Opportunities to improve clinical trial design in urothelial bladder cancer

Abstract Treatment of urothelial cancer (UC) has seen limited advances over the last three decades. As new agents become available, a critical look at trial design across the spectrum of UC is needed. Early UC trials should aim to stratify patients by risk level, defined by molecular features to reduce the heterogeneity and improve interpretation of trial results. For muscle invasive UC, the practice of neoadjuvant chemotherapy should be encouraged, especially as complete pathological response could be used as a surrogate end-point measure on trials and has the potential for garnering expedited drug approval. The neoadjuvant setting also provides a unique opportunity for evaluating biomarkers and targeted therapy given the availability of tumor tissue. For advanced disease, more emphasis should be placed on studies for patients who are cisplatin-ineligible or have poorer performance status, which represents many UC patients. Bladder-sparing therapy, incorporating agents targeting the HER2 or PI3K/AKT/mTOR pathway, or immunotherapy are potential new directions in UC. The importance of quality-of-life as an end-point in clinical trials in UC should also not be overlooked. Ultimately, multidisciplinary large-scale collaborations will be the key to move this field forwards.