Background: Pembro has shown clinical activity across many stages of bladder cancer (BC), including metastatic BC, MIBC, and NMIBC. Current NCCN and AUA/ASCO/ASTRO/SUO guidelines recommend CRT as a bladder-preserving treatment option for selected pts with MIBC. This phase 3 study was designed to investigate the safety and efficacy of pembro + CRT in pts with MIBC who opt for bladder preservation. Ongoing phase 2 studies (NCT02662062; NCT02621151) have shown that pembro + CRT may be a promising therapeutic option in MIBC. Methods: KEYNOTE-992 (NCT04241185) is a phase 3, global, multicenter, double-blind, placebo-controlled, randomized trial to evaluate the efficacy and safety of pembro + CRT versus placebo + CRT in pts with previously untreated MIBC. Adults (≥18 years) opting for bladder preservation with histologically confirmed cT2-T4a, nonmetastatic (N0M0) MIBC after maximal TURBT are eligible. An estimated 636 pts will be randomly assigned 1:1 to receive CRT + either pembro 400 mg IV every 6 weeks (Q6W) or placebo. Treatment will continue with pembro or placebo Q6W for up to 9 doses. CRT regimens will be decided by the investigator before randomization. Accepted radiotherapy regimens are conventional radiotherapy consisting of 64 Gy at 2 Gy/fraction over 6.5 weeks (whole bladder with or without pelvic nodes) or hypofractionated radiotherapy consisting of 55 Gy at 2.75 Gy/fraction over 4 weeks (whole bladder only). Accepted concurrent radiosensitizing chemotherapy regimens are 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), or gemcitabine monotherapy (27 mg/m² IV twice weekly). Randomization will be stratified by ECOG PS (PS 0/1 vs 2), PD-L1 combined positive score ( < 10 vs ≥10), T stage (T2 vs T3/4), and geographic region (US vs Europe vs rest of world). Pts must provide tissue for biomarker analysis. Efficacy will be assessed by cystoscopy (± biopsy), CT or MRI (with blinded independent central review), and urine cytology at 10 weeks after CRT, then Q12W up to the end of year 2, and then Q24W thereafter. The primary end point is bladder-intact event-free survival, defined as time from randomization to residual/recurrent MIBC, nodal or distant metastasis, radical cystectomy, or death from any cause. Key secondary end points are OS, metastasis-free survival, time to occurrence of NMIBC, and safety. Clinical trial information: NCT04241185.