Antibody-drug conjugates in gynecologic cancers

Antibody-drug conjugates (ADCs) have emerged as a promising therapeutic class in the treatment of gynecologic malignancies, offering a targeted therapy approach that links tumor specific monoclonal antibodies with cytotoxic payloads. By selectively delivering chemotherapy to tumor cells expressing specific antigens, ADCs aim to enhance efficacy while potentially minimizing off-target toxicity. In recent years, several ADCs have entered clinical trials in ovarian, cervical, and endometrial cancers, with encouraging activity observed in tumors expressing targets such as folate-receptor α, human epidermal growth factor receptor 2, and tissue factor. This review provides an overview of the ADC treatment landscape in gynecologic oncology, highlighting approved agents, key clinical trials, and emerging ADC candidates. The authors critically examine ongoing challenges in the development and clinical integration of ADCs, including sequencing strategies, the impact of type of payload (particularly topoisomerase-I inhibitors and microtubule-disrupting agents), tumor target expression, linker and drug-antibody ratio characteristics on both the toxicity and therapeutic index. Additionally, the authors address potential mechanisms of resistance that may limit durability of response and impact potential treatment sequences. Future challenges include the potential for ADCs to serve as maintenance therapies, and the rationale for combination strategies with immunotherapy, antiangiogenics, chemotherapy or targeted agents. As the understanding of ADC pharmacology deepens, these agents will play an increasingly central role in the rapidly evolving treatment paradigm of gynecologic cancers.