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Ref Type 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 Journal of Clinical Oncology
Vol 39
Issue 15_suppl
Date 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...