Bladder cancer is a significant health concern, with the majority of cases being urothelial carcinoma, a malignancy arising from the cells lining the urinary tract. Urothelial carcinoma accounts for approximately nine out of ten bladder cancer diagnoses. While historically challenging to treat when advanced, the last few years have introduced a rapid evolution in therapeutic options. The latest treatments have moved beyond traditional chemotherapy and surgery, focusing on harnessing the body’s immune system and developing specialized targeted drugs.
Understanding the Treatment Landscape
Treatment strategies for bladder cancer are determined by how far the cancer has invaded the bladder wall. The disease is primarily categorized into three groups based on this staging, which directs the subsequent therapeutic approach.
The most common form, Non-Muscle Invasive Bladder Cancer (NMIBC), accounts for about 75% of new diagnoses and is confined to the inner lining of the bladder. Treatment for NMIBC is localized, often involving surgery to remove the tumor followed by intravesical therapy delivered directly into the bladder.
When the tumor grows into the deeper muscle layer of the bladder, it is classified as Muscle-Invasive Bladder Cancer (MIBC), a more aggressive disease. Advanced and Metastatic Bladder Cancer is defined by cancer that has spread beyond the bladder to lymph nodes or distant organs. These advanced stages require systemic treatments, which are therapies given throughout the body.
The fundamental distinction between localized and systemic disease explains why the newest drug therapies primarily benefit patients with advanced or metastatic disease. However, significant advancements are also emerging for patients with early-stage disease who face recurrence or treatment failure.
The Expansion of Immunotherapy
Immunotherapy has fundamentally changed the landscape for advanced urothelial carcinoma, offering a new path for patients with locally advanced or metastatic disease. This approach uses checkpoint inhibitors, a class of drugs that essentially remove the brakes on the immune system’s T-cells. These inhibitors block the interaction between the PD-1 protein on T-cells and the PD-L1 protein on cancer cells, which the tumor uses to evade detection.
A major recent advancement is the combination of the antibody-drug conjugate enfortumab vedotin with the PD-1 inhibitor pembrolizumab, now a preferred first-line treatment for metastatic urothelial carcinoma. This combination demonstrated superior overall survival compared to traditional platinum-based chemotherapy in clinical trials. For patients ineligible for this combination or who cannot tolerate standard platinum-based chemotherapy, immunotherapy remains an important option. Certain checkpoint inhibitors, such as pembrolizumab, can be used as a single agent in the first-line setting for those ineligible for cisplatin-based chemotherapy.
Another established approach uses the checkpoint inhibitor avelumab as a maintenance therapy. For patients with advanced or metastatic disease whose cancer has responded to initial platinum-based chemotherapy, avelumab is given indefinitely to maintain the response. This maintenance strategy significantly prolonged overall survival compared to observation alone in a large clinical trial, establishing it as a standard of care.
Targeted Treatments and Antibody-Drug Conjugates
Beyond broad immune system activation, recent treatments have become precise, targeting specific molecular characteristics of the cancer cell. One such precision therapy involves Fibroblast Growth Factor Receptor (FGFR) inhibitors, such as erdafitinib. This oral medication is used for patients with locally advanced or metastatic urothelial carcinoma that harbor specific genetic alterations, usually in the FGFR2 or FGFR3 genes.
Erdafitinib works by inhibiting the tyrosine kinase activity of the FGFR protein, thereby disrupting the signaling pathways that drive cancer cell growth and survival. Since these gene alterations are present in only a fraction of urothelial tumors, a companion diagnostic test is necessary to identify eligible patients. Treatment is thus tailored based on the tumor’s unique genetic signature.
Another major development is the rise of Antibody-Drug Conjugates (ADCs), which function as “guided missiles” that deliver a potent chemotherapy payload directly to the cancer cells. An ADC consists of an antibody that recognizes a specific protein on the tumor cell surface, a linker, and a cytotoxic drug. Enfortumab vedotin (EV) is a leading example, targeting the Nectin-4 protein highly expressed on most urothelial cancer cells.
Once EV binds to Nectin-4, the cancer cell internalizes the ADC, releasing the chemotherapy payload inside to kill the cell while minimizing systemic toxicity. Another ADC, sacituzumab govitecan, targets the Trop-2 protein, but its accelerated approval for urothelial carcinoma was voluntarily withdrawn in late 2024 after a confirmatory trial failed to demonstrate an overall survival benefit compared to chemotherapy. The success and failure of these ADCs highlight the delicate balance between targeted delivery and clinical efficacy in advanced disease.
Advancements for Early-Stage Disease
For patients with Non-Muscle Invasive Bladder Cancer (NMIBC), the standard intravesical treatment is the Bacillus Calmette-Guérin (BCG) vaccine. However, for the subset of patients whose cancer recurs despite adequate BCG treatment, known as BCG-unresponsive NMIBC, the traditional option was often surgical removal of the bladder. New intravesical therapies are now available, offering a bladder-sparing alternative for these patients.
One such treatment is nadofaragene firadenovec, the first gene therapy approved for bladder cancer. This treatment uses a non-replicating adenoviral vector to deliver the gene for interferon alpha-2b directly into the bladder lining. The bladder cells then produce the interferon protein, a powerful immune-stimulating substance that targets the cancer cells.
Another recent advancement is nogapendekin alfa inbakicept-pmln, an interleukin-15 (IL-15) receptor agonist. This biologic is administered intravesically in combination with BCG for BCG-unresponsive NMIBC. The drug works by mimicking the action of the immune signaling molecule IL-15, leading to the proliferation and activation of natural killer cells and T-cells to enhance the immune response against the tumor.