CTNI-62. A SURGICAL WINDOW-OF-OPPORTUNITY TRIAL OF NIRAPARIB IN RECURRENT IDH-MUTANT GLIOMAS

Abstract BACKGROUND Excess D-2-hydroxyglutarate (2-HG) produced by mutant IDH enzymes hampers the ability of gliomas to repair DNA damage. We conducted a surgical window-of-opportunity trial of the selective PARP1/2 inhibitor niraparib in recurrent IDH-mutant glioma to assess tumor drug penetration and pharmacodynamics. METHODS Subjects with progressive, surgically accessible IDH-mutant glioma were randomized 1:1 to receive niraparib or no treatment for 4 weeks prior to tumor resection. Following surgery, all patients received niraparib (300 or 200 mg daily) until disease progression. Enhancing and non-enhancing tumor tissue were collected at surgery. Drug concentration and 2-HG levels were measured with MALDI-MSI. The primary objective was to measure intratumoral drug concentration. Secondary objectives included safety, target engagement and anti-tumor effect. RESULTS Seven patients (F=0%, M=100%) with a median age of 37 years (range 23-47 years) were enrolled; three received pre-operative niraparib. The mean intratumoral niraparib concentration was 19.0 mM (n=5 samples, 3 patients), with 30.8 mM in enhancing (n=2) and 16.4 mM in non-enhancing (n=3) tissue. Mean 2-HG concentration was 2.3 mM (n=9 samples from 6 patients; range 0.3 – 7.9), 2-HG was below the level of detection in one patient who was subsequently found to not have active tumor at surgery. No correlation was found between 2HG level and receipt of pre-operative niraparib. Grade ≥ 3 hematologic toxicities occurred in 2/6 patients, including one grade 4 lymphopenia and one grade 3 anemia. Other treatment-related adverse events were grade 1–2. Median PFS and OS were 1.94 (95 % CI, 1.0–2.7) and 15.5 months (95% CI of 4 - NA), respectively. CONCLUSION Niraparib was generally well tolerated but demonstrated limited anti-tumor activity in this patient population despite evidence of sufficient drug penetration in both enhancing and non-enhancing tumor. Results from ongoing spatial metabolomics and transcriptomics (Visium) to further evaluate pharmacodynamic effects will be presented. GSK provided funding and drug [NCT05406700].