Emerging Therapeutic targets and Early-phase drug Development in Gynecological Malignancies.

Abstract

Gynecological malignancies remain a major cause of cancer-related morbidity and mortality, particularly in recurrent and treatment-resistant settings. Advances in molecular profiling have accelerated the development of biomarker-driven therapies, expanding treatment options beyond conventional chemotherapy and first-generation targeted agents. Novel strategies targeting DNA damage response pathways, including WEE1, PKMYT1, and WRN, as well as vulnerabilities associated with CCNE1 amplification and actionable alterations such as TP53 Y220C, are showing encouraging clinical activity. Antibody-drug conjugates have emerged as a major therapeutic class, while immunotherapeutic approaches are evolving beyond immune checkpoint inhibitors to include bispecific antibodies, T-cell engagers, engineered T-cell receptor therapies, and CAR-T cells. Despite these advances, tumor heterogeneity, biomarker complexity, and acquired resistance remain major challenges. This review highlights recent developments in targeted and immune-based therapies across gynecological cancers and discusses future directions for biomarker-driven drug development and therapeutic sequencing.