The role of dordaviprone in the multidisciplinary management of diffuse midline glioma

Background: Diffuse midline glioma (DMG) is a rare and aggressive pediatric and young adult brain tumor arising from midline structures of the central nervous system. Surgical resection is not possible due to its infiltrative nature, and radiotherapy remains the only standard treatment with limited benefit. Chemotherapy has failed to improve survival because of poor blood–brain barrier (BBB) penetration. Dordaviprone (ONC201), a dopamine receptor D type 2 (DRD2/3) antagonist and caseinolytic protease proteolytic (ClpP) agonist that crosses the BBB, has shown promising and durable activity in H3K27M-mutant DMG and was granted Food and Drug Administration accelerated approval in 2025. Methods: A structured narrative search of the literature was conducted using PubMed, Scopus, Google Scholar, and ClinicalTrials.gov from 2015 to 2025, with emphasis on studies published in the past 5 years. Search terms included ONC201, dordaviprone, H3K27M, H3 K27-altered DMG, ClpP, DRD2 antagonism, integrated stress response, and DMG clinical trials. Reference lists of key articles were also screened to identify additional sources. Results: Dordaviprone acts through dual mechanisms involving ClpP activation and DRD2 antagonism, leading to mitochondrial dysfunction and tumor cell death. It has demonstrated selective efficacy in preclinical and clinical studies, with manageable side effects such as fatigue, nausea, and headache. The drug is administered orally once weekly and is well tolerated. Conclusion: Dordaviprone offers a new targeted systemic therapy for DMG with proven safety, good tolerability, and meaningful clinical benefit.