Background: This phase 3 study (NCT01343277) showed statistically significant improvement in disease control by T vs. D in patients (pts) with metastatic LMS and LPS (Demetri et al., JCO, 2016). WES was done to explore associations between genomic alterations and clinical outcomes in this prospective database. Methods: Of 518 pts enrolled on study, archival tumor samples were collected from 456 (88%) pts: 180 uterine LMS (uLMS), 149 non-uterine LMS (non-uLMS), 66 de-differentiated LPS (ddLPS), 46 myxoid LPS (mLPS) and 15 pleomorphic LPS (pLPS). Peripheral blood samples from a subset of 346 patients were also analyzed as matched normal to filter noise from nonpathogenic variants in WES. Results: Consistent with sarcoma TCGA data, these LMS and LPS samples had frequent homozygous gene deletions with relatively low mutational load. TP53 & RB1 alterations were frequent in LMS compared to LPS, and showed no association with clinical outcomes. Analyses of 103 DNA damage response (DDR) genes showed frequent ( > 20%) somatic alterations across subtypes, correlating with improved PFS only in uLMS tumors (HR: 0.63, p = 0.03). Genomic alterations in PI3K pathway genes were noted in 30% of mLPS and associated with worse PFS (HR: 3.0, p = 0.045). A trend towards better OS was noted in ddLPS tumors with MDM2 amplification (90%) compared to normal MDM2 copy number. Certain subtype-specific genomic aberrations in immune modulation pathways (uLMS and ddLPS) were associated with worse clinical outcomes, whereas alterations in immune suppressors (non-uLMS) and lipid metabolism (ddLPS) were associated with improved clinical outcomes. Conclusions: This detailed genomic analysis of a large cohort of metastatic LMS and LPS pts matched with prospective data on treatment outcomes suggests that aberrations in oncogenic pathways (DDR, PI3K, MDM2-p53) and immune modulation may contribute to response or resistance to treatment with T or D. Further analyses should inform our understanding of sarcomas and may aid clinical decision making for LMS and LPS.