Soft tissue sarcomas (STS) are rare, heterogeneous tumors with poor survival outcomes, primarily due to reliance on cytotoxic chemotherapy and lack of targeted therapies. Given the uniquely individualized nature of STS, we hypothesized that the ex vivo drug sensitivity platform, quadratic phenotypic optimization platform (QPOP), can predict treatment response and enhance combination therapy design for STS. Using QPOP, we screened 45 primary STS patient samples, and showed improved or concordant patient outcomes that are attributable to QPOP predictions. From a panel of approved and investigational agents, QPOP identified AZD5153 (BET inhibitor) and pazopanib (multi-kinase blocker) as the most effective combination with superior efficacy compared to standard regimens. Validation in a panel of established patient lines and in vivo models supported its synergistic interaction, accompanied by repressed oncogenic MYC and related pathways. These findings provide preliminary clinical evidence for QPOP to predict STS treatment outcomes and guide the development of novel therapeutic strategies for STS patients.