Background: Targeted sequencing of circulating tumor cell DNA (ctDNA) has been well studied in patients with metastatic castration-resistant prostate cancer (mCRPC), while its application in patients with castrate-sensitive prostate cancer (CSPC) is relatively limited. This study aimed to analyze the concordance of somatic alterations in ctDNA and matched tumor tissue samples oand investgate the clinical significance of genomic alterations in CSPC patients. Methods: 184 CSPC patients from three Chinese Hospitals were included (24 with localized PCa (LP), 46 with lymph node metastases (LNM), 42 with distant metastases of low tumor burden (LTB), and 72 with distant metastases of high tumor burden (HTB)). All patients had ctDNA samples and matched tumor tissues collected at time of primary biopsy (n = 78) or radical surgery (n = 106) for high-throughput targeted sequencing of multiple-gene. 36 prostate cancer clinical relevant genes were selected for analysis. Kaplan–Meier survival curves and Cox regression analyses were used to determine the associations of genomic alterations and the time to CRPC. Results: Overall, 70.6% of CSPC patients had somatic alterations in tumor tissues, which was much higher than that in ctDNA (31.5%). The concordance for alterations detected in ctDNA and matched tumor tissue was 29.2%. In subgroup analysis, the concordance for LP, LNM, LTB and HTB group were 0%, 5.3%, 3.3%, and 49.1%, respectively. Most of alterations identified were unique in tumor tissues or ctDNA. Number of alterations in tumor tissue alone was 23, 54, 58 and 56 in LP, LN, LTB and HTB group, respectively. Number of alterations alone in ctDNA was 16, 27, 9 and 37 in LP, LN, LTB and HTB group, respectively. Combined analysis of the genomic alterations identified in ctDNA and tumor tissue demonstrated that the most frequent altered gene was FOXA1 (35%), TP53 (16%), SPOP (12%), CDK12 (12%) and NCOR2 (9%). For patients with distant metastases harboring any pathogenic somatic or germline alterations of CDK12/TP53/BRCA1/BRCA2/PTEN/RB1, the median time to CRPC was significantly shorter than wide-type patients (median, 17.3 mo vs Not reached；p＜0.005). In the multivariate COX analysis, alterations of CDK12/TP53/BRCA1/BRCA2/PTEN/RB1 was still found to be significant (P = 0.00737). Conclusions: The concordance of gene alterations in ctDNA and mathced tumor tissue in CSPC patients increased with disease progression. ctDNA or tumor tissue alone was insufficient to capture all clinically relevant alterations, and therefore combined use of them may provide more comprehensive information about prognosis and clinical treatment guidance for CSPC patients. Alteration of CDK12/TP53/BRCA1/BRCA2/PTEN/RB1 was an independent prognostic factor for the time to CRPC.