630 Background: mPDAC patients (pts) that tolerate 1L FFX may increase their survival with 2L therapy, most often gemcitabine + nab-paclitaxel (GnP). However, some pts discontinue treatment due to the toxic effects of 1L FFX and consequently experience disease progression and reduced survival. Reasons for discontinuation are typically not available in RW sources. To assess whether AEs are more frequent per unit time in pts that stop treatment after 1L, we calculated the RW incidence rates (IRs) of AEs during 1L treatment for two RW cohorts: mPDAC pts treated with 1L FFX and no 2L (FFX-only) vs. pts treated with 1L FFX and 2L GnP (FFX + GnP). Methods: This retrospective observational study utilized the Ontada Clinical Data View: Pancreatic Cancer database. Adult pts diagnosed with mPDAC between November 2018 and November 2021 who initiated treatment with 1L FFX ≤90 days from their metastatic diagnosis were included. Diarrhea, fatigue, nausea and vomiting, and neuropathy were available in the data as ungraded AEs abstracted from clinician notes. Hematologic and hepatic AEs were based on observed lab values and were graded according to the Common Terminology Criteria for AEs v5. Pts were required to have ≥1 year of follow-up unless death occurred first. We evaluated differences in IRs of AEs per pt-month of 1L treatment for statistical significance using the test-based method. Results: 587 pts met study inclusion criteria. 300 pts received FFX-only prior to death or end of follow-up, while 287 received FFX + GnP. For FFX-only vs. FFX + GnP pts, median age was 66 vs. 64 (IQR: 59–71 vs. 57–69), 57% in both groups were male, 70% vs. 69% were white, 55% vs. 62% had an ECOG of 0–1, and 8% vs. 3% had an ECOG of 2. Median 1L duration of therapy (DoT) was 2.1 (IQR: 0.7–5.0) vs. 4.6 months (IQR: 2.1–7.4). Among ungraded AEs, fatigue was more frequent per pt-month of 1L therapy for FFX-only vs. FFX + GnP pts (IR=0.037 vs. 0.027; p=.041). AEs based on lab values were higher per pt-month of 1L therapy for FFX-only vs. FFX + GnP pts for grade 3/4 thrombocytopenia (IR=0.012 vs. 0.006, p=.013), grade 1/2 anemia (IR=0.203 vs. 0.142, p<.001), grade 1/2 and 3/4 hypokalemia (IR=0.099 vs. 0.074, p<.001; IR=0.040 vs. 0.028, p=.010), grade 1/2 elevated ALT (IR=0.138 vs. 0.098, p<.001), grade 1/2 and 3/4 elevated AST (IR=0.150 vs. 0.109, p<.001; IR=0.018 vs. 0.011, p=.021), and grade 1/2 and 3/4 elevated ALP (IR=0.172 vs. 0.123, p<.001; IR=0.034 vs. 0.025, p=.035). IRs of all other AEs were numerically higher for FFX-only pts but differences were not statistically significant. Conclusions: A RW cohort of mPDAC pts receiving FFX-only experienced more AEs per pt-month of 1L and reduced likelihood of proceeding to subsequent lines of therapy compared to pts treated with FFX + GnP. Identifying predictive biomarkers may distinguish FFX non-responders and obviate AEs.