The addition of Radium-223 (Xofigo) to enzalutamide (Xtandi) significantly improves radiological progression-free survival (rPFS) and overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) and predominant bone metastases. These findings come from the phase 3 PEACE-3 trial (NCT02194842), presented at the 2024 ESMO Congress. The study also emphasized the necessity of using a bone-protecting agent when using this combination.
Silke Gillessen, MD, a medical oncologist at Università della Svizzera italiana in Lugano, Switzerland, stated that the results support the combination of enzalutamide plus Radium-223, along with a bone-protecting agent, as a potential new first-line mCRPC treatment option for patients with prostate cancer and bone metastases who have not previously received an androgen-receptor pathway inhibitor.
Improved rPFS and OS
The PEACE-3 trial showed a statistically significant improvement in the primary endpoint of rPFS in patients who received Radium-223 plus enzalutamide (n = 222) compared to those who received enzalutamide alone (n = 224). The median rPFS was 19.4 months (95% CI, 17.1-25.3) in the combination arm versus 16.4 months (95% CI, 13.8-19.2) in the monotherapy arm (HR, 0.69; 95% CI, 0.54-0.87; log-rank P = .0009). The 24-month rPFS rates were 45% and 36%, respectively. Gillessen noted that the treatment effect on rPFS with the doublet versus monotherapy was consistent across all subgroups analyzed.
At the interim analysis, with 80% of OS events having occurred, the median OS was 42.3 months (95% CI, 36.8-49.1) in the Radium-223 plus enzalutamide 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).
Gillessen stated that the hazard ratio for OS was also 0.69 with a statistically significant positive P value. Due to the non-proportional hazards, it was recommended to continue to the final OS analysis to confirm the observed treatment effect. Time to next systemic treatment (TTNT) was also statistically significantly prolonged in the combination arm compared to the monotherapy arm (HR, 0.57; 95% CI, 0.44-0.75; P < .0001).
Trial Design and Patient Characteristics
The global PEACE-3 study enrolled patients from 12 countries with mCRPC and bone metastases who were receiving androgen deprivation therapy. Patients were required 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 permitted, and patients with known visceral metastases were excluded.
Patients were randomized 1:1 and stratified by country, baseline pain, prior use of docetaxel, prior use of abiraterone, and use of bone-protecting agents. After 119 patients were enrolled, the use of bone-protecting agents became mandatory.
Patients received enzalutamide 160 mg once daily in both arms. Those in the combination arm also received Radium-223 at 55 kBq/kg intravenously every 4 weeks for 6 cycles. The primary endpoint was rPFS, and key secondary endpoints included safety, OS, TTNT, time to pain progression, and time to first symptomatic skeletal event (SSE).
The median age of patients enrolled was 70.0 years in both arms. Baseline patient characteristics were generally well balanced.
Time to Pain Progression and SSE
While patients experienced a significant improvement in TTNT with the combination of Radium-223 plus enzalutamide, there was no difference in time to pain progression or time to SSE. The high percentage of patients receiving bone-protecting agents in both arms, due to the amendment, likely influenced these outcomes.
Safety Profile
Safety data revealed that 84% of patients in the Radium-223 plus enzalutamide arm experienced drug-related adverse effects (AEs), compared to 71% in the enzalutamide monotherapy arm. The combination arm also saw higher rates of serious AEs (43% vs 30%), serious drug-related AEs (8% vs 1%), grade 3 to 5 AEs (66% vs 56%), and grade 3 to 5 drug-related AEs (28% vs 19%).
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.
Karim Fizazi, MD, PhD, a medical oncologist at Institute Gustave Roussy in Villejuif, France, emphasized the need for more data before fully implementing this combination in clinical practice, noting that data from more phase 3 trials evaluating Radium-223 are currently maturing. He also highlighted that the treatment should be viewed as a "quadruplet" comprising enzalutamide, radium-223, a bone-protecting agent (denosumab or zoledronate), and androgen-deprivation therapy, with potential hypertension treatment for some patients.
