Activity of datopotamab deruxtecan in TROP2-expressing low-grade serous ovarian cancer: a preclinical study

Introduction Low-grade serous ovarian carcinoma (LGSOC) is a rare ovarian cancer subtype with limited sensitivity to chemotherapy and modest benefit from endocrine and MEK-directed therapy. New therapeutic targets are needed. We evaluated trophoblast cell-surface antigen 2 (TROP2) expression in LGSOC and the activity of datopotamab deruxtecan (Dato-DXd), a TROP2-directed antibody-drug conjugate, in an LGSOC patient-derived xenograft (PDX) model. Methods TROP2 expression was assessed by immunohistochemistry in a retrospective single-center cohort of 29 LGSOC cases treated at Yale University. Antitumor activity of Dato-DXd was evaluated in a TROP2-expressing PDX model derived from a heavily pretreated patient with LGSOC resistant to chemotherapy, aromatase inhibitors, and MEK inhibitors. Results TROP2 expression was detected in 29 of 29 cases, and 23 tumors showed moderate-to-strong expression. In vivo, Dato-DXd significantly inhibited tumor growth versus vehicle/saline control in a treatment-resistant LGSOC PDX model ( p < 0.0001) without relevant toxicity. Median survival was 22 days in control animals and was not reached by day 50 in the Dato-DXd group. Conclusion TROP2 is frequently expressed in LGSOC and may represent a therapeutically relevant target. Dato-DXd showed marked antitumor activity in a treatment-resistant LGSOC PDX model. Clinical evaluation in patients with recurrent LGSOC is warranted.