Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer
Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer
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DOI：
10.1056/nejmoa2022485
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发表时间：
2020-12-10
影响因子：
158.5
通讯作者：
de Bono, Johann
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文献类型：
--
作者：
Hussain, Maha;Mateo, Joaquin;de Bono, Johann
背景我们之前曾报道，在转移性去势抵抗前列腺癌患者中，奥拉帕利导致基于影像的无进展生存期比医生选择的苯扎鲁胺或阿比特龙要长得多，这些患者具有同源重组修复基因的合格改变，并且在以前使用下一代激素制剂治疗期间病情进展。总生存率的最终分析结果尚未公布。方法在一项开放的3期试验中，我们按2：1的比例随机分配患者接受奥拉帕利(256例)或医生选择的苯扎鲁胺或阿比特龙加强的松作为对照治疗(131例)。队列A包括245名BRCA1、BRCA2或ATM至少有一个改变的患者，而队列B包括142名其他12个预先指定的基因中的任何一个至少有一个改变的患者。对于符合特定标准的患者，在基于成像的疾病进展后，允许交叉使用奥拉帕利。在数据成熟度约为60%的情况下，采用阿尔法控制的分层对数等级检验对A组(一个关键的次要终点)的总体生存率进行分析。结果A组患者的中位生存期为19.1个月，对照组为14.7个月(死亡风险比为0.69；95%可信区间为0.50~0.97；P=0.02)。在队列B中，使用奥拉帕利的中位生存期为14.1个月，而使用对照治疗的中位生存期为11.5个月。在总体人群(A组和B组)中，相应的持续时间分别为17.3个月和14.0个月。总体而言，对照组131名患者中有86名(66%)转而接受奥拉帕利治疗(A组83名患者中有56名接受奥拉帕利治疗，占67%)。经交叉和奥拉帕利调整后的敏感性分析显示，A组死亡的风险比为0.42(95%CI，0.19~0.91)，B组为0.83(95%CI，0.11~5.98)，总体人群为0.55(95%CI，0.29~1.06)。结论：在转移性去势抵抗前列腺癌患者中，肿瘤在BRCA1、BRCA2或ATM中至少有一种改变，且在以前使用下一代激素制剂治疗期间病情进展，那些最初被分配接受奥拉帕利布治疗的人比那些被分配接受苯扎鲁胺或阿比特龙加泼尼松作为对照治疗的人的总生存期要长得多，尽管从对照治疗到奥拉帕利治疗有很大的交叉。(由阿斯利康和默克·夏普和Dohme提供资金；Inepth ClinicalTrials.gov编号，NCT02987543。)这项深入的试验表明，在肿瘤包含同源重组修复基因BRCA1、BRCA2或ATM缺陷的患者中，奥拉帕利延长了基于成像的无进展生存期。随着更长时间的随访，试验现在表明，奥拉帕利延长了这些患者的总生存期。毒性反应包括贫血、恶心和虚弱。
BackgroundWe previously reported that olaparib led to significantly longer imaging-based progression-free survival than the physician's choice of enzalutamide or abiraterone among men with metastatic castration-resistant prostate cancer who had qualifying alterations in homologous recombination repair genes and whose disease had progressed during previous treatment with a next-generation hormonal agent. The results of the final analysis of overall survival have not yet been reported.MethodsIn an open-label, phase 3 trial, we randomly assigned patients in a 2:1 ratio to receive olaparib (256 patients) or the physician's choice of enzalutamide or abiraterone plus prednisone as the control therapy (131 patients). Cohort A included 245 patients with at least one alteration in BRCA1, BRCA2, or ATM, and cohort B included 142 patients with at least one alteration in any of the other 12 prespecified genes. Crossover to olaparib was allowed after imaging-based disease progression for patients who met certain criteria. Overall survival in cohort A, a key secondary end point, was analyzed with the use of an alpha-controlled, stratified log-rank test at a data maturity of approximately 60%. The primary and other key secondary end points were reported previously.ResultsThe median duration of overall survival in cohort A was 19.1 months with olaparib and 14.7 months with control therapy (hazard ratio for death, 0.69; 95% confidence interval [CI], 0.50 to 0.97; P=0.02). In cohort B, the median duration of overall survival was 14.1 months with olaparib and 11.5 months with control therapy. In the overall population (cohorts A and B), the corresponding durations were 17.3 months and 14.0 months. Overall, 86 of 131 patients (66%) in the control group crossed over to receive olaparib (56 of 83 patients [67%] in cohort A). A sensitivity analysis that adjusted for crossover to olaparib showed hazard ratios for death of 0.42 (95% CI, 0.19 to 0.91) in cohort A, 0.83 (95% CI, 0.11 to 5.98) in cohort B, and 0.55 (95% CI, 0.29 to 1.06) in the overall population.ConclusionsAmong men with metastatic castration-resistant prostate cancer who had tumors with at least one alteration in BRCA1, BRCA2, or ATM and whose disease had progressed during previous treatment with a next-generation hormonal agent, those who were initially assigned to receive olaparib had a significantly longer duration of overall survival than those who were assigned to receive enzalutamide or abiraterone plus prednisone as the control therapy, despite substantial crossover from control therapy to olaparib. (Funded by AstraZeneca and Merck Sharp and Dohme; PROfound ClinicalTrials.gov number, NCT02987543.)The PROfound trial showed that olaparib prolonged imaging-based progression-free survival among patients whose tumors contained defects in the homologous recombination repair genes BRCA1, BRCA2, or ATM. With longer follow-up, the trial now shows that olaparib prolonged overall survival in these patients. Toxic effects included anemia, nausea, and asthenia.