Background: Epigenetic modulators may sensitize platinum-resistant ovarian cancer (PROC) to immune checkpoint inhibition by reprogramming the tumor microenvironment.
Methods: We report clinical and translational findings from a phase II non-randomized study of pembrolizumab and oral azacitidine in 34 women with PROC (NCT02900560). Key eligibility criteria included age 18 years or older, performance status of 0-1, 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.
Results: We show that the combination is moderately well tolerated and most common grade 3-4 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 + T-cells. Patients with a CA-125 and/or clinical response show an enrichment of adaptive and conserved immune response gene sets on-therapy.
Conclusions: 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.
A type of cancer immunotherapy called immune checkpoint inhibition (ICI) has shown limited effectiveness in ovarian cancer. This might be because of few active immune cells in the area surrounding the tumor, called the tumor microenvironment. Additional treatments called epigenetic modulators can be used to increase anti-tumor immune responses. Here we investigate if the combination of an epigenetic modulator with ICI can be used in women with ovarian cancer who have not significantly benefited from standard chemotherapy. The combination of epigenetic therapy with ICI was moderately well tolerated, and tumor growth was controlled in half of the women in the study. There was evidence that the tumor microenvironment changed by inducing an inflammatory profile. These findings show the potential of this combination therapy to alter the tumor microenvironment, and that this could enhance outcomes to cancer treatments.
© 2026. The Author(s).