Reference Detail

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Abstract

PMID

Authors

Francois Ducray, Marc Sanson, Olivier L. Chinot, Maxime Fontanilles, Romain Rivoirard, Laure Thomas-Maisonneuve, Stephanie Cartalat, Emeline Tabouret, Alice Bonneville-Levard, Amelie Darlix, Roxana Ameli, David Meyronet, Francois Gueyffier, Laurent Remontet, Delphine Maucort-Boulch, Caroline Dehais, Jerôme Honnorat, POLA Network

Title

Olaparib in recurrent IDH-mutant high-grade glioma (OLAGLI).

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of Clinical Oncology	39	15_suppl	May 20, 2021

URL

https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.15_suppl.2007

Abstract Text

Background: There is a need to develop new treatments in IDH-mutant high-grade gliomas recurring after radiotherapy and chemotherapy. Based on preclinical studies showing that IDH-mutant tumors could be vulnerable to PARP inhibition we launched a phase II study to test the efficacy of olaparib (Lynparza) monotherapy in this population. Methods: Adults with recurrent high-grade IDH-mutant gliomas after radiotherapy and at least one line of alkylating chemotherapy (PCV or TMZ), KPS > 60, normal organ function were enrolled. The primary endpoint was 6 months PFS according to RANO criteria. Patients were treated with olaparib 300 mg twice daily. We used a single-stage Fleming design with p0 = 30%, p1 = 50%, a type I unilateral error rate of 5% and a power of 80%. Results: 35 patients with recurrent IDH-mutant gliomas (IDH1R132H-mutant n = 32, other IDH mutation n = 3, 1p/19 codeleted n = 16, 1p/19q non-codeleted n = 14) were enrolled (malignantly transformed low-grade gliomas n = 21, anaplastic gliomas n = 8, glioblastomas n = 6). Median time since diagnosis was 7.4 years (1-22 years), median time since radiotherapy was 2.8 years (0.6-18 years), median number of previous chemotherapy lines was 2 (1-5). With a median follow-up of 11 months, 30 patients had stopped treatment due to tumor progression and 2 patients were still on treatment 16 to 18 months after treatment start. At 6 months, 11/35 patients were progression-free (31 %). According to RANO criteria, based on local investigator analysis, 2 patients (5%) had a partial response and 14 patients a stable disease (37%) with a median duration of response of 9 months (4-18 months+). Median PFS and OS were 2.3 and 15.9 months and were similar in 1p/19q codeleted and non-codeleted patients. A grade 3 olaparib-related adverse event was observed in 5 patients (14%, lymphopenia n = 3, fatigue n = 2, diarrhea n = 1) and a grade 2 in 15 patients (43%), most frequently consisting in fatigue (23%), gastrointestinal disorders (20%) and lymphopenia (20%). No patient definitively stopped olaparib due to side effects. Conclusions: In this heavily pre-treated population of recurrent IDH-mutant gliomas, olaparib monotherapy was well tolerated and resulted in some activity supporting its evaluation in association with alkylating chemotherapy in recurrent IDH-mutant gliomas in future studies.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
IDH1 R132H	high grade glioma	predicted - sensitive	Olaparib	Phase II	Actionable	In a Phase II trial (OLAGLI), Lynparza (olaparib) therapy was well tolerated in high grade glioma patients harboring IDH1 R132 (32/35) or other IDH mutations (3/35), and led to a partial response in 5% (2/35) and stable disease in 37% (14/35) of 35 evaluable patients, median progression-free survival (PFS) of 2.3 mo, median overall survival of 15.9 mo, a median duration of response of 9 mo, and a 6-mo PFS of 31% (11/35) (J Clin Oncol 39, no. 15_suppl (May 20, 2021) 2007-2007; NCT03561870).	detail...