Background: Curative treatment of pancreatic adenocarcinoma (PDAC) remains a challenge, as most patients present with advanced disease that has spread to other organs. The main opportunity for cure for these individuals remains systemic therapy. An improved understanding of the tumor biology is needed to appropriately target therapies for individual patients. We present cohort of Stage IV PDAC patients who underwent prospective comprehensive genomic profiling (CGP) in a national cancer network to evaluate genomic mutations, treatment patterns and survival. Methods: Between 2013 and 2021, 458 patients with Stage IV 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 59 years (range, 26-84) and a majority were male (55%). Median overall survival was 15 months. Most patients were treated with first line chemotherapy, predominantly gemcitabine or FOLFIRINOX. GA were identified in 98% (n = 447) of PDAC patients. The most common genomic alterations were in KRAS (85%), TP53 (75%), CDKN2A (52%), SMAD4 (21%), ARID1A (9%), BRCA2 (5%), RNF43 (4%), and BRCA1 (1%). A mutation in one of the four commonly mutated genes (KRAS, TP53, CDKN2A, or SMAD4) was identified in 94% (n = 426). Median overall survival was significantly worse for patients with mutations in KRAS or TP53 (both, P < 0.05). 185 patients (40%) had an actionable mutation based on the Know Your Tumor registry trial, including mutations in BRCA1, BRCA2, BRAF, CHEK2, ATM, ATK and STK11. MSI status was noted for 226 patients; only one patient was MSI-high. Tumor Mutational Burden (TMB) was known for 228 patients and was split as follows: 199 TMB-low (87%), 27 TMB-intermediate (12%), and 2 TMB-high (1%). TMB status was not associated with OS (P = 0.21). PD-L1 status was obtained in 20 patients, with 9 PD-L1 positive (45%); this was not associated with OS (P = 0.66). Of the 38 patients with a BRCA1 or BRCA2 mutation, 31 (82%) were treated with Olaparib. Other commonly utilized therapies included Niraparib (n = 56), Regorafenib (n = 8), Everolimus (n = 34), Erlotinib (n = 8), and Cetuximab (n = 6). Conclusions: In a large series of Stage IV PDAC patients assayed with CGP, GA were identified in 98% of tumors but only 40% had an actionable mutation. Most patients continue to be treated with conventional chemotherapy despite a sizeable group with targetable mutations. Further work is needed to identify targeted therapies for the more common mutations in PDAC given their impact on overall survival.