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Ref Type Abstract
Authors Erica S. Tsang, Grainne M. O'Kane, Jennifer J. Knox, Eric X Chen
Title A phase II study of olaparib and durvalumab in patients with IDH-mutated cholangiocarcinoma.
Abstract Text Background: IDH1/2 mutations (m) occur in approximately 25% of cholangiocarcinomas (CCAs) (20% intrahepatic, < 5% extrahepatic) and result in the accumulation of R-2-hydroxyglutarate (R2HG). R2HG, suppresses homologous recombination repair and as a result IDH1/2m are hypothesized to predict PARP inhibitor sensitivity. PARP inhibition upregulates PD-L1 and the combination is thought to be synergistic. We conducted a phase II trial of olaparib with durvalumab for patients with IDH-mutated cholangiocarcinoma. Methods: Patients with advanced IDHm CCA were enrolled in this phase II open-label study (NCT03991832). Patients received olaparib 300 mg twice daily continuously and durvalumab 1500 mg IV every 4 weeks. Simon’s optimal two-stage design was used, with an interim analysis planned for efficacy. 10 patients were accrued in the first stage, with a plan for expansion if ≥2 responses were observed. The primary objective was to determine the overall response rate (RECIST 1.1) and disease control rate (DCR). Secondary objectives included progression-free survival, overall survival, and safety of the olaparib and durvalumab combination. Results: 10 patients with IDH1m were enrolled in this study between January 2020-August 2021. Median age was 63.5 years (range 49-78), and 50% were female. All patients had a baseline ECOG PS of 0-1. 40% of patients had prior surgical resections and subsequently developed recurrent disease. 20% of patients had ³2 lines of prior chemotherapy, with 90% receiving prior platinum. Median duration of treatment was 1.95 months (range 1.8-13.5). There were no treatment-related grade 3-4 toxicities. Any grade toxicities included fatigue (100%), nausea (60%), anemia (20%), hypothyroidism (20%), elevated liver enzymes (20%). We did not observe any complete or partial responses. The DCR was 30% with 3 patients demonstrating stable disease. One patient remained on treatment for 13.5 months, and was eventually taken off study due to clinical progression. The median PFS was 1.97 months (95% CI 1.73-3.93). Given that no responses were seen in the initial 10 patients, the study did not proceed to Stage 2. Conclusions: While the combination of olaparib and durvalumab was well-tolerated, this study was discontinued after Stage I due to lack of efficacy. IDH1/2m may not induce a BRCAness phenotype and further correlative studies are planned to evaluate this. Clinical trial information: NCT03991832.


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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 mutant cholangiocarcinoma no benefit Durvalumab + Olaparib Phase II Actionable In a Phase II trial, combination treatment with Lynparza (olaparib) and Imfinzi (durvalumab) was well tolerated but failed to demonstrate efficacy in patients with advanced cholangiocarcinoma harboring mutations in IDH1 or IDH2, with no objective responses, a disease control rate of 30% (3/10, 3 stable disease), and a median progression-free survival of 1.97 months (J Clin Oncol 41, 2023 (suppl 16; abstr 4099); NCT03991832). detail...