Dr Yu on Factors Influencing PARP Inhibitor Selection in mCRPC

“I don’t envision a world where [talazoparib plus enzalutamide] is approved for all-comers, but I do believe the current [FDA] approval will get a reasonable amount of utility because, unlike the other combinations, it had an overall survival benefit and looking at the gene-by-gene breakdown, there are promising results for [patients with] some gene mutations that some of the other PARP inhibitors do not have.”

Evan Ya-Wen Yu, MD, section head, medical oncology, professor, Clinical Research Division, Fred Hutchinson Cancer Center, discussed the PARP inhibitors that are available for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) and the differences that he considers when selecting between them.

First, investigators must decide whether they are using monotherapy or a combination approach, Yu began. FDA-approved monotherapies include rucaparib (Rubraca) and olaparib (Lynparza). In May 2020, rucaparib was approved by the FDA for patients with deleterious BRCA-mutated mCRPC who have been treated with androgen receptor (AR)–directed therapy and taxane-based chemotherapy. Olaparib was first approved by the FDA in May 2020 for patients with homologous recombination repair (HRR) gene–mutated mCRPC who experienced disease progression following prior enzalutamide (Xtandi) or abiraterone acetate (Zytiga).

In May 2023, olaparib was also approved by the FDA in combination with abiraterone and prednisone or prednisolone for patients with deleterious or suspected deleterious BRCA-mutated mCRPC. In terms of other combination therapies, niraparib and abiraterone (Akeega) earned FDA approval in August 2023 for patients with deleterious BRCA-mutated mCRPC, Yu said.

A unique study leading in mCRPC was the phase 3 TALAPRO-2 trial (NCT03395197), which supported the June 2023 approval of talazoparib (Talzenna) plus enzalutamide in patients with HRR gene–mutated mCRPC, Yu noted. Data from the study demonstrated a radiographic progression-free survival benefit vs enzalutamide plus placebo in patients with and without DNA repair gene alterations, he explained.

Additionally, at the 2025 Genitourinary Cancers Symposium, updated data from TALAPRO-2 showed that patients who received the combination (n = 200) achieved a median overall survival (OS) of 45.1 months (95% CI, 35.4-not reached) vs 31.1 months (95% CI, 27.3-35.4) among patients who received placebo plus enzalutamide (n = 199). This is the first combination of an AR pathway inhibitor and a PARP inhibitor to show an OS benefit in frontline mCRPC, Yu said. However, the benefit was mostly driven by patients with BRCA1/2 gene alterations, Yu noted.