PCa Commentary | Volume 206 – October 2025

Posted by Edward Weber, MD | October 2025

The BRCA Family of Mutated DNA Damage Repair Genes Influence Therapy

A rapid increase has occurred in the discovery of biomarkers to guide therapeutic decisions. A mutated BRCA2 gene, for example, is a predictive biomarker that indicates greater cancer aggressiveness and a poor response to some therapies. But it also offers benefits when combined with other agents. Traditionally, these markers have been found by genomic analysis of tissues – prostate biopsies or prostatectomy specimens. Currently, biomarkers can be discovered in blood, urine, and circulating DNA. This Commentary will highlight some examples of biomarkers useful for guiding patient management.

A recent article makes a strong recommendation that all men should be tested for biomarkers when they are diagnosed: “Implementation of Universal Germline Genetic Testing into Standard of Care for Patients with Prostate Cancer: The Time Is Now,” by Shore et al., (JCO Oncol Practice. 2024). To emphasize the importance and consensus on this recommendation, the article was co-authored by twenty-five acknowledged prostate cancer experts! To accomplish testing, a request would be made to the pathologist for the genomic assay, or saliva could be submitted, for example, to MyRisk at Myriad Genetics. The rationale for the search for pathogenic germline variants is their important role in treatment and management decisions and “their known association with familial cancer.” Universal germline testing avoids the confusion resulting from the various conflicting current guidelines”.

Pathogenic germline variants (i.e., inherited) occur in 3% to 11% of men with localized disease, and somatic mutations (developed during therapy) are found in 12% to 20% of men with advanced or metastatic cancer. (Shore, Ibid). The most common variants are members of the BRCA family (BRCA1 and BRCA2; ATM and CHEK2, HOXB13). Variants are less frequently found in one of the five Mismatch Repair Deficiency genes (dMMR) – rare (2- 3%), but highly actionable.

1) Background: Biology of BRCA Mutations

• BRCA1 and BRCA2 are termed DNA Damage Repair genes. Their function is to protect the fidelity of DNA duplication at cell division. Mutated BRCA genes fail in this function, leaving the back-up PARP system (Poly (ADP-ribose) polymerase), to repair the damaged DNA. PARP inhibitors, such as olaparib, rucaparib, talazoparib, further prevent repair, resulting in the death of the cells harboring the mutated BRCA genes.

2) New Therapies Combining PARP Inhibitors with Other Agents

• Fizazi et al., (Lancet Aug 2025) reported in the 155-man TALAPRO-2 trial showing that men with BRCA mutations treated in combination with the PARP inhibitor talazoparib and enzalutamide experienced a survival advantage as compared to enzalutamide alone.

Results: at median follow-up of 44.2 months, the median radiographic progression-free survival was 31.1 months for the combination vs 12.3 months for enzalutamide alone. The median overall survival was >45.1 months in the combination group vs 28 months for enzalutamide alone. Talazoparib + enzalutamide is now FDA-approved as first-line therapy for mCRPC for men with mutated BRCA genes.

• A recently reported abstract by Attard at ASCO 2025 is the Phase 3 AMPLITUDE trial comparing the PARP inhibitor Niraparib + abiraterone acetate/Prednisone/ADT versus abiraterone acetate/Prednisone/ADT in 696 men with high-risk metastatic castration-sensitive PC carrying BRCA or BRCA-like mutations. The median radiographic progression-free survival for mutated BRCA 1&2 men was not reached versus 26 months for the abiraterone acetate/Prednisone/ADT group. Attard commented that this represented a 48% reduction in the “risk of radiographic progression or death”. Major adverse effects were anemia and hypertension, greater in the Nira+AAP group.

• Van der Doelen (European Journal of Cancer. Sept 2020) reported that when the alpha emitter Rad-223 was employed in men with a mutation in one of the BRCA2, ATM, or CDK12 genes as compared to those men lacking mutations, the median overall survival was 36.3 months compared to 17.0 months for men lacking mutations.
• The VISION trial, which studied 177Lu-PSMA-617 as a treatment for men with advanced metastatic cancer, revealed that a third had primary resistance to 177Lu-PSMA-617 and only half showed a >50% drop in PSA. The ongoing protocol LuPARP (NCT03874884) is evaluating the combination of 177Lu-PSMA-617 with the PARP inhibitor olaparib in men with mCRPC with high tumor proliferative activity on PSMA PET scan. Mutated BRCA genes are not required. Early results were promising, with 62% of men showing a PSA decline of >50% and 48% with a >90% PSA reduction. (Abstract 5005, 2023 ASCO Annual Meeting.)

3) Mutations that Confer Sensitivity to Immunotherapy

• Rarer mutations that respond to immunotherapy include CDK12, PALB2, and Mismatch Repair Genes (EPCAM,  MLH1, MSH2, MSH6, and PMS2).
• Inactivation mutations in CDK12 (seen in 5% – 7% of men with mCRPC) offer potential sensitivity to the immune checkpoint inhibitor PD-1, as reviewed by Antonarakis et al. (JCO Precis Oncol 2020). After heavy pretreatment for advanced disease, “33.3% of men had PSA response and median progression-free survival of 5.4 months.”  The authors suggest that “anti-PD-1 agents should be initiated earlier in the disease.”

4) A Recommendation

Stressing the importance of early detection of adverse mutations, Bradley McGregor (Director of Clinical Research, Dana-Farber Cancer Institute) noted that when PARP inhibitors are used in late disease, resistance develops in about one year. Commenting further: “It really highlights that you don’t know if you don’t test. It’s going to be incredibly important that patients who are diagnosed with castration-sensitive prostate cancer undergo somatic and germline testing to see if they have these mutations so they can be offered the right treatment at the right time.”

BOTTOM LINE:

Identification of mutations in the BRCA 1 and 2 genes and in other DNA Damage Repair genes can guide therapy decisions. Early testing is recommended.

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