Enzalutamide plus radium-223 boosts OS in mCRPC

Adding enzalutamide to radium-223 significantly improves overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) compared with enzalutamide alone, according to the phase III EORTC 1333/PEACE-3 trial presented at ASCO GU 2026.

“The combination of enzalutamide and six cycles of radium-223 demonstrated a significant OS benefit and confirmed the previously reported improvement in radiographic progression-free survival (rPFS),” said study author Dr Enrique Gallardo from Park Taulí Hospital Universitari in Sabadell, Spain.

The PEACE-3 trial involved 446 patients (median age 70 years) with mCRPC and ≥2 bone metastases who had previously been treated with docetaxel (30 percent) and abiraterone (3 percent). Participants were randomized in a 1:1 ratio to receive enzalutamide 160 mg daily plus radium-223 55 kBq/kg Q4W for six cycles (n=222) or enzalutamide alone (n=224).

According to Gallardo, as of March 2018, the mandatory use of bone-protecting agents was implemented in response to concerns regarding fracture risk.

At the time of the final analysis (database locked on January 12, 2026), 317 deaths were documented, with 152 patients in the combination arm and 165 patients in the enzalutamide alone arm.

Final OS results

At a median follow-up of 58 months, patients who received enzalutamide plus radium-223 achieved a significant improvement in OS compared with those treated with enzalutamide alone (median 38.21 vs 32.62 months; hazard ratio [HR], 0.76; one-sided p=0.0096). [ASCO GU 2026, abstract 15]

At 36 months, 54.2 percent of patients in the combination arm remained alive compared with 47.4 percent of those in the enzalutamide monotherapy arm. Notably, as early as 12 months, “the benefit clearly and consistently favoured the combination arm,” said Gallardo.

The OS benefit observed with enzalutamide plus radium-223 was consistent across all subgroups. However, the treatment effect was less pronounced in older patients (≥75 years) and in those with prior docetaxel exposure and WHO performance status 1.

Final rPFS results

This longer follow-up confirmed the improvement in rPFS, with a median rPFS of 19.19 months in the combination arm vs 16.43 months in the enzalutamide-alone arm (HR, 0.71), consistent with the findings from the primary analysis.

Gallardo noted that this finding supports the durability of the benefits of the enzalutamide and radium-223 combination therapy.

Safety

In terms of safety, grade 3–5 drug-related treatment-emergent adverse events (TEAEs) occurred more frequently in the combination arm than in the enzalutamide-only arm (28.9 percent vs 18.8 percent), with hypertension being the most common TEAE (69.3 percent vs 57.6 percent).

There was also a slight increase in the frequency of drug-related fatigue (4.1 percent vs 1.4 percent), anaemia (2.8 percent vs 0 percent), and neutropenia (3.2 percent vs 0 percent) in patients receiving enzalutamide plus radium-223 compared with those receiving enzalutamide alone, although Gallardo emphasized that no individual AE increased >5 percent.

No drug-related deaths were observed in either group, and treatment discontinuation rates due to toxicity were low (5.5 percent for enzalutamide plus radium-223 and 5.4 percent for enzalutamide alone).

As Gallardo noted, although TEAEs were moderately increased in the combination arm, they were manageable.

Overall, the combination of enzalutamide and radium-223 with a bone-protecting agent is an option for first-line treatment of mCRPC patients with bone metastases and should be considered as the standard of care for this patient population, Gallardo concluded.