Antibody–drug conjugates (ADCs) have transformed the cancer therapeutic landscape over the past two decades, profoundly shaping treatment outcomes across a wide array of indications. Three ADCs are currently approved for previously treated gynaecological cancers: mirvetuximab soravtansine for folate receptor-α-positive ovarian cancer, trastuzumab deruxtecan for solid tumours expressing HER2 (defined as a staining intensity on immunohistochemistry of 3+) and tisotumab vedotin for cervical cancer (independent of tissue factor expression). Current research priorities include identifying novel targets, better understanding mechanisms of resistance and sequencing strategies, and optimal management of the toxicities of ADCs. Moreover, rational combinations could reinforce and extend the clinical potential of these agents, as has already been demonstrated with the addition of ADCs to immune checkpoint inhibitors in an effort to amplify antitumour immunity and prolong the durability of clinical responses. In this Review, we provide an overview of the current landscape of ADCs in gynaecological malignancies, highlighting key advances and future opportunities.
Antibody–drug conjugates (ADCs) have transformed the cancer therapeutic landscape over the past two decades, profoundly shaping treatment outcomes across a wide array of indications. Three ADCs are currently approved for previously treated gynaecological cancers: mirvetuximab soravtansine for folate receptor-α-positive ovarian cancer, trastuzumab deruxtecan for solid tumours expressing HER2 (defined as a staining intensity on immunohistochemistry of 3+) and tisotumab vedotin for cervical cancer (independent of tissue factor expression). Current research priorities include identifying novel targets, better understanding mechanisms of resistance and sequencing strategies, and optimal management of the toxicities of ADCs. Moreover, rational combinations could reinforce and extend the clinical potential of these agents, as has already been demonstrated with the addition of ADCs to immune checkpoint inhibitors in an effort to amplify antitumour immunity and prolong the durability of clinical responses. In this Review, we provide an overview of the current landscape of ADCs in gynaecological malignancies, highlighting key advances and future opportunities.
Antibody–drug conjugates (ADCs) are a rapidly growing drug class in gynaecological cancers; three agents are currently approved by the FDA in specific clinical settings in ovarian, endometrial and cervical cancer, and many additional ADCs are in active development for these tumours.
The clinical use of ADCs in gynaecological cancers spans a large and growing number of targets. The importance of target selection and target expression thresholds varies by specific agent, and biomarker development is complicated by factors including assay reproducibility, spatial heterogeneity and temporal stability.
ADCs currently approved or in development have distinct safety profiles that can vary by agent and can have both off-target, and on-target and off-tumour effects; specific toxicities of interest with ADCs include ocular toxicity, stomatitis and interstitial lung disease, and clinicians should be familiar with the specific monitoring and management considerations for these adverse events.
Mechanisms of ADC resistance and questions of ADC sequencing in gynaecological cancers are important areas for future development; whether tumours can be re-treated with ADCs that target the same antigen or use a similar payload class, and whether target-specific ADCs or target-agnostic ADCs yield superior outcomes are key questions.
Considerations of quality of life, clinical efficacy and duration of therapy are important in ADC development, especially as ADCs are clinically tested in earlier line and maintenance settings.
Colombo, R., Tarantino, P., Rich, J. R., LoRusso, P. M. & de Vries, E. G. E. The journey of antibody–drug conjugates: lessons learned from 40 years of development. Cancer Discov. 14 , 2089–2108 (2024).
Liu, K. et al. A review of the clinical efficacy of FDA-approved antibody‒drug conjugates in human cancers. Mol. Cancer 23 , 62 (2024).
Liu, J. F. et al. Phase I study of safety and pharmacokinetics of the anti-MUC16 antibody-drug conjugate DMUC5754A in patients with platinum-resistant ovarian cancer or unresectable pancreatic cancer. Ann. Oncol. 27 , 2124–2130 (2016).
Hassan, R. et al. First-in-human, multicenter, phase I dose-escalation and expansion study of anti-mesothelin antibody-drug conjugate anetumab ravtansine in advanced or metastatic solid tumors. J. Clin. Oncol. 38 , 1824–1835 (2020).
Bast, R. C. Jr. et al. A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer. N. Engl. J. Med. 309 , 883–887 (1983).
Ordóñez, N. G. Application of mesothelin immunostaining in tumor diagnosis. Am. J. Surg. Pathol. 27 , 1418–1428 (2003).
James, R. L. et al. Development of an FRα companion diagnostic immunohistochemical assay for mirvetuximab soravtansine. Arch. Pathol. Lab. Med. 148 , 1226–1233 (2024).
Moore, K. N. et al. Phase III, randomized trial of mirvetuximab soravtansine versus chemotherapy in patients with platinum-resistant ovarian cancer: primary analysis of FORWARD I. Ann. Oncol. 32 , 757–765 (2021).
Matulonis, U. A. et al. Efficacy and safety of mirvetuximab soravtansine in patients with platinum-resistant ovarian cancer with high folate receptor alpha expression: results from the SORAYA study. J. Clin. Oncol. 41 , 2436–2445 (2023).
Alvarez Secord, A. et al. The efficacy and safety of mirvetuximab soravtansine in FRα-positive, third-line and later, recurrent platinum-sensitive ovarian cancer: the single-arm phase II PICCOLO trial. Ann. Oncol. 36 , 321–330 (2025).
Manning-Geist, B. L. et al. Folate receptor alpha expression in low-grade serous ovarian cancer: exploring new therapeutic possibilities. Gynecol. Oncol. 188 , 52–57 (2024).
Rushton, T. et al. Characterizing the genomic landscape through the lens of FOLR1 status in low and high grade serous ovarian carcinoma. Gynecol. Oncol. 191 , 80–85 (2024).