PEACE-3 (EORTC 1333)

ERA 223 combined radium-223 with abiraterone and produced more fractures and more deaths, and the trial was unblinded early. PEACE-3 is the trial that tested the same idea properly, with enzalutamide instead of abiraterone and, from March 2018, with bone-protecting agents made mandatory for every participant.

From November 2015 to March 2023, 446 men were randomly assigned to enzalutamide alone (224) or enzalutamide with six cycles of radium-223 (222). The final overall survival analysis was triggered on 1 May 2025.

With a median follow-up of 58 months and 317 deaths, the hazard ratio for overall survival was 0.76 (95 percent confidence interval 0.60 to 0.96, p=0.0096), crossing the predefined significance level of 0.0248. Median overall survival was 32.6 months (29.3 to 38.2) with enzalutamide alone and 38.2 months (33.1 to 44.8) with the combination. The hazard ratio for radiological progression-free survival, the primary endpoint, was 0.71 (0.57 to 0.89).

The combination costs toxicity. Grade 3 or worse treatment-emergent adverse events rose from 57.6 to 69.3 percent and treatment-related grade 3 or worse events from 18.8 to 28.9 percent, most frequently hypertension. The trial's own conclusion is that co-administration of a bone-protecting agent is required.

PEACE-3 is the rare case of a field going back to a combination that harmed people, working out why, fixing it and proving it works.