What question did this study set out to answer?

To characterize time-dependent treatment effects of enzalutamide plus radium-223 in metastatic castration-resistant prostate cancer.

February 11, 2026

Delayed Survival Benefit of Enzalutamide Plus Radium‐223 in Metastatic Castration‐Resistant Prostate Cancer: A Time‐Dependent Analysis of Reconstructed Individual Patient Data From the PEACE ‐3 Trial

Key Points

To characterize time-dependent treatment effects of enzalutamide plus radium-223 in metastatic castration-resistant prostate cancer.
Reconstructed individual patient data from Kaplan-Meier curves of the PEACE-3 trial.
Evaluated treatment effects using restricted mean survival time analysis.
Applied time-dependent Cox regression with treatment-by-time interaction.
Conducted piecewise Cox regression across six time intervals.
Implemented landmark analyses and Fleming-Harrington weighted log-rank tests.
Initial 18 months showed no survival advantage (RMST difference: −0.36 months, p = 0.20).
Increased hazard observed during the first 18 months (HR = 2.14, p < 0.001).
Significant survival benefits noted beyond 60 months with RMST differences of 4.34 months (p = 0.03) at 60 months.
At 72 months, the survival advantage was 6.25 months (p = 0.01).
Piecewise analysis revealed the greatest benefit between 60-72 months (HR = 0.20, p = 0.02).

Abstract

ABSTRACT Background and Objective 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. Methods 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. Results 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. Conclusions 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. of the Study/Trial Not applicable.

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