FDA does not approve talazoparib plus enzalutamide for non-HRR gene mutated mCRPC

The FDA declined to approve expanded labeling for the combination of talazoparib (Talzenna) plus enzalutamide (Xtandi) to include broader use in the treatment of patients with non-HRR gene mutated metastatic castration-resistant prostate cancer (mCRPC), Pfizer announced in a news release.¹

The FDA did approve updated labeling for the combination’s existing indication to include updated OS data.

The combination of talazoparib plus enzalutamide is currently approved for the treatment of patients with HRR-gene mutated mCRPC as of an FDA decision in June 2023.²

The agency’s current decision on the combination follows a negative vote from the FDA’s Oncologic Drugs Advisory Committee (ODAC) in May, where the committee unanimously voted 0-8 against a favorable risk-benefit profile for the combination. The FDA sided with ODAC in their decision on Pfizer’s supplemental new drug application (sNDA), noting that the TALAPRO-2 data were insufficient to support an expanded label in the subgroup of patients with non-HRR gene-mutated mCRPC.

Pfizer will no longer pursue an expanded indication for talazoparib plus enzalutamide in non-HRR gene mutated mCRPC in the US as a result of this decision.

However, in their review of the sNDA, the FDA did approve updated labeling for the combination’s existing indication to include final overall survival (OS) data from the phase 3 TALAPRO-2 trial (NCT03395197).

“Men with metastatic castration-resistant prostate cancer are often faced with a poor prognosis and limited treatment options, and TALZENNA in combination with XTANDI has redefined the standard-of-care for patients living with HRR gene-mutated mCRPC,” said Johanna Bendell, MD, Oncology Chief Development Officer at Pfizer, in the news release.¹ “We are pleased that the statistically significant final overall survival data reaffirming the current indication has been added to the label, based on the strong results from TALAPRO-2.”

Overall, the TALAPRO-2 trial included 2 cohorts: patients unselected for HRR gene mutations (cohort 1; n = 805) and patients selected for HRR gene mutations (cohort 2; n = 399).

The initial approval of talazoparib plus enzalutamide in 2023 was supported by data from cohort 2 of the trial, which found that the combination led to a statistically significant improvement in radiographic progression-free survival (rPFS) vs placebo plus enzalutamide in patients with HRR-gene mutated mCRPC.³ At the time of data report, the median rPFS had not been reached in the talazoparib/enzalutamide arm and was 13.8 months in the placebo/enzalutamide arm (HR, 0.45; 95% CI, 0.33 to 0.61; P < .0001).

Updated data from the TALAPRO-2 trial were presented at the 2025 American Society of Clinical Oncology Genitourinary Cancers Symposium in San Francisco, California.^4,5 At a median follow-up of 44.2 months, the median OS in cohort 2 was 45.1 months in the talazoparib plus enzalutamide arm vs 31.1 months with enzalutamide alone (HR, 0.62; 95% CI, 0.48 to 0.81; P = .0005).

Findings from cohort 1 included data from median follow-up of 52.5 months. In these patients, the median OS was 45.8 months in the talazoparib/enalutamide arm vs 37 months in the placebo/enzalutamide arm (HR, 0.80; 95% CI, 0.66 to 0.96; P = .015).

At the time of final analysis, updated rPFS and other secondary efficacy end point data showed maintained clinical benefit with the combination in both cohorts and were consistent with primary analyses.

Safety data on the combination was also consistent with the known safety profiles of each therapy. The most common adverse events in the combination arm were anemia, neutropenia, and fatigue. The most common grade 3 to 4 adverse events were anemia (49%) and neutropenia (19.3%).

In total, the double-blind, phase 3 TALAPRO-2 trial enrolled 1,035 patients with mCRPC through clinical trial sites in the US, Canada, Europe, South America, and the Asia-Pacific region. Patients were eligible for enrollment if they had not received new life-prolonging systemic treatments for mCRPC.

The trial included 2 cohorts: all-comers (n = 805, of whom 169 had HRR mutations and 636 did not) and those with HRR gene mutations (n = 399, including 169 patients from cohort 1 and 230 patients subsequently enrolled to cohort 2). Those included in the study were randomly assigned to receive 0.5 mg per day of talazoparib plus 160 mg per day of enzalutamide or to 160 mg per day of enzalutamide alone.

The primary end point for the trial was rPFS. Secondary end points include OS, objective response rate, duration of response, and prostate-specific antigen response.

REFERENCES

1. Pfizer provides update on U.S. regulatory review of TALZENNA in combination with XTANDI for broader use in metastatic castration-resistant prostate cancer. News release. Pfizer. June 13, 2025. Accessed June 17, 2025. https://www.pfizer.com/news/announcements/pfizer-provides-update-us-regulatory-review-talzenna-combination-xtandi-broader

2. FDA approves talazoparib with enzalutamide for HRR gene-mutated metastatic castration-resistant prostate cancer. News release. US Food & Drug Administration. June 20, 2023. Accessed June 17, 2025. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-talazoparib-enzalutamide-hrr-gene-mutated-metastatic-castration-resistant-prostate

3. Fay AP, Fizazi K, Matsubara N, et al. First-line talazoparib plus enzalutamide versus placebo plus enzalutamide in men with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations: patient-reported outcomes from the randomised, double-blind, placebo-controlled, phase 3 TALAPRO-2 trial. Lancet Oncol. 2025 Apr;26(4):481-490. doi: 10.1016/S1470-2045(25)00031-2

4. Agarwal N, Azad A, Carles J, et al. Final overall survival (OS) with talazoparib (TALA) + enzalutamide (ENZA) as first-line treatment in unselected patients with metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 TALAPRO-2 trial. J Clin Oncol. 2025 (suppl 5; abstr LBA18). doi:10.1200/JCO.2025.43.5_suppl.LBA18

5. Pfizer’s TALZENNA in combination with XTANDI improves survival outcomes in metastatic castration resistant prostate cancer. News release. Pfizer. February 13, 2025. Accessed June 17, 2025. https://www.pfizer.com/news/press-release/press-release-detail/pfizers-talzennar-combination-xtandir-improves-survival