Background: Immune checkpoint blockade (ICB) has a modest signal in the treatment of patients with genomically unselected pancreatic cancer (PDAC). Synergistic effects of combined radiotherapy and ICB are postulated. Preliminary results of a phase 1/2 trial of anti-PD-L1 antibody durvalumab (D) and SABR in locally advanced (LA) and borderline resectable PDAC (Tuli, AACR; 2019; Abstr B58), noted SABR and D to be safe and tolerable following induction chemotherapy. We sought to further evaluate the tolerability and efficacy of D and SABR, in LA PDAC. Methods: A single-arm, open-label phase 2 trial was conducted at Memorial Sloan Kettering (MSK). Key eligibility: histologically confirmed LA unresectable PDAC, with stable or responding disease following 4-6 months (m) of FOLFIRINOX (FFX), ECOG 0-2. Therapy: D and SABR; D dosed on day 1 750mg x 4 doses Q14 days, and subsequently 1500mg Q 28 days x 11 doses (1 year total), or until progression of disease (POD), or limiting toxicity. All patients received MRI adaptive ablative radiation, 50Gy in 5 fractions between doses 1 and 2 of D. Primary endpoint: 6-m progression free survival (6 m PFS) by RECIST v1.1. Secondary endpoints were Duration of Response, Overall Response Rate (ORR), CA 19-9 response, rates of downstaging/resection, and survival outcomes (overall survival (OS) and progression-free survival (PFS)) calculated from date of enrolment. OS and PFS were estimated using Kaplan-Meier method. Pre- and on-treatment tissue, blood and microbiome samples were collected to evaluate tumor-intrinsic and peripheral immunogenomic correlates of response. Results: Between 09/2020 and 05/2022, N = 18 enrolled. Median age 67.5 years (IQR; 62.5, 71.5), 28% (5/18) female. Baseline Performance Status: N = 8 (44%) ECOG 0; N = 10 (56%) ECOG 1. Tumor location: Head/uncinate N = 9 (50%), body N = 7 (39%), neck N = 2 (11%). Median # doses FFX prior to enrolment: 8.5 (IQR; 8.0- 11.0). At median follow-up of 13.8 m, 6-m PFS: 62% (95% CI 43%, 91%). Median PFS: 10.2 m (95% CI; 5.03, NA) and median OS 17.2 m (95% CI; 12.98, NA). Disease progression (any time) N = 12, of which local POD in N = 7 (58%). N = 3 completed maintenance D; N = 5 on active treatment. ORR: N = 17 (94.4%) stable disease (95% CI; 64.6%, 99.4%). Toxicity endpoints of special interest: Grade 3 ICB-related: in N = 4 patients; diarrhea N = 2; elevated AST/ALT N = 2; G3 lipase elevation N = 1; attribution uncertain. Conclusions: D and SABR following FFX in LA PDAC had an encouraging 6-m PFS of 62% (43-91%) and a tolerable safety profile. Immuno-genomic analyses of correlative biospecimens is underway. Funding support AstraZeneca. Clinical trial information: NCT03245541.