The combination of talazoparib (Talzenna) and enzalutamide (Xtandi) has demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) for patients with metastatic castration-resistant prostate cancer (mCRPC), according to results from the Phase III TALAPRO-2 trial. This benefit was observed regardless of HRR gene mutation status.
Key Findings from TALAPRO-2
The TALAPRO-2 trial (NCT03395197) enrolled 1,035 patients with mCRPC who had not received prior life-prolonging systemic therapy after mCRPC diagnosis. The study included an all-comer cohort (Cohort 1, n=805) and a cohort specifically enriched for patients with HRR gene mutations (Cohort 2, n=399). Patients were randomized to receive either talazoparib 0.5 mg/day plus enzalutamide 160 mg/day or placebo plus enzalutamide 160 mg/day.
The primary endpoint was radiographic progression-free survival (rPFS), while secondary endpoints included OS, objective response rate, duration of response, and prostate-specific antigen response.
Final analysis of the TALAPRO-2 trial revealed that the combination of talazoparib and enzalutamide significantly improved OS compared to enzalutamide alone in both the all-comer and HRR-deficient cohorts. The clinically meaningful improvement in rPFS observed in the primary analysis was also maintained across both cohorts.
In the primary analysis, talazoparib plus enzalutamide reduced the risk of disease progression or death by 37% compared to placebo plus enzalutamide (HR: 0.63; 95% CI, 0.51–0.78; P< 0.001). Median rPFS was not reached in the talazoparib plus enzalutamide arm versus 21.9 months in the placebo plus enzalutamide arm.
Expert Commentary
"These [OS] results indicate potentially practice-changing efficacy for [talazoparib] in combination with [enzalutamide] for [patients] with metastatic [CRPC],” said Neeraj Agarwal, MD, FASCO, professor and Presidential Endowed Chair of Cancer Research at Huntsman Cancer Institute, University of Utah, and global lead investigator for the TALAPRO-2 trial. “Metastatic [CRPC] is the most advanced and aggressive stage of the disease, and the TALAPRO-2 results provide much-needed hope to patients who remain in high unmet need for effective treatment options.”
Implications for Treatment
The FDA approved talazoparib in combination with enzalutamide in June 2023 for patients with HRR gene-mutated mCRPC. The TALAPRO-2 trial's findings support the potential expansion of this approval to a broader population of mCRPC patients, regardless of HRR mutation status.
Neeraj Agarwal discussed a post-hoc analysis of the TALAPRO-2 Phase III study, which evaluates the efficacy of talazoparib and enzalutamide in metastatic castrate-resistant prostate cancer patients with prior ARPI or docetaxel treatment. The analysis shows promising results for the combination therapy, particularly in patients with HRR-deficient tumors. Dr. Agarwal emphasizes the potential benefits of combining talazoparib and enzalutamide, even for patients previously treated with ARPI or docetaxel in the hormone-sensitive setting.
Safety Profile
The safety profile of talazoparib plus enzalutamide in the TALAPRO-2 trial was consistent with previous reports for each individual agent. No new safety signals were identified.
Study Design
The TALAPRO-2 trial was a multicenter, randomized, double-blind, placebo-controlled study. Patients with castrate testosterone levels were randomly assigned to receive talazoparib 0.5 mg/day plus enzalutamide 160 mg/day, or placebo plus enzalutamide 160 mg/day. The primary endpoint was rPFS, and secondary endpoints included OS, objective response rate, duration of response, and prostate-specific antigen response.
