PARP inhibitors are targeted therapies for patients with metastatic castration-resistant prostate cancer (mCRPC) who carry HRR mutations (eg, BRCA1/2 and ATM). More recently, several US Food and Drug Administration (FDA) approvals have provided additional monotherapy and combination therapy treatment options in the PARP inhibitor space, enabling increased access to these life-prolonging therapies. Genetic testing is imperative to ensure that patients with mCRPC are receiving appropriate treatment.

Looking at PARP inhibitor monotherapy in mCRPC, olaparib is FDA approved for patients with HRR mutations who have progressed following treatment with enzalutamide or abiraterone based on the PROfound trial data. In this trial, among patients with mCRPC who carried HRR mutations in ATM or BRCA1/2 and were previously treated with an ARPI, those receiving olaparib had an increased median radiographic progression-free survival (rPFS; 7.4 vs 3.6 months) and median overall survival (OS; 19.1 vs 14.7 months) compared with those receiving the investigator’s choice of ARPI therapy.

Rucaparib is also FDA approved as monotherapy in mCRPC for patients with a deleterious BRCA mutation who previously received an ARPI based on the TRITON3 trial results. In this trial, we saw the benefit with rucaparib therapy compared with ARPI therapy or chemotherapy (ie, docetaxel) in patients with BRCA1/2 or ATM mutations.

If you look at combination therapy for patients with mCRPC who have not received prior systemic therapy in the metastatic setting, the PROpel and MAGNITUDE trial data showed improved rPFS in patients with HRR mutations, but no OS benefit. Based on these data, abiraterone acetate plus olaparib and prednisone/prednisolone as well as abiraterone acetate plus niraparib and prednisone are FDA approved for patients with mCRPC and BRCA1/2 mutations.

Also, based on results from the TALAPRO-2 trial, the combination of enzalutamide plus talazoparib is FDA approved for patients with mCRPC and HRR mutations. In this study, enzalutamide plus talazoparib significantly improved both rPFS and OS in HRR mutation–positive patients compared with enzalutamide monotherapy.

The last thing I will mention is pembrolizumab monotherapy for patients with tumor mutational burden–high/microsatellite instability–high (TMB-high/MSI-high) mCRPC; in these patients, pembrolizumab may be an option under its tumor-agnostic FDA indications. If you combine these 2 patient populations, we are talking about up to 5% of patients with mCRPC, which is not trivial. There has not been a randomized trial yet, but pembrolizumab thus far has demonstrated clinically meaningful benefit in patients with TMB-high/MSI-high disease in retrospective and prospective cohorts.

The message here is that every patient with metastatic prostate cancer should undergo both germline and somatic testing. For one thing, we have life-prolonging therapy available (ie, PARP inhibitors) for these patients. Further, based on somatic testing, a significant proportion of HRR mutation–positive patients also have germline mutations. This has significant implications for them and their family members.