As many as 20% to 25% of patients with metastatic prostate cancer harbor a mutation or aberration in a gene involved in the DNA damage repair (DDR) pathway.^1,2 The most commonly mutated genes are BRCA1 and BRCA2, encoding proteins critical for homologous recombination repair (HRR). Patients with germline BRCA1/2 mutations are known to be at higher risk of cancer diagnosis and require frequent screening for various malignancies,³ and men with prostate adenocarcinoma and either somatic or germline BRCA1/2 mutations have a more aggressive phenotype.^3-6

Patients with either pathogenic DDR germline or somatic mutations have been shown to be sensitive to poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition.^3-6 This finding led to FDA approvals for olaparib (2020) and rucaparib (2021) in patients who had failed androgen receptor therapy (ART; olaparib) or ART+chemotherapy (rucaparib). While olaparib was approved for a wide array of corresponding HRR mutations, the PROFOUND study clearly showed a greater benefit to the BRCA 1/2 mutation subgroup, and this is the group for which rucaparib was subsequently approved as well.^6,7 Adverse events in the trial population were manageable and related to bone marrow toxicity (anemia and thrombocytopenia), gastrointestinal side effects (nausea), and fatigue. Management of these adverse events could require dose interruption in approximately half of patients, with approximately one-fourth of patients requiring a dose reduction.^6,7

As PARPs have become a larger part of the advanced prostate cancer landscape, newer trial protocols have evaluated these treatments in combination with ART. Preclinical in vitro studies have suggested androgen receptor suppression can lead to a BRCA-like state in cells that may lead to synergistic sensitivity to PARP inhibition. Consistent with prior data, much of the benefit, even in combination studies, appears to be in BRCA-mutated patients. This led in 2023 to an FDA approval of olaparib and abiraterone combination therapy in BRCA1/2-mutated patients only.⁸ A similar limited approval soon followed for the dual action tablet of niraparib+abiraterone based on the MAGNITUDE study.⁹ Lastly, the Talapro-2 study evaluating talazoparib+enzalutamide did include and see benefit in a broader mutational group and got approved based on this larger cohort (Figure).¹⁰ The typical patient for these trials was first-line mCRPC patients with or without minimal prior androgen receptor–directed therapy, a cohort that is somewhat challenging to find in modern practice today. The most striking outcome of these studies was the relatively rapid failure of the comparator arm (ART) for men with BRCA mutations. Men with BRCA mutations appear to fare much worse than the average patient from the PREVAIL and COU-302 studies, which led to mCRPC approval of enzalutamide and abiraterone, respectively.

Figure. Mutational cohorts in recent combination androgen receptor therapy/poly (ADP-ribose) polymerase inhibitor trials.

As mentioned, these recent approvals have proved challenging for real-world application. Many centers of excellence push doublet hormonal therapy in mCSPC as supported by AUA and National Comprehensive Cancer Network guidelines. The transition of men with prior ART to first-line mCRPC therapy with combination ART/PARP is largely unstudied. BRCAAway, which was recently presented, evaluated abiraterone, followed by olaparib vs olaparib followed by abiraterone vs simultaneous combination therapy in 61 men with mostly BRCA mutations. In that population, combination therapy had a longer PFS than the sequential approach, which has supported its use today in previously untreated patients.¹¹

Finding appropriate patients for these therapies hinges on timely germline and somatic testing. These approvals have pushed many providers to evaluate and update current testing protocols in their practices. Testing can be based on archival tissue (typically if within that last 5–10 years), new biopsies of metastatic lesions, or liquid testing of circulating tumor or cell-free DNA. The trials showed good concordance between tissue and liquid, but obtaining a result from liquid testing requires substantial tumor burden that is often difficult to achieve in those with minimal PSA/radiographic disease levels. In our experience, there is still significant variation across both urologic and medical oncology providers regarding who, when, and how to test, impacting patient access to PARP inhibitors across all practice settings.

Moving forward, further trials and data will help us understand the correlation between genotype and resultant disease behavior and responsiveness to therapies. Not all BRCA mutations are equivalent, and genomic testing often yields complex, quantitative results. The presence or absence of genomic instability, loss of heterozygosity, and other indices may convert a “nonresponder” to a “responder.” Improved patient identification and dissemination of toxicity and efficacy data to more providers should cause more widespread utilization of PARP inhibitors for men with prostate cancer in the years ahead. We anticipate these therapies soon will enter the hormone-sensitive space, and potentially even play a role for high-risk localized prostate cancer patients who carry the appropriate biomarker.