Olaparib well-tolerated but misses efficacy endpoint in high-grade glioma subset
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Olaparib monotherapy appeared well-tolerated and demonstrated evidence of antitumor activity among patients with heavily pretreated isocitrate dehydrogenase-mutant high-grade glioma, according to results of the phase 2 OLAGLI study.
Although the single-arm study, presented during the virtual ASCO Annual Meeting, did not achieve a predefined threshold for success in terms of PFS, the results support evaluation of the poly(ADP-ribose) polymerase (PARP) inhibitor with alkylating chemotherapy among this population in future studies, according to researchers.
“IDH [isocitrate dehydrogenase]-mutant high-grade gliomas recurring after surgery and chemotherapy represent an unmet medical need,” Francois Ducray, MD, neuro-oncologist at Hospices Civils de Lyon in France, said during a presentation. “Chemotherapy only leads to modest 6-month PFS rates, ranging from 30% to 50%, and IDH inhibitors seem to have limited efficacy in contrast-enhanced tumors. Therefore, we need new strategies and new clinical trials, and one of those strategies is the use of PARP inhibitors. Based on the promising results of studies showing IDH-mutant tumors could be vulnerable to PARP inhibition, we decided to test the efficacy of olaparib (Lynparza; AstraZeneca, Merck) monotherapy.”
Ducray and colleagues analyzed 35 patients with recurrent IDH-mutant glioma (median age, 48 years; range, 25-64) after radiotherapy and one or more lines (median, 2) of alkylating chemotherapy who received treatment at seven centers between March 2019 and October 2019. Initial diagnoses included low-grade glioma (60%), anaplastic glioma (28%) and glioblastoma (14%), with a median time since diagnosis of 7.4 years (range, 1-22) and median time since radiotherapy of 2.8 years (range, 0.6-18). All patients had a Karnofsky performance score of at least 60 (median, 80).
The most common IDH mutation was IDH1 R132H (91%). Sixteen patients (46%) had 1p/19d co-deletion.
Patients received 300 mg olaparib twice daily.
Six-month PFS according to Response Assessment in Neuro-Oncology (RANO) criteria served as the primary endpoint.
Ducray and colleagues hypothesized that olaparib monotherapy would result in a 6-month PFS rate of 50%. They analyzed PFS using a single-stage Fleming design with 80% power, for which the study would be deemed positive if 16 of the 35 patients were progression free at 6 months.
Median follow-up was 11 months.
Thirty patients stopped treatment due to tumor progression, whereas two remained on treatment 16 to 18 months after beginning the regimen.
The study did not meet its primary endpoint for efficacy: results showed 11 of the 35 patients were progression free at 6 months, for a 6-month PFS rate of 31%. Median PFS was 2.3 months.
Researchers reported no complete responses according to local investigator assessment. Two patients (5%) had a partial response and 14 patients (40%) had stable disease, with a median duration response of 9 months (range, 4-18). Median OS was 15.9 months.
Researchers observed similar median PFS and OS among patients with and without 1p/19d co-deletion.
Safety results showed five patients (14%) had grade 3 treatment-related adverse events, including diarrhea, fatigue, lymphopenia and aphasia, and 15 patients had grade 2 adverse events, with the majority reporting fatigue and/or lymphopenia. No grade 4 or grade 5 treatment-related adverse events occurred, and no patients had to discontinue olaparib due to adverse effects.
“In conclusion, olaparib monotherapy was well-tolerated; however, the PFS rate at 6 months did not reach the predefined threshold for success,” Ducray said. “We observed some evidence of antitumor activity in this heavily-treated population of IDH-mutant, high-grade gliomas. However, in this population, PARP inhibition alone doesn’t seem sufficient. Combining PARP inhibitors with chemotherapy may be a more effective strategy, and in our opinion, should be tested in the future in these patients.”
Perspective
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Manmeet S. Ahluwalia, MD, MBA
Elegant preclinical work from the lab of Ranjit Bindra, MD, PhD, at Yale University School of Medicine, demonstrated that IDH1/IH2-mutated glioma cells not only have reduced DNA repair capability, but also that 2-hydroxyglutarate (2-HG) may be the driving force of their cellular weakness. IDH mutations in glioma are neomorphic, inducing a change in the traditional function of the IDH protein. Mutated IDH generates the 2-HG oncometabolite that amplifies homologous recombinant deficiency, creating sensitivity to PARP inhibitors. This decreased homologous recombinant repair implies that this IDH-mutated disease has a “BRCA-ness”-type phenotype that can respond to PARP inhibitors. Xenograft models implanted with IDH-mutated human tumor cells were noted to be sensitive to PARP inhibition. Mice treated with olaparib monotherapy showed tumor growth delay that favored olaparib over the control. In the operative study, olaparib penetrated the contrast-enhanced glioma of patients.
In this phase 2 study, although olaparib was well-tolerated, it failed to meet its primary endpoint. Clinical activity seen in this select group of patients will need further exploration, including a biomarker that may predict efficacy. Future potential combination of PARP inhibition with either radiation, alkylating agents and/or immunotherapies will need additional mechanistic preclinical work.
Reference:
Sulkowski PL, et al. Sci Transl Med. 2017;doi:10.1126/scitranslmed.aal2463.
Miami Cancer Institute
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Ducray, F, et al. Abstract 2007. Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.
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