Talazoparib/Enzalutamide Shows Improved Radiographic PFS in Metastatic Castration-Sensitive Prostate Cancer

Topline results from the phase 3 TALAPRO-3 trial (NCT04821622) evaluating talazoparib (Talzenna) and enzalutamide (Xtandi) vs placebo plus enzalutamide resulted in improvement in radiographic progression-free survival (rPFS) in patients with homologous recombination repair (HRR) gene-mutated metastatic castration-sensitive prostate cancer (mCSPC), according to a release from the manufacturer.¹ The observed hazard ratio exceeded the prespecified target of 0.63, and the majority of enrolled patients remained progression-free at the time of the interim analysis. Consistent efficacy benefit was observed across patients with both BRCA and non-BRCA HRR gene alterations, supporting the applicability of these findings across the broader HRR-mutated population.

At the time of the interim analysis, results showed a strong trend toward improved overall survival (OS), a key secondary end point. Additional secondary end points also favored the talazoparib and enzalutamide arm, including overall response rate (ORR), duration of response (DOR), and time to PSA progression.

Current treatment approaches leave many patients with HRR gene-mutated metastatic castration-sensitive prostate cancer vulnerable to early disease progression,” Neeraj Agarwal, MD, FASCO, professor and presidential endowed chair of cancer research at Huntsman Cancer Institute at the University of Utah, and global lead investigator for TALAPRO-3, said in the release.¹ “The TALAPRO-3 results demonstrate that treatment with Talzenna in combination with [enzalutamide] earlier in the disease course significantly extends the time patients can live without their cancer worsening.”

Trial Design

TALAPRO-3 is a multicenter, randomized, double-blind, placebo-controlled Phase 3 trial that enrolled 599 patients with mCSPC across sites in the United States, Canada, Europe, South America, and the Asia-Pacific region. Eligible patients had histologically or cytologically confirmed prostatic adenocarcinoma without neuroendocrine differentiation, small cell, or signet cell features, and had received no more than 3 months of androgen deprivation therapy (ADT) with or without an approved androgen receptor pathway inhibitor (ARPI) in the mCSPC setting.

Patients were required to have alterations in one or more HRR genes per the HRR12 gene panel and were randomly assigned to talazoparib 0.5 mg/day plus enzalutamide 160 mg/day, or placebo plus enzalutamide 160 mg/day.²

The primary end point was investigator-assessed rPFS, defined as time from randomization to radiographic progression in soft tissue per RECIST v1.1 or in bone per PCWG3 criteria, or death, whichever occurred first. Secondary end points included OS, ORR, DOR, PSA response, and patient-reported outcomes.

Safety

The safety profile of the combination was consistent with the known profiles of each individual agent. No new safety signals were identified in this patient population

Talazoparib is an oral PARP inhibitor. Preclinical studies have demonstrated that talazoparib blocks PARP enzyme activity and traps PARP at the site of DNA damage, resulting in decreased cancer cell growth and cancer cell death.

“Alterations in DNA damage repair genes, such as HRR genes, are found in approximately 25% of metastatic prostate cancers and associated with a worse prognosis and are less responsive to current standards of care, representing a group with a high unmet need,” Jeff Legos, chief oncology officer, Pfizer said in the release.¹ “[Talazoparib] plus [enzalutamide] is already a standard of care in HRR gene-mutated metastatic castration-resistant prostate cancer, and these results demonstrate the potential to deliver benefit earlier in the disease course.”

REFERENCES

1. TALZENNA Plus XTANDI Significantly Improves Radiographic Progression-Free Survival in Metastatic Prostate Cancer. News release. March 19, 2026. Accessed March 19, 2026. https://tinyurl.com/539e6k6m

2. Study of Talazoparib With Enzalutamide in Men With DDR Gene Mutated mCSPC. Clinicaltrials.gov. https://clinicaltrials.gov/study/NCT04821622