Objective. To evaluate the preclinical activity of Dato-DXd in vitro against CS cell lines with various TROP2 expression and in vivo against CS xenografts in mice. Design. Preclinical and Animal Studies Setting. Academic medical institution Population. Uterine and ovarian carcinosarcoma cell lines harvested from primary and metastatic patients harvested during staging procedures. Methods. TROP2 expression was determined using flow-cytometry. Cells were treated with Dato-DXd and a control ADC (CTL ADC) to evaluate IC 50 values. Double-strand DNA-breakage assay evaluated DNA damage while a 4-hour chromium-release assay evaluated antibody-dependent-cell-cytotoxicity (ADCC). Mice harboring CS xenografts were treated via retro-orbital Dato-DXd administration. Main Outcome Measures. TROP2 Expression, ADC-induced cell death, bystander effect, ADC-induced tumor inhibition, overall survival Results. TROP2 expressing CS lines were highly sensitive to killing induced by Dato-DXd . In contrast, low-expressing CS cell lines (SARARK1 and SARARK14) had no significant difference in cell cytotoxicity. Dato-DXd induced ADCC in the presence of peripheral blood lymphocytes. When TROP2 negative cells were admixed with TROP2 overexpressing cells, a significant bystander effect with Dato-DXd was appreciated. In vivo, mouse xenografts overexpressing TROP2 treated with Dato-DXd demonstrated tumor growth suppression and longer overall survival compared to CTL ADC treated xenografts. Conclusions. Dato-DXd is remarkably active against primary and metastatic uterine and ovarian CS overexpressing TROP2 in vitro and in vivo. Financial support: NIH U01 CA176067-01A1, the Deborah Bunn Alley Foundation, the Domenic Cicchetti Foundation, the Discovery to Cure Foundation, the Guido Berlucchi Foundation, NIH Research Grant CA-16359 from NCI and Standup-to-cancer (SU2C) convergence grant 2.0 to AS.