Background: Weight loss (WL)/cachexia is common in APDAC and associated with multiple adverse pt outcomes. Current NCCN guidelines recommend PERT in PDAC patients with PEI. However, little evidence exists regarding PERT use and clinical outcomes in PDAC, especially APDAC. We present here data on impact of PERT use from our institution. Methods: Study pts were identified from the Virginia Mason PDAC database (01-2010-12/2019). Eligibility criteria included: 1) No upfront resection, 2) no prior PDAC therapy, 3) FE 1 < 200 µg/g or documented evidence of PEI at diagnosis, 4) treatment at least to initial restaging event (8 wks), and 5) data regarding PERT use/dosage available. Pts were stratified by PERT/non-PERT usage. PERT use was defined by prescription for >50% of time from initial Rx to 1st restage using recommended dosing per package insert. Pts on PERT for < 50% of time during this time frame and/or prescribed less than recommended dose were excluded from analysis. Results: 505 total pts were study eligible, PERT 197(39%), non-PERT 308(61%). WL (80 vs 65%, p< 0.001) and cachexia (74 v 54%, p<0.001) were more common in PERT pts. ECOG PS 2 (4 vs 9%, p=0.02) and non-metastatic disease (51 vs 40%, p=0.02) more common in non-PERT pts. Other pt characteristics (age, sex, diabetes at dx, serum albumin, NLR, BMI distribution, % obese) were similar in both groups. OS after adjustment for PS and stage was 15.7 mo (95% CI 13.6-18.3 mo) among PERT users vs. !2.6 mo non-PERT users (95% CI 11.0 -13.7 mo, p=0.02, adjusted hazard ratio 0.81 (95% CI 0.67-0.99). Pts receiving PERT also tended to have a higher therapeutic response rate by both Ca 19.9 and CT: but without statistical significance (p=0.10, 0.09, respectively). Regarding nutrition, PERT vs. non-PERT pts at 8 weeks experienced less WL (-0.4 vs. -1.5 kg, p=0.03) and less change in BMI (-0.3 vs -1.6, p=0.02). This was true even in cachectic pts at dx (change in BMI + 0.1 vs -1.7, p=0.01). Additional analyses of impact of PERT on QOL are ongoing, including in a subset of patients who underwent serial PG-SGA scoring. Conclusions: In this pt cohort, APDAC pts prescribed PERT per recommended dosing had a statistically significant improvement in median OS vs. those not prescribed PERT. This remained true in multivariate analysis after adjustment for population imbalances. PERT use was also associated with a statistically significant reduction in weight loss and change in BMI at 8 weeks, even in those patients defined as cachectic at diagnosis. Further investigation into a) impact of PERT on quality of life, b) mechanisms producing the above observations, c) confirmatory observations in independent datasets, and d) additional therapeutic interventions designed to mitigate weight loss/cachexia in PDAC are needed.