BRCA1/2 – therapy guidance (PARP inhibitor response)

Germline pathogenic variants in BRCA1 or BRCA2 are associated with hereditary breast and ovarian cancer syndrome (HBOC). The condition is characterised by increased risks of female breast cancer, male breast cancer and epithelial ovarian cancer, including fallopian tube and primary peritoneal carcinoma. Germline BRCA variants are also associated with increased risks of pancreatic and prostate cancer. Associated cancers generally occur in adulthood, although the age at diagnosis and tumour spectrum vary according to the affected gene and individual or familial factors.

The prevalence of germline BRCA1/2 pathogenic variants varies according to ancestry, tumour type, age at diagnosis and family history. In populations without a recognised founder effect, approximately 1 in 400 to 1 in 800 individuals carry a germline pathogenic variant in BRCA1 or BRCA2. The prevalence is substantially higher in certain founder populations.

A germline BRCA1/2-associated cancer predisposition is inherited in an autosomal dominant manner. Each child of an individual with a germline pathogenic or likely pathogenic variant has a 50% probability of inheriting that variant. Cancer penetrance is incomplete and varies according to the gene, cancer type, age and other modifying factors. Consequently, not every individual who carries a pathogenic variant will develop cancer.1

A germline BRCA1/2-associated cancer predisposition is established by identifying a heterozygous pathogenic or likely pathogenic variant in BRCA1 or BRCA2 by molecular genetic testing of a constitutional sample, typically peripheral blood. This test determines germline status. It does not reliably identify a pathogenic variant confined to the tumour. Consequently, a negative germline result does not exclude a somatic BRCA1/2 alteration or another tumour biomarker that may be relevant to PARP inhibitor treatment. Depending on the tumour type and clinical setting, complementary tumour testing may therefore be indicated.

Tumours with loss of BRCA1 or BRCA2 function may be particularly sensitive to inhibition of poly(ADP-ribose) polymerase, or PARP. PARP inhibition interferes with DNA-damage repair and replication-fork stability. In cells with deficient homologous-recombination repair, the resulting DNA damage may lead to tumour-cell death. This interaction is commonly described as synthetic lethality. However, the presence of a pathogenic BRCA1/2 variant does not guarantee an individual treatment response, and primary or acquired resistance may occur.

In the European Union, Olaparib has authorised indications in defined clinical settings that include:

• Breast cancer: Olaparib is authorised for patients with a germline BRCA1/2 mutation and HER2-negative, high-risk early breast cancer previously treated with neoadjuvant or adjuvant chemotherapy. It is also authorised for patients with a germline BRCA1/2 mutation and HER2-negative locally advanced or metastatic breast cancer, subject to the additional treatment criteria specified in the product information.
• Ovarian cancer: Olaparib is authorised in selected maintenance-treatment settings involving high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer. Depending on the treatment setting, eligibility may be based on a germline or somatic BRCA1/2 mutation, homologous-recombination deficiency, or response to platinum-based chemotherapy. Some authorised ovarian cancer indications do not require the detection of a BRCA1/2 mutation.
• Pancreatic cancer: Olaparib is authorised as maintenance monotherapy for patients with a germline BRCA1/2 mutation and metastatic pancreatic adenocarcinoma whose disease has not progressed after at least 16 weeks of platinum-containing first-line chemotherapy.
• Prostate cancer: Olaparib is authorised as monotherapy for patients with metastatic castration-resistant prostate cancer and a germline or somatic BRCA1/2 mutation whose disease has progressed following previous treatment that included a new hormonal agent. Further olaparib-containing treatment options may apply in other clinically defined settings specified in the current product information.

Accordingly, germline analysis from blood can identify therapeutically relevant BRCA1/2 variants in all four tumour types. In ovarian and prostate cancer, however, tumour-based or other validated somatic testing may identify additional patients with non-inherited BRCA1/2 alterations who would not be detected by germline testing alone. Treatment decisions must be based on the complete clinical context and the current product information and professional guidelines.

• In a patient with breast, ovarian, pancreatic or prostate cancer, identification of a germline pathogenic or likely pathogenic variant in BRCA1 or BRCA2 may inform treatment planning, including assessment of eligibility for Olaparib in an approved clinical setting.
• The finding establishes an inherited cancer predisposition and may influence tumour-specific surveillance, risk-reducing measures and management of additional cancer risks.
• A negative germline result does not exclude a somatic BRCA1/2 alteration. Depending on the tumour type and clinical setting, complementary tumour testing may therefore be indicated.
• A variant of uncertain significance does not confirm a hereditary cancer predisposition and should not, on its own, guide PARP inhibitor treatment or predictive testing in relatives.
• Once a germline pathogenic or likely pathogenic variant has been identified, adult relatives at risk can be offered targeted testing for the familial variant, accompanied by appropriate genetic counselling.

• Petrucelli N, Daly MB, Pal T. BRCA1- and BRCA2-associated hereditary breast and ovarian cancer. 1998 Sep 4 [updated 2026 Mar 25]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews®. Seattle, WA: University of Washington, Seattle; 1993–2026. PMID: .
• European Medicines Agency. Lynparza: EPAR product information. Summary of Product Characteristics. Amsterdam: European Medicines Agency. Current European product information for olaparib. Available from:
• Russo A, Incorvaia L, Capoluongo E, et al. Implementation of preventive and predictive BRCA testing in patients with breast, ovarian, pancreatic, and prostate cancer: a position paper of Italian Scientific Societies. ESMO Open. 2022;7(3):100459. PMID: .
• National Cancer Institute. BRCA1 and BRCA2: Cancer Risks and Management (PDQ®), Health Professional Version. Bethesda, MD: National Cancer Institute; updated May 14, 2025. Available from:
• Khalizieva A, Moser SC, Bouwman P, Jonkers J. BRCA1 and BRCA2: from cancer susceptibility to synthetic lethality. Genes Dev. 2025;39(1–2):86–108. doi:10.1101/gad.352083.124. PMID: .
• Tutt ANJ, Garber JE, Kaufman B, et al. Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer. N Engl J Med. 2021;384(25):2394–2405. doi:10.1056/NEJMoa2105215. PMID: .
• Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377(6):523–533. doi:10.1056/NEJMoa1706450. PMID: .
• DiSilvestro P, Banerjee S, Colombo N, et al. Overall survival with maintenance olaparib at a 7-year follow-up in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation: the SOLO1/GOG 3004 trial. J Clin Oncol. 2023;41(3):609–617. doi:10.1200/JCO.22.01549. PMID: .
• Golan T, Hammel P, Reni M, et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med. 2019;381(4):317–327. doi:10.1056/NEJMoa1903387. PMID: .
• Mateo J, de Bono JS, Fizazi K, et al. Olaparib for the treatment of patients with metastatic castration-resistant prostate cancer and alterations in BRCA1 and/or BRCA2 in the PROfound trial. J Clin Oncol. 2024;42(5):571–583. doi:10.1200/JCO.23.00339. PMID: .