Introduction: The combination of PARP inhibitor and Immune Checkpoint Inhibitors have been proposed as a potentially synergistic combinatorial treatment in IDH mutant high-grade glioma, targeting dysregulated homologous recombination repair pathways. This study analyzed the cell-free DNA methylome of patients in a phase 2 trial using the PARP inhibitor Olaparib and the PD-L1 inhibitor Durvalumab. The goal was to evaluate cfDNA methylome as a non-invasive biomarker of therapy response.
Methods: Patients with recurrent high-grade IDH-mutant gliomas were enrolled in a phase II open-label study (NCT03991832). Patients received Olaparib 300 mg twice daily and durvalumab 1500 mg IV every 4 weeks. Serum was collected at baseline and monthly and cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq) was performed. The plasma samples were separated into 50 random discovery and validation sets with an 80:20 split. Binomial GLMnet models were developed for each response class versus others and model performance was assessed using validation set data. Area under receiver operating characteristic (ROC) curve (AUROC) values were calculated for each model in validation set data.
Results: 29 patients (median age 40.5; 41% female) enrolled between January 2020–February 2023. The tumor grade was 2 (n=9), 3 (n=8), and 4 (n=12). 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 ± 0.03). Additionally, samples that were taken while on treatment 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.
Conclusion : The cell-free plasma DNA methylome exhibits highly specific signatures that enable accurate prediction of response to therapy in a combinatorial trial of Olaparib and Durvalumab in recurrent IDH-mutant glioma.
.jpg)
