Antibody-Drug Conjugates Poised to Revolutionize Treatment of Urothelial Carcinoma

Novel treatments for the myriad types of cancer that circulate throughout our communities are sorely needed. Chemotherapy is a common, standard treatment option for patients with cancer but is typically associated with significant toxicity to functioning, healthy tissues and a poor response. Antibody-drug conjugates (ADCs) present as an intriguing, effective new treatment option for patients with cancer that does not lead to harming healthy cells and features fewer complications.¹

Urothelial carcinoma presents as the most common form of bladder cancer. | Image Credit: © Lisa - stock.adobe.com

ADCs and Their Role in Urothelial Cancer

ADCs are monoclonal antibodies (mAbs) that are designed to package the capabilities of mAbs and cytotoxic agents to provide a targeted therapy for a specific disease. The mechanism of action for ADCs involves the targeting and killing of tumor cells through the integration of the antigen specificity of mAbs with antibody fragments, allowing for the sparing of healthy cells. Linker agents also are utilized to help aid in the payload release. ADCs take advantage of the best aspects of both mAbs and cytotoxic agents and have demonstrated meaningful improvements in the management and treatment of patients with cancer.^1-3

“ADCs aim to improve efficacy, reduce toxicity, and expand the therapeutic index,” Di Maria Jiang, MD, MSc, FRCPC, of Princess Margaret Hospital, University Health Network, explained during a presentation at the 2025 ASCO Genitourinary Cancers Symposium. “Many ADCs exhibit bystander effects, where release payloads reach and kill neighboring tumor cells.”³

Specifically, ADCs stand to play a transformative role in the treatment of bladder cancer, including urothelial carcinoma (UC), known as the most common type of bladder cancer. Also known as transitional cell carcinoma, this cancer forms in the urothelial cells that line the bladder and other parts of the urinary tract. Further risks exist with the possible development of UC into muscle-invasive bladder cancer (MIBC), in which tumors spread into the muscle layer of the bladder and present as difficult to treat.⁴

Enfortunab Vedotin Presents as a Safe, Effective ADC for UC

Luckily, a series of ADCs have been developed or are currently under development to help better treat and manage patients with UC. Most prominently, enfortumab vedotin (EV, Padcev; Pfizer), a novel agent composed of a humanized anti-nectin-4 antibody, a cleavable linker, and monomethyl auristatin E, has demonstrated robust safety and efficacy in patients with UC. It was approved in 2019 as a monotherapy or in combination with pembrolizumab (Keytruda; Merck & Co) for patients with locally advanced or metastatic UC, and the ADC continues to be studied in combination with other agents.^1,4

The global, open-label, phase 3 EV-301 clinical trial (NCT03474107) provided backing for EV’s FDA approval for patients with UC. In the trial, which enrolled 608 patients to be randomized between EV and chemotherapy, OS was found to be longer in the EV group compared with the chemotherapy group, while PFS was also superior in patients treated with EV compared with chemotherapy. Critically, there was a similar incidence of treatment-related adverse events (TRAEs) in each group, signifying the broad safety of EV in this population.⁵

In data presented at the 2025 ASCO Genitourinary Cancers Symposium, the effectiveness of first-line EV in combination with pembrolizumab was reaffirmed. Results from the KEYNOTE-A39 trial (NCT03223856) indicated superior progression-free survival (PFS) and overall survival (OS) with EV compared with chemotherapy in patients with previously untreated, locally advanced or metastatic UC. Importantly, EV induced a superior overall response rate compared with chemotherapy, regardless of patient eligibility for cisplatin or the presence of liver metastases.⁶

It is important to note that there was a higher incidence of grade 3 or higher TRAEs in both the EV/pembrolizumab and chemotherapy arms in KEYNOTE-A39 compared with EV-301; however, there remained a lower rate of TRAEs in the EV/pembrolizumab arm, indicating sustained, superior safety to chemotherapy but demonstrating a slightly increased risk with the combination of pembrolizumab. It will be critical for health care providers to manage patient considerations and utilize the treatment regimen—whether it be EV monotherapy or in combination with another agent—that works best for the patient.^5,6

The role of ADCs in UC and the treatment of other cancers is rapidly growing. With research initiatives ongoing to elucidate more aspects of ADCs such as EV, their role in the treatment paradigm for patients with UC is poised to increase. Accordingly, pharmacists play a critical part in selecting the right ADC for patients, determining optimal dosage, and managing TRAEs.

REFERENCES

1. Pettinato MC. Introduction to antibody-drug conjugates. Antibodies (Basel). 2021;10(4):42. doi:10.3390/antib10040042

2. Ducry L, Stump B. Antibody−Drug Conjugates: Linking Cytotoxic Payloads to Monoclonal Antibodies. Bioconjugate Chem. 2009;21(1):5-13. doi:10.1021/bc9002019

3. Gerlach A. Targeting Nectin-4 and HER2 in Urothelial Cancer: The Evolving Role of ADCs. Pharmacy Times. Published February 15, 2025. Accessed August 20, 2025. https://www.pharmacytimes.com/view/targeting-nectin-4-and-her2-in-urothelial-cancer-the-evolving-role-of-adcs

4. American Cancer Society. What is bladder cancer? The American Cancer Society Medical and Editorial Content Team. Last Updated March 12, 2024. Accessed August 20, 2025. https://www.cancer.org/cancer/types/bladder-cancer/about/what-is-bladder-cancer.html

5. Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med. 2021;384(12):1125-1135. doi:10.1056/NEJMoa2035807

6. Gerlach A. First-Line Enfortumab Vedotin, Pembrolizumab Superior to Chemotherapy in Patients With Urothelial Carcinoma. Pharmacy Times. Published February 14, 2025. Accessed August 20, 2025.