Advanced Bladder Cancer: Latest Treatment and Future Directions

The clinical management of advanced bladder cancer has improved dramatically in recent years. For decades, first-line treatment options for patients have been limited to platinum-based chemotherapy. As our understanding of genomic heterogeneity and cell signaling pathways in cancer has advanced, several new therapies have been developed and approved for patients with advanced urothelial carcinoma (UC; Figure 1).

Figure 1. Milestones in the Approval of Novel Therapies for Advanced Urothelial Carcinoma

Immune Checkpoint Inhibitors

Immuno-oncology has been revolutionized by the development of immune checkpoint inhibitors (ICIs). Tumor cells evade the immune system by activating immune checkpoint pathways to suppress antitumor responses. The disruption of signaling pathways by ICIs activates antitumor responses and promotes the elimination of tumor cells. Targeting the signaling pathway mediated by programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) has proved to be an effective strategy in targeted cancer therapy.

Atezolizumab, a PD-L1 inhibitor, was demonstrated to have antitumor activity in the IMvigor211 phase 2 clinical trial. Based on this efficacy, it was approved by the FDA in 2016 for use in patients with UC who had progressed after platinum-based chemotherapy. In a subsequent evaluation in the IMvigor211 phase 3 trial, the drug did not perform as anticipated; however, approval was continued based on consistent observations of improved outcomes, its overall tolerability, and the lack of alternative therapies for patients with advanced UC. Pembrolizumab, which targets PD-1 and inhibits its interaction with PDL1, was shown in the KEYNOTE-045 phase 3 trial to have improved efficacy and safety compared to chemotherapy for the treatment of metastatic platinum-refractory UC. Both atezolizumab and pembrolizumab were approved in 2017 for first-line treatment for cisplatin-ineligible patients. In 2018, both drugs were approved for patients not eligible for any platinum-based chemotherapy and whose tumors express a high level of PD-L1.

Three additional ICIs have been approved for use in patients with platinum-refractory advanced UC. The CheckMate-032 study demonstrated the efficacy of nivolumab, a PD-1 inhibitor, in platinum-refractory patients with advanced UC. Durvalumab, a high-affinity antibody against PD-L1, was evaluated in UC patients with advanced solid tumors. Avelumab, an anti-PD-L1 antibody, was evaluated in the JAVELIN phase 1 trial. Nivolumab, durvalumab, and avelumab all received accelerated approval in 2017 in the platinum-resistant setting based on data from these studies.

Despite these successes, not all patients achieve long-term overall survival when treated with ICIs as monotherapies. Strategies using combinations of ICIs with chemotherapy or dual ICI treatment are thus being pursued. For example, tremelimumab, which targets cytotoxic T-lymphocyte-associated protein 4 (CTLA4), is being investigated as a complement to durvalumab in the DANUBE phase 3 trial. ICIs are also being examined in ongoing clinical trials for their use as maintenance therapy for patients without disease progression after first-line chemotherapy (Table 1).

Fibroblast Growth Factor Receptor Inhibitors

Fibroblast growth factor receptors (FGFRs) play a key role in cell differentiation, with the FGFR signaling pathway linked to tumorigenesis. Genomic aberrations in FGFRs are observed in approximately 20% of advanced-stage UC and are thus a therapeutic target of interest. Erdafitinib is currently the only FDA-approved FGFR inhibitor for the treatment of advanced UC. It received accelerated approval in 2019 for patients with genetic alterations in FGFR2 or FGFR3 and advanced UC that has progressed despite platinum-based chemotherapy. Currently, the THOR phase 3 clinical trial is in progress to compare erdafitinib with standard chemotherapy or pembrolizumab in patients with advanced bladder cancer and somatic FGFR variants.

Antibody-Drug Conjugates

Antibody-drug conjugates are designed to target specific surface antigens on tumor cells with a combination of a monoclonal antibody linked to a chemotherapeutic agent. The drug enfortumab vedotin is comprised of a monoclonal antibody targeted to nectin-4, a cell adhesion molecule highly expressed in UC. The antibody is linked to the cytotoxic payload monomethyl auristatin E. Once bound to the cell surface, enfortumab vedotin is internalized and processed by lysosomes, liberating the cytotoxin. Enfortumab vedotin was approved in 2019 for patients with advanced UC previously treated with platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor, as it was shown to significantly prolong survival compared with standard chemotherapy. The EV-302 phase 3 trial is currently underway to assess enfortumab vedotin and pembrolizumab combination therapy.

Summary

Recent advances in immunotherapy and targeted therapy have led to the development of several efficacious treatments that have less toxicity compared to standard chemotherapy. Ongoing clinical trials of both monotherapy and combination therapy are aimed at optimizing treatment for patients with advanced disease and applying treatments at earlier stages of bladder cancer. As new molecular targets are identified and developed, options and care for all patients with bladder cancer continue to improve.

Table 1. Select Ongoing Clinical Trials for Advanced Bladder Cancer

Reference: Patel VG, Oh WK, Galsky MD. Treatment of muscle-invasive and advanced bladder cancer in 2020. CA Cancer J Clin. 2020 Sep;70(5):404-423. doi: 10.3322/caac.21631

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