Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial
Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial
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DOI：
10.1016/s1470-2045(17)30469-2
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发表时间：
2017-09-01
期刊：
影响因子：
51.1
通讯作者：
Pautier, Patricia
中科院分区：
文献类型：
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作者：
Pujade-Lauraine, Eric;Ledermann, Jonathan A.;Pautier, Patricia
背景：奥拉帕利布是一种聚(ADP-核糖)聚合酶(PARP)抑制剂，以前在一项2期研究中显示出对铂敏感的、复发的高级别浆液性卵巢癌患者以胶囊制剂治疗的有效性。我们的目标是在BRCA1或BRCA2(BRCA1/2)突变患者中使用奥拉帕布片剂来证实这些发现。方法这项国际性、多中心、双盲、随机、安慰剂对照的3期试验评估了奥拉帕利片维持治疗BRCA1/2突变的铂类敏感复发卵巢癌患者的效果，这些患者以前至少接受过两个疗程的化疗。符合条件的患者年龄为18岁或以上，东方合作肿瘤组表现状态基线为0-1，组织学确诊、复发、高级别浆液性卵巢癌或高级别子宫内膜样癌，包括原发腹膜或输卵管癌。患者被随机分成2：1的奥拉帕利布(300毫克在两片150毫克片剂中，每天两次)或匹配的安慰剂片剂，使用交互式语音和网络响应系统。根据既往铂类化疗的反应(完全和部分)和无铂间隔的时间长短(6-12个月和12个月)进行随机分组，患者、给予干预措施的患者、数据收集器和数据分析器的治疗分配被掩盖。主要终点是研究人员评估的无进展存活率，我们报告了这项正在进行的研究的初步分析。疗效分析是在意向治疗人群上进行的；安全性分析包括接受至少一剂研究治疗的患者。这项试验已在临床试验中注册。GOV，编号NCT01874353，正在进行中，不再招募患者。2013年9月3日至2014年11月21日，我们招募了295名符合条件的患者，他们被随机分配接受奥拉帕利(n=196)或安慰剂(n=99)。奥拉帕利组中的一名患者被错误地随机分组，没有接受研究治疗。研究者评估的中位无进展生存期，奥拉帕利组(19.1月[95%可信区间16.3-25.7])显著长于安慰剂组(5.5个月[5.2-5.8]；危险比[HR]0.30[95%可信区间0.22-0.41]，p<；0.0001)。最常见的3级或更严重的不良事件是贫血(奥拉帕利组195名患者中38名[19%]，安慰剂组99名患者中2名[2%])，疲劳或虚弱(8名[4%]对2名[2%])，以及中性粒细胞减少(10名[5%]对4名[4%])。奥拉帕利组有35名患者(18%)和安慰剂组有8名患者(8%)发生了严重的不良事件。奥拉帕利组中最常见的是贫血(7例[4%])、腹痛(3例[2%])和肠梗阻(3例[2%])。安慰剂组中最常见的是便秘(2[2%]患者)和肠梗阻(2[2%]患者)。奥拉帕利组中有1名(1%)患者发生了与治疗相关的不良事件(急性髓系白血病)，并导致死亡。奥拉帕利布片剂维持治疗显著改善了对铂敏感的复发性卵巢癌患者的无进展存活率，对生活质量没有不利影响，并伴有BRCA1/2突变。除贫血外，奥拉帕利布的毒性较低且可控。
Background Olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, has previously shown efficacy in a phase 2 study when given in capsule formulation to all-comer patients with platinum-sensitive, relapsed high-grade serous ovarian cancer. We aimed to confirm these findings in patients with a BRCA1 or BRCA2 (BRCA1/ 2) mutation using a tablet formulation of olaparib.Methods This international, multicentre, double-blind, randomised, placebo-controlled, phase 3 trial evaluated olaparib tablet maintenance treatment in platinum-sensitive, relapsed ovarian cancer patients with a BRCA1/ 2 mutation who had received at least two lines of previous chemotherapy. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status at baseline of 0-1 and histologically confirmed, relapsed, high-grade serous ovarian cancer or high-grade endometrioid cancer, including primary peritoneal or fallopian tube cancer. Patients were randomly assigned 2: 1 to olaparib (300 mg in two 150 mg tablets, twice daily) or matching placebo tablets using an interactive voice and web response system. Randomisation was stratified by response to previous platinum chemotherapy (complete vs partial) and length of platinum-free interval (> 6-12 months vs > 12 months) and treatment assignment was masked for patients, those giving the interventions, data collectors, and data analysers. The primary endpoint was investigator-assessed progression-free survival and we report the primary analysis from this ongoing study. The efficacy analyses were done on the intention-to-treat population; safety analyses included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials. gov, number NCT01874353, and is ongoing and no longer recruiting patients.Findings Between Sept 3, 2013, and Nov 21, 2014, we enrolled 295 eligible patients who were randomly assigned to receive olaparib (n=196) or placebo (n=99). One patient in the olaparib group was randomised in error and did not receive study treatment. Investigator-assessed median progression-free survival was significantly longer with olaparib (19.1 months [95% CI 16.3-25.7]) than with placebo (5.5 months [5.2-5.8]; hazard ratio [HR] 0.30 [95% CI 0.22-0.41], p< 0.0001). The most common adverse events of grade 3 or worse severity were anaemia (38 [19%] of 195 patients in the olaparib group vs two [2%] of 99 patients in the placebo group), fatigue or asthenia (eight [4%] vs two [2%]), and neutropenia (ten [5%] vs four [4%]). Serious adverse events were experienced by 35 (18%) patients in the olaparib group and eight (8%) patients in the placebo group. The most common in the olaparib group were anaemia (seven [4%] patients), abdominal pain (three [2%] patients), and intestinal obstruction (three [2%] patients). The most common in the placebo group were constipation (two [2%] patients) and intestinal obstruction (two [2%] patients). One (1%) patient in the olaparib group had a treatment-related adverse event (acute myeloid leukaemia) with an outcome of death.Interpretation Olaparib tablet maintenance treatment provided a significant progression-free survival improvement with no detrimental effect on quality of life in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation. Apart from anaemia, toxicities with olaparib were low grade and manageable.