From the Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago (M.H.), and Astellas Pharma, Northbrook (D.P., A.K.) - both in Illinois; Institut Gustave Roussy, University of Paris Sud, Villejuif, France (K.F.); the University of Montreal Hospital Center, Montreal (F.S.); Herlev Hospital, Herlev, Denmark (P.R.); Carolina Urologic Research Center, Myrtle Beach, SC (N.S.); State University of Campinas (Unicamp), Campinas, Brazil (U.F.); Kiev City Clinical Hospital 3, Kiev, Ukraine (P.I.); Pfizer, San Francisco (E.D., K.M.); and the Department of Medical Oncology, San Camillo Forlanini Hospital, Rome (C.N.S.).
N Engl J Med. 2018 Jun 28;378(26):2465-2474. doi: 10.1056/NEJMoa1800536.
Men with nonmetastatic, castration-resistant prostate cancer and a rapidly rising prostate-specific antigen (PSA) level are at high risk for metastasis. We hypothesized that enzalutamide, which prolongs overall survival among patients with metastatic, castration-resistant prostate cancer, would delay metastasis in men with nonmetastatic, castration-resistant prostate cancer and a rapidly rising PSA level.
In this double-blind, phase 3 trial, we randomly assigned, in a 2:1 ratio, men with nonmetastatic, castration-resistant prostate cancer and a PSA doubling time of 10 months or less who were continuing androgen-deprivation therapy to receive enzalutamide (at a dose of 160 mg) or placebo once daily. The primary end point was metastasis-free survival (defined as the time from randomization to radiographic progression or as the time to death without radiographic progression).
A total of 1401 patients (median PSA doubling time, 3.7 months) underwent randomization. As of June 28, 2017, a total of 219 of 933 patients (23%) in the enzalutamide group had metastasis or had died, as compared with 228 of 468 (49%) in the placebo group. The median metastasis-free survival was 36.6 months in the enzalutamide group versus 14.7 months in the placebo group (hazard ratio for metastasis or death, 0.29; 95% confidence interval, 0.24 to 0.35; P<0.001). The time to the first use of a subsequent antineoplastic therapy was longer with enzalutamide treatment than with placebo (39.6 vs. 17.7 months; hazard ratio, 0.21; P<0.001; such therapy was used in 15% vs. 48% of patients) as was the time to PSA progression (37.2 vs. 3.9 months; hazard ratio, 0.07; P<0.001; progression occurred in 22% vs. 69% of patients). At the first interim analysis of overall survival, 103 patients (11%) receiving enzalutamide and 62 (13%) receiving placebo had died. Adverse events of grade 3 or higher occurred in 31% of the patients receiving enzalutamide, as compared with 23% of those receiving placebo.
Among men with nonmetastatic, castration-resistant prostate cancer with a rapidly rising PSA level, enzalutamide treatment led to a clinically meaningful and significant 71% lower risk of metastasis or death than placebo. Adverse events were consistent with the established safety profile of enzalutamide. (Funded by Pfizer and Astellas Pharma; PROSPER ClinicalTrials.gov number, NCT02003924 .).
对于非转移性去势抵抗性前列腺癌（nmCRPC）且 PSA 水平快速升高的患者，其存在发生转移的高风险。我们假设，在转移性去势抵抗性前列腺癌患者中，恩扎鲁胺可以延长总生存期，那么它可能会延迟 PSA 水平快速升高的非转移性去势抵抗性前列腺癌患者发生转移。
在这项双盲、3 期临床试验中，我们以 2:1 的比例，随机分配 PSA 倍增时间为 10 个月或更短且正在接受雄激素剥夺治疗的非转移性去势抵抗性前列腺癌患者，接受恩扎鲁胺（剂量为 160 mg）或安慰剂每日一次治疗。主要终点是无转移生存期（定义为从随机分组到影像学进展的时间，或无影像学进展的死亡时间）。
共 1401 例患者（中位 PSA 倍增时间为 3.7 个月）接受了随机分组。截至 2017 年 6 月 28 日，恩扎鲁胺组 933 例患者中有 219 例（23%）发生转移或死亡，安慰剂组 468 例患者中有 228 例（49%）发生转移或死亡。恩扎鲁胺组无转移生存期的中位数为 36.6 个月，安慰剂组为 14.7 个月（转移或死亡的风险比为 0.29；95%置信区间为 0.24 至 0.35；P<0.001）。与安慰剂相比，恩扎鲁胺治疗组首次使用后续抗肿瘤治疗的时间更长（39.6 个月 vs. 17.7 个月；风险比为 0.21；P<0.001；15% vs. 48%的患者使用了这种治疗），PSA 进展的时间也更长（37.2 个月 vs. 3.9 个月；风险比为 0.07；P<0.001；22% vs. 69%的患者发生了 PSA 进展）。在首次进行的总生存期中期分析中，103 例（11%）接受恩扎鲁胺治疗的患者和 62 例（13%）接受安慰剂治疗的患者死亡。恩扎鲁胺组发生 3 级或更高级别的不良事件的比例为 31%，安慰剂组为 23%。
在 PSA 水平快速升高的非转移性去势抵抗性前列腺癌患者中，与安慰剂相比，恩扎鲁胺治疗使转移或死亡的风险降低了 71%，具有显著的临床意义。不良事件与恩扎鲁胺的既定安全性特征一致。（由辉瑞公司和安斯泰来制药公司资助；PROSPER 临床试验.gov 编号，NCT02003924）。
