Background: Pancreatic cancer remains one of the most lethal cancers in the United States (US) with a 5-year relative survival of 9%. Among patients who received liposomal irinotecan + 5-fluorouracil (5-FU) and leucovorin in the NAPOLI-1 study, a randomized phase 3 study in patients with mPDAC previously treated with gemcitabine-based therapy, 25% (n = 29) were alive at ≥ 1 year. This study examines the real world one-year survival of patients with mPDAC treated with liposomal irinotecan as a doublet with 5-FU in the NAPOLI-1 based regimen. Methods: This retrospective observational study utilized the Flatiron Health EHR database from over 280 cancer clinics in the US. Data were analyzed for adult patients with mPDAC treated with liposomal irinotecan-based regimens between November 2015 and July 2020. Patient characteristics and one-year overall survival (OS) based on Kaplan-Meier estimates were assessed. Cycles were defined as unique days with an administration of liposomal irinotecan. Results: There were 669 patients (median age: 69y, IQR: 62-75) included in the study. ECOG performance status (PS) of 0-1 and 2+ were reported for 78.3% (n = 396) and 21.7% (n = 110) of patients, respectively. ECOG PS was not captured for 24.4% (n = 163) of patients. 16.3% (n = 109) of patients initiated liposomal irinotecan-based in the first line (1L) metastatic setting, 47.5% (n = 318) in second line (2L), and 36.2% (n = 242) in the third line or later (3L+). The median number of cycles received was 4 (IQR: 2 – 8). Among all patients, one-year OS was 17.2% (95% CI: 14.3% - 20.7%). One-year OS was 31.5% (22.1% – 41.3%) for patients treated in 1L, 16.4% (12.2% - 21.1%) for patients treated in 2L, and 12.2% (7.5% - 18.0%) for patients treated in 3L. The median number of cycles for 1L, 2L, and 3L were 5, 4, and 3, respectively. One-year OS increased as patients were able to receive more cycles of liposomal irinotecan. Patients who received at least 2 cycles of liposomal irinotecan (n = 551) had a one-year OS of 20.4% (16.8% - 24.2%). Among patients who received at least 4 cycles (n = 359) and at least 8 cycles (n = 170), the one-year OS estimates were 29.1% (24.0% - 34.3%) and 47.9% (39.7% - 55.7%), respectively. Conclusions: In this real-world cohort of patients with mPDAC treated with liposomal irinotecan, as expected, one-year OS increased as patients remained on therapy. Patients in this cohort were older, had more prior lines of therapy, worse ECOG PS, and similar exposure to treatment compared with patients in the registrational phase 3 NAPOLI-1 study. Among patients who received at least 4 cycles of liposomal irinotecan, one-year OS (29%) was similar to both the intent-to-treat (25%) and per protocol treated patient populations in the NAPOLI-1 trial (34%). Further studies are needed to understand the predictors of long-term survival among patients with mPDAC.