TPS4621 Background: Muscle invasive bladder cancer (MIBC) is an aggressive disease with poor survival rates that are not improving. Curative treatment includes systemic neoadjuvant chemotherapy prior to radical cystectomy and adjuvant immunotherapy. However, many patients do not respond to chemotherapy or immunotherapy. Histologically similar MIBCs can be classified using gene expression patterns into unique molecular subtypes. Retrospective studies have shown that molecular subtypes each have unique biology and consequently respond differently to treatment. The GUSTO trial tests the hypothesis that outcomes can be optimized through subtype-guided allocation. Methods: Eligible participants are those with confirmed non-metastatic MIBC, an ECOG performance status 0-1, being considered for cisplatin-based neoadjuvant chemotherapy and radical cystectomy. Formalin-fixed diagnostic (TURBT) tumor samples undergo gene expression microarray analysis and characterization using the GUSTO Classifier (consisting of the Veracyte Decipher assay and TCGA_2017 classification system) to determine the molecular subtype: basal, neuronal, luminal infiltrated, luminal or luminal papillary. A total of 320 eligible patients (T2-4a N0 M0 or T(any) N1 M0 MIBC) will be randomized 1:1 to either standard of care treatment (neoadjuvant cisplatin and gemcitabine) or subtype-guided treatment (basal and neuronal subtypes - neoadjuvant cisplatin, gemcitabine, durvalumab and tremelimumab and adjuvant durvalumab; luminal infiltrated - neoadjuvant durvalumab and tremelimumab and adjuvant durvalumab; luminal and luminal papillary - proceeding directly to radical cystectomy). Sites are notified when a patient has been assigned a molecular subtype. Patients and sites in the standard of care arm remain blind to the genomic subtype. The trial has three stages: Stage 1 (after 6 months of recruitment) will assess feasibility of recruitment and molecular subtyping in clinical timelines. Outcomes include recruitment rate, time to, and success of subtype allocation. Stage 2 (after 24 months of recruitment) will confirm recruitment feasibility and assess sample size assumptions. Outcomes are recruitment numbers, distributions of subtypes, and pathological complete response (pCR) in the standard of care arm. A re-estimation of the sample size for stage 3 will be considered. Stage 3 (after 12 months post-cystectomy for the last participant randomized) will assess treatment outcomes using this stratified approach. The primary outcome for Stage 3 is the rate of pCR in each molecular subtype within the experimental arm. Progression between trial stages will be dependent upon achieving pre-defined criteria. Recruitment began in September 2023. The study will open the first 20 sites ready to proceed and is accepting expressions of interest. Clinical trial information: 17378733.