Recent approvals are driving a shift toward biomarker-informed treatment strategies, rational combinations and personalised sequencing
For patients with advanced ovarian, cervical or endometrial cancer, the therapeutic landscape has historically been dominated by sequential chemotherapy, often associated with cumulative toxicity and modest response rates, particularly in later lines of treatment. The recent availability of multiple antibody–drug conjugates (ADCs) offers a new treatment paradigm in which tumour-associated antigen expression, payload sensitivity and toxicity profiles may increasingly inform more effective and rational therapeutic strategies.
The clearest example is mirvetuximab soravtansine (MIRV), a folate receptor alpha (FRα)-directed ADC delivering the maytansinoid microtubule inhibitor, DM4. MIRV initially received accelerated approval on the basis of SORAYA, a single-arm phase II trial in patients with FRα-high, platinum-resistant ovarian, fallopian tube or primary peritoneal cancer who had previously received bevacizumab (J Clin Oncol. 2023;41:2436–2445). In this difficult-to-treat population, MIRV produced clinically meaningful antitumour activity, with an objective response rate in approximately one-third of patients and durable responses in a subset. In 2024, the agent was approved by the U.S. Food and Drug Administration based on the results of the MIRASOL study, a randomised phase III trial comparing MIRV with investigator’s choice chemotherapy in patients with FRα-positive, platinum-resistant ovarian cancer (N Engl J Med. 2023;389:2162–2174). MIRASOL demonstrated significant improvements in progression-free survival, objective response rate and overall survival, establishing MIRV as the first biomarker-selected ADC to improve survival in platinum-resistant ovarian cancer. The practice-changing data came with new challenges for ovarian cancer clinics: the need for FRα testing and proactive management of treatment-related ocular toxicity.
Major advances in the field also came with tisotumab vedotin (TV) in recurrent or metastatic cervical cancer. TV targets tissue factor and delivers the microtubule-disrupting payload monomethyl auristatin E (MMAE). Its accelerated approval was based on innovaTV 204, a single-arm phase II trial in patients with recurrent or metastatic cervical cancer who had progressed after chemotherapy, in which TV showed reproducible activity in a population with limited treatment options (Lancet Oncol. 2021;22:609–619). Full approval of TV was later granted on the basis of innovaTV 301, a global randomised phase III trial comparing TV with investigator’s choice chemotherapy in patients with previously treated recurrent or metastatic cervical cancer (N Engl J Med. 2024;391:44–55). Importantly, the study demonstrated an overall survival benefit, together with improvements in progression-free survival and objective response rate, moving this ADC from an active late-line option to a potentially practice-changing treatment. Similar to MIRV, clinical adoption of TV requires familiarity with toxicities that are not routinely encountered with conventional chemotherapy, including ocular events, bleeding and peripheral neuropathy.
More recently, trastuzumab deruxtecan (T-DXd), delivering a topoisomerase I inhibitor, has expanded the relevance of ADCs beyond tumour-type boundaries. Its tumour-agnostic accelerated approval for previously treated, unresectable or metastatic HER2-positive immunohistochemistry (IHC) 3+ solid tumours was supported by data from several phase II studies. In the IHC 3+ population, T-DXd achieved high response rates and durable disease control across tumour types, supporting HER2 overexpression as an actionable biomarker beyond breast and gastric cancers. This development is especially relevant for gynaecological oncology, where HER2-positive subsets exist across endometrial, cervical and ovarian cancers. It also highlights a broader conceptual shift: in selected patients, histology remains central, but antigen biology can become therapeutically decisive.
Together, the approval of these agents illustrates three complementary paths for ADC development in gynaecological cancers: biomarker-selected therapy within a specific disease, as exemplified by MIRV in FRα-positive ovarian cancer; target-directed therapy in a historically difficult-to-treat tumour type, as shown with TV in cervical cancer; and tumour-agnostic antigen-driven treatment, as illustrated by T-DXd in HER2-positive solid tumours.
However, the availability of multiple ADCs in gynaecological cancers raises important questions. Which ADC should be used first when more than one target is present? Can resistance to one ADC be overcome by switching target, payload, or both? How should clinicians sequence agents with overlapping toxicities, such as neuropathy or ocular events? These issues will become increasingly relevant as ADC development expands beyond single-agent late-line therapy.
Importantly, the diversity of payloads may create opportunities for research, such as enabling rational sequencing, particularly if resistance is driven more by payload biology than antigen loss. Also, it may support rational combinations, as long as safety is carefully managed. Early experiences in other tumour types like urothelial cancer illustrate that ADC combinations are no longer merely theoretical, although they require careful dose optimisation and toxicity monitoring (Ann Oncol. 2024;35:91–97).
The next phase for ADCs in gynaecological oncology should therefore move beyond simply adding new agents to late-line algorithms. The greatest opportunity lies in implementing a therapeutic framework: selecting patients with robust biomarkers, anticipating class-specific toxicities, defining optimal sequencing and testing combinations in biologically-informed settings. If achieved, ADCs may not only expand the therapeutic armamentarium for gynaecological cancers but also reshape the concept of precision oncology in diseases historically treated with largely non-selective chemotherapy.
