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GR.5 Identification of molecular biomarkers of response to combinatorial PARP inhibition and immune checkpoint blockade in IDH-Mutant Gliomas

Published online by Cambridge University Press:  10 July 2025

Y Ellenbogen
Affiliation:
(Toronto)*
K Wang
Affiliation:
(Toronto)
V Patil
Affiliation:
(Toronto)
A Landry
Affiliation:
(Toronto)
J Liu
Affiliation:
(Toronto)
A Ajisebutu
Affiliation:
(Toronto)
L Yefet
Affiliation:
(Toronto)
C Gui
Affiliation:
(Toronto)
F Nassiri
Affiliation:
(Toronto)
E Chen
Affiliation:
(Toronto)
G Zadeh
Affiliation:
(Toronto)
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Abstract

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Background: The combination of PARP inhibitor and immune checkpoint inhibitors have been proposed as a potentially synergistic combinatorial treatment in IDH mutant 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-1 inhibitor Durvalumab. Methods: Patients with recurrent high-grade IDH-mutant gliomas were enrolled in a phase II open-label study (NCT03991832). Serum was collected at baseline and monthly and cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq) was performed. Binomial GLMnet models were developed and model performance was assessed using validation set data. Results: 29 patients were enrolled between 2020–2023. Patients received olaparib 300mg twice daily and durvalumab 1500mg IV every 4 weeks. The overall response rate was 10% via RANO criteria. 144 plasma samples were profiled with cfMeDIP-seq along with 30 healthy 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). Conclusions: The cell-free plasma DNA methylome exhibits highly specific signatures that enable accurate prediction of response to therapy.

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Abstracts
Copyright
© The Author(s), 2025. Published by Cambridge University Press on behalf of Canadian Neurological Sciences Federation