Adding the PARP inhibitor talazoparib (Talzenna) to enzalutamide (Xtandi) improved radiographic progression-free survival (rPFS) versus enzalutamide alone in patients with metastatic castration-resistant prostate cancer (mCRPC), regardless of homologous recombination repair (HRR) gene mutation status, according to topline results from the phase 3 TALAPRO-2 trial.1
The study met its primary endpoint, as the hazard ratio for rPFS exceeded the pre-specified threshold of 0.696, meaning the combination reduced the risk of disease progression or death by at least 30.4% versus enzalutamide alone.
The talazoparib/enzalutamide combination was also shown to have benefits in key secondary end points, including prostate specific antigen (PSA) response, time to PSA progression, and overall response rate (ORR). Although overall survival (OS) data from TALAPRO-2 trial remain immature, there was a trend toward an OS improvement with the combination observed at the time of the analysis.
Overall the 2-part, 2-cohort, multicenter, double-blind TALAPRO-2 trial (NCT03395197) enrolled 1095 patients with systemic therapy–naïve mCRPC at clinical sites in the United States, Canada, Europe, South America, and the Asia-Pacific region. The study included an all-comer cohort of 750 patients and a HRR mutation–positive cohort of 380 patients. Patients were randomized to enzalutamide at 160 mg/day plus either talazoparib at 0.5 mg/day or placebo.
The trial remains ongoing for the HRR mutation–positive cohort. At the time of the analysis, there were no new safety signals with talazoparib or enzalutamide compared with those previously reported.
Pfizer, which develops both study treatments, reported in a press release that it intends to submit the TALAPRO-2 findings for presentation at an upcoming medical meeting.
“Xtandi is a global standard of care, with overall survival demonstrated in mCRPC, non-metastatic CRPC, and metastatic castration-sensitive prostate cancer (mCSPC),” Chris Boshoff, MD, PhD, chief development officer, Oncology and Rare Disease, Pfizer Global Product Development, stated in the press release. “We are very pleased with the strong findings from TALAPRO-2, and although no definitive conclusions can be made across trials, the rPFS appears to be the longest observed in a randomized trial in this setting. These data highlight the potential for Talzenna in combination with Xtandi, if approved, to become a new standard of care for mCRPC, irrespective of HRR gene mutation status. We look forward to discussing these data with global health authorities.”
Previously reported data from the phase 2 TALAPRO-1 trial showed antitumor activity with single-agent in patients with heavily pretreated mCRPC that harbored DNA damage response (DDR)-HRR gene alterations.2
In the study, patients received at least 1 dose of 1 mg daily of oral talazoparib at 43 medical facilities around the globe. Patients were previously treated with at least 1 taxane-based chemotherapy, as well as abiraterone acetate (Zytiga)/prednisone, enzalutamide, or both hormonal agents.
All patients had at least 1 HHR gene alteration from a panel of 11 genes likely to sensitize their tumor to PARP inhibition: ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C.
At a median follow-up of 16.4 months (interquartile range, 11.1-22.1), the ORR was 29.8% (95% CI, 21.2%-39.6%) among 104 evaluable patients. Antitumor effects were most notable in patients with BRCA1/2 mutations, with a confirmed ORR of 45.9% and a median rPFS of 11.2 months.
In the safety analysis of 127 patients, the most common grade 3/4 treatment-emergent adverse events (TEAEs) were anemia (31%), thrombocytopenia (9%), and neutropenia (8%). Investigators observed serious TEAEs in 34% of patients. There were no treatment-related deaths.
Other study from the TALAPRO program,the phase 3 TALAPRO-3 study (NCT04821622), is evaluating the combination of talazoparib and enzalutamide in patients with DDR gene–mutated mCSPC.
1. Pfizer Announces Positive Topline Results from Phase 3 TALAPRO-2 Trial. Published online and accessed October 4, 2022. https://bit.ly/3SQBHn2
2. de Bono JS, Mehra N, Scagliotti GV, et al. Talazoparib monotherapy in metastatic castration-resistant prostate cancer with DNA repair alterations (TALAPRO-1): an open-label, phase 2 trial. Lancet Oncol. 2021;22(9):1250-1264. doi:10.1016/S1470-2045(21)00376-4