Enzalutamide and Radium-223 Combo Improves Survival in Metastatic Prostate Cancer
核心洞察
The combination of enzalutamide and radium-223 significantly improved overall survival in men with castration-resistant prostate cancer (搜索) and bone metastases.
Radiographic progression-free survival was also improved with the combination therapy compared to enzalutamide alone, 19.4 months versus 16.4 months, respectively.
The addition of radium-223 to enzalutamide led to a higher incidence of grade 3 or higher drug-related adverse events, increasing from 19% to 28%.
Men with castration-resistant prostate cancer (搜索) (CRPC) and asymptomatic or mildly symptomatic bone metastases experienced significantly longer survival when treated with a combination of enzalutamide (Xtandi) and radium-223 (Ra-223, Xofigo), according to results from the large, randomized PEACE-3 trial. The study, presented at the European Society for Medical Oncology (ESMO) congress in Barcelona, indicates a potential new first-line treatment option for these patients.
Improved Survival and Progression-Free Survival
The trial's primary endpoint, radiographic progression-free survival (rPFS), improved from a median of 16.4 months with enzalutamide alone to 19.4 months with the addition of Ra-223. Median overall survival (OS) also saw a significant increase, from 35.0 months to 42.3 months with the combination therapy.
Silke Gillessen, MD, of the Oncology Institute of Southern Switzerland in Bellinzona, stated that these results support the combination of enzalutamide plus radium-223, along with a bone-protecting agent, as a potential new first-line option for mCRPC patients with bone metastases who have not previously received an androgen receptor-pathway inhibitor.
Safety and Tolerability
While the combination therapy demonstrated improved survival outcomes, it was also associated with increased toxicity. Grade ≥3 drug-related adverse events (DRAEs) occurred more frequently in the combination arm, increasing from 19% to 28%. However, relatively few patients discontinued treatment due to DRAEs.
The most common treatment-emergent adverse event was hypertension, observed in approximately one-third of patients in each arm. Serious adverse events (AEs) and serious DRAEs also occurred more often in the combination arm (43% vs 30%, and 8% vs 1%, respectively).
Trial Design and Key Findings
The PEACE-3 trial enrolled patients with mCRPC and bone metastases who were asymptomatic or mildly symptomatic, had not received prior treatment with enzalutamide or Ra-223, and were undergoing androgen deprivation therapy (ADT). Patients were randomized to receive either single-agent enzalutamide or the combination of enzalutamide and Ra-223. A bone-protecting agent was mandated after the initial enrollment of 119 patients.
The primary analysis revealed that the addition of Ra-223 was associated with a 31% reduction in the rPFS hazard ratio (95% CI 0.54-0.87, P = 0.0009). An interim analysis of OS also demonstrated a 31% reduction in the hazard ratio with the combination therapy (95% CI 0.52-0.90, P = 0.0031), meeting the prespecified level for statistical significance (P < 0.0034).
Time to next systemic treatment was significantly prolonged in the combination arm, with 51% of patients on enzalutamide alone initiating a subsequent treatment after 24 months, compared to 30% in the combination arm (HR 0.57, 95% CI 0.44-0.75, P < 0.0001).
Expert Commentary
Karim Fizazi, MD, of the Gustave Roussy Institute in Villejuif, France, an invited discussant at ESMO, noted that the PEACE-3 trial results are potentially practice-changing, while also highlighting the need for long-term OS data and data on osteonecrosis of the jaw.
"Combining enzalutamide and radium clearly improves the primary endpoint of the trial and most likely also overall survival," said Fizazi. He emphasized the importance of prescribing a bone-protecting agent when using this combination and noted that the trial suggests that patients without bone pain may also benefit, contrasting with earlier radium-223 trials that focused on symptomatic patients.
Fizazi also stressed the importance of monitoring blood pressure in patients receiving enzalutamide and managing hypertension accordingly.
Implications for Clinical Practice
The PEACE-3 trial offers compelling evidence for the combination of enzalutamide and radium-223 as a potential first-line treatment option for men with mCRPC and bone metastases. However, clinicians should carefully consider the increased risk of adverse events and ensure appropriate monitoring and management of potential toxicities.