Skip NavigationSkip to Content
Return Return to Search Results

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

  1. Author:
    Cecchini, Michael [ORCID]
    Pilat, Mary Jo
    Uboha, Nataliya
    Azad, Nilofer S
    Cho, May
    Davis, Elizabeth J [ORCID]
    Ahnert, Jordi Rodon
    Tinoco, Gabriel
    Shapiro, Geoffrey I
    Khagi, Simon
    Powers, Benjamin
    Spencer, Kristen
    Groisberg, Roman
    Drappatz, Jan
    Chen, Li
    Das,Bishu
    Bao, Xun
    Li, Jing
    Narayan, Azeet
    Vu, Dennis
    Patel, Abhijit
    Niger, Monica
    Doroshow, Deborah
    Durecki, Diane [ORCID]
    Boerner, Scott A
    Bindra, Ranjit
    Ivy, Percy [ORCID]
    Shyr, Derek [ORCID]
    Shyr, Yu
    LoRusso, Patricia M

  2. Author Address

    Yale University School of Medicine, New Haven, Connecticut, USA., Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, USA., University of Wisconsin, Madison, Wisconsin, USA., Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., University of California, Irvine, California, USA., Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA., MD Anderson Cancer Center, Houston, Texas, USA., The Ohio State University, Columbus, Ohio, USA., Dana-Farber Cancer Institute, Boston, Massachusetts, USA., Hoag Memorial Hospital Presbyterian, Newport Beach, California, USA., University of Kansas Cancer Center, Overland Park, Kansas, USA., New York University, New York, New York, USA., Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA., University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA., Medical Oncology Department, Fondazione IRCCS Instituto Nazionale dei Tumori di Milano, Milan, Italy., Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland, USA., Department of Biostatistics, Harvard University, Boston, Massachusetts, USA., Department of Biostatistics, Vanderbilt University, Nashville, Tennessee, USA.,
    1. Year: 2025
    2. Date: Feb 15
  2. Journal: Cancer
    1. 131
    2. 4
    3. Pages: e35755
  4. Type of Article: Article
  5. Article Number: e35755
  1. Abstract:

    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. © 2025 American Cancer Society.

    See More

  1. Keywords:

External Sources

  1. View Full Text
  2. DOI: 10.1002/cncr.35755
  3. PMID: 39917990

Library Notes

  1. Fiscal Year: FY2024-2025
NCI at Frederick

You are leaving a government website.

This external link provides additional information that is consistent with the intended purpose of this site. The government cannot attest to the accuracy of a non-federal site.

Linking to a non-federal site does not constitute an endorsement by this institution or any of its employees of the sponsors or the information and products presented on the site. You will be subject to the destination site's privacy policy when you follow the link.

ContinueCancel