PLATINUM-RESISTANT ovarian cancer showed evidence of tumour microenvironment reprogramming towards an inflamed immune phenotype following combined epigenetic and immune checkpoint therapy, according to findings from a phase two clinical study.
Unmet Need in Platinum-Resistant Ovarian Cancer
Platinum-resistant ovarian cancer is associated with poor outcomes and limited treatment options, with immune checkpoint inhibition demonstrating modest clinical benefit to date. One proposed explanation is the immunologically cold tumour microenvironment, characterised by low immune cell infiltration. Epigenetic modulators have been suggested as a means of sensitising tumours to immunotherapy by altering gene expression and immune signalling pathways. Investigators therefore evaluated the combination of pembrolizumab and oral azacitidine to assess safety, clinical activity, and biological effects within the tumour microenvironment.
Clinical Activity and Safety
The non-randomised phase two study enrolled 34 women with platinum-resistant ovarian cancer, including epithelial ovarian, fallopian tube, and primary peritoneal carcinoma. All participants had measurable disease and good performance status. Primary endpoints included safety, tolerability, overall response rate, and disease control rate.
The combination was reported to be moderately well tolerated. The most common grade three to four adverse events were gastrointestinal toxicities and anaemia. The overall response rate was 2.9%, while disease control was achieved in 50% of patients. Among the 27 evaluable patients, three achieved a CA-125 response, indicating biochemical evidence of disease control despite limited radiological responses.
Immune Reprogramming of the Tumour Microenvironment
Translational analyses were performed using transcriptomic profiling of 72 serial tumour biopsies. On-therapy assessments at six weeks demonstrated significant upregulation of inflammatory and cytolytic genes, alongside increased expression of co-inhibitory immune checkpoints. Gene sets related to interferon signalling, antigen presentation, and immune cell adhesion and migration were also enriched during treatment.
An increase in CD8 positive T cell density within tumours was observed, supporting enhanced immune infiltration. Importantly, patients who achieved a CA-125 and or clinical response showed greater enrichment of adaptive and conserved immune response gene signatures during therapy.
Overall, the findings suggest that epigenetic modulation can reshape the tumour microenvironment in platinum-resistant ovarian cancer towards a more inflamed and immunologically active state.
Reference
Landon BV et al. Pembrolizumab and epigenetic modification with azacitidine reshapes the tumor microenvironment of platinum-resistant epithelial ovarian cancer: a phase 2 non-randomized clinical trial. Communications Medicine. 2026; doi:10.1038/s43856-026-01404-0.
