4 CTDNA METHYLATION PREDICTS RESPONSE TO PARP AND PD-1 BLOCKADE IN IDH-MUTANT GLIOMA

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Abstract The combination of PARP and immune checkpoint inhibitors has been proposed as a synergistic treatment strategy for IDH-mutant high-grade glioma, targeting homologous recombination repair deficiencies. This study evaluated circulating tumor DNA (ctDNA) methylation profiles in a phase II trial of the PARP inhibitor Olaparib and the PD-1 inhibitor Durvalumab. Methods: Patients with recurrent IDH-mutant high-grade gliomas were enrolled in an open-label phase II trial (NCT03991832). Serum samples were collected at baseline and monthly, followed by cell-free methylated DNA immunoprecipitation sequencing (cfMeDIP-seq). Plasma samples were randomly split into 50 discovery-validation sets (80:20). Binomial GLMnet models were trained to classify response status, with performance assessed in validation sets. Results: Among 29 patients (median age 40.5 years, 41% female) enrolled between January 2020 and February 2023, treatment included Olaparib 300 mg twice daily and Durvalumab 1500 mg IV every 4 weeks. The overall response rate was 10% (95% CI: 2.2–27%) per RANO criteria. cfMeDIP-seq identified a ctDNA methylation signature that differentiated responders from non-responders (AUC 0.98 ± 0.03). Multiomic analysis, including spatial transcriptomics, bulk gene expression, and DNA methylation, revealed enhanced immune infiltration and greater tumor heterogeneity in responders. Conclusions: ctDNA methylation profiling serves as a predictive biomarker for response to Olaparib-Durvalumab in recurrent IDH-mutant glioma, supporting its role in noninvasive treatment stratification.

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