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Purpose <p>The therapeutic landscape of advanced urothelial carcinoma has evolved rapidly with the introduction of immune checkpoint inhibitors, antibody-drug conjugates, and combination regimens. However, optimal treatment sequencing remains incompletely defined. This review examines critical sequencing dilemmas in contemporary practice.</p> Methods <p>This narrative review synthesizes pivotal phase 3 trials in advanced urothelial carcinoma (2019–2024), real-world registry and population-based cohort data, and current NCCN and EAU guidelines. We focus on two key clinical scenarios: first-line therapy selection in the post-EV-302 era, and therapeutic strategies following progression on enfortumab vedotin-based regimens.</p> Results <p>First-line options now include enfortumab vedotin plus pembrolizumab (median OS 31.5 months), nivolumab plus gemcitabine-cisplatin (median OS 21.7 months), and platinum-based chemotherapy with avelumab maintenance (median OS 21.4 months), yet comparative sequencing data are absent. Real-world attrition is substantial: only 49% of patients receive first-line therapy, 23% receive second-line, and 11% receive third-line treatment in claims-based analyses. Post-enfortumab vedotin options remain limited to platinum chemotherapy (for platinum-naïve patients), erdafitinib (for FGFR-altered disease), and clinical trial enrollment. No validated biomarkers exist to guide sequencing decisions.</p> Conclusion <p>Optimal sequencing of systemic therapies in advanced urothelial carcinoma represents a critical evidence gap. Patient-centered approaches incorporating fitness assessment, real-world attrition patterns, and multidisciplinary input are essential pending prospective sequencing trials.</p>

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Unresolved questions in the sequencing of systemic therapy for advanced urothelial carcinoma

  • 期刊论文

  • 发表日期：

    2026年4月14日

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  • Prasanna Ram,
  • Axel S. Merseburger,
  • Matchima Huabkong,
  • Yoichiro Tohi

摘要

Purpose

The therapeutic landscape of advanced urothelial carcinoma has evolved rapidly with the introduction of immune checkpoint inhibitors, antibody-drug conjugates, and combination regimens. However, optimal treatment sequencing remains incompletely defined. This review examines critical sequencing dilemmas in contemporary practice.

Methods

This narrative review synthesizes pivotal phase 3 trials in advanced urothelial carcinoma (2019–2024), real-world registry and population-based cohort data, and current NCCN and EAU guidelines. We focus on two key clinical scenarios: first-line therapy selection in the post-EV-302 era, and therapeutic strategies following progression on enfortumab vedotin-based regimens.

Results

First-line options now include enfortumab vedotin plus pembrolizumab (median OS 31.5 months), nivolumab plus gemcitabine-cisplatin (median OS 21.7 months), and platinum-based chemotherapy with avelumab maintenance (median OS 21.4 months), yet comparative sequencing data are absent. Real-world attrition is substantial: only 49% of patients receive first-line therapy, 23% receive second-line, and 11% receive third-line treatment in claims-based analyses. Post-enfortumab vedotin options remain limited to platinum chemotherapy (for platinum-naïve patients), erdafitinib (for FGFR-altered disease), and clinical trial enrollment. No validated biomarkers exist to guide sequencing decisions.

Conclusion

Optimal sequencing of systemic therapies in advanced urothelial carcinoma represents a critical evidence gap. Patient-centered approaches incorporating fitness assessment, real-world attrition patterns, and multidisciplinary input are essential pending prospective sequencing trials.