The FDA has granted priority review to a supplemental application for talazoparib plus enzalutamide in HRR-altered mCSPC.
The FDA has accepted for priority review a supplemental new drug application (sNDA) for talazoparib (Talzenna) plus enzalutamide (Xtandi) in men with homologous recombination repair (HRR)–gene-altered metastatic castration-sensitive prostate cancer (mCSPC).1 The FDA has set a Prescription Drug User Fee Act action date in the fourth quarter of 2026 and the application is under review by the European Medicines Agency.
The sNDA is supported by data from the phase 3 TALAPRO-3 trial (NCT04821622), in which the combination reduced the risk of radiographic progression or death by 52% vs placebo plus enzalutamide (HR, 0.48; 95% CI, 0.36-0.65; P < .0001).2 The median progression-free survival (PFS) values were not calculable (NC) and 45.8 months (95% CI, 37.7-NC), respectively.
“For men living with metastatic prostate cancer, intervening during the hormone-sensitive stage represents an important opportunity to delay progression before the disease becomes more difficult to manage,” Jeff Legos, chief oncology officer at Pfizer, said in a news release. “If approved, [talazoparib] plus [enzalutamide] would offer patients with HRR-driven disease a new treatment option that could help them live longer without their cancer progressing. The data supporting this application also reinforce the importance of biomarker testing to inform treatment decisions as early as possible.”
TALAPRO-3 was a multicenter, randomized, double-blind, placebo-controlled trial that enrolled 599 patients with mCSPC and HRR gene alterations who had received 3 months or less of androgen deprivation therapy, with or without an approved androgen receptor pathway inhibitor, in the mCSPC setting.1,2 Eligible patients had histologically confirmed prostate adenocarcinoma without neuroendocrine, small cell, or signet cell features and at least 1 HRR gene alteration per a 12-gene panel.¹
Patients were randomly assigned 1:1 to talazoparib at 0.5 mg/day (0.35 mg/day in patients with moderate renal impairment) plus enzalutamide at 160 mg/day, or to placebo plus enzalutamide at 160 mg/day. Randomization was stratified by de novo vs relapsed mCSPC, disease volume, and BRCA vs non-BRCA mutation status.²
The primary end point was investigator-assessed radiographic progression-free survival (rPFS) per RECIST 1.1 in soft tissue or PCWG3 criteria in bone.¹ Secondary end points included overall survival (OS), objective response rate, duration of response, and patient-reported outcomes.
Talazoparib plus enzalutamide showed consistent benefit across HRR gene subgroups.² In the BRCA1/2-mutated subgroup, the combination was associated with a 63% reduction in risk of radiographic progression or death (HR, 0.37; 95% CI, 0.22-0.61), and in the non-BRCA HRR-altered subgroup, a 43% reduction was observed (HR, 0.57; 95% CI, 0.39-0.82).² Interim OS data were immature but numerically favored the combination (HR, 0.77; 95% CI, 0.56-1.04).²
The safety profile of talazoparib plus enzalutamide was consistent with the known profiles of each agent individually, with no new safety signals identified.¹ Grade 3 or higher treatment-emergent adverse effects occurred more frequently with the combination than with placebo plus enzalutamide, and the most common adverse events included anemia, fatigue, and decreased neutrophil count.²
