Multicenter phase 2 trial of the PARP inhibitor (PARPi) olaparib in recurrent IDH1 and IDH2-mutant contrast-enhancing glioma.
Authors: Fanucci Kristina , Pilat Mary Josephine Paula , Shah Ritu , Boerner Scott Anthony , Li Jing , Durecki Diane E. , Drappatz Jan , Collichio Frances A. , Puduvalli Vinay K. , Lieberman Frank S. , Gonzalez Javier , Giglio Pierre , Bao Xun , Ivy S. Percy , Bindra Ranjit , Omuro Antonio Marcilio Padula , LoRusso Patricia 
Published: June 2022

2035 Background: Isocitrate dehydrogenase ( IDH) 1 and IDH2 mutations ( IDH1/2mt) are the most common mutations in gliomas, occurring in over 70% of low grade and 20% of higher grade gliomas. IDH1/2mts are associated with improved prognosis, although tumors typically recur and progress to a higher grade despite first lines of treatment. Recent preclinical studies have suggested IDHmt and accumulation of 2-HG confer a “BRCAness” phenotype, a vulnerability that can be targeted through PARPi. To test this hypothesis, we conducted a multicenter study of olaparib monotherapy in patients (pts) with IDH1/2mt gliomas that had progressed despite standard therapy. Methods: Eligible pts had contrast enhancing and biopsy confirmed IDH1/2mt glioma that progressed despite standard therapy. Pts with prior treatment with PARPi or IDHmt inhibitors were excluded. The primary endpoint was overall response rate (ORR). Secondary objectives were progression free survival (PFS), overall survival (OS) and duration of response (DR). Olaparib 300 mg orally twice daily was given. A standard Simon 2 stage design was used. Stage 1 included 15 pts. If 2/15 pts responded stage 2 would expand by 30 pts. Responses were assessed with RANO criteria and reviewed centrally. Results: 15 evaluable pts were enrolled. Most recent histology as per 2021 WHO classification was 12 astrocytoma (4 grade 2, 3 grade 3, 5 grade 4) and 3 oligodendroglioma (2 grade 2, 1 grade 3). A total of 13 pts’ tumors had IDH1 R132H mutations; 2 pts had IDH2mt (R172G, R172K). All pts had >1 and 10 pts had >2 prior lines of systemic therapy (median 2, range 1-4). Most toxicities were grade 1 or 2. Nausea (67%) and fatigue (47%) were most frequent. Grade 3 lymphopenia, thrombocytopenia, and hypertension were seen in 1 patient each. Best response was stable disease (SD) in 9 pts and 6 pts had disease progression (PD). The median PFS was 3.6 months, 6-month PFS rate 26.7%, median OS 13.2 months. For pts with SD, median PFS was 5.5 months; 4 pts had SD for > 6 months. 2/6 pts with PD had confirmed WHO grade 4 by histology; 4 had CDKN2A deletion. CDKN2A deletion was unknown for 2 pts. Conclusions: Olaparib was well tolerated in this pt population. The study did not meet the pre-specified response-based threshold for moving to step 2, but prolonged SD was observed in pts with grades 2 and 3 histologies, suggesting olaparib monotherapy could be of clinical benefit in select pts. Grade 4 tumors per the 2021 WHO classification defined by histology or CDKN2A mutation derived minimal to no benefit from this drug highlighting the usefulness of this new classification for future patient stratification and trial design and suggesting investigation of this treatment earlier in the disease course might be of interest. Further studies are needed to identify other molecular or clinical predictive markers of benefit from PARPi as well as novel drug combinations for improved efficacy in this population. Clinical trial information: NCT03212274.