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Updated data from the final analysis of the Phase III TALAPRO-2 trial (NCT03395197) show a statistically significant and clinically meaningful benefit in overall survival (OS) with the combination of Talzenna (talazoparib; Pfizer) plus Xtandi (enzalutamide; Astellas and Pfizer) in patients with metastatic castration-resistant prostate cancer (mCRPC), with or without homologous recombination repair (HRR) gene mutations.1,2 Earlier results from the trial released in October 2024 found the combination produced a statistically significant improvement in OS in patients with mCRPC regardless of mutation status, potentially establishing a new standard of care for this patient population.3
“Since its approval, Talzenna in combination with Xtandi has redefined the standard of care for those living with homologous recombination repair gene-mutated mCRPC. These latest data from TALAPRO-2 are extremely compelling, demonstrating that the combination significantly extended overall survival, in patients selected and unselected for HRR gene alterations, potentially shifting the treatment paradigm for all men living with mCRPC,” Roger Dansey, MD, chief oncology officer, Pfizer, said in a press release. “Although definitive conclusions cannot be drawn across studies, these results appear to represent the longest median overall survival reported in a randomized, controlled Phase III trial in mCRPC. We look forward to continuing to work with global authorities to potentially update the Talzenna label with these results.”1
Talzenna plus Xtandi was approved by the FDA in June 2023 to treat patients with HRR gene–mutated mCRPC. Talzenna is also indicated to treat adults with deleterious or suspected deleterious germline BRCA-mutated HER2-negative locally advanced or metastatic breast cancer.4
Xtandi has multiple approvals in prostate cancer, most recently in November 2023 to treat nonmetastatic castration-sensitive prostate cancer (nmCSPC) with biochemical recurrence at high risk for metastasis. To date, more than 300,000 patients in the United States have been prescribed Xtandi, which has demonstrated improved OS in those with mCRPC, nmCSPC, and metastatic castration-sensitive prostate cancer.5
Trial Design
The multicenter, randomized, double-blind, placebo-controlled TALAPRO-2 trial enrolled 1,035 patients with mCRPC who had not previously been administered life-prolonging systemic therapy after confirmed diagnosis of mCRPC.
Cohort 1 of the trial was comprised of all-comers (n=805), with 169 having HRR gene-mutated mCRPC and 636 who did not. Cohort 2 was comprised of patients with HRR gene mutations (n=399), which included 169 patients from Cohort 1 and 230 who were enrolled in Cohort 2. Patients with castrate testosterone levels were randomly assigned to receive Talzenna 0.5 mg/day plus Xtandi 160 mg/day or placebo plus Xtandi 160 mg/day.
The primary endpoint was radiographic progression-free survival defined in both cohorts as time from the date of randomization to first objective evidence of radiographic progression as determined by blinded independent review or death, whichever occurred first. The trial’s secondary endpoints included OS, objective response rate, duration of response, and prostate-specific antigen response.
At a median follow-up of 52.5 months, median OS in cohort 1 was 45.8 months in patients administered Talzenna plus Xtandi compared to 37.0 months in patients administered Xtandi with placebo (Hazard Ratio [HR] of 0.80; 95% Confidence Interval [CI], 0.66-0.96; p=0.015). This translates to a 20% decrease in the risk of death and an approximately nine-month improvement in median OS compared to standard of care Xtandi.
For patients in cohort 2, at a median follow-up of 44.2 months, median OS was 45.1 months in patients administered Talzenna plus Xtandi compared to 31.1 months in patients administered Xtandi with placebo (HR of 0.62; 95% CI, 0.48-0.81; p=0.0005). This translates to a 38% decrease in the risk of death and a 14-month improvement in median OS compared to standard of care Xtandi. The gain in OS among patients with HRR-mutated disease was demonstrated among those with BRCA and non-BRCA gene alterations.
“TALAPRO-2 is the first study demonstrating a significant and clinically meaningful survival benefit using a combination of PARP and androgen receptor inhibitors in mCRPC,” TALAPRO-2 global lead investigator Neeraj Agarwal, MD, FASCO, Professor and Presidential Endowed Chair of Cancer Research at Huntsman Cancer Institute, University of Utah, said in the release. “Survival rates in metastatic castration-resistant prostate cancer are poor due to the advanced and aggressive stage of the disease. Today’s results demonstrate the potential for Talzenna in combination with Xtandi to be a practice-changing treatment to help improve patient survival in mCRPC.”1
References
1. Pfizer’s TALZENNA® in Combination with XTANDI® Improves Survival Outcomes in Metastatic Castration Resistant Prostate Cancer. News release. Pfizer. February 13, 2025. Accessed February 14, 2025. https://www.pfizer.com/news/press-release/press-release-detail/pfizers-talzennar-combination-xtandir-improves-survival
2. Talazoparib+Enzalutamide vs. Enzalutamide Monotherapy in mCRPC (TALAPRO-2). ClinicalTrials.gov. Updated September 5, 2024. Accessed February 14, 2025. https://www.clinicaltrials.gov/study/NCT03395197
3. Pfizer’s TALZENNA® in Combination with XTANDI® Prolongs Overall Survival in Phase 3 TALAPRO-2 Trial. News release. Pfizer. October 10, 2024. Accessed February 14, 2025. https://www.pfizer.com/news/press-release/press-release-detail/pfizers-talzennar-combination-xtandir-prolongs-overall
4. Pfizer’s Talzenna in Combination with Xtandi Receives US FDA Approval. News release. Pfizer. June 20, 2023. Accessed February 14, 2025. https://www.pfizer.com/news/press-release/press-release-detail/pfizers-talzennar-combination-xtandir-receives-us-fda
5. Pfizer and Astellas’ XTANDI® Approved by U.S. FDA in Earlier Prostate Cancer Treatment Setting. Astellas Pharma Inc. News release. November 17, 2023. Accessed February 14, 2025. https://www.astellas.com/en/news/28626