Talazoparib/enzalutamide significantly boosts OS in mCRPC

Results from the phase 3 TALAPRO-2 study (NCT03395197) indicate that treatment with the PARP inhibitor talazoparib (Talzenna) plus enzalutamide (Xtandi) was associated with a statistically significant and clinically meaningful improvement in final overall survival (OS) in both all-comers as well as patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC).¹

The safety profile of the treatment combination was found to be “generally consistent with the known safety profile of each medicine,” according to a news release from Pfizer. The company reported that detailed data from TALAPRO-2 will be submitted to be presented at an upcoming medical conference.

Neeraj Agarwal, MD, FASCO

“These overall survival results indicate potentially practice-changing efficacy for TALZENNA in combination with XTANDI for men with metastatic castration-resistant prostate cancer,” 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 TALAPRO-2, in the news release.¹ “Metastatic castration-resistant prostate cancer 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.”

Talazoparib is currently approved in the US for the treatment of HRR gene-mutated mCRPC. The approval was based on previously reported findings from TALAPRO-2, in which talazoparib/enzalutamide reduced the risk of disease progression or death by 55% vs enzalutamide alone in a subgroup of patients with HRR gene–altered mCRPC.^2,3 The median radiographic progression-free survival (rPFS) was not yet reached (95% CI, 21.9-NR) in patients receiving talazoparib/enzalutamide (n = 200) vs 13.8 months (95% CI, 11.0-16.7) in the control arm (HR, 0.45; 95% CI, 0.33-0.61; P <.0001).

The rPFS benefit extended to all subgroups of HRR deficient patients, including those with BRCA1/2 mutations. In the BRCA mutation–positive group, the talazoparib combination led to an 80% reduction in the risk of disease progression or death versus the control arm (HR, 0.20; 95% CI, 0.11-0.36, P <.0001). Among patients without BRCA1/2 mutations, there was a much smaller rPFS benefit observed in the talazoparib arm (HR, 0.72; 95% CI, 0.49-1.07; P = 0.10).

TALAPRO-2 is a multicenter, randomized, double-blind, placebo-controlled study. It enrolled a total of 1035 patients with mCRPC and was divided into 2 cohorts; the first was all-comers and the second was men with HRR gene mutations. Patients were randomly assigned to receive talazoparib 0.5 mg/day plus enzalutamide 160 mg/day or placebo plus enzalutamide 160 mg/day. The study's primary end point was rPFS ,"defined as the time from the date of randomization to first objective evidence of radiographic progression by blinded independent review, or death, whichever occurred first."¹ OS, objective response rate, duration of response, and prostate-specific antigen response comprised the secondary end points.

REFERENCES

1. Pfizer’s TALZENNA®in combination with XTANDI® prolongs overall survival in phase 3 TALAPRO-2 trial. News release. Pfizer. October 10, 2024. Accessed October 10, 2024. https://www.pfizer.com/news/press-release/press-release-detail/pfizers-talzennar-combination-xtandir-prolongs-overall

2. Fizazi K, Azad A, Matsubara N, et al. TALAPRO-2: Phase 3 study of talazoparib (TALA) + enzalutamide (ENZA) versus placebo (PBO) + ENZA as first-line (1L) treatment for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) harboring homologous recombination repair (HRR) gene alterations. J Clin Oncol. 2023;5004(suppl 16). doi:10.1200/JCO.2023.41.16_suppl.5004

3. Agarwal N, Azad A, Carles J, et al. Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial. Lancet. 2023. doi:10.1016/S0140-6736(23)01055-3