Enzalutamide Plus Radium-223 Extends OS in Bone-Predominant mCRPC

According to final data from the phase 3 EORTC 1333/PEACE-3 trial (NCT02194842), enzalutamide (Xtandi) in combination with radium-223 significantly prolonged overall survival (OS) among patients with metastatic castration-resistant prostate cancer (mCRPC) with bone metastases.¹

Results were presented by Enrique Gallardo, MD, at the 2026 ASCO Genitourinary Cancers Symposium.

The combination of enzalutamide plus radium-223 significantly improved OS compared with enzalutamide alone. The median OS was 38.21 months (95% CI, 33.08-44.75) with the combination vs 32.62 months (95% CI, 29.31-38.24) for enzalutamide alone (HR, 0.76; one-sided log-rank P =.0096).

Findings also confirmed a durable improvement in radiographic progression-free survival (rPFS) with manageable toxicity in the combination arm, supporting enzalutamide plus radium-223 as a valid first-line treatment option for patients with bone-predominant mCRPC.

“The combination of enzalutamide and 6 cycles of radium-223 demonstrated a significant [OS] benefit, confirming the previously reported improvement in [rPFS], with a moderate increase in adverse events [AEs],” Gallardo, of the Parc Taulí Hospital Universitar, said during his presentation.

Background: EORTC 1333/PEACE-3 trial

Enzalutamide and radium-223 independently have shown OS benefit in mCRPC, leading to the hypothesis that combining these agents could provide complementary mechanisms of action and enhanced outcomes. Earlier analyses from the PEACE-3 trial, reported at previous ESMO Congresses and published in Annals of Oncology, demonstrated that enzalutamide plus radium-223 significantly improved rPFS compared with enzalutamide alone. Notably, the combination led to a moderate increase in toxicity.

The current presentation updates these findings with final OS data as a key prespecified secondary end point.

Trial Design and Methods

PEACE-3 was a multicenter, randomized, open-label phase 3 trial conducted across 56 centers in 12 countries, enrolling patients with asymptomatic or mildly symptomatic mCRPC with bone metastases and no visceral disease. Patients were randomized 1:1 to receive 160 mg of enzalutamide once daily plus 55Bq/kg of IV radium-223 every 4 weeks for 6 cycles (n = 222) or 160 mg of enzalutamide once daily alone (n = 224). Stratification factors included country, baseline pain, prior docetaxel use, use of bone-targeting agents, and prior abiraterone therapy. After March 2018, bone-protecting agents were mandated due to fracture risk data.

From November 2015 to March 2023, 446 patients were enrolled. Median age was 70 years across both treatment arms. In total, 30.2% of patients in the enzalutamide combination arm had received prior docetaxel compared with 30.0% in the enzalutamide alone arm; 2% of patients in the combination arm received prior abiraterone (Zytiga) vs 3% with enzalutamide alone. In the combination arm, 42% of patients had 10 or more bone lesions vs 44% in the singlet arm; for patients with less than 10 bone lesions, these numbers were 49% and 47%, respectively. Additionally, 35% vs 33% of patients in each group had extra-skeletal disease at baseline.

The median follow-up for the final OS analysis was 4.8 years.

Efficacy Findings

At the time of final analysis, 317 deaths had occurred: 152 in the combination arm and 165 in the singlet arm. Progression of disease was the primary cause of death in both arms (72.4% vs 72.1%). Other causes of death were listed as cardiovascular disease (4.6%; 4.8%), non-malignant disease (0%; 1.8%), new malignancy not associated with prostate cancer (1.3%; 1.2%), other (9.2%; 9.5%), and unknown (11.8%; 13.3%). No drug-related deaths were reported.

Survival rates for the combination and singlet therapy at each time point were as follows:

1. 6-month survival rates were 96.8% (95% CI, 93.5-98.5) and 99.1% (96.5-99.8), respectively.
2. 12-month survival rates were 90.5% (95% CI, 85.9-93.7) and 92.9% (88.6-95.6), respectively.
3. 18-month survival rates were 81.1% (95% CI, 75.3-85.6) and 80.8% (74.9-85.3), respectively.
4. 24-month survival rates were 71.1% (95% CI, 64.7-76.6) and 67.7% (61.2-73.4), respectively.
5. 36-month survival rates were 54.2% (95% CI, 47.1-60.6) and 47.4% (40.6-54.0), respectively.

Gallardo noted that, “The survival curves crossed around month 18, with a small number of early deaths in the combination arm, but after 18 months, the benefit clearly favored the combination.”

Subgroup analyses showed consistent OS benefit across most populations, though less pronounced in older patients (< 75 years old: HR, 0.66; ≥ 75 years old: HR, 1.01), those with prior docetaxel exposure, or with poorer performance status.

The previously reported rPFS improvement was confirmed with longer follow-up, with median rPFS of 19.19 months (95% CI, 16.92-24.57) in the combination arm vs 16.43 months (95% CI, 13.77-19.15) for enzalutamide alone (HR, 0.71), demonstrating the durability of benefit for the combination arm.

Safety Profile

Treatment with enzalutamide plus radium-223 was associated with a moderate increase in toxicity. Treatment-emergent AEs (TEAEs) occurred in 100% of the combination group and 97.8% of the singlet; drug-related TEAEs occurred in 83.0% and 71.4% of patients, respectively; serious TEAEs occurred in 49.1% and 32.6% of patients, respectively; serious drug-related TEAEs occurred in 10.6% and 1.3% of patients; grade 3 to 5 TEAEs occurred in 69.3% and 57.6% of patients; and grade 3 to 5 drug-related AEs occurred in 28.9% and 18.8% of patients, respectively.

Death rates due to drug-related AEs were 4.6% in the combination arm and 2.7% in the singlet arm.

Discontinuation rates due to toxicity were low for both treatments.

“Hypertension was the most common grade 3 to 5 AE in both arms,” Gallardo reported. “We observed modest increases in fatigue, fractures, anemia, and neutropenia, but importantly, no individual grade 3 to 5 AE increased by more than 5% in the combination arm.”

Three cases of hematologic malignancies were reported in the combination arm (one case of myelodysplastic syndrome, one of acute myeloid leukemia, and one of chronic myelomonocytic leukemia), along with 14 cases of osteonecrosis compared with 5 in the control arm, five of which were grade 3.

Overall, the safety findings support the combination as manageable for appropriately selected patients.

Additional Findings and Limitations

While the combination provides meaningful survival benefit, the trial population primarily included patients previously treated with androgen deprivation therapy (ADT) alone or in combination with chemotherapy, which represents a limitation for the study.

Gallardo concluded by stating: “With a median follow-up of 58 months, enzalutamide plus six cycles of radium-223 demonstrated statistically significant and clinically meaningful OS benefit with a median gain of 5.6 months and a one-sided P value of .0096. The improvement in rPFS is confirmed, and the safety profile shows a moderate but manageable increase in toxicity. Based on these results, this combination represents a first-line option for patients with mCRPC with bone metastases, in conjunction with a bone-protecting agent as standard of care.”

REFERENCE

1. Gallardo E, Gillessen S, 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. J Clin Oncol. 2026;44(suppl 7):15. doi:10.1200/JCO.2026.44.7_suppl.15.