{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T22:18:11Z","timestamp":1788214691398,"version":"build-2803163510"},"reference-count":23,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Immune checkpoint inhibitors (ICIs) yield heterogeneous benefit in metastatic castration-resistant prostate cancer (mCRPC), underscoring the unmet need for robust predictive biomarkers. DNA damage repair (DDR) gene defects encompass mechanistically distinct subtypes\u2014homologous recombination repair (HRR) deficiency, mismatch repair deficiency\/microsatellite instability-high (MMRd\/MSI-H), and CDK12 inactivation\u2014that may differentially modulate anti-tumor immunity. This study evaluated the combined predictive value of DDR mutation profiles, tumor mutational burden (TMB), and PD-L1 expression for ICI efficacy in mCRPC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this single-center retrospective cohort study conducted at PKUCare CNOOC Hospital (Tianjin, China), 152 patients with mCRPC who received ICI-containing therapy following \u22652 prior lines of systemic treatment were enrolled (January 2018\u2013December 2023). Of these, 127 (83.6%) underwent tissue-based profiling with a validated 520-gene targeted NGS panel, and 25 (16.4%) were profiled by a validated 168-gene liquid biopsy panel. Patients were classified into four DDR subgroups: HRR-deficient, MMRd\/MSI-H, CDK12-mutant, and DDR wild-type. Primary endpoints were objective response rate (ORR) and progression-free survival (PFS). Secondary endpoints included overall survival (OS), disease control rate (DCR), and prostate-specific antigen (PSA) response. Kaplan-Meier analysis, multivariate Cox regression, and ROC analysis were performed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Among 152 patients, 101 (66.4%) harbored DDR alterations: 58 HRR-deficient (38.2%), 24 MMRd\/MSI-H (15.8%), and 19 CDK12-mutant (12.5%). ORR was highest in MMRd\/MSI-H (50.0%), followed by CDK12-mutant (26.3%), HRR-deficient (22.4%), and DDR wild-type (9.8%; p &amp;lt; 0.001). Median PFS was significantly longer across all DDR-mutant groups versus DDR wild-type (MMRd\/MSI-H: 8.1 months; HR 0.31, 95% CI 0.18\u20130.53; p &amp;lt; 0.001). On multivariate analysis, DDR mutation subtype, TMB \u226510 mut\/Mb, and liver metastasis were independent predictors of PFS. A composite biomarker integrating DDR status, TMB, and PD-L1 achieved the highest predictive accuracy (AUC 0.83, 95% CI 0.75\u20130.91). irAE rates did not differ significantly across subgroups (p = 0.614).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>DDR gene mutation profiling, integrated with TMB and PD-L1 expression, provides clinically actionable stratification of mCRPC patients for ICI therapy. A composite DDR\/TMB\/PD-L1 biomarker panel warrants prospective validation in dedicated clinical trials.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fgene.2026.1933643","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T22:10:23Z","timestamp":1788214223000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["DNA damage repair gene defects combined predict the efficacy of immune checkpoint inhibitors in metastatic castration-resistant prostate cancer: a retrospective cohort study"],"prefix":"10.3389","volume":"17","author":[{"given":"Kesong","family":"Qin","sequence":"first","affiliation":[{"name":"Department of Urology, PKUCare CNOOC Hospital","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gangqiang","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Urology, Ezhou Central Hospital","place":["Ezhou City, Hubei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erli","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Urology, Huai\u2019an People\u2019s Hospital of Hongze District","place":["Huai\u2019an City, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2487","DOI":"10.1158\/1078-0432.CCR-20-0394","article-title":"Non-BRCA DNA damage repair gene alterations and response to the PARP inhibitor rucaparib in metastatic castration-resistant prostate cancer: analysis from the phase II TRITON2 study","volume":"26","author":"Abida","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1016\/S0140-6736(23)01055-3","article-title":"Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial","volume":"402","author":"Agarwal","year":"2023","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","first-page":"2207","DOI":"10.1056\/NEJMoa2017699","article-title":"Pembrolizumab in microsatellite-instability-high advanced colorectal cancer","volume":"383","author":"Andr\u00e9","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"B4","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1001\/jamaoncol.2021.5788","article-title":"Outcome correlates of germline DNA repair mutations in men with metastatic prostate cancer receiving systemic treatment","volume":"8","author":"Annala","year":"2022","journal-title":"JAMA Oncol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1200\/JCO.19.01638","article-title":"Pembrolizumab for treatment-refractory metastatic castration-resistant prostate cancer: multicohort, open-label phase II KEYNOTE-199 study","volume":"38","author":"Antonarakis","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1200\/PO.19.00399","article-title":"CDK12-Altered prostate cancer: clinical features and therapeutic outcomes to standard systemic therapies, Poly(ADP-Ribose) polymerase inhibitors, and PD-1 inhibitors","volume":"4","author":"Antonarakis","year":"","journal-title":"JCO Precis. Oncol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"3339","DOI":"10.1200\/JCO.22.01649","article-title":"Niraparib and abiraterone acetate for metastatic castration-resistant prostate cancer","volume":"41","author":"Chi","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"2091","DOI":"10.1056\/NEJMoa1911440","article-title":"Olaparib for metastatic castration-resistant prostate cancer","volume":"382","author":"de Bono","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1094","DOI":"10.1016\/S1470-2045(23)00382-0","article-title":"Olaparib and abiraterone in patients with metastatic castration-resistant prostate cancer (PROpel): final prespecified overall survival analysis of a randomised, double-blind, phase 3 trial","volume":"24","author":"Fizazi","year":"2023","journal-title":"Lancet Oncol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"2798","DOI":"10.1200\/JCO.20.00046","article-title":"Implementation of germline testing for prostate cancer: philadelphia prostate cancer consensus conference 2019","volume":"38","author":"Giri","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1158\/2159-8290.CD-21-1059","article-title":"Hallmarks of cancer: new dimensions","volume":"12","author":"Hanahan","year":"2022","journal-title":"Cancer Discov."},{"key":"B12","doi-asserted-by":"publisher","first-page":"4702","DOI":"10.3390\/ijms23094702","article-title":"Pathogenesis of immune escape and therapeutic resistance in castration-resistant prostate cancer: the role of the tumor microenvironment","volume":"23","author":"Kim","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"B13","doi-asserted-by":"publisher","first-page":"4246","DOI":"10.3390\/curroncol30040323","article-title":"Metastatic castration-resistant prostate cancer, immune checkpoint inhibitors, and beyond","volume":"30","author":"Lanka","year":"2023","journal-title":"Curr. Oncol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"113","DOI":"10.5847\/wjem.j.1920-8642.2025.031","article-title":"Early identification of high-risk patients admitted to emergency departments using vital signs and machine learning","volume":"16","author":"Liu","year":"2025","journal-title":"World J. Emerg. Med."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1353","DOI":"10.1016\/S1470-2045(20)30445-9","article-title":"Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study","volume":"21","author":"Marabelle","year":"2020","journal-title":"Lancet Oncol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1743","DOI":"10.1172\/JCI132031","article-title":"Genomics of lethal prostate cancer at diagnosis and castration resistance","volume":"130","author":"Mateo","year":"2020","journal-title":"J. Clin. Invest"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1502","DOI":"10.3390\/cancers12061502","article-title":"Combined PARP inhibition and immune checkpoint therapy in solid tumors: a systematic review","volume":"12","author":"Peyraud","year":"2020","journal-title":"Cancers (Basel)"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1245","DOI":"10.3390\/cancers14051245","article-title":"Immune checkpoint inhibitors in advanced prostate cancer: current data and future perspectives","volume":"14","author":"Rebuzzi","year":"2022","journal-title":"Cancers (Basel)"},{"key":"B19","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1016\/j.eururo.2019.09.036","article-title":"Clinical outcomes in cyclin-dependent kinase 12-Mutated advanced prostate cancer","volume":"79","author":"Reimers","year":"2020","journal-title":"Eur. Urol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1158\/1078-0432.CCR-20-2371","article-title":"Characterizing CDK12-Mutated prostate cancers","volume":"27","author":"Rescigno","year":"2021","journal-title":"Clin. Cancer Res."},{"key":"B21","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1016\/j.ccell.2020.08.007","article-title":"Nivolumab plus ipilimumab for metastatic castration-resistant prostate cancer: preliminary analysis of patients in the CheckMate 650 trial","volume":"38","author":"Sharma","year":"2020","journal-title":"Cancer Cell."},{"key":"B22","doi-asserted-by":"publisher","first-page":"220","DOI":"10.5847\/wjem.j.1920-8642.2025.048","article-title":"Development of an emergency department length-of-stay prediction model based on machine learning","volume":"16","author":"Wu","year":"2025","journal-title":"World J. Emerg. Med."},{"key":"B23","doi-asserted-by":"publisher","first-page":"153","DOI":"10.5847\/wjem.j.1920-8642.2025.037","article-title":"A predictive model for intracranial hemorrhage in adult patients receiving extracorporeal membrane oxygenation","volume":"16","author":"Zhu","year":"2025","journal-title":"World J. Emerg. Med."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2026.1933643\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T22:10:24Z","timestamp":1788214224000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2026.1933643\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,1]]},"references-count":23,"alternative-id":["10.3389\/fgene.2026.1933643"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2026.1933643","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,1]]},"article-number":"1933643"}}