To investigate the genetic alterations of prostate cancer (PCa) patients with and without intraductal carcinoma of the prostate (IDC-P).We performed targeted sequencing of plasma cell-free DNA on 161 patients of prostate adenocarcinoma (PAC) with IDC-P and 84 cases without IDC-P. Genomic alterations were compared between these two groups. The association between genetic alterations and patients' survival outcomes was also explored.Totally, we identified 29.8% (48/161) and 21.4% (18/84) patients with and without IDC-P harbored genomic alterations in DNA repair pathway, respectively (P=0.210). Pathogenic germline DNA repair alterations were frequently detected in IDC-P carriers compared to IDC-P non-carries (11.8% [19/161] vs. 2.4% [2/84], P=0.024). Germline BRCA2 and somatic CDK12 defects were specifically identified in IDC-P carriers relative to PAC (BRCA2: 8.7% [14/161] vs. 0% and CDK12: 6.8% [11/161] vs. 1.2% [1/84]). Patients with IDC-P had a distinct AR pathway alteration, characterized by an enrichment of NCOR2 mutations against patients with pure PAC (21.1% [34/161] vs. 6.0% [5/84], P=0.004). Increased AR alterations were detected in patients harbouring tumors with IDC-P proportion≥10% versus cohort with IDC-P proportion<10% (6.4% [5/78] vs. 18.1% [15/83], P=0.045). For IDC-P carries, TP53 mutation was associated with shorter castration-resistant free survival (median 10.9-Mo vs. 28.9-Mo, P=0.026), and BRCA2 alteration was related to rapid PSA progression for those receiving abiraterone treatment (median 9.1-Mo vs 11.9-Mo, P=0.036).Our findings provide genomic evidence explaining the aggressive phenotype of tumors with IDC-P, highlighting the potential therapeutic strategies for this patient population.This article is protected by copyright. All rights reserved.