In the final analysis of the phase III EORTC 1333/PEACE-3 trial, with a median follow-up of 58 months, the addition of radium-223 to the androgen receptor inhibitor enzalutamide significantly prolonged overall survival in patients with bone-dominant metastatic castration-resistant prostate cancer (mCRPC), researchers reported at the 2026 ASCO Genitourinary Cancers Symposium.¹ The results were concurrently published in the Annals of Oncology.²

“The combination of enzalutamide and six cycles of radium-223 demonstrated a significant overall survival benefit… Enzalutamide plus radium-223, plus a bone-protecting agent, is an option in the first-line treatment of mCRPC in patients with bone metastases,” said Enrique Gallardo, MD, of Parc Taulí University Hospital and Autonomous University of Barcelona in Spain.

Enrique Gallardo, MD

The combination reduced the risk of prostate cancer mortality by 24% (log-rank P = .0096) over enzalutamide alone and increased overall survival time by almost 6 months. The analysis confirmed the earlier benefit observed in radiographic progression-free survival, he reported.

Enzalutamide, an oral androgen receptor inhibitor, is a standard-of-care treatment in prostate cancer and the most frequently used first-line option in mCRPC. In 2013, the U.S. Food and Drug Administration approved radium-223, an α-particle–emitting agent, as treatment for mCRPC that has metastasized to the bones but not to other organs. In the primary analysis of EORTC 1333/PEACE-3,³ the combination showed a significant improvement in radiographic progression-free survival, meeting the study’s primary endpoint. The final analysis of overall survival is a key secondary endpoint and was the subject of this presentation.

Study Details

The EORTC 1333/PEACE-3 trial was a collaboration of the European Organisation for Research and Treatment of Cancer, Cancer Trials Ireland, Canadian Urological Oncology Group,Latin American Cooperative Oncology Group, and the French group GETUG/UNICANCER. The randomized study evaluated the benefit of adding a total of six cycles of radium-223 at 55 kBq/kg IV once every 4 weeks to enzalutamide 160 mg/day in 446 patients with bone metastases and asymptomatic or mildly symptomatic disease.

Results presented in September 2025 showed that the study met its primary endpoint of radiologic progression-free survival.³ In addition, the interim overall survival was 42 months vs 35 months, respectively, with enzalutamide monotherapy.

Study Results

At the final data cutoff of January 12, 2026, after a median follow-up of 58 months and 317 deaths, the median overall survival was 38 months with enzalutamide plus radium-223 compared with 32.6 months with enzalutamide alone (hazard ratio [HR], 0.76; P = .0096). Overall survival at 36 months was 54.2% and 47.4%, respectively, Dr. Gallardo reported.

Subgroup analysis showed the treatment effect was reduced in older patients (≥75 years old) (HR, 0.66 vs < 75) and was also less pronounced in patients with prior docetaxel treatment (HR, 0.94) and WHO performance status 1 (HR, 0.94), though patient subsets were small, he cautioned.

“The [Kaplan-Meier] curves crossed before 18 months, where a small number of additional deaths were observed in the combination arm, but after month 18 the benefit favored the combination arm. To try to understand this crossing, we looked at the reason for the deaths before and after 12 months,” he said.

Before 12 months, there were six additional deaths in the combination arm, four being from progressive disease. After 12 months, more deaths were observed in the enzalutamide-alone arm. At every subsequent timepoint, the benefit clearly and consistently favored the combination across almost all subgroups. No conclusion regarding the early crossover of the Kaplan-Meier curve, therefore, could be drawn, he said.

The final median radiographic progression-free survival was 19 months with enzalutamide plus radium-223 and 16 months with enzalutamide alone (HR, 0.71), with 44.1% vs 37.2%, respectively, free of radiographic progression at 24 months.“The radiographic progression-free survival results were confirmed with longer follow-up and appear little changed from the primary analysis,” he said.

Safety Summary and Study Limitations

As observed in the primary analysis, the number of grade 3 or greater treatment-emergent adverse events was greater with the combination, totaling 69.3% vs 57.6%, respectively. Hypertension was overwhelmingly the most common toxicity in both arms, reported in approximately 36% of each group. There were also 14 cases of osteonecrosis of the jaw in the combination cohort and 3 in the enzalutamide group.

Adverse events of special interest include one case each of myelodysplastic syndrome, acute myeloid leukemia, and chronic myeloid leukemia—all occurring in the combination arm.

Dr. Gallardo acknowledged a couple of study limitations. Most of the study population included patients with bone metastases who progressed after treatment with androgen-deprivation therapy (ADT) with or without chemotherapy in metastatic hormone-sensitive prostate cancer. And since the current standard of care in this setting is ADT plus an androgen receptor pathway inhibitor (ARPI) and/or docetaxel, most contemporary patients resistant to ADT will also have received an ARPI, he said. 

DISCLOSURE: Dr. Gallardo had disclosures for Advanced Accelerator Applications, AstraZeneca Spain, Bayer, Bristol-Myers Squibb, Eisai, GlaxoSmithKline, Ipsen, LEO Pharma, Pfizer, Recordati, Rovi, Sanofi, and MSD Oncology.

REFERENCES

1. Gallardo E, et al: Final overall survival results from EORTC 1333/PEACE-3. ASCO GU Cancers Symposium. Abstract 15. Presented February 26, 2026.

2. Gillessen S, et al: Final overall survival results from EORTC 1333/PEACE-3 trial of enzalutamide plus radium-223 in mCRPC. Ann Oncol 37:736-742, 2026.

3. Tambol B, et al: Enzalutamide plus radium-223 in metastatic castration-resistant prostate cancer: results of the EORTC 1333/PEACE-3 trial. Ann Oncol 36:1058-1067, 2025.

EXPERT POINT OF VIEW

Invited discussant Evan Yu, MD, Professor of Medicine and Oncology at the University of Washington and Section Head of Medical Oncology, Clinical Research Division, at Fred Hutch Cancer Center, Seattle, commented, “The data of EORTC 1333/PEACE-3 trial are very convincing, with a significant median overall survival benefit of 5.6 months with enzalutamide plus radium-223 over enzalutamide alone (HR, 0.76; P = .0096),^1,2 and I would argue the results are not surprising.”

Evan Yu, MD

“A statistically significant overall survival benefit is a difficult endpoint to achieve in clinical trials,” Dr. Yu noted, “When it is achieved, we should try very hard to figure out how to incorporate it into our practice. This requires careful determination of efficacy, balanced with safety and quality of life, and should be individualized for the patient.”

This regimen has already been incorporated into the National Comprehensive Cancer Network^® Clinical Practice Guidelines in Oncology^®, albeit limited to patients without prior treatment with an androgen receptor pathway inhibitor (ARPI), he said.

“I think the study limitations are really clinical limitations,” he said. “One can argue the patient population is not contemporary, where many patients have already received prior androgen receptor antagonists or abiraterone. It’s tough to rationalize enzalutamide plus radium-223 in patients progressing on prior ADT with enzalutamide, apalutamide or darolutamide, but if they have had prior abiraterone? Then it could be considered, since about 20% to 30% of patients still respond to enzalutamide after abiraterone,” he maintained.

“And it’s easy to say that the data are not applicable to a patient population that has received prior treatment intensification, but I would argue that radium-223 has already shown a survival benefit, and now you have the opportunity to use it in an earlier patient population,” he continued. “Recall that you can respond to enzalutamide after abiraterone.”

Additionally, another criticism has been that crossover to the combination was not permitted for patients on enzalutamide monotherapy, but Dr. Yu disagrees with this perspective. “Most of our patients don’t receive radium-223 because it’s saved for late-stage disease where patients are very symptomatic. Why would there be crossover when there is no label in the patient setting of asymptomatic mCRPC?” he questioned.

Another point often heard pertains to the possibility of overlapping toxicities when radium-223 is used early and then followed later by ¹⁷⁷Lu-PSMA-617 or chemotherapy. Data from the RALU registry³ suggest the toxicity profile is acceptable, he said.

In patients receiving enzalutamide plus radium-223, Dr. Yu emphasized giving bone-protective agents and encouraging good dental care as the incidence of osteonecrosis of the jaw was 6.4% in the study. 

DISCLOSURE: Dr.Yu had disclosures for Astellas Pharma, AstraZeneca, Bayer, Johnson & Johnson, Lantheus Medical Imaging, Merck, Novartis, and Tolmar.

REFERENCES

1. Gallardo E, Gillessen S, Choudhury A, Saad F, et al: Final overall survival results from EORTC 1333/PEACE-3: Enzalutamide with or without radium-223 in metastatic castration-resistant prostate cancer. 2026 ASCO Genitourinary Cancers Symposium. Abstract 15. Presented February 26, 2026.

2. Gillessen S, Gallardo E, Choudhury A, et al: Final overall survival results from EORTC 1333/PEACE-3 trial of enzalutamide plus radium-223 in metastatic castration-resistant prostate cancer. Ann Oncol 37:736-742, 2026.

3. Rahbar K, Essler M, Pabst KM, et al : Safety and survival outcomes of 177Lu-prostate-specific membrane antigen therapy in patients with metastatic castration-resistant prostate cancer with prior 223Ra treatment: The RALU Study. J Nucl Med 64:574-578, 2023.