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  • Review Article
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Progress in systemic therapy for advanced-stage urothelial carcinoma

Nature Reviews Clinical Oncology volume 21, pages 8–27 (2024)Cite this article

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Abstract

Despite recent advances, advanced-stage urothelial carcinoma (aUC) remains incurable, with 5-year survival rates of approximately 10%. Platinum-based chemotherapy has a major role as first-line therapy for most patients with aUC. The approval of the anti-PD-L1 antibody avelumab as maintenance therapy for patients without initial disease progression on platinum-based chemotherapy is an important development that has improved the survival outcomes of patients with this disease. Otherwise, the use of first-line immune-checkpoint inhibitors (ICIs) targeting PD-1 or PD-L1 has been restricted to patients who are ineligible for platinum-containing chemotherapy regimens. Other important developments include the FDA-accelerated approval of first-line enfortumab vedotin plus pembrolizumab for patients ineligible to receive cisplatin and the availability of FGFR inhibitors, enfortumab vedotin and sacituzumab govitecan for subsequent lines of therapy. Several research questions remain unaddressed including the lack of adequate biomarkers, how to assign priority to the different treatment options for individual patients and which agents can be effective as monotherapies. The future is promising with the emergence of modalities such as antibody–drug conjugate-like drugs, next-generation ICIs, bispecific antibodies and cellular therapies. In this Review, we summarize the evolution of systemic therapy for patients with aUC and provide insights into the unmet needs.

Key points

  • With the advent of effective frontline non-chemotherapy-based regimens, the currently adopted approach for selection of frontline therapy based on cisplatin fitness is insufficient.

  • Treatment with immune-checkpoint inhibitors (ICIs) is already consolidated in the treatment of patients with aUC. Currently, the main benefit is seen with the anti-PD-L1 antibody avelumab as switch maintenance therapy following first-line chemotherapy.

  • Antibody–drug conjugates as monotherapies are already part of the therapeutic portfolio for patients with aUC and are indicated in patients with disease progression on platinum-based therapy and/or ICIs.

  • ICI-containing combinations are now positioned as the most promising treatments for patients with aUC, especially the combination of enfortumab vedotin and pembrolizumab.

  • Greater knowledge of the molecular biology of aUC has enabled the identification of several therapeutic targets, including FGFR. Erdafitinib has become the standard-of-care therapy for patients with FGFR2/3 alterations, after previous treatment with platinum-based chemotherapy and ICIs.

  • Designing clinical trials with adequate correlative biomarker studies is essential for broadening our knowledge of tumour biology, identifying new targets and developing more effective treatment combinations.

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Fig. 1: Advances in the treatment of patients with advanced-stage urothelial carcinoma.
Fig. 2: Antibody–drug conjugates in advance-stage urothelial carcinoma.
Fig. 3: Current standard of care for patients with advanced-stage urothelial carcinoma.

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Authors and Affiliations

  1. National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    Rosa Nadal

  2. Hospital Virgen del Rocio, University Hospital Virgen del Rocío, Seville, Spain

    Begoña P. Valderrama

  3. Dana-Farber Cancer Institute/Brigham and Women’s Hospital Harvard Medical School, Boston, MA, USA

    Joaquim Bellmunt

  4. Hospital del Mar Research Inst Lab (IMIM), Barcelona, Spain

    Joaquim Bellmunt

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  1. Rosa Nadal
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  2. Begoña P. Valderrama
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  3. Joaquim Bellmunt
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B.P.V. has acted as an adviser of AAA, Astellas Pharma, Bayer, Bristol-Myers Squibb, EUSA Pharma, Ipsen, Merck, MSD, Novartis and Pfizer; has been an invited speaker for Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, EUSA Pharma, Janssen, Merck, MSD, Pfizer and Roche; and has received travel support from Merck and Pfizer. J.B. has acted as a consultant and/or adviser of Astellas Pharma, AstraZeneca/MedImmune, Bristol-Myers Squibb, Genentech, Merck, Pierre Fabre, Pfizer and Takeda; has received research funding from Pfizer/EMD Serono, Millennium and Sanofi and trial sponsorship from Associació per a la Recerca Oncológia (APRO); has received royalties from UpToDate; owns stocks in Rainier Therapeutics; and declares a non-financial interest as President of APRO. R.N. declares no competing interests.

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Nadal, R., Valderrama, B.P. & Bellmunt, J. Progress in systemic therapy for advanced-stage urothelial carcinoma. Nat Rev Clin Oncol 21, 8–27 (2024). https://doi.org/10.1038/s41571-023-00826-2

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