Data from Multicenter Phase II Trial of the PARP Inhibitor Olaparib in Recurrent <i>IDH1-</i> and <i>IDH2</i>-mutant Glioma

Abstract

<div>Purpose:<p>Isocitrate dehydrogenase (<i>IDH</i>) <i>1</i> and <i>IDH2</i> mutations (<i>IDH1/2</i>mt) are frequent in glioma. Preclinical studies suggest <i>IDH1/2</i>mts confer “BRCAness” phenotype, a vulnerability that can be targeted through PARP inhibition. To test this hypothesis, we conducted a multicenter study of olaparib monotherapy in patients with <i>IDH1/2</i>mt gliomas.</p>Methods:<p>Patients with recurrent, contrast-enhancing <i>IDH1/2</i>mt gliomas were enrolled in a two-step phase II trial; the primary endpoint was overall response rate per Response Assessment in Neuro-Oncology (RANO) criteria. Olaparib 300 mg orally twice daily was given.</p>Results:<p>A total of 15 evaluable patients were enrolled. Histology was astrocytoma (<i>N</i> = 12) and oligodendroglioma (<i>N</i> = 3). Most toxicities were grade 1 or 2. Best response was stable disease (SD) in 9 (60%) patients. Median progression-free survival (PFS) was 3.63 months and median overall survival was 20.7 months. For patients with SD, median PFS was 5.53 months; 4 patients had SD for >6 months. Among patients with best response progressive disease (<i>N</i> = 6), 5 had grade 4 tumor and 4 had known <i>CDKN2A</i> alteration. PFS was 5.23 months for grades 2 or 3 tumors (<i>N</i> = 10) versus 1.8 months for grade 4 (<i>N</i> = 5; <i>P</i> = 0.0013).</p>Conclusion:<p>The study did not meet the prespecified response-based activity threshold for moving to step 2. However, prolonged SD was observed in patients with grades 2 and 3 histologies, suggesting olaparib monotherapy could be of clinical benefit in select populations. Grade 4 tumors per 2021 World Health Organization classification defined by histology or <i>CDKN2A</i> alteration derived no benefit from this drug, highlighting the usefulness of this classification for future patient stratification and trial design.</p>Significance:<p>A single-arm phase II trial of olaparib in <i>IDH</i>-mutant glioma demonstrated clinically significant prolonged SD for select patients with grade 2/3 disease, suggesting potential benefit of olaparib in <i>IDH</i>-mutant gliomas.</p></div>