FDA grants priority review to talazoparib plus enzalutamide for HRR gene-altered mCSPC

The FDA has granted priority review to a supplemental New Drug Application (sNDA) for talazoparib (Talzenna) plus enzalutamide (Xtandi) in patients with homologous recombination repair (HRR) gene-altered metastatic castration-sensitive prostate cancer (mCSPC).¹

The agency issued a PDUFA target action date in the fourth quarter of 2026.

Talazoparib plus enzalutamide is currently approved in the US for patients with HRR gene-altered metastatic castration-resistant prostate cancer. The use of the combination in HRR-gene mutated mCSPC is also under regulatory review by the European Medicines Agency.

Data on talazoparib plus enzalutamide

The application is supported by data from the phase 3 TALAPRO-3 trial (NCT04821622), which were presented at the 2026 American Society of Clinical Oncology Annual Meeting and concurrently published in the New England Journal of Medicine.² The study demonstrated that talazoparib plus enzalutamide significantly reduced the risk of radiographic progression or death compared with placebo plus enzalutamide, with benefits observed across patients with BRCA and non-BRCA HRR gene alterations.

The phase 3, multicenter, double-blind TALAPRO-3 trial enrolled 599 patients with histologically or cytologically confirmed adenocarcinoma of the prostate harboring alterations in at least 1 predefined HRR gene. HRR gene alterations eligible for enrollment included mutations in ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, and RAD51C.

Participants were randomly assigned 1:1 to talazoparib 0.5 mg plus enzalutamide 160 mg once daily (n = 300) or placebo plus enzalutamide 160 mg once daily (n = 299). The primary end point was rPFS by investigator assessment, with OS as a key secondary end point.

Baseline characteristics were well balanced between arms. Approximately 35% of patients in each arm had BRCA1/2 mutations, 71% had high-volume disease, and 84% had de novo metastatic disease. The most common gene alterations were BRCA2 (30%), ATM (28%), CDK12 (19%), and CHEK2 (15%).

TALAPRO-3 met its primary end point, showing that treatment with TALA + ENZA led to a 52% reduction in the risk of radiographic progression or death vs the enzalutamide control arm (HR, 0.48; 95% CI, 0.36 to 0.65; P < .001). Median rPFS was not reached in the TALA + ENZA arm (95% CI, not reached [NR] to NR) vs 45.8 months (95% CI, 37.7 to NR) in the PBO + ENZA arm.

Subgroup analyses by BRCA mutation status demonstrated benefit in both subgroups. In the BRCA1/2-mutated subgroup, TALA + ENZA was associated with a 63% reduction in risk of radiographic progression or death (HR, 0.37; 95% CI, 0.22 to 0.61). In the non–BRCA1/2-mutated subgroup, a 43% reduction in risk was observed (HR, 0.57; 95% CI, 0.39 to 0.82).

OS data were immature at the time of analysis, but interim OS trends favored TALA + ENZA. At the time of data report, 74 deaths had occurred in the TALA + ENZA arm and 91 in the PBO + ENZA arm (HR, 0.77; 95% CI, 0.56 to 1.04).

Clinically relevant secondary end points were consistent with the primary rPFS results. Time to PSA progression significantly favored TALA + ENZA, with a 49% reduction in risk of PSA progression (HR, 0.51; 95% CI, 0.37 to 0.71). Time to subsequent antineoplastic therapy was also prolonged with TALA + ENZA (HR, 0.51; 95% CI, 0.38 to 0.70).

Grade 3 or higher adverse events (AEs) occurred in 81% of patients in the TALA + ENZA arm vs 44% in the PBO + ENZA arm. Serious AEs were reported in 42% and 32% of patients, respectively. The most common AEs (≥25% of patients) in the TALA + ENZA arm were anemia, fatigue, and decreased neutrophil count.

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