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. 2024 May 27;6(1):vdae078.
doi: 10.1093/noajnl/vdae078. eCollection 2024 Jan-Dec.

Olaparib in recurrent isocitrate dehydrogenase mutant high-grade glioma: A phase 2 multicenter study of the POLA Network

Ines Esparragosa Vazquez  1 , Marc Sanson  2   3 , Olivier L Chinot  4   5 , Maxime Fontanilles  6   7 , Romain Rivoirard  8 , Laure Thomas-Maisonneuve  1 , Stéphanie Cartalat  1 , Emeline Tabouret  4   5 , Romain Appay  4   9 , Alice Bonneville-Levard  10 , Amélie Darlix  11 , David Meyronet  12   13 , Marc Barritault  12   13 , François Gueyffier  14 , Laurent Remontet  15 , Delphine Maucort-Boulch  15 , Jérôme Honnorat  1   16 , Caroline Dehais  3 , François Ducray  1   12 ; POLA Network
Collaborators, Affiliations

Olaparib in recurrent isocitrate dehydrogenase mutant high-grade glioma: A phase 2 multicenter study of the POLA Network

Ines Esparragosa Vazquez et al. Neurooncol Adv. .

Abstract

Background: Based on preclinical studies showing that IDH-mutant (IDHm) gliomas could be vulnerable to PARP inhibition we launched a multicenter phase 2 study to test the efficacy of olaparib monotherapy in this population.

Methods: Adults with recurrent IDHm high-grade gliomas (HGGs) after radiotherapy and at least one line of alkylating chemotherapy were enrolled. The primary endpoint was a 6-month progression-free survival rate (PFS-6) according to response assessment in neuro-oncology criteria. Pre-defined threshold for study success was a PFS-6 of at least 50%.

Results: Thirty-five patients with recurrent IDHm HGGs were enrolled, 77% at ≥ 2nd recurrence. Median time since diagnosis and radiotherapy were 7.5 years and 33 months, respectively. PFS-6 was 31.4% (95% CI [16.9; 49.3%]). Two patients (6%) had an objective response and 14 patients (40%) had a stable disease as their best response. Median PFS and median overall survival were 2.05 and 15.9 months, respectively. Oligodendrogliomas (1p/19q codeleted) had a higher PFS-6 (53.4% vs. 15.7%, P = .05) than astrocytomas while an initial diagnosis of grade 4 astrocytoma tended to be associated with a lower PFS-6 compared to grade 2/3 gliomas (0% vs 31.4%, P = .16). A grade 2 or 3 treatment-related adverse event was observed in 15 patients (43%) and 5 patients (14%), respectively. No patient definitively discontinued treatment due to side effects.

Conclusions: Although it did not meet its primary endpoint, the present study shows that in this heavily pretreated population, olaparib monotherapy was well tolerated and resulted in some activity, supporting further PARP inhibitors evaluation in IDHm HGGs, especially in oligodendrogliomas.

Keywords: IDH; clinical trial; high-grade gliomas; olaparib.

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Conflict of interest statement

I.E.: none. M.S.: none. O.C.: none. M.F.: research purposes from Servier company, benefits for interventions from Seagen and Novocure, and payment of congress fees from Gilead and Pfizer. R.R.: Advisory board (Daiichi Sankyo, Lilly), travel grants (Amgen, Astra Zeneca, Bayer HealthCare SAS, Daiichi Sankyo, Lilly, MSD France, Novartis Pharma SAS, Pfizer, Roche). S.C.: MSD (travel grant). E.T.: Gliocure, Leo Pharma (advisory board), Leo Pharma (research grant), Novocure, Servier (symposium. A.B-L.: none. A. D.: Servier, Novocure (advisory board), Servier (travel grants). D.M.: none. M.B.: none. F.G.: none. L.R.: none. D.M-B.: none. J.H.: Novocure (travel grants, advisory board). C.D.: none. F.D.: Servier, Novocure (advisory board, symposium).

Figures

Figure 1.
Figure 1.
Swimmer plot showing time on therapy, time to events (progression according to RANO criteria, death), and best response (per local investigator) for each patient.
Figure 2.
Figure 2.
Progression-free survival and overall survival curves in the whole series (top left and right) and according to 1p/19q codeletion status and to grade at diagnosis (bottom left and right). PFS and OS in the whole series are shown with their corresponding 95% confidence interval.
See this image and copyright information in PMC

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