BACKGROUND Radium-223 prolongs overall survival and delays symptomatic skeletal events (SSEs) in patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases. The approved radium-223 regimen is 55 kBq/kg every 4 weeks (q4w) for six cycles (standard dose). We investigated different radium-223 regimens in patients with mCRPC. PATIENTS AND METHODS Patients were randomised 1 : 1 : 1 to radium-223 standard-dose, high-dose (88 kBq/kg q4w for six cycles) or extended-schedule arms (55 kBq/kg q4w for 12 cycles). The primary end point, SSE-free survival (SSE-FS), was compared in patients treated with a high- versus standard-dose regimen, or with a standard dose in an extended (>6 to 12 cycles) versus standard schedule (six cycles). RESULTS A total of 391 patients were randomised; baseline characteristics were balanced between arms. On-treatment SSEs developed in 37/130 (28%), 42/130 (32%) and 48/131 (37%) patients in the standard-dose, high-dose and extended-schedule arms, respectively. There was no statistically significant difference in SSE-FS in the high- versus standard-dose arms [median 12.9 months versus 12.3 months; hazard ratio (HR) 1.06, 80% confidence interval (CI) 0.88-1.27, P = 0.70], and in the extended- versus standard-schedule arms (median 10.8 months versus 13.2 months; HR 1.26, 80% CI 0.94-1.69, P = 0.31). Overall survival in the three treatment arms was similar. As many as 370 (95%) patients received treatment (median of six cycles) in each arm. Grade ≥3 treatment-emergent adverse events (TEAEs) affected 34% of patients in the standard-dose, 48% in the high-dose and 53% in the extended-schedule arm, causing permanent discontinuation in 9%, 16% and 17% of patients, respectively. CONCLUSION Radium-223 high-dose or extended-schedule regimens resulted in no change in SSE-FS or other efficacy end points and were associated with more grade ≥3 TEAEs. The extended-schedule regimen (beyond six doses) could not be implemented in a large proportion of patients due to disease progression. Therefore, the standard-dose schedule remains one of the standard therapies for patients with symptomatic mCRPC. TRIAL REGISTRATION ClinicalTrials.govNCT02023697.

中文翻译：

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一项针对骨转移性去势抵抗性前列腺癌患者的三种镭 223 给药方案的随机 II 期试验。

背景 Radium-223 可延长转移性去势抵抗性前列腺癌 (mCRPC) 和骨转移患者的总生存期并延迟症状性骨骼事件 (SSE)。批准的镭 223 方案是每 4 周 (q4w) 55 kBq/kg，共 6 个周期（标准剂量）。我们研究了 mCRPC 患者的不同镭 223 方案。患者和方法 患者以 1:1:1 的比例随机分配到镭 223 标准剂量、高剂量（88 kBq/kg q4w 六个周期）或扩展计划组（55 kBq/kg q4w 共 12 个周期）。主要终点，无 SSE 生存期 (SSE-FS)，在接受高剂量方案治疗的患者与标准剂量方案或延长标准剂量（>6 至 12 个周期）与标准方案（6循环）。结果 共有 391 名患者被随机分组​​；各组之间的基线特征是平衡的。在标准剂量组、高剂量组和延长计划组中，分别有 37/130 (28%)、42/130 (32%) 和 48/131 (37%) 名患者出现了治疗中的 SSE。高剂量组和标准剂量组的 SSE-FS 没有统计学上的显着差异[中位数 12.9 个月对 12.3 个月；风险比 (HR) 1.06, 80% 置信区间 (CI) 0.88-1.27, P = 0.70]，并且在扩展与标准计划组中（中位数 10.8 个月与 13.2 个月；HR 1.26, 80% CI 0.94-1.69 , P = 0.31)。三个治疗组的总生存期相似。每组多达 370 名 (95%) 患者接受了治疗（中位数为 6 个周期）。34% 的标准剂量患者、48% 的高剂量患者和 53% 的延长计划组患者发生 3 级以上治疗出现的不良事件 (TEAE)，分别导致 9%、16% 和 17% 的患者永久停药。结论 Radium-223 高剂量或延长计划方案导致 SSE-FS 或其他疗效终点没有变化，并且与更多的 3 级 TEAE 相关。由于疾病进展，大部分患者无法实施延长计划方案（超过六剂）。因此，标准剂量方案仍然是症状性 mCRPC 患者的标准疗法之一。试验注册 ClinicalTrials.govNCT02023697。由于疾病进展，大部分患者无法实施延长计划方案（超过六剂）。因此，标准剂量方案仍然是症状性 mCRPC 患者的标准疗法之一。试验注册 ClinicalTrials.govNCT02023697。由于疾病进展，大部分患者无法实施延长计划方案（超过六剂）。因此，标准剂量方案仍然是症状性 mCRPC 患者的标准疗法之一。试验注册 ClinicalTrials.govNCT02023697。