FGFR Inhibition in Urothelial Carcinoma

Although FGFR inhibitors are approved for advanced bladder cancer refractory to chemotherapy, they may provide a significant therapeutic benefit in patients with early-stage non–muscle-invasive bladder cancer. With an increasing understanding of the molecular underpinnings of FGFR-driven cancer formation, advanced diagnostic tests, and new drug delivery platforms, we are at the dawn of precision oncology in bladder cancer. The 2024 US Food and Drug Administration approval of erdafitinib for the treatment of metastatic urothelial carcinoma (mUC) with FGFR3 alterations ushered in the era of targeted therapy for bladder cancer. In this review, we summarize the effects of FGFR pathway alterations in oncogenesis, clinical data supporting FGFR inhibitors in the management of bladder cancer, and the challenges that remain. Original articles relevant to FGFR inhibitors in urothelial cancer between 1995 and 2024 were systematically identified in the PubMed and MEDLINE databases using the search terms “FGFR” and “bladder cancer”. An international expert panel with extensive experience in FGFR inhibitor treatment was convened to synthesize a collaborative narrative review. Somatic FGFR3 alterations are found in up to 70% of low-grade non–muscle-invasive bladder cancers; these activate downstream signaling cascades and culminate in cellular proliferation. Beyond a link to lower-grade/lower-stage tumors, there is little consistency regarding whether these alterations confer prognostic risks for cancer recurrence or progression. FGFR3-altered tumors have been linked to a non-inflamed tumor microenvironment, but paradoxically do not seem to impact the response to systemic immunotherapy. Several pan-FGFR inhibitors have been investigated in mUC. With the introduction of novel intravesical drug delivery systems, FGFR inhibitors are poised to transform the therapeutic landscape for early-stage UC. With deepening understanding of the biology of bladder cancer, novel diagnostics, and improved drug delivery methods, we posit that FGFR inhibition will lead the way in advancing precision treatment of bladder cancer.