New Advances in Metastatic Urothelial Cancer: A Narrative Review on Recent Developments and Future Perspectives

Abstract

The standard of care for advanced or metastatic urothelial carcinoma (mUC) was historically identified with platinum-based chemotherapy. Thanks to the advances in biological and genetic knowledge and technologies, new therapeutic agents have emerged in this setting recently: the immune checkpoint inhibitors and the fibroblast growth factor receptor inhibitors as the target therapy for patients harboring alterations in the fibroblast growth factor receptor (FGFR) pathway. However, chasing a tumor's tendency to recur and progress, a new class of agents has more recently entered the scene, with promising results. Antibody-drug conjugates (ADCs) are in fact the latest addition, with enfortumab vedotin being the first to receive accelerated approval by the U.S. Food and Drug Administration in December 2019, followed by sacituzumab govitecan. Many other ADCs are still under investigation. ADCs undoubtedly represent the new frontier, with the potential of transforming the management of mUC treatment in the future. Therefore, we reviewed the landscape of mUC treatment options, giving an insight into the molecular basis and mechanisms, and evaluating new therapeutic strategies in the perspective of more and more personalized treatments.

Keywords: FGFR; HER2; antibody–drug conjugate; enfortumab vedotin; erdafitinib; immune checkpoint inhibitors; sacituzumab govitecan; urothelial cancer.

Figure 1

Representation of ADCs structure and the main ones tested for UC. DXD: Deruxtecan, DM-1: Emtansine, MMAE: Monomethyl Auristatin E, HER2: Human Epidermal Growth Factor Receptor 2, T-DM1: Trastuzumab Emtansine, TROP-2: Trophoblast Cell Surface Antigen 2.

Figure 2

The general mechanism of action of ADCs. ADC molecules circulate in the blood stream until recognizing and binding to their specific antigen. The antigen–ADC complexes are later endocytosed: a few of them are recycled and exposed on the cell membrane, while the majority, thanks to the intracellular environment, pH and lysosomal proteases, end up releasing the cytotoxic agent attached by cleavable or non-cleavable linkers. At this point, the drug is able to induce apoptosis by either interfering with tubulin polymerization and microtubules assembling (EV, DV, TDM-1) or inducing DNA damage, directly or through the inhibition of Topoisomerase I (SG, T-DXd). Some drug molecules are also released in the extracellular space and determine the so-called “bystander killing effect” by inducing apoptosis in neighboring cells too.

Figure 3

Visual representation of main genomic alterations involved in mUC.