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Key eligibility criteria included age 18 years or older, performance status of 0\u20131, measurable disease, platinum-resistant disease and histologically confirmed epithelial ovarian cancer, fallopian tube carcinoma or primary peritoneal carcinoma. Primary endpoints included safety, tolerability, overall response rate (ORR) and disease control rate (DCR). Secondary endpoints included CA-125 response. The effect of combined epigenetic and immunotherapy was evaluated by transcriptomic analyses of 72 serially biopsied tumors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We show that the combination is moderately well tolerated and most common grade 3\u20134 adverse events are gastrointestinal side effects and anemia. ORR is 2.9% and DCR is 50%; with 3 of the 27 evaluable patients attaining a CA-125 response. Differential gene expression analyses reveal an upregulation of inflammatory and cytolytic genes and co-inhibitory checkpoints 6 weeks on-therapy. Upregulation of interferon signaling, antigen presentation and immune cell adhesion and migration gene sets are prominent on-therapy, together with an increase in density of CD8\u2009+\u2009T-cells. Patients with a CA-125 and\/or clinical response show an enrichment of adaptive and conserved immune response gene sets on-therapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings highlight the potential of epigenetic modulators to re-shape the tumor microenvironment of PROC toward a more inflammed phenotype and may point to approaches to augment immunotherapy response.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1038\/s43856-026-01404-0","type":"journal-article","created":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T09:38:52Z","timestamp":1770370732000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Pembrolizumab and epigenetic modification with azacitidine reshapes the tumor microenvironment of platinum-resistant epithelial ovarian cancer: a phase 2 non-randomized clinical trial"],"prefix":"10.1038","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5235-7410","authenticated-orcid":false,"given":"Blair V.","family":"Landon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5637-2696","authenticated-orcid":false,"given":"Julia L.","family":"Boland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea E.","family":"Wahner Hendrickson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah K.","family":"Armstrong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boris","family":"Winterhoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaime","family":"Wehr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9097-6511","authenticated-orcid":false,"given":"Akshaya V.","family":"Annapragada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Cherry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Archana","family":"Balan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guneet","family":"Kaleka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1195-438X","authenticated-orcid":false,"given":"Victor E.","family":"Velculescu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3697-3798","authenticated-orcid":false,"given":"Stephen B.","family":"Baylin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia A.","family":"Zahnow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis J.","family":"Slamon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gottfried E.","family":"Konecny","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9480-3047","authenticated-orcid":false,"given":"Valsamo","family":"Anagnostou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John A.","family":"Glaspy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,6]]},"reference":[{"key":"1404_CR1","first-page":"17","volume":"73","author":"RL Siegel","year":"2023","unstructured":"Siegel, R. 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V.A. is an inventor on patent applications (63\/276,525, 17\/779,936, 16\/312,152, 16\/341,862, 17\/047,006 and 17\/598,690) submitted by Johns Hopkins University related to cancer genomic analyses, ctDNA therapeutic response monitoring and immunogenomic features of response to immunotherapy that have been licensed to one or more entities. V.E.V. is a founder of Delfi Diagnostics\u00a0and Artemyx, serves on the Board of Directors\u00a0and owns stock of both organizations, which are subject to certain restrictions under university policy. Additionally, Johns Hopkins University owns equity in Delfi Diagnostics. V.E.V. divested his equity in Personal Genome Diagnostics (PGDx) to LabCorp in February 2022. V.E.V. is an inventor on multiple patent applications submitted by Johns Hopkins University related to cancer genomic and cell-free DNA analyses that have been licensed to one or more entities, including Delfi Diagnostics, Artemyx,\u00a0LabCorp, Qiagen, Sysmex, Agios, Genzyme, Esoterix, Ventana and ManaT Bio. Under the terms of these license agreements, the University and inventors are entitled to fees and royalty distributions. V.E.V. is an advisor to Viron Therapeutics and Epitope. These arrangements have been reviewed and approved by the Johns Hopkins University in accordance with its conflict-of-interest policies. A. A. is an inventor on patent applications submitted by Johns Hopkins University related to cfDNA and cancer detection that have been licensed to Delfi Diagnostics. D.S. is a corporate board member for BioMarin, TORL BioTherapeutics, and 1200 Pharma, is a consultant for Lilly, Novartis, Pfizer, and Seagen, has equity ownership in Amgen, Biomarin, Merck Sharp & Dohme, Pfizer, Seagen, Vertex, TORL BioTherapeutics, and 1200 Pharma, is on the speaker bureau (compensated) for Novartis, receives research funding from Novartis, Pfizer, and Seagen, receives travel support from Novartis and Pfizer, and receives honoraria from Novartis. G.E.K. is on speaker bureaus (compensated) for AstraZeneca, Merck, Immunogen\/Genmab, receives research funding (to the institution) from Lilly Inc., and Merck, receives travel support from TORL Biotherapeutics, and receives honoraria from Foundation Medicine for expert testimony. All other authors declare no conflicts of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"142"}}