Background: CRT is recommended by treatment guidelines as a bladder-preserving treatment option for selected pts with MIBC. Pembro has shown clinical activity across many stages of bladder cancer (BC), including metastatic BC, MIBC, and non–MIBC (NMIBC). The interim results of 2 ongoing phase II studies (ANZUP 1502, NCT02662062; NCT02621151) evaluating the combination of pembro plus CRT are promising. The KEYNOTE-992 (NCT04241185) study will further investigate the safety and efficacy of pembro + CRT in pts with MIBC who opt for bladder preservation. Methods: KEYNOTE-992 is a global, randomized, double-blind, placebo-controlled, multicenter phase III trial that will evaluate the efficacy and safety of pembro + CRT versus placebo + CRT in pts with previously untreated MIBC. Eligibility criteria include age ≥18 years, histologically confirmed cT2-T4a, nonmetastatic (N0M0) MIBC, and decision to pursue bladder-preserving therapy. Approximately 636 pts will be randomly assigned 1:1 to receive CRT + either pembro 400 mg IV every 6 weeks (Q6W) or placebo (pembro or placebo limited to 9 doses). The study’s stratification factors are ECOG PS (0 or 1 vs 2), PD-L1 combined positive score (<10 vs ≥10), T stage (T2 vs T3 or T4), and geographic region (US vs Europe vs rest of world). The investigator must determine the CRT regimen before randomization. The following radiotherapy (RT) regimens are allowed in the trial: conventional RT consisting of 64 Gy at 2 Gy/fraction over 6.5 weeks (whole bladder with or without pelvic nodes) or hypofractionated RT consisting of 55 Gy at 2.75 Gy/fraction over 4 weeks (whole bladder only). The following radiosensitizing chemotherapy regimens are allowed: cisplatin monotherapy (35 mg/m² IV weekly), 5-fluorouracil (500 mg/m² on days 1-5 and days 22-26) + mitomycin C (12 mg/m² on day 1), and gemcitabine monotherapy (27 mg/m² IV twice weekly). Efficacy will be assessed by cystoscopy (± biopsy), CT or MRI with blinded independent central review, and by urine cytology at 10 weeks after CRT, then Q12W until the end of year 2, and Q24W thereafter. The primary end point is bladder-intact event-free survival (BI-EFS), defined as the following: time from randomization to residual/recurrent MIBC, nodal or distant metastases, radical cystectomy, or death from any cause. The key secondary end point is overall survival (OS), and additional secondary end points are metastasis-free survival, time to any NMIBC, time to cystectomy, and safety. Safety and tolerability will be evaluated using a tiered approach. Both the primary (BI-EFS) and key secondary (OS) end points will be evaluated using a stratified log-rank test, and treatment differences will be estimated using the stratified Cox proportional hazards model with Efron’s tie handling method. KEYNOTE-992 is currently enrolling at sites in 19 countries globally. Clinical trial information: NCT04241185