Health-related quality of life and patient-centred outcomes with olaparib maintenance after chemotherapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT Ov-21): a placebo-controlled, phase 3 randomised trial.
Health-related quality of life and patient-centred outcomes with olaparib maintenance after chemotherapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT Ov-21): a placebo-controlled, phase 3 randomised trial.
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DOI：
10.1016/s1470-2045(18)30343-7
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发表时间：
2018-08
期刊：
影响因子：
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通讯作者：
Pujade-Lauraine E
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作者：
Friedlander M;Gebski V;Gibbs E;Davies L;Bloomfield R;Hilpert F;Wenzel LB;Eek D;Rodrigues M;Clamp A;Penson RT;Provencher D;Korach J;Huzarski T;Vidal L;Salutari V;Scott C;Nicoletto MO;Tamura K;Espinoza D;Joly F;Pujade-Lauraine E
在3期SOLO2试验（ENGOT Ov-21）中，与安慰剂相比，奥拉帕尼片剂维持治疗显著延长了生殖系BRCA 1或BRCA 2（BRCA 1/2）突变和铂类敏感性复发性卵巢癌患者的无进展生存期（主要终点），这些患者既往接受过两种或更多种化疗。最常见的主观不良反应包括疲劳、恶心和呕吐，这些不良反应通常为低度和自限性。我们的先验假设是，奥拉帕尼维持治疗不会对健康相关生活质量（HRQOL）产生负面影响，此外，奥拉帕尼延长无进展生存期将得到以患者为中心的额外获益的支持。在SOLO 2中，196例患者被随机分配至奥拉帕尼片剂组（300 mg，每日两次），99例患者被随机分配至安慰剂组。随机化按对既往化疗的反应（完全与部分）和无铂间隔时间（>6-12与>12个月）进行分层。预先规定的主要HRQOL分析评价了研究前12个月期间试验结局指数（TOI）评分较基线的变化。为了可评估，患者必须在基线时有可评估的评分和至少一份可评估的随访表。次要计划生活质量（QOL）分析包括良好生活质量的持续时间（定义为无显著毒性症状的时间[TWiST]和质量调整的无进展生存期[QAPFS]）。在所有随机分配的患者（全分析集）中分析疗效和QOL结局，并在所有随机分配的接受至少一剂研究药物的患者中分析安全性结局。这项正在进行的研究已在ClinicalTrials.gov注册，编号为NCT 01874353，并对新参与者关闭。在前12个月内，奥拉帕尼组TOI较基线的校正平均变化为−2·90（95% CI −4·13至−1·67），安慰剂组为−2·87（−4·64至−1·10）（估计差异为−0·03; 95% CI −2·19至2·13; p=0·98）。奥拉帕尼组的平均QAPFS（13.96 [SD 10.96] vs 7.28 [5.22]个月;差异6.68，95%CI 4.98 - 8.54）和TWiST的平均持续时间（15.03 [SD 12.79] vs 7.70 [6.42]个月;差异7.33，95%CI 4.70 - 8.96）显著长于安慰剂组。与安慰剂相比，奥拉帕尼维持治疗对HRQOL没有显著的不利影响。尽管存在与奥拉帕尼相关的不良反应，但在TWiST和QAPFS中均存在具有临床意义的以患者为中心的获益。这些以患者为中心的终点支持无进展生存期的改善，这是SOLO 2的主要终点，应纳入未来的维持治疗试验中。
In the phase 3 SOLO2 trial (ENGOT Ov-21), maintenance therapy with olaparib tablets significantly prolonged progression-free survival (primary endpoint) compared with placebo in patients with a germline BRCA1 or BRCA2 (BRCA1/2) mutation and platinum-sensitive, relapsed ovarian cancer who had received two or more lines of previous chemotherapy. The most common subjective adverse effects included fatigue, nausea, and vomiting, which were typically low grade and self-limiting. Our a-priori hypothesis was that maintenance olaparib would not negatively affect health-related quality of life (HRQOL) and additionally that the prolongation of progression-free survival with olaparib would be underpinned by additional patient-centred benefits. In SOLO2, 196 patients were randomly assigned to olaparib tablets (300 mg twice daily) and 99 to placebo. Randomisation was stratified by response to previous chemotherapy (complete vs partial) and length of platinum-free interval (>6–12 vs >12 months). The prespecified primary HRQOL analysis evaluated the change from baseline in the Trial Outcome Index (TOI) score during the first 12 months of the study. To be assessable, patients had to have an evaluable score at baseline and at least one evaluable follow-up form. Secondary planned quality-of-life (QOL) analyses included the duration of good quality of life (defined as time without significant symptoms of toxicity [TWiST] and quality-adjusted progression-free survival [QAPFS]). Efficacy and QOL outcomes were analysed in all randomly assigned patients (the full analysis set), and safety outcomes were analysed in all randomly assigned patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01874353, and is closed to new participants. The adjusted average mean change from baseline over the first 12 months in TOI was −2·90 (95% CI −4·13 to −1·67) with olaparib and −2·87 (−4·64 to −1·10) with placebo (estimated difference −0·03; 95% CI −2·19 to 2·13; p=0·98). Mean QAPFS (13·96 [SD 10·96] vs 7·28 [5·22] months; difference 6·68, 95% CI 4·98–8·54) and mean duration of TWiST (15·03 [SD 12·79] vs 7·70 [6·42] months; difference 7·33, 95% CI 4·70–8·96) were significantly longer with olaparib than with placebo. Olaparib maintenance therapy did not have a significant detrimental effect on HRQOL compared with placebo. There were clinically meaningful patient-centred benefits in both TWiST and QAPFS despite the adverse effects associated with olaparib. These patient-centred endpoints support the improvement in progression-free survival, the primary endpoint in SOLO2, and should be included in future trials of maintenance therapies.