BRCA1, BRCA2, and ATM

  • BRCA1 (BRCA1 DNA repair associated) and BRCA2 (BRCA2 DNA repair associated) are tumor suppressor genes central to homologous recombination repair (HRR) of DNA double-strand breaks.1,2
  • ATM (ATM serine/threonine kinase) senses DNA double-strand breaks and phosphorylates TP53, CHK2, H2AX, and BRCA1 to coordinate repair.1,3
  • Gene Location: Chromosome 17 (17q21.31) for BRCA1; chromosome 13 (13q13.1) for BRCA2; chromosome 11 (11q22.3) for ATM.1
  • Other HRR genes used for patient selection: the olaparib label covers 14 genes (ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, RAD54L); the talazoparib label covers 12 (ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C).13,16

Biology

  • BRCA1 coordinates cell-cycle checkpoints and DNA end resection; BRCA2 loads RAD51 onto resected DNA to drive strand invasion and error-free repair.2
  • Loss of both alleles produces HRR deficiency and reliance on error-prone repair. In metastatic castration-resistant prostate cancer (mCRPC), BRCA2 loss is biallelic in about 90% of affected tumors.6
  • Synthetic lethality: PARP inhibitors block single-strand break repair and trap PARP on DNA, causing replication-fork collapse and double-strand breaks that HRR-deficient cells cannot repair. The same defect underlies platinum sensitivity.4
  • PARP plus androgen receptor pathway inhibitor (ARPI) rationale: androgen receptor signaling maintains HRR gene expression; AR inhibition suppresses it and produces a functional HRR-deficient ("BRCAness") state that is synthetically lethal with PARP inhibition in preclinical models.5

Etiology and Epidemiology

  • Germline: 11.8% (82 of 692) of men with metastatic prostate cancer carry a presumed pathogenic germline DNA-repair gene mutation, most often BRCA2 (5.3%), ATM (1.6%), and BRCA1 (0.9%). Frequency does not differ by age at diagnosis or family history.7
  • Somatic plus germline: DNA repair gene alterations are found in at least 22.7% of mCRPC biopsies; BRCA2, BRCA1, or ATM aberrations in 19.3%; BRCA2 loss in 12.7%.6
  • PROfound screening: 28% (778 of 2792) of successfully sequenced samples carried a qualifying alteration in 1 of 15 HRR genes.8
  • Prognosis: germline BRCA carriers more often present with Gleason 8 or higher, nodal involvement, and metastases, with shorter cause-specific survival (8.6 vs 15.7 years). In PROREPAIR-B, germline BRCA2 was an independent adverse prognostic factor in mCRPC (cause-specific survival 17.4 vs 33.2 months; HR, 2.11).9,10

Testing

When to Test:

  • Germline: all patients with metastatic prostate cancer, regardless of age or family history. Germline variants are present from birth, so a prior germline result does not need to be repeated at progression.7,11,12
  • Somatic (tumor): patients with metastatic disease, castration-sensitive or castration-resistant, being considered for biomarker-directed therapy. BRCA2 status now informs treatment in metastatic castration-sensitive prostate cancer (mCSPC) as well as mCRPC.11,15
  • Repeat somatic testing: may be offered after a meaningful change in status or plan, especially if prior results were negative or uninformative.11

Testing Methodologies:

  • Tumor tissue next-generation sequencing (NGS): archival primary or metastatic tissue. In PROfound, NGS results were obtained from 58% of samples (69% of patients); newly obtained samples succeeded more often than archival samples (63.9% vs 56.9%).17
  • Plasma circulating tumor DNA (ctDNA) NGS: an option when tissue is unavailable or fails; 76.8% of PROfound cohort A plasma samples yielded a result. A negative plasma result does not rule out a tumor alteration.14,18
  • Clonal hematopoiesis (CHIP): CHIP variants in DNA repair genes (mostly ATM) were found in plasma from 10% of men with advanced prostate cancer and can cause false-positive ctDNA calls; a paired whole-blood control helps.19
  • Germline testing: multigene panel NGS with deletion/duplication analysis on blood or saliva. A pathogenic BRCA finding on tumor-only sequencing needs germline confirmation; variants of uncertain significance are not actionable.7,12
  • Companion diagnostics: olaparib, FoundationOne CDx (tissue; 14 HRR genes), BRACAnalysis CDx (blood; germline BRCA1/2), and FoundationOne Liquid CDx (plasma); rucaparib, FoundationOne Liquid CDx (plasma; BRCA1/2); niraparib/abiraterone acetate, FoundationOne CDx and FoundationOne Liquid CDx (BRCA-mutated mCRPC); talazoparib plus enzalutamide, FoundationOne CDx and FoundationOne Liquid CDx (approved June 1, 2026).13-16

Guideline Recommendations

  • ASCO (2025): all patients with metastatic prostate cancer should undergo germline testing with NGS, and those being considered for biomarker-directed therapy should undergo somatic NGS. Archival tissue is preferred initially; ctDNA is preferred when no metastatic site can be biopsied or for sequential testing.11
  • AUA/SUO (amended 2026): offer germline testing to all patients with advanced prostate cancer; for metastatic disease, offer somatic tumor testing as well.20
  • NCCN (Prostate Cancer, V.5.2026): recommends germline and somatic tumor testing for HRR gene alterations in metastatic prostate cancer, with multigene tumor testing at metastatic diagnosis and consideration of retesting at progression to mCRPC. NCCN added niraparib/abiraterone acetate plus ADT for BRCA2-mutated mCSPC in 2026.21

Targeted Therapy

Approved Agents

Olaparib (Lynparza)

FDA-Approved Indication:

  • Deleterious or suspected deleterious germline or somatic HRR gene-mutated mCRPC after progression on enzalutamide or abiraterone.13
  • In combination with abiraterone and prednisone or prednisolone for deleterious or suspected deleterious BRCA-mutated mCRPC.13

Mechanism of Action:

  • Inhibitor of PARP1, PARP2, and PARP3; traps PARP-DNA complexes, causing lethal double-strand breaks in HRR-deficient cells.13

Drug Information: Learn more about Olaparib ›

Patient Resources: https://www.lynparza.com/

Rucaparib (Rubraca)

FDA-Approved Indication:

  • Deleterious BRCA mutation (germline and/or somatic)-associated mCRPC previously treated with androgen receptor-directed therapy (regular approval December 17, 2025; prior taxane no longer required).14

Mechanism of Action:

  • Inhibitor of PARP1, PARP2, and PARP3 with PARP-trapping activity.14

Drug Information: Learn more about Rucaparib ›

Patient Resources: https://www.rubraca.com/

Niraparib and Abiraterone Acetate (Akeega)

FDA-Approved Indication:

  • With prednisone, for deleterious or suspected deleterious BRCA2-mutated mCSPC (approved December 12, 2025) and BRCA-mutated mCRPC.15

Mechanism of Action:

  • Fixed-dose tablet combining niraparib, a PARP1/2 inhibitor, with abiraterone acetate, a CYP17 inhibitor that suppresses androgen biosynthesis.15

Drug Information: Learn more about Niraparib and Abiraterone Acetate ›

Patient Resources: https://www.akeega.com/

Talazoparib (Talzenna)

FDA-Approved Indication:

  • In combination with enzalutamide for HRR gene-mutated mCRPC. In June 2025, the FDA added final overall survival data to the label and declined to extend the indication to patients without HRR gene mutations.16

Mechanism of Action:

  • Inhibitor of PARP1 and PARP2 with potent PARP trapping.16

Drug Information: Learn more about Talazoparib ›

Patient Resources: https://www.talzenna.com/

Related Considerations

  • Benefit is concentrated in BRCA-mutated, particularly BRCA2-mutated, disease. In TRITON3, rucaparib showed no rPFS benefit for ATM (HR, 0.95) or BRCA1 (HR, 1.01) alterations; ATM is in the olaparib label but not the rucaparib label.14
  • ASCO identifies patients with BRCA1/2 alterations as candidates for PARP inhibitor monotherapy, PARP inhibitor plus ARPI combinations, and platinum-based chemotherapy.11

References

  1. MedlinePlus Genetics. BRCA1, BRCA2, and ATM genes. National Library of Medicine. Cytobands per NCBI Gene and Human Protein Atlas. Accessed October 2026.
  2. Roy R, Chun J, Powell SN. BRCA1 and BRCA2: different roles in a common pathway of genome protection. Nat Rev Cancer. 2011;12(1):68-78. doi:10.1038/nrc3181
  3. Choi M, Kipps T, Kurzrock R. ATM mutations in cancer: therapeutic implications. Mol Cancer Ther. 2016;15(8):1781-1791. doi:10.1158/1535-7163.MCT-15-0945
  4. Ashworth A, Lord CJ. Synthetic lethal therapies for cancer: what's next after PARP inhibitors? Nat Rev Clin Oncol. 2018;15(9):564-576. doi:10.1038/s41571-018-0055-6
  5. Asim M, Tarish F, Zecchini HI, et al. Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer. Nat Commun. 2017;8(1):374. doi:10.1038/s41467-017-00393-y
  6. Robinson D, Van Allen EM, Wu YM, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161(5):1215-1228. doi:10.1016/j.cell.2015.05.001
  7. Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016;375(5):443-453. doi:10.1056/NEJMoa1603144
  8. de Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med. 2020;382(22):2091-2102. doi:10.1056/NEJMoa1911440
  9. Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013;31(14):1748-1757. doi:10.1200/JCO.2012.43.1882
  10. Castro E, Romero-Laorden N, Del Pozo A, et al. PROREPAIR-B: a prospective cohort study of the impact of germline DNA repair mutations on the outcomes of patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2019;37(6):490-503. doi:10.1200/JCO.18.00358
  11. Yu EY, Rumble RB, Agarwal N, et al. Germline and somatic genomic testing for metastatic prostate cancer: ASCO guideline. J Clin Oncol. 2025;43(6):748-758. doi:10.1200/JCO-24-02608
  12. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate V.3.2026. © National Comprehensive Cancer Network, Inc. 2026. All rights reserved. Accessed October 2026. To view the most recent and complete version of the guideline, go online to NCCN.org.
  13. Lynparza (olaparib) tablets. Prescribing information. AstraZeneca Pharmaceuticals LP; revised 07/2025. Accessed October 2026.
  14. Rubraca (rucaparib) tablets. Prescribing information. pharmaand GmbH; revised 12/2025. Accessed October 2026.
  15. Akeega (niraparib and abiraterone acetate) tablets. Prescribing information. Janssen Biotech, Inc; revised 12/2025. Accessed October 2026.
  16. Talzenna (talazoparib) capsules. Prescribing information. Pfizer Inc; revised 06/2025. Accessed October 2026.
  17. Hussain M, Corcoran C, Sibilla C, et al. Tumor genomic testing for >4,000 men with metastatic castration-resistant prostate cancer in the phase III trial PROfound (olaparib). Clin Cancer Res. 2022;28(8):1518-1530. doi:10.1158/1078-0432.CCR-21-3940
  18. Matsubara N, de Bono J, Olmos D, et al. Olaparib efficacy in patients with metastatic castration-resistant prostate cancer and BRCA1, BRCA2, or ATM alterations identified by testing circulating tumor DNA. Clin Cancer Res. 2023;29(1):92-99. doi:10.1158/1078-0432.CCR-21-3577
  19. Jensen K, Konnick EQ, Schweizer MT, et al. Association of clonal hematopoiesis in DNA repair genes with prostate cancer plasma cell-free DNA testing interference. JAMA Oncol. 2021;7(1):107-110. doi:10.1001/jamaoncol.2020.5161
  20. Scarpato KR, Cookson MS, Dreicer R, et al. Advanced prostate cancer: AUA/SUO guideline amendment (2026) part I. J Urol. 2026;216(4):479-486. doi:10.1097/JU.0000000000005220
  21. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer V.5.2026. © National Comprehensive Cancer Network, Inc. 2026. All rights reserved. Accessed October 2026. To view the most recent and complete version of the guideline, go online to NCCN.org.