Navigating the Evolving Second-Line Landscape of Metastatic Urothelial Carcinoma

The latest Oncology Decoded discussion with Manojkumar Bupathi, MD, MS, executive cochair of the Genitourinary Cancer Research Executive Committee at Sarah Cannon Research Institute (SCRI) and medical oncologist with Rocky Mountain Cancer Centers specializing in solid tumors and genitourinary cancers, and Benjamin Garmezy, MD, associate director of genitourinary research and executive cochair of the Genitourinary Cancer Research Executive Committee at SCRI and medical oncologist at SCRI Oncology Partners specializing in genitourinary cancers, dissects the current management of metastatic urothelial carcinoma, with a focus on treatment strategies beyond standard first-line therapies. The conversation highlights the recent paradigm shift with the approval of enfortumab vedotin-ejfv (Padcev) in combination with pembrolizumab (Keytruda). This combination’s efficacy, as demonstrated in the phase 3 EV-302 trial (NCT04223856), has positioned it as a new standard of care for many patients. The alternative, gemcitabine plus cisplatin with nivolumab (Opdivo), supported by the phase 3 CheckMate 901 trial (NCT03036098), remains a crucial first-line option, particularly for patients who are cisplatin-eligible.

The hosts delve into the nuances of second-line therapy, which has become a more complex and critical area. For patients who progress on enfortumab vedotin/pembrolizumab, the discussion covers options such as platinum-based chemotherapy with gemcitabine/cisplatin or carboplatin. The importance of biomarker-driven therapy is also emphasized, particularly the role of molecular testing for FGFR gene alterations. The FDA-approved FGFR inhibitor erdafitinib (Balversa) is highlighted as a viable option for patients with susceptible genetic alterations. Furthermore, the discussion touches on the evolving role of HER2-targeted agents and other novel early-phase assets that are being developed to address the unmet need in this patient population.

Management of toxicities is also a significant theme. The clinicians share insights on mitigating adverse effects such as peripheral neuropathy from enfortumab vedotin, and the challenges of managing hyperglycemia and skin toxicities. The need for more data-driven guidance on treatment duration and maintenance therapy is also underscored, with the observation that treatment discontinuation is a common clinical challenge lacking clear guidelines.

Reference

FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. News release. FDA. December 15, 2023. Accessed August 13, 2025. https://tinyurl.com/45wkm3bd