FDA approves talazoparib plus enzalutamide for HRR-mutated hormone-sensitive prostate cancer

The FDA has approved talazoparib (Talzenna; Pfizer) plus enzalutamide (Xtandi; Pfizer and Astellas) for metastatic hormone-sensitive prostate cancer (mHSPC) with homologous recombination repair (HRR) gene mutations, ajmc.com reports. ajmc.comajmc.comajmc.comOpen source ↗ The combination moves into an earlier disease setting. Patients are eligible only if an FDA-authorized test detects the HRR mutations. ajmc.comajmc.comajmc.comOpen source ↗

Until now, the regimen was approved in the US only for HRR-mutated metastatic castration-resistant disease, an indication granted in June 2023 on the basis of the TALAPRO-2 trial. In that study the combination lowered the risk of progression or death by 55% in the HRR-mutated cohort. ajmc.comajmc.comajmc.comOpen source ↗

TALAPRO-3 design and efficacy

The approval rests on the double-blind, placebo-controlled phase 3 TALAPRO-3 trial (NCT04821622). It randomly assigned 599 patients 1:1 to talazoparib 0,5 mg or placebo once daily, each with enzalutamide 160 mg daily and continued androgen deprivation therapy. Eligibility required a mutation in at least 1 of 12 HRR genes, identified by sequencing tumor tissue or circulating tumor DNA. ajmc.comajmc.comajmc.comOpen source ↗

The primary end point was investigator-assessed radiographic progression-free survival (rPFS). Adding talazoparib reduced the risk of radiographic progression or death by 52% (HR 0,48; 95% CI 0,36–0,65). Median rPFS had not been reached with talazoparib versus 45,8 months with placebo. At 3 years, 77% of patients on the combination were alive without radiographic progression versus 56% in the control group. ajmc.comajmc.comajmc.comOpen source ↗

Investigators presented the data at the ASCO 2026 Annual Meeting, with a simultaneous publication in the New England Journal of Medicine. ajmc.comajmc.comajmc.comOpen source ↗

Safety and open questions

Grade 3 or higher adverse events occurred in 81% of patients with talazoparib and 44% with placebo; serious adverse events occurred in 42% and 32%. Anemia was the most frequent grade 3 or higher event, in 51% versus 3%, and 5% of patients stopped talazoparib because of it. The trial recorded 2 treatment-related deaths, both in the talazoparib group. ajmc.comajmc.comajmc.comOpen source ↗

The prescribing information carries warnings about embryo-fetal toxicity, myelosuppression and myelodysplastic syndrome/acute myeloid leukemia, and calls for monthly blood count monitoring. In pooled data, 41% of patients on the combination needed a red blood cell transfusion. ajmc.comajmc.comajmc.comOpen source ↗

Overall survival, the key secondary end point, was immature at the rPFS analysis. At an interim analysis, 3-year overall survival was 78% with talazoparib and 72% with placebo (HR 0,77), a difference that did not meet the prespecified threshold for statistical significance. The European Medicines Agency is evaluating a parallel application. ajmc.comajmc.comajmc.comOpen source ↗