The PEACE-3 trial demonstrated overall survival benefit for enzalutamide plus radium-223 versus enzalutamide alone in metastatic castration-resistant prostate cancer (mCRPC), but survival curves showed initial crossing followed by progressive separation, indicating non-proportional hazards. We aimed to characterize the time-dependent treatment effects through comprehensive analysis.
Individual patient datas (IPD) were reconstructed from published Kaplan-Meier curves of the PEACE-3 trial. Time-dependent treatment effects were evaluated by restricted mean survival time (RMST) analysis at predefined time points (18-72 months), time-dependent Cox regression with treatment-by-time interaction, piecewise Cox regression across 6 time intervals, landmark analyses, and Fleming-Harrington weighted log-rank tests.
A total of 446 IPDs were reconstructed. Validation confirmed consistency with the original trial. During the initial 18 months, combination therapy showed no survival advantage (RMST difference: -0.36 months, 95% CI, -0.90 to 0.18, p = 0.20) and was associated with increased hazard (HR = 2.14, 95% CI, 1.48-3.10, p < 0.001). Significant survival benefits were observed after 60 months, with RMST differences of 4.34 months (95% CI, 0.49-8.19, p = 0.03) at 60 months and 6.25 months (95% CI, 1.56-10.95, p = 0.01) at 72 months. Time-dependent Cox regression confirmed a significant treatment-by-time interaction (p < 0.01). Piecewise analysis revealed the most substantial benefit for 60-72 months (HR = 0.20, 95% CI, 0.05-0.77, p = 0.02). Landmark analyses consistently demonstrated increasing treatment benefit with longer follow-up.
Enzalutamide plus radium-223 demonstrates delayed but substantial survival benefit in mCRPC, becoming statistically significant after 60 months with over 6 months survival advantage at 72 months. REGISTRY AND THE REGISTRATION NO.
Not applicable.
International journal of urology : official journal of the Japanese Urological Association. 2026 Feb [Epub]
Wei Chen, Soichiro Yoshida, Shugo Yajima, Kenji Tanabe, Motohiro Fujiwara, Hiroshi Fukushima, Hajime Tanaka, Akihiro Hirakawa, Hitoshi Masuda, Yasuhisa Fujii
Department of Urology, Institute of Science Tokyo, Tokyo, Japan., Department of Urology, National Cancer Center Hospital East, Chiba, Japan., Department of Urology, Teikyo University Hospital, Kawasaki, Japan., Department of Clinical Biostatistics, Institute of Science Tokyo, Tokyo, Japan.