4003 Background: Evidence-based data is lacking to guide the care of vulnerable older adults with newly diagnosed metastatic pancreatic ductal adenocarcinoma (mPDAC) resulting in extrapolation of the treatment approach utilizing data from younger patients. EA2186 is a phase II randomized controlled trial, and the first prospective study aiming to define the optimal treatment approach for vulnerable older adults with newly diagnosed mPDAC. Methods: EA2186 enrolled vulnerable patients ≥70 years of age with histologically confirmed mPDAC, ECOG PS 0-2 and adequate organ function. Vulnerability was defined by a screening geriatric assessment (GA) demonstrating mild abnormalities in functional status, comorbidities, cognition, or age ≥80 years. Patients were randomized to Arm A: Gemcitabine (1000mg/m2) and Nab-Paclitaxel (125mg/m2) every 14 days or Arm B: 5-Fluorouracil (2400mg/m2 over 46hr) Leucovorin (400mg/m2) and Liposomal Irinotecan (50mg/m2) every 14 days. A comprehensive GA and quality of life (QOL) evaluation were completed at baseline and 3 time points. Primary endpoint was overall survival (OS); secondary endpoints included progression free survival (PFS), response rate (RR), safety, and QOL. The study had 90% power to detect a difference in median OS of 7.7 vs. 10.7 months (HR of 0.72) using a one-sided log-rank test at the 0.10 significance level. Stratification factors included age 70-74 vs ≥75, and ECOG PS 0-1 vs 2. The study met the planned futility boundary for OS at its single interim analysis (60.6% information) and was closed early by the DSMC. Results: 176 patients were enrolled at 92 US sites between 6/2020 – 10/2023, 88 patients per arm. Median age of enrolled patients was 77 (range 70-90), 49% females, 24% ECOG-0, 64% ECOG-1 and 12% ECOG-2. Majority of patients were deemed vulnerable by cognition (46%), age (36%) or co-morbidities (31.4%), with some patients meeting vulnerability criteria in multiple domains. No significant difference was seen in median OS between the arms (4.7 vs. 4.4 months in Arms A and B respectively; p = 0.72). PFS, RR, and factors contributing to early treatment discontinuation and affecting the lower-than-expected survival will be presented at the meeting. At the time of data cut off rates of ≥grade 3 toxicity was 45.6% in Arm A and 58.7% in Arm B (p = 0.10); rates of ≥grade 4 toxicity were 7.6% in Arm A vs 14.7% in Arm B (p = 0.16). Most common ≥grade 3 toxicities included anemia, neutropenia, fatigue in both Arms, and diarrhea in Arm B. Conclusions: EA2186 did not demonstrate a significant difference in efficacy or overall toxicity between two attenuated regimens tested in vulnerable older adults with mPDAC. These results provide important data to guide treatment decisions and goals of care discussions in this vulnerable patient population. Clinical trial information: NCT04233866 .