Simple SummaryUrothelial carcinoma (UC) is a common type of bladder cancer. Patients with UC that has not improved after previous treatment or has spread to other parts of the body need new treatment options. Ibrutinib is a drug approved for the treatment of blood cancers and chronic graft-versus-host disease. It works by blocking Bruton’s tyrosine kinase, an enzyme important for cancer cell survival. Other drugs, pembrolizumab and paclitaxel, are considered standard treatments for UC. This study aimed to understand if ibrutinib alone or combined with pembrolizumab or paclitaxel could lessen disease in patients with UC and help them live longer without their disease getting worse. More patients previously treated for UC had disease improvement with the combinations of ibrutinib and pembrolizumab or ibrutinib and paclitaxel than with pembrolizumab, paclitaxel or ibrutinib alone or compared to historical data. Based on these results, additional studies of ibrutinib combinations in UC are needed.AbstractIbrutinib is a first-in-class Bruton’s tyrosine kinase inhibitor approved for the treatment of various B-cell malignancies and chronic graft-versus-host disease. We evaluated the safety and efficacy of ibrutinib, alone or combined with standard-of-care regimens, in adults with advanced urothelial carcinoma (UC). Once-daily ibrutinib was administered orally at 840 mg (single-agent or with paclitaxel) or at 560 mg (with pembrolizumab). Phase 1b determined the recommended phase 2 dose (RP2D) of ibrutinib, and phase 2 assessed progression-free survival (PFS), overall response rate (ORR), and safety. Thirty-five, eighteen, and fifty-nine patients received ibrutinib, ibrutinib plus pembrolizumab, and ibrutinib plus paclitaxel at the RP2D, respectively. Safety profiles were consistent with those of the individual agents. The best-confirmed ORRs were 7% (two partial responses) with single-agent ibrutinib and 36% (five partial responses) with ibrutinib plus pembrolizumab. Median PFS was 4.1 months (range, 1.0–37.4+) with ibrutinib plus paclitaxel. The best-confirmed ORR was 26% (two complete responses). In previously treated patients with UC, ORR was higher with ibrutinib plus pembrolizumab than with either agent alone (historical data in the intent-to-treat population). ORR with ibrutinib plus paclitaxel was greater than historical values for single-agent paclitaxel or ibrutinib. These data warrant further evaluation of ibrutinib combinations in UC.