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Whether other HRR\u2010gene alterations confer PARPi sensitivity remains unclear. In the Drug Rediscovery Protocol, patients receive off\u2010label drugs matched to their tumor molecular profile. Here, olaparib efficacy and safety were evaluated in adult patients with treatment\u2010refractory, progressive malignancies harboring LoF alterations in\n                    <jats:italic>ATM<\/jats:italic>\n                    (cohort A) or other HRR\u2010genes including\n                    <jats:italic>CDK12<\/jats:italic>\n                    ,\n                    <jats:italic>PPP2R2A<\/jats:italic>\n                    ,\n                    <jats:italic>CHEK1\/2<\/jats:italic>\n                    , and\n                    <jats:italic>RAD51B<\/jats:italic>\n                    (cohort B). Primary endpoints were clinical benefit (CB: confirmed objective response or stable disease \u226516\u2009weeks) and safety. Pre\u2010treatment biopsies were analyzed by whole\u2010genome sequencing (WGS) for target validation. CB was observed in 8\/25 patients (32%) in cohort A (prostate cancer:\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20096, adenoid cystic carcinoma:\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20091, endometrial cancer:\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20091). No effectiveness was seen in patients with colorectal cancer (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20098). Median progression\u2010free survival (PFS) and overall survival (OS) were 3.4\u2009months (95% CI 1.8\u20135.3) and 9.2\u2009months (95% CI 5.2\u201321.3), respectively. In cohort B, the CB rate was 41.7% (10\/24) with median PFS and OS of 3.5\u2009months (95% CI 3.4\u20136.6) and 8.1\u2009months (95% CI 6.6\u201314.2), respectively. CB was observed in\n                    <jats:italic>CKD12<\/jats:italic>\n                    (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20097),\n                    <jats:italic>RAD51B<\/jats:italic>\n                    (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20092), and\n                    <jats:italic>CHEK2<\/jats:italic>\n                    \u2010altered tumors (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20091), but not in\n                    <jats:italic>PPP2R2A<\/jats:italic>\n                    (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20096) or\n                    <jats:italic>CHEK1<\/jats:italic>\n                    \u2010altered tumors (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20091). No unexpected toxicities occurred. WGS confirmed inclusion target in 84% of tested patients. In conclusion, PARPi sensitivity varies across HRR\u2010genes, indicating that relying solely on an altered common mechanistic pathway is insufficient to predict response. Future studies should target specific HRR\u2010genes to assess subgroup\u2010specific benefits and determine proper use of molecular diagnostics.\n                  <\/jats:p>","DOI":"10.1002\/ijc.70191","type":"journal-article","created":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T13:36:06Z","timestamp":1760621766000},"page":"1617-1627","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Olaparib for patients with tumors harboring alterations in homologous recombination repair genes: Results from the drug rediscovery protocol"],"prefix":"10.1002","volume":"158","author":[{"given":"Ilse A. C.","family":"Spiekman","sequence":"first","affiliation":[{"name":"Department of Medical Oncology Erasmus MC Cancer Institute, Erasmus MC  Rotterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niven","family":"Mehra","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology Radboud University Medical Center  Nijmegen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurien J.","family":"Zeverijn","sequence":"additional","affiliation":[{"name":"Department of Molecular Oncology &amp; Immunology The Netherlands Cancer Institute  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgit S.","family":"Geurts","sequence":"additional","affiliation":[{"name":"Department of Molecular Oncology &amp; Immunology The Netherlands Cancer Institute  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karlijn","family":"Verkerk","sequence":"additional","affiliation":[{"name":"Department of Molecular Oncology &amp; Immunology The Netherlands Cancer Institute  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soemeya F.","family":"Haj Mohammad","sequence":"additional","affiliation":[{"name":"Department of Molecular Oncology &amp; Immunology The Netherlands Cancer Institute  Amsterdam the Netherlands"},{"name":"Department of Medical Oncology Leiden University Medical Center  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"van der Noort","sequence":"additional","affiliation":[{"name":"Department of Biometrics Netherlands Cancer Institute  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Roepman","sequence":"additional","affiliation":[{"name":"Hartwig Medical Foundation  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy W. 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