The landscape of metastatic castration-resistant prostate cancer (mCRPC) treatment has been significantly advanced with new data from the phase 3 TALAPRO-2 trial, demonstrating superior outcomes for the combination of talazoparib and enzalutamide compared to enzalutamide monotherapy.
Landmark Overall Survival Benefits
The combination therapy achieved a median overall survival of 45.8 months compared to 37.0 months with enzalutamide alone, representing a 20.4% reduction in mortality risk (HR=0.796; 95% CI, 0.661-0.958; P=0.0155). This 8.8-month improvement in survival marks a significant milestone in mCRPC treatment.
Particularly noteworthy was the enhanced benefit observed in patients with homologous recombination repair (HRR)-deficient tumors, who experienced a remarkable 14-month survival advantage. In this subgroup, median overall survival reached 45.1 months with the combination therapy, compared to 31.1 months with enzalutamide alone (HR=0.622; P=0.0005).
Subgroup Analysis and Biomarker Findings
The trial revealed compelling outcomes across various genetic subgroups. Patients with BRCA1/2 alterations showed particularly impressive results, with median overall survival not reached in the combination arm compared to 28.5 months in the control group (HR=0.497; P=0.0017). Even patients without detected HRR alterations demonstrated benefit, with a median overall survival of 46.6 months versus 37.4 months in the control arm.
Disease Progression and Clinical Impact
The study's primary endpoint of radiographic progression-free survival (rPFS) showed significant improvement, with the combination therapy achieving a median of 33.1 months compared to 19.5 months with enzalutamide alone (HR=0.667; P<0.0001). In HRR-deficient patients, this benefit was even more pronounced, with rPFS reaching 30.7 months versus 12.3 months.
Safety Profile and Quality of Life
Dr. Neeraj Agarwal, director of the Genitourinary Oncology Program at Huntsman Cancer Institute, emphasized the trial's significance: "TALAPRO-2 is the first PARP inhibitor plus ARPI combination study to show not only a statistically significant but also a clinically meaningful improvement in overall survival."
While grade 3/4 anemia emerged as the primary adverse event, affecting 49% of patients in the unselected population, it proved manageable through dose adjustments. The discontinuation rate due to adverse events was 21.6%, with anemia accounting for 8.5% of discontinuations. Importantly, patients maintained their quality of life throughout the extended treatment duration.
Trial Design and Patient Population
TALAPRO-2, a double-blind, placebo-controlled study, enrolled 805 patients, randomized to receive either talazoparib (0.5 mg) with enzalutamide (160 mg daily) or placebo with enzalutamide. All patients underwent prospective tumor tissue testing, with 20% found to have HRR alterations. BRCA1/2 mutations were present in approximately 7% of patients.
The FDA's approval of the talazoparib/enzalutamide combination in June 2023 for HRR gene-mutant mCRPC was based on earlier data showing a 55% reduction in disease progression or death risk. These updated results further validate and strengthen the combination's position in the treatment paradigm for mCRPC.
