FGFR Inhibitors in Urothelial Cancer: From Scientific Rationale to Clinical Development

Abstract

In the past decade, the treatment of metastatic urothelial cancer (mUC), including bladder cancer (BC), has transformed significantly with the introduction of diverse therapies, such as immune checkpoint inhibitors, targeted therapies, and antibody-drug conjugates. This change is partly due to advancements in genomic understanding, particularly next- generation sequencing, which has identified numerous mutations in UC. Among these therapies, erdafitinib, a pan-fibroblast growth factor receptor (FGFR) inhibitor for specific FGFR2 and FGFR3 alterations, is the only targeted therapy approved till now. In 2019, erdafitinib became pivotal for the treatment of mUC, particularly in patients with specific FGFR alterations. Recent studies have highlighted the benefits of combining erdafitinib with immunotherapy, thereby broadening the treatment options. Ongoing investigations exist on its use in non-muscle-invasive BC and in combination with drugs such as enfortumab vedotin in mUC. Other FGFR-targeted agents are under development; however, overcoming FGFR resistance and ensuring the safety of combination therapies remain major hurdles. FGFR3 mutations are particularly prevalent in BC, a heterogeneous form of UC, and account for a considerable proportion of new cancer diagnoses annually. Approximately half of these cancers have FGFR3 mutations, with gene rearrangements being a common feature. These FGFR3 genomic alterations often occur independently of mutations in other BC oncogenes, such as TP53 and RB1. This review emphasizes the importance of FGFR inhibition in UC and the optimization of its use in clinical practice. Moreover, it underscores the ongoing efforts to evaluate combination strategies and early treatment testing to enhance the effectiveness of targeted therapies for UC.