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

Background: The PARP inhibitor olaparib is used for first-line maintenance of patients with BRCA-mutated advanced ovarian cancer. 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. Methods: This randomised, double-blind, active-controlled, placebo-controlled, phase 3 trial was conducted at 224 gynaecological oncology centres in 22 countries. 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). 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. Treatment allocation was stratified by PD-L1 combined positive score (CPS <10 vs ≥10), planned bevacizumab use, and surgery status. 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. 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. This study is registered with ClinicalTrials.gov, NCT03740165 and is complete. Findings: 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). 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. 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 survival versus 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). At the final analysis (Aug 26, 2024; median follow-up 49·6 months [IQR 43·4-56·5]), progression-free survival with 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). 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 survival in 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%]). 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%]). 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). Interpretation: Pembrolizumab plus chemotherapy followed by maintenance with pembrolizumab-olaparib showed a statistically significant and clinically meaningful improvement in progression-free survival versus chemotherapy, suggesting that this regimen might have potential for patients with newly diagnosed BRCA non-mutated stage III-IV epithelial ovarian cancer. Funding: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA.