Trastuzumab deruxtecan (T-DXd) in HER2-expressing gynecological malignancies: Clinical evidence, safety profile, and future directions

Endometrial, ovarian, and cervical cancers in advanced or recurrent stages are associated with unfavorable outcomes, emphasizing the need for effective targeted approaches. While HER2 has been identified as a key biomarker in selected high-grade tumors, prior HER2-targeted therapies have yielded inconsistent results. This review discusses the underlying biology, clinical outcomes, safety considerations, and evolving application of trastuzumab deruxtecan (T-DXd) in HER2-positive gynecological cancers. T-DXd is a HER2-directed antibody-drug conjugate of a monoclonal antibody linked to a potent topoisomerase I inhibitor, allowing targeted delivery and a bystander killing effect. Evidence from trials such as DESTINY-PanTumor02 and STATICE demonstrates meaningful and sustained responses across HER2-positive gynecological malignancies, with the greatest benefit observed in IHC 3 + tumors. While the overall safety profile of T-DXd is manageable, interstitial lung disease or pneumonitis represents a key adverse event and requires timely recognition and intervention. T-DXd represents an emerging therapeutic option for HER2-positive gynecological malignancies after prior treatment, especially in advanced lines of therapy. Further studies focusing on biomarker refinement, sequencing approaches, and toxicity mitigation will be key to establishing its place in clinical practice.