Background: Outcomes in BR and LA PDAC remain historically poor, in part due to low rates of R0 resection. A prior phase II study demonstrated that losartan (L) as a TGF-beta inhibitor combined with FOLFIRINOX (FFX) and radiation in LA PDAC led to a 61% R0 resection rate. Additionally, prior phase II studies suggest potential synergy with SBRT and nivolumab (N) in PDAC. We conducted a multi-center, randomized phase II trial to evaluate the effect of L and L+N in combination with TNT using FFX and SBRT. Methods: Patients with BR or LA PDAC by NCCN criteria, pathologically confirmed, ACE/ARB naïve, were randomized to TNT with FFX and SBRT (Arm 1), TNT + L (Arm 2), and TNT+L+N (Arm 3), stratified by BR/LA. Patients already on an ACE or ARB were enrolled on an exploratory arm of TNT+N (Arm 4) and will be reported separately. TNT consisted of FFX x 8 followed by SBRT (6.6 Gy x 5). L was given at 50 mg qd throughout TNT and for 6 mo after surgery. N was given at 240 mg flat dosing q2 wks concurrent with SBRT and for 12 doses postoperatively. All patients were recommended for surgical exploration after TNT. The study was designed to compare the R0 resection rate on each of Arms 2 and 3 independently versus Arm 1 at a one-sided 0.10 level. Secondary endpoints were PFS, OS, and pCR rates and analyzed using two-sided tests with Arm 1 as the control arm. Intent-to-treat analysis was based on eligible patients who started therapy on protocol. Results: Patients with BR or LA PDAC by NCCN criteria, pathologically confirmed, ACE/ARB naïve, were randomized to TNT with FFX and SBRT (Arm 1), TNT + L (Arm 2), and TNT+L+N (Arm 3), stratified by BR/LA. Patients already on an ACE or ARB were enrolled on an exploratory arm of TNT+N (Arm 4) and will be reported separately. TNT consisted of FFX x 8 followed by SBRT (6.6 Gy x 5). L was given at 50 mg qd throughout TNT and for 6 mo after surgery. N was given at 240 mg flat dosing q2 wks concurrent with SBRT and for 12 doses postoperatively. All patients were recommended for surgical exploration after TNT. The study was designed to compare the R0 resection rate on each of Arms 2 and 3 independently versus Arm 1 at a one-sided 0.10 level. Secondary endpoints were PFS, OS, and pCR rates and analyzed using two-sided tests with Arm 1 as the control arm. Intent-to-treat analysis was based on eligible patients who started therapy on protocol. Conclusions: We did not observe effects of L and L+N on the R0 resection rate, PFS, OS, and pCR rate when added to TNT with FFX and SBRT for BR or LA PDAC. The lack of differences may reflect heterogeneity in surgical opinion as the decision for proceeding to surgery following TNT tends to be highly variable in a population with historically low resection rates. Clinical trial information: NCT03563248.