Final overall survival results from EORTC 1333/PEACE-3 trial of enzalutamide plus radium-223 in metastatic castration-resistant prostate cancer

BACKGROUND: The primary analysis of the European Organisation for Research and Treatment of Cancer (EORTC) 1333/PEACE-3 study demonstrated that enzalutamide plus radium-223 (Ra223) improved radiological progression-free survival (rPFS) compared with enzalutamide alone in patients with metastatic castration-resistant prostate cancer (mCRPC). The primary endpoint was rPFS, while overall survival (OS) was a key secondary endpoint. Interim OS results were reported at the time of primary analysis. Here, we report the final OS analysis. PATIENTS AND METHODS: From November 2015 to March 2023, 446 patients were randomly assigned to receive enzalutamide alone or enzalutamide combined with six cycles of Ra223. Co-administration of bone-protecting agents (BPAs) became mandatory for all patients from March 2018. Final analysis of OS was triggered on 1 May 2025. RESULTS: With a median follow-up of 58 months and 317 reported deaths, the hazard ratio (HR) was 0.76 [95% confidence interval (CI) 0.60-0.96, P = 0.0096] for OS in favor of the enzalutamide + Ra223 arm, reaching the predefined level of statistical significance of <0.0248. Median OS was 32.6 months (95% CI 29.3-38.2 months) in the enzalutamide arm (n = 224) and 38.2 months (95% CI 33.1-44.8 months) in the combination arm (n = 222). The HR for rPFS was 0.71 (95% CI 0.57-0.89). Grade ≥3 treatment-emergent adverse events (TEAEs) increased from 57.6% to 69.3% in the combination arm, as did treatment-related grade ≥3 TEAEs (18.8% versus 28.9%), with the most frequent being hypertension. CONCLUSIONS: The final analysis of this study confirmed that the combination of enzalutamide with Ra223 significantly improved not only rPFS but also OS as first-line therapy for mCRPC versus enzalutamide alone. Co-administration of a BPA is required to reduce skeletal complications.