Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer
Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer
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DOI：
10.1056/nejmoa1903387
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发表时间：
2019-07-25
影响因子：
158.5
通讯作者：
Kindler, Hedy L.
中科院分区：
文献类型：
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作者：
Golan, Talia;Hammel, Pascal;Kindler, Hedy L.
背景 具有种系 BRCA1 或 BRCA2 突变的患者是转移性胰腺癌患者的一小部分。聚（腺苷二磷酸核糖）聚合酶 (PARP) 抑制剂奥拉帕尼在此人群中具有抗肿瘤活性。方法我们进行了一项随机、双盲、安慰剂对照的 3 期试验，以评估奥拉帕尼作为维持治疗对具有种系 BRCA1 或 BRCA2 突变、转移性胰腺癌以及在一线铂类化疗期间未进展的疾病的患者的疗效。患者以 3:2 的比例随机分配接受奥拉帕尼维持片剂（300 毫克，每日两次）或安慰剂治疗。主要终点是无进展生存期，通过盲法独立中央审查进行评估。结果在接受筛查的 3315 名患者中，154 名接受随机分组并被分配至试验干预组（92 名接受奥拉帕尼，62 名接受安慰剂）。奥拉帕尼组的中位无进展生存期显着长于安慰剂组（7.4 个月 vs. 3.8 个月；疾病进展或死亡的风险比，0.53；95% 置信区间 [CI]，0.35 至 0.82；P=0.004）。数据成熟度为 46% 的总体生存期中期分析显示，奥拉帕尼组和安慰剂组之间没有差异（中位生存期为 18.9 个月 vs. 18.1 个月；死亡风险比为 0.91；95% CI，0.56 至 1.46；P=0.68）。根据欧洲癌症研究和治疗组织的生活质量问卷调查，全球生活质量评分（100分制，分数越高表明生活质量越好）相对于基线的总体变化表明，健康相关生活质量没有显着的组间差异（组间差异，-2.47分；95% CI，-7.27至2.33）。奥拉帕尼组 3 级或以上不良事件的发生率为 40%，安慰剂组为 23%（组间差异，16 个百分点；95% CI，-0.02 至 31）；分别有 5% 和 2% 的患者因不良事件而停止试验干预。 结论 在患有种系 BRCA 突变和转移性胰腺癌的患者中，维持奥拉帕尼组的无进展生存期比安慰剂组更长。
BackgroundPatients with a germline BRCA1 or BRCA2 mutation make up a small subgroup of those with metastatic pancreatic cancer. The poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor olaparib has had antitumor activity in this population.MethodsWe conducted a randomized, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy of olaparib as maintenance therapy in patients who had a germline BRCA1 or BRCA2 mutation and metastatic pancreatic cancer and disease that had not progressed during first-line platinum-based chemotherapy. Patients were randomly assigned, in a 3:2 ratio, to receive maintenance olaparib tablets (300 mg twice daily) or placebo. The primary end point was progression-free survival, which was assessed by blinded independent central review.ResultsOf the 3315 patients who underwent screening, 154 underwent randomization and were assigned to a trial intervention (92 to receive olaparib and 62 to receive placebo). The median progression-free survival was significantly longer in the olaparib group than in the placebo group (7.4 months vs. 3.8 months; hazard ratio for disease progression or death, 0.53; 95% confidence interval [CI], 0.35 to 0.82; P=0.004). An interim analysis of overall survival, at a data maturity of 46%, showed no difference between the olaparib and placebo groups (median, 18.9 months vs. 18.1 months; hazard ratio for death, 0.91; 95% CI, 0.56 to 1.46; P=0.68). There was no significant between-group difference in health-related quality of life, as indicated by the overall change from baseline in the global quality-of-life score (on a 100-point scale, with higher scores indicating better quality of life) based on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (between-group difference, -2.47 points; 95% CI, -7.27 to 2.33). The incidence of grade 3 or higher adverse events was 40% in the olaparib group and 23% in the placebo group (between-group difference, 16 percentage points; 95% CI, -0.02 to 31); 5% and 2% of the patients, respectively, discontinued the trial intervention because of an adverse event.ConclusionsAmong patients with a germline BRCA mutation and metastatic pancreatic cancer, progression-free survival was longer with maintenance olaparib than with placebo.