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Background: Several Wnt pathway genes (RNF43, GNAS, CTNNB1, APC) are mutated in PDAC but their clinical implications remain unclear. Both RNF43, a membrane E3 ubiquitin ligase that negatively regulates Wnt via FZD, and GNAS, a mediator of GPCR signaling, are enriched in IPMN-associated PDAC whereas CTNNB1 is a hallmark of solid pseudopapillary neoplasms. Here, we retrospectively analyzed progression-free survival (PFS) and overall survival (OS) in a PDAC cohort to understand potential therapeutic and prognostic differences between tumors with (MUT) or without (WT) Wnt pathway mutations. Methods: We analyzed longitudinal outcomes across 774 patients (pts) with NGS results from Perthera’s Real-World Evidence database who received at least 1 line of therapy in the advanced setting for PDAC. PFS was evaluated from initiation of 1st line for advanced disease until discontinuation due to disease progression. Hazard ratios and p-values were computed via Cox regression when comparing PFS within subsets that received either 1st line FOLFIRINOX (FFX) or 1st line gemcitabine/nab-paclitaxel (GA). Differences in frequencies of genomic alterations outside the Wnt pathway were analyzed by Fisher’s exact test. Results: Within the analysis cohort (N = 774), Wnt pathway alterations were present in 72 (9.3%) of PDAC tumors based on mutations in either RNF43 (4%), GNAS (3%), CTNNB1 (<1%), or APC (2%). Median OS (relative to advanced diagnosis) was significantly longer in the MUT subgroup compared to WT (Table). Median PFS on 1st line GA was significantly longer in MUT pts, and a similar insignificant trend was noted for PFS on 1st line FFX (Table). MSI-high and PIK3CA mutations were enriched for co-occurrence with Wnt pathway alterations whereas common PDAC mutations in KRAS and TP53 were less frequent in MUT pts (Table). Gene-specific trends and potential confounders will be discussed in the context of multivariate OS/PFS analyses. Conclusions: The presence of Wnt pathway alterations identifies a subgroup of advanced PDAC with improved PFS and OS.