FDA Approves Label Update But Not Expansion for Talazoparib/Enzalutamide in mCRPC

The FDA has approved an update to the labeling for talazoparib (Talzenna) in combination with enzalutamide (Xtandi) for men with metastatic castration-resistant prostate cancer (mCRPC).¹ This regulatory action incorporates the final overall survival (OS) data for the combination within its existing indication for the treatment of adults with homologous recombination repair (HRR) gene-mutated mCRPC.

While this update strengthens the evidence for the combination's benefit in the HRR-mutated subgroup, the FDA did not expand the indication to include patients with non-HRR gene mutated mCRPC. As a result, Pfizer will not pursue an expanded indication for this combination in mCRPC in the US.

This updated labeling is supported by data from the phase 3 TALAPRO-2 trial (NCT03395197). Detailed data from the phase 3 TALAPRO-2 trial were previously presented at the 2025 American Society of Clinical Oncology Genitourinary Cancers Symposium.^2,3 The trial demonstrated a statistically significant and clinically meaningful improvement in OS for patients with HRR-mutated mCRPC. Specifically, at a median follow-up of 44.2 months, the median OS for patients treated with talazoparib in combination with enzalutamide was 45.1 months, which compares favorably to 31.1 months for patients receiving enzalutamide and placebo.¹ This represents a substantial 14-month gain in median OS. The hazard ratio (HR) for this benefit was 0.62 (95% CI, 0.48-0.81; P =.0005), indicating a 38% reduction in the risk of death for patients with HRR-mutated mCRPC treated with the combination.

“Men with metastatic castration-resistant prostate cancer 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,” said Johanna Bendell, MD, oncology chief development officer, Pfizer, in a press release. “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.”

The FDA's decision to only approve the updated labeling for the HRR-mutated subgroup stems from their assessment that the TALAPRO-2 trial data were not sufficient to establish a favorable benefit-risk profile for expanding the indication to include patients with non-HRR gene mutated mCRPC.

The FDA’s Oncologic Drugs Advisory Committee played a pivotal role in this decision, with a unanimous 8-0 vote on May 21, 2025, deeming the TALAPRO-2 results insufficient to support the expansion to the non-HRR mutated mCRPC population.⁴ Committee members expressed significant concerns regarding the lack of a prespecified, statistically powered analysis in the non-HRR mutated subgroup, which constitutes the majority of the target population. Without such prospective biomarker stratification, the reliability of any perceived survival benefit in non-HRR mutated patients remained uncertain for the panel.

In June 2023, the FDA granted approval to the talazoparib/enzalutamide combination for the treatment of HRR gene-mutant mCRPC, as supported by initial findings from TALAPRO-2.⁵ The data the FDA considered at the time showed that the combination led to a 55% reduction in the risk of disease progression or death (HR, 0.45; 95% CI, 0.33-0.61; P <.0001). The median radiographic progression-free survival at the time was not reached (NR, 95% CI, 27.5 months-NR) with talazoparib and enzalutamide vs 21.9 months (range, 16.6-25.1) with placebo plus enzalutamide.

The inclusion of final OS data on the label provides definitive evidence of the long-term survival benefit offered by the talazoparib and enzalutamide combination in HRR-mutated mCRPC.

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. June 13, 2025. Accessed June 17, 2025. https://tinyurl.com/4zue6n4t

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. J Clin Oncol. 2025,43(suppl 5):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):LBA141. doi:10.1200/JCO.2024.42.4_suppl.LBA185.doi:10.1200/JCO.2024.42.4_suppl.LBA359

4. Meeting of the Oncologic Drug Advisory Committee. FDA. May 21, 2025. Accessed May 21, 2025. https://tinyurl.com/5n7mwvjt

5. Pfizer’s TALZENNA® in combination with XTANDI® receives U.S. FDA approval. News release. Pfizer. June 20, 2023. Accessed June 17, 2025. https://tinyurl.com/bdh36t4s