First-Line Talazoparib plus Enzalutamide for Metastatic Castration-Resistant Prostate Cancer

The prior PROpel trial (NEJM Evid 2022; 1:EVIDoa2200043) demonstrated the efficacy of adding a poly(ADP-ribose) polymerase (PARP) inhibitor (olaparib) to an androgen receptor inhibitor (ARI; abiraterone) in the first-line setting for patients with metastatic castration-resistant prostate cancer (mCRPC). The benefit was achieved irrespective of homologous recombination repair (HRR) gene mutation status, including BRCA1/2, but was greater in HRR-deficient patients. HRR gene alterations are found in approximately 25% of patients and can increase sensitization to PARP inhibitor therapy.

Now, investigators have conducted a similar industry-sponsored, international, randomized, double-blind, placebo-controlled, phase 3 trial (TALAPRO-2) to evaluate adding the PARP inhibitor talazoparib to the standard-of-care ARI enzalutamide in the first-line setting. The study was divided into two cohorts, an all-comer group (Cohort 1) and an HRR-deficient–only group (Cohort 2). The current report presents data from Cohort 1 in which 805 mCRPC patients were enrolled. The median age of patients was 71 years, 64%–67% had performance status 0, 20%–21% were HRR-deficient, 7%–8% had BRCA1/2 alterations, and 5%–6% had received prior abiraterone.

At a median follow-up of approximately 25 months, median radiographic progression-free survival (the primary outcome) was longer for patients receiving talazoparib plus enzalutamide versus enzalutamide alone (not reached vs. 21.9 months; hazard ratio, 0.63; P<0.0001). Grade 3–4 anemia was more common with talazoparib plus enzalutamide than with enzalutamide alone (46% vs. 4%).