Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New York, New York.
Department of Hematology/Medical Oncology, OHSU Knight Cancer Institute, Oregon Health and Science University, Portland.
JAMA Oncol. 2018 May 1;4(5):694-701. doi: 10.1001/jamaoncol.2017.5808.
Drug development for metastatic castration-resistant prostate cancer has been limited by a lack of clinically relevant trial end points short of overall survival (OS). Radiographic progression-free survival (rPFS) as defined by the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) is a candidate end point that represents a clinically meaningful benefit to patients.
To demonstrate the robustness of the PCWG2 definition and to examine the relationship between rPFS and OS.
DESIGN, SETTING, AND PARTICIPANTS: PREVAIL was a phase 3, randomized, double-blind, placebo-controlled multinational study that enrolled 1717 chemotherapy-naive men with metastatic castration-resistant prostate cancer from September 2010 through September 2012. The data were analyzed in November 2016.
Patients were randomized 1:1 to enzalutamide 160 mg or placebo until confirmed radiographic disease progression or a skeletal-related event and initiation of either cytotoxic chemotherapy or an investigational agent for prostate cancer treatment.
Sensitivity analyses (SAs) of investigator-assessed rPFS were performed using the final rPFS data cutoff (May 6, 2012; 439 events; SA1) and the interim OS data cutoff (September 16, 2013; 540 events; SA2). Additional SAs using investigator-assessed rPFS from the final rPFS data cutoff assessed the impact of skeletal-related events (SA3), clinical progression (SA4), a confirmatory scan for soft-tissue disease progression (SA5), and all deaths regardless of time after study drug discontinuation (SA6). Correlations between investigator-assessed rPFS (SA2) and OS were calculated using Spearman ρ and Kendall τ via Clayton copula.
In the 1717 men (mean age, 72.0 [range, 43.0-93.0] years in enzalutamide arm and 71.0 [range, 42.0-93.0] years in placebo arm), enzalutamide significantly reduced risk of radiographic progression or death in all SAs, with hazard ratios of 0.22 (SA1; 95% CI, 0.18-0.27), 0.31 (SA2; 95% CI, 0.27-0.35), 0.21 (SA3; 95% CI, 0.18-0.26), 0.21 (SA4; 95% CI, 0.17-0.26), 0.23 (SA5; 95% CI, 0.19-0.30), and 0.23 (SA6; 95% CI, 0.19-0.30) (P < .001 for all). Correlations of rPFS and OS in enzalutamide-treated patients were 0.89 (95% CI, 0.86-0.92) by Spearman ρ and 0.72 (95% CI, 0.68-0.77) by Kendall τ.
Sensitivity analyses in PREVAIL demonstrated the robustness of the PCWG2 rPFS definition using additional measures of progression. There was concordance between central and investigator review and a positive correlation between rPFS and OS among enzalutamide-treated patients.
clinicaltrials.gov Identifier: NCT01212991.
由于缺乏临床相关的试验终点（除总生存期[OS]外），转移性去势抵抗性前列腺癌的药物研发受到限制。前列腺癌临床试验工作组 2（PCWG2）定义的放射学无进展生存期（rPFS）是一个候选终点，代表对患者有临床意义的获益。
证明 PCWG2 定义的稳健性，并研究 rPFS 与 OS 之间的关系。
设计、地点和参与者：PREVAIL 是一项 3 期、随机、双盲、安慰剂对照的多国研究，纳入了 2010 年 9 月至 2012 年 9 月间 1717 例化疗初治的转移性去势抵抗性前列腺癌男性患者。数据分析于 2016 年 11 月进行。
患者以 1:1 的比例随机分配至恩扎卢胺 160mg 或安慰剂，直至确认影像学疾病进展或发生骨骼相关事件，并开始使用细胞毒性化疗或前列腺癌治疗的研究药物。
使用最终 rPFS 数据截止（2012 年 5 月 6 日；439 例事件；SA1）和 OS 数据截止（2013 年 9 月 16 日；540 例事件；SA2）进行研究者评估的 rPFS 的敏感性分析（SA）。使用最终 rPFS 数据截止的研究者评估 rPFS 的其他敏感性分析（SA2）评估了骨骼相关事件（SA3）、临床进展（SA4）、软组织疾病进展的确认性扫描（SA5）以及所有无论停药后何时发生的死亡事件（SA6）的影响。通过 Clayton copula 计算研究者评估的 rPFS（SA2）与 OS 之间的 Spearman ρ 和 Kendall τ 相关性。
在 1717 例男性患者（平均年龄 72.0 [范围 43.0-93.0]岁，恩扎卢胺组；71.0 [范围 42.0-93.0]岁，安慰剂组）中，恩扎卢胺在所有敏感性分析中均显著降低了影像学进展或死亡风险，风险比分别为 0.22（SA1；95%CI，0.18-0.27）、0.31（SA2；95%CI，0.27-0.35）、0.21（SA3；95%CI，0.18-0.26）、0.21（SA4；95%CI，0.17-0.26）、0.23（SA5；95%CI，0.19-0.30）和 0.23（SA6；95%CI，0.19-0.30）（所有 P<0.001）。恩扎卢胺治疗患者 rPFS 和 OS 的相关性分别为 Spearman ρ 0.89（95%CI，0.86-0.92）和 Kendall τ 0.72（95%CI，0.68-0.77）。
PREVAIL 的敏感性分析证明了 PCWG2 rPFS 定义使用其他进展测量方法的稳健性。中央和研究者评估之间具有一致性，并且恩扎卢胺治疗患者的 rPFS 和 OS 之间存在正相关。
clinicaltrials.gov 标识符：NCT01212991。
