The Role of Antibody-Drug Conjugates in Urothelial Cancer: A Review of Recent Advances in the Treatment of Locally Advanced and Metastatic Urothelial Cancer

Abstract

Locally advanced and metastatic urothelial cancer (la/mUC) is an aggressive disease with poor prognosis. Platinum-based chemotherapy has remained the first-line treatment for decades and until recently no other treatment options existed. Today, novel agents called antibody drug conjugates (ADCs), including enfortumab vedotin (EV) and sacituzumab govitecan (SG), have been approved for la/mUC offering patients treatment options following or instead of traditional chemotherapy. The EV consists of the chemotherapy monomethyl auristatin E linked to anti-nectin-4 antibody. Single-agent response rates for EV are 40% to 52% including activity in patients with liver metastases, a phenotype associated with worse outcomes. In 2023, EV in combination with pembrolizumab almost doubled progression-free and overall survival versus platinum-based chemotherapy, which led to accelerated FDA approval as first-line treatment for all patients with la/mUC. Safety profile of EV monotherapy and combination with pembrolizumab is generally manageable with peripheral neuropathy and cutaneous toxicity among the most common treatment-related adverse events (TRAEs). The SG is another ADC targeting TROP-2 with SN-38 as payload. It is approved as late-line treatment for la/mUC with ORR 27% and most common TRAEs include gastrointestinal symptoms and neutropenia. Finally, a recent cancer agnostic accelerated approval for trastuzumab deruxtecan (T-DXd) in HER2-positive (IHC3+) solid tumors provides another active ADC option for biomarker-selected patients with treatment refractory la/mUC. Several new ADCs are being investigated in urothelial cancer (UC) clinical trials. This review summarizes the clinical studies and real-world data regarding the use of ADCs in UC.