Background: Metastatic pancreatic ductal adenocarcinoma (PDAC) is incurable for most patients. While immune checkpoint inhibitors (ICIs) have limited efficacy in microsatellite stable (MSS) tumors, radiation therapy (RT) may promote responsiveness to ICIs. In our phase 2 trial (NCT03104439), 25 patients with metastatic MSS PDAC were enrolled to receive ipilimumab and nivolumab with RT (24 Gy/3 fractions) starting on C2D1. The disease control rate (DCR) was 20% (5/25) and overall response rate (ORR) was 12% (3/25). In 17 patients who received RT (32% dropout rate), DCR was 29% (5/17) and ORR was 18% (3/17). To confirm this signal and address dropout prior to RT, we conducted a phase 2 study of nivolumab and ipilimumab with RT moved to C1D1. Methods: In this open-label, single-arm, phase 2 study (NCT04361162), eligible patients had histologically confirmed metastatic MSS PDAC, ECOG PS 0-2, and progressed on at least one line of chemotherapy. Treatment consisted of ipilimumab 1 mg/kg q6weeks for the first 4 cycles, nivolumab 240 mg q2weeks on a 6-week cycle, and RT (24 Gy/3 fractions) to a single site starting on C1D1. Treatment continued until disease progression, discontinuation, or withdrawal. The primary endpoint was RECIST 1.1 ORR by centrally reviewed imaging q3months. Secondary endpoints included DCR, PFS, OS, and safety. 30 patients were enrolled in a single-stage design for intention-to-treat (ITT) analysis of patients receiving at least one dose of study treatment. The per protocol analysis included patients who completed C1D1. The treatment regimen was considered to have promising activity if at least 3 of 30 patients had an objective response, providing 85% power to reject 5% ORR in favor of 15% ORR at a significance level of 20%. Results: We enrolled 30 patients (median age 68 years [range 52-80], 60% male, 90% white, 97% ECOG PS 0-1, median 3 [range 2-6] prior lines of chemotherapy) from 05/2020 to 11/2021. ITT ORR was 3% (1/30; 95% CI, 0-17%), DCR was 10% (3/30; 95% CI, 2-27%), median PFS was 2.2 months (95% CI, 1.5-2.6), and median OS was 2.8 months (95% CI, 2.1-5.2). In the per protocol analysis, ORR was 4% (1/28; 95% CI, 0-18%), DCR was 11% (3/28; 95% CI, 2-28%), PFS was 2.3 months (range, 1.6-2.7), and OS was 2.9 months (range, 2.2-5.5). One patient enrolled in hospice after 1 month, had a complete response at 13 months, and is alive at 21 months. 7 patients had grade 3-4 treatment-related serious adverse events, including lymphopenia (grade 4 in 1 patient), neutropenia, fatigue, muscle weakness, ALT/AST increase, hepatobiliary dysfunction, acute kidney injury, hyperglycemia, and hypokalemia. Conclusions: The treatment regimen of ipilimumab and nivolumab with RT did not meet the pre-specified criteria for promising activity in metastatic MSS PDAC. Further correlative analyses of the patient with a complete response and evaluation of in-field responses are ongoing. Clinical trial information: NCT04361162.