{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:39:49Z","timestamp":1786977589157,"version":"build-2736575974"},"reference-count":19,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T00:00:00Z","timestamp":1738886400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100008222","name":"Ben and Catherine Ivy Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008222","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100016982","name":"Rising Tide Foundation","doi-asserted-by":"publisher","award":["CCR\u201018\u2010700"],"award-info":[{"award-number":["CCR\u201018\u2010700"]}],"id":[{"id":"10.13039\/501100016982","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["1K08CA255465\u201001A1"],"award-info":[{"award-number":["1K08CA255465\u201001A1"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["NIH\u20101UM1CA186689"],"award-info":[{"award-number":["NIH\u20101UM1CA186689"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acsjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer"],"published-print":{"date-parts":[[2025,2,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Neomorphic isocitrate dehydrogenase (\n                      <jats:italic>IDH<\/jats:italic>\n                      ) mutations lead to the accumulation of 2\u2010hydroxyglutarate (2\u2010HG), an oncometabolite implicated in tumor progression via inhibitory effects on alpha\u2010ketoglutarate. Moreover, mutant\n                      <jats:italic>IDH<\/jats:italic>\n                      \u2013dependent accumulation of 2\u2010HG 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\n                      <jats:italic>IDH<\/jats:italic>\n                      \u2010mutant solid tumors basket trial are reported.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Olaparib 300 mg twice daily was evaluated in an open\u2010label, phase 2 clinical trial for treatment\u2010refractory\n                      <jats:italic>IDH<\/jats:italic>\n                      \u2010mutant solid tumors. Patients in the\n                      <jats:italic>IDH<\/jats:italic>\n                      \u2010mutant CCA arm enrolled in two cohorts: (1) IDH inhibitor (IDHi) pretreated and (2) IDHi untreated, with a primary end point of overall response rate.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      NCI 10129 enrolled 30 patients with\n                      <jats:italic>IDH<\/jats:italic>\n                      \u2010mutant CCA with no objective responses seen, and recruitment was closed early. Median progression\u2010free 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 \u22656 months. Patients with CB had lower baseline 2\u2010HG levels compared to those without CB (1.4 vs. 5.9 \u00b5mol\/L;\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a0.01).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Olaparib does not have sufficient single\u2010agent activity to warrant further development in\n                      <jats:italic>IDH<\/jats:italic>\n                      \u2010mutant CCA. However, a subgroup of patients demonstrated CB, and exploratory analysis revealed this subgroup to be enriched for lower baseline 2\u2010HG levels. Future clinical trials leveraging the HRD properties of\n                      <jats:italic>IDH<\/jats:italic>\n                      mutations are warranted with enhanced patient selection and novel combination therapies.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cncr.35755","type":"journal-article","created":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T06:05:26Z","timestamp":1738908326000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Olaparib in treatment\u2010refractory isocitrate dehydrogenase 1 (\n                    <i>IDH1<\/i>\n                    )\u2013 and\n                    <i>IDH2<\/i>\n                    \u2010mutant cholangiocarcinoma: Safety and antitumor activity from the phase 2 National Cancer Institute 10129 trial"],"prefix":"10.1002","volume":"131","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3504-0128","authenticated-orcid":false,"given":"Michael","family":"Cecchini","sequence":"first","affiliation":[{"name":"Yale University School of Medicine  New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary Jo","family":"Pilat","sequence":"additional","affiliation":[{"name":"Karmanos Cancer Institute Wayne State University  Detroit Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nataliya","family":"Uboha","sequence":"additional","affiliation":[{"name":"University of Wisconsin  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nilofer S.","family":"Azad","sequence":"additional","affiliation":[{"name":"Johns Hopkins University School of Medicine  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"May","family":"Cho","sequence":"additional","affiliation":[{"name":"University of California  Irvine California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7626-2435","authenticated-orcid":false,"given":"Elizabeth J.","family":"Davis","sequence":"additional","affiliation":[{"name":"Vanderbilt\u2010Ingram Cancer Center  Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordi Rodon","family":"Ahnert","sequence":"additional","affiliation":[{"name":"MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Tinoco","sequence":"additional","affiliation":[{"name":"The Ohio State University  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geoffrey 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 Detroit Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Azeet","family":"Narayan","sequence":"additional","affiliation":[{"name":"Yale University School of Medicine  New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis","family":"Vu","sequence":"additional","affiliation":[{"name":"Yale University School of Medicine  New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhijit","family":"Patel","sequence":"additional","affiliation":[{"name":"Yale University School of Medicine  New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Niger","sequence":"additional","affiliation":[{"name":"Medical Oncology Department Fondazione IRCCS Instituto Nazionale dei Tumori di Milano  Milan 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