FDA Accepts sNDA for Talazoparib/Enzalutamide in HRR-Mutant mCRPC

The decision was supported by results from the phase 3 TALAPRO-2 study, in which a statistically significant and clinically meaningful improvement in overall survival was observed with the combination vs enzalutamide monotherapy in patients with HRR-mutant metastatic CRPC.

The FDA has accepted a supplemental new drug application (sNDA) for talazoparib (Talzenna) plus enzalutamide (Xtandi) in patients with homologous recombination repair (HRR) gene

The decision was supported by results from the phase 3 TALAPRO-2 study, in which a statistically significant and clinically meaningful improvement in overall survival was observed with the combination vs enzalutamide monotherapy in patients with HRR-mutant metastatic CRPC.

The FDA has accepted a supplemental new drug application (sNDA) for talazoparib (Talzenna) plus enzalutamide (Xtandi) in patients with homologous recombination repair (HRR) gene–mutated metastatic castration-resistant prostate cancer (CRPC), according to a news release from the drug’s developer, Pfizer Inc.1

The decision was supported by results from the phase 3 TALAPRO-2 study (NCT03395197), in which a statistically significant and clinically meaningful improvement in overall survival (OS) was observed with the combination vs enzalutamide monotherapy in patients with HRR-mutant metastatic CRPC. According to an OS analysis presented at the 2025 American Society of Clinical Oncology Genitourinary Cancers Symposium, the median OS between patients with HRR-mutant disease treated with talazoparib/enzalutamide vs enzalutamide alone was 45.1 months (95% CI, 35.4-not reached) vs 31.1 months (95% CI, 27.3-35.4), respectively, a 38% reduction in the risk of death (HR, 0.622; 95% CI, 0.475-0.814; P = .0005) after a median follow-up of 44.2 months.2,3

“Men with metastatic [CRPC] 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 metastatic CRPC,” said Johanna Bendell, MD, oncology chief development officer at Pfizer, in the news release.1 “We are pleased that the statistically significant final [OS] data reaffirming the current indication have been added to the label based on the strong results from TALAPRO-2.”

Of note, the FDA did not expand the indication to include patients with non–HRR gene mutated metastatic CRPC. Comparatively, among patients without HRR alterations detected, treatment with the combination elicited a median OS of 46.6 months (95% CI, 33.0-54.1) vs 37.4 months (95% CI, 30.0-40.9) with enzalutamide alone, which did not achieve statistical significance (HR, 0.782; 95% CI, 0.582-1.050; P = .1008). The FDA suggested that the trial findings were not sufficient to conclude a favorable benefit-risk profile for this non-HRR subgroup, and Pfizer will not pursue an expanded indication for the combination in the US among patients with metastatic CRPC.

Patients in the phase 3 TALAPRO-2 study were randomly assigned 1:1 to receive frontline talazoparib/enzalutamide or placebo/enzalutamide. Patients were assessed in 2 cohorts: the unselected cohort, including patients with nondeficient or unknown HRR mutation status (n = 805), and the HRR-deficient cohort (n = 399). The data cutoff for both cohorts was September 3, 2024.

Among patients with HRR mutation in the combination (n = 402) and control (n = 403) cohorts, 14.2% vs 14.4% had evaluable circulating tumor DNA samples. Additionally, 21.1% vs 20.3% had 1 or more alterations in the corresponding gene, with the most common non-HRR mutations including those in CDK12 (5.7% vs 7.2%), BRCA2 (5.7% vs 6.9%), and ATM (5.7% vs 3.5%).

The primary end point of the study was radiographic progression-free survival (PFS) assessed by blinded independent committee review. The key secondary end point was OS, and other secondary end points included time to cytotoxic chemotherapy, PFS to second disease progression or death, overall response rate, patient-reported outcomes, and safety.

Among patients with HRR-deficient disease, the median duration of talazoparib treatment was 20.3 months. The most common treatment-emergent adverse effects (AEs) with the combination included anemia, fatigue, and neutropenia. In this treatment group, grade 3/4 anemia was observed in 43.4% of patients, with a median onset time of 3.4 months.

Additionally, among these patients, the rate of AE-related talazoparib discontinuation of 13.1% was similar to the primary analysis. Of note, 4.5% of patients discontinued due to anemia. Furthermore, investigators found that global health status and quality of life were maintained for patients taking talazoparib.

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 Inc. June 13, 2025. Accessed June 18, 2025. https://tinyurl.com/2f4zkhp8
2. Fizazi K, Azad A, Matsubara N, et al. Presentation on abstract LBA 141 final overall survival (OS) with talazoparib (TALA) + enzalutamide (ENZA) as first-line (1L) treatment in patients (pts) with homologous recombination repair (HRR)-deficient metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 TALAPRO-2 trial. Abstract presented at: 2025 American Society of Clinical Oncology Genitourinary Cancers Symposium; February 13-15, 2025; San Francisco, CA. Abstract LBA141.
3. 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):LBA18. doi:10.1200/JCO.2025.43.5_suppl.LBA18