Medical Oncology Department, Université Paris Descartes, AP-HP, Paris, France.
Department of Oncology, University College London, London, UK.
Lancet Oncol. 2017 Sep;18(9):1274-1284. doi: 10.1016/S1470-2045(17)30469-2. Epub 2017 Jul 25.
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.
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.
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.
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.
AstraZeneca.
奥拉帕利是一种聚（ADP-核糖）聚合酶（PARP）抑制剂，在以胶囊制剂给予所有对铂敏感、复发性高级别浆液性卵巢癌患者的 2 期研究中显示出疗效。我们旨在使用奥拉帕利片剂制剂在携带 BRCA1 或 BRCA2（BRCA1/2）突变的患者中确认这些发现。
这是一项国际、多中心、双盲、随机、安慰剂对照、3 期临床试验，评估了奥拉帕利片剂维持治疗对携带 BRCA1/2 突变、至少接受过两线化疗的铂敏感、复发性卵巢癌患者的疗效。合格患者为年龄在 18 岁或以上、基线东部合作肿瘤学组（ECOG）表现状态为 0-1 级且组织学证实、复发性高级别浆液性卵巢癌或高级别子宫内膜样癌（包括原发性腹膜或输卵管癌）患者。患者使用交互式语音和网络应答系统以 2:1 的比例随机分配至奥拉帕利（每日两次，每次 150mg 片剂两片，每次 300mg）或匹配的安慰剂片剂。随机分组根据对先前铂类化疗的反应（完全缓解与部分缓解）和铂类无进展间期（6-12 个月与≥12 个月）进行分层，并且对患者、给予干预措施的人员、数据收集人员和数据分析人员对治疗分配进行了屏蔽。主要终点是研究者评估的无进展生存期，我们报告了这项正在进行的研究的主要分析结果。疗效分析基于意向治疗人群进行；安全性分析包括至少接受过一剂研究治疗的患者。这项试验在 ClinicalTrials.gov 上注册，编号为 NCT01874353，正在进行中，不再招募患者。
在 2013 年 9 月 3 日至 2014 年 11 月 21 日期间，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）治疗。奥拉帕利组中有一名患者随机分配错误，未接受研究治疗。研究者评估的中位无进展生存期在奥拉帕利组显著延长（19.1 个月[95%CI 16.3-25.7]），而安慰剂组为 5.5 个月[5.2-5.8]；风险比（HR）为 0.30[95%CI 0.22-0.41]，p<0.0001）。最常见的 3 级或更高级别的不良事件为贫血（奥拉帕利组 195 例患者中有 38 例[19%]，安慰剂组 99 例患者中有 2 例[2%]）、疲乏或乏力（奥拉帕利组 8 例[4%]，安慰剂组 2 例[2%]）和中性粒细胞减少症（奥拉帕利组 10 例[5%]，安慰剂组 4 例[4%]）。奥拉帕利组有 35 例（18%）患者发生严重不良事件，安慰剂组有 8 例（8%）患者发生严重不良事件。奥拉帕利组最常见的是贫血（7 例[4%]患者）、腹痛（3 例[2%]患者）和肠梗阻（3 例[2%]患者）。安慰剂组最常见的是便秘（2 例[2%]患者）和肠梗阻（2 例[2%]患者）。奥拉帕利组有 1 例（1%）患者发生治疗相关不良事件（急性髓性白血病），结果为死亡。
奥拉帕利片剂维持治疗在携带 BRCA1/2 突变的铂敏感、复发性卵巢癌患者中显著改善了无进展生存期，且对生活质量没有不利影响。除贫血外，奥拉帕利的毒性反应均为低级别且可管理。
阿斯利康。
