Background: Advanced PDAC has limited therapeutic options. BPM31510-IV, a novel nano formulation of Ubidecarenone was evaluated in Phase 2 in patients with advanced PDAC. In addition to response and safety, the study included FDG-PET and omics as exploratory analyses. Multi-omics analyses from longitudinally collected patient samples including a subset of Adequately Treated Analysis Set (ATAS) (n=19) were performed to determine potential biomarkers associated with clinical outcomes. Methods: Metastatic PDAC patients (N=45) who had previously received between one and three lines of prior therapy were enrolled in this study. Omics analyses including proteomic, structural lipidomic, signaling lipidomic, and metabolomic measurements were performed on patient buffy coat and plasma samples. Biomolecules with significant association to patient outcome (PFS, OS & TTP) were identified by linear regression analysis. Additional analysis with mixed effect linear modeling approach was used to relate omic values during ten weeks of treatment and patient ATAS status and time on study. Previous analysis of proteomics from patients in a phase 1 solid tumor study was mapped onto a similar omics output for phase 2 to reveal predictive biomarkers for disease status. Results: Proteomics analysis on patient buffy coats revealed enrichment of dicarboxylic and tricarboxylic metabolic processes, mitochondrial membrane space proteins, pyruvate metabolism, and malate/aspartate shuttle pathway with a positive correlation with TTP in the model, demonstrating an integrated connectivity to Ubidecarenone’s functional effects on metabolism. Medium chain acyl carnitines and c-reactive protein (CRP) were identified as having the most significant differences in trajectories between patient ATC status by mixed effect linear modeling. Medium chain acyl carnitines differences could likely be the result of an integrated adaptation of liver homeostasis and physiological activity impacted by treatment. Analysis of RECIST1.1 evaluated in Phase 1 clinical trial and subsequently validated in Phase 2 trial identified 4 proteins with predictive utility at the start of treatment (t=0) (SERPINA5, Vitronectin, Lumican, Proteosome 20S subunit alpha 4), 5 lipid molecular species, and 1 metabolite (2-keto-isovalerate). These markers exhibited differential expression in both clinical trials related to clinical outcome, thus demonstrating a biological relevance to BPM31510 treatment. Conclusions: Our results point to biomarkers associated with (a) length on trial, (b) outcome and (c) involvement of mitochondrial biology in the mechanism of BPM31510-IV in the adequately treated PDAC population. The data herein supports further study of these biomarkers in late-stage trials to confirm the biological mechanism of BPM31510 in PDAC patients. Clinical trial information: NCT02650804.