Chemotherapy with or without pembrolizumab followed by maintenance pembrolizumab with or without olaparib as first-line treatment of patients with advanced BRCA non-mutated epithelial ovarian cancer (ENGOT-OV43/GOG-3036/KEYLYNK-001): a randomised, double-blind, placebo-controlled, phase 3 trial.

We aimed to evaluate the efficacy and safety of pembrolizumab plus chemotherapy followed by pembrolizumab plus olaparib maintenance with or without bevacizumab as first-line treatment for patients with advanced BRCA1/2 non-mutated epithelial ovarian cancer.

我们旨在评估帕博利珠单抗联合化疗后继以帕博利珠单抗联合奥拉帕利维持治疗，有或无贝伐珠单抗作为一线治疗方案，对于BRCA1/2未突变的晚期上皮性卵巢癌患者的疗效和安全性。

Methods

This randomised, double-blind, active-controlled, placebo-controlled, phase 3 trial was conducted at 224 gynaecological oncology centres in 22 countries.

这是一项随机、双盲、活性对照、安慰剂对照的III期试验，在22个国家的224个妇科肿瘤中心进行。

Eligible participants were aged 18 years or older; had histologically confirmed stage III-IV epithelial ovarian, primary peritoneal, or fallopian tube cancer with no BRCA mutation; did not receive previous anti-PD-1, anti-PD-L1, or anti-PD-L2 therapy or an agent directed at another stimulatory or coinhibitory T-cell receptor or a PARP inhibitor; had an Eastern Cooperative Oncology Group performance status score of 0 or 1; and evaluable disease as per Response Evaluation Criteria in Solid Tumors (RECIST).

符合条件的参与者年龄在18岁或以上；经组织学证实为III-IV期上皮性卵巢癌、原发性腹膜癌或输卵管癌，且无BRCA突变；未接受过抗PD-1、抗PD-L1或抗PD-L2治疗，或针对其他刺激性或共抑制性T细胞受体的药物，或PARP抑制剂；东部肿瘤协作组（ECOG）表现状态评分为0或1；根据实体瘤反应评估标准（RECIST）有可评估的疾病。

After one lead-in chemotherapy cycle, participants were randomly assigned (1:1:1), using an integrated interactive voice and web response system, to receive pembrolizumab plus chemotherapy followed by pembrolizumab plus olaparib maintenance (pembrolizumab-olaparib group); pembrolizumab plus chemotherapy followed by pembrolizumab plus placebo maintenance (pembrolizumab group); or placebo plus chemotherapy followed by placebo maintenance (control group); and could receive bevacizumab at the investigators discretion.

经过一个引导性化疗周期后，参与者使用集成的互动语音和网络响应系统随机分配（1:1:1），接受帕博利珠单抗联合化疗后继以帕博利珠单抗联合奥拉帕利维持治疗（帕博利珠单抗-奥拉帕利组）；帕博利珠单抗联合化疗后继以帕博利珠单抗联合安慰剂维持治疗（帕博利珠单抗组）；或安慰剂联合化疗后继以安慰剂维持治疗（对照组）；并可根据研究者判断接受贝伐珠单抗。

Treatment allocation was stratified by PD-L1 combined positive score (CPS <10 vs ≥10), planned bevacizumab use, and surgery status.

治疗分配按PD-L1综合阳性评分（CPS <10 vs ≥10）、计划使用贝伐珠单抗和手术状态进行分层。

Planned treatment was intravenous pembrolizumab 200 mg (or matching placebo) every 3 weeks for 35 cycles, carboplatin plus paclitaxel (or docetaxel) chemotherapy according to local standard of care for five cycles, and maintenance oral olaparib 300 mg (or matching placebo) twice per day until discontinuation or up to 2 years.

计划的治疗是每3周静脉注射帕博利珠单抗200 mg（或匹配的安慰剂）共35个周期，根据当地标准护理使用卡铂加紫杉醇（或多西他赛）化疗共五个周期，以及维持口服奥拉帕利300 mg（或匹配的安慰剂）每日两次，直到停药或最多2年。

The primary endpoint was progression-free survival, tested first in the CPS (≥10) population and then in the intention-to-treat(ITT) population using a hierarchical testing strategy.

主要终点是无进展生存期，在CPS（≥10）人群中首先测试，然后在意向治疗（ITT）人群中使用分层测试策略进行测试。

This study is registered with ClinicalTrials.gov, NCT03740165 and is complete.

该研究已在ClinicalTrials.gov注册，编号为NCT03740165，研究已完成。

Results

Between Jan 30, 2019, and Aug 6, 2021, 2547 patients were assessed for eligibility, and 1367 were randomly assigned (ITT population) to receive pembrolizumab-olaparib (n=455), pembrolizumab (n=458), or the control (n=454).

在2019年1月30日至2021年8月6日期间，共有2547名患者接受了资格评估，其中1367名患者被随机分配（意向治疗人群）接受pembrolizumab-olaparib（n=455），pembrolizumab（n=458）或对照治疗（n=454）。

All participants were female and the median age was 61 years (IQR 52-68). 1084 (79%) of 1364 participants were White, 233 (17%) were Asian, 27 (2%) were of multiple race, 15 (1%) were Black or African American, and 5 (<1%) were American Indian or Alaska Native.

所有参与者均为女性，中位年龄为61岁（四分位数间距52-68）。在1364名参与者中，有1084名（79%）为白人，233名（17%）为亚洲人，27名（2%）为多种族，15名（1%）为黑人或非裔美国人，5名（<1%）为美洲印第安人或阿拉斯加原住民。

At the first interim analysis (Jan 9, 2023; median follow-up 30·1 months [IQR 23·9-37·0]), pembrolizumab-olaparib significantly improved progression-free survivalversus the control in the CPS (≥10; HR 0·63 [95% CI 0·49-0·80]; p<0·0001) and ITT populations (HR 0·68 [0·58-0·81]; p<0·0001).

在首次中期分析时（2023年1月9日；中位随访时间为30.1个月[四分位数间距23.9-37.0]），pembrolizumab-olaparib显著改善了CPS（≥10；风险比0.63[95%置信区间0.49-0.80]；p<0.0001）和ITT人群（风险比0.68[0.58-0.81]；p<0.0001）的无进展生存期，与对照组相比。

At the final analysis (Aug 26, 2024; median follow-up 49·6 months [IQR 43·4-56·5]), progression-free survivalwith pembrolizumab-olaparib was maintained (HR 0·66 [95% CI 0·53-0·83] in the CPS [≥10] population and 0·71 [0·61-0·84] in the ITT population).

在最终分析时（2024年8月26日；中位随访时间为49.6个月[四分位数间距43.4-56.5]），pembrolizumab-olaparib的无进展生存期得以维持（CPS[≥10]人群的风险比为0.66[95%置信区间0.53-0.83]，ITT人群的风险比为0.71[0.61-0.84]）。

Pembrolizumab alone compared with the control group remained non-significant in the CPS (≥10) population (HR 0·95 [0·77-1·19]; p=0·33); therefore, there was no formal testing of progression-free survivalin the ITT population. 297 (66%) of 452 participants in the pembrolizumab-olaparib group, 255 (56%) of 456 in the pembrolizumab group, and 232 (51%) of 454 in the control group had a grade 3 or higher treatment-related adverse event; the most common being neutropenia (102 [23%], 78 [17%], and 89 [20%]), anaemia (100 [22%], 59 [13%], and 48 [11%]), and neutrophil count decreased (66 [15%], 66 [15%], 68 [15%]).

与对照组相比，pembrolizumab单独使用在CPS（≥10）人群中的效果仍不显著（风险比0.95[0.77-1.19]；p=0.33）；因此，在ITT人群中没有进行无进展生存期的正式测试。在pembrolizumab-olaparib组的452名参与者中，有297名（66%）出现了3级或更高级别的治疗相关不良事件；最常见的为中性粒细胞减少症（102名[23%]，78名[17%]，89名[20%]），贫血（100名[22%]，59名[13%]，48名[11%]）和中性粒细胞计数减少（66名[15%]，66名[15%]，68名[15%]）。

Serious treatment-related adverse events were reported in 110 (24%) participants in the pembrolizumab-olaparib group, 96 (21%) in the pembrolizumab group, and 39 (9%) in the control group, with the most common being febrile neutropenia (19 [4%], 16 [4%], and nine [2%]).

在pembrolizumab-olaparib组中有110名（24%）参与者报告了严重的治疗相关不良事件，pembrolizumab组中有96名（21%），对照组中有39名（9%），最常见的为发热性中性粒细胞减少症（分别为19名[4%]，16名[4%]，9名[2%]）。

Treatment-related adverse events led to death in four (1%) participants in the pembrolizumab-olaparib group (cerebral haemorrhage, cholangitis sclerosing, haemophagocytic lymphohistiocytosis, and colitis), and one (<1%) in the pembrolizumab group (gastrointestinal haemorrhage).

治疗相关不良事件导致pembrolizumab-olaparib组中有四名（1%）参与者死亡（脑出血，硬化性胆管炎，噬血细胞性淋巴组织细胞增多症和结肠炎），而pembrolizumab组中有一名（<1%）参与者死亡（胃肠道出血）。

interpretation

Pembrolizumab plus chemotherapy followed by maintenance with pembrolizumab-olaparib showed a statistically significant and clinically meaningful improvement in progression-free survivalversus chemotherapy, suggesting that this regimen might have potential for patients with newly diagnosed BRCA non-mutated stage III-IV epithelial ovarian cancer.

帕博利珠单抗联合化疗后以帕博利珠单抗-奥拉帕利维持治疗显示出与单纯化疗相比，在无进展生存期上有统计学意义和临床意义的改善，这表明该方案可能对新诊断的BRCA非突变型III-IV期上皮性卵巢癌患者具有潜力。

funding

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA.

默克夏普与多姆有限责任公司，默克公司的子公司，位于美国新泽西州拉威。