The Next Wave: ADCs, Targeted Therapies, and Emerging Strategies in Ovarian Cancer

From Discovery to Delivery: Charting Progress in Gynecologic Oncology, hosted by Ursula A. Matulonis, MD, brings expert insights into the most recent breakthroughs, evolving standards, and emerging therapies across gynecologic cancers. Dr Matulonis is chief of the Division of Gynecologic Oncology and the Brock-Wilson Family Chair at the Dana-Farber Cancer Institute, as well as a professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

In this episode, Dr Matulonis was joined by Joyce F. Liu, MD, MPH, a medical oncologist and associate professor of medicine at Harvard Medical School, associate chief and director of clinical research in the Division of Gynecologic Oncology at Dana-Farber Cancer Institute, and associate clinical research officer for the clinical research program at Dana-Farber, all in Boston, Massachusetts. Together, they explored the rapidly expanding landscape of novel therapies for ovarian cancer, spanning the next generation of antibody-drug conjugates (ADCs), resistance mechanisms, cell cycle targets, and emerging strategies for rare histologic subtypes.

Dr Liu opened by surveying the current ADC pipeline in ovarian cancer, noting that while mirvetuximab soravtansine-gynx (Elahere) and fam-trastuzumab deruxtecan-nxki (Enhertu) are already in clinical use, a substantial wave of next-generation agents is now advancing through phase 2 and phase 3 development. She organized these agents by target and payload, highlighting three folate receptor alpha-targeting ADCs with topoisomerase 1 inhibitor payloads: rinatabart sesutecan, sofetabart mipitecan, and torvutatug samrotecan as well as the B7-H4-targeting agent rocertatug rezetecan, CDH6-targeting agents, and Trop-2-directed ADCs including sacituzumab tirumotecan and sacituzumab govitecan-hziy (Trodelvy). Dr Liu noted that early-phase data across several of these agents have shown response rates of 50% or higher, even in heavily pretreated, platinum-resistant populations. Though meaningful, questions remain about response durability as these data continue to mature. A key advantage shared by many of these agents, she emphasized, is the potential for use without high levels of biomarker expression, which could extend eligibility well beyond what current approved ADCs allow.

The conversation then turned to ADC resistance mechanisms and the feasibility of sequential ADC use. Dr Liu described three broad categories of resistance: target-mediated mechanisms, payload-dependent mechanisms, and mechanisms independent of both target and payload. Drawing on evidence from the breast cancer setting, she noted that switching payloads while maintaining the same target can preserve activity, a pattern now emerging in early ovarian cancer data with folate receptor alpha-directed ADCs. Sequential use of two topoisomerase 1 payload ADCs, however, remains a concern, with prospective phase 2 breast cancer trial data suggesting limited activity in that setting. Dr Liu cautioned against drawing direct lines between breast and ovarian cancer biology while acknowledging the question must be actively studied. She and Dr Matulonis also discussed the possibility of ADC rechallenge in patients whose disease progressed in a different treatment context as the settings in which ADCs are introduced continue to evolve.

Dr Liu also addressed dual-payload ADCs, describing them conceptually as analogous to combination chemotherapy, pairing microtubule inhibitor and topoisomerase 1 inhibitor payloads to potentially overcome resistance and improve depth of response. She highlighted a further frontier of novel ADC payloads, including immune-stimulating antibody conjugates, protein degraders, and ATR inhibitors as representing the earliest translational steps from preclinical models into clinical investigation.

Drs Matulonis and Liu then discussed therapeutic strategies for CCNE1-amplified ovarian cancer, a molecularly distinct subset characterized by overexpression of cyclin E1 protein and dependency on the G2/M cell cycle checkpoint. Dr Liu explained that CCNE1 amplification drives constitutive CDK2 activation, forcing cells into premature DNA replication and creating vulnerability to agents that abrogate the compensatory G2/M checkpoint. Two therapeutic approaches have emerged: WEE1 inhibition with azenosertib, which has shown response rates of approximately 30% to 35% in cyclin E1-high platinum-resistant ovarian cancer by immunohistochemistry, compared with 10% to 15% for standard chemotherapy, and CDK2 inhibition and degradation strategies showing similar early signals in CCNE1-amplified tumors. Both approaches are now entering phase 3 evaluation. Dr Liu noted that while CCNE1 amplification is detectable on next-generation sequencing, a validated immunohistochemistry assay for cyclin E1 protein expression is not yet commercially available, though one may emerge as a companion diagnostic if protein-level expression proves to be the more predictive biomarker.

The discussion also covered KIF18A, a kinesin motor protein that stabilizes chromosomes at the metaphase plate during mitosis. In cancers with high chromosomal instability KIF18A activity is critical for cell survival; its inhibition leads to mitotic errors and cell death. Several KIF18A inhibitors are now in active clinical development, with early signals of activity emerging. Dr Liu noted that chromosomal instability alone may not be sufficient to identify optimal candidates for these agents and that additional biomarker refinement will likely be necessary.

Turning to rare histologic subtypes, Dr Liu highlighted two areas of recent progress. In low-grade serous ovarian cancer, the combination of avutometinib, a RAS/RAF clamp that suppresses signaling through the RAS/RAF/MEK pathway, and the FAK inhibitor defactinib (Avmapki Fakzynja Co-pack) received accelerated FDA approval for patients with KRAS-mutated low-grade serous ovarian cancer, supported by phase 2 data demonstrating meaningful activity in this molecularly defined population. A confirmatory international phase 3 trial is ongoing. In clear cell ovarian cancer, emerging phase 2 data for immunotherapy combinations suggest that immunotherapy may hold particular relevance for this subtype, though randomized phase 3 evidence specific to clear cell disease remains limited.

Dr Liu concluded by highlighting two additional areas of interest: BCL-XL inhibition and degradation combinations, which have shown activity in preclinical models and early clinical signals in ovarian cancer; and next-generation immunotherapy approaches, including bispecific antibodies and evolving cellular therapy strategies, which she views as holding genuine potential to generate durable responses in a disease where conventional PD-1/PD-L1 inhibition has had limited reach.