Enzalutamide plus radium-223 in metastatic castration-resistant prostate cancer: results of the EORTC 1333/PEACE-3 trial

BACKGROUND: The EORTC 1333 'PEACE-3' study investigated the combination of enzalutamide and 6 monthly injections of radium-223 (Ra223) in patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases. MATERIALS AND METHODS: From November 2015 to March 2023, 446 patients, including 11 who received abiraterone, were randomized to enzalutamide (without placebo) or enzalutamide combined with six cycles of Ra223. As of March 2018, the co-administration of zoledronic acid or denosumab was mandatory. The primary endpoint was radiological progression-free survival (rPFS) by investigator assessment. Key secondary endpoints included overall survival (OS), time to subsequent systemic treatment, pain progression, and symptomatic skeletal event. RESULTS: The hazard ratio (HR) for rPFS was 0.69 [95% confidence interval (CI) 0.54-0.87, P = 0.0009], with a median rPFS of 16.4 months (95% CI 13.8-19.2 months) in the enzalutamide arm and 19.4 months (95% CI 17.1-25.3 months) in the combination arm. At the preplanned interim analysis conducted at 80% of the OS events, the HR for OS was 0.69 (95% CI 0.52-0.90, P = 0.0031), with a median OS of 35.0 months (95% CI 28.8-38.9 months) in the enzalutamide arm and 42.3 months (95% CI 36.8-49.1 months) in the combination arm. Due to non-proportional hazards, this will be tested further at the final OS analysis. Treatment-emergent adverse events (TEAEs) ≥ grade 3 were recorded in 55.8% and 65.6% of the patients in the enzalutamide and combination arms, respectively. The most frequent grade ≥3 TEAEs in the combination arm were hypertension (34%), fatigue (6%), fracture (5%), anemia (5%), and neutropenia (5%). Fractures [either treatment-emergent or post-treatment, symptomatic or pathologic, or with or without bone-protecting agent (BPA) use] were reported in 30 (13.4%) patients in the enzalutamide arm and 53 patients (24.3%) in the combination arm. CONCLUSION: PEACE-3 demonstrates that combining enzalutamide with Ra223 as first-line therapy for mCRPC significantly improves rPFS. Although statistically significant at the OS interim boundary, the study will continue to the final OS analysis.