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Genomic sequencing has made precision oncology of pancreatic ductal adenocarcinoma (PDAC) feasible and is recommended by numerous clinical guidelines. The clinical significance of genomic alterations in PDAC remains to be revealed. This study was designed to bridge this gap by elucidating the clinical relevance of genomic profiling in a diverse PDAC population. From January 1, 2021 to April 30, 2023, we prospectively collected tumor tissues and peripheral blood from 1135 patients diagnosed with PDAC at Fudan University Shanghai Cancer Center (FUSCC). Germline and somatic mutations were identified using a 676-gene panel. PDAC with KRAS/ARID1A co-mutation was featured with early metastasis and poor prognosis. Patients with BRCA1/2 and PALB2 mutations showed a trend towards improved survival with platinum-containing regimens, although statistical significance was not reached. In contrast, we observed a statistical preference for platinum-containing adjuvant chemotherapy in KRAS wild-type PDAC patients. For the mutational landscape, the current cohort had a lower mutation rate of KRAS, while mutations related to the WNT, Hippo, and PI3K signaling pathways were more prevalent, compared with Caucasian PDAC. Somatic RAD50 p.L719fs, ATR p.I774fs, and germline RAD51D p.K91fs were homologous recombination repair (HRR) gene mutations enriched in this Chinese cohort relative to reported Caucasian series. These results highlighted that genomic sequencing could guide the management of PDAC, including prognosis prediction and chemotherapy regimen selection. Trial Registration: Chinese Clinical Trial Registry registration number: ChiCTR2500097983.