The primary analysis of the EORTC 1333/PEACE-3 study demonstrated that enzalutamide plus radium-223 (Ra223) improved radiological progression-free survival (rPFS) compared to 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 overall survival (OS) results were reported at time of primary analysis. Here, we report the final overall survival (OS) analysis.

From November 2015 to March 2023, 446 patients were randomised to receive enzalutamide alone or enzalutamide combined with six cycles of Ra223. Co-administration of bone-protecting agents (BPA) became mandatory for all patients from March 2018. Final analysis of OS was triggered on 1 May 2025.

With a median follow-up of 58 months and 317 reported deaths, the hazard ratio (HR) was 0.76 [95% CI 0.60-0.96, p=0.0096] for OS in favour 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) in the enzalutamide arm (n=224) and 38.2 months (95%CI 33.1-44.8) in the combination arm (n=222). The HR for rPFS was 0.71 (95% 0.57-0.89). Treatment-emergent grade ≥3 adverse events increased from 57.6% to 69.3% in the combination arm, as did treatment-related grade ≥3 TEAEs (18.8% vs 28.9%), the most frequent being hypertension.

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 bone-protecting agent is required to reduce skeletal complications.