text: '2017 Oct;9(10):1331-1333. doi: 10.15252/emmm.201708194.'
evidence:
- reference: PMID:28835508
reference_title: 'Thwarting endogenous stress: BRCA protects against aldehyde toxicity.'
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: '2017 Oct;9(10):1331-1333. doi: 10.15252/emmm.201708194.'
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:29021619
title: Pan-cancer analysis of bi-allelic alterations in homologous recombination DNA repair genes.
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: '2017 Oct 11;8(1):857. doi: 10.1038/s41467-017-00921-w.'
supporting_text: '2017 Oct 11;8(1):857. doi: 10.1038/s41467-017-00921-w.'
evidence:
- reference: PMID:29021619
reference_title: Pan-cancer analysis of bi-allelic alterations in homologous recombination DNA repair genes.
supports: SUPPORT
evidence_source: OTHER
snippet: '2017 Oct 11;8(1):857. doi: 10.1038/s41467-017-00921-w.'
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:31537406
title: 'Interim Results from the IMPACT Study: Evidence for Prostate-specific Antigen Screening in BRCA2 Mutation Carriers.'
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: Mutations in BRCA2 cause a higher risk of early-onset aggressive prostate cancer (PrCa).
supporting_text: Mutations in BRCA2 cause a higher risk of early-onset aggressive prostate cancer (PrCa).
evidence:
- reference: PMID:31537406
reference_title: 'Interim Results from the IMPACT Study: Evidence for Prostate-specific Antigen Screening in BRCA2 Mutation Carriers.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Mutations in BRCA2 cause a higher risk of early-onset aggressive prostate cancer (PrCa).
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:31591549
title: Towards precision oncology in advanced prostate cancer.
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: '2019 Nov;16(11):645-654. doi: 10.1038/s41585-019-0237-8.'
supporting_text: '2019 Nov;16(11):645-654. doi: 10.1038/s41585-019-0237-8.'
evidence:
- reference: PMID:31591549
reference_title: Towards precision oncology in advanced prostate cancer.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2019 Nov;16(11):645-654. doi: 10.1038/s41585-019-0237-8.'
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:32171277
title: 'Polyclonal BRCA2 mutations following carboplatin treatment confer resistance to the PARP inhibitor rucaparib in a patient with mCRPC: a case report.'
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: 'Polyclonal BRCA2 mutations following carboplatin treatment confer resistance to the PARP inhibitor rucaparib in a patient with mCRPC: a case report'
supporting_text: Poly (ADP-ribose) polymerase (PARP) inhibitors are approved for the treatment of breast cancer susceptibility genes 1 and 2 (BRCA1/2) mutant ovarian and breast cancers, and are now being evaluated in metastatic castration-resistant prostate cancer (mCRPC).
evidence:
- reference: PMID:32171277
reference_title: 'Polyclonal BRCA2 mutations following carboplatin treatment confer resistance to the PARP inhibitor rucaparib in a patient with mCRPC: a case report.'
supports: SUPPORT
evidence_source: OTHER
snippet: Poly (ADP-ribose) polymerase (PARP) inhibitors are approved for the treatment of breast cancer susceptibility genes 1 and 2 (BRCA1/2) mutant ovarian and breast cancers, and are now being evaluated in metastatic castration-resistant prostate cancer (mCRPC).
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:33091561
title: A meta-analysis of reversion mutations in BRCA genes identifies signatures of DNA end-joining repair mechanisms driving therapy resistance.
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: Germline mutations in the BRCA1 or BRCA2 (BRCA) genes predispose to hereditary breast and ovarian cancer and, mostly in the case of BRCA2, are also prevalent in cases of pancreatic and prostate malignancies.
supporting_text: Germline mutations in the BRCA1 or BRCA2 (BRCA) genes predispose to hereditary breast and ovarian cancer and, mostly in the case of BRCA2, are also prevalent in cases of pancreatic and prostate malignancies.
evidence:
- reference: PMID:33091561
reference_title: A meta-analysis of reversion mutations in BRCA genes identifies signatures of DNA end-joining repair mechanisms driving therapy resistance.
supports: SUPPORT
evidence_source: OTHER
snippet: Germline mutations in the BRCA1 or BRCA2 (BRCA) genes predispose to hereditary breast and ovarian cancer and, mostly in the case of BRCA2, are also prevalent in cases of pancreatic and prostate malignancies.
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:34065235
title: 'Imprecise Medicine: BRCA2 Variants of Uncertain Significance (VUS), the Challenges and Benefits to Integrate a Functional Assay Workflow with Clinical Decision Rules.'
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: '2021 May 20;12(5):780. doi: 10.3390/genes12050780.'
supporting_text: '2021 May 20;12(5):780. doi: 10.3390/genes12050780.'
evidence:
- reference: PMID:34065235
reference_title: 'Imprecise Medicine: BRCA2 Variants of Uncertain Significance (VUS), the Challenges and Benefits to Integrate a Functional Assay Workflow with Clinical Decision Rules.'
supports: SUPPORT
evidence_source: OTHER
snippet: '2021 May 20;12(5):780. doi: 10.3390/genes12050780.'
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:34884926
title: Genomic Features and Clinical Implications of Intraductal Carcinoma of the Prostate.
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: '2021 Dec 4;22(23):13125. doi: 10.3390/ijms222313125.'
supporting_text: '2021 Dec 4;22(23):13125. doi: 10.3390/ijms222313125.'
evidence:
- reference: PMID:34884926
reference_title: Genomic Features and Clinical Implications of Intraductal Carcinoma of the Prostate.
supports: SUPPORT
evidence_source: OTHER
snippet: '2021 Dec 4;22(23):13125. doi: 10.3390/ijms222313125.'
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:35229141
title: 'Olaparib in patients with mCRPC with homologous recombination repair gene alterations: PROfound Asian subset analysis.'
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: 'Olaparib in patients with mCRPC with homologous recombination repair gene alterations: PROfound Asian subset analysis'
supporting_text: The Phase III PROfound study (NCT02987543) evaluated olaparib versus abiraterone or enzalutamide (control; randomized 2:1 to olaparib or control) in men with homologous recombination repair gene alterations and metastatic castration-resistant prostate cancer whose disease progressed on prior next-generation hormonal agent.
evidence:
- reference: PMID:35229141
reference_title: 'Olaparib in patients with mCRPC with homologous recombination repair gene alterations: PROfound Asian subset analysis.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The Phase III PROfound study (NCT02987543) evaluated olaparib versus abiraterone or enzalutamide (control; randomized 2:1 to olaparib or control) in men with homologous recombination repair gene alterations and metastatic castration-resistant prostate cancer whose disease progressed on prior next-generation hormonal agent.
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:35476551
title: Homologous Recombination Repair Gene Variants and Outcomes Among Patients With Prostate Cancer Treated With Poly (ADP-ribose) Polymerase Inhibitors.
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: '2022 Apr;6(1):e2100461. doi: 10.1200/PO.21.00461.'
supporting_text: '2022 Apr;6(1):e2100461. doi: 10.1200/PO.21.00461.'
evidence:
- reference: PMID:35476551
reference_title: Homologous Recombination Repair Gene Variants and Outcomes Among Patients With Prostate Cancer Treated With Poly (ADP-ribose) Polymerase Inhibitors.
supports: SUPPORT
evidence_source: OTHER
snippet: '2022 Apr;6(1):e2100461. doi: 10.1200/PO.21.00461.'
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:35652618
title: The impact of genetic aberrations on response to radium-223 treatment for castration-resistant prostate cancer with bone metastases.
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: Radium (Ra)-223 is an established treatment option for patients with metastatic castrate-resistant prostate cancer (mCRPC) who have symptomatic bone metastases without soft tissue disease.
supporting_text: Radium (Ra)-223 is an established treatment option for patients with metastatic castrate-resistant prostate cancer (mCRPC) who have symptomatic bone metastases without soft tissue disease.
evidence:
- reference: PMID:35652618
reference_title: The impact of genetic aberrations on response to radium-223 treatment for castration-resistant prostate cancer with bone metastases.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Radium (Ra)-223 is an established treatment option for patients with metastatic castrate-resistant prostate cancer (mCRPC) who have symptomatic bone metastases without soft tissue disease.
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:35785170
title: Homologous Recombination Deficiency in Ovarian, Breast, Colorectal, Pancreatic, Non-Small Cell Lung and Prostate Cancers, and the Mechanisms of Resistance to PARP Inhibitors.
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: '2022 Jun 17;12:880643. doi: 10.3389/fonc.2022.880643. eCollection 2022.'
supporting_text: '2022 Jun 17;12:880643. doi: 10.3389/fonc.2022.880643. eCollection 2022.'
evidence:
- reference: PMID:35785170
reference_title: Homologous Recombination Deficiency in Ovarian, Breast, Colorectal, Pancreatic, Non-Small Cell Lung and Prostate Cancers, and the Mechanisms of Resistance to PARP Inhibitors.
supports: SUPPORT
evidence_source: OTHER
snippet: '2022 Jun 17;12:880643. doi: 10.3389/fonc.2022.880643. eCollection 2022.'
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:35944490
title: DNA-Damage-Repair Gene Alterations in Genitourinary Malignancies.
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: DDR alterations are commonly found in genitourinary malignancies involving either DSB repair by the homologous recombination (HR) repair (HRR) system (BRCA1/2 pathway) or the SSB repair through the poly (ADP-ribose) polymerase (PARP) pathway.
supporting_text: DDR alterations are commonly found in genitourinary malignancies involving either DSB repair by the homologous recombination (HR) repair (HRR) system (BRCA1/2 pathway) or the SSB repair through the poly (ADP-ribose) polymerase (PARP) pathway.
evidence:
- reference: PMID:35944490
reference_title: DNA-Damage-Repair Gene Alterations in Genitourinary Malignancies.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: DDR alterations are commonly found in genitourinary malignancies involving either DSB repair by the homologous recombination (HR) repair (HRR) system (BRCA1/2 pathway) or the SSB repair through the poly (ADP-ribose) polymerase (PARP) pathway.
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:35986085
title: Prognostic significance of pathogenic variants in BRCA1, BRCA2, ATM and PALB2 genes in men undergoing hormonal therapy for advanced prostate cancer.
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: The prognostic significance of germline variants in homologous recombination repair genes in advanced prostate cancer (PCa), especially with regard to hormonal therapy, remains controversial.
supporting_text: The prognostic significance of germline variants in homologous recombination repair genes in advanced prostate cancer (PCa), especially with regard to hormonal therapy, remains controversial.
evidence:
- reference: PMID:35986085
reference_title: Prognostic significance of pathogenic variants in BRCA1, BRCA2, ATM and PALB2 genes in men undergoing hormonal therapy for advanced prostate cancer.
supports: SUPPORT
evidence_source: OTHER
snippet: The prognostic significance of germline variants in homologous recombination repair genes in advanced prostate cancer (PCa), especially with regard to hormonal therapy, remains controversial.
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:36103646
title: Addition of Germline Testing to Tumor-Only Sequencing Improves Detection of Pathogenic Germline Variants in Men With Advanced Prostate Cancer.
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: '2022 Aug;6:e2200329. doi: 10.1200/PO.22.00329.'
supporting_text: '2022 Aug;6:e2200329. doi: 10.1200/PO.22.00329.'
evidence:
- reference: PMID:36103646
reference_title: Addition of Germline Testing to Tumor-Only Sequencing Improves Detection of Pathogenic Germline Variants in Men With Advanced Prostate Cancer.
supports: SUPPORT
evidence_source: OTHER
snippet: '2022 Aug;6:e2200329. doi: 10.1200/PO.22.00329.'
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:36243543
title: Emergence of BRCA Reversion Mutations in Patients with Metastatic Castration-resistant Prostate Cancer After Treatment with Rucaparib.
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors are approved in the USA for the treatment of patients with BRCA1 or BRCA2 (BRCA) mutated (BRCA+) metastatic castration-resistant prostate cancer (mCRPC).
supporting_text: Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors are approved in the USA for the treatment of patients with BRCA1 or BRCA2 (BRCA) mutated (BRCA+) metastatic castration-resistant prostate cancer (mCRPC).
evidence:
- reference: PMID:36243543
reference_title: Emergence of BRCA Reversion Mutations in Patients with Metastatic Castration-resistant Prostate Cancer After Treatment with Rucaparib.
supports: SUPPORT
evidence_source: OTHER
snippet: Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors are approved in the USA for the treatment of patients with BRCA1 or BRCA2 (BRCA) mutated (BRCA+) metastatic castration-resistant prostate cancer (mCRPC).
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:36318705
title: Olaparib Efficacy in Patients with Metastatic Castration-resistant Prostate Cancer and BRCA1, BRCA2, or ATM Alterations Identified by Testing Circulating Tumor DNA.
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: '2023 Jan 4;29(1):92-99. doi: 10.1158/1078-0432.CCR-21-3577.'
supporting_text: '2023 Jan 4;29(1):92-99. doi: 10.1158/1078-0432.CCR-21-3577.'
evidence:
- reference: PMID:36318705
reference_title: Olaparib Efficacy in Patients with Metastatic Castration-resistant Prostate Cancer and BRCA1, BRCA2, or ATM Alterations Identified by Testing Circulating Tumor DNA.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2023 Jan 4;29(1):92-99. doi: 10.1158/1078-0432.CCR-21-3577.'
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:37497748
title: 'Poly-ADP ribose polymerase inhibitor and androgen receptor signaling inhibitor for all comers for first-line treatment of metastatic castration-resistant prostate cancer: is gene sequencing out?'
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: '2023 Sep 1;33(5):396-403. doi: 10.1097/MOU.0000000000001114.'
supporting_text: '2023 Sep 1;33(5):396-403. doi: 10.1097/MOU.0000000000001114.'
evidence:
- reference: PMID:37497748
reference_title: 'Poly-ADP ribose polymerase inhibitor and androgen receptor signaling inhibitor for all comers for first-line treatment of metastatic castration-resistant prostate cancer: is gene sequencing out?'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2023 Sep 1;33(5):396-403. doi: 10.1097/MOU.0000000000001114.'
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:37722977
title: Poly (ADP-ribose) Polymerase Inhibitors Have Comparable Efficacy with Platinum Chemotherapy in Patients with BRCA-positive Metastatic Castration-resistant Prostate Cancer. A Systematic Review and Meta-analysis.
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: '2024 Jun;7(3):365-375. doi: 10.1016/j.euo.2023.09.001.'
supporting_text: '2024 Jun;7(3):365-375. doi: 10.1016/j.euo.2023.09.001.'
evidence:
- reference: PMID:37722977
reference_title: Poly (ADP-ribose) Polymerase Inhibitors Have Comparable Efficacy with Platinum Chemotherapy in Patients with BRCA-positive Metastatic Castration-resistant Prostate Cancer. A Systematic Review and Meta-analysis.
supports: SUPPORT
evidence_source: OTHER
snippet: '2024 Jun;7(3):365-375. doi: 10.1016/j.euo.2023.09.001.'
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:38182487
title: Tumour-based Mutational Profiles Predict Visceral Metastasis Outcome and Early Death in Prostate Cancer Patients.
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: Visceral metastases are known to occur in advanced prostate cancer, usually when the tumour is resistant to androgen deprivation and, have worse outcomes regardless of therapies.
supporting_text: Visceral metastases are known to occur in advanced prostate cancer, usually when the tumour is resistant to androgen deprivation and, have worse outcomes regardless of therapies.
evidence:
- reference: PMID:38182487
reference_title: Tumour-based Mutational Profiles Predict Visceral Metastasis Outcome and Early Death in Prostate Cancer Patients.
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: Visceral metastases are known to occur in advanced prostate cancer, usually when the tumour is resistant to androgen deprivation and, have worse outcomes regardless of therapies.
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:38355834
title: Convergent evolution of BRCA2 reversion mutations under therapeutic pressure by PARP inhibition and platinum chemotherapy.
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: '2024 Feb 14;8(1):34. doi: 10.1038/s41698-024-00526-9.'
supporting_text: '2024 Feb 14;8(1):34. doi: 10.1038/s41698-024-00526-9.'
evidence:
- reference: PMID:38355834
reference_title: Convergent evolution of BRCA2 reversion mutations under therapeutic pressure by PARP inhibition and platinum chemotherapy.
supports: SUPPORT
evidence_source: OTHER
snippet: '2024 Feb 14;8(1):34. doi: 10.1038/s41698-024-00526-9.'
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:38461085
title: Mainstream Model of Genetic Testing for Prostate Cancer at a Large Tertiary Cancer Centre.
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: An estimated 20% to 30% of men with advanced prostate cancer carry a mutation in DNA damage repair genes, of which half are estimated to be germline.
supporting_text: An estimated 20% to 30% of men with advanced prostate cancer carry a mutation in DNA damage repair genes, of which half are estimated to be germline.
evidence:
- reference: PMID:38461085
reference_title: Mainstream Model of Genetic Testing for Prostate Cancer at a Large Tertiary Cancer Centre.
supports: SUPPORT
evidence_source: OTHER
snippet: An estimated 20% to 30% of men with advanced prostate cancer carry a mutation in DNA damage repair genes, of which half are estimated to be germline.
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:38851712
title: 'The efficacy and safety of PARP inhibitors in mCRPC with HRR mutation in second-line treatment: a systematic review and bayesian network meta-analysis.'
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: Poly (ADP- ribose) polymerase inhibitors (PARPi) has been increasingly adopted for metastatic castration-resistance prostate cancer (mCRPC) patients with homologous recombination repair deficiency (HRD).
supporting_text: Poly (ADP- ribose) polymerase inhibitors (PARPi) has been increasingly adopted for metastatic castration-resistance prostate cancer (mCRPC) patients with homologous recombination repair deficiency (HRD).
evidence:
- reference: PMID:38851712
reference_title: 'The efficacy and safety of PARP inhibitors in mCRPC with HRR mutation in second-line treatment: a systematic review and bayesian network meta-analysis.'
supports: SUPPORT
evidence_source: OTHER
snippet: Poly (ADP- ribose) polymerase inhibitors (PARPi) has been increasingly adopted for metastatic castration-resistance prostate cancer (mCRPC) patients with homologous recombination repair deficiency (HRD).
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:38958846
title: Feasibility of Indirect Treatment Comparisons Between Niraparib Plus Abiraterone Acetate and Other First-Line Poly ADP-Ribose Polymerase Inhibitor Treatment Regimens for Patients with BRCA1/2 Mutation-Positive Metastatic Castration-Resistant Prostate Cancer.
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: '2024 Aug;41(8):3039-3058. doi: 10.1007/s12325-024-02918-6.'
supporting_text: '2024 Aug;41(8):3039-3058. doi: 10.1007/s12325-024-02918-6.'
evidence:
- reference: PMID:38958846
reference_title: Feasibility of Indirect Treatment Comparisons Between Niraparib Plus Abiraterone Acetate and Other First-Line Poly ADP-Ribose Polymerase Inhibitor Treatment Regimens for Patients with BRCA1/2 Mutation-Positive Metastatic Castration-Resistant Prostate Cancer.
supports: SUPPORT
evidence_source: OTHER
snippet: '2024 Aug;41(8):3039-3058. doi: 10.1007/s12325-024-02918-6.'
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:39577422
title: Elucidating acquired PARP inhibitor resistance in advanced prostate cancer.
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: '2024 Dec 9;42(12):2113-2123.e4. doi: 10.1016/j.ccell.2024.10.015.'
supporting_text: '2024 Dec 9;42(12):2113-2123.e4. doi: 10.1016/j.ccell.2024.10.015.'
evidence:
- reference: PMID:39577422
reference_title: Elucidating acquired PARP inhibitor resistance in advanced prostate cancer.
supports: SUPPORT
evidence_source: OTHER
snippet: '2024 Dec 9;42(12):2113-2123.e4. doi: 10.1016/j.ccell.2024.10.015.'
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:39901204
title: 'Molecular pathways in reproductive cancers: a focus on prostate and ovarian cancer.'
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: '2025 Feb 3;25(1):33. doi: 10.1186/s12935-025-03658-5.'
supporting_text: '2025 Feb 3;25(1):33. doi: 10.1186/s12935-025-03658-5.'
evidence:
- reference: PMID:39901204
reference_title: 'Molecular pathways in reproductive cancers: a focus on prostate and ovarian cancer.'
supports: SUPPORT
evidence_source: OTHER
snippet: '2025 Feb 3;25(1):33. doi: 10.1186/s12935-025-03658-5.'
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:40027043
title: 'Chest Pain as a Symptom of Early-Onset Metastatic Prostate Cancer: Exploring the Role of Screening.'
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: '2025 Jan 28;17(1):e78143. doi: 10.7759/cureus.78143. eCollection 2025 Jan.'
supporting_text: '2025 Jan 28;17(1):e78143. doi: 10.7759/cureus.78143. eCollection 2025 Jan.'
evidence:
- reference: PMID:40027043
reference_title: 'Chest Pain as a Symptom of Early-Onset Metastatic Prostate Cancer: Exploring the Role of Screening.'
supports: SUPPORT
evidence_source: OTHER
snippet: '2025 Jan 28;17(1):e78143. doi: 10.7759/cureus.78143. eCollection 2025 Jan.'
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:40086424
title: 'Deciphering the mechanisms of PARP inhibitor resistance in prostate cancer: Implications for precision medicine.'
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: '2025 Apr;185:117955. doi: 10.1016/j.biopha.2025.117955.'
supporting_text: '2025 Apr;185:117955. doi: 10.1016/j.biopha.2025.117955.'
evidence:
- reference: PMID:40086424
reference_title: 'Deciphering the mechanisms of PARP inhibitor resistance in prostate cancer: Implications for precision medicine.'
supports: SUPPORT
evidence_source: OTHER
snippet: '2025 Apr;185:117955. doi: 10.1016/j.biopha.2025.117955.'
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:40257527
title: Genetic characterization of BRCA1 and BRCA2 variants in cancer and high-risk family screening cohorts in the UAE population.
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: '2025 Apr 21;151(4):146. doi: 10.1007/s00432-025-06188-9.'
supporting_text: '2025 Apr 21;151(4):146. doi: 10.1007/s00432-025-06188-9.'
evidence:
- reference: PMID:40257527
reference_title: Genetic characterization of BRCA1 and BRCA2 variants in cancer and high-risk family screening cohorts in the UAE population.
supports: SUPPORT
evidence_source: OTHER
snippet: '2025 Apr 21;151(4):146. doi: 10.1007/s00432-025-06188-9.'
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:40397306
title: Olaparib Monotherapy or in Combination with Abiraterone for the Treatment of Patients with Metastatic Castration-Resistant Prostate Cancer (mCRPC) and a BRCA Mutation.
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: '2025 May;20(3):445-466. doi: 10.1007/s11523-025-01146-4.'
supporting_text: '2025 May;20(3):445-466. doi: 10.1007/s11523-025-01146-4.'
evidence:
- reference: PMID:40397306
reference_title: Olaparib Monotherapy or in Combination with Abiraterone for the Treatment of Patients with Metastatic Castration-Resistant Prostate Cancer (mCRPC) and a BRCA Mutation.
supports: SUPPORT
evidence_source: OTHER
snippet: '2025 May;20(3):445-466. doi: 10.1007/s11523-025-01146-4.'
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:40467032
title: 'BRCA1/2 and homologous recombination repair alterations in high- and low-volume metastatic hormone-sensitive prostate cancer: prevalence and impact on outcomes.'
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: Alterations in BRCA1/2 (BRCA) and other homologous recombination repair (HRR) genes have a negative impact on outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC).
supporting_text: Alterations in BRCA1/2 (BRCA) and other homologous recombination repair (HRR) genes have a negative impact on outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC).
evidence:
- reference: PMID:40467032
reference_title: 'BRCA1/2 and homologous recombination repair alterations in high- and low-volume metastatic hormone-sensitive prostate cancer: prevalence and impact on outcomes.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Alterations in BRCA1/2 (BRCA) and other homologous recombination repair (HRR) genes have a negative impact on outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC).
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:40503579
title: Genetic determinants of prostate cancer predisposition in Ashkenazi Jews.
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: Prostate cancer (PCa) is the most prevalent cancer among men in the European Union, the USA and Israel, with heritability being a key risk factor.
supporting_text: Prostate cancer (PCa) is the most prevalent cancer among men in the European Union, the USA and Israel, with heritability being a key risk factor.
evidence:
- reference: PMID:40503579
reference_title: Genetic determinants of prostate cancer predisposition in Ashkenazi Jews.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Prostate cancer (PCa) is the most prevalent cancer among men in the European Union, the USA and Israel, with heritability being a key risk factor.
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:40795806
title: Questions and answers on PARP inhibitor use in somatic BRCA-mutated breast cancers.
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: '2026 Feb 1;118(2):205-213. doi: 10.1093/jnci/djaf205.'
supporting_text: '2026 Feb 1;118(2):205-213. doi: 10.1093/jnci/djaf205.'
evidence:
- reference: PMID:40795806
reference_title: Questions and answers on PARP inhibitor use in somatic BRCA-mutated breast cancers.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2026 Feb 1;118(2):205-213. doi: 10.1093/jnci/djaf205.'
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:40875208
title: Established Cancer Predisposition Genes in Single and Multiple Cancer Diagnoses.
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: '2025 Oct 1;11(10):1222-1230. doi: 10.1001/jamaoncol.2025.2879.'
supporting_text: '2025 Oct 1;11(10):1222-1230. doi: 10.1001/jamaoncol.2025.2879.'
evidence:
- reference: PMID:40875208
reference_title: Established Cancer Predisposition Genes in Single and Multiple Cancer Diagnoses.
supports: SUPPORT
evidence_source: OTHER
snippet: '2025 Oct 1;11(10):1222-1230. doi: 10.1001/jamaoncol.2025.2879.'
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:41219045
title: Integrating Pathogenic Variants, Polygenic Risk Score, and Family History for Prostate Cancer Risk Estimation in Men of African Ancestry.
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: '2025 Nov 5:S0302-2838(25)04720-7. doi: 10.1016/j.eururo.2025.09.4161.'
supporting_text: '2025 Nov 5:S0302-2838(25)04720-7. doi: 10.1016/j.eururo.2025.09.4161.'
evidence:
- reference: PMID:41219045
reference_title: Integrating Pathogenic Variants, Polygenic Risk Score, and Family History for Prostate Cancer Risk Estimation in Men of African Ancestry.
supports: SUPPORT
evidence_source: OTHER
snippet: '2025 Nov 5:S0302-2838(25)04720-7. doi: 10.1016/j.eururo.2025.09.4161.'
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:41423785
title: Revisiting the impact of BRCA1 pathogenic variants on the aggressiveness of prostate cancer.
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: '2026 Jan 9;10(1):pkaf118. doi: 10.1093/jncics/pkaf118.'
supporting_text: '2026 Jan 9;10(1):pkaf118. doi: 10.1093/jncics/pkaf118.'
evidence:
- reference: PMID:41423785
reference_title: Revisiting the impact of BRCA1 pathogenic variants on the aggressiveness of prostate cancer.
supports: SUPPORT
evidence_source: OTHER
snippet: '2026 Jan 9;10(1):pkaf118. doi: 10.1093/jncics/pkaf118.'
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:41595443
title: 'Prevalence and Clinical Associations of Germline DDR Variants in Prostate Cancer: Real-World Evidence from a 122-Patient Turkish Cohort.'
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: Germline alterations in DNA damage repair (DDR) genes represent a clinically important subset of prostate cancer (PCa), but real-world data from Middle Eastern and Turkish populations remain limited.
supporting_text: Germline alterations in DNA damage repair (DDR) genes represent a clinically important subset of prostate cancer (PCa), but real-world data from Middle Eastern and Turkish populations remain limited.
evidence:
- reference: PMID:41595443
reference_title: 'Prevalence and Clinical Associations of Germline DDR Variants in Prostate Cancer: Real-World Evidence from a 122-Patient Turkish Cohort.'
supports: SUPPORT
evidence_source: OTHER
snippet: Germline alterations in DNA damage repair (DDR) genes represent a clinically important subset of prostate cancer (PCa), but real-world data from Middle Eastern and Turkish populations remain limited.
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:41690056
title: 'The Bone Microenvironment and Therapeutic Resistance in Spinal Metastases: Mechanisms and Clinical Implications.'
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: Spinal metastases represent a biologically distinct manifestation of systemic cancer, frequently progressing despite durable visceral response.
supporting_text: Spinal metastases represent a biologically distinct manifestation of systemic cancer, frequently progressing despite durable visceral response.
evidence:
- reference: PMID:41690056
reference_title: 'The Bone Microenvironment and Therapeutic Resistance in Spinal Metastases: Mechanisms and Clinical Implications.'
supports: SUPPORT
evidence_source: OTHER
snippet: Spinal metastases represent a biologically distinct manifestation of systemic cancer, frequently progressing despite durable visceral response.
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:41714267
title: 'Targeted Prostate Cancer Screening in Carriers of BRCA1 or BRCA2 Pathogenic Germline Variants Detects Clinically Relevant Disease: 5-year Results from the IMPACT Study.'
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: '2026 Feb 18:S0302-2838(26)00057-6. doi: 10.1016/j.eururo.2026.01.031.'
supporting_text: '2026 Feb 18:S0302-2838(26)00057-6. doi: 10.1016/j.eururo.2026.01.031.'
evidence:
- reference: PMID:41714267
reference_title: 'Targeted Prostate Cancer Screening in Carriers of BRCA1 or BRCA2 Pathogenic Germline Variants Detects Clinically Relevant Disease: 5-year Results from the IMPACT Study.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2026 Feb 18:S0302-2838(26)00057-6. doi: 10.1016/j.eururo.2026.01.031.'
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:41729953
title: Prevalence and spectrum of homologous recombination repair mutations in patients with metastatic prostate cancer from India.
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: Prevalence and spectrum of homologous recombination repair mutations in patients with metastatic prostate cancer from India
supporting_text: Alterations in genes involved in homologous recombination repair (HRR) occur in approximately 20%-25% of patients with metastatic prostate cancer and are associated with aggressive biology, poor outcomes, and potential sensitivity to poly (ADP-ribose) polymerase inhibitors (PARPi).
evidence:
- reference: PMID:41729953
reference_title: Prevalence and spectrum of homologous recombination repair mutations in patients with metastatic prostate cancer from India.
supports: SUPPORT
evidence_source: OTHER
snippet: Alterations in genes involved in homologous recombination repair (HRR) occur in approximately 20%-25% of patients with metastatic prostate cancer and are associated with aggressive biology, poor outcomes, and potential sensitivity to poly (ADP-ribose) polymerase inhibitors (PARPi).
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:41776557
title: 'Risks of non-breast, non-ovarian cancers for BRCA1 and BRCA2 pathogenic variant carriers: a prospective cohort study.'
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: The non-breast non-ovarian cancers associated with BRCA1 and BRCA2 pathogenic variants (PVs) are controversial.
supporting_text: The non-breast non-ovarian cancers associated with BRCA1 and BRCA2 pathogenic variants (PVs) are controversial.
evidence:
- reference: PMID:41776557
reference_title: 'Risks of non-breast, non-ovarian cancers for BRCA1 and BRCA2 pathogenic variant carriers: a prospective cohort study.'
supports: SUPPORT
evidence_source: OTHER
snippet: The non-breast non-ovarian cancers associated with BRCA1 and BRCA2 pathogenic variants (PVs) are controversial.
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
- reference: PMID:41850312
title: 'Genomic Profiling in Localized Prostate Cancer: Associations With Biochemical Recurrence and Response to Salvage Radiotherapy.'
found_in:
- BRCA_Mutant_Prostate_Cancer-deep-research-openscientist.md
findings:
- statement: '2026 May;117(5):1469-1480. doi: 10.1111/cas.70367.'
supporting_text: '2026 May;117(5):1469-1480. doi: 10.1111/cas.70367.'
evidence:
- reference: PMID:41850312
reference_title: 'Genomic Profiling in Localized Prostate Cancer: Associations With Biochemical Recurrence and Response to Salvage Radiotherapy.'
supports: SUPPORT
evidence_source: OTHER
snippet: '2026 May;117(5):1469-1480. doi: 10.1111/cas.70367.'
explanation: Deep research cited this publication as relevant literature for BRCA Mutant Prostate Cancer.
Question: You are an expert researcher providing comprehensive, well-cited information.
Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies
Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.
Please provide a comprehensive research report on BRCA-Mutant Prostate Cancer covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.
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Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease
This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details
BRCA‑mutant prostate cancer refers to prostate cancer with pathogenic alterations in BRCA1 and/or BRCA2, which encode key homologous recombination repair proteins. These alterations are clinically important because they (i) are associated with an aggressive phenotype and poorer prognosis in metastatic settings and (ii) predict benefit from PARP inhibitor therapy, including PARP inhibitor combinations with androgen receptor pathway inhibitors in selected biomarker-defined populations (mateo2024olaparibforthe pages 1-2, fettke2023brcadeficientmetastaticprostate pages 1-2).
Commonly used terms in the literature include: - BRCA1/2‑altered prostate cancer - BRCA‑altered metastatic castration‑resistant prostate cancer (BRCA‑altered mCRPC) - HRR‑mutated or HRR‑deficient prostate cancer (often includes BRCA but is broader) (fizazi2024firstlinetalazoparibwith pages 1-2, chi2023niraparibandabiraterone pages 1-2).
The information in this report is derived from: - Aggregated evidence: systematic review/meta-analysis of BRCA mutation frequencies across stages (Valsecchi 2023) (valsecchi2023frequencyofgermline pages 1-2) - Randomized clinical trials / subgroup analyses: PROfound (olaparib) subgroup analysis; MAGNITUDE (niraparib + abiraterone) (mateo2024olaparibforthe pages 1-2, chi2023niraparibandabiraterone pages 1-2) - Real‑world cohorts: cfDNA/ctDNA studies in advanced disease (e.g., Fettke 2023; PROfound screening concordance studies) (fettke2023brcadeficientmetastaticprostate pages 1-2, chi2023detectionofbrca1 pages 1-2).
Primary causal factor (genetic): - Pathogenic alterations (germline or somatic) in BRCA2 (more common) and BRCA1 lead to homologous recombination repair deficiency (HRD), genomic instability, and therapeutic vulnerabilities (synthetic lethality with PARP inhibition) (inoue2023rolesofthe pages 2-4, fizazi2024firstlinetalazoparibwith pages 1-2).
The retrieved evidence base emphasized genetic risk and did not provide high-quality quantified environmental/lifestyle risk modifiers specific to BRCA‑mutant prostate cancer.
No disease-specific protective genetic variants or protective environmental factors for BRCA‑mutant prostate cancer were identified in the retrieved evidence.
A 2023 systematic review/meta-analysis (literature search through Nov 2022) provides pooled frequencies by disease setting (random-effects estimates): - Any-stage PC: - BRCA1 germline 0.73%; BRCA1 somatic 1.20% - BRCA2 germline 3.25%; BRCA2 somatic 6.29% - Combined BRCA1/2 germline 4.47%; somatic 7.18% (valsecchi2023frequencyofgermline pages 1-2, valsecchi2023frequencyofgermline pages 2-5) - Metastatic PC: - BRCA1 germline 0.94%; somatic 1.10% - BRCA2 germline 4.51%; somatic 10.26% - Combined BRCA1/2 germline 5.84%; somatic 10.94% (valsecchi2023frequencyofgermline pages 1-2) - mCRPC: - BRCA1 germline 1.21%; somatic 1.10% - BRCA2 germline 3.90%; somatic 10.52% - Combined BRCA1/2 germline 5.26%; somatic 11.26% (valsecchi2023frequencyofgermline pages 1-2, valsecchi2023frequencyofgermline pages 25-27)
Interpretation: Somatic BRCA alterations are more common than germline across settings, and BRCA2 predominates, with higher frequencies in metastatic disease (valsecchi2023frequencyofgermline pages 1-2).
A compact synthesis of these stage-specific frequencies is provided in:
| Setting | Germline BRCA1 % | Somatic BRCA1 % | Germline BRCA2 % | Somatic BRCA2 % | Notes | Source |
|---|---|---|---|---|---|---|
| Any-stage prostate cancer | 0.73% | 1.20% | 3.25% | 6.29% | Meta-analysis: somatic mutations more common than germline; BRCA2 more common than BRCA1. Combined BRCA1/2 frequency: 4.47% germline, 7.18% somatic. (valsecchi2023frequencyofgermline pages 8-10) | Valsecchi et al., 2023, Cancers; https://doi.org/10.3390/cancers15092435 |
| Metastatic prostate cancer | 0.94% | 1.10% | 4.51% | 10.26% | Frequency rises in metastatic disease; BRCA2 predominates; combined BRCA1/2 frequency: 5.84% germline, 10.94% somatic. (valsecchi2023frequencyofgermline pages 8-10) | Valsecchi et al., 2023, Cancers; https://doi.org/10.3390/cancers15092435 |
| Metastatic castration-resistant prostate cancer (mCRPC) | 1.21% | 1.10% | 3.90% | 10.52% | In mCRPC, somatic BRCA2 is especially enriched; combined BRCA1/2 frequency: 5.26% germline, 11.26% somatic. (valsecchi2023frequencyofgermline pages 8-10) | Valsecchi et al., 2023, Cancers; https://doi.org/10.3390/cancers15092435 |
| Metastatic prostate cancer, germline DDR pathogenic variants | — | — | ~6% (BRCA1/2 combined) | — | Review states ~12% of metastatic prostate cancer patients harbor germline DDR pathogenic variants, with BRCA1/2 the most frequent DDR genes (~6% combined). Also notes germline and somatic BRCA1/2 frequencies are reported as similar enough that both should be evaluated. (inoue2023rolesofthe pages 2-4) | Inoue et al., 2023, Cancers; https://doi.org/10.3390/cancers15092662 |
| BRCA2-altered mCRPC PARPi-treated cohort (clinical provenance split) | — | — | 50% of BRCA2-altered cases were germline overall; 58% among responders | 50% of BRCA2-altered cases were somatic overall; 39% among responders | Clinical cohort provenance rather than population prevalence: in BRCA2-altered mCRPC treated with PARP inhibitors, mutation origin was roughly evenly split overall (56/110 germline, 54/110 somatic), with germline enrichment among responders. (taza2021differentialactivityof pages 20-21) | Taza et al., 2021, JCO Precision Oncology; https://doi.org/10.1200/PO.21.00070 |
| Real-world ctDNA metastatic prostate cancer cohort | not separately reported | not separately reported | not separately reported | not separately reported | ctDNA cohort found BRCA1/2 alterations (germline or somatic) in 21% of patients with metastatic prostate cancer; this row reflects assay-detected prevalence in a progression-enriched real-world blood cohort, not stage-specific tissue prevalence. (valsecchi2023frequencyofgermline pages 8-10) | Bang et al., 2023, Cancers; https://doi.org/10.3390/cancers15153998 |
Table: This table summarizes reported BRCA1/2 mutation frequencies and mutation provenance in prostate cancer across disease settings. It combines meta-analytic prevalence estimates with review and cohort data to distinguish population frequency from clinical provenance in advanced disease.
Across advanced prostate cancer cohorts, BRCA alterations—particularly BRCA2—are associated with aggressive disease features and poorer outcomes. - In a multicenter retrospective cohort of BRCA-altered mCRPC treated with PARP inhibitors, 72% had Gleason 8–10 at diagnosis, and BRCA1 cases more often presented with metastatic disease (69% vs 37%) (taza2021differentialactivityof pages 1-2). - In a real-world cfDNA cohort (375 men with mCRPC), BRCA alterations were associated with lower PSA response rates to AR pathway inhibitors (32% vs 60%) (fettke2023brcadeficientmetastaticprostate pages 1-2).
In a retrospective multicenter analysis of PARP inhibitor–treated BRCA-altered mCRPC (n=123): - PSA50 responses were 23% in BRCA1‑altered vs 63% in BRCA2‑altered disease (P=.01) (taza2021differentialactivityof pages 1-2). - BRCA1 cases more often had metastatic presentation and more monoallelic alterations and TP53 co-alterations, potentially contributing to reduced PARP inhibitor sensitivity (taza2021differentialactivityof pages 1-2).
The retrieved primary evidence set emphasizes survival and progression endpoints; systematic, quantitative health-related QoL outcomes specific to BRCA-mutant subsets were not captured in the available excerpts.
A structured mapping (including treatment-related phenotypes such as anemia/fatigue) is proposed in:
| Section | Suggested term(s) | Evidence/rationale |
|---|---|---|
| Disease concept | prostate cancer — MONDO:0008315; BRCA-mutant prostate cancer — MONDO: not clearly established in available context; prostate carcinoma — EFO:0001663 | Open Targets evidence links BRCA1/2 to prostate cancer/prostate carcinoma; BRCA-mutant prostate cancer is best modeled as a molecularly defined subtype of prostate cancer rather than a clearly separate MONDO disease in the provided context (fizazi2024firstlinetalazoparibwith pages 1-2, heiss2024usfoodand pages 2-4) |
| Key genes | BRCA2 (HGNC:1101); BRCA1 (HGNC:1100); ATM (HGNC:795) | BRCA2 is the dominant altered gene in prostate cancer and is more common than BRCA1; ATM is a major comparator/HRR gene in trials and testing panels (inoue2023rolesofthe pages 2-4, alakhras2024parpinhibitorsin pages 10-11, heiss2024usfoodand pages 2-4) |
| Key genes | TP53 (HGNC:11998); AR (HGNC:644); CDK12 (HGNC:24243) | BRCA1-altered disease shows more concurrent TP53 alterations and worse PARPi outcomes; AR biology underlies PARP/AR combination rationale; CDK12 is a frequent HRR-panel gene in advanced disease studies (taza2021differentialactivityof pages 1-2, alakhras2024parpinhibitorsin pages 10-11, fizazi2024firstlinetalazoparibwith pages 1-2) |
| Phenotypes (HPO) | Aggressive prostate carcinoma phenotype — HPO likely prefix HP:; High Gleason score — HPO likely prefix HP:; Early adult onset/neoplasm onset younger than typical — HPO likely prefix HP:0003581/HP: | BRCA2 carriers show more clinically significant disease, younger onset, and high-grade tumors; BRCA-deficient metastatic disease has adverse prognosis (inoue2023rolesofthe pages 2-4, taza2021differentialactivityof pages 1-2) |
| Phenotypes (HPO) | Metastatic prostate adenocarcinoma — HPO likely prefix HP:0004409/HP:; Bone metastasis — HPO likely prefix HP:0002664; Castration-resistant disease — HPO likely prefix HP: | BRCA1 patients more often present metastatic at diagnosis; BRCA2 cohorts show frequent M1 disease and bone metastases; advanced trials focus on mCRPC (taza2021differentialactivityof pages 1-2, taza2021differentialactivityof pages 20-21, mateo2024olaparibforthe pages 1-2) |
| Phenotypes (HPO) | Anemia — HP:0001903; Fatigue — HP:0012378; Neutropenia — HP:0001875 | Common toxicities of PARP inhibitors/combination therapy include anemia, fatigue, and neutropenia; anemia is the most frequent grade ≥3 hematologic adverse event (tisseverasinghe2023advancesinparp pages 10-11, fizazi2024firstlinetalazoparibwith pages 1-2) |
| Anatomical entities (UBERON) | prostate gland — UBERON:0002367; prostate epithelium — UBERON likely prefix UBERON:; prostate stromal tissue — UBERON likely prefix UBERON: | Primary organ and tissue compartments involved in prostate carcinoma biology (fizazi2024firstlinetalazoparibwith pages 1-2, heiss2024usfoodand pages 2-4) |
| Anatomical entities (UBERON) | bone of skeletal system — UBERON:0001474; lymph node — UBERON:0000029; blood/plasma — UBERON:0000178 / body fluid term likely needed | Bone metastases are common; lymph nodes are common metastatic sites; plasma is important for ctDNA diagnostics (taza2021differentialactivityof pages 20-21, chi2023detectionofbrca1 pages 1-2) |
| Biological processes (GO) | homologous recombination — GO:0000724; DNA repair — GO:0006281; double-strand break repair — GO:0006302 | Core BRCA biology in prostate cancer is homologous recombination repair deficiency and impaired DSB repair (inoue2023rolesofthe pages 2-4, fizazi2024firstlinetalazoparibwith pages 1-2) |
| Biological processes (GO) | response to DNA damage stimulus — GO:0006974; DNA replication fork processing — GO likely prefix GO:; cell cycle process — GO:0022402 | PARP inhibition exploits replication-fork collapse and DNA damage accumulation; BRCA2-mutant tumors are enriched for cell-cycle programs (inoue2023rolesofthe pages 2-4, fizazi2024firstlinetalazoparibwith pages 1-2) |
| Biological processes (GO) | androgen receptor signaling pathway — GO likely prefix GO:; regulation of transcription by RNA polymerase II — GO:0006357; synthetic lethal interaction context — no direct GO term, represent via DNA repair dependency | TALAPRO-2 and FDA summary emphasize AR–PARP interplay: AR inhibition downregulates HRR genes and PARP inhibition suppresses AR transcriptional activity (fizazi2024firstlinetalazoparibwith pages 1-2, heiss2024usfoodand pages 2-4) |
| Cell types (CL) | prostate gland epithelial cell — CL likely prefix CL:; luminal epithelial cell of prostate — CL likely prefix CL:; basal cell of prostate epithelium — CL likely prefix CL: | Prostate cancer arises from epithelial compartments; organoid/PDX models preserve epithelial tumor features (fizazi2024firstlinetalazoparibwith pages 1-2, fizazi2024firstlinetalazoparibwith pages 2-3) |
| Cell types (CL) | metastatic prostate cancer cell — CL likely prefix CL: cancer cell term; osteoblast — CL:0000062; osteoclast — CL:0000097 | Bone metastasis is a hallmark clinical site and relevant microenvironmental context (taza2021differentialactivityof pages 20-21, chi2023detectionofbrca1 pages 1-2) |
| Treatments (MAXO) | PARP inhibitor therapy — MAXO likely prefix MAXO:; olaparib treatment — MAXO likely prefix MAXO:; talazoparib treatment — MAXO likely prefix MAXO: | Olaparib improves rPFS/OS/ORR in BRCA-altered mCRPC; talazoparib + enzalutamide improves rPFS in HRR-mutated disease, especially BRCA-mutant subgroup (mateo2024olaparibforthe pages 1-2, mateo2024olaparibforthe pages 8-9, heiss2024usfoodand pages 2-4) |
| Treatments (MAXO) | niraparib plus abiraterone therapy — MAXO likely prefix MAXO:; enzalutamide therapy — MAXO likely prefix MAXO:; androgen receptor pathway inhibitor therapy — MAXO likely prefix MAXO: | MAGNITUDE supports niraparib + abiraterone in BRCA1/2-mutated mCRPC; ARPI backbone is central to current implementation (chi2023niraparibandabiraterone pages 1-2, chi2023niraparibandabiraterone pages 5-6) |
| Treatments (MAXO) | circulating tumor DNA testing-guided targeted therapy — MAXO likely prefix MAXO:; germline genetic testing — MAXO likely prefix MAXO:; supportive treatment for anemia — MAXO likely prefix MAXO: | Tissue and ctDNA testing are used to identify eligible patients; anemia management is a key supportive action during PARPi therapy (chi2023detectionofbrca1 pages 1-2, chi2023detectionofbrca1 pages 2-4, tisseverasinghe2023advancesinparp pages 10-11) |
Table: This table proposes practical ontology mappings for a BRCA-mutant prostate cancer knowledge-base entry, spanning disease concept, genes, phenotypes, anatomy, processes, cell types, and treatments. It is grounded in the provided evidence on aggressive disease biology, metastatic behavior, PARP inhibitor response, and treatment toxicity.
BRCA-deficient metastatic prostate cancer shows enrichment of additional potentially actionable alterations: - In a 2023 cfDNA cohort, BRCA-deficient tumors were enriched for AR and PI3K pathway alterations (fettke2023brcadeficientmetastaticprostate pages 1-2). - Additional genomic enrichments reported include PI3K pathway alterations (PIK3CA/PTEN), FGFR1 copy gain, CDK6 alterations, and enrichment for aggressive disease-associated drivers (e.g., TP53/RB1/MYC) (fettke2023brcadeficientmetastaticprostate pages 7-8).
BRCA promoter methylation and broader epigenetic HRD (“BRCAness”) are conceptually relevant but were not supported by prostate-cancer-specific quantitative data in the retrieved excerpts.
No BRCA‑subtype–specific environmental exposures were identified in the retrieved evidence. Established prostate cancer environmental/lifestyle associations are outside the scope of the current evidence set.
TALAPRO‑2 explicitly describes preclinical rationale for co-inhibition: - “Androgen receptor inhibition is associated with upregulated PARP activity and downregulated HRR gene expression… while PARP inhibition suppresses androgen receptor transcriptional activity” (fizazi2024firstlinetalazoparibwith pages 1-2).
Candidate GO biological processes and CL cell types are included in:
| Section | Suggested term(s) | Evidence/rationale |
|---|---|---|
| Disease concept | prostate cancer — MONDO:0008315; BRCA-mutant prostate cancer — MONDO: not clearly established in available context; prostate carcinoma — EFO:0001663 | Open Targets evidence links BRCA1/2 to prostate cancer/prostate carcinoma; BRCA-mutant prostate cancer is best modeled as a molecularly defined subtype of prostate cancer rather than a clearly separate MONDO disease in the provided context (fizazi2024firstlinetalazoparibwith pages 1-2, heiss2024usfoodand pages 2-4) |
| Key genes | BRCA2 (HGNC:1101); BRCA1 (HGNC:1100); ATM (HGNC:795) | BRCA2 is the dominant altered gene in prostate cancer and is more common than BRCA1; ATM is a major comparator/HRR gene in trials and testing panels (inoue2023rolesofthe pages 2-4, alakhras2024parpinhibitorsin pages 10-11, heiss2024usfoodand pages 2-4) |
| Key genes | TP53 (HGNC:11998); AR (HGNC:644); CDK12 (HGNC:24243) | BRCA1-altered disease shows more concurrent TP53 alterations and worse PARPi outcomes; AR biology underlies PARP/AR combination rationale; CDK12 is a frequent HRR-panel gene in advanced disease studies (taza2021differentialactivityof pages 1-2, alakhras2024parpinhibitorsin pages 10-11, fizazi2024firstlinetalazoparibwith pages 1-2) |
| Phenotypes (HPO) | Aggressive prostate carcinoma phenotype — HPO likely prefix HP:; High Gleason score — HPO likely prefix HP:; Early adult onset/neoplasm onset younger than typical — HPO likely prefix HP:0003581/HP: | BRCA2 carriers show more clinically significant disease, younger onset, and high-grade tumors; BRCA-deficient metastatic disease has adverse prognosis (inoue2023rolesofthe pages 2-4, taza2021differentialactivityof pages 1-2) |
| Phenotypes (HPO) | Metastatic prostate adenocarcinoma — HPO likely prefix HP:0004409/HP:; Bone metastasis — HPO likely prefix HP:0002664; Castration-resistant disease — HPO likely prefix HP: | BRCA1 patients more often present metastatic at diagnosis; BRCA2 cohorts show frequent M1 disease and bone metastases; advanced trials focus on mCRPC (taza2021differentialactivityof pages 1-2, taza2021differentialactivityof pages 20-21, mateo2024olaparibforthe pages 1-2) |
| Phenotypes (HPO) | Anemia — HP:0001903; Fatigue — HP:0012378; Neutropenia — HP:0001875 | Common toxicities of PARP inhibitors/combination therapy include anemia, fatigue, and neutropenia; anemia is the most frequent grade ≥3 hematologic adverse event (tisseverasinghe2023advancesinparp pages 10-11, fizazi2024firstlinetalazoparibwith pages 1-2) |
| Anatomical entities (UBERON) | prostate gland — UBERON:0002367; prostate epithelium — UBERON likely prefix UBERON:; prostate stromal tissue — UBERON likely prefix UBERON: | Primary organ and tissue compartments involved in prostate carcinoma biology (fizazi2024firstlinetalazoparibwith pages 1-2, heiss2024usfoodand pages 2-4) |
| Anatomical entities (UBERON) | bone of skeletal system — UBERON:0001474; lymph node — UBERON:0000029; blood/plasma — UBERON:0000178 / body fluid term likely needed | Bone metastases are common; lymph nodes are common metastatic sites; plasma is important for ctDNA diagnostics (taza2021differentialactivityof pages 20-21, chi2023detectionofbrca1 pages 1-2) |
| Biological processes (GO) | homologous recombination — GO:0000724; DNA repair — GO:0006281; double-strand break repair — GO:0006302 | Core BRCA biology in prostate cancer is homologous recombination repair deficiency and impaired DSB repair (inoue2023rolesofthe pages 2-4, fizazi2024firstlinetalazoparibwith pages 1-2) |
| Biological processes (GO) | response to DNA damage stimulus — GO:0006974; DNA replication fork processing — GO likely prefix GO:; cell cycle process — GO:0022402 | PARP inhibition exploits replication-fork collapse and DNA damage accumulation; BRCA2-mutant tumors are enriched for cell-cycle programs (inoue2023rolesofthe pages 2-4, fizazi2024firstlinetalazoparibwith pages 1-2) |
| Biological processes (GO) | androgen receptor signaling pathway — GO likely prefix GO:; regulation of transcription by RNA polymerase II — GO:0006357; synthetic lethal interaction context — no direct GO term, represent via DNA repair dependency | TALAPRO-2 and FDA summary emphasize AR–PARP interplay: AR inhibition downregulates HRR genes and PARP inhibition suppresses AR transcriptional activity (fizazi2024firstlinetalazoparibwith pages 1-2, heiss2024usfoodand pages 2-4) |
| Cell types (CL) | prostate gland epithelial cell — CL likely prefix CL:; luminal epithelial cell of prostate — CL likely prefix CL:; basal cell of prostate epithelium — CL likely prefix CL: | Prostate cancer arises from epithelial compartments; organoid/PDX models preserve epithelial tumor features (fizazi2024firstlinetalazoparibwith pages 1-2, fizazi2024firstlinetalazoparibwith pages 2-3) |
| Cell types (CL) | metastatic prostate cancer cell — CL likely prefix CL: cancer cell term; osteoblast — CL:0000062; osteoclast — CL:0000097 | Bone metastasis is a hallmark clinical site and relevant microenvironmental context (taza2021differentialactivityof pages 20-21, chi2023detectionofbrca1 pages 1-2) |
| Treatments (MAXO) | PARP inhibitor therapy — MAXO likely prefix MAXO:; olaparib treatment — MAXO likely prefix MAXO:; talazoparib treatment — MAXO likely prefix MAXO: | Olaparib improves rPFS/OS/ORR in BRCA-altered mCRPC; talazoparib + enzalutamide improves rPFS in HRR-mutated disease, especially BRCA-mutant subgroup (mateo2024olaparibforthe pages 1-2, mateo2024olaparibforthe pages 8-9, heiss2024usfoodand pages 2-4) |
| Treatments (MAXO) | niraparib plus abiraterone therapy — MAXO likely prefix MAXO:; enzalutamide therapy — MAXO likely prefix MAXO:; androgen receptor pathway inhibitor therapy — MAXO likely prefix MAXO: | MAGNITUDE supports niraparib + abiraterone in BRCA1/2-mutated mCRPC; ARPI backbone is central to current implementation (chi2023niraparibandabiraterone pages 1-2, chi2023niraparibandabiraterone pages 5-6) |
| Treatments (MAXO) | circulating tumor DNA testing-guided targeted therapy — MAXO likely prefix MAXO:; germline genetic testing — MAXO likely prefix MAXO:; supportive treatment for anemia — MAXO likely prefix MAXO: | Tissue and ctDNA testing are used to identify eligible patients; anemia management is a key supportive action during PARPi therapy (chi2023detectionofbrca1 pages 1-2, chi2023detectionofbrca1 pages 2-4, tisseverasinghe2023advancesinparp pages 10-11) |
Table: This table proposes practical ontology mappings for a BRCA-mutant prostate cancer knowledge-base entry, spanning disease concept, genes, phenotypes, anatomy, processes, cell types, and treatments. It is grounded in the provided evidence on aggressive disease biology, metastatic behavior, PARP inhibitor response, and treatment toxicity.
See ontology mapping table (artifact-03).
A key implementation challenge is insufficient or failed tissue testing in advanced disease: - In PROfound screening, 31% of tumor tissue samples failed molecular screening (insufficient/inadequate tissue or tumor content, DNA quality/quantity, or downstream assay failures) (chi2023detectionofbrca1 pages 1-2).
ctDNA as a complement to tissue testing: - PROfound matched analysis: 81% (503/619) of ctDNA samples yielded an NGS result; comparing tissue to ctDNA showed 81% positive percentage agreement and 92% negative percentage agreement; concordance was high for nonsense (93%), splice (87%), frameshift (86%) but lower for large rearrangements (63%) and homozygous deletions (27%); low ctDNA fraction was limiting (chi2023detectionofbrca1 pages 1-2).
A detailed diagnostic synthesis (including structural-variant limitations) is provided in:
| Specimen/test | Yield | Agreement metrics | Strengths | Limitations | Source |
|---|---|---|---|---|---|
| Tumor tissue NGS (FoundationOne CDx–based screening in PROfound) | Tissue molecular screening failure rate ~31% | Used as reference standard for matched analyses; when compared with ctDNA, corresponding ctDNA PPA/sensitivity 81% and NPA/specificity 92% | Current gold-standard approach for HRR testing; better detection of structural events such as homozygous deletions and large rearrangements; avoids some plasma false negatives (chi2023detectionofbrca1 pages 2-2, chi2023detectionofbrca1 pages 6-8) | Invasive biopsy; frequent insufficiency/quality failures, especially with small samples and bone-predominant disease; decalcification and low DNA quantity/quality can impair testing | Chi et al., 2023, Clin Cancer Res, doi:10.1158/1078-0432.CCR-22-0931 (chi2023detectionofbrca1 pages 1-2, chi2023detectionofbrca1 pages 2-4, chi2023detectionofbrca1 pages 2-2) |
| Plasma ctDNA NGS (FoundationOne Liquid CDx in matched PROfound cohort) | 81% (503/619) yielded an NGS result; ~90% yield after excluding technical batch failures; plasma volume ≥7 mL improved yield (82% vs 69%) | Overall BRCA/ATM status vs tissue: PPA 81%, NPA 92%, PPV 0.68, NPV 0.96; variant-level sensitivity 74% and overall variant concordance 71% (146/207 shared variants) | Minimally invasive; complements tissue when tissue is unavailable/insufficient; identified additional patients potentially eligible for PARP inhibitor treatment; high specificity even at lower ctDNA fractions | False negatives occur, especially with low ctDNA fraction/non-shedders; ~20% of qualifying mutations identified by tissue only; ctDNA fraction not evaluable in 13% | Chi et al., 2023, Clin Cancer Res, doi:10.1158/1078-0432.CCR-22-0931 (chi2023detectionofbrca1 pages 1-2, chi2023detectionofbrca1 pages 4-5, chi2023detectionofbrca1 pages 2-4, chi2023detectionofbrca1 pages 6-8) |
| Plasma ctDNA NGS performance by ctDNA fraction | 428/491 (87%) had evaluable ctDNA fraction | At ctDNA fraction ≥10%: sensitivity 87%, specificity 90%; at 1% to <10%: sensitivity 92%, specificity 95%; at <1%/not evaluable: sensitivity fell to 68%/56% while specificity remained high (92%/100%) | Best performance when tumor shedding is adequate; useful for dynamic testing in metastatic disease | Low-shedding tumors markedly reduce sensitivity; negative plasma test does not exclude actionable BRCA/ATM alteration | Chi et al., 2023, Clin Cancer Res, doi:10.1158/1078-0432.CCR-22-0931 (chi2023detectionofbrca1 pages 4-5, chi2023detectionofbrca1 pages 6-8) |
| Variant subtype concordance: nonsense / splice / frameshift | Not applicable | High concordance versus tissue: nonsense 93%, splice 87%, frameshift 86% | ctDNA performs well for many short variants/indels relevant to BRCA/ATM | Some splice and missense variants show lower overlap when assessed from ctDNA perspective | Chi et al., 2023, Clin Cancer Res, doi:10.1158/1078-0432.CCR-22-0931 (chi2023detectionofbrca1 pages 1-2, chi2023detectionofbrca1 pages 5-6) |
| Variant subtype concordance: large rearrangements / homozygous deletions | Not applicable | Large rearrangements 63% concordance from tissue reference; homozygous deletions only 27% concordance from tissue reference | Tissue testing better captures these lesion classes | Major plasma blind spot, especially at low ctDNA fraction; important because BRCA2 homozygous deletions can predict strong PARP inhibitor sensitivity | Chi et al., 2023, Clin Cancer Res, doi:10.1158/1078-0432.CCR-22-0931 (chi2023detectionofbrca1 pages 1-2, chi2023detectionofbrca1 pages 4-5, chi2023detectionofbrca1 pages 5-6) |
| Clinical interpretation of negative plasma test | Not applicable | Approx. 80% concordance overall with tissue in PROfound-era analyses | ctDNA is clinically useful to complement tissue and can support identification of BRCA/ATM-altered mCRPC for olaparib | FoundationOne Liquid CDx not validated for some homozygous BRCA deletions/large rearrangements; low tumor content and CHIP can confound results; FDA label cautions that a negative liquid test does not rule out actionable alterations and tissue testing should be pursued if feasible | Matsubara et al., 2023, Clin Cancer Res, doi:10.1158/1078-0432.CCR-21-3577 (matsubara2023olaparibefficacyin pages 5-6); Chi et al., 2023 (chi2023detectionofbrca1 pages 6-8) |
Table: This table compares tumor tissue NGS and plasma ctDNA testing for BRCA/ATM alterations in mCRPC, emphasizing test yield, concordance, and important structural-variant limitations. It is useful for selecting testing strategies and interpreting negative liquid-biopsy results.
Visual evidence (PROfound tissue vs ctDNA concordance): key tables/figures were retrieved from the PROfound screening paper (chi2023detectionofbrca1 media 1d7942c2, chi2023detectionofbrca1 media 19a57459, chi2023detectionofbrca1 media c50e82d1, chi2023detectionofbrca1 media 89bfe680).
A 2024 JAMA Oncology systematic review/meta-analysis of MRI in screening pathways (12 studies; ~80k men) found that, compared with PSA-only pathways, MRI-based screening: - Reduced biopsies (OR 0.28, 95% CI 0.22–0.36) - Reduced detection of insignificant cancers (OR 0.34, 95% CI 0.23–0.49) - Maintained overall clinically significant cancer detection (OR 1.02, 95% CI 0.75–1.37) - Increased PPV for clinically significant cancer among positives (OR 4.15, 95% CI 2.93–5.88) (fazekas2024magneticresonanceimaging pages 1-6, fazekas2024magneticresonanceimaging pages 21-25).
BRCA-mutant prostate cancer is not a separate histologic diagnosis; differential diagnosis is primarily across prostate cancer clinical/molecular subtypes (e.g., AR-driven adenocarcinoma vs AR-negative/neuroendocrine/double-negative phenotypes). A relevant model of AR-negative DNPC with BRCA2 variant is described under model systems (turnham2024developmentandcharacterisation pages 1-2).
In a 2023 cfDNA cohort of men with mCRPC: - BRCA alterations were associated with significantly worse PFS (HR 3.3, 95% CI 1.9–6.0; p<0.001) and worse OS (HR 2.2, 95% CI 1.1–4.5; p=0.02) (fettke2023brcadeficientmetastaticprostate pages 1-2). - PSA response rates to AR pathway inhibitors were lower in BRCA-altered patients (32% vs 60%) (fettke2023brcadeficientmetastaticprostate pages 1-2).
More granular hazard ratios by BRCA2 alteration type/zygosity were also reported (e.g., BRCA2 homozygous deletion HR 7.0 for OS in one analysis; and elevated hazards across point mutations, heterozygous/homozygous deletions, and mono/biallelic loss) (fettke2023brcadeficientmetastaticprostate pages 8-10, fettke2023brcadeficientmetastaticprostate pages 7-8).
In PROfound BRCA subgroup analysis, olaparib improved rPFS and OS versus control, supporting BRCA alterations as predictive biomarkers of PARP inhibitor benefit (mateo2024olaparibforthe pages 1-2).
PROfound BRCA subgroup (2024): - Olaparib improved rPFS (HR 0.22, 95% CI 0.15–0.32) and OS (HR 0.63, 95% CI 0.42–0.95) vs abiraterone or enzalutamide in BRCA-altered mCRPC after prior NHA (mateo2024olaparibforthe pages 1-2). - Confirmed ORR was 43.9% (25/57) vs 0% (0/33) (mateo2024olaparibforthe pages 4-5). - Benefit was strong in biallelic alterations (rPFS HR 0.08) and also present in heterozygous/unknown zygosity (HR 0.30) (mateo2024olaparibforthe pages 1-2).
MAGNITUDE (JCO 2023): niraparib + abiraterone - In BRCA1/2 subgroup: median rPFS 16.6 vs 10.9 months, HR 0.53 (95% CI 0.36–0.79), P=.001 (chi2023niraparibandabiraterone pages 1-2). - “Treatment … was tolerable, with anemia and hypertension as the most reported grade ≥3 adverse events” (exact frequencies not present in provided excerpt) (chi2023niraparibandabiraterone pages 1-2).
TALAPRO‑2 (Nature Medicine 2024): talazoparib + enzalutamide - In HRR-deficient population: median rPFS not reached vs 13.8 months, HR 0.45 (95% CI 0.33–0.61), P<0.0001; OS immature but favored talazoparib (HR 0.69; P=0.07) (fizazi2024firstlinetalazoparibwith pages 1-2).
FDA approval summary (JCO 2024): talazoparib + enzalutamide - FDA limited approval to HRR gene–mutated mCRPC based on clinically meaningful rPFS in HRRm population (HR 0.45, 95% CI 0.33–0.61). In exploratory BRCA-mutated subgroup (n=155), rPFS HR 0.20 (95% CI 0.11–0.36) (heiss2024usfoodand pages 1-2).
A compact synthesis of major therapy evidence is provided in:
| Study (name; phase; publication) | Population/biomarker | Intervention vs control | Key efficacy results | Key safety notes | URL/DOI |
|---|---|---|---|---|---|
| PROfound BRCA subgroup; phase III post hoc subgroup analysis; Mateo et al., J Clin Oncol 2024 | mCRPC with BRCA1/2 alterations after prior NHA; 160 patients with BRCA alterations; subgroup analyses by germline vs somatic and zygosity (mateo2024olaparibforthe pages 1-2, mateo2024olaparibforthe pages 8-9, mateo2024olaparibforthe pages 4-5) | Olaparib vs physician’s choice abiraterone or enzalutamide (mateo2024olaparibforthe pages 1-2, mateo2024olaparibforthe pages 4-5) | rPFS HR 0.22 (95% CI 0.15–0.32); OS HR 0.63 (95% CI 0.42–0.95). Confirmed ORR 43.9% (25/57) vs 0% (0/33). Biallelic subgroup rPFS HR 0.08; heterozygous/unknown HR 0.30. BRCA2 homozygous deletion subset median rPFS 16.6 mo (95% CI 9.3–NR). Germline BRCA: median rPFS 10.4 vs 1.9 mo, HR 0.08; somatic BRCA: 11.1 vs 2.3 mo, HR 0.16 (mateo2024olaparibforthe pages 1-2, mateo2024olaparibforthe pages 8-9, mateo2024olaparibforthe pages 6-8, mateo2024olaparibforthe pages 4-5) | Safety details not quantified in provided context for this subgroup analysis; efficacy benefit observed across germline and somatic subgroups (mateo2024olaparibforthe pages 1-2, mateo2024olaparibforthe pages 8-9) | https://doi.org/10.1200/JCO.23.00339 |
| MAGNITUDE; phase III; Chi et al., J Clin Oncol 2023 | First-line mCRPC with prospectively defined HRR+, including prespecified BRCA1/2 subgroup; HRR testing by tissue and/or plasma assays (chi2023niraparibandabiraterone pages 1-2, chi2023niraparibandabiraterone pages 5-6, chi2023niraparibandabiraterone pages 3-4) | Niraparib + abiraterone acetate + prednisone (AAP) vs placebo + AAP (chi2023niraparibandabiraterone pages 1-2, chi2023niraparibandabiraterone pages 5-6) | In BRCA1/2 subgroup: median rPFS 16.6 vs 10.9 mo, HR 0.53 (95% CI 0.36–0.79), P=.001; investigator-assessed rPFS 19.3 vs 12.4 mo, HR 0.50 (95% CI 0.33–0.75). In overall HRR+ cohort: median rPFS 16.5 vs 13.7 mo, HR 0.73, P=.022 (chi2023niraparibandabiraterone pages 1-2, chi2023niraparibandabiraterone pages 5-6) | Combination described as tolerable; most frequently reported grade ≥3 AEs were anemia and hypertension. Exact subgroup frequencies not available in provided context (chi2023niraparibandabiraterone pages 1-2) | https://doi.org/10.1200/JCO.22.01649 |
| TALAPRO-2; phase III; Fizazi et al., Nature Medicine 2024 | First-line mCRPC with HRR-deficient tumors; combined HRR-deficient population N=399; prospective tumor testing, with later protocol allowance for ctDNA testing; common alterations included BRCA2, ATM, CDK12 (fizazi2024firstlinetalazoparibwith pages 1-2, fizazi2024firstlinetalazoparibwith pages 2-3) | Talazoparib + enzalutamide vs placebo + enzalutamide (fizazi2024firstlinetalazoparibwith pages 1-2, fizazi2024firstlinetalazoparibwith pages 2-3) | HRR-deficient population: median rPFS not reached vs 13.8 mo, HR 0.45 (95% CI 0.33–0.61), P<0.0001. Time to PSA progression HR 0.41; time to cytotoxic chemotherapy HR 0.46. OS immature but favored talazoparib, HR 0.69 (95% CI 0.46–1.03), P=.07 (fizazi2024firstlinetalazoparibwith pages 1-2, fizazi2024firstlinetalazoparibwith pages 5-5) | Common AEs: anemia, fatigue, neutropenia; detailed rates not provided in the sampled publication excerpt (fizazi2024firstlinetalazoparibwith pages 1-2) | https://doi.org/10.1038/s41591-023-02704-x |
| TALAPRO-2 FDA approval summary; regulatory review of phase III data; Heiss et al., J Clin Oncol 2024 | HRR gene-mutated mCRPC; exploratory BRCA-mutated subgroup within combined HRRm population; NGS-based 12-gene panel with tumor tissue initially and blood ctDNA allowed by amendment (heiss2024usfoodand pages 2-4) | Talazoparib + enzalutamide vs placebo + enzalutamide (heiss2024usfoodand pages 2-4) | Combined HRRm population rPFS HR 0.45 (95% CI 0.33–0.61), P<.0001. Exploratory BRCA-mutated subgroup rPFS HR 0.20 (95% CI 0.11–0.36); OS HR 0.61 (95% CI 0.31–1.23). FDA judged benefit clinically meaningful in HRRm disease, not broad all-comers population (heiss2024usfoodand pages 2-4) | Primary safety population noted, but specific event rates not provided in context excerpt (heiss2024usfoodand pages 2-4) | https://doi.org/10.1200/JCO.23.02182 |
| Multicenter retrospective PARPi analysis; retrospective; Taza et al., JCO Precis Oncol 2021 | BRCA1- vs BRCA2-altered mCRPC treated with PARP inhibitors; n=123 total (13 BRCA1, 110 BRCA2) (taza2021differentialactivityof pages 1-2) | PARPi cohort only: olaparib (most), rucaparib, talazoparib, veliparib; no randomized control arm (taza2021differentialactivityof pages 1-2) | PSA50 response: 23% BRCA1 vs 63% BRCA2 (P=.01). BRCA2 patients had longer PSA-PFS (HR 1.94), PFS (HR 2.08), and OS (HR 3.01, 95% CI 1.32–6.83, P=.008) relative to BRCA1 group. Predictors of PARPi sensitivity: biallelic status, truncating mutations, absence of TP53 co-alteration (taza2021differentialactivityof pages 1-2) | Safety not the main focus in provided excerpt; study supports diminished PARPi activity in BRCA1 vs BRCA2 disease (taza2021differentialactivityof pages 1-2) | https://doi.org/10.1200/PO.21.00070 |
Table: This table summarizes major clinical evidence for BRCA/HRR-mutant prostate cancer focused on PARP inhibitor monotherapy and PARP inhibitor combinations, including efficacy, biomarker context, and available safety findings from the cited studies.
Hematologic toxicity is a major class consideration. In the retrieved evidence: - PARP inhibitor combinations frequently report anemia as a prominent toxicity signal (chi2023niraparibandabiraterone pages 1-2, fizazi2024firstlinetalazoparibwith pages 1-2). - TALAPRO-1 safety analyses show anemia as the most common AE class and emphasize supportive care and dose modifications (fizazi2024firstlinetalazoparibwith pages 2-3).
See ontology mapping table (artifact-03).
The major preventive lever is identifying germline BRCA1/2 carriers for: - cascade testing of relatives - risk-adapted screening Cheng et al. emphasize under-recognition and under-testing of male carriers, despite growing clinical actionability (cheng2024brca1brca2and pages 1-3).
Cheng et al. summarize the IMPACT trial approach and downstream implications: - Annual PSA screening; biopsy threshold PSA >3.0 ng/mL - After four rounds: biopsy PPV higher in BRCA2 carriers (39% vs 28) and intermediate/high-risk disease more frequent (77% vs 40%) (cheng2024brca1brca2and pages 5-6). - Guidelines recommend PSA screening start age 40–45 years for male BRCA2 PV carriers (cheng2024brca1brca2and pages 5-6).
MRI-based screening pathways reduce biopsies and overdiagnosis while maintaining clinically significant cancer detection in general screening populations, and are noted as effective in genetically predisposed groups, but BRCA2-specific pooled estimates are limited in the meta-analysis (fazekas2024magneticresonanceimaging pages 10-13).
Not assessed in the retrieved evidence.
| Study (name; phase; publication) | Population/biomarker | Intervention vs control | Key efficacy results | Key safety notes | URL/DOI |
|---|---|---|---|---|---|
| PROfound BRCA subgroup; phase III post hoc subgroup analysis; Mateo et al., J Clin Oncol 2024 | mCRPC with BRCA1/2 alterations after prior NHA; 160 patients with BRCA alterations; subgroup analyses by germline vs somatic and zygosity (mateo2024olaparibforthe pages 1-2, mateo2024olaparibforthe pages 8-9, mateo2024olaparibforthe pages 4-5) | Olaparib vs physician’s choice abiraterone or enzalutamide (mateo2024olaparibforthe pages 1-2, mateo2024olaparibforthe pages 4-5) | rPFS HR 0.22 (95% CI 0.15–0.32); OS HR 0.63 (95% CI 0.42–0.95). Confirmed ORR 43.9% (25/57) vs 0% (0/33). Biallelic subgroup rPFS HR 0.08; heterozygous/unknown HR 0.30. BRCA2 homozygous deletion subset median rPFS 16.6 mo (95% CI 9.3–NR). Germline BRCA: median rPFS 10.4 vs 1.9 mo, HR 0.08; somatic BRCA: 11.1 vs 2.3 mo, HR 0.16 (mateo2024olaparibforthe pages 1-2, mateo2024olaparibforthe pages 8-9, mateo2024olaparibforthe pages 6-8, mateo2024olaparibforthe pages 4-5) | Safety details not quantified in provided context for this subgroup analysis; efficacy benefit observed across germline and somatic subgroups (mateo2024olaparibforthe pages 1-2, mateo2024olaparibforthe pages 8-9) | https://doi.org/10.1200/JCO.23.00339 |
| MAGNITUDE; phase III; Chi et al., J Clin Oncol 2023 | First-line mCRPC with prospectively defined HRR+, including prespecified BRCA1/2 subgroup; HRR testing by tissue and/or plasma assays (chi2023niraparibandabiraterone pages 1-2, chi2023niraparibandabiraterone pages 5-6, chi2023niraparibandabiraterone pages 3-4) | Niraparib + abiraterone acetate + prednisone (AAP) vs placebo + AAP (chi2023niraparibandabiraterone pages 1-2, chi2023niraparibandabiraterone pages 5-6) | In BRCA1/2 subgroup: median rPFS 16.6 vs 10.9 mo, HR 0.53 (95% CI 0.36–0.79), P=.001; investigator-assessed rPFS 19.3 vs 12.4 mo, HR 0.50 (95% CI 0.33–0.75). In overall HRR+ cohort: median rPFS 16.5 vs 13.7 mo, HR 0.73, P=.022 (chi2023niraparibandabiraterone pages 1-2, chi2023niraparibandabiraterone pages 5-6) | Combination described as tolerable; most frequently reported grade ≥3 AEs were anemia and hypertension. Exact subgroup frequencies not available in provided context (chi2023niraparibandabiraterone pages 1-2) | https://doi.org/10.1200/JCO.22.01649 |
| TALAPRO-2; phase III; Fizazi et al., Nature Medicine 2024 | First-line mCRPC with HRR-deficient tumors; combined HRR-deficient population N=399; prospective tumor testing, with later protocol allowance for ctDNA testing; common alterations included BRCA2, ATM, CDK12 (fizazi2024firstlinetalazoparibwith pages 1-2, fizazi2024firstlinetalazoparibwith pages 2-3) | Talazoparib + enzalutamide vs placebo + enzalutamide (fizazi2024firstlinetalazoparibwith pages 1-2, fizazi2024firstlinetalazoparibwith pages 2-3) | HRR-deficient population: median rPFS not reached vs 13.8 mo, HR 0.45 (95% CI 0.33–0.61), P<0.0001. Time to PSA progression HR 0.41; time to cytotoxic chemotherapy HR 0.46. OS immature but favored talazoparib, HR 0.69 (95% CI 0.46–1.03), P=.07 (fizazi2024firstlinetalazoparibwith pages 1-2, fizazi2024firstlinetalazoparibwith pages 5-5) | Common AEs: anemia, fatigue, neutropenia; detailed rates not provided in the sampled publication excerpt (fizazi2024firstlinetalazoparibwith pages 1-2) | https://doi.org/10.1038/s41591-023-02704-x |
| TALAPRO-2 FDA approval summary; regulatory review of phase III data; Heiss et al., J Clin Oncol 2024 | HRR gene-mutated mCRPC; exploratory BRCA-mutated subgroup within combined HRRm population; NGS-based 12-gene panel with tumor tissue initially and blood ctDNA allowed by amendment (heiss2024usfoodand pages 2-4) | Talazoparib + enzalutamide vs placebo + enzalutamide (heiss2024usfoodand pages 2-4) | Combined HRRm population rPFS HR 0.45 (95% CI 0.33–0.61), P<.0001. Exploratory BRCA-mutated subgroup rPFS HR 0.20 (95% CI 0.11–0.36); OS HR 0.61 (95% CI 0.31–1.23). FDA judged benefit clinically meaningful in HRRm disease, not broad all-comers population (heiss2024usfoodand pages 2-4) | Primary safety population noted, but specific event rates not provided in context excerpt (heiss2024usfoodand pages 2-4) | https://doi.org/10.1200/JCO.23.02182 |
| Multicenter retrospective PARPi analysis; retrospective; Taza et al., JCO Precis Oncol 2021 | BRCA1- vs BRCA2-altered mCRPC treated with PARP inhibitors; n=123 total (13 BRCA1, 110 BRCA2) (taza2021differentialactivityof pages 1-2) | PARPi cohort only: olaparib (most), rucaparib, talazoparib, veliparib; no randomized control arm (taza2021differentialactivityof pages 1-2) | PSA50 response: 23% BRCA1 vs 63% BRCA2 (P=.01). BRCA2 patients had longer PSA-PFS (HR 1.94), PFS (HR 2.08), and OS (HR 3.01, 95% CI 1.32–6.83, P=.008) relative to BRCA1 group. Predictors of PARPi sensitivity: biallelic status, truncating mutations, absence of TP53 co-alteration (taza2021differentialactivityof pages 1-2) | Safety not the main focus in provided excerpt; study supports diminished PARPi activity in BRCA1 vs BRCA2 disease (taza2021differentialactivityof pages 1-2) | https://doi.org/10.1200/PO.21.00070 |
Table: This table summarizes major clinical evidence for BRCA/HRR-mutant prostate cancer focused on PARP inhibitor monotherapy and PARP inhibitor combinations, including efficacy, biomarker context, and available safety findings from the cited studies.
| Specimen/test | Yield | Agreement metrics | Strengths | Limitations | Source |
|---|---|---|---|---|---|
| Tumor tissue NGS (FoundationOne CDx–based screening in PROfound) | Tissue molecular screening failure rate ~31% | Used as reference standard for matched analyses; when compared with ctDNA, corresponding ctDNA PPA/sensitivity 81% and NPA/specificity 92% | Current gold-standard approach for HRR testing; better detection of structural events such as homozygous deletions and large rearrangements; avoids some plasma false negatives (chi2023detectionofbrca1 pages 2-2, chi2023detectionofbrca1 pages 6-8) | Invasive biopsy; frequent insufficiency/quality failures, especially with small samples and bone-predominant disease; decalcification and low DNA quantity/quality can impair testing | Chi et al., 2023, Clin Cancer Res, doi:10.1158/1078-0432.CCR-22-0931 (chi2023detectionofbrca1 pages 1-2, chi2023detectionofbrca1 pages 2-4, chi2023detectionofbrca1 pages 2-2) |
| Plasma ctDNA NGS (FoundationOne Liquid CDx in matched PROfound cohort) | 81% (503/619) yielded an NGS result; ~90% yield after excluding technical batch failures; plasma volume ≥7 mL improved yield (82% vs 69%) | Overall BRCA/ATM status vs tissue: PPA 81%, NPA 92%, PPV 0.68, NPV 0.96; variant-level sensitivity 74% and overall variant concordance 71% (146/207 shared variants) | Minimally invasive; complements tissue when tissue is unavailable/insufficient; identified additional patients potentially eligible for PARP inhibitor treatment; high specificity even at lower ctDNA fractions | False negatives occur, especially with low ctDNA fraction/non-shedders; ~20% of qualifying mutations identified by tissue only; ctDNA fraction not evaluable in 13% | Chi et al., 2023, Clin Cancer Res, doi:10.1158/1078-0432.CCR-22-0931 (chi2023detectionofbrca1 pages 1-2, chi2023detectionofbrca1 pages 4-5, chi2023detectionofbrca1 pages 2-4, chi2023detectionofbrca1 pages 6-8) |
| Plasma ctDNA NGS performance by ctDNA fraction | 428/491 (87%) had evaluable ctDNA fraction | At ctDNA fraction ≥10%: sensitivity 87%, specificity 90%; at 1% to <10%: sensitivity 92%, specificity 95%; at <1%/not evaluable: sensitivity fell to 68%/56% while specificity remained high (92%/100%) | Best performance when tumor shedding is adequate; useful for dynamic testing in metastatic disease | Low-shedding tumors markedly reduce sensitivity; negative plasma test does not exclude actionable BRCA/ATM alteration | Chi et al., 2023, Clin Cancer Res, doi:10.1158/1078-0432.CCR-22-0931 (chi2023detectionofbrca1 pages 4-5, chi2023detectionofbrca1 pages 6-8) |
| Variant subtype concordance: nonsense / splice / frameshift | Not applicable | High concordance versus tissue: nonsense 93%, splice 87%, frameshift 86% | ctDNA performs well for many short variants/indels relevant to BRCA/ATM | Some splice and missense variants show lower overlap when assessed from ctDNA perspective | Chi et al., 2023, Clin Cancer Res, doi:10.1158/1078-0432.CCR-22-0931 (chi2023detectionofbrca1 pages 1-2, chi2023detectionofbrca1 pages 5-6) |
| Variant subtype concordance: large rearrangements / homozygous deletions | Not applicable | Large rearrangements 63% concordance from tissue reference; homozygous deletions only 27% concordance from tissue reference | Tissue testing better captures these lesion classes | Major plasma blind spot, especially at low ctDNA fraction; important because BRCA2 homozygous deletions can predict strong PARP inhibitor sensitivity | Chi et al., 2023, Clin Cancer Res, doi:10.1158/1078-0432.CCR-22-0931 (chi2023detectionofbrca1 pages 1-2, chi2023detectionofbrca1 pages 4-5, chi2023detectionofbrca1 pages 5-6) |
| Clinical interpretation of negative plasma test | Not applicable | Approx. 80% concordance overall with tissue in PROfound-era analyses | ctDNA is clinically useful to complement tissue and can support identification of BRCA/ATM-altered mCRPC for olaparib | FoundationOne Liquid CDx not validated for some homozygous BRCA deletions/large rearrangements; low tumor content and CHIP can confound results; FDA label cautions that a negative liquid test does not rule out actionable alterations and tissue testing should be pursued if feasible | Matsubara et al., 2023, Clin Cancer Res, doi:10.1158/1078-0432.CCR-21-3577 (matsubara2023olaparibefficacyin pages 5-6); Chi et al., 2023 (chi2023detectionofbrca1 pages 6-8) |
Table: This table compares tumor tissue NGS and plasma ctDNA testing for BRCA/ATM alterations in mCRPC, emphasizing test yield, concordance, and important structural-variant limitations. It is useful for selecting testing strategies and interpreting negative liquid-biopsy results.
| Setting | Germline BRCA1 % | Somatic BRCA1 % | Germline BRCA2 % | Somatic BRCA2 % | Notes | Source |
|---|---|---|---|---|---|---|
| Any-stage prostate cancer | 0.73% | 1.20% | 3.25% | 6.29% | Meta-analysis: somatic mutations more common than germline; BRCA2 more common than BRCA1. Combined BRCA1/2 frequency: 4.47% germline, 7.18% somatic. (valsecchi2023frequencyofgermline pages 8-10) | Valsecchi et al., 2023, Cancers; https://doi.org/10.3390/cancers15092435 |
| Metastatic prostate cancer | 0.94% | 1.10% | 4.51% | 10.26% | Frequency rises in metastatic disease; BRCA2 predominates; combined BRCA1/2 frequency: 5.84% germline, 10.94% somatic. (valsecchi2023frequencyofgermline pages 8-10) | Valsecchi et al., 2023, Cancers; https://doi.org/10.3390/cancers15092435 |
| Metastatic castration-resistant prostate cancer (mCRPC) | 1.21% | 1.10% | 3.90% | 10.52% | In mCRPC, somatic BRCA2 is especially enriched; combined BRCA1/2 frequency: 5.26% germline, 11.26% somatic. (valsecchi2023frequencyofgermline pages 8-10) | Valsecchi et al., 2023, Cancers; https://doi.org/10.3390/cancers15092435 |
| Metastatic prostate cancer, germline DDR pathogenic variants | — | — | ~6% (BRCA1/2 combined) | — | Review states ~12% of metastatic prostate cancer patients harbor germline DDR pathogenic variants, with BRCA1/2 the most frequent DDR genes (~6% combined). Also notes germline and somatic BRCA1/2 frequencies are reported as similar enough that both should be evaluated. (inoue2023rolesofthe pages 2-4) | Inoue et al., 2023, Cancers; https://doi.org/10.3390/cancers15092662 |
| BRCA2-altered mCRPC PARPi-treated cohort (clinical provenance split) | — | — | 50% of BRCA2-altered cases were germline overall; 58% among responders | 50% of BRCA2-altered cases were somatic overall; 39% among responders | Clinical cohort provenance rather than population prevalence: in BRCA2-altered mCRPC treated with PARP inhibitors, mutation origin was roughly evenly split overall (56/110 germline, 54/110 somatic), with germline enrichment among responders. (taza2021differentialactivityof pages 20-21) | Taza et al., 2021, JCO Precision Oncology; https://doi.org/10.1200/PO.21.00070 |
| Real-world ctDNA metastatic prostate cancer cohort | not separately reported | not separately reported | not separately reported | not separately reported | ctDNA cohort found BRCA1/2 alterations (germline or somatic) in 21% of patients with metastatic prostate cancer; this row reflects assay-detected prevalence in a progression-enriched real-world blood cohort, not stage-specific tissue prevalence. (valsecchi2023frequencyofgermline pages 8-10) | Bang et al., 2023, Cancers; https://doi.org/10.3390/cancers15153998 |
Table: This table summarizes reported BRCA1/2 mutation frequencies and mutation provenance in prostate cancer across disease settings. It combines meta-analytic prevalence estimates with review and cohort data to distinguish population frequency from clinical provenance in advanced disease.
| Section | Suggested term(s) | Evidence/rationale |
|---|---|---|
| Disease concept | prostate cancer — MONDO:0008315; BRCA-mutant prostate cancer — MONDO: not clearly established in available context; prostate carcinoma — EFO:0001663 | Open Targets evidence links BRCA1/2 to prostate cancer/prostate carcinoma; BRCA-mutant prostate cancer is best modeled as a molecularly defined subtype of prostate cancer rather than a clearly separate MONDO disease in the provided context (fizazi2024firstlinetalazoparibwith pages 1-2, heiss2024usfoodand pages 2-4) |
| Key genes | BRCA2 (HGNC:1101); BRCA1 (HGNC:1100); ATM (HGNC:795) | BRCA2 is the dominant altered gene in prostate cancer and is more common than BRCA1; ATM is a major comparator/HRR gene in trials and testing panels (inoue2023rolesofthe pages 2-4, alakhras2024parpinhibitorsin pages 10-11, heiss2024usfoodand pages 2-4) |
| Key genes | TP53 (HGNC:11998); AR (HGNC:644); CDK12 (HGNC:24243) | BRCA1-altered disease shows more concurrent TP53 alterations and worse PARPi outcomes; AR biology underlies PARP/AR combination rationale; CDK12 is a frequent HRR-panel gene in advanced disease studies (taza2021differentialactivityof pages 1-2, alakhras2024parpinhibitorsin pages 10-11, fizazi2024firstlinetalazoparibwith pages 1-2) |
| Phenotypes (HPO) | Aggressive prostate carcinoma phenotype — HPO likely prefix HP:; High Gleason score — HPO likely prefix HP:; Early adult onset/neoplasm onset younger than typical — HPO likely prefix HP:0003581/HP: | BRCA2 carriers show more clinically significant disease, younger onset, and high-grade tumors; BRCA-deficient metastatic disease has adverse prognosis (inoue2023rolesofthe pages 2-4, taza2021differentialactivityof pages 1-2) |
| Phenotypes (HPO) | Metastatic prostate adenocarcinoma — HPO likely prefix HP:0004409/HP:; Bone metastasis — HPO likely prefix HP:0002664; Castration-resistant disease — HPO likely prefix HP: | BRCA1 patients more often present metastatic at diagnosis; BRCA2 cohorts show frequent M1 disease and bone metastases; advanced trials focus on mCRPC (taza2021differentialactivityof pages 1-2, taza2021differentialactivityof pages 20-21, mateo2024olaparibforthe pages 1-2) |
| Phenotypes (HPO) | Anemia — HP:0001903; Fatigue — HP:0012378; Neutropenia — HP:0001875 | Common toxicities of PARP inhibitors/combination therapy include anemia, fatigue, and neutropenia; anemia is the most frequent grade ≥3 hematologic adverse event (tisseverasinghe2023advancesinparp pages 10-11, fizazi2024firstlinetalazoparibwith pages 1-2) |
| Anatomical entities (UBERON) | prostate gland — UBERON:0002367; prostate epithelium — UBERON likely prefix UBERON:; prostate stromal tissue — UBERON likely prefix UBERON: | Primary organ and tissue compartments involved in prostate carcinoma biology (fizazi2024firstlinetalazoparibwith pages 1-2, heiss2024usfoodand pages 2-4) |
| Anatomical entities (UBERON) | bone of skeletal system — UBERON:0001474; lymph node — UBERON:0000029; blood/plasma — UBERON:0000178 / body fluid term likely needed | Bone metastases are common; lymph nodes are common metastatic sites; plasma is important for ctDNA diagnostics (taza2021differentialactivityof pages 20-21, chi2023detectionofbrca1 pages 1-2) |
| Biological processes (GO) | homologous recombination — GO:0000724; DNA repair — GO:0006281; double-strand break repair — GO:0006302 | Core BRCA biology in prostate cancer is homologous recombination repair deficiency and impaired DSB repair (inoue2023rolesofthe pages 2-4, fizazi2024firstlinetalazoparibwith pages 1-2) |
| Biological processes (GO) | response to DNA damage stimulus — GO:0006974; DNA replication fork processing — GO likely prefix GO:; cell cycle process — GO:0022402 | PARP inhibition exploits replication-fork collapse and DNA damage accumulation; BRCA2-mutant tumors are enriched for cell-cycle programs (inoue2023rolesofthe pages 2-4, fizazi2024firstlinetalazoparibwith pages 1-2) |
| Biological processes (GO) | androgen receptor signaling pathway — GO likely prefix GO:; regulation of transcription by RNA polymerase II — GO:0006357; synthetic lethal interaction context — no direct GO term, represent via DNA repair dependency | TALAPRO-2 and FDA summary emphasize AR–PARP interplay: AR inhibition downregulates HRR genes and PARP inhibition suppresses AR transcriptional activity (fizazi2024firstlinetalazoparibwith pages 1-2, heiss2024usfoodand pages 2-4) |
| Cell types (CL) | prostate gland epithelial cell — CL likely prefix CL:; luminal epithelial cell of prostate — CL likely prefix CL:; basal cell of prostate epithelium — CL likely prefix CL: | Prostate cancer arises from epithelial compartments; organoid/PDX models preserve epithelial tumor features (fizazi2024firstlinetalazoparibwith pages 1-2, fizazi2024firstlinetalazoparibwith pages 2-3) |
| Cell types (CL) | metastatic prostate cancer cell — CL likely prefix CL: cancer cell term; osteoblast — CL:0000062; osteoclast — CL:0000097 | Bone metastasis is a hallmark clinical site and relevant microenvironmental context (taza2021differentialactivityof pages 20-21, chi2023detectionofbrca1 pages 1-2) |
| Treatments (MAXO) | PARP inhibitor therapy — MAXO likely prefix MAXO:; olaparib treatment — MAXO likely prefix MAXO:; talazoparib treatment — MAXO likely prefix MAXO: | Olaparib improves rPFS/OS/ORR in BRCA-altered mCRPC; talazoparib + enzalutamide improves rPFS in HRR-mutated disease, especially BRCA-mutant subgroup (mateo2024olaparibforthe pages 1-2, mateo2024olaparibforthe pages 8-9, heiss2024usfoodand pages 2-4) |
| Treatments (MAXO) | niraparib plus abiraterone therapy — MAXO likely prefix MAXO:; enzalutamide therapy — MAXO likely prefix MAXO:; androgen receptor pathway inhibitor therapy — MAXO likely prefix MAXO: | MAGNITUDE supports niraparib + abiraterone in BRCA1/2-mutated mCRPC; ARPI backbone is central to current implementation (chi2023niraparibandabiraterone pages 1-2, chi2023niraparibandabiraterone pages 5-6) |
| Treatments (MAXO) | circulating tumor DNA testing-guided targeted therapy — MAXO likely prefix MAXO:; germline genetic testing — MAXO likely prefix MAXO:; supportive treatment for anemia — MAXO likely prefix MAXO: | Tissue and ctDNA testing are used to identify eligible patients; anemia management is a key supportive action during PARPi therapy (chi2023detectionofbrca1 pages 1-2, chi2023detectionofbrca1 pages 2-4, tisseverasinghe2023advancesinparp pages 10-11) |
Table: This table proposes practical ontology mappings for a BRCA-mutant prostate cancer knowledge-base entry, spanning disease concept, genes, phenotypes, anatomy, processes, cell types, and treatments. It is grounded in the provided evidence on aggressive disease biology, metastatic behavior, PARP inhibitor response, and treatment toxicity.
References
(heiss2024usfoodand pages 2-4): Brian L. Heiss, Elaine Chang, Xin Gao, Tien Truong, Michael H. Brave, Erik Bloomquist, Ankit Shah, Salaheldin Hamed, Jeffrey Kraft, Haw-Jyh Chiu, Tiffany K. Ricks, Amy Tilley, William F. Pierce, Liuya Tang, Abdelrahmman Abukhdeir, Shyam Kalavar, Reena Philip, Shenghui Tang, Richard Pazdur, Laleh Amiri-Kordestani, Paul G. Kluetz, and Daniel L. Suzman. Us food and drug administration approval summary: talazoparib in combination with enzalutamide for treatment of patients with homologous recombination repair gene-mutated metastatic castration-resistant prostate cancer. Journal of Clinical Oncology, 42:1851-1860, May 2024. URL: https://doi.org/10.1200/jco.23.02182, doi:10.1200/jco.23.02182. This article has 29 citations and is from a highest quality peer-reviewed journal.
(mateo2024olaparibforthe pages 1-2): Joaquin Mateo, Johann S. de Bono, Karim Fizazi, Fred Saad, Neal Shore, Shahneen Sandhu, Kim N. Chi, Neeraj Agarwal, David Olmos, Antoine Thiery-Vuillemin, Mustafa Özgüroğlu, Niven Mehra, Nobuaki Matsubara, Jae Young Joung, Charles Padua, Ernesto Korbenfeld, Jinyu Kang, Helen Marshall, Zhongwu Lai, Alan Barnicle, Christian Poehlein, Natalia Lukashchuk, and Maha Hussain. Olaparib for the treatment of patients with metastatic castration-resistant prostate cancer and alterations in brca1 and/or brca2 in the profound trial. Journal of Clinical Oncology, 42:571-583, Feb 2024. URL: https://doi.org/10.1200/jco.23.00339, doi:10.1200/jco.23.00339. This article has 91 citations and is from a highest quality peer-reviewed journal.
(fettke2023brcadeficientmetastaticprostate pages 1-2): Heidi Fettke, Chao Dai, Edmond M. Kwan, Tiantian Zheng, Pan Du, Nicole Ng, Patricia Bukczynska, Maria Docanto, Louise Kostos, Siavash Foroughi, Stephen Brown, Lisa-Jane K. Graham, Kate Mahon, Lisa G. Horvath, Shidong Jia, Manish Kohli, and Arun A. Azad. Brca-deficient metastatic prostate cancer has an adverse prognosis and distinct genomic phenotype. eBioMedicine, 95:104738, Sep 2023. URL: https://doi.org/10.1016/j.ebiom.2023.104738, doi:10.1016/j.ebiom.2023.104738. This article has 41 citations and is from a peer-reviewed journal.
(fizazi2024firstlinetalazoparibwith pages 1-2): Karim Fizazi, Arun A. Azad, Nobuaki Matsubara, Joan Carles, Andre P. Fay, Ugo De Giorgi, Jae Young Joung, Peter C. C. Fong, Eric Voog, Robert J. Jones, Neal D. Shore, Curtis Dunshee, Stefanie Zschäbitz, Jan Oldenburg, Dingwei Ye, Xun Lin, Cynthia G. Healy, Nicola Di Santo, A. Douglas Laird, Fabian Zohren, and Neeraj Agarwal. First-line talazoparib with enzalutamide in hrr-deficient metastatic castration-resistant prostate cancer: the phase 3 talapro-2 trial. Nature Medicine, 30:257-264, Dec 2024. URL: https://doi.org/10.1038/s41591-023-02704-x, doi:10.1038/s41591-023-02704-x. This article has 152 citations and is from a highest quality peer-reviewed journal.
(chi2023niraparibandabiraterone pages 1-2): Kim N. Chi, Dana Rathkopf, Matthew R. Smith, Eleni Efstathiou, Gerhardt Attard, David Olmos, Ji Youl Lee, Eric J. Small, Andrea J. Pereira de Santana Gomes, Guilhem Roubaud, Marniza Saad, Bogdan Zurawski, Valerii Sakalo, Gary E. Mason, Peter Francis, George Wang, Daphne Wu, Brooke Diorio, Angela Lopez-Gitlitz, Shahneen Sandhu, Maria Alvarez, Gabriela Gatica, Martin Greco, Ernesto Korbenfeld, Esteban Metrebian, Jorge Salinas, Alejandro Salvatierra, Marcelo Tatangelo, Tom Ferguson, Howard Gurney, Elizabeth Hovey, Anthony Joshua, Matos Marco, Gavin Marx, Michelle Morris, Siobhan Ng, David Pook, Shahneen Sandhu, Ali Tafreshi, Thean Hsiang Tan, Tsvetanka Tosheva, Livia Andrade, Felipe Cruz, Luiza Faria, Jose Figueiredo, Fabio Franke, Andrea Juliana Gomes, Ariel Kann, Celio Kussumoto, Suelen Martins, Andre Murad, Helio Pinczowski, Giovani Pioner, Luis Pires, Daniel Preto, Gisele Santos, Eduardo Silva, Jamile Silva, Luciano Viana, Karina Vianna, Adriano Paula, Zhiwen Chen, Kim Chi, Urban Emmenegger, Neil Fleshner, Sunil Parimi, Fred Saad, Francisco Vera-Badillo, Hongqian Guo, Hong Luo, Lulin Ma, Mingxing Qui, Wei Xue, Guo Yonglian, Lei Li, Jinxian Pu, Song Zheng, Qing Zou, Milos Brodak, Milan Hora, Vladimir Samal, Vladimir Student, Jaroslav Vanasek, Emmanuelle Bompas, Philippe Barthelemy, Delphine Borchiellini, Aude Flechon, Hakim Mahammedi, Guilhem Roubaud, Antoine Thiery-Vuillemin, Diego Tosi, Spaeth Dominique, Carole Helissey, Martin Boegemann, Susan Feyerabend, Eva Hellmis, Martin Schostak, Gerhardt Attard, Anna Lydon, Ian Sayers, Omi Parikh, Duncan Wheatley, Peter Arkosy, Jozsef Erfan, Lajos Geczi, Peter Nyirady, Judit Olah, Istvan Papos, Bela Piko, Raanan Berger, Avivit Peer, Umberto Basso, Sergio Bracarda, Orazio Caffo, Francesco Carrozza, Gianluca Del Conte, Luca Galli, Donatello Gasparro, Sandro Pignata, Riccardo Ricotta, Daniele Santini, Giampaolo Tortora, Seoksoo Byun, SeolHo Choo, ByungHa Chung, Jaeyoung Joung, Wonho Jung, Taek Won Kang, Cheol Kwak, TaeGyun Kwon, Hyo Jin Lee, Ji Youl Lee, SeongIl Seo, YoungDeuk Choi, HongKoo Ha, ChoungSoo Kim, Flora Li Tze Chong, Chun Sen Lim, Vijayan Manogran, Hwoei Fen Soo Hoo, Guan Chou Teh, Marniza Saad, David Calvo Dominguez, Abraham Cardenas, Julia Saenz, Andre Bergman, Helgi Helgason, C.B. Hunting, Rik Somford, Tomasz Byrski, Tomasz Drewa, Dorota Filarska, Jolanta LuniewskaBury, Adam Marcheluk, Konrad Talasiewicz, Krzysztof Tupikowski, Renata Zaucha, Bogdan Zurawski, Pedro Madeira, Andre Mansinho, Nuno Vau, Anna Alyasova, Victoria Chistyakova, Denis Khvorostenko, Dmitry Kirtbaya, Gennady Kolesnikov, Evgeny Kopyltsov, Igor Lifirenko, Alexander Lykov, Konstantin Penkov, Andrey Semenov, Mikhail Shkolnik, Pavel Skopin, Roman Smirnov, Evgeny Usynin, Sergey Varlamov, Vladimir Vladimirov, Teresa Alonso, Sara Breijo, Elena Castro, Enrique Gallardo, Jose Gutierrez Banos, Alvaro Juarez, Rebeca Lozano, Pablo Maroto, Javier Puente, Alejo Rodriguez-Vida, Regina Girones, Begona Mellado, Enrique Castellanos, Chunde Li, Chao-Hsiang Chang, Hsiao-Jen Chung, Kuan-Hua Huang, Yen-Chuan Ou, Yu-Chieh Tsai, Shian-Shiang Wang, Wen-Jeng Wu, See Tong Pang, Cagatay Arslan, Devrim Cabuk, Hasan Coskun, Mahmut Gumus, Mustafa Ozguroglu, Berna Oksuzoglu, Berksoy Sahin, Deniz Tural, Bulent Yalcin, Irfan Cicin, Igor Bondarenko, Yaroslav Gotsuliak, Yevhen Hotko, Gennadii Khareba, Oleksandr Lychkovskyy, Iryna Lytvyn, Taron Nalbandyan, Viktor Paramonov, Valerii Sakalo, Eduard Stakhovsky, Viktor Stus, Sunil Babu, Alan Bryce, David Cahn, Herta Chao, Franklin Chu, Curtis Dunshee, Oscar Goodman, Michael Grable, Jason Hafron, Joelle Hamilton, Ralph Hauke, Joseph Maly, David Morris, Gregg Newman, Patrick Pilie, Neal Shore, Paul Sieber, Matthew Smith, Andrew Trainer, and Ronald Tutrone. Niraparib and abiraterone acetate for metastatic castration-resistant prostate cancer. Journal of Clinical Oncology, 41:3339-3351, Jun 2023. URL: https://doi.org/10.1200/jco.22.01649, doi:10.1200/jco.22.01649. This article has 380 citations and is from a highest quality peer-reviewed journal.
(valsecchi2023frequencyofgermline pages 1-2): Anna Amela Valsecchi, Rossana Dionisio, Olimpia Panepinto, Jessica Paparo, Andrea Palicelli, Francesca Vignani, and Massimo Di Maio. Frequency of germline and somatic brca1 and brca2 mutations in prostate cancer: an updated systematic review and meta-analysis. Cancers, 15:2435, Apr 2023. URL: https://doi.org/10.3390/cancers15092435, doi:10.3390/cancers15092435. This article has 38 citations.
(chi2023detectionofbrca1 pages 1-2): Kim N. Chi, Alan Barnicle, Caroline Sibilla, Zhongwu Lai, Claire Corcoran, J. Carl Barrett, Carrie A. Adelman, Ping Qiu, Ashley Easter, Simon Dearden, Geoffrey R. Oxnard, Neeraj Agarwal, Arun Azad, Johann de Bono, Joaquin Mateo, David Olmos, Antoine Thiery-Vuillemin, and Elizabeth A. Harrington. Detection of brca1, brca2, and atm alterations in matched tumor tissue and circulating tumor dna in patients with prostate cancer screened in profound. Clinical Cancer Research, 29:81-91, Aug 2023. URL: https://doi.org/10.1158/1078-0432.ccr-22-0931, doi:10.1158/1078-0432.ccr-22-0931. This article has 79 citations and is from a highest quality peer-reviewed journal.
(inoue2023rolesofthe pages 2-4): Takahiro Inoue, Sho Sekito, Takumi Kageyama, Yusuke Sugino, and Takeshi Sasaki. Roles of the parp inhibitor in brca1 and brca2 pathogenic mutated metastatic prostate cancer: direct functions and modification of the tumor microenvironment. Cancers, 15:2662, May 2023. URL: https://doi.org/10.3390/cancers15092662, doi:10.3390/cancers15092662. This article has 18 citations.
(cheng2024brca1brca2and pages 5-6): Heather H. Cheng, Jeffrey W. Shevach, Elena Castro, Fergus J. Couch, Susan M. Domchek, Rosalind A. Eeles, Veda N. Giri, Michael J. Hall, Mary-Claire King, Daniel W. Lin, Stacy Loeb, Todd M. Morgan, Kenneth Offit, Colin C. Pritchard, Edward M. Schaeffer, Brittany M. Szymaniak, Jason L. Vassy, Bryson W. Katona, and Kara N. Maxwell. brca1, brca2, and associated cancer risks and management for male patients. JAMA Oncology, 10:1272, Sep 2024. URL: https://doi.org/10.1001/jamaoncol.2024.2185, doi:10.1001/jamaoncol.2024.2185. This article has 40 citations and is from a highest quality peer-reviewed journal.
(cheng2024brca1brca2and pages 16-19): Heather H. Cheng, Jeffrey W. Shevach, Elena Castro, Fergus J. Couch, Susan M. Domchek, Rosalind A. Eeles, Veda N. Giri, Michael J. Hall, Mary-Claire King, Daniel W. Lin, Stacy Loeb, Todd M. Morgan, Kenneth Offit, Colin C. Pritchard, Edward M. Schaeffer, Brittany M. Szymaniak, Jason L. Vassy, Bryson W. Katona, and Kara N. Maxwell. brca1, brca2, and associated cancer risks and management for male patients. JAMA Oncology, 10:1272, Sep 2024. URL: https://doi.org/10.1001/jamaoncol.2024.2185, doi:10.1001/jamaoncol.2024.2185. This article has 40 citations and is from a highest quality peer-reviewed journal.
(valsecchi2023frequencyofgermline pages 2-5): Anna Amela Valsecchi, Rossana Dionisio, Olimpia Panepinto, Jessica Paparo, Andrea Palicelli, Francesca Vignani, and Massimo Di Maio. Frequency of germline and somatic brca1 and brca2 mutations in prostate cancer: an updated systematic review and meta-analysis. Cancers, 15:2435, Apr 2023. URL: https://doi.org/10.3390/cancers15092435, doi:10.3390/cancers15092435. This article has 38 citations.
(valsecchi2023frequencyofgermline pages 25-27): Anna Amela Valsecchi, Rossana Dionisio, Olimpia Panepinto, Jessica Paparo, Andrea Palicelli, Francesca Vignani, and Massimo Di Maio. Frequency of germline and somatic brca1 and brca2 mutations in prostate cancer: an updated systematic review and meta-analysis. Cancers, 15:2435, Apr 2023. URL: https://doi.org/10.3390/cancers15092435, doi:10.3390/cancers15092435. This article has 38 citations.
(valsecchi2023frequencyofgermline pages 8-10): Anna Amela Valsecchi, Rossana Dionisio, Olimpia Panepinto, Jessica Paparo, Andrea Palicelli, Francesca Vignani, and Massimo Di Maio. Frequency of germline and somatic brca1 and brca2 mutations in prostate cancer: an updated systematic review and meta-analysis. Cancers, 15:2435, Apr 2023. URL: https://doi.org/10.3390/cancers15092435, doi:10.3390/cancers15092435. This article has 38 citations.
(taza2021differentialactivityof pages 20-21): Fadi Taza, Albert E. Holler, Wei Fu, Hao Wang, Nabil Adra, Costantine Albany, Ryan Ashkar, Heather H. Cheng, Alexandra O. Sokolova, Neeraj Agarwal, Adam Kessel, Alan Bryce, Nellie Nafissi, Pedro Barata, A. Oliver Sartor, Diogo Bastos, Oren Smaletz, Jacob E. Berchuck, Mary-Ellen Taplin, Rahul Aggarwal, Cora N. Sternberg, Panagiotis J. Vlachostergios, Ajjai S. Alva, Christopher Su, Catherine H. Marshall, and Emmanuel S. Antonarakis. Differential activity of parp inhibitors inbrca1- versusbrca2-altered metastatic castration-resistant prostate cancer. JCO Precision Oncology, pages 1200-1220, Nov 2021. URL: https://doi.org/10.1200/po.21.00070, doi:10.1200/po.21.00070. This article has 68 citations and is from a peer-reviewed journal.
(taza2021differentialactivityof pages 1-2): Fadi Taza, Albert E. Holler, Wei Fu, Hao Wang, Nabil Adra, Costantine Albany, Ryan Ashkar, Heather H. Cheng, Alexandra O. Sokolova, Neeraj Agarwal, Adam Kessel, Alan Bryce, Nellie Nafissi, Pedro Barata, A. Oliver Sartor, Diogo Bastos, Oren Smaletz, Jacob E. Berchuck, Mary-Ellen Taplin, Rahul Aggarwal, Cora N. Sternberg, Panagiotis J. Vlachostergios, Ajjai S. Alva, Christopher Su, Catherine H. Marshall, and Emmanuel S. Antonarakis. Differential activity of parp inhibitors inbrca1- versusbrca2-altered metastatic castration-resistant prostate cancer. JCO Precision Oncology, pages 1200-1220, Nov 2021. URL: https://doi.org/10.1200/po.21.00070, doi:10.1200/po.21.00070. This article has 68 citations and is from a peer-reviewed journal.
(alakhras2024parpinhibitorsin pages 10-11): Ashaar Al-Akhras, Chadi Hage Chehade, Arshit Narang, and Umang Swami. Parp inhibitors in metastatic castration-resistant prostate cancer: unraveling the therapeutic landscape. Life, 14:198, Jan 2024. URL: https://doi.org/10.3390/life14020198, doi:10.3390/life14020198. This article has 22 citations.
(tisseverasinghe2023advancesinparp pages 10-11): Steven Tisseverasinghe, Boris Bahoric, Maurice Anidjar, Stephan Probst, and Tamim Niazi. Advances in parp inhibitors for prostate cancer. Cancers, 15:1849, Mar 2023. URL: https://doi.org/10.3390/cancers15061849, doi:10.3390/cancers15061849. This article has 27 citations.
(fizazi2024firstlinetalazoparibwith pages 2-3): Karim Fizazi, Arun A. Azad, Nobuaki Matsubara, Joan Carles, Andre P. Fay, Ugo De Giorgi, Jae Young Joung, Peter C. C. Fong, Eric Voog, Robert J. Jones, Neal D. Shore, Curtis Dunshee, Stefanie Zschäbitz, Jan Oldenburg, Dingwei Ye, Xun Lin, Cynthia G. Healy, Nicola Di Santo, A. Douglas Laird, Fabian Zohren, and Neeraj Agarwal. First-line talazoparib with enzalutamide in hrr-deficient metastatic castration-resistant prostate cancer: the phase 3 talapro-2 trial. Nature Medicine, 30:257-264, Dec 2024. URL: https://doi.org/10.1038/s41591-023-02704-x, doi:10.1038/s41591-023-02704-x. This article has 152 citations and is from a highest quality peer-reviewed journal.
(mateo2024olaparibforthe pages 8-9): Joaquin Mateo, Johann S. de Bono, Karim Fizazi, Fred Saad, Neal Shore, Shahneen Sandhu, Kim N. Chi, Neeraj Agarwal, David Olmos, Antoine Thiery-Vuillemin, Mustafa Özgüroğlu, Niven Mehra, Nobuaki Matsubara, Jae Young Joung, Charles Padua, Ernesto Korbenfeld, Jinyu Kang, Helen Marshall, Zhongwu Lai, Alan Barnicle, Christian Poehlein, Natalia Lukashchuk, and Maha Hussain. Olaparib for the treatment of patients with metastatic castration-resistant prostate cancer and alterations in brca1 and/or brca2 in the profound trial. Journal of Clinical Oncology, 42:571-583, Feb 2024. URL: https://doi.org/10.1200/jco.23.00339, doi:10.1200/jco.23.00339. This article has 91 citations and is from a highest quality peer-reviewed journal.
(chi2023niraparibandabiraterone pages 5-6): Kim N. Chi, Dana Rathkopf, Matthew R. Smith, Eleni Efstathiou, Gerhardt Attard, David Olmos, Ji Youl Lee, Eric J. Small, Andrea J. Pereira de Santana Gomes, Guilhem Roubaud, Marniza Saad, Bogdan Zurawski, Valerii Sakalo, Gary E. Mason, Peter Francis, George Wang, Daphne Wu, Brooke Diorio, Angela Lopez-Gitlitz, Shahneen Sandhu, Maria Alvarez, Gabriela Gatica, Martin Greco, Ernesto Korbenfeld, Esteban Metrebian, Jorge Salinas, Alejandro Salvatierra, Marcelo Tatangelo, Tom Ferguson, Howard Gurney, Elizabeth Hovey, Anthony Joshua, Matos Marco, Gavin Marx, Michelle Morris, Siobhan Ng, David Pook, Shahneen Sandhu, Ali Tafreshi, Thean Hsiang Tan, Tsvetanka Tosheva, Livia Andrade, Felipe Cruz, Luiza Faria, Jose Figueiredo, Fabio Franke, Andrea Juliana Gomes, Ariel Kann, Celio Kussumoto, Suelen Martins, Andre Murad, Helio Pinczowski, Giovani Pioner, Luis Pires, Daniel Preto, Gisele Santos, Eduardo Silva, Jamile Silva, Luciano Viana, Karina Vianna, Adriano Paula, Zhiwen Chen, Kim Chi, Urban Emmenegger, Neil Fleshner, Sunil Parimi, Fred Saad, Francisco Vera-Badillo, Hongqian Guo, Hong Luo, Lulin Ma, Mingxing Qui, Wei Xue, Guo Yonglian, Lei Li, Jinxian Pu, Song Zheng, Qing Zou, Milos Brodak, Milan Hora, Vladimir Samal, Vladimir Student, Jaroslav Vanasek, Emmanuelle Bompas, Philippe Barthelemy, Delphine Borchiellini, Aude Flechon, Hakim Mahammedi, Guilhem Roubaud, Antoine Thiery-Vuillemin, Diego Tosi, Spaeth Dominique, Carole Helissey, Martin Boegemann, Susan Feyerabend, Eva Hellmis, Martin Schostak, Gerhardt Attard, Anna Lydon, Ian Sayers, Omi Parikh, Duncan Wheatley, Peter Arkosy, Jozsef Erfan, Lajos Geczi, Peter Nyirady, Judit Olah, Istvan Papos, Bela Piko, Raanan Berger, Avivit Peer, Umberto Basso, Sergio Bracarda, Orazio Caffo, Francesco Carrozza, Gianluca Del Conte, Luca Galli, Donatello Gasparro, Sandro Pignata, Riccardo Ricotta, Daniele Santini, Giampaolo Tortora, Seoksoo Byun, SeolHo Choo, ByungHa Chung, Jaeyoung Joung, Wonho Jung, Taek Won Kang, Cheol Kwak, TaeGyun Kwon, Hyo Jin Lee, Ji Youl Lee, SeongIl Seo, YoungDeuk Choi, HongKoo Ha, ChoungSoo Kim, Flora Li Tze Chong, Chun Sen Lim, Vijayan Manogran, Hwoei Fen Soo Hoo, Guan Chou Teh, Marniza Saad, David Calvo Dominguez, Abraham Cardenas, Julia Saenz, Andre Bergman, Helgi Helgason, C.B. Hunting, Rik Somford, Tomasz Byrski, Tomasz Drewa, Dorota Filarska, Jolanta LuniewskaBury, Adam Marcheluk, Konrad Talasiewicz, Krzysztof Tupikowski, Renata Zaucha, Bogdan Zurawski, Pedro Madeira, Andre Mansinho, Nuno Vau, Anna Alyasova, Victoria Chistyakova, Denis Khvorostenko, Dmitry Kirtbaya, Gennady Kolesnikov, Evgeny Kopyltsov, Igor Lifirenko, Alexander Lykov, Konstantin Penkov, Andrey Semenov, Mikhail Shkolnik, Pavel Skopin, Roman Smirnov, Evgeny Usynin, Sergey Varlamov, Vladimir Vladimirov, Teresa Alonso, Sara Breijo, Elena Castro, Enrique Gallardo, Jose Gutierrez Banos, Alvaro Juarez, Rebeca Lozano, Pablo Maroto, Javier Puente, Alejo Rodriguez-Vida, Regina Girones, Begona Mellado, Enrique Castellanos, Chunde Li, Chao-Hsiang Chang, Hsiao-Jen Chung, Kuan-Hua Huang, Yen-Chuan Ou, Yu-Chieh Tsai, Shian-Shiang Wang, Wen-Jeng Wu, See Tong Pang, Cagatay Arslan, Devrim Cabuk, Hasan Coskun, Mahmut Gumus, Mustafa Ozguroglu, Berna Oksuzoglu, Berksoy Sahin, Deniz Tural, Bulent Yalcin, Irfan Cicin, Igor Bondarenko, Yaroslav Gotsuliak, Yevhen Hotko, Gennadii Khareba, Oleksandr Lychkovskyy, Iryna Lytvyn, Taron Nalbandyan, Viktor Paramonov, Valerii Sakalo, Eduard Stakhovsky, Viktor Stus, Sunil Babu, Alan Bryce, David Cahn, Herta Chao, Franklin Chu, Curtis Dunshee, Oscar Goodman, Michael Grable, Jason Hafron, Joelle Hamilton, Ralph Hauke, Joseph Maly, David Morris, Gregg Newman, Patrick Pilie, Neal Shore, Paul Sieber, Matthew Smith, Andrew Trainer, and Ronald Tutrone. Niraparib and abiraterone acetate for metastatic castration-resistant prostate cancer. Journal of Clinical Oncology, 41:3339-3351, Jun 2023. URL: https://doi.org/10.1200/jco.22.01649, doi:10.1200/jco.22.01649. This article has 380 citations and is from a highest quality peer-reviewed journal.
(chi2023detectionofbrca1 pages 2-4): Kim N. Chi, Alan Barnicle, Caroline Sibilla, Zhongwu Lai, Claire Corcoran, J. Carl Barrett, Carrie A. Adelman, Ping Qiu, Ashley Easter, Simon Dearden, Geoffrey R. Oxnard, Neeraj Agarwal, Arun Azad, Johann de Bono, Joaquin Mateo, David Olmos, Antoine Thiery-Vuillemin, and Elizabeth A. Harrington. Detection of brca1, brca2, and atm alterations in matched tumor tissue and circulating tumor dna in patients with prostate cancer screened in profound. Clinical Cancer Research, 29:81-91, Aug 2023. URL: https://doi.org/10.1158/1078-0432.ccr-22-0931, doi:10.1158/1078-0432.ccr-22-0931. This article has 79 citations and is from a highest quality peer-reviewed journal.
(fettke2023brcadeficientmetastaticprostate pages 7-8): Heidi Fettke, Chao Dai, Edmond M. Kwan, Tiantian Zheng, Pan Du, Nicole Ng, Patricia Bukczynska, Maria Docanto, Louise Kostos, Siavash Foroughi, Stephen Brown, Lisa-Jane K. Graham, Kate Mahon, Lisa G. Horvath, Shidong Jia, Manish Kohli, and Arun A. Azad. Brca-deficient metastatic prostate cancer has an adverse prognosis and distinct genomic phenotype. eBioMedicine, 95:104738, Sep 2023. URL: https://doi.org/10.1016/j.ebiom.2023.104738, doi:10.1016/j.ebiom.2023.104738. This article has 41 citations and is from a peer-reviewed journal.
(fettke2023brcadeficientmetastaticprostate pages 8-10): Heidi Fettke, Chao Dai, Edmond M. Kwan, Tiantian Zheng, Pan Du, Nicole Ng, Patricia Bukczynska, Maria Docanto, Louise Kostos, Siavash Foroughi, Stephen Brown, Lisa-Jane K. Graham, Kate Mahon, Lisa G. Horvath, Shidong Jia, Manish Kohli, and Arun A. Azad. Brca-deficient metastatic prostate cancer has an adverse prognosis and distinct genomic phenotype. eBioMedicine, 95:104738, Sep 2023. URL: https://doi.org/10.1016/j.ebiom.2023.104738, doi:10.1016/j.ebiom.2023.104738. This article has 41 citations and is from a peer-reviewed journal.
(cheng2024brca1brca2and pages 1-3): Heather H. Cheng, Jeffrey W. Shevach, Elena Castro, Fergus J. Couch, Susan M. Domchek, Rosalind A. Eeles, Veda N. Giri, Michael J. Hall, Mary-Claire King, Daniel W. Lin, Stacy Loeb, Todd M. Morgan, Kenneth Offit, Colin C. Pritchard, Edward M. Schaeffer, Brittany M. Szymaniak, Jason L. Vassy, Bryson W. Katona, and Kara N. Maxwell. brca1, brca2, and associated cancer risks and management for male patients. JAMA Oncology, 10:1272, Sep 2024. URL: https://doi.org/10.1001/jamaoncol.2024.2185, doi:10.1001/jamaoncol.2024.2185. This article has 40 citations and is from a highest quality peer-reviewed journal.
(chi2023detectionofbrca1 pages 2-2): Kim N. Chi, Alan Barnicle, Caroline Sibilla, Zhongwu Lai, Claire Corcoran, J. Carl Barrett, Carrie A. Adelman, Ping Qiu, Ashley Easter, Simon Dearden, Geoffrey R. Oxnard, Neeraj Agarwal, Arun Azad, Johann de Bono, Joaquin Mateo, David Olmos, Antoine Thiery-Vuillemin, and Elizabeth A. Harrington. Detection of brca1, brca2, and atm alterations in matched tumor tissue and circulating tumor dna in patients with prostate cancer screened in profound. Clinical Cancer Research, 29:81-91, Aug 2023. URL: https://doi.org/10.1158/1078-0432.ccr-22-0931, doi:10.1158/1078-0432.ccr-22-0931. This article has 79 citations and is from a highest quality peer-reviewed journal.
(chi2023detectionofbrca1 pages 6-8): Kim N. Chi, Alan Barnicle, Caroline Sibilla, Zhongwu Lai, Claire Corcoran, J. Carl Barrett, Carrie A. Adelman, Ping Qiu, Ashley Easter, Simon Dearden, Geoffrey R. Oxnard, Neeraj Agarwal, Arun Azad, Johann de Bono, Joaquin Mateo, David Olmos, Antoine Thiery-Vuillemin, and Elizabeth A. Harrington. Detection of brca1, brca2, and atm alterations in matched tumor tissue and circulating tumor dna in patients with prostate cancer screened in profound. Clinical Cancer Research, 29:81-91, Aug 2023. URL: https://doi.org/10.1158/1078-0432.ccr-22-0931, doi:10.1158/1078-0432.ccr-22-0931. This article has 79 citations and is from a highest quality peer-reviewed journal.
(chi2023detectionofbrca1 pages 4-5): Kim N. Chi, Alan Barnicle, Caroline Sibilla, Zhongwu Lai, Claire Corcoran, J. Carl Barrett, Carrie A. Adelman, Ping Qiu, Ashley Easter, Simon Dearden, Geoffrey R. Oxnard, Neeraj Agarwal, Arun Azad, Johann de Bono, Joaquin Mateo, David Olmos, Antoine Thiery-Vuillemin, and Elizabeth A. Harrington. Detection of brca1, brca2, and atm alterations in matched tumor tissue and circulating tumor dna in patients with prostate cancer screened in profound. Clinical Cancer Research, 29:81-91, Aug 2023. URL: https://doi.org/10.1158/1078-0432.ccr-22-0931, doi:10.1158/1078-0432.ccr-22-0931. This article has 79 citations and is from a highest quality peer-reviewed journal.
(chi2023detectionofbrca1 pages 5-6): Kim N. Chi, Alan Barnicle, Caroline Sibilla, Zhongwu Lai, Claire Corcoran, J. Carl Barrett, Carrie A. Adelman, Ping Qiu, Ashley Easter, Simon Dearden, Geoffrey R. Oxnard, Neeraj Agarwal, Arun Azad, Johann de Bono, Joaquin Mateo, David Olmos, Antoine Thiery-Vuillemin, and Elizabeth A. Harrington. Detection of brca1, brca2, and atm alterations in matched tumor tissue and circulating tumor dna in patients with prostate cancer screened in profound. Clinical Cancer Research, 29:81-91, Aug 2023. URL: https://doi.org/10.1158/1078-0432.ccr-22-0931, doi:10.1158/1078-0432.ccr-22-0931. This article has 79 citations and is from a highest quality peer-reviewed journal.
(matsubara2023olaparibefficacyin pages 5-6): N. Matsubara, J. D. de Bono, D. Olmos, G. Procopio, S. Kawakami, Y. Ürün, R. van Alphen, A. Fléchon, M. Carducci, Y. Choi, S. Hotte, Ernesto Korbenfeld, G. Kramer, N. Agarwal, K. Chi, S. Dearden, C. Gresty, Jinyu Kang, C. Poehlein, E. Harrington, and M. Hussain. Olaparib efficacy in patients with metastatic castration-resistant prostate cancer and brca1, brca2, or atm alterations identified by testing circulating tumor dna. Clinical Cancer Research, 29:92-99, Nov 2023. URL: https://doi.org/10.1158/1078-0432.ccr-21-3577, doi:10.1158/1078-0432.ccr-21-3577. This article has 48 citations and is from a highest quality peer-reviewed journal.
(chi2023detectionofbrca1 media 1d7942c2): Kim N. Chi, Alan Barnicle, Caroline Sibilla, Zhongwu Lai, Claire Corcoran, J. Carl Barrett, Carrie A. Adelman, Ping Qiu, Ashley Easter, Simon Dearden, Geoffrey R. Oxnard, Neeraj Agarwal, Arun Azad, Johann de Bono, Joaquin Mateo, David Olmos, Antoine Thiery-Vuillemin, and Elizabeth A. Harrington. Detection of brca1, brca2, and atm alterations in matched tumor tissue and circulating tumor dna in patients with prostate cancer screened in profound. Clinical Cancer Research, 29:81-91, Aug 2023. URL: https://doi.org/10.1158/1078-0432.ccr-22-0931, doi:10.1158/1078-0432.ccr-22-0931. This article has 79 citations and is from a highest quality peer-reviewed journal.
(chi2023detectionofbrca1 media 19a57459): Kim N. Chi, Alan Barnicle, Caroline Sibilla, Zhongwu Lai, Claire Corcoran, J. Carl Barrett, Carrie A. Adelman, Ping Qiu, Ashley Easter, Simon Dearden, Geoffrey R. Oxnard, Neeraj Agarwal, Arun Azad, Johann de Bono, Joaquin Mateo, David Olmos, Antoine Thiery-Vuillemin, and Elizabeth A. Harrington. Detection of brca1, brca2, and atm alterations in matched tumor tissue and circulating tumor dna in patients with prostate cancer screened in profound. Clinical Cancer Research, 29:81-91, Aug 2023. URL: https://doi.org/10.1158/1078-0432.ccr-22-0931, doi:10.1158/1078-0432.ccr-22-0931. This article has 79 citations and is from a highest quality peer-reviewed journal.
(chi2023detectionofbrca1 media c50e82d1): Kim N. Chi, Alan Barnicle, Caroline Sibilla, Zhongwu Lai, Claire Corcoran, J. Carl Barrett, Carrie A. Adelman, Ping Qiu, Ashley Easter, Simon Dearden, Geoffrey R. Oxnard, Neeraj Agarwal, Arun Azad, Johann de Bono, Joaquin Mateo, David Olmos, Antoine Thiery-Vuillemin, and Elizabeth A. Harrington. Detection of brca1, brca2, and atm alterations in matched tumor tissue and circulating tumor dna in patients with prostate cancer screened in profound. Clinical Cancer Research, 29:81-91, Aug 2023. URL: https://doi.org/10.1158/1078-0432.ccr-22-0931, doi:10.1158/1078-0432.ccr-22-0931. This article has 79 citations and is from a highest quality peer-reviewed journal.
(chi2023detectionofbrca1 media 89bfe680): Kim N. Chi, Alan Barnicle, Caroline Sibilla, Zhongwu Lai, Claire Corcoran, J. Carl Barrett, Carrie A. Adelman, Ping Qiu, Ashley Easter, Simon Dearden, Geoffrey R. Oxnard, Neeraj Agarwal, Arun Azad, Johann de Bono, Joaquin Mateo, David Olmos, Antoine Thiery-Vuillemin, and Elizabeth A. Harrington. Detection of brca1, brca2, and atm alterations in matched tumor tissue and circulating tumor dna in patients with prostate cancer screened in profound. Clinical Cancer Research, 29:81-91, Aug 2023. URL: https://doi.org/10.1158/1078-0432.ccr-22-0931, doi:10.1158/1078-0432.ccr-22-0931. This article has 79 citations and is from a highest quality peer-reviewed journal.
(fazekas2024magneticresonanceimaging pages 1-6): Tamás Fazekas, Sung Ryul Shim, Giuseppe Basile, Michael Baboudjian, Tamás Kói, Mikolaj Przydacz, Mohammad Abufaraj, Guillaume Ploussard, Veeru Kasivisvanathan, Juan Gómez Rivas, Giorgio Gandaglia, Tibor Szarvas, Ivo G. Schoots, Roderick C. N. van den Bergh, Michael S. Leapman, Péter Nyirády, Shahrokh F. Shariat, and Pawel Rajwa. Magnetic resonance imaging in prostate cancer screening. JAMA Oncology, 10:745, Jun 2024. URL: https://doi.org/10.1001/jamaoncol.2024.0734, doi:10.1001/jamaoncol.2024.0734. This article has 95 citations and is from a highest quality peer-reviewed journal.
(fazekas2024magneticresonanceimaging pages 21-25): Tamás Fazekas, Sung Ryul Shim, Giuseppe Basile, Michael Baboudjian, Tamás Kói, Mikolaj Przydacz, Mohammad Abufaraj, Guillaume Ploussard, Veeru Kasivisvanathan, Juan Gómez Rivas, Giorgio Gandaglia, Tibor Szarvas, Ivo G. Schoots, Roderick C. N. van den Bergh, Michael S. Leapman, Péter Nyirády, Shahrokh F. Shariat, and Pawel Rajwa. Magnetic resonance imaging in prostate cancer screening. JAMA Oncology, 10:745, Jun 2024. URL: https://doi.org/10.1001/jamaoncol.2024.0734, doi:10.1001/jamaoncol.2024.0734. This article has 95 citations and is from a highest quality peer-reviewed journal.
(turnham2024developmentandcharacterisation pages 1-2): Daniel J. Turnham, Manisha S. Mullen, Nicholas P. Bullock, Kathryn L. Gilroy, Anna E. Richards, Radhika Patel, Marcos Quintela, Valerie S. Meniel, Gillian Seaton, Howard Kynaston, Richard W. E. Clarkson, Toby J. Phesse, Peter S. Nelson, Michael C. Haffner, John N. Staffurth, and Helen B. Pearson. Development and characterisation of a new patient-derived xenograft model of ar-negative metastatic castration-resistant prostate cancer. Cells, 13:673, Apr 2024. URL: https://doi.org/10.3390/cells13080673, doi:10.3390/cells13080673. This article has 2 citations.
(mateo2024olaparibforthe pages 4-5): Joaquin Mateo, Johann S. de Bono, Karim Fizazi, Fred Saad, Neal Shore, Shahneen Sandhu, Kim N. Chi, Neeraj Agarwal, David Olmos, Antoine Thiery-Vuillemin, Mustafa Özgüroğlu, Niven Mehra, Nobuaki Matsubara, Jae Young Joung, Charles Padua, Ernesto Korbenfeld, Jinyu Kang, Helen Marshall, Zhongwu Lai, Alan Barnicle, Christian Poehlein, Natalia Lukashchuk, and Maha Hussain. Olaparib for the treatment of patients with metastatic castration-resistant prostate cancer and alterations in brca1 and/or brca2 in the profound trial. Journal of Clinical Oncology, 42:571-583, Feb 2024. URL: https://doi.org/10.1200/jco.23.00339, doi:10.1200/jco.23.00339. This article has 91 citations and is from a highest quality peer-reviewed journal.
(heiss2024usfoodand pages 1-2): Brian L. Heiss, Elaine Chang, Xin Gao, Tien Truong, Michael H. Brave, Erik Bloomquist, Ankit Shah, Salaheldin Hamed, Jeffrey Kraft, Haw-Jyh Chiu, Tiffany K. Ricks, Amy Tilley, William F. Pierce, Liuya Tang, Abdelrahmman Abukhdeir, Shyam Kalavar, Reena Philip, Shenghui Tang, Richard Pazdur, Laleh Amiri-Kordestani, Paul G. Kluetz, and Daniel L. Suzman. Us food and drug administration approval summary: talazoparib in combination with enzalutamide for treatment of patients with homologous recombination repair gene-mutated metastatic castration-resistant prostate cancer. Journal of Clinical Oncology, 42:1851-1860, May 2024. URL: https://doi.org/10.1200/jco.23.02182, doi:10.1200/jco.23.02182. This article has 29 citations and is from a highest quality peer-reviewed journal.
(mateo2024olaparibforthe pages 6-8): Joaquin Mateo, Johann S. de Bono, Karim Fizazi, Fred Saad, Neal Shore, Shahneen Sandhu, Kim N. Chi, Neeraj Agarwal, David Olmos, Antoine Thiery-Vuillemin, Mustafa Özgüroğlu, Niven Mehra, Nobuaki Matsubara, Jae Young Joung, Charles Padua, Ernesto Korbenfeld, Jinyu Kang, Helen Marshall, Zhongwu Lai, Alan Barnicle, Christian Poehlein, Natalia Lukashchuk, and Maha Hussain. Olaparib for the treatment of patients with metastatic castration-resistant prostate cancer and alterations in brca1 and/or brca2 in the profound trial. Journal of Clinical Oncology, 42:571-583, Feb 2024. URL: https://doi.org/10.1200/jco.23.00339, doi:10.1200/jco.23.00339. This article has 91 citations and is from a highest quality peer-reviewed journal.
(chi2023niraparibandabiraterone pages 3-4): Kim N. Chi, Dana Rathkopf, Matthew R. Smith, Eleni Efstathiou, Gerhardt Attard, David Olmos, Ji Youl Lee, Eric J. Small, Andrea J. Pereira de Santana Gomes, Guilhem Roubaud, Marniza Saad, Bogdan Zurawski, Valerii Sakalo, Gary E. Mason, Peter Francis, George Wang, Daphne Wu, Brooke Diorio, Angela Lopez-Gitlitz, Shahneen Sandhu, Maria Alvarez, Gabriela Gatica, Martin Greco, Ernesto Korbenfeld, Esteban Metrebian, Jorge Salinas, Alejandro Salvatierra, Marcelo Tatangelo, Tom Ferguson, Howard Gurney, Elizabeth Hovey, Anthony Joshua, Matos Marco, Gavin Marx, Michelle Morris, Siobhan Ng, David Pook, Shahneen Sandhu, Ali Tafreshi, Thean Hsiang Tan, Tsvetanka Tosheva, Livia Andrade, Felipe Cruz, Luiza Faria, Jose Figueiredo, Fabio Franke, Andrea Juliana Gomes, Ariel Kann, Celio Kussumoto, Suelen Martins, Andre Murad, Helio Pinczowski, Giovani Pioner, Luis Pires, Daniel Preto, Gisele Santos, Eduardo Silva, Jamile Silva, Luciano Viana, Karina Vianna, Adriano Paula, Zhiwen Chen, Kim Chi, Urban Emmenegger, Neil Fleshner, Sunil Parimi, Fred Saad, Francisco Vera-Badillo, Hongqian Guo, Hong Luo, Lulin Ma, Mingxing Qui, Wei Xue, Guo Yonglian, Lei Li, Jinxian Pu, Song Zheng, Qing Zou, Milos Brodak, Milan Hora, Vladimir Samal, Vladimir Student, Jaroslav Vanasek, Emmanuelle Bompas, Philippe Barthelemy, Delphine Borchiellini, Aude Flechon, Hakim Mahammedi, Guilhem Roubaud, Antoine Thiery-Vuillemin, Diego Tosi, Spaeth Dominique, Carole Helissey, Martin Boegemann, Susan Feyerabend, Eva Hellmis, Martin Schostak, Gerhardt Attard, Anna Lydon, Ian Sayers, Omi Parikh, Duncan Wheatley, Peter Arkosy, Jozsef Erfan, Lajos Geczi, Peter Nyirady, Judit Olah, Istvan Papos, Bela Piko, Raanan Berger, Avivit Peer, Umberto Basso, Sergio Bracarda, Orazio Caffo, Francesco Carrozza, Gianluca Del Conte, Luca Galli, Donatello Gasparro, Sandro Pignata, Riccardo Ricotta, Daniele Santini, Giampaolo Tortora, Seoksoo Byun, SeolHo Choo, ByungHa Chung, Jaeyoung Joung, Wonho Jung, Taek Won Kang, Cheol Kwak, TaeGyun Kwon, Hyo Jin Lee, Ji Youl Lee, SeongIl Seo, YoungDeuk Choi, HongKoo Ha, ChoungSoo Kim, Flora Li Tze Chong, Chun Sen Lim, Vijayan Manogran, Hwoei Fen Soo Hoo, Guan Chou Teh, Marniza Saad, David Calvo Dominguez, Abraham Cardenas, Julia Saenz, Andre Bergman, Helgi Helgason, C.B. Hunting, Rik Somford, Tomasz Byrski, Tomasz Drewa, Dorota Filarska, Jolanta LuniewskaBury, Adam Marcheluk, Konrad Talasiewicz, Krzysztof Tupikowski, Renata Zaucha, Bogdan Zurawski, Pedro Madeira, Andre Mansinho, Nuno Vau, Anna Alyasova, Victoria Chistyakova, Denis Khvorostenko, Dmitry Kirtbaya, Gennady Kolesnikov, Evgeny Kopyltsov, Igor Lifirenko, Alexander Lykov, Konstantin Penkov, Andrey Semenov, Mikhail Shkolnik, Pavel Skopin, Roman Smirnov, Evgeny Usynin, Sergey Varlamov, Vladimir Vladimirov, Teresa Alonso, Sara Breijo, Elena Castro, Enrique Gallardo, Jose Gutierrez Banos, Alvaro Juarez, Rebeca Lozano, Pablo Maroto, Javier Puente, Alejo Rodriguez-Vida, Regina Girones, Begona Mellado, Enrique Castellanos, Chunde Li, Chao-Hsiang Chang, Hsiao-Jen Chung, Kuan-Hua Huang, Yen-Chuan Ou, Yu-Chieh Tsai, Shian-Shiang Wang, Wen-Jeng Wu, See Tong Pang, Cagatay Arslan, Devrim Cabuk, Hasan Coskun, Mahmut Gumus, Mustafa Ozguroglu, Berna Oksuzoglu, Berksoy Sahin, Deniz Tural, Bulent Yalcin, Irfan Cicin, Igor Bondarenko, Yaroslav Gotsuliak, Yevhen Hotko, Gennadii Khareba, Oleksandr Lychkovskyy, Iryna Lytvyn, Taron Nalbandyan, Viktor Paramonov, Valerii Sakalo, Eduard Stakhovsky, Viktor Stus, Sunil Babu, Alan Bryce, David Cahn, Herta Chao, Franklin Chu, Curtis Dunshee, Oscar Goodman, Michael Grable, Jason Hafron, Joelle Hamilton, Ralph Hauke, Joseph Maly, David Morris, Gregg Newman, Patrick Pilie, Neal Shore, Paul Sieber, Matthew Smith, Andrew Trainer, and Ronald Tutrone. Niraparib and abiraterone acetate for metastatic castration-resistant prostate cancer. Journal of Clinical Oncology, 41:3339-3351, Jun 2023. URL: https://doi.org/10.1200/jco.22.01649, doi:10.1200/jco.22.01649. This article has 380 citations and is from a highest quality peer-reviewed journal.
(fizazi2024firstlinetalazoparibwith pages 5-5): Karim Fizazi, Arun A. Azad, Nobuaki Matsubara, Joan Carles, Andre P. Fay, Ugo De Giorgi, Jae Young Joung, Peter C. C. Fong, Eric Voog, Robert J. Jones, Neal D. Shore, Curtis Dunshee, Stefanie Zschäbitz, Jan Oldenburg, Dingwei Ye, Xun Lin, Cynthia G. Healy, Nicola Di Santo, A. Douglas Laird, Fabian Zohren, and Neeraj Agarwal. First-line talazoparib with enzalutamide in hrr-deficient metastatic castration-resistant prostate cancer: the phase 3 talapro-2 trial. Nature Medicine, 30:257-264, Dec 2024. URL: https://doi.org/10.1038/s41591-023-02704-x, doi:10.1038/s41591-023-02704-x. This article has 152 citations and is from a highest quality peer-reviewed journal.
(fazekas2024magneticresonanceimaging pages 10-13): Tamás Fazekas, Sung Ryul Shim, Giuseppe Basile, Michael Baboudjian, Tamás Kói, Mikolaj Przydacz, Mohammad Abufaraj, Guillaume Ploussard, Veeru Kasivisvanathan, Juan Gómez Rivas, Giorgio Gandaglia, Tibor Szarvas, Ivo G. Schoots, Roderick C. N. van den Bergh, Michael S. Leapman, Péter Nyirády, Shahrokh F. Shariat, and Pawel Rajwa. Magnetic resonance imaging in prostate cancer screening. JAMA Oncology, 10:745, Jun 2024. URL: https://doi.org/10.1001/jamaoncol.2024.0734, doi:10.1001/jamaoncol.2024.0734. This article has 95 citations and is from a highest quality peer-reviewed journal.
(kulkarni2024lp184anovel pages 8-9): Aditya Kulkarni, Jianli Zhou, Neha Biyani, Umesh Kathad, Partha P. Banerjee, Shiv Srivastava, Zsombor Prucsi, Kamil Solarczyk, Kishor Bhatia, Reginald B. Ewesuedo, and Panna Sharma. Lp-184, a novel acylfulvene molecule, exhibits anticancer activity against diverse solid tumors with homologous recombination deficiency. Cancer Research Communications, 4:1199-1210, May 2024. URL: https://doi.org/10.1158/2767-9764.crc-23-0554, doi:10.1158/2767-9764.crc-23-0554. This article has 5 citations and is from a peer-reviewed journal.
BRCA-mutant prostate cancer refers to prostate adenocarcinoma arising in the context of germline or somatic pathogenic variants in BRCA1 (OMIM: 113705) or BRCA2 (OMIM: 600185). These genes encode proteins essential for high-fidelity DNA double-strand break repair via homologous recombination. Loss of BRCA function leads to homologous recombination deficiency (HRD), genomic instability, and increased cancer susceptibility. While prostate cancer is the most common non-skin malignancy in men, BRCA-mutant prostate cancer represents a clinically distinct molecular entity distinguished by its aggressive phenotype — and also by its unique therapeutic vulnerability to PARP inhibitors and platinum-based chemotherapy through the principle of synthetic lethality.
BRCA2 mutations account for the majority of BRCA-associated prostate cancer cases and confer a higher relative risk (~3.6–8.6-fold) than BRCA1 mutations (~1.7-fold) (PMID: 41776557; PMID: 24389137).
| Identifier | Value |
|---|---|
| OMIM | BRCA2: 600185; BRCA1: 113705; Prostate cancer susceptibility: 176807 |
| Orphanet | Hereditary breast and ovarian cancer syndrome: ORPHA:145 |
| ICD-10 | C61 (Malignant neoplasm of prostate); Z15.01 (Genetic susceptibility) |
| ICD-11 | 2C82 (Malignant neoplasm of prostate) |
| MeSH | D011471 (Prostatic Neoplasms); D024182 (BRCA2 Protein); D019313 (BRCA1 Protein) |
| MONDO | MONDO:0008315 (prostate cancer); MONDO:0003582 (hereditary breast ovarian cancer syndrome) |
| HPO | HP:0012125 (Prostate cancer) |
Information is derived from aggregated disease-level resources including large prospective clinical trials (PROfound, PROpel, MAGNITUDE, TRITON2/3, TALAPRO-2, IMPACT), population-based cohort studies, meta-analyses, genomic sequencing studies (TCGA, institutional cohorts), and clinical practice guidelines (NCCN, EAU-ESTRO-SIOG).
Primary Cause: Genetic — Germline or somatic loss-of-function mutations in BRCA1/BRCA2
BRCA-mutant prostate cancer is fundamentally a genetic disease driven by bi-allelic inactivation of BRCA1 or BRCA2 tumor suppressor genes. The first hit is typically a germline heterozygous pathogenic variant (inherited), followed by somatic loss of the remaining wild-type allele (loss of heterozygosity, LOH), leading to complete loss of HRR function. In some cases, both hits are somatic (PMID: 40795806).
As stated: "Germline mutations affecting a single copy of the HR factors BRCA1 and BRCA2 predispose individuals to cancers of the breast, ovary, prostate, and pancreas. Cells deficient for BRCA proteins display high levels of genome instability due to defective repair of endogenous DSBs" (PMID: 28835508).
Bi-allelic pathogenic alterations in HR DNA repair-related genes are prevalent across many malignancies and associate with genomic features of HR deficiency; in ovarian, breast and prostate cancers, bi-allelic alterations are mutually exclusive of each other (PMID: 29021619).
BRCA2 germline mutations (highest risk):
BRCA1 germline mutations (moderate risk):
Other HRR gene mutations (contributing risk):
While BRCA-mutant prostate cancer is primarily genetic, standard prostate cancer risk factors likely modify penetrance: age, family history, and ethnicity/ancestry (Ashkenazi Jewish ancestry carries higher prevalence of BRCA founder mutations). No specific gene-environment interactions unique to BRCA-mutant prostate cancer have been definitively established, although BRCA proteins protect against endogenous DNA damage from aldehydes and other reactive metabolites (PMID: 28835508).
| Phenotype | Characteristics | Evidence | HPO Term |
|---|---|---|---|
| Aggressive adenocarcinoma | Higher Gleason grades (OR 3.2 for GS 7–10 in BRCA2); 65% NCCN intermediate-unfavorable/high-risk in BRCA2 carriers vs 32% noncarriers (p = 0.029) | PMID: 19188187; PMID: 41714267 | HP:0012125 |
| Earlier age of onset | BRCA2 carriers diagnosed at median 61 vs 64 years (p = 0.04); rare cases as young as age 35 | PMID: 31537406; PMID: 40027043 | HP:0003581 |
| Elevated PSA | 66.7% with high PSA in BRCA1 carriers vs 27.9% noncarriers (p = 7.61 × 10⁻³) | PMID: 41423785 | HP:0030088 |
| Advanced T stage | T3–4 in 36.4% BRCA1 carriers vs 23.2% noncarriers | PMID: 41423785 | HP:0012125 |
| Early metastasis | 10-year MFS 50% vs 84% in noncarriers (p < 0.001) | PMID: 25454609 | HP:0002664 |
| Rapid castration resistance | Shorter time to CRPC (HR 1.99; 95% CI 1.15–3.44) | PMID: 35986085 | HP:0012125 |
| Intraductal carcinoma (IDC-P) | Enriched in BRCA-mutant tumors; prevalence increases from 2.1% in low-risk to 56% in metastatic/recurrent disease | PMID: 28342640; PMID: 34884926 | HP:0012125 |
| Visceral metastases | BRCA2 and TP53 co-mutations associated with visceral dissemination and earlier death | PMID: 38182487 | HP:0002664 |
BRCA-mutant prostate cancer has significant quality of life impacts due to earlier and more aggressive disease, higher likelihood of requiring systemic therapy (chemotherapy, PARP inhibitors, ADT), complications from bone metastases (pain, fractures, spinal cord compression), and the psychological burden of carrying a known hereditary cancer predisposition gene affecting the patient and their family.
| Gene | HGNC ID | OMIM | Chromosome | Role |
|---|---|---|---|---|
| BRCA2 | HGNC:1101 | 600185 | 13q13.1 | Primary; highest prostate cancer risk; RAD51 loading |
| BRCA1 | HGNC:1100 | 113705 | 17q21.31 | Secondary; moderate prostate cancer risk; DNA damage sensing/HRR |
BRCA2 variants (most common in prostate cancer): - 6174delT (c.5946delT): Ashkenazi Jewish founder mutation; frameshift leading to premature truncation. Population carrier frequency ~1.1% in Ashkenazi Jews (PMID: 19064968) - Variant types: frameshift (most common), nonsense, splice-site, large deletions/rearrangements - 10–20% of BRCA sequencing results are VUS; >50% of VUS are missense mutations (PMID: 34065235) - Genotype-phenotype correlations by mutation position within the gene (PMID: 15131399)
BRCA1 variants: - 185delAG (c.68_69delAG), 5382insC (c.5266dupC): Ashkenazi/Eastern European founder mutations - Additional variants including deletion frameshifts and nonsense variants described across diverse populations (PMID: 40257527)
Somatic vs germline origin: - Germline alterations present in ~30–50% of HRR-altered cases (PMID: 35944490) - Tumor-only sequencing fails to report >17% of pathogenic germline variants; both germline and somatic testing recommended (PMID: 36103646): "When integrating tumor-only sequencing with germline testing results, 33% of patients harbored clinically actionable alterations."
BRCA1/2 Germline Mutation (one allele)
│
▼
Somatic Loss of Wild-Type Allele (LOH)
│
▼
Biallelic BRCA Inactivation
│
├──► Defective DNA Double-Strand Break Repair (GO:0000724)
│ │
│ ▼
│ Genomic Instability → Accumulation of Mutations
│ │
│ ▼
│ Activation of Error-Prone Repair (NHEJ, MMEJ/POLQ)
│
├──► Defective Replication Fork Protection
│ │
│ ▼
│ Nuclease-Mediated Fork Degradation
│
└──► Defective DNA Interstrand Crosslink Repair (GO:0036297)
│
▼
Co-occurring TP53/PTEN/RB1 Mutations
│
▼
MALIGNANT TRANSFORMATION → AGGRESSIVE PROSTATE ADENOCARCINOMA
PARP Inhibition → Blocks Single-Strand Break Repair
│
▼
SSBs Convert to DSBs at Replication Forks
│
┌─────────────┴─────────────┐
▼ ▼
HR-Proficient Cells HR-Deficient (BRCA-mut) Cells
Repair DSBs via HR Cannot Repair DSBs
│ │
▼ ▼
SURVIVE CELL DEATH (Synthetic Lethality)
"The blockade of both HR and base excision repair pathways is the basis of PARPI therapy" (PMID: 35785170).
BRCA reversion mutations are the dominant acquired resistance mechanism:
Other resistance mechanisms: Loss of PARP1 expression, BRCA promoter demethylation, non-degradation of partially functional mutated BRCA proteins, overactivation of base excision repair pathway, tumor microenvironment-mediated resistance (PMID: 40086424)
| Level | Structure | UBERON Term |
|---|---|---|
| Primary | Prostate gland | UBERON:0002367 |
| Secondary | Bone (vertebrae, pelvis, ribs) | UBERON:0002481 |
| Secondary | Lymph nodes (pelvic, retroperitoneal) | UBERON:0000029 |
| Secondary | Liver | UBERON:0002107 |
| Secondary | Lung | UBERON:0002048 |
| Secondary | Spine | UBERON:0001130 |
| Compartment | GO Term | Relevance |
|---|---|---|
| Nucleus | GO:0005634 | Site of BRCA function and DNA repair |
| Chromatin | GO:0000785 | BRCA1 mediates chromatin remodeling |
| Replication fork | GO:0005657 | BRCA2 protects stalled forks |
| Stage | Description | BRCA-Specific Features |
|---|---|---|
| Localized | Confined to prostate | Higher Gleason grades at presentation |
| Locally advanced | Extracapsular extension, SV invasion | Higher proportion T3–4 |
| mHSPC | Metastatic, hormone-sensitive | BRCA mutations in 12.4% |
| mCRPC | Castration-resistant | HRR mutations in up to 27%; shorter time to CRPC (HR 1.99) |
| Treatment-resistant | Post-PARP inhibitor progression | Reversion mutations in 39–79% |
HRR mutation prevalence in prostate cancer across populations:
| Population | HRR Prevalence | BRCA Frequency | Source |
|---|---|---|---|
| Metastatic CRPC (global) | 20–27% | BRCA2 most common | PMID: 35944490 |
| Indian mCRPC cohort | 30.5% | BRCA1 5.3%, BRCA2 4.2% | PMID: 41729953 |
| Turkish cohort | 30.3% germline | BRCA2 most frequent P/LP | PMID: 41595443 |
| Japanese advanced PCa | 8% germline | n=19 of 549 (BRCA2) | PMID: 35986085 |
| Canadian mainstream testing | 8% germline (all DDR) | BRCA1/2 included | PMID: 38461085 |
| European mHSPC cohort | 28.6% HRR; 12.4% BRCA | — | PMID: 40467032 |
Ashkenazi Jewish population: - Three founder mutations: BRCA1 185delAG, BRCA1 5382insC, BRCA2 6174delT - Combined carrier frequency ~2.5% of general Ashkenazi population (PMID: 10945492) - "Certain founder mutations in Ashkenazi Jews, especially 6174delT in BRCA2, are linked to increased risk and aggressive forms of PCa" (PMID: 40503579)
Other populations: French-Canadian, Icelandic, Turkish, Japanese, Indian, and UAE populations all have population-specific variant spectra (PMID: 41595443; PMID: 40257527; PMID: 35986085).
Recommended approach: Universal germline and somatic testing for men with metastatic prostate cancer. "An estimated 20% to 30% of men with advanced prostate cancer carry a mutation in DNA damage repair genes, of which half are estimated to be germline" (PMID: 38461085).
| Test | Utility | Notes |
|---|---|---|
| Multigene panel (germline) | First-line; 15–27 gene panels | Blood/saliva; identifies germline PVs |
| Tumor NGS (somatic) | Detects somatic + germline alterations | FoundationOne CDx, Myriad MyChoice |
| ctDNA testing (liquid biopsy) | Alternative when tissue unavailable | Consistent with tissue-based results (PMID: 36318705) |
| HRD score | Functional readout of HR deficiency | HRD score >25 predictive of FANC/BRCA mutations |
Critical finding: Personal and family history cannot reliably predict carrier status — 43% of BRCA carriers had no first- or second-degree relatives with BRCA-associated cancers (PMID: 38461085). Addition of germline testing to tumor-only sequencing improves PGV detection, as tumor-only sequencing missed >17% of pathogenic germline variants (PMID: 36103646).
IMPACT Study (62 centers, 20 countries, 3027 patients): Annual PSA screening from age 40 for BRCA1/BRCA2 carriers. 5-year results: "csPC incidence was significantly higher for BRCA2 PGV carriers than for noncarriers (3.1% vs 1.3%; p = 0.04). Among men with PC, the proportion of tumours with National Comprehensive Cancer Network intermediate unfavourable/high risk was higher in the BRCA1/BRCA2 PGV groups versus the corresponding group without PGVs (BRCA2: 65% vs 32%, p = 0.029; BRCA1: 56% vs 18%, p = 0.0017)" (PMID: 41714267).
PPV of PSA >3.0 ng/mL in BRCA2 carriers: 48% — double that of population screening (PMID: 24484606).
BRCA mutations are independent prognostic factors for poor outcomes after radical treatment (PMID: 25454609):
"At 3, 5, and 10 yr after treatment, 97%, 94%, and 84% of noncarriers and 90%, 72%, and 50% of carriers were free from metastasis (p<0.001). The 3-, 5- and 10-yr CSS rates were significantly better in the noncarrier cohort (99%, 97%, and 85%, respectively) than in carriers (96%, 76%, and 61%, respectively; p<0.001). Multivariate analysis confirmed BRCA mutations as an independent prognostic factor for MFS (hazard ratio [HR]: 2.36; 95% confidence interval [CI], 1.38-4.03; p=0.002) and CSS (HR: 2.17; 95% CI, 1.16-4.07; p=0.016)."
| Outcome | BRCA Carriers | Noncarriers | HR / p-value |
|---|---|---|---|
| 10-yr MFS | 50% | 84% | p < 0.001 |
| 10-yr CSS | 61% | 85% | p < 0.001 |
| MFS (multivariate) | — | — | HR 2.36 (1.38–4.03), p = 0.002 |
| CSS (multivariate) | — | — | HR 2.17 (1.16–4.07), p = 0.016 |
| OS with hormonal therapy | — | — | HR 2.36 (1.23–4.51) |
Disease volume: BRCA alterations worsen prognosis regardless of disease volume in both low- and high-volume mHSPC (PMID: 40467032).
| Regimen | Setting | Key Trial | Efficacy in BRCAm | MAXO Term |
|---|---|---|---|---|
| Olaparib monotherapy | mCRPC post-NHA | PROfound | rPFS HR 0.22 (0.15–0.32); OS HR 0.63 (0.42–0.95) | MAXO:0001298 |
| Olaparib + abiraterone | 1L mCRPC | PROpel | rPFS HR 0.23 (0.12–0.43); OS HR 0.29 (0.14–0.56) | MAXO:0001298 |
| Niraparib + abiraterone | 1L mCRPC, BRCA1/2+ | MAGNITUDE | rPFS benefit in BRCAm | MAXO:0001298 |
| Talazoparib + enzalutamide | 1L mCRPC, HRRm | TALAPRO-2 | OS benefit regardless of HRR status | MAXO:0001298 |
| Rucaparib | mCRPC post-NHA | TRITON3 | rPFS benefit in BRCA+ | MAXO:0001298 |
The greatest clinical benefit is consistently seen in BRCA-mutated patients. As summarized: "the greatest clinical benefit with olaparib was seen in patients with BRCA1 and/or BRCA2 mutations (BRCAm): PROfound rPFS hazard ratio (HR) 0.22 (95% confidence interval [CI] 0.15-0.32); PROpel rPFS HR 0.23 (95% CI 0.12-0.43). Clinical benefit was also observed in terms of overall survival: PROfound HR 0.63 (95% CI 0.42-0.95); PROpel HR 0.29 (95% CI 0.14-0.56)" (PMID: 40397306).
PSA response rates: PSA50 response rate for PARPi in BRCA+ mCRPC is 69% (CI: 53–82%) (PMID: 37722977).
Asian subgroup: Efficacy maintained in Asian patients: rPFS 9.3 vs 3.5 months (HR 0.17; 95% CI 0.06–0.49) for BRCA-altered patients (PMID: 35229141).
Treatment Algorithm: 1. Localized disease: Radical prostatectomy or radiation therapy; active surveillance may be less appropriate given aggressive biology 2. mHSPC: ADT + ARPI; clinical trials investigating early PARP inhibitor use 3. 1L mCRPC: PARP inhibitor + ARPI combination (per PROpel, MAGNITUDE, TALAPRO-2) 4. 2L mCRPC post-ARPI: PARP inhibitor monotherapy (per PROfound, TRITON3) 5. Post-PARPi progression: Monitor for reversions (liquid biopsy); platinum (caution re: cross-resistance); taxane chemotherapy; clinical trials
Pharmacogenomics: BRCA1/BRCA2 mutation status is the primary pharmacogenomic biomarker guiding PARP inhibitor selection. FDA restricted olaparib + abiraterone approval to BRCAm patients (PMID: 37497748).
IMPACT Study Protocol — gold standard for BRCA carrier screening: - Annual PSA screening beginning at age 40 for BRCA1/BRCA2 carriers - PSA threshold >3.0 ng/mL for prostate biopsy referral - PPV for biopsy: 47.6% in mutation carriers — remarkably high (PMID: 20840664) - No T4 or metastatic cases detected in screened cohort, suggesting screening catches disease early (PMID: 41714267) - MAXO: MAXO:0000640 (cancer screening)
Integration of PV status, PRS, and family history enables refined risk estimation: "PV carriers with a positive family history and a PRS in the 90th percentile had seven, 18, and 34 times the risks of overall, aggressive, and metastatic PCa, respectively, compared with average-risk individuals" (PMID: 41219045).
BRCA genes are highly conserved across vertebrates:
| Species | Gene | NCBI Gene ID | Notes |
|---|---|---|---|
| Mouse (Mus musculus, Taxon: 10090) | Brca2 | 12190 | Conditional knockout models available |
| Rat (Rattus norvegicus, Taxon: 10116) | Brca2 | 361521 | Knockout model with multi-organ tumors |
| Dog (Canis familiaris, Taxon: 9615) | BRCA2 | 476939 | Natural prostate cancer occurs in intact males |
BRCA-associated prostate cancer has not been specifically documented in companion animals. Dogs develop prostate cancer but typically of different histological subtypes.
Brca2 conditional prostate knockout (PMID: 20585617): - Prostate-specific Brca2 deletion → focal hyperplasia and low-grade PIN after 12 months - Combined Brca2;Trp53 deletion → high-grade PIN from 12 months - "Epithelial cells in these lesions show an increase in DNA damage and have higher levels of proliferation, but also elevated apoptosis" - Castration causes PIN regression but atypical AR-positive cells persist — models castration-resistant disease - Limitation: Does not progress to frank invasive carcinoma
Brca2 knockout rat (PMID: 16964288): - Nonsense mutation in exon 11; truncated protein produced - Unlike mice, Brca2⁻/⁻ rats are 100% viable and most live >1 year - Phenotype: "growth inhibition and sterility in both sexes...Long-term phenotypes include underdeveloped mammary glands, cataract formation and lifespan shortening due to the development of tumors and cancers in multiple organs"
A landmark prospective cohort study of BRCA1/2 pathogenic variant carriers demonstrated that BRCA2 carriers have SIR = 3.6 (95% CI 1.9–6.8) for prostate cancer with a cumulative risk to age 80 of 82.0% (PMID: 41776557). The IMPACT study's 5-year data confirmed that clinically significant prostate cancer incidence was 3.1% vs 1.3% in BRCA2 carriers vs noncarriers (p = 0.04), with 65% of tumors classified as NCCN intermediate unfavorable/high risk versus 32% in noncarriers (p = 0.029) (PMID: 41714267). In Ashkenazi Jewish men, BRCA2 6174delT carriers had an OR of 3.2 (95% CI 1.4–7.3) specifically for high-grade (Gleason 7–10) disease (PMID: 19188187).
The PROfound and PROpel trials established olaparib as a transformative therapy: rPFS HR 0.22 (95% CI 0.15–0.32) and OS HR 0.63 (95% CI 0.42–0.95) for BRCAm patients in PROfound; rPFS HR 0.23 (95% CI 0.12–0.43) and OS HR 0.29 (95% CI 0.14–0.56) in PROpel (PMID: 40397306). Meta-analysis confirmed PSA50 response rates of 69% for PARPi and 74% for platinum, with no significant OS difference between these modalities (HR 0.86; p = 0.6), highlighting platinum as a valid treatment alternative (PMID: 37722977).
After radical treatment for localized disease, 10-year metastasis-free survival was 50% in carriers vs 84% in noncarriers (p < 0.001), and 10-year cause-specific survival was 61% vs 85% (p < 0.001). Multivariate analysis confirmed BRCA mutations as independent prognostic factors for MFS (HR 2.36; 95% CI 1.38–4.03; p = 0.002) and CSS (HR 2.17; 95% CI 1.16–4.07; p = 0.016) (PMID: 25454609). This poor prognosis persists regardless of disease volume or treatment regimen in the metastatic setting (PMID: 40467032).
Reversion mutations restoring BRCA function are the dominant acquired resistance mechanism: 39% prevalence post-rucaparib progression (PMID: 36243543), 79% by end of treatment in TOPARP-B (PMID: 39577422). These reversions are polyclonal (74% have ≥2 unique reversions), frequently generated by POLQ-mediated microhomology-dependent repair (60% of frameshift deletions flanked by microhomologies), and their detection timing correlates with clinical outcomes (p < 0.01). The role of mutagenic end-joining DNA repair pathways in generating reversions suggests that pharmacological inhibition of these pathways could improve durability of PARP inhibitor treatment (PMID: 33091561).
Somatic HRR mutations are found in approximately 20–27% of mCRPC patients, with "somatic mutations in HRR pathway observed in up to 27% of metastatic resistant-to-castration PCa (mCRPC)...and mainly involving BRCA2, ATM, CHEK2, and BRCA1" (PMID: 35944490). Cross-population studies confirm this prevalence: 30.5% in an Indian cohort with "Sixty-eight pathogenic HRR alterations detected across 51 patients (30.5%). ATM was the most frequently altered gene (13.2%), followed by BRCA1 (5.3%), BRCA2 (4.2%), and CDK12 (4.2%)" (PMID: 41729953), 30.3% in a Turkish cohort (PMID: 41595443), and 28.6% in a European mHSPC cohort (PMID: 40467032).
The pathophysiology of BRCA-mutant prostate cancer can be understood as a multi-step process driven by the convergence of hereditary DNA repair deficiency and acquired genomic alterations:
Step 1 — Germline vulnerability: Inheritance of a heterozygous BRCA1/2 pathogenic variant creates a state of haploinsufficiency in every prostate epithelial cell, reducing but not eliminating HR capacity.
Step 2 — Somatic second hit: Loss of the wild-type allele through LOH, somatic mutation, or epigenetic silencing completes biallelic BRCA inactivation, creating HR deficiency in the affected cell lineage.
Step 3 — Genomic instability cascade: HR-deficient cells accumulate DNA double-strand breaks repaired by error-prone pathways (NHEJ, POLQ-mediated MMEJ), generating chromosomal rearrangements, copy number alterations, and point mutations. This creates the "BRCAness" genomic signature (elevated LOH, LST, TAI scores).
Step 4 — Cooperating driver events: Acquisition of TP53, PTEN, or RB1 mutations (frequent co-occurring events) removes additional tumor suppressor barriers, accelerating malignant transformation. The Brca2;Trp53 mouse model demonstrates this cooperativity.
Step 5 — Aggressive clinical phenotype: The resulting tumor exhibits high Gleason grade, propensity for intraductal growth patterns, rapid castration resistance, and early metastatic spread, explaining the 2.4-fold worse MFS and 2.2-fold worse CSS in BRCA carriers.
Step 6 — Therapeutic vulnerability and resistance: The same HR deficiency that drives aggressive behavior creates vulnerability to PARP inhibitors and platinum agents (synthetic lethality). However, selective pressure from these therapies drives convergent evolution of BRCA reversion mutations, predominantly through POLQ-mediated repair, restoring HR function in resistant clones.
This mechanistic framework explains both the paradox of aggressive-yet-treatable disease and identifies the critical resistance bottleneck (reversion mutations) as the highest-priority therapeutic target.
| Trial | Design | Key Result in BRCAm | PMID |
|---|---|---|---|
| PROfound | Phase III, olaparib vs NHA, HRRm mCRPC | rPFS HR 0.22; OS HR 0.63 | Multiple |
| PROpel | Phase III, olaparib+abi vs placebo+abi | rPFS HR 0.23; OS HR 0.29 | 38127780 |
| MAGNITUDE | Phase III, niraparib+AAP vs placebo+AAP | rPFS benefit in BRCA1/2+ | 38958846 |
| TALAPRO-2 | Phase III, talazoparib+enza vs placebo+enza | OS benefit in HRRm | Multiple |
| TRITON3 | Phase III, rucaparib vs NHA | rPFS benefit in BRCA+ | Multiple |
| IMPACT | Prospective screening, BRCA1/2 carriers | Higher csPC in BRCA2; PPV 48% | 41714267 |
BRCA1 vs BRCA2 distinction: While BRCA2 is well characterized in prostate cancer, the role of BRCA1 mutations remains less clear, with smaller sample sizes and less consistent risk estimates. The IMPACT study found no significant differences for BRCA1 carriers vs noncarriers at 3 years for overall cancer incidence, though 5-year data show more aggressive features when cancer does occur.
Ethnic diversity: Most clinical trial data come from predominantly White/European populations (95% in IMPACT). Data from African, Asian, and Middle Eastern populations are emerging but limited, though cross-population HRR prevalence studies are encouraging (PMID: 41729953; PMID: 41595443).
Optimal treatment sequencing: Head-to-head comparisons between PARP inhibitors are lacking; indirect treatment comparisons are not feasible due to disconnected networks and population heterogeneity (PMID: 38958846).
Resistance monitoring: ctDNA has limitations in detecting reversion mutations due to variable shedding across metastatic sites — "Variable cfDNA shed was seen across tumor sites, emphasizing a potential shortcoming of cfDNA monitoring for PARPi resistance" (PMID: 38355834).
VUS interpretation: 10–20% of BRCA sequencing results are VUS, creating clinical uncertainty, particularly in under-represented populations with limited genomic annotation (PMID: 34065235; PMID: 41595443).
Non-BRCA HRR genes: PARPi efficacy varies by gene; "neither olaparib nor rucaparib showed significant superior effectiveness to ARAT in patients with ATM mutations" (PMID: 38851712).
Early-stage disease: Most targeted therapy data are in the mCRPC setting; the role of PARPi in localized or hormone-sensitive BRCA-mutant prostate cancer is under investigation.
Genetic counseling access: Only 16.6% of patients with HRR variants were referred for genetic counseling in one real-world study (PMID: 35476551), highlighting an implementation gap.
POLQ inhibitor clinical trials: Given that 60% of BRCA reversion mutations are mediated by POLQ-dependent microhomology repair, POLQ inhibitors should be tested in combination with PARPi to prevent/delay reversion-mediated resistance.
Prospective screening in diverse populations: Expand IMPACT-like targeted screening to African-ancestry and Asian populations where prostate cancer burden is high but BRCA carrier data are limited.
Longitudinal ctDNA monitoring: Design studies with serial ctDNA sampling across multiple time points to characterize temporal dynamics of reversion mutation emergence and clonal evolution.
PARPi in mHSPC: Complete ongoing trials evaluating PARPi combinations in the hormone-sensitive setting for BRCA-mutant patients to determine if earlier intervention improves outcomes.
Functional VUS classification pipeline: Implement systematic functional assays (HDR reporter assays, RAD51 foci formation) for BRCA2 VUS, particularly for under-represented populations with high VUS rates.
Combination immunotherapy: Test PARPi + immune checkpoint inhibitor combinations specifically in BRCA-mutant prostate cancer, leveraging potential increased neoantigen load.
Single-cell and spatial transcriptomics: Characterize the tumor microenvironment of BRCA-mutant prostate cancer at single-cell resolution to identify immune evasion mechanisms.
Improved preclinical models: Create genetically engineered mouse models that progress beyond PIN to invasive/metastatic carcinoma through additional cooperating alterations (PTEN loss, AR amplification).
Real-world evidence registries: Establish multi-center registries tracking outcomes of BRCA-mutant prostate cancer patients across treatment lines to inform clinical decision-making.
Head-to-head PARPi comparisons: Design clinical trials directly comparing different PARPi regimens in BRCA-mutant mCRPC to enable evidence-based treatment selection.
Report generated: 2026-05-05. Based on systematic review of 75 publications spanning epidemiology, genetics, clinical trials, resistance mechanisms, screening, and preclinical models of BRCA-mutant prostate cancer.