Cabozantinib Versus Mitoxantrone-prednisone in Symptomatic Metastatic Castration-resistant Prostate Cancer: A Randomized Phase 3 Trial with a Primary Pain Endpoint
Cabozantinib Versus Mitoxantrone-prednisone in Symptomatic Metastatic Castration-resistant Prostate Cancer: A Randomized Phase 3 Trial with a Primary Pain Endpoint
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DOI：
10.1016/j.eururo.2018.11.033
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发表时间：
2019-06-01
期刊：
影响因子：
23.4
通讯作者：
Scher, Howard, I
中科院分区：
文献类型：
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作者：
Basch, Ethan M.;Scholz, Mark;Scher, Howard, I
背景：转移性去势抵抗性前列腺癌 (mCRPC) 患者的骨转移与衰弱性疼痛和功能损害相关。目的：使用患者报告的结果指标，比较卡博替尼与米托蒽醌-泼尼松作为主要终点的疼痛缓解作用，用于治疗患有 mCRPC 和症状性骨转移的男性患者。设计、设置和受试者：一项随机、双盲 3 期试验 (COMET-2； NCT01522443) 患有 mCRPC 和骨转移麻醉依赖性疼痛且在多西紫杉醇联合阿比特龙或恩杂鲁胺治疗后病情进展的男性。干预：卡博替尼 60 mg 每日一次口服对比米托蒽醌 12 mg/m(2) 每 3 周加泼尼松 5 mg 每日两次口服。结果测量和统计分析：主要终点是疼痛反应第 6 周在第 12 周得到确认（在不增加麻醉剂使用的情况下，患者通过简短疼痛清单报告的平均每日最严重疼痛评分较基线下降 >= 30%）。计划的样本量为 246，以实现 >= 90% 的功效。结果和限制：入组提前终止，因为卡博替尼在配套的 COMET-1 试验中没有表现出任何生存获益。研究结束时，119 名参与者被随机分配（卡博替尼：N = 61；米托蒽醌-泼尼松：N = 58）。 73/106 (69%) 患者在基线、第 6 周和第 12 周获得了完整的疼痛和麻醉药物使用数据。卡博替尼与米托蒽醌-泼尼松的疼痛反应没有显着差异：反应者比例分别为 15% 和 17%，差异为 -2%（95% 置信区间：-16% 至 11%，p = 0.8）。累积障碍包括对先前抗癌治疗的清除期的预处理要求以及最大化镇痛剂量的麻醉剂优化期。结论：对于经过大量预处理的 mCRPC 和有症状骨转移的患者，卡博替尼治疗并未表现出比米托蒽醌-泼尼松更好的疼痛缓解效果。未来的镇痛试验应包括从入组到开始治疗的更短的时间线。 患者总结：对于去势抵抗性前列腺癌患者的疼痛缓解和骨转移引起的衰弱性疼痛，卡博替尼并不比米托蒽醌-泼尼松更好。
Background: Bone metastases in patients with metastatic castration-resistant prostate cancer (mCRPC) are associated with debilitating pain and functional compromise.Objective: To compare pain palliation as the primary endpoint for cabozantinib versus mitoxantrone-prednisone in men with mCRPC and symptomatic bone metastases using patient-reported outcome measures.Design, setting, and participants: A randomized, double-blind phase 3 trial (COMET-2; NCT01522443) in men with mCRPC and narcotic-dependent pain from bone metastases who had progressed after treatment with docetaxel and either abiraterone or enzalutamide.Intervention: Cabozantinib 60 mg once daily orally versus mitoxantrone 12 mg/m(2) every 3 wk plus prednisone 5 mg twice daily orally.Outcome measurements and statistical analysis: The primary endpoint was pain response at week 6 confirmed at week 12 (>= 30% decrease from baseline in patient-reported average daily worst pain score via the Brief Pain Inventory without increased narcotic use). The planned sample size was 246 to achieve >= 90% power.Results and limitations: Enrollment was terminated early because cabozantinib did not demonstrate any survival benefit in the companion COMET-1 trial. At study closure, 119 participants were randomized (cabozantinib: N = 61; mitoxantrone-prednisone: N= 58). Complete pain and narcotic use data were available at baseline, week 6, and week 12 for 73/106 (69%) patients. There was no significant difference in the pain response with cabozantinib versus mitoxantrone-prednisone: the proportions of responders were 15% versus 17%, a -2% difference (95% confidence interval: -16% to 11%, p = 0.8). Barriers to accrual included pretreatment requirements for a washout period of prior anticancer therapy and a narcotic optimization period to maximize analgesic dosing.Conclusions: Cabozantinib treatment did not demonstrate better pain palliation than mitoxantrone-prednisone in heavily pretreated patients with mCRPC and symptomatic bone metastases. Future pain-palliation trials should incorporate briefer timelines from enrollment to treatment initiation.Patient summary: Cabozantinib was not better than mitoxantrone-prednisone for pain relief in patients with castration-resistant prostate cancer and debilitating pain from bone metastases.