《柳叶刀肿瘤分册》2017年7月25日在线先发
http://thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30469-2/fulltext
奥拉帕尼片对BRCA1/2突变、铂类敏感的复发性卵巢癌患者进行维持治疗（SOLO2/ENGOT-Ov21试验）：一项双盲、随机化、安慰剂对照的3期临床试验
背景
奥拉帕尼是一种多聚（ADP-核糖）聚合酶（PARP）抑制剂，在既往的一项2期研究中，对铂类敏感、复发性、高级别的浆液性卵巢癌患者来者不拒地给予奥拉帕尼胶囊，显现出疗效。，我们旨在采用奥拉帕尼片剂，在BRCA1或BRCA2（BRCA1/2）突变的患者中证实这些结果。
方法
这项国际性、多中心、双盲、随机化、安慰剂对照的3期临床试验，对BRCA1/2突变、铂类敏感的复发性卵巢癌患者，且这些患者既往已经接受过至少两线以上的化疗，评价了奥拉帕尼片维持治疗的效果。符合条件的患者为≥18岁、入组时ECOG体能状况评分0-1分、经组织学证实、复发性、高级别浆液性卵巢癌或高级别子宫内膜样癌，包括原发性腹膜癌或原发性输卵管癌。采用交互式语音及网络应答系统，将患者按2：1的比例随机分组，奥拉帕尼组（2片150mg共300mg，每日两次，）或相匹配的安慰剂组。对随机化分组根据既往铂类化疗疗效（完全缓解对比部分缓解）、无铂治疗间隔时间（6-12个月对比≥12个月）进行分层（分亚组），患者、治疗干预人员、资料收集者和数据分析人员对治疗分组情况不知晓。主要终点为研究人员评价的无进展生存期，我们从这项仍在进行中的研究中报告了初步分析结果。对意向性治疗患者进行疗效分析，安全性分析纳入了至少接受过一个研究治疗剂量的患者。这项试验在ClinicalTrials.gov网站注册，注册号NCT01874353，试验仍在进行，但不再招募患者。
结果
2013年9月3日至2014年11月21日，我们入组了295名符合条件的患者，这些患者随机分组到奥拉帕尼组（n=196）或安慰剂组（n=99）。奥拉帕尼组中有1名患者因随机化分组错误，未接受研究性治疗。研究人员评价的无进展生存期中位值，奥拉帕尼组（19.1个月[95%CI，16.3–25.7]）明显长于安慰剂组（5.5个月[5.2–5.8]，风险比[HR]，0.30[95%CI，0.22–0.41]，p<0.0001）。最常见的≥3级不良事件为贫血（奥拉帕尼组195名患者中有38名[19%]对比安慰剂组99名患者中有2名[2%]）、疲乏或虚弱（8名[4%对比2名[2%]）、中性粒细胞减少症（10名[5%]对比4名[4%]）。奥拉帕尼组有35名患者（18%）经历了严重不良事件，安慰剂组有8名（8%）。奥拉帕尼组最常见者为贫血（7名[4%]）、腹痛（3名[2%]）和肠梗阻（3名[2%]），安慰剂组最常见者为便秘（2名[2%]）和肠梗阻（2名[2%]）。奥拉帕尼组中1名患者有治疗相关性不良事件（急性髓性白血病），结果死亡。
解释
在BRCA1/2突变、铂类敏感、复发性卵巢癌患者中，奥拉帕尼片维持治疗使得无进展生存期明显延长，且对患者生活质量没有产生有害影响。除贫血以外，奥拉帕尼的毒性低且可控。
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
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.
Funding
AstraZeneca.
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