Background: Curative treatment of pancreatic adenocarcinoma (PDAC) remains a challenge. Improved understanding of the tumor biology is needed to adequately target therapies for individual patients. Tumor genomic profiling is a critical component of precision medicine for these patients to identify potential genomic alterations that can be targeted for therapy. We present a cohort of PDAC patients who underwent prospective comprehensive genomic profiling (CGP) in a national cancer network. Methods: Between 2013 and 2021, 731 patients with PDAC underwent CGP with hybrid capture of up to 406 cancer-related genes on tumor tissue for treatment decision-making. Clinically relevant genomic alterations (CRGA) were defined as associated with targeted therapies or mechanism-driven clinical trials. Patient demographics and outcomes were retrospectively reviewed with IRB approval. Results: Median patient age at presentation was 58 years (range, 26-87) and a slight majority were male (54%). Most patients presented with stage IV disease (n=457; 63%). Median overall survival (OS) was 26 months for stages I-III and 15 months for stage IV disease. A majority of patients were treated with first line chemotherapy, predominantly gemcitabine or FOLFIRINOX. Surgical resection was performed in 198 patients (27%). Genomic alterations (GA) were identified in 96% of PDAC patients. The most common GA were in KRAS (86%), TP53 (75%), CDKN2A (49%), SMAD4 (21%), ARID1A (7.8%), RNF43 (5%), BRCA2 (4%), and BRCA1 (1%). A mutation in one of the four commonly mutated genes (KRAS, TP53, CDKN2A, or SMAD4) was identified in 92% (n=675). Common KRAS mutations were G12D(43%), G12V (30%), and G12R(16%). Median OS was significantly worse for patients with mutations in KRAS, TP53 and CDK2NA, while wild type RNF43 demonstrated improved OS (all, P<0.05). 206 patients (28%) had a CRGA based on the Know Your Tumor registry trial, including mutations in BRCA1, BRCA2, BRAF, ATM, CHEK2, and ATK. Tumor Mutational Burden (TMB) was known for 345 patients and included: 292 TMB-low (85%), 49 TMB-intermediate (14%), and 4 TMB-high (1%). PD-L1 status was obtained in 33 patients, with 18 PD-L1 positive (55%). MSI status was noted for 345 patients; only 5 patients (1%) were MSI-high. Of the 39 patients with a BRCA1 or BRCA2 mutation, 30 (77%) were treated with Olaparib. Other commonly utilized therapies included Niraparib (n=56), Regorafenib (n=8), Everolimus (n=35), Erlotinib (n=8), and Cetuximab (n=7). Conclusions: In a large series of PDAC patients assayed with CGP, GA were identified in 96% but only 28% had an actionable mutation. Access to the TAPUR trial allowed for an increase in the patients identified for targeted immunotherapy between 2013 and 2019, although overall use remained low for PDAC. Further research is needed to identify therapies based on the more commonly mutated genes given their association with overall survival.