Olaparib in treatment‐refractory isocitrate dehydrogenase 1 (IDH1)– and IDH2‐mutant cholangiocarcinoma: Safety and antitumor activity from the phase 2 National Cancer Institute 10129 trial

Abstract Background Neomorphic isocitrate dehydrogenase ( IDH ) mutations lead to the accumulation of 2‐hydroxyglutarate (2‐HG), an oncometabolite implicated in tumor progression via inhibitory effects on alpha‐ketoglutarate. Moreover, mutant IDH –dependent accumulation of 2‐HG results in homologous recombination deficiency (HRD), which preclinically renders tumors sensitive to poly(adenosine diphosphate ribose) polymerase inhibitors. Here, the results of the cholangiocarcinoma (CCA) arm of the National Cancer Institute (NCI) 10129 olaparib in IDH ‐mutant solid tumors basket trial are reported. Methods Olaparib 300 mg twice daily was evaluated in an open‐label, phase 2 clinical trial for treatment‐refractory IDH ‐mutant solid tumors. Patients in the IDH ‐mutant CCA arm enrolled in two cohorts: (1) IDH inhibitor (IDHi) pretreated and (2) IDHi untreated, with a primary end point of overall response rate. Results NCI 10129 enrolled 30 patients with IDH ‐mutant CCA with no objective responses seen, and recruitment was closed early. Median progression‐free survival (PFS) was 2.4 months (95% CI, 1.9 to 6.5 months) and median overall survival was 12.9 months (95% CI, 6.3 months to not reached). Eight patients (27%) had clinical benefit (CB), with a PFS of ≥6 months. Patients with CB had lower baseline 2‐HG levels compared to those without CB (1.4 vs. 5.9 µmol/L; p = .01). Conclusions Olaparib does not have sufficient single‐agent activity to warrant further development in IDH ‐mutant CCA. However, a subgroup of patients demonstrated CB, and exploratory analysis revealed this subgroup to be enriched for lower baseline 2‐HG levels. Future clinical trials leveraging the HRD properties of IDH mutations are warranted with enhanced patient selection and novel combination therapies.