The combination of radium-223 (Xofigo) and enzalutamide (Xtandi) has shown a statistically significant improvement in radiological progression-free survival (rPFS) and overall survival (OS) for patients with metastatic castration-resistant prostate cancer (mCRPC) that has spread to the bones. The findings come from the phase 3 PEACE-3 trial (NCT02194842), presented at the 2024 ESMO Congress. The study also emphasized the necessity of using bone-protecting agents in conjunction with this combination therapy.
Silke Gillessen, MD, a medical oncologist at Università della Svizzera Italiana, noted, "These results support the combination of enzalutamide plus Radium-223, plus a bone protecting agent, as a potential new first line mCRPC treatment option for patients with prostate cancer and bone metastases who have not received a prior androgen-receptor pathway inhibitor."
Efficacy Outcomes
The trial randomized 446 patients with mCRPC and bone metastases to receive either radium-223 plus enzalutamide (n = 222) or enzalutamide alone (n = 224). The median rPFS was 19.4 months (95% CI, 17.1-25.3) in the combination arm compared to 16.4 months (95% CI, 13.8-19.2) in the monotherapy arm, demonstrating a significant improvement (HR, 0.69; 95% CI, 0.54-0.87; log-rank P = .0009). The 24-month rPFS rates were 45% and 36%, respectively.
An interim analysis, with 80% of OS events reported, showed a median OS of 42.3 months (95% CI, 36.8-49.1) in the combination arm versus 35.0 months (95% CI, 28.8-38.9) in the enzalutamide arm (HR, 0.69; 95% CI, 0.52-0.90; log-rank P = .0031).
Time to next systemic treatment (TTNT) was also significantly prolonged in the combination arm (HR, 0.57; 95% CI, 0.44-0.75; P < .0001). However, no significant differences were observed in time to pain progression or time to first symptomatic skeletal event (SSE).
Trial Design and Patient Population
The global PEACE-3 study enrolled patients from 12 countries with mCRPC and bone metastases who were receiving androgen deprivation therapy. Patients had to have a WHO performance score of 0 or 1 and asymptomatic or mildly symptomatic disease. Prior treatment with radium-223 or enzalutamide was not allowed, and patients with known visceral metastases were excluded.
Patients were randomized 1:1 and stratified by country, baseline pain, prior docetaxel use, prior abiraterone use, and use of bone-protecting agents. After the initial enrollment of 119 patients, the use of bone-protecting agents became mandatory.
Both arms received enzalutamide 160 mg once daily, while the combination arm also received radium-223 at 55 kBq/kg intravenously every 4 weeks for 6 cycles. The primary endpoint was rPFS, with key secondary endpoints including safety, OS, TTNT, time to pain progression, and time to first SSE.
Safety Profile
The safety analysis revealed that 84% of patients in the radium-223 plus enzalutamide arm experienced drug-related adverse events (AEs) compared to 71% in the enzalutamide monotherapy arm. Serious AEs occurred in 43% and 30% of patients, respectively. Grade 3 to 5 AEs were more frequent in the combination arm (66%) than in the monotherapy arm (56%).
Treatment discontinuation rates due to toxicity were 11% in the combination arm and 7% in the monotherapy arm. Common grade 3 to 5 treatment-emergent AEs included hypertension, fatigue, fracture, anemia, and neutropenia. Seven patients in the combination arm died due to an AE, compared to four in the monotherapy arm; none of these deaths were drug-related.
Expert Commentary
Karim Fizazi, MD, PhD, a medical oncologist at Institute Gustave Roussy, commented on the findings, stating, "In general, before using this combination fully in our patients, I believe we need more data." He also noted that data from other phase 3 trials evaluating radium-223 are currently maturing.
