Antibody-drug conjugates and beyond in platinum-resistant ovarian cancer: A comprehensive review of emergent strategies

Abstract

Antibody-drug conjugates (ADCs) have emerged as a major therapeutic advance in ovarian cancer, particularly when platinum-based chemotherapy is not a treatment option. By selectively delivering potent cytotoxic payloads to tumor cells, ADCs such as mirvetuximab soravtansine (MIRV), targeting FRα, and trastuzumab deruxtecan (T-DXd), targeting HER2, have demonstrated clinically meaningful activity in selected populations. However, resistance to ADCs inevitably develops through diverse mechanisms, including payload resistance and target antigen downregulation. Continued translational research is therefore essential to identify predictive biomarkers and to optimize novel combination strategies. Beyond ADCs, other systemic approaches have demonstrated survival improvements in PROC even in biomarker-unselected populations, including the addition of the glucocorticoid receptor antagonist relacorilant to nab-paclitaxel and immune–chemotherapy combinations such as pembrolizumab plus paclitaxel with or without bevacizumab. Future directions aim to prioritize synergistic combinations to overcome resistance. This includes pairing ADCs with replication stress inhibitors like ATR inhibitors and WEE1 inhibitors or integrating them with next-generation immuno-oncology platforms such as bispecifics, T-cell engagers, and cancer vaccines, as well as the integration of dynamic biomarkers and quantitative tools to define optimal treatment sequencing and improve patient outcomes in this challenging disease setting.