FDA Approves Label Update But Not Expansion for Talazoparib/Enzalutamide in mCRPC
FDA updates talazoparib and enzalutamide labeling, confirming survival benefits for HRR-mutated mCRPC, while excluding non-HRR patients.
3D rendered medically accurate illustration of prostate cancer: © SciePro - stock.adobe.com
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.
