Abstract 3680: Plasma DNA methylome profiling predicts response to olaparib and durvalumab in recurrent IDH-mutant gliomas: Results from a phase II trial

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Abstract Background: Combing PARP and Immune Checkpoint inhibition has been proposed as a potentially synergistic strategy in IDH mutant glioma, targeting dysregulated homologous recombination repair pathways. We analyzed the cell-free DNA (cfDNA) methylome of patients in a phase 2 trial using the PARP inhibitor olaparib and the PD-1 inhibitor durvalumab. The primary objective was to evaluate cfDNA methylome as a non-invasive biomarker of response. Methods: Patients with recurrent IDH-mutant gliomas were enrolled in a phase II open-label study (NCT03991832). Blood samples were collected at baseline and monthly while on treatment. Cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq) was performed. Samples were separated into 50 random discovery and validation sets with an 80:20 split. Binomial regularized regression models were developed for each response class versus others using the discovery set and model performance was assessed using the validation set. Area under receiver operating characteristic (ROC) curve (AUROC) values were calculated for each model in the validation set. Results: 29 patients (median age 40.5; 41% female) enrolled between January 2020-February 2023. The initial tumor grade was 2 (n=9), 3 (n=8), and 4 (n=12). Patients received olaparib 300 mg twice daily and durvalumab 1500 mg IV every 4 weeks. The overall response rate was 10% (95% CI 2.2-27%) via RANO criteria. 144 plasma samples (from 29 patients) were profiled with cfMeDIP-seq along with 30 healthy controls. The circulating tumour DNA methylome was enriched by normalizing to differentially methylated regions not found within the normal controls. The enriched circulating tumour DNA methylome during response periods exhibited a highly specific signature, accurately discriminating response versus failure (AUC 0.98 ± 0.02). Additionally, on-treatment samples were able to be discriminated from samples off therapy (AUC 0.74 + 0.11). Lastly, the specific differentially methylated gene pathways between groups were comprehensively examined in both plasma samples and baseline tumor tissue. Conclusions: Plasma cfDNA methylome exhibits highly specific signatures that enable accurate prediction of response to olaparib and durvalumab in recurrent IDH-mutant glioma. Citation Format: Yosef Ellenbogen, Xin Wang, Vikas Patil, Alexander Landry, Justin Wang, Jeffrey Zuccato, Mathew Voisin, Andrew Ajisebutu, Leeor Yefet, Farshad Nassiri, Eric Chen, Gelareh Zadeh. Plasma DNA methylome profiling predicts response to olaparib and durvalumab in recurrent IDH-mutant gliomas: Results from a phase II trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3680.

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