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

Int J Urol. 2026 Feb;33(2):e70376. doi: 10.1111/iju.70376.

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.

Keywords: enzalutamide; metastatic castration‐resistant prostate cancer; non‐proportional hazards; radium‐223; shiny method.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Antineoplastic Combined Chemotherapy Protocols* / therapeutic use
  • Benzamides / therapeutic use
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Nitriles
  • Phenylthiohydantoin* / administration & dosage
  • Phenylthiohydantoin* / analogs & derivatives
  • Phenylthiohydantoin* / therapeutic use
  • Prostatic Neoplasms, Castration-Resistant* / drug therapy
  • Prostatic Neoplasms, Castration-Resistant* / mortality
  • Prostatic Neoplasms, Castration-Resistant* / pathology
  • Prostatic Neoplasms, Castration-Resistant* / therapy
  • Radium* / administration & dosage
  • Radium* / therapeutic use
  • Time Factors
  • Treatment Outcome

Substances

  • enzalutamide
  • Benzamides
  • Nitriles
  • Phenylthiohydantoin
  • Radium
  • Radium-223