This study examines which patients who have undergone surgical removal of bladder, kidney, ureter or urethra, require an additional treatment called immunotherapy to help prevent their urinary tract (urothelial) cancer from coming back and if those patients can be identified by a blood test. This study also aims to find out if this approach is better or worse than the usual approach for urothelial cancer.

Many types of tumors tend to lose cells or release different types of cellular products, including their DNA which is referred to as circulating tumor DNA (ctDNA) into the bloodstream before changes can be seen on scans. In this study, a blood test called Signatera is used to measure ctDNA and see if there is still cancer somewhere in the body after surgery and if giving a treatment will help eliminate the cancer. 

Participants will be assigned to one of two groups based on the results of the Signatera test: Group A (“positive” Signatera test) or Group B (“negative Signatera test”). 

Group A is randomized to receive either a single immunotherapy drug, called nivolumab, or a combination of two immunotherapy drugs, called nivolumab plus relatlimab.

Group B is randomized to receive either an immunotherapy drug called nivolumab or be on close monitoring without receiving initial immunotherapy. 

Randomization is like flipping a coin and there is an equal chance of being assigned either treatment within both groups.

Nivolumab is approved by the U.S. Food and Drug Administration (FDA) for use in urothelial cancer after surgery to remove the bladder, ureter, or kidney. Relatlimab is not approved by the FDA for use in bladder cancer after surgery to remove the bladder and is considered investigational in this study.

Study participation also entails standard scans of the body, blood tests, and Signatera tests. Total study participation can last up to 5 years.