FDA Declines to Expand Label for Talazoparib/Enzalutamide in mCRPC

FDA

The FDA has declined to expand the label for the combination of talazoparib (Talzenna) and enzalutamide (Xtandi) to include patients with non–homologous recombination repair (HRR) gene–mutated metastatic castration-resistant prostate cancer (mCRPC).1

In a news release, Pfizer announced the FDA updated the label to include overall survival (OS) data from the phase 3 TALAPRO-2 trial (NCT03395197) to support the existing indication for the combination. In June 2023, the FDA approved talazoparib plus enzalutamide for use in patients with HRR gene–mutated mCRPC.2 The approval was supported by data from TALAPRO-2.

Notably, in May 2025, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 8 to 0 against the risk/benefit profile of talazoparib plus enzalutamide for patients with non-HRR–mutant mCRPC, based on data from TALAPRO-2.3

“Men with mCRPC are often faced with a poor prognosis and limited treatment options, and [talazoparib] in combination with [enzalutamide] has redefined the standard-of-care for patients living with HRR gene–mutated mCRPC,” Johanna Bendell, MD, oncology chief development officer at Pfizer, stated in a news release.1 “We are pleased that the statistically significant final OS data reaffirming the current indication has been added to the label, based on the strong results from TALAPRO-2.”

OS Data From TALAPRO-2

Updated findings from the study presented at the 2025 Genitourinary Cancers Symposium showed that among the cohort of patients who were unselected for HRR mutations, those treated with talazoparib plus enzalutamide (n = 402) achieved a median OS of 45.8 months (95% CI, 39.4-50.8) compared with 37.0 months (95% CI, 34.1-40.4) for those given placebo plus enzalutamide (n = 403; HR, 0.796; 95% CI, 0.661-0.958; P = .0155).4

Within the overall unselected cohort (n = 805), the majority of patients did not have HRR mutations or had unknown HRR mutation status (n = 636), and the remainder of patients (n = 169) harbored HRR gene mutations. In the HRR-positive subgroup, the hazard ratio for death was 0.542 (95% CI, 0.361-0.814) compared with 0.874 (95% CI, 0.711-1.076) in the HRR-negative group.

TALAPRO-2 Background

The randomized, placebo-controlled study enrolled patients with first-line mCRPC who had an ECOG performance status of 0 or 1 and were receiving ongoing androgen deprivation therapy (ADT). Along with the unselected cohort, the second cohort included patients only if they harbored HRR gene mutations.

Patients were randomly assigned 1:1 to receive talazoparib plus enzalutamide or placebo plus enzalutamide. Stratification factors for the unselected cohort included prior abiraterone acetate (Zytiga) or docectaxel for castration-sensitive prostate cancer (yes vs no), and HRR status (deficient vs non-deficient/unknown).

The study's primary end point was radiographic progression-free survival (rPFS) per blinded independent central review. OS was a key secondary end point, and other secondary objectives comprised time to cytotoxic chemotherapy, time to second progression, overall response rate, patient-reported outcomes, and safety.

Additional Data for the Unselected Cohort

At the time of the primary analysis, with a data cutoff of August 16, 2022, and a median follow-up of 24.9 months for the experimental arm and 24.6 months for the placebo arm, the median rPFS was not reached (NR; 95% CI, 27.5-NR) in the talazoparib arm vs 21.9 months (95% CI, 16.6-25.1) for the placebo arm (HR, 0.627; 95% CI, 0.506-0.777; P < .0001).

Updated data at a median follow-up of 47.0 months and 46.9 months for the respective arms showed that the median rPFS was 33.1 months (95% CI, 27.4-39.0) for the talazoparib regimen vs 19.5 months (95% CI, 16.6-24.7) for the placebo regimen (HR, 0.667; 95% CI, 0.551-0.807; P < .0001).

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 13, 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 metastaic castration-resistant prostate cancer. FDA. June 20, 2023. Accessed June 13, 2025. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-talazoparib-enzalutamide-hrr-gene-mutated-metastatic-castration-resistant-prostate
3. May 21, 2025, Meeting of the Oncologic Drugs Advisory Committee (ODAC). FDA. Accessed June 13, 2025. https://www.youtube.com/live/5ecyDbK9ezc
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;43(suppl 5):LBA15. doi:10.1200/JCO.2025.43.5_suppl.LBA18