Emerging Star in Ovarian Cancer Tx

BARCELONA, Spain — Antibody-drug conjugates (ADCs) could address significant challenges in ovarian cancer treatment, as highlighted in a session at the European Society for Medical Oncology (ESMO) Annual Meeting 2024.

These molecules have become a part of many oncologists’ therapeutic arsenal, with numerous studies assessing their potential across various cancers. 

Susana Banerjee, MBBS, PhD, lead oncologist at the Gynaecology Unit of The Royal Marsden NHS Foundation Trust and professor in women’s cancers at The Institute of Cancer Research, both in London, England, chaired the session. She emphasized that these molecules were developed to meet a critical unmet need in patients with cancer: To increase the therapeutic index of cytotoxic treatments and reduce their toxicity.

Conjugated antibodies can theoretically achieve this goal, earning them the label of “smart chemotherapy.” They are designed to deliver the drug directly to the target through antigen-antibody interaction.

A Complex and Evolving Structure

“The interest in these molecules is rapidly growing, and for this reason, understanding their structure and mechanism of action is crucial,” Banerjee explained, before delving into more technical aspects of ADCs that are necessary for understanding their function.

Identifying the target is essential. Ideally, this should be a molecule abundantly expressed by cancer cells and absent in healthy ones. The structure of ADCs comprises three main components: The antibody, the chemotherapeutic agent (payload), and the linker, which connects the antibody to the chemotherapeutic agent. The antibody is crucial for recognizing the target and facilitating the payload’s entry into the cell. The payloads can be broadly categorized into two types: Drugs that damage DNA, such as topoisomerase inhibitors, and drugs that destroy microtubules, like auristatins. Finally, the linker can be cleavable or non-cleavable.

“A parameter that oncologists using ADCs must be familiar with is the drug-antibody ratio (DAR),” Banerjee said. “This ratio represents the average number of cytotoxic molecules conjugated to the antibody and impacts the efficacy and safety of the ADC.”

Thanks to advancements in available technologies, the structure of ADCs is continually evolving to optimize the molecule’s mechanism of action. Theoretically, it must recognize the cancer cell and be introduced into the cell through endocytosis. Once internalized, the ADC releases the payload, leading to the destruction of the cancer cell.

Focus on Ovarian Cancer

“These drugs will make a difference in the treatment of ovarian cancer,” said Domenica Lorusso, MD, PhD, professor of obstetrics and gynecology at Humanitas University and head of the Gynecological Oncology Unit at Humanitas San Pio X, both in Milan, Italy, speaking with Univadis Italy, a Medscape Network platform.

She noted that aside from the recent introduction of PARP inhibitors, especially in maintenance therapy, the treatment of ovarian cancer still represents a significant unmet clinical need. Attempts to introduce immunotherapy have not been successful, and the prognosis remains dire for forms resistant to platinum, so new therapeutic options are needed.

“In this scenario, ADCs are emerging stars in the therapeutic arsenal of oncologists,” said Lorusso, noting that more than 260 drugs have been tested with 12 already approved by the US Food and Drug Administration.

From the perspective of potential targets, ovarian cancer is the most interesting neoplasm, with numerous molecules potentially usable in ADC-based therapies, including the folate receptor (FR) alpha, cadherin 6 (CDH6), human epidermal growth factor receptor 2 (HER-2), TROP-2, and NaPi2b. Based on this premise, more than 40 ADCs are currently in clinical development for ovarian cancer, and the list is constantly growing.

Early Successes and Ongoing Challenges

Mirvetuximab soravtansine was the first ADC to show efficacy as a therapy for platinum-resistant ovarian cancer. Despite high expectations from early-phase studies, the drug initially did not meet the primary endpoint of progression-free survival (PFS). 

“This happened because we were unable to identify the suitable patients for the treatment,” Lorusso who was involved in these studies explained, noting that a subsequent reanalysis of the data allowed for the selection of a different population and thus demonstrated benefits in terms of PFS and overall survival.

The molecule has continued its clinical development and is now approved in the United States. “We hope the drug will soon be available to European patients as well,” she said. Of note, mirvetuximab soravtansine also shows activity in patients previously treated with PARP inhibitors, a group for which new effective treatment options are needed.

Other studies are exploring the role of this mirvetuximab soravtansine in populations sensitive to platinum, in combination with bevacizumab.

But this is just one of the ADCs under study for ovarian cancer. Other drugs mentioned during the session included luveltamab tazevibulin and farletuzumab ecteribulin, which target FR alpha; trastuzumab deruxtecan, which recognizes HER2, a target present in 35% of high-grade serous tumors and in even higher percentages in other histotypes; and others.

Side Effects to Manage

These new drugs bring with them some side effects that doctors and patients must confront. “Generally, these side effects are manageable, but they are new and, consequently, we must pay particular attention to them. There is a learning curve to understand how to manage them best,” Lorusso said.

She mentioned specific side effects of different ADCs, including ocular toxicity, myelotoxicity, and interstitial pneumonia. 

“ADCs were originally presented as targeted drugs, with complete internalization into the cancer cell. However, data show that internalization stops at 1%-3%, with the cytotoxic drug consequently present outside the target cell,” Lorusso explained to Univadis Italy. “We should expect some side effects similar to those of chemotherapy, which must still be monitored,” she added.

While optimistic about the future, Lorusso concluded by listing a series of unanswered questions, such as the correct identification of patients for trials, the setting, the duration and dose of treatment, possible mechanisms of resistance, and the best combination with other therapies.

Banerjee declared receiving research contributions from various pharmaceutical companies, including AstraZeneca and GSK, as well as receiving research grants from the Lady Garden Foundation and Wellbeing of Women charities. She also reported receiving honoraria and travel grants from numerous other pharmaceutical companies. 

Lorusso declared receiving research funding from Clovis Oncology, Merck, PharmaMar, and TESARO/GSK and honoraria from several other pharmaceutical companies.

Cristina Ferrario is a molecular biologist and former researcher in molecular oncology at three institutes in Milan. She has a master’s degree in communication and health from the University of Milan, Milan, and a master’s degree in cancer genetics from the University of Pavia, Pavia, Italy. She has worked as a science journalist for more than 20 years.

This story was translated, with slight adaptation, from Univadis Italy using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.