Dr Moore on Novel ADCs Under Development in FRα+ Ovarian Cancer

"As we have more and more of these [ADCs] available, full understanding of the molecular settings in which these medications work, along with [their toxicity profiles], will be very important for [treatment] selection."

Kathleen N. Moore, MD, MS, a professor in the Section of Gynecologic Oncology, associate director of Clinical Research at Stephenson Cancer Center, and director of the Oklahoma TSET Phase I Program at The University of Oklahoma College of Medicine, The University of Oklahoma Health Sciences, discusses the ongoing evaluation of novel folate receptor alpha (FRα)–targeted antibody-drug conjugates (ADCs) in ovarian cancer.

The development of antibody-drug conjugates (ADCs) targeting FRα continues to be a focus in ovarian cancer, with approximately 20 potential agents under investigation, Moore begins. One such agent, luveltamab tazevibulin (luvelta; STRO-002) is a microtubule toxin with a distinct chemical composition from mirvetuximab soravtansine-gynx (Elahere), warranting independent clinical evaluation, she details. Similarly, the novel FRα-targeted ADC rinatabart sesutecan (Rina-S; PRO1184) received FDA fast track designation in January 2024 for the treatment of patients with FRα-expressing high-grade serous or endometrioid platinum-resistant ovarian cancer. Rina-S consists of an FRα-directed antibody conjugated via a cleavable hydrophilic linker to the topoisomerase 1 inhibitor payload, exatecan. The agent is currently being evaluated in this patient population in a phase 3 trial (NCT06619236), Moore notes.

Evaluating the efficacy of these ADCs requires a thorough understanding of biomarker expression and its role in predicting response, Moore states. Beyond determining whether an agent is active, it is necessary to assess whether the level of FRα expression influences the magnitude and duration of response, she says, adding that a clearer delineation of biomarker thresholds will aid in optimizing patient selection. Additionally, the mechanism of action of these agents, often described in simplified terms as a “Trojan horse” delivering chemotherapy, may involve more complex interactions within the tumor microenvironment that remain underexplored, Moore explains.

As the ovarian cancer therapeutic paradigm expands, determining the optimal application of ADCs will require a deeper understanding of molecular contexts, toxicity profiles, and administration schedules, Moore continues. Future research must incorporate robust correlative and translational data to refine patient selection strategies, she says. The ideal ADCs will demonstrate significant activity, have manageable toxicity, be affordable, and provide meaningful improvements in overall survival compared with other agents, she adds. With continued investigation, a more precise framework for integrating these agents into clinical practice is expected to emerge, Moore concludes.