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Background: The efficacy and feasibility of pembrolizumab combined with chemotherapy in frontline management of advanced high-grade epithelial ovarian cancer (EOC) is unknown. Additionally, modification of the tumor microenvironment following neoadjuvant therapy is not well understood., Methods: In this single-arm phase 2 trial (this study was registered at ClinicalTrials.gov: NCT02520154), eligible patients received up to 4 cycles of neoadjuvant chemotherapy followed by interval cytoreduction, 3 cycles of adjuvant intravenous carboplatin/weekly paclitaxel/pembrolizumab, and finally maintenance pembrolizumab until progression or toxicity (maximum 20 cycles). The primary endpoint was progression-free survival (PFS). Secondary endpoints included feasibility, toxicity, and overall survival (OS). PD-L1 staining, multiplex immunofluorescence staining, RNA sequencing, reverse-phase protein array analyses were performed on pre- and post-chemotherapy samples., Findings: Thirty-one eligible patients were enrolled. Median PFS and OS was 14.88 (95% CI 12.39-23.00) and 57.43 months (95% CI 30.88-not reached), respectively. Among those with PD-L1 combined positive score (CPS) ≥10, the median PFS and OS were not reached compared to those with CPS <10 (10.50 and 30.90 months, respectively). Feasibility was met, with all patients completing their planned adjuvant cycles. Treatment discontinuation due to immune-related toxicity occurred in 6 patients (20%). Chemotherapy resulted in an infiltration of anti-tumor immune cells in the tumor microenvironment. Samples of patients with the best PFS demonstrated increased expression of NF-κB, TGF-β, and β-catenin signaling., Conclusions: Pembrolizumab with chemotherapy was feasible and resulted in PFS within the historical range for this EOC population. Patients with CPS ≥10 may benefit more from this regimen, and future studies should investigate this potential biomarker., Funding: This investigator-initiated trial was funded by Merck., Competing Interests: Declaration of interests S.N.W. reports grants from NIH, GOG Foundation, Cotinga Pharmaceuticals, Bayer, and ArQule during the conduct of the study. She also reports grants and personal fees from AstraZeneca, Clovis Oncology, GlaxoSmithKline/Tesaro, Roche/Genentech, and Novartis. She reports personal fees from Merck, Pfizer, Eisai, CIrculogene, Zentalis, and Agenus outside the submitted work. N.D.F. reports personal fees from Tesaro, Pfizer, Bristol Myers Squibb, and GlaxoSmithKline outside the submitted work. A.K.S. discloses the following competing interests: consulting (Merck, GSK, ImmunoGen, Iylon, Kiyatec, Astra Zeneca, Onxeo) and shareholder (BioPath). R.C. reports the following competing interests: consulting (Clovis Oncology, Genentech/Roche, AstraZeneca/MedImmune, Genmab, OncoMed, Immunogen, AbbVie, Agenus, Novocure, Merck, OncXerna Therapeutics, Alkermes, Gradalis, GlaxoSmithKline, Alkermes, Eisai, GOG Foundation, Karyopharm Therapeutics), employment (Vanium Group, US Oncology Network), leadership (Onsexo), stock and other ownership interests (McKesson/US Oncology Network), and research funding (AstraZeneca/MedImmune, Clovis Oncology, Merck, Roche/Genentech, Immunogen, Mirati Therapeutics, Amgen, Pfizer, Lilly, Regeneron, Alkermes, Karyopharm Therapeutics). A.A.J. reports personal fees from Gerson Lehrman Group, Guidepoint, Iovance advisory board, NuProbe, Simcere, PACT Pharma, Genentech-Roche, Eisai, Agenus, and Macrogenics. He also reports grants from AstraZeneca, Bristol Myers Squibb, Iovance, Aravive, Pfizer, Immatics US, Eli Lilly, and Merck, and stock/stock options from AvengeBio outside the submitted work., (Copyright © 2024 Elsevier Inc. All rights reserved.)