From Centre Léon Bérard (I.R.-C., D.P.), University Claude Bernard Lyon 1 (I.R.-C.), and Centre Hospitalier Lyon-Sud (B.Y.), Lyon, Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens (GINECO) (I.R.-C., P.P., F.S., C.L.-P., A.L., P.C., M.R., C.D., B.Y., E.P.-L.), Groupe Hospitalier Diaconesses Croix Saint-Simon (F.S.), Hôpital Européen Georges Pompidou (P.C.), Institut Curie, Hôpital Claudius Régaud (M.R.), and Association de Recherche Cancers Gynécologiques (ARCAGY) (E.P.-L.), Paris, Gustave Roussy, Villejuif (P.P.), Centre Eugène Marquis, Rennes (C.L.-P.), Centre Catherine de Sienne Hôpital Privé du Confluent, Nantes (A.L.), and Institut Curie, Hôpital René Huguenin, Saint Cloud (C.D.) - all in France; the Department of Urology and Gynecology, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, and Multicenter Italian Trials in Ovarian Cancer and Gynecologic Malignancies (MITO), Naples (S.P.), University of Milan-Bicocca and European Institute of Oncology IRCCS, and Mario Negri Gynecologic Oncology Group (MANGO) (N.C.), and Fondazione IRCCS Istituto Nazionale Tumori and MITO (D.L.), Milan, and Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica, and MITO, Rome (G.S.) - all in Italy; M.D. Anderson Cancer Center Madrid (A.G.-M.), Grupo Español de Investigación en Cáncer de Ovario (GEICO) (A.G.-M., E.M.G.A.), and Hospital Universitario Ramón y Cajal (E.M.G.A.) - all in Madrid; Medical University of Innsbruck, University Clinic for Gynecology and Obstetrics (R.B.), and Arbeitsgemeinschaft Gynäkologische Onkologie Study Group (AGO)-Austria (R.B., A.R.), Innsbruck, and Medical University of Vienna, Vienna (A.R.) - all in Austria; Saitama Medical University International Medical Center, Hidaka (K.F.), Gynecologic Oncology Trial and Investigation Consortium (GOTIC), Moroyama-cho (K.F., S.N.), and Hyogo Cancer Center, Akashi (S.N.) - all in Japan; University Hospital Leuven, Leuven Cancer Institute, and Belgium and Luxembourg Gynecologic Oncology Group (BGOG) - both in Leuven, Belgium (I.V.); Tampere University and University Hospital, Tampere, Finland (J.M.); the Nordic Society of Gynecologic Oncology (NSGO), Copenhagen (J.M.); and Charité-Medical University of Berlin (Campus Virchow Klinikum), Berlin (J.S.), German Society of Gynecologic Oncology (AGO) (J.S., U.C., F.M., N.G., P.B., A.B., P.H.), Universitätsklinikum Essen (P.B.), and Kliniken Essen Mitte (P.H.), Essen, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden (U.C.), Universitätsklinikum Heidelberg, Heidelberg (F.M.), Universitätsklinikum Ulm, Ulm (N.G.), and Klinikum der Universität München, Munich (A.B.) - all in Germany.
N Engl J Med. 2019 Dec 19;381(25):2416-2428. doi: 10.1056/NEJMoa1911361.
BACKGROUND: Olaparib has shown significant clinical benefit as maintenance therapy in women with newly diagnosed advanced ovarian cancer with a mutation. The effect of combining maintenance olaparib and bevacizumab in patients regardless of mutation status is unknown. METHODS: We conducted a randomized, double-blind, international phase 3 trial. Eligible patients had newly diagnosed, advanced, high-grade ovarian cancer and were having a response after first-line platinum-taxane chemotherapy plus bevacizumab. Patients were eligible regardless of surgical outcome or mutation status. Patients were randomly assigned in a 2:1 ratio to receive olaparib tablets (300 mg twice daily) or placebo for up to 24 months; all the patients received bevacizumab at a dose of 15 mg per kilogram of body weight every 3 weeks for up to 15 months in total. The primary end point was the time from randomization until investigator-assessed disease progression or death. RESULTS: Of the 806 patients who underwent randomization, 537 were assigned to receive olaparib and 269 to receive placebo. After a median follow-up of 22.9 months, the median progression-free survival was 22.1 months with olaparib plus bevacizumab and 16.6 months with placebo plus bevacizumab (hazard ratio for disease progression or death, 0.59; 95% confidence interval [CI], 0.49 to 0.72; P<0.001). The hazard ratio (olaparib group vs. placebo group) for disease progression or death was 0.33 (95% CI, 0.25 to 0.45) in patients with tumors positive for homologous-recombination deficiency (HRD), including tumors that had mutations (median progression-free survival, 37.2 vs. 17.7 months), and 0.43 (95% CI, 0.28 to 0.66) in patients with HRD-positive tumors that did not have mutations (median progression-free survival, 28.1 vs. 16.6 months). Adverse events were consistent with the established safety profiles of olaparib and bevacizumab. CONCLUSIONS: In patients with advanced ovarian cancer receiving first-line standard therapy including bevacizumab, the addition of maintenance olaparib provided a significant progression-free survival benefit, which was substantial in patients with HRD-positive tumors, including those without a mutation. (Funded by ARCAGY Research and others; PAOLA-1 ClinicalTrials.gov number, NCT02477644.).
背景：奥拉帕利作为维持治疗药物，在携带 BRCA1/2 突变的新诊断晚期卵巢癌患者中显示出显著的临床获益。在无论 BRCA 突变状态如何的患者中，联合使用维持奥拉帕利和贝伐珠单抗的效果尚不清楚。
方法：我们开展了一项随机、双盲、国际 3 期临床试验。入组患者为新诊断的晚期高级别卵巢癌，在接受一线含铂类紫杉类化疗联合贝伐珠单抗治疗后有缓解。无论手术结果或 BRCA 突变状态如何，患者均有资格入组。患者按 2:1 的比例随机分配，接受奥拉帕利片（每日 2 次，每次 300mg）或安慰剂治疗，最长 24 个月；所有患者接受贝伐珠单抗治疗，剂量为每公斤体重 15mg，每 3 周 1 次，总疗程最多 15 个月。主要终点为自随机分组至研究者评估的疾病进展或死亡时间。
结果：在 806 例接受随机分组的患者中，537 例患者被分配接受奥拉帕利治疗，269 例患者接受安慰剂治疗。中位随访 22.9 个月时，奥拉帕利联合贝伐珠单抗组的无进展生存期为 22.1 个月，安慰剂联合贝伐珠单抗组为 16.6 个月（疾病进展或死亡风险的 HR，0.59；95%CI，0.49 至 0.72；P<0.001）。在同源重组缺陷（HRD）阳性的患者中（包括存在 BRCA 突变的患者[中位无进展生存期，37.2 个月 vs. 17.7 个月]），疾病进展或死亡的 HR 为 0.33（95%CI，0.25 至 0.45）；在 HRD 阳性但无 BRCA 突变的患者中（中位无进展生存期，28.1 个月 vs. 16.6 个月），HR 为 0.43（95%CI，0.28 至 0.66）。不良事件与奥拉帕利和贝伐珠单抗的既定安全性特征一致。
结论：在接受包括贝伐珠单抗在内的一线标准治疗的晚期卵巢癌患者中，添加维持奥拉帕利可显著改善无进展生存期，在 HRD 阳性肿瘤患者中获益更大，包括那些无 BRCA 突变的患者。（由 ARCAGY Research 等资助；PAOLA-1 ClinicalTrials.gov 编号，NCT02477644。）
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