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
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 recombinati...
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| Published in | Cancer Vol. 131; no. 4; pp. e35755 - n/a |
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| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
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United States
Wiley Subscription Services, Inc
15.02.2025
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| Online Access | Get full text |
| ISSN | 0008-543X 1097-0142 1097-0142 |
| DOI | 10.1002/cncr.35755 |
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| 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.
Olaparib did not reveal radiographic response for patients with isocitrate dehydrogenase 1 (IDH1)– and IDH2‐mutant cholangiocarcinoma. However, prolonged disease control was seen in a subset of patients, which correlated with lower tumor 2‐hydroxyglutarate levels and prior treatment with an IDH inhibitor. |
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| AbstractList | 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.
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.
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).
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. Olaparib did not reveal radiographic response for patients with isocitrate dehydrogenase 1 ( IDH1 )– and IDH2 ‐mutant cholangiocarcinoma. However, prolonged disease control was seen in a subset of patients, which correlated with lower tumor 2‐hydroxyglutarate levels and prior treatment with an IDH inhibitor. 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. Olaparib did not reveal radiographic response for patients with isocitrate dehydrogenase 1 (IDH1)– and IDH2‐mutant cholangiocarcinoma. However, prolonged disease control was seen in a subset of patients, which correlated with lower tumor 2‐hydroxyglutarate levels and prior treatment with an IDH inhibitor. BackgroundNeomorphic 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.MethodsOlaparib 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.ResultsNCI 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).ConclusionsOlaparib 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. 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.BACKGROUNDNeomorphic 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.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.METHODSOlaparib 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.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).RESULTSNCI 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).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.CONCLUSIONSOlaparib 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. |
| Author | Ahnert, Jordi Rodon Niger, Monica Davis, Elizabeth J. Pilat, Mary Jo LoRusso, Patricia M. Chen, Li Boerner, Scott A. Patel, Abhijit Cho, May Drappatz, Jan Bindra, Ranjit Ivy, Percy Groisberg, Roman Narayan, Azeet Cecchini, Michael Khagi, Simon Shyr, Derek Shyr, Yu Bao, Xun Vu, Dennis Tinoco, Gabriel Doroshow, Deborah Li, Jing Uboha, Nataliya Azad, Nilofer S. Shapiro, Geoffrey I. Powers, Benjamin Das, Biswajit Spencer, Kristen Durecki, Diane |
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/39917990$$D View this record in MEDLINE/PubMed |
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| Keywords | poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor isocitrate dehydrogenase (IDH) mutation DNA repair cholangiocarcinoma olaparib |
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Neomorphic isocitrate dehydrogenase (IDH) mutations lead to the accumulation of 2‐hydroxyglutarate (2‐HG), an oncometabolite implicated in tumor... Olaparib did not reveal radiographic response for patients with isocitrate dehydrogenase 1 ( IDH1 )– and IDH2 ‐mutant cholangiocarcinoma. However, prolonged... Neomorphic isocitrate dehydrogenase (IDH) mutations lead to the accumulation of 2-hydroxyglutarate (2-HG), an oncometabolite implicated in tumor progression... BackgroundNeomorphic isocitrate dehydrogenase (IDH) mutations lead to the accumulation of 2‐hydroxyglutarate (2‐HG), an oncometabolite implicated in tumor... |
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| SubjectTerms | Accumulation Adenosine diphosphate Adult Aged Aged, 80 and over Antitumor activity Bile Duct Neoplasms - drug therapy Bile Duct Neoplasms - genetics Bile Duct Neoplasms - pathology Cancer Cholangiocarcinoma Cholangiocarcinoma - drug therapy Cholangiocarcinoma - genetics Cholangiocarcinoma - pathology Clinical trials Dehydrogenase Dehydrogenases DNA repair Drug Resistance, Neoplasm Female Homologous recombination Humans Isocitrate dehydrogenase isocitrate dehydrogenase (IDH) mutation Isocitrate Dehydrogenase - genetics Male Middle Aged Mutants Mutation National Cancer Institute (U.S.) olaparib Patients Phthalazines - administration & dosage Phthalazines - adverse effects Phthalazines - therapeutic use Piperazines - administration & dosage Piperazines - adverse effects Piperazines - therapeutic use poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor Poly(ADP-ribose) Polymerase Inhibitors - adverse effects Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use Ribose Solid tumors Subgroups Survival Tumors United States |
| Title | 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 |
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