Background: The Cellworks Singula Therapeutic Response Index (TRI) has been developed to assist clinicians and GBM patients in choosing between competing therapeutic options. In contrast to approaches that consider single aberrations, which often yield limited benefit, Cellworks utilizes an individual patient’s next generation sequencing results and a mechanistic multi-omics biology model, the Cellworks Omics Biology Model (CBM), to biosimulate downstream molecular effects of cell signaling, drugs, and radiation on patient-specific in silico diseased cells. For any individual patient and alternative therapy, Cellworks integrates this biologically modeled multi-omics information into a continuous Singula TRI Score, scaled from 0 (low therapeutic benefit) to 100 (high therapeutic benefit). We demonstrate that Singula is strongly associated with OS and DFS beyond standard clinical factors, including patient age, patient gender, and physician prescribed treatments (PPT). Methods: In this study, Singula’s ability to predict response was evaluated in a retrospective cohort of 100 GBM patients with OS and DFS data from The Cancer Genome Atlas (TCGA) project, treated with PPT. As a primary analysis of the CBM and TRI Score, Cox Proportional Hazards (PH) regression and likelihood ratio (LR) tests were used to assess the hypothesis that Singula is predictive of OS and DFS above and beyond patient age, patient gender, and PPT. A p-value < 0.05 for the corresponding likelihood ratio statistic was required to be considered significant. Results: Multivariate analyses were performed to assess the performance of the Singula Therapy Response Index after adjusting for the contribution of standard clinical factors. The same Singula TRI algorithm and clinical cutoffs were used for all clinical outcome measures. These analyses, shown in the table, suggests that the proposed Singula TRI provides predictive value of OS and DFS above and beyond patient age, patient gender, and PPT. Conclusions: The Singula TRI Score provides a continuous measure scaled from 0 (low benefit) to 100 (high benefit) for alternative GBM therapeutic options. In this retrospective cohort, Singula was strongly predictive of OS and DFS and provided predictive value beyond PPT, patient age and gender. These results will be further validated in larger scale, prospectively designed clinical studies.