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Treatment Sequencing in Advanced Urothelial Cancer.

Irbaz B Riaz1, Muhammad Abdullah Humayun1, Ali Raza Khaki2

  • 1Mayo Clinic, Phoenix, AZ, USA.

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|January 18, 2026
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Summary

New urothelial carcinoma treatments like enfortumab vedotin plus pembrolizumab offer survival benefits but face access barriers. Alternative therapies and sequencing strategies are crucial for broader patient access and effective care.

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Area of Science:

  • Oncology
  • Urothelial Carcinoma Treatment
  • Cancer Therapeutics

Background:

  • Advanced urothelial carcinoma treatment has evolved with antibody-drug conjugates and immunotherapy.
  • Enfortumab vedotin plus pembrolizumab shows superior survival versus chemotherapy but has cost and availability issues.
  • Established alternatives include gemcitabine-cisplatin with nivolumab and platinum-based chemotherapy with maintenance avelumab.

Purpose of the Study:

  • To review current evidence on advanced urothelial carcinoma treatment paradigms.
  • To address challenges in treatment sequencing after enfortumab vedotin plus pembrolizumab failure.
  • To highlight practical considerations for global implementation, balancing innovation with access and cost-effectiveness.

Main Methods:

  • Literature review of recent clinical trials and evidence for advanced urothelial carcinoma.
  • Synthesis of data on novel agents and sequencing strategies.
  • Analysis of cost, availability, and global applicability of treatment options.

Main Results:

  • Enfortumab vedotin plus pembrolizumab offers significant survival gains but is limited by cost and access.
  • Alternative regimens remain vital, especially for cisplatin-eligible patients or in resource-limited settings.
  • Post-progression options include enfortumab vedotin monotherapy, erdafitinib for FGFR3 alterations, and trastuzumab deruxtecan for HER2-positive disease.

Conclusions:

  • Treatment sequencing after enfortumab vedotin plus pembrolizumab requires further research.
  • Circulating tumor DNA shows promise for personalized sequencing but is investigational.
  • Future priorities include balancing innovation with equitable access, cost-effectiveness, and global applicability in urothelial carcinoma treatment.