(UroToday.com) The 2025 South Central AUA annual meeting included a session on prostate cancer, featuring a presentation from Michael Cookson, MD, FACS, MMHC, discussing PEACE-III, assessing enzalutamide versus a combination of radium-223 and enzalutamide in asymptomatic/mildly symptomatic patients with bone metastatic castration-resistant prostate cancer (mCRPC). Abiraterone and enzalutamide are standard of care options for the first line treatment of patients with mCRPC progressing on androgen deprivation therapy.
On the other hand, radium-223 dichloride is an alpha particle-emitting calcium mimetic that selectively targets bone metastases and induces double-stranded DNA breaks. In the ALSYMPCA trial, radium-223 improved overall survival (HR: 0.7) in a treatment era prior to the introduction of abiraterone and enzalutamide.1
EORTC-GUCG 1333 (PEACE-III) is a prospective phase III trial of mCRPC patients with bone metastases who were asymptomatic or mildly symptomatic. Eligible patients had not received prior enzalutamide or radium-223 and had no known visceral metastases. Prior treatment with abiraterone and docetaxel in the hormone-sensitive setting was permissible. Study participants underwent 1:1 randomization to:
- Experimental arm: radium-223 55 kBq/kg intravenously every 4 weeks for 6 cycles + enzalutamide 160 mg orally once daily
- Control arm: Enzalutamide 160 mg orally once daily
The primary endpoint was radiographic progression-free survival. Key secondary endpoints included:
- Safety
- Overall survival
- Time to next treatment
- Time to pain progression
- Time to first symptomatic skeletal event
Given the increased rate of skeletal fractures reported in the ERA-223 trial,2 a study amendment was introduced following the enrollment of the initial 119 patients to mandate the use of bone-protecting agents:
Between November 2015 and March 2023, 446 patients were enrolled from 12 countries. The median study follow-up was 42.2 months. The median patient age was 70, the median PSA was 23–25 ng/ml, ~30% of patients had received prior docetaxel in the hormone-sensitive setting, and only 2–3% had received prior abiraterone:
Of the 222 patients in the radium-223 + enzalutamide arm, 215 (97%) received both treatments. Of the patients who received radium-223, 88% completed all 6 planned cycles:
The addition of radium-223 to enzalutamide was associated with significant improvement in the primary endpoint of radiographic progression-free survival (median: 19.4 versus 16.4 months; HR 0.69, 95% CI 0.54–0.87, p = 0.0009). At 24 months, 45% of patients in the radium-223 combination arm were free of radiographic progression, compared to 36% of patients in the enzalutamide monotherapy arm:
An overall survival benefit was observed with a combination radium-223 + enzalutamide. The median overall survival was 42.3 months versus 35 months for enzalutamide monotherapy (HR 0.69, 95% CI 0.52–0.90, p = 0.0031). While the p-value was below the pre-specified α threshold of 0.0034, there was evidence of non-proportional hazards (i.e., the curves cross during initial follow-up). Given this plus the lack of unequivocal significance for restricted mean survival time sensitivity analysis, the study will continue to the final overall survival analysis:
From a safety standpoint, grade ≥3 drug-related adverse events were observed in 28% and 19% of patients in the experimental and control arms, respectively. Deaths due to adverse events were observed in 3% and 2% of patients, respectively, none specifically related to the drugs used:
The most common grade ≥3 adverse events in the radium-223 + enzalutamide arm were hypertension (34%), fatigue (5.5%), and fractures (5.1%):
Dr. Cookson concluded his presentation discussing PEACE-III with the following take home points:
- In PEACE-III, 6 cycles of radium-223 in combination with enzalutamide as first-line therapy significantly improved radiographic progression free survival in patients with mCRPC
- This interim analysis demonstrated a statistically significant overall survival benefit favoring the combination of radium-223 with enzalutamide
- A final overall survival analysis will be performed to further confirm these results
Presenter: Michael Cookson, MD, FACS, MMHC, University of Oklahoma Medical Center, Oklahoma City, OK
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2025 South Central American Urological Association (AUA) Annual Meeting, Orlando, FL, Wed, Sept 10 – Sat, Sept 13, 2025.
References:
- Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013;369(3):213-223.
- Smith M, Parker C, Saad F, et al. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): A randomized, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2019 Mar;20(3):408-419.