Abstract

Urothelial carcinoma (UC) is a common cancer associated with a poor prognosis in patients with advanced disease. Platinum-based chemotherapy has remained the cornerstone of systemic anticancer treatment for many years, and recent developments in the treatment landscape have improved outcomes. In this review, we provide an overview of systemic treatment for UC, including clinical data supporting the current standard of care at each point in the treatment pathway and author interpretations from a UK perspective. Neoadjuvant cisplatin-based chemotherapy is recommended for eligible patients with muscle-invasive bladder cancer and is preferable to adjuvant treatment. For first-line treatment of advanced UC, platinum-eligible patients should receive cisplatin- or carboplatin-based chemotherapy, followed by avelumab maintenance in those without disease progression. Among patients unable to receive platinum-based chemotherapy, immune checkpoint inhibitor (ICI) treatment is an option for those with programmed death ligand 1 (PD-L1)–positive tumours. Second-line or later treatment options depend on prior treatment, and enfortumab vedotin is preferred after prior ICI and chemotherapy, although availability varies between countries. Additional options include rechallenge with platinum-based chemotherapy, an ICI, or non–platinum-based chemotherapy. Areas of uncertainty include the optimal number of first-line chemotherapy cycles for advanced UC and the value of PD-L1 testing for UC.

Future perspectives

In the UK, only 30% of patients with advanced UC receive 1L treatment [87]; across global real-world studies, ≈40% of patients receive 1L treatment, with only 15–20% receiving 2L or later treatment [88,89,90,91]. Therefore, a significant unmet need remains, particularly in the 1L setting.

Two novel agents have been approved for later-line treatment of advanced UC outside Europe based on single-arm studies. Firstly, sacituzumab govitecan (ADC targeted to trophoblast cell-surface antigen 2), which has shown activity in patients with advanced UC following disease progression with platinum-based chemotherapy and ICI therapy [92]; an ongoing Phase 3 trial is assessing sacituzumab govitecan vs chemotherapy. Secondly, erdafitinib has shown significantly improved efficacy vs chemotherapy in the randomised Phase 3 THOR trial in a cohort of patients with prior treatment including an ICI [76]. Other ongoing Phase 3 trials of systemic anticancer therapy that are registered on ClinicalTrials.gov are summarised in Table 2. A Phase 3 trial that assessed nivolumab + ipilimumab (anti–cytotoxic T lymphocyte antigen-4) vs platinum-based chemotherapy as 1L treatment for patients with advanced UC did not meet its primary endpoint of prolonged OS in patients with PD-L1–positive tumours [93]. However, as discussed previously, in a substudy from this trial, significantly improved OS and PFS were reported with 1L nivolumab + cisplatin-based chemotherapy followed by nivolumab monotherapy vs cisplatin-based chemotherapy [46]. Considerable improvements in OS and PFS were seen with EV + pembrolizumab vs platinum-based chemotherapy in the Phase 3 EV-302 trial, which enrolled platinum-eligible patients [58]. Results from these trials have the potential to provide additional options in the 1L setting, but the relevance of these regimens to UK clinical practice will depend on regulatory and economic assessments.Table 2 Ongoing Phase 3 trials in UC registered on ClinicalTrials.gov.

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Conclusions

The information summarised in this review provides an overview, from a UK perspective, of key data and clinical developments that support the current standard of care for systemic treatment in patients with UC. Platinum-based chemotherapy remains the cornerstone of systemic treatment for patients with UC. However, the treatment landscape has and continues to evolve rapidly with the development of several new treatments, including different ICIs and ADCs, which have been shown to provide long-term clinical benefits in different populations. Although treatment options available in the UK and other countries depend on local approvals and reimbursement decisions, these developments have improved the prognosis for patients with UC. Despite this, outcomes remain poor overall, particularly in patients with advanced UC; therefore, it is imperative that eligible patients receive optimal treatment at each decision point.