Abstract
Gliomas remain one of the most formidable challenges in neuro-oncology due to their diffuse infiltration, treatment resistance, and high recurrence rates. A major subset of these tumours harbour mutations in isocitrate dehydrogenase (IDH), which lead to epigenetic reprogramming and impaired homologous recombination (HR) DNA repair, presenting a unique vulnerability to synthetic lethality-based interventions. Poly (ADP-ribose) polymerase (PARP) inhibitors, which target HR-deficient cells, have demonstrated preclinical efficacy against IDH-mutant gliomas. Despite the promise of both IDH and PARP inhibitors, monotherapy has yielded limited durable clinical responses. This paper explores the rationale for a dual-target approach combining IDH and PARP inhibitors, supported by mechanistic insights, preclinical studies, and emerging clinical trial data. It also addresses the challenges posed by tumour heterogeneity, clonal evolution, and toxicity management. Furthermore, it evaluates the potential of integrating immune checkpoint inhibitors and radiotherapy as part of combinatorial strategies. We conclude that while a dual-target approach holds great promise, its clinical success will depend on biomarker-driven stratification, adaptive trial designs, and a deeper understanding of glioma biology.