PARP Inhibitors and Radioligand Therapies Advance Prostate Cancer Care with Biomarker-Driven Strategies

The role of PARP inhibitors and radioligand therapies is rapidly evolving in advanced prostate cancer, with increasing focus on biomarker-driven strategies and earlier use in the treatment course. PARP inhibition remains most effective in patients with BRCA1/2 mutations, as confirmed by data with niraparib (Zejula) plus ADT and abiraterone (Zytiga) in metastatic castration-sensitive prostate cancer (mCSPC).

In a previous article, Matthew R. Smith, MD, PhD, discussed how treatment intensification continues to shape the mCSPC landscape. Building on that perspective, emerging findings with lutetium-177 PSMA (Pluvicto) and results from the PEACE-3 trial (NCT02194842) with radium-223 (Xofigo) plus enzalutamide (Xtandi) in bone-dominant mCRPC are redefining clinical practice.

In an interview with OncLive®, Matthew R. Smith, MD, PhD, director of the Genitourinary Oncology Program at Massachusetts General Hospital Cancer Center and associate professor of medicine at Harvard Medical School, discussed how these data are shaping treatment decisions and the implications for patients with advanced disease.

OncLive: Which emerging studies, novel agents, or research directions hold the most promise in mCRPC, and what developments are you most interested in following?

A lot is going on in the field. One of the issues we are still working through is identifying the best use of PARP inhibitors. Unequivocally, in mCRPC, they are an appropriate therapy for patients with DNA repair mutations, particularly those with BRCA1 and BRCA2 mutations.

The concise way of describing it is that their role in combination with [androgen receptor pathway inhibitors (ARPIs)] in patients without DNA repair mutations remains more controversial. That approach is not yet an approved indication in the United States, although it is approved in Europe. We can agree that most of the benefit is conferred to patients with DNA repair mutations. The presence of a DNA repair mutation is a robust biomarker of benefit from a PARP inhibitor.

At the 2024 ASCO Annual Meeting, we saw data on niraparib in [metastatic castration-sensitive prostate cancer (mCSPC)] in combination with ADT and abiraterone in patients with DNA repair mutations. As expected, those results confirmed the important role of PARP inhibition in that biomarker-selected patient population. More studies of other PARP inhibitors in this space are ongoing.

In this very important molecular subgroup—particularly those with BRCA1 and BRCA2 mutations—we may be moving PARP inhibitors earlier into the course of therapy.

How do recent findings with radium-223 and other ASCO updates in radioligand therapy inform clinical practice in prostate cancer?

Radioligand therapy is here to stay in prostate cancer. There are a lot of new data, and that flow of data will continue. For example, we now have lutetium-177 PSMA, which is [FDA-]approved [for] patients with mCRPC post-chemotherapy, and now pre-chemotherapy.1

We’ve also heard topline data on its use as part of initial therapy in castration-sensitive prostate cancer (CSPC), which is another triplet regimen with ADT, an ARPI, [with or without] Pluvicto/PSMA-617. We’re looking forward to more data from that, particularly overall survival results.

How do results with radium-223 plus enzalutamide influence its role in mCRPC, particularly for patients with bone-dominant disease?

The PEACE-3 trial with radium-223 came out of the blue, in a way, because a prior study, ERA-223 [NCT02043678], failed to show any benefit for ADT plus abiraterone [Zytiga] with radium-223, and not only failed to show benefit but also showed increased fractures with radium-223.

At the time PEACE-3 was ongoing, they incorporated bone-protective agents, and to many people’s surprise, that study produced evidence of a benefit when adding radium to enzalutamide in mCRPC.

It’s revisiting the role of radium in that space, and it’s a reasonable consideration for patients starting enzalutamide with mCRPC who have bone-only or bone-dominant disease. That was an unexpected but positive result that could have relevance in daily clinical practice.

Reference

FDA expands Pluvicto’s metastatic castration-resistant prostate cancer indication. FDA. March 28, 2025. Accessed August 21, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-expands-pluvictos-metastatic-castration-resistant-prostate-cancer-indication