Talzenna (talazoparib) in combination with Xtandi (enzalutamide) improves survival outcomes in metastatic castration-resistant prostate cancer – Pfizer

Pfizer Inc. announced positive results from the Phase III TALAPRO-2 study of Talzenna, an oral poly ADP-ribose polymerase (PARP) inhibitor, in combination with Xtandi (enzalutamide), an androgen receptor pathway inhibitor (ARPI), demonstrating a statistically significant and clinically meaningful improvement in overall survival (OS) compared to placebo plus Xtandi in patients with metastatic castration-resistant prostate cancer (mCRPC), with or without homologous recombination repair (HRR) gene mutations. The TALAPRO-2 results will be presented at the American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium in San Francisco and featured in the ASCO GU official Press Program.

The TALAPRO-2 study evaluated two sets of patients, unselected (cohort 1) and selected for HRR gene-mutations (cohort 2). Overall survival was a prespecified, alpha-protected key secondary endpoint. After more than four years of median follow-up (52.5 months), the median OS in cohort 1 was 45.8 months with Talzenna  in combination with Xtandi and 37.0 months with Talzenna + Xtandi and placebo (Hazard Ratio [HR] of 0.80; 95% Confidence Interval [CI], 0.66-0.96; p=0.015), representing a 20% reduction in the risk of death. This represents a nearly 9-month gain in median OS versus standard of careXtandi . Data from cohort 1 will be presented at ASCO GU in an oral presentation (Abstract LBA18) by Dr. Neeraj Agarwal, global lead investigator for TALAPRO-2.

In Cohort 2, a statistically significant and clinically meaningful improvement in OS was observed in patients with HRR-mutated mCRPC. At a median follow-up of 44.2 months, the median OS was 45.1 months with Talzenna in combination with Xtandi and 31.1 months with Xtandi and placebo (HR of 0.62; 95% CI, 0.48-0.81; p=0.0005), a 38% reduction in the risk of death. This result represents a 14-month gain in median OS versus standard of care Xtandi in a patient population with a historically poor prognosis. The OS improvement in the HRR-mutated population was observed in patients in both BRCA and non-BRCA gene alterations. Dr. Karim Fizazi, Institut Gustave Roussy, University of Paris-Saclay will share data from Cohort 2 at ASCO GU.  (Abstract LBA141).

At the time of the final analysis, updated radiographic progression free survival (rPFS) and other secondary efficacy endpoints demonstrated maintained clinical benefit in both cohorts and were consistent with the primary analyses previously reported and published in The Lancet and Nature Medicine . The safety profile of Talzenna  plus Xtandi  was generally consistent with the known safety profile of each medicine. The most common all-cause adverse events in the Talzenna group (≥30% of patients) were anemia, neutropenia, and fatigue, and the most common (≥10% of patients) grade 3–4 adverse events were anemia (49%) and neutropenia (19.3%). Adverse events were generally manageable with dose modification and supportive care.

In addition to the FDA, these data have been shared with the EMA and other global health authorities to support potential updates of the approved labels for  Talzenna.

The Phase III TALAPRO-2 trial (NCT0339519)  is a multicenter, randomized, double-blind, placebo-controlled study that enrolled 1,035 unique patients with mCRPC who had not received new life-prolonging systemic treatments after documentation of mCRPC at sites in the U.S., Canada, Europe, South America, and the Asia-Pacific region. The study included two patient cohorts: unselected (n=805, of whom 169 had HRR mutations and 636 did not) and those with HRR gene mutations (n=399, including 169 patients from Cohort 1 and 230 subsequently enrolled to comprise Cohort 2). Patients with castrate testosterone levels were randomized to receive Talzenna  0.5 mg/day plus Xtandi  160mg/day, or placebo plus Xtandi 160mg/day.

The primary endpoint of the trial was rPFS, defined as the time from the date of randomization to first objective evidence of radiographic progression by blinded independent central review (BICR), or death, whichever occurred first, in both Cohort 1 (unselected) and Cohort 2 (those with HRRm). Secondary endpoints included OS, objective response rate (ORR), duration of response (DoR), prostate-specific antigen (PSA) response, time to cytotoxic chemotherapy and PFS2.

“Since its approval, Talzenna in combination with XtandiI 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,” said Dr. Roger Dansey, Chief Oncology Officer, Pfizer. “Although definitive conclusions cannot be drawn across studies, these results appear to represent the longest median overall survival reported in a randomized, controlled Phase 3 trial in mCRPC. We look forward to continuing to work with global authorities to potentially update the Talzenna label with these results.”

“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,” said Dr. Neeraj Agarwal, Huntsman Cancer Institute, University of Utah, and global lead investigator for TALAPRO-2. “Survival rates in metastatic castration-resistant prostate cancer are poor due to the advanced and aggressive stage of the disease. The results demonstrate the potential for Talzenna in combination with Xtandi to be a practice-changing treatment to help improve patient survival in mCRPC.”

See citations- Agarwal N, Azad AA, Carles J, Fay AP et al.  Talazoparib plus enzalutamide in men with first- line metastatic castration resistant prostate cancer (TALAPRO-2) a randomised placebo-controlled phase III trial.  Lancet. 2023, 402:291 https://doi.org/10.1016/S0140-6736(23)01055-3..

Fizazi, K., Azad, A.A., Matsubara, N. et al. First-line talazoparib with enzalutamide in HRR-deficient metastatic castration-resistant prostate cancer: the phase 3 TALAPRO-2 trial. Nat Med 2024, 30,:257 (https://doi.org/10.1038/s41591-023-02704-x