Background: Frontline treatment for advanced pancreatic ductal adenocarcinoma (PDAC) has been either 5-fluorouracil, oxaliplatin and irinotecan (FOLFIRINOX) or gemcitabine and nab-paclitaxel (GP) for the past decade. While the NAPOLI-3 trial, utilizing liposomal irinotecan, highlighted the superiority of a triplet regimen over GP, the question remains whether certain subgroups may derive particular benefit from GP. Pre-clinical data in lung cancer suggest that KRAS G12C may facilitate enhanced DNA adduct removal after platinum chemotherapy and confer resistance to this drug class. While multiple KRAS G12C inhibitors have shown early promise in PDAC, multi-agent chemotherapy remains the frontline standard and will likely remain an important therapeutic tool. This study aimed to investigate clinical outcomes after platinum and non-platinum-based chemotherapy in patients with advanced KRAS G12C-mutated PDAC. Methods: PDAC samples were tested using whole transcriptome sequencing (WTS; Illumina NovaSeq) and NextGen DNA sequencing (NextSeq, 592 Genes and NovaSEQ, WES) at Caris Life Sciences (Phoenix, AZ). Significance was determined by X² and Fisher-Exact and p adjusted for multiple comparisons (q). Real-world overall survival (rwOS) was obtained from insurance claims data and calculated from first of treatment to last contact with comparison done by Kaplan-Meier test. Results: A total of 5,555 PDAC patients harboring KRAS pathogenic variants were identified, including 109 with a G12C mutation. For KRAS G12C mutants, median overall survival was 470 days for those who received GP (n=22) compared to 240 days for patients who received FOLFIRINOX (n=9) with a median difference of 230 days (HR 0.32, CI 0.12-0.82, p=0.013). In contrast, median overall survival was higher for patients harboring G12D (392 vs 297 days, p=0.003), G12V (500 vs 356 days, p=0.012) or G12R (469 vs 391 days, p=0.095) mutations who received FOLFIRINOX compared to GP. KRAS G12C mutated PDAC showed the highest rate of PDL1+ staining (27%) compared to other variants (G12R 13% and G12D 19%, q<0.01). TMB-H and MSI-H prevalence were highest in G12C compared to other variants (no statistical significance observed). Conclusions: In patients with advanced PDAC and a G12C mutation, median overall survival appears significantly longer in those treated with GP compared to FOLFIRINOX. The opposite trend was seen in patients with other KRAS variants including G12D, G12V, and G12R, consistent with the recently presented NAPOLI-3 trial. PDL1 staining was also highest in the KRAS G12C cohort. While this is the largest reported analysis of outcomes to frontline chemotherapy in KRAS G12C-mutated PDAC, the sample size is small and needs validation in additional datasets. Next steps include evaluating DNA mutational status and RNA expression of genes involved in DNA repair in G12C vs other KRAS variants to better understand the outcome data presented here.