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Talazoparib plus enzalutamide significantly increased radiographic progression-free survival compared with placebo plus enzalutamide in men with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC), according to results of the phase 3 TALAPRO-3 trial.

Increased overall survival was associated with the combination treatment in an interim analysis of the same trial, but the difference was not statistically significant (hazard ratio [HR], 0.77). 

“These results support the use of talazoparib and enzalutamide as a potential treatment option for patients with HRR-gene-altered mCRPC,” said lead author Neeraj Agarwal, MD, while presenting the findings of TALAPRO-3 at the American Society of Clinical Oncology (ASCO) 2026. The results were simultaneously published in The New England Journal of Medicine. 

Background and Set Up

The research builds on the previous TALAPRO-2 trial that demonstrated the addition of the PARP inhibitor t alazoparib to the androgen receptor pathway inhibitor enzalutamide significantly improved radiographic progression-free survival (rPFS) and overall survival in men with mCRPC. Participants who were HRR-deficient reaped the greatest benefit. 

The TALAPRO-3 safety and efficacy trial evaluates this subgroup further. Researchers randomly assigned 300 participants to 0.5 mg talazoparib (0.35 mg if moderate renal impairment) plus 160 mg enzalutamide once daily and another 299 men to placebo plus 160 mg enzalutamide once daily. Participants also had one or more of these HRR gene alterations: ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, or RAD51C.

Inclusion criteria included ECOG performance status 0 or 1, ongoing androgen deprivation therapy, and no prior treatment with docetaxel. The study’s primary endpoint was rPFS and overall survival was the secondary endpoint. 

Survival Outcomes

At a median follow-up of almost 38 months, the talazoparib + enzalutamide group experienced significantly improved rPFS compared with the placebo plus enzalutamide group (HR, 0.48; 2-sided P < .0001). Median rPFS was not reached in the combination treatment group vs 46 months in the active control group.

Agarwal and colleagues stratified participants by BRCA vs non-BRCA mutational status , de novo vs relapsed disease, and high-volume vs low-volume disease.

The hazard ratio for rPFS was 0.37 in the 35% of participants with BRCA-mutations and 0.57 in the 65% of participants with a non-BRCA-mutated status.

“A consistent treatment effect for rPFS was observed across prespecified subgroups by tumor and disease characteristics, including the stratification factors,” said Agarwal, professor of medicine and the presidential endowed chair of cancer research at the University of Utah’s Huntsman Cancer Institute in Salt Lake City. 

There were 74 deaths in the combination treatment group vs 91 deaths in the placebo plus enzalutamide group.

Safety Findings

No new safety signals were identified in the study.

The most common all-grade treatment-related adverse events (TEAE) in the combination treatment group was anemia in 71%. In response to a question from a meeting attendee, Agarwal explained the trial criteria required patients develop grade 3 or 4 anemia before treating it. In his practice, however, he monitors blood work earlier, starting treatment when people show signs of developing anemia.

Other TEAEs seen in the combination group included fatigue in 28%, neutrophil count decreases in 27%, neutropenia in 22%, asthenia in 21%, and white blood cell count decreases in 21%.

A total of 56 participants (18.7%) discontinued talazoparib because of TEAEs.

Outside Perspectives

“TALAPRO-3 reinforces an androgen receptor pathway inhibitor plus a PARP inhibitor as standard of care for patients with BRCA 1/2 mCSPC [metastatic castration-sensitive prostate cancer],” said invited commenter David Olmos, MD, PhD. 

Select patients with non-BRCA HRR defects may also benefit from the combination of enzalutamide plus talazoparib, added Olmos, a medical oncologist at the Biomedical Research Institute at Instituto de Investigacion Hospital 12 de Octubre in Madrid, Spain. 

Olmos noted that 5 patients in the combination treatment group developed myelodysplastic syndrome or acute myeloid leukemia vs 1 in the comparator arm. He added that the use of a PARP inhibitor and an androgen receptor pathway inhibitor in mCSPC “should be biomarker-driven and based on a balance of benefit vs tolerability.”

Asked by Medscape Medical News to comment, session co-moderator Laura S. Graham, MD , said, “This is a potentially practice-changing trial showing robust activity of talazoparib/enzalutamide in patients with HRR-mutated APMN/S [androgen pathway modulation naive or sensitive] prostate cancer, especially in patients with BRCA-mutated tumors.” 

“Interestingly, there was also activity for patients with CDK12 and ATM mutations, which has not been shown in other PARP inhibitor/ARP inhibitor combinations,” added Graham, director of clinical genitourinary research and assistant professor at the University of Colorado in Aurora. “Limitations in applicability include the lack of docetaxel in the study with a high proportion of high volume/high-risk patients, as well as the relatively low uptake of post-protocol PARP inhibitor use in patients on the placebo arm.” 

The study was funded by Pfizer. Astellas Pharma provided enzalutamide. 

Agarwal disclosed that he receives travel, accommodations, and expenses from Exelixis and Pfizer, and that his institution receives research funding from Amgen, Arvinas, AstraZeneca, Bayer, Bristol-Myers Squibb, Calithera Biosciences, Celldex, CRISPR Therapeutics, Eisai, Exelixis, Genentech, Gilead Sciences, Immunomedics, Janssen, Lilly, Merck, Nektar, ORIC Pharmaceuticals, Pfizer, and Takeda. 

Olmos disclosed he is a consultant or advisor for AstraZeneca, Bayer, Janssen, Merck Serono, MSD Oncology, and Pfizer; receives travel, accommodations, and expenses from AstraZeneca Spain, Bayer, and Janssen; and that his institution receives research funding from Johnson & Johnson/Janssen and Pfizer. 

Damian McNamara is a freelance contributor to Medscape Medical News. He worked full-time for Medscape and WebMD from 2018 to 2024. Damian has a BA in chemistry and an MA in science, health, and environmental reporting/journalism.