Multicenter Phase II Trial of the PARP Inhibitor Olaparib in Recurrent and -mutant Glioma.

PURPOSE

Isocitrate dehydrogenase () and mutations (mt) are frequent in glioma. Preclinical studies suggest 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 mt gliomas.

METHODS

Patients with recurrent, contrast-enhancing 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.

RESULTS

A total of 15 evaluable patients were enrolled. Histology was astrocytoma ( = 12) and oligodendroglioma ( = 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 ( = 6), 5 had grade 4 tumor and 4 had known alteration. PFS was 5.23 months for grades 2 or 3 tumors ( = 10) versus 1.8 months for grade 4 ( = 5; = 0.0013).

CONCLUSION

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 alteration derived no benefit from this drug, highlighting the usefulness of this classification for future patient stratification and trial design.

SIGNIFICANCE

A single-arm phase II trial of olaparib in -mutant glioma demonstrated clinically significant prolonged SD for select patients with grade 2/3 disease, suggesting potential benefit of olaparib in -mutant gliomas.