FDA Grants Priority Review to Talazoparib Plus Enzalutamide for HRR-Altered mCSPC

The FDA accepted a supplemental new drug application (sNDA) for talazoparib (Talzenna), an oral PARP inhibitor, in combination with enzalutamide (Xtandi), an androgen receptor pathway inhibitor (ARPI), for patients with homologous recombination repair (HRR) gene-altered metastatic castration-sensitive prostate cancer (mCSPC), according to a news release from Pfizer. The FDA has set a Prescription Drug User Fee Act action date for the priority review in the fourth quarter of 2026.¹

Talazoparib plus enzalutamide is currently approved in the United States for men with HRR gene-mutated metastatic castration-resistant prostate cancer (mCRPC). If approved, the sNDA would expand the combination's indication to mCSPC, an earlier stage of disease; the combination is also under review by the European Medicines Agency for this earlier-stage indication.

Supporting Trial Data

The application is supported by data from the phase 3 TALAPRO-3 trial (NCT04821622), a multicenter, randomized, double-blind, placebo-controlled study that enrolled 599 patients with mCSPC who had received 3 months or less of androgen deprivation therapy, with or without an approved ARPI, at sites across the United States, Canada, Europe, South America, and the Asia-Pacific region. Eligible patients had histologically or cytologically confirmed prostate adenocarcinoma without neuroendocrine, small cell, or signet cell features, along with alterations in 1 or more HRR genes per a 12-gene HRR panel.

Patients were randomly assigned to receive talazoparib 0.5 mg/day plus enzalutamide 160 mg/day or placebo plus enzalutamide 160 mg/day. The primary end point is investigator-assessed radiographic progression-free survival (rPFS) defined per RECIST v1.1 for soft tissue and Prostate Cancer Working Group 3 criteria for bone; secondary end points include overall survival, objective response rate, duration of response, and patient-reported outcomes.

According to Pfizer, talazoparib plus enzalutamide reduced the risk of radiographic progression or death by 52% compared with placebo plus enzalutamide, with consistent benefit across patients with BRCA and non-BRCA HRR gene alterations and had a safety profile consistent with the known profiles of each individual agent, with no new safety signals identified. These results were presented at the 2026 American Society of Clinical Oncology Annual Meeting and simultaneously published in The New England Journal of Medicine.^2,3

At a median follow-up of 37.6 months in the experimental arm and 37.7 months in the comparator arm, the median rPFS was not reached vs 45.8 months, respectively (HR, 0.481; 95% CI, 0.357-0.647; P <.0001). The rPFS benefit was consistent regardless of BRCA status, and there was a strong trend toward improved overall survival (HR, 0.767; 95% CI, 0.564-1.044; P =.0905), a key secondary end point, though those survival data remained immature at approximately 41 months’ follow-up.

Common adverse events with the combination included anemia, fatigue, neutropenia, asthenia, and leukopenia, and serious adverse events were reported in 42% of patients with the combination vs 32% with enzalutamide and placebo.

Disease Background and Significance

Approximately 5% to 10% of newly diagnosed prostate cancer cases are mCSPC, and up to 30% of these patients harbor HRR gene alterations.⁴

“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,” said Jeff Legos, PhD, MBA, chief oncology officer at Pfizer, in the 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.”¹

REFERENCES

1. FDA Grants Priority Review for Pfizer’s TALZENNA Plus XTANDI for the Treatment of Metastatic Prostate Cancer. News release. Pfizer. July 23, 2026. Accessed July 23, 2026. https://tinyurl.com/ms7ufmfc

2. Agarwal N, Matsubara N, Azad AA, et al. TALAPRO-3: Talazoparib (TALA) + enzalutamide (ENZA) compared with placebo (PBO) + ENZA for the treatment of patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) harboring homologous recombination repair (HRR) gene alterations. J Clin Oncol. 2026;44(suppl 17):LBA5007.

3. Agarwal N, Matsubara N, Azad AA, et al. PARP and androgen-signaling inhibition plus ADT in metastatic prostate cancer. N Engl J Med. Published online May 30, 2026. doi:10.1056/NEJMoa2604126

4. Olmos D, Lorente D, Jambrina A, et al. BRCA1/2 and homologous recombination repair alterations in high- and low-volume metastatic hormone-sensitive prostate cancer: prevalence and impact on outcomes. Ann Oncol. 2025;36:1190-202. doi:10.1016/j.annonc.2025.05.534