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Purpose: Isocitrate dehydrogenase-mutant (IDH-mt) gliomas are incurable primary brain tumors characterized by a slow-growing phase over several years followed by a rapid-growing malignant phase. We hypothesized that tumor volume growth rate (TVGR) on MRI may act as an earlier measure of clinical benefit during the active surveillance period., Experimental Design: We integrated three-dimensional volumetric measurements with clinical, radiologic, and molecular data in a retrospective cohort of IDH-mt gliomas that were observed after surgical resection in order to understand tumor growth kinetics and the impact of molecular genetics., Results: Using log-linear mixed modeling, the entire cohort (n = 128) had a continuous %TVGR per 6 months of 10.46% [95% confidence interval (CI), 9.11%-11.83%] and a doubling time of 3.5 years (95% CI, 3.10-3.98). High molecular grade IDH-mt gliomas, defined by the presence of homozygous deletion of CDKN2A/B, had %TVGR per 6 months of 19.17% (95% CI, 15.57%-22.89%) which was significantly different from low molecular grade IDH-mt gliomas with a growth rate per 6 months of 9.54% (95% CI, 7.32%-11.80%; P < 0.0001). Using joint modeling to comodel the longitudinal course of TVGR and overall survival, we found each one natural logarithm tumor volume increase resulted in more than a 3-fold increase in risk of death (HR = 3.83; 95% CI, 2.32-6.30; P < 0.0001)., Conclusions: TVGR may be used as an earlier measure of clinical benefit and correlates well with the WHO 2021 molecular classification of gliomas and survival. Incorporation of TVGR as a surrogate endpoint into future prospective studies of IDH-mt gliomas may accelerate drug development., (©2023 American Association for Cancer Research.)

Background and Objectives: To report the tolerability and efficacy of olaparib with temozolomide (TMZ) for glioma., Methods: Single-center retrospective series of patients with glioma treated with olaparib/TMZ from September 2018 to December 2021., Results: Twenty patients (median age: 42 years, median Karnofsky Performance Status: 90) received olaparib/TMZ for diagnoses of IDH -mutant oligodendroglioma (n = 5), IDH- mutant astrocytoma grade 2-3 (n = 4), IDH -mutant astrocytoma grade 4 (n = 7), or IDH- wildtype glioma (n = 4). One patient was treated upfront and 19 at recurrence (median = 3). Olaparib 150 mg was administered 3 times/week concurrent with TMZ 50-75 mg/m 2 daily. Fatigue, gastrointestinal symptoms, and hematologic toxicity were common. Six of 20 patients required dose reduction (n = 4) or discontinuation (n = 2) due to toxicity. Radiographic response was evaluable in 16 and observed (complete + partial) in 4/8 with IDH -mutant grade 2-3 glioma. No responses were seen in patients with grade 4 IDH -mutant astrocytomas (0/5) or IDH -wildtype gliomas (0/3). Progression-free survival was 7.8, 1.3, and 2.0 months, respectively., Discussion: Olaparib/TMZ resulted in objective radiographic response in 50% of evaluable patients with recurrent IDH -mutant grade 2-3 gliomas with encouraging progression-free survival and manageable toxicity. This supports a prospective trial of olaparib/TMZ for this population., Classification of Evidence: This case series provides Class IV evidence that treatment with olaparib/TMZ may result in radiographic response in patients with glioma., (© 2022 American Academy of Neurology.)