Background: Diffuse gliomas are primary brain tumors characterized by substantial morbidity and mortality. Standard treatment includes maximal safe surgical resection followed by combination radiation and chemotherapy. Despite aggressive treatment, diffuse gliomas inevitably recur. Alkylating agents, and in particular temozolomide, play an important role in the treatment of gliomas, resulting in single-strand DNA breakages which require PARP activity for detection and repair. Gliomas with mutations in isocitrate dehydrogenase (IDH) 1 or 2 have an accumulation of 2-hydroxyglutarate (2HG) which results in a BRCA-like state of homologous recombination deficiency (HRD). When PARP is inhibited in the setting of HRD, single-strand DNA damage progresses to double-strand breaks resulting in synthetic lethality. PARP inhibition has also been shown to increase mutational burden and neoantigen expression (“immune-priming”) and increases tumor-infiltrating lymphocytes and expression of PD-L1. Here, we present an ongoing clinical trial combining the checkpoint inhibitor pembrolizumab, the PARP inhibitor olaparib, and temozolomide for treatment of recurrent gliomas with HRD. Methods: This is an open-label, non-randomized phase II trial of combination pembrolizumab, olaparib, and temozolomide for patients with recurrent glioma. The main study cohort (A) will consist of 52 patients with recurrent enhancing grade 2 or 3 IDH-mutant gliomas. An exploratory cohort (B) will consist of 5 patients with recurrent IDH-wildtype gliomas and mutations associated HRD. Study intervention is administered in 21-day cycles and includes pembrolizumab (200mg IV q3 weeks day 1), olaparib (200mg bid orally days 8-14) and temozolomide (50mg/m2 orally days 8-14). The primary outcome is overall response rate (ORR) in cohort A. Secondary objectives include safety and toxicity of triplet therapy, overall and progression-free survival, and best radiographic response. Exploratory objectives will describe outcomes in the IDH-wildtype cohort and associate response to tumor markers obtained through archival tissue and cell free DNA of cerebrospinal fluid. The trial includes a 6-patient safety lead-in to assess tolerability of triplet therapy. Cohort A patients must have grade 2 or 3 IDH-mutant glioma without known CDKN2A/B loss. Patients in Cohort B must have IDH-wildtype glioma with an alternate deleterious mutation involved in homologous recombination. Additional inclusion criteria include age ≥ 18, ECOG 0-1, and glioma recurrent after prior therapy with measurable disease by RANO. Patients must be on a stable dose of corticosteroids not to exceed 2mg/day. There are no restrictions regarding number of recurrences or prior therapies if an appropriate washout has been completed. To date, seven of 57 patients have enrolled. The safety-lead in was completed without dose-limiting toxicities. Clinical trial information: NCT05188508.