Final analysis confirms enzalutamide/radium-223 survival advantage in PEACE-3

Final overall survival (OS) results from the EORTC 1333/PEACE-3 trial (NCT02194842) show that adding radium-223 (Xofigo) to enzalutamide (Xtandi) significantly improves OS and radiographic progression-free survival (rPFS) in patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases, with a manageable increase in toxicity.¹

Describing the background for the study, presenting author Enrique Gallardo, MD, of Parc Tauli Sabadell Hospital Universitari in Sabadell, Spain, explained that enzalutamide and radium-223 have each demonstrated efficacy individually in the treatment of mCRPC.^2,3

“The primary analysis of the PEACE-3 trial showed that enzalutamide plus radium-223 demonstrated a significant improvement in radiographic progression-free survival as the primary objective. This was supported by a significantly improved overall survival in an interim analysis. Also, the combination was associated with moderate increased toxicity,” Gallardo said.⁴ At ASCO GU 2026, Gallardo presented the final OS data from the study.

Patients with mCRPC and bone metastases who were asymptomatic or mildly symptomatic, had an WHO Performance Status of 0 or 1, had not received prior treatment with either agent, had no known visceral metastases, and were receiving ongoing androgen deprivation therapy were eligible for inclusion in the study. A total of 446 patients were randomly assigned 1:1 to receive enzalutamide 160 mg once daily plus radium-223 55 kBq/kg intravenously every 4 weeks for 6 cycles, or enzalutamide 160 mg once daily. The primary end point was rPFS, and secondary end points included OS, time to next treatment, time to pain progression, time to first symptomatic skeletal event, as well as treatment-emergent Common Terminology Criteria for Adverse Events. The inclusion of bone-protecting agents in the study was made mandatory following the inclusion of the first 119 patients.

Median patient age was 70 years in both treatment arms. A nearly identical number of patients in both the enzalutamide/radium-223 arm and enzalutamide-only arm had received prior docetaxel (153 and 154 patients, respectively). The cohorts also had a similar rate of prior abiraterone acetate (Zytiga) use at 67 and 66 patients respectively. Gallardo also noted that in each cohort, more than 40% of patients had at least 10 bone lesions.

Median follow-up was 4.8 years. “At the time of the final analysis, 317 patients had died, 152 in the combination arm, [and] 165 in the control arm,” Gallardo said. Progression of disease accounted for the deaths of 72% of patients in each cohort. The investigators reported no drug-related deaths.

Median OS for the enzalutamide/radium-223 group was 38.21 months (95% CI, 33.08-44.75) and 32.62 months (95% CI, 29.31-38.24) in the enzalutamide-only arm (HR: 0.76; 95% CI, 0.60-0.96; logrank 1-sided P = .0096). Subgroup analysis of final OS data indicated that treatment effect is reduced in patients 75 years of age or older (HR for patients younger than 75: 0.66; HR for patients 75 or older: 1.01).

Final rPFS data showed a median rPFS of 19.19 months (95% CI, 16.92-24.57; HR: 0.71 [95% CI: 0.57-0.89]) in the enzalutamide/radium-223 arm vs 16.43 months (95% CI, 13.77-19.15; HR: Reference) in the enzalutamide-only arm.

“Regarding safety, there was a moderate increase in toxicity for the combination arm,” Gallardo said. Sixty-three (28.9%) grade 3-5 drug-related treatment-emergent adverse events (TEAEs) were observed in the enzalutamide/radium-223 arm vs 42 (18.8%) in the enzalutamide-only arm. In the enzalutamide/radium-223 arm, there were 12 (5.5%) discontinuations of enzalutamide due to toxicity and 7 (3.2%) discontinuations of radium-223 due to toxicity. In the enzalutamide-only arm, there were 12 (5.4%) discontinuations due to toxicity.

The most common grade 3 or higher TEAE in either arm was hypertension, occurring in 78 (35.8%) patients in the enzalutamide/radium-223 arm and 80 (35.7%) patients in the enzalutamide-only arm. Gallardo also noted that there were 17 total cases of osteonecrosis of the jaw; 14 of these occurred in the enzalutamide/radium-223 group, and 5 cases were grade 5. The remaining 3 cases occurred in the enzalutamide-only arm.

“With a medium follow-up of 58 months and a data lock in January 2026, the combination of enzalutamide and 6 cycles of radium-223 demonstrated a statistically significant and clinically meaningful benefit in overall survival, with a hazard ratio of 0.76 and a median overall survival gain of 5.6 months, with a logrank P-value of .0096. The improvement in radiographic progression-free survival is confirmed with this longer follow-up, and the safety profile observed a moderate but manageable increase in toxicity for the combination. Based on this, enzalutamide plus radium-223 is an option in first-line treatment for mCRPC patients with bone metastases. The use of a bone-protecting should be a standard of care for metastatic CRPC patients,” Gallardo concluded.

REFERENCES

1. Gallardo E, Tombal BF, Choudhury A, et al. Final overall survival results from the EORTC 1333/PEACE-3 trial: Enzalutamide with or without radium-223 in metastatic castration-resistant prostate cancer. Presented at: 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium. February 26-28, 2026. San Francisco, California. Abstract 15. https://meetings.asco.org/meetings/2026-asco-genitourinary-cancers-symposium/334/16923?presentation=256832

2. Raval AD, Chen G, Korn MJ, Bernthaler A, Constantinovici N, Freedland SJ. Real-world treatment patterns and survival in people with metastatic castration-resistant prostate cancer following metastatic hormone-sensitive disease between 2020 and 2023 in the United States. Clin Genitourin Cancer. 2025;23(5):102386. doi:10.1016/j.clgc.2025.102386

3. 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):213-23. doi:10.1056/NEJMoa1213755

4. Tombal B, Choudhury A, Saad F, et al. Enzalutamide plus radium-223 in metastatic castration-resistant prostate cancer: results of the EORTC 1333/PEACE-3 trial. Ann Oncol. 2025;36(9):1058-1067. doi:10.1016/j.annonc.2025.05.011