Enzalutamide/Radium-223 Extends Survival in mCRPC

A clinically menaingful improvement in overall survival (OS) was observed when patients with metastatic castration-resistant prostate cancer were treated with enzalutamide (Xtandi) plus radium-223 (Xofigo), according to results from the phase 3 EORTC 1333/PEACE-3 trial (NCT02194842) presented at the 2026 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium.

Moreover, 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 overall survival benefit, confirming the previously reported improvement in radiographic progression-free survival, with a moderate increase in adverse events [AEs],” Enrique Gallardo, MD, of the Parc Taulí Hospital Universitar, said during his presentation.

The combination of enzalutamide plus radium-223 significantly improved OS compared with enzalutamide alone. The median OS was 38.21 months (with the combination vs 32.62 months for enzalutamide alone.

PEACE-3 Trial Design and Methods

PEACE-3 was a multicenter, randomized, open-label phase 3 trial conducted across 56 centers in 12 countries. It enrolled patients with asymptomatic or mildly symptomatic mCRPC with bone metastases and no visceral disease. Patients were randomly assigned 1:1 to receive 160 mg of enzalutamide once daily plus 55 Bq/kg of intravenous 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 chemotherapy with docetaxel, 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. The median age was 70 years across both treatment arms. In the combination arm, 30% of patients had received prior docetaxel compared with 30% in the enzalutamide-alone arm. Two percent 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 compared with 44% in the single-agent arm; for patients with fewer 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 single-agent arm. Disease progression was the primary cause of death in both arms (72% in each group). Other causes included cardiovascular disease (4.6% vs 4.8%), non-malignant disease (0% vs 1.8%), new malignancy not related to prostate cancer (1.3% vs 1.2%), other causes (9.2% vs 9.5%), and unknown causes (11.8% vs 13.3%). No drug-related deaths were reported.

Survival rates for the combination and single-agent therapy at key time points were as follows: 6-month survival was 97% and 99%, 12-month survival was 91% and 93%, 18-month survival was 81% and 81%, 24-month survival was 71% and 68%, and 36-month survival was 54% and 47%, respectively.

Gallardo noted, “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 it was less pronounced in older patients, those with prior docetaxel exposure, or those with poorer performance status. The previously reported rPFS improvement was confirmed with longer follow-up, with median rPFS of 19.2 months in the combination arm versus 16.4 months for enzalutamide alone, demonstrating the durability of benefit for the combination.

Safety Profile of Enzalutamide plus Radium-223

Treatment with enzalutamide plus radium-223 was associated with a moderate increase in adverse effects (AEs). Treatment-emergent AEs occurred in nearly all patients in both groups, with drug-related AES reported in most patients. Serious AEs occurred in approximately half of patients in the combination group compared with one-third in the single-agent group. Grade 3 to 5 AEs occurred in 69% of patients in the combination arm and 58% in the single-agent arm. Deaths due to drug-related AEs were rare, 4.6% in the combination arm vs 2.7% in the single-agent arm. Discontinuation due to toxicity was low in both groups.

“Hypertension was the most common severe AEs in both arms,” Gallardo reported. “We observed modest increases in fatigue, fractures, anemia, and low white blood cell counts, but no individual severe AEs increased by more than 5% in the combination arm.” Three cases of blood cancers were reported in the combination arm, along with 14 cases of osteonecrosis compared with 5 in the control arm, five of which were severe. Overall, the safety findings support the combination as manageable for appropriately selected patients.

Additional Findings and Limitations

While the combination provided meaningful survival benefit, the trial population primarily included patients previously treated with androgen deprivation therapy alone or in combination with chemotherapy, which represents a limitation.

Gallardo concluded, “With a median follow-up of nearly 5 years, enzalutamide plus 6 cycles of radium-223 demonstrated clinically meaningful OS benefit with a median gain of 5.6 months. 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

Gallardo E, Tombal BF, Saad F, 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