Navigating Second-Line Treatment Options in Urothelial Carcinoma

This episode of Oncology Decoded focuses on a discussion between hosts 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, in a recent live session with US Oncology Network and the Pathways Task Force, discussing the evolving landscape of second-line and beyond therapy for urothelial carcinoma, particularly in the context of recent advancements in first-line treatment.

First Line Strategies

The current standard of care for frontline metastatic urothelial carcinoma is enfortumab vedotin-ejfv (Padcev) in combination with pembrolizumab (Keytruda). Recent data from the phase EV-302 trial (NCT04223856) presented at the 2025 American Society of Clinical Oncology (ASCO) highlighted the remarkable durability of responses with this combination, showing a 2-year durability in a significant proportion of responders, including 75% of complete responders.¹ While this combination is favored for most patients, the hosts acknowledged a subgroup for whom it may not be suitable due to unique toxicities such as neuropathy, skin toxicity, and hyperglycemia.

The phase 3 Checkmate901 trial (NCT03036098), evaluating cisplatin/gemcitabine with nivolumab (Opdivo), is also mentioned as a prior standard of care, though generally superseded by enfortumab vedotin/pembrolizumab. For patients with lymph-node-only disease, both cisplatin/gemcitabine and nivolumab or enfortumab vedotin/pembrolizumab show comparable high response rates, necessitating shared decision-making.

Second Line Strategies

For patients progressing on enfortumab vedotin/pembrolizumab, the subsequent treatment landscape becomes more complex. Platinum-based chemotherapy doublets (cisplatin/gemcitabine or carboplatin/gemcitabine) are considered, though their efficacy in this heavily pretreated setting is limited and associated with significant toxicity.

Molecular testing for FGFR alterations is crucial, as erdafitinib (Balversa) offers a targeted option with a 40% response rate in patients who are FGFR-positive. Managing erdafitinib toxicities, including nail changes, skin reactions, and phosphate level elevations, requires close monitoring and patient education. The potential role of HER2-targeted antibody-drug conjugates is also discussed, particularly for HER2 3+ expression, though data in urothelial carcinoma are limited.

For patients without actionable biomarkers, single-agent taxanes (docetaxel, paclitaxel) have historically shown dismal response rates (~15-17%). Sacituzumab govitecan-hziy (Trodelvy), despite its accelerated approval withdrawal due to the confirmatory phase 2 TROPHY-U-01 trial (NCT03547973) not meeting statistical significance against single-agent chemotherapy, is still utilized by the speakers. They emphasize that with appropriate growth factor support, sacituzumab govitecan can be less toxic and equally efficacious as carboplatin/gemcitabine in select patients.

References

1. Bedke J, Powles TB, Valderrama BP, et al. EV-302: long-term subgroup analysis from the phase 3 global study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (chemo) in previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC). J Clin Oncol. 2025;43(suppl 16):4571. doi:10.1200/JCO.2025.43.16_suppl.4571
2. Van der Heijden M, Galsky M, Powles T, et al. Nivolumab plus ipilimumab (NIVO+IPI) vs gemcitabine-carboplatin (gem-carbo) chemotherapy for previously untreated unresectable or metastatic urothelial carcinoma (mUC): Final results for cisplatin-ineligible patients from the CheckMate 901 trial. J Clin Oncol. 2025;43(suppl 17):4500. doi:10.1200/JCO.2025.43.16_suppl.4500
3. Gilead provides update on U.S. Indication for Trodelvy in metastatic urothelial cancer. News release. Gilead Sciences, Inc. October 18, 2024. Accessed July 30, 2025. https://tinyurl.com/2aku377j