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  • Review Article
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Towards biomarker-driven therapies for urothelial carcinoma

Nature Reviews Clinical Oncology volume 23, pages 92–106 (2026)Cite this article

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Abstract

Molecularly targeted agents and immune checkpoint inhibitors (ICIs) are transforming the treatment landscape for patients with advanced-stage urothelial carcinoma (aUC), although trials testing these novel agents have shown mixed results. In this context, the identification of biomarkers has seen limited success: while activating mutations in FGFR3 are now established as an actionable biomarker to guide treatment with FGFR inhibitors, PD-L1 expression has shown inconsistent value as a predictive biomarker of response to ICIs. The identification of prognostic and predictive biomarkers for ICIs, antibody–drug conjugates and targeted therapies is an active area of research; promising candidates include tumour mutational burden and HER2 overexpression. In the past few years, circulating tumour DNA has emerged as a minimally invasive biomarker, with increasing data supporting its prognostic value and utility for monitoring clinical responses. In this Review, we address these developments and discuss biomarkers that could have clinical utility in patients with aUC.

Key points

  • The identification of predictive biomarkers in patients with advanced-stage urothelial carcinoma (aUC) has been hampered by the variability of the assessment methods. Standardizing the assessment of these biomarkers will help to overcome these heterogeneous results.

  • Activating mutations in FGFR3 are now an established biomarker guiding the choice of targeted therapies for patients with aUC. HER2 is becoming an increasingly important biomarker in this setting.

  • In patients with aUC receiving immune checkpoint inhibitors, PD-L1 expression has shown inconsistent value as a predictive biomarker and thus, standardized, robust validation methods are needed to avoid the interpretation errors from previous studies. Experimental biomarkers, such as tumour mutational burden, have shown promise in this setting but need validation.

  • Integrating data from several biomarkers using artificial intelligence and spatial analysis could improve the predictive value of conventional tissue-based approaches focusing on a single biomarker.

  • Circulating tumour DNA offers minimally invasive monitoring of treatment response and recurrence risk.

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  1. Barts Cancer Institute, Queen Mary University of London, Barts Health NHS Trust Biomedical Research Centre, London, UK

    Sara Coca Membribes, Bernadett Szabados & Thomas Powles

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S.C.M. and T.P. researched data for the article and contributed substantially to discussions of content. All authors wrote the article, and reviewed and/or edited the manuscript before submission.

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Coca Membribes, S., Szabados, B. & Powles, T. Towards biomarker-driven therapies for urothelial carcinoma. Nat Rev Clin Oncol 23, 92–106 (2026). https://doi.org/10.1038/s41571-025-01095-x

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