Background: Pancreatic cancer remains one of the most lethal cancers in the United States (US) with a 5-year relative survival of 10%. Liposomal irinotecan is a topoisomerase inhibitor indicated, in combination with 5-fluorouracil and leucovorin, for pts with mPDAC following disease progression on gemcitabine-based therapy. This study examines the real-world use and therapeutic management of pts with mPDAC treated with liposomal irinotecan. Methods: This retrospective observational study utilized the Flatiron Health EHR-derived de-identified database from over 280 cancer clinics in the US. Data were analyzed for adult pts with mPDAC treated with liposomal irinotecan based regimens between Nov 2015 and Oct 2019. Pts were categorized into two starting dose groups: 70mg/m² and < 65mg/m². Pt characteristics, overall survival (OS), duration of treatment (DOT), and impact of dose reductions (DR, reduction ≥ 7mg/m²) were assessed among pts who received ≥3 cycles of treatment (tx). Results: Of the 532 pts (median age: 69y, IQR: 62-75) included in the study, 95 (18%) had an ECOG score of 2+ at tx initiation. Of the 184 pts (69y, 42 – 84) that did not receive 3 cycles of tx, 47 (25%) had an ECOG score of 2+ and 83 (45%) had two or more prior lines of tx. 348 pts (69y, 43 – 85) received ≥3 cycles of tx. 116 (33%) pts had two or more prior lines of tx, 209 (60%) had an ECOG score of 0-1, 48 (14%) had an ECOG score of 2+, and 91 (26%) had missing scores. 220 (63%) initiated tx at 70mg/m² and 128 (37%) initiated at < 65mg/m². 83 (38%) 70mg/m² and 26 (20%) < 65mg/m² pts experienced a DR during tx. 43 (52%) and 14 (54%) of the DRs occurred within the first 6 wks of tx in the 70mg/m² and < 65mg/m² cohorts, respectively. Median DOT was 12.6 weeks for 70mg/mg² and 9.1 wks for < 65mg/m² pts; DOT was longer among pts with a DR: 19.0 wks and 16.1 wks, respectively. Median OS (mOS) was 7.2 months (95% CI: 6.2 – 8.1) and 6.2 mos (5.0 – 7.4) for pts receiving 70mg/m² and < 65mg/m², respectively. mOS for pts with a DR was 8.9 mos (7.3 – 10.8) and 7.7 mos (5.0 – 14.9) for pts receiving 70mg/m² and < 65mg/m², respectively. mOS for pts with no DR was 6.0 mos (4.8 – 7.2) and 6.0 mos (4.7 - 7.2) for those receiving 70mg/m² and < 65mg/m², respectively. Conclusions: In this descriptive study among pts who were able to receive ≥3 cycles of liposomal irinotecan and remain on tx for ≥4 wks, DRs were effective in extending DOT and OS, independent of starting dose. The longest DOT and OS were observed in the pts who received 70mg/m² with DRs. Pts who received 70mg/m² and < 65mg/m² had similar OS in the absence of DRs.