Mulati Yelin, Fan Yu, Yu Wei, Zhang Qian, He Zhisong
Department of Urology, Peking University First Hospital, Beijing, China.
Institute of Urology, Peking University, Beijing, China.
Front Oncol. 2021 Oct 15;11:733202. doi: 10.3389/fonc.2021.733202. eCollection 2021.
Enzalutamide, apalutamide, and darolutamide have all been approved by Food and Drug Administration to treat high-risk non-metastatic castration-resistant prostate cancer (nmCRPC) since 2018 based on interim results of several phase III clinical trials. Final analyses of long-term overall survival (OS) and adverse events (AEs) results of these trials have been successively published recently. To help clinical practice to precisely select optimal treatment for high-risk nmCRPC patients, we performed a network meta-analysis to indirectly compare the final long-term results among these medications.
PubMed, EMBASE, and Cochrane Libraries were searched for phase III clinical trial that reports OS and AEs results in nmCRPC patients published before January 30, 2021. Primary outcome was OS; secondary outcomes were Time to first chemotherapy, Subsequent antineoplastic therapy rate, and AEs. Firstly, class-level effect was assessed as the second-generation androgen receptor antagonists (SGARAs) were regarded as one whole class compared with placebo through traditional meta-analysis by using Revman 5.4, then a Bayesian network meta-analysis was conducted to give indirect comparison among SGARAs by using R 3.5.3 software. Subgroup analysis of OS was only conducted in the certain subgroups which were available in all included studies.
Three eligible studies including 4,104 participants were finally selected. OS was significantly improved by the SGARAs as a class compared with placebo (HR, 0.74; 95% CI, 0.66-0.84). Darolutamide had the highest likelihood of providing best OS (p-score=0.802). SGARAs also significantly delayed the first time to chemotherapy (HR, 0.58; 95% CI, 0.50-0.66). Patients who received darolutamide experienced similar toxicity compared with placebo regarding AEs of grade 3 or higher (OR, 1.3; 95% CI, 1.0-1.7) and serious AEs (OR, 1.3; 95% CI, 0.99-1.6). When compared with darolutamide, enzalutamide caused significantly higher toxicity in terms of any AEs (OR, 2.3; 95% CI,1.5-3.7) and AEs of grade 3 or higher (OR, 1.6; 95% CI, 1.1-2.2), apalutamide caused significantly more AEs of grade 3 or higher (OR, 1.9; 95% CI, 1.4-2.7) and serious AEs (OR, 1.9; 95% CI, 1.3-2.8). Subgroup analysis showed that SGARAs as a group significantly improved OS in ECOG=1 population, although insignificant results were found in these patients from included studies.
SGARAs combined with ADT significantly improved OS when compared with ADT alone in high-risk nmCRPC patients. Darolutamide may not only provide best OS but also have the most favorable safety profile among the included SGARAs in high-risk nmCRPC patients.
自2018年以来，恩杂鲁胺、阿帕鲁胺和达罗他胺均已获美国食品药品监督管理局批准，基于多项III期临床试验的中期结果用于治疗高危非转移性去势抵抗性前列腺癌（nmCRPC）。这些试验的长期总生存期（OS）和不良事件（AE）结果的最终分析最近相继发表。为帮助临床实践为高危nmCRPC患者精确选择最佳治疗方案，我们进行了一项网状Meta分析，以间接比较这些药物的最终长期结果。
检索PubMed、EMBASE和Cochrane图书馆，查找2021年1月30日前发表的报告nmCRPC患者OS和AE结果的III期临床试验。主要结局为OS；次要结局为首次化疗时间、后续抗肿瘤治疗率和AE。首先，通过使用Revman 5.4进行传统Meta分析，将第二代雄激素受体拮抗剂（SGARA）作为一个整体类别与安慰剂进行比较，评估类别水平效应，然后使用R 3.5.3软件进行贝叶斯网状Meta分析，以在SGARA之间进行间接比较。仅在所有纳入研究中均有的特定亚组中进行OS的亚组分析。
最终入选三项符合条件的研究，共4104名参与者。与安慰剂相比，SGARA作为一个类别显著改善了OS（风险比[HR]，0.74；95%置信区间[CI]，0.66 - 0.84）。达罗他胺提供最佳OS的可能性最高（p值 = 0.802）。SGARA也显著延迟了首次化疗时间（HR，0.58；95% CI，0.50 - 0.66）。在3级或更高等级AE（比值比[OR]，1.3；95% CI，1.0 - 1.7）和严重AE（OR，1.3；95% CI，0.99 - 1.6）方面，接受达罗他胺治疗的患者与接受安慰剂治疗的患者经历的毒性相似。与达罗他胺相比，恩杂鲁胺在任何AE（OR，2.3；95% CI，1.5 - 3.7）和3级或更高等级AE（OR，1.6；95% CI，1.1 - 2.2）方面导致的毒性显著更高，阿帕鲁胺导致的3级或更高等级AE（OR，1.9；95% CI，1.4 - 2.7）和严重AE（OR，1.9；95% CI，1.3 - 2.8）显著更多。亚组分析表明，SGARA作为一组在东部肿瘤协作组（ECOG）体能状态评分为1的人群中显著改善了OS，但纳入研究中的这些患者结果不显著。
与单独雄激素剥夺治疗（ADT）相比，SGARA联合ADT在高危nmCRPC患者中显著改善了OS。在高危nmCRPC患者中，达罗他胺在纳入的SGARA中可能不仅提供最佳OS，而且具有最有利的安全性。
