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Background <p>Systemic treatment of advanced or metastatic urothelial carcinoma (UC) is undergoing rapid change. The phase&#xa0;III EV-302/KEYNOTE-A39 trial established the combination of enfortumab vedotin and pembrolizumab (EV/P) as the new first-line standard. This paradigm shift fundamentally alters strategies for subsequent therapies and limits the relevance of previously generated evidence.</p> Objective <p>The aim of this review is to summarize the current evidence on second-line and subsequent treatments in metastatic UC in the context of new first-line standards and to outline implications for clinical practice.</p> Materials and methods <p>A&#xa0;comprehensive literature search was conducted in PubMed and complemented by an evaluation of recent abstracts and presentations from major congresses (American Society of Clinical Oncology, ASCO; American Society of Clinical Oncology—Genitourinary, ASCO GU; European Society for Medical Oncology, ESMO) as well as of data from clinicaltrials.gov.</p> Results <p>The evidence for second-line options after EV/P remains limited. International guidelines currently recommend platinum-based chemotherapy without subsequent avelumab maintenance. Erdafitinib provides an effective targeted therapy for patients with <i>FGFR3/2</i> alterations, with activity confirmed even after EV. Sacituzumab govitecan demonstrated relevant response rates in early studies but did not meet the primary endpoint of overall survival in the phase&#xa0;III TROPiCS-04&#xa0;trial. Monochemotherapies, particularly vinflunine and taxanes, play only a&#xa0;minor role. Ongoing phase&#xa0;II/III studies are investigating novel antibody–drug conjugates (ADCs) such as datopotamab deruxtecan, disitamab vedotin, and bispecific ADCs.</p> Conclusion <p>The choice of second-line therapy requires careful consideration of prior treatments, molecular alterations, target protein expression, and individual patient factors. As many previously published data lose relevance in the context of EV/P as the first-line standard, there is an urgent need for prospective studies to define optimal sequencing strategies in metastatic UC.</p>

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Zweitlinien- und Folgetherapien des fortgeschrittenen Urothelkarzinoms

  • 期刊论文

  • 发表日期：

    2025年12月2日

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  • Gunhild von Amsberg,
  • Sergey Dyshlovoy,
  • Anja Coym

摘要

Background

Systemic treatment of advanced or metastatic urothelial carcinoma (UC) is undergoing rapid change. The phase III EV-302/KEYNOTE-A39 trial established the combination of enfortumab vedotin and pembrolizumab (EV/P) as the new first-line standard. This paradigm shift fundamentally alters strategies for subsequent therapies and limits the relevance of previously generated evidence.

Objective

The aim of this review is to summarize the current evidence on second-line and subsequent treatments in metastatic UC in the context of new first-line standards and to outline implications for clinical practice.

Materials and methods

A comprehensive literature search was conducted in PubMed and complemented by an evaluation of recent abstracts and presentations from major congresses (American Society of Clinical Oncology, ASCO; American Society of Clinical Oncology—Genitourinary, ASCO GU; European Society for Medical Oncology, ESMO) as well as of data from clinicaltrials.gov.

Results

The evidence for second-line options after EV/P remains limited. International guidelines currently recommend platinum-based chemotherapy without subsequent avelumab maintenance. Erdafitinib provides an effective targeted therapy for patients with FGFR3/2 alterations, with activity confirmed even after EV. Sacituzumab govitecan demonstrated relevant response rates in early studies but did not meet the primary endpoint of overall survival in the phase III TROPiCS-04 trial. Monochemotherapies, particularly vinflunine and taxanes, play only a minor role. Ongoing phase II/III studies are investigating novel antibody–drug conjugates (ADCs) such as datopotamab deruxtecan, disitamab vedotin, and bispecific ADCs.

Conclusion

The choice of second-line therapy requires careful consideration of prior treatments, molecular alterations, target protein expression, and individual patient factors. As many previously published data lose relevance in the context of EV/P as the first-line standard, there is an urgent need for prospective studies to define optimal sequencing strategies in metastatic UC.