Episode 9: Advancing Beyond First-Line Options in Urothelial Carcinoma Treatment

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, hosted an Oncology Decoded episode where the topic focused on evolving therapeutic landscape for advanced urothelial carcinoma, specifically addressing strategies for second-line and subsequent treatments, building upon recent breakthroughs in initial therapy.

The episode highlights the current preferred first-line regimen for metastatic urothelial carcinoma: the combination of enfortumab vedotin-ejfv (Padcev) and pembrolizumab (Keytruda) from the phase EV-302 trial (NCT04223856).1 Data recently unveiled at 2025 American Society of Clinical Oncology (ASCO) underscored the impressive longevity of responses observed with this pairing, demonstrating 2-year durability in a notable percentage of patients who responded, with 75% of those achieving a complete response maintaining it. While this combination is generally favored for most patients, the speakers acknowledge specific patient subsets for whom it might be less suitable due to distinct adverse effects, including peripheral neuropathy, dermatologic toxicities, and elevated blood glucose levels.

The phase 3 Checkmate901 trial (NCT03036098), which assessed cisplatin/gemcitabine with nivolumab (Opdivo), is also referenced as a previous standard, though it has largely been supplanted by the enfortumab vedotin/pembrolizumab combination. In cases of lymph-node-only disease, both the cisplatin/gemcitabine/nivolumab and enfortumab vedotin/pembrolizumab regimens exhibit similarly high response rates, necessitating a collaborative decision-making process with the patient.

When patients experience disease progression following enfortumab vedotin/pembrolizumab, the subsequent therapeutic pathway becomes more intricate. Platinum-based chemotherapy doublets, such as cisplatin/gemcitabine or carboplatin/gemcitabine, are options, yet their effectiveness in this heavily pretreated population is modest and often accompanied by considerable toxicity.

Molecular profiling for FGFR alterations is paramount, as erdafitinib (Balversa) presents a targeted therapeutic avenue, achieving a 40% response rate in patients who are FGFR-positive. Effective management of erdafitinib-related toxicities, including ungual changes, cutaneous reactions, and hyperphosphatemia, demands vigilant monitoring and thorough patient education. The potential utility of HER2-targeted antibody-drug conjugates is also explored, particularly for patients with HER2 immunohistochemistry 3+ expression, although clinical data in urothelial carcinoma remain limited.

For individuals lacking identifiable actionable biomarkers, single-agent taxanes (e.g., docetaxel, paclitaxel) have historically yielded poor response rates. Sacituzumab govitecan-hziy (Trodelvy), despite the withdrawal of its accelerated approval following the confirmatory phase 2 TROPHY-U-01 trial (NCT03547973) not achieving statistical significance vs single-agent chemotherapy, is still employed by the presenting clinicians.3 They stress that with appropriate growth factor support, sacituzumab govitecan may demonstrate reduced toxicity and comparable efficacy to carboplatin/gemcitabine in carefully selected patients.

The episode concludes by underscoring the critical importance of comprehensive molecular testing, utilizing both tissue and liquid biopsies, to pinpoint actionable therapeutic targets. The ongoing development of novel FGFR inhibitors and other antibody-drug conjugates is highlighted as essential for broadening the available treatment spectrum in this challenging malignancy. Furthermore, the dynamic nature of HER2 expression necessitates re-evaluation at metastatic sites.

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