Background: MIUBC is a systemic disease and > 40% of pts develop recurrence after Cy. Despite neoadjuvant chemotherapy yields Level 1 evidence, it is underutilized worldwide and a small survival improvement is deemed over Cy alone. PEM (MK-3475) is the standard-of-care for second-line metastatic UC and is being evaluated as single-agent neoadjuvant therapy for MIUBC (NCT02736266). EPA, an anti-IDO1 agent, combined with PEM, safely improved the response-rate in metastatic UC. Our hypothesis is that PEM+EPA, given neoadjuvantly, could further improve downstaging MIUBC. Methods: Pts with T2-T4a N0 UC with residual disease after transurethral resection of the bladder (TURB, surgical opinion, cystoscopy or radiological presence), regardless of cisplatin eligibility, will receive 3 cycles of PEM 200mg intravenously, q3 weekly. EPA will be orally taken at the dose of 100 mg BID, from d1 until 10 days before Cy. Cy should be performed within 3 weeks of the last PEM dose. Computed tomography (CT) scan, ¹⁸FDG-PET/CT scan, and multiparametric bladder MRI (mpMRI) will be done during screening and before Cy to stage and evaluate response. After Cy, pts will be managed according to EAU guidelines. Adjuvant anti PD-1 therapy is not allowed. PD-L1 status will be assessed on TURB specimen (Dako, clone 22C3), relying on the combined positivity score (CPS, 10% cutoff). Pathologic complete response (pT0) is the primary endpoint. All pts enrolled who receive at least 1 cycle of study drug will be includes in the ITT analysis. The H₁ is pT0≥20% and H₀ pT0≤10%. A 2-stage design will be used to estimate the number of pts required. Out of 90 pts overall, with the first stage of 49 pts, ≥6 pT0 will be required in the first stage, and ≥13 pT0 in the whole study population (80% power and a 2-sided test of significance at the 10% level). Correlative research on tissue/blood samples will include immune-cell profiling, cytokine assessment, gene expression analyses and next-generation sequencing (FoundationOne). Radiologic findings from mpMRI will be associated with pathologic response (EudraCT number 2017-002379-24). Clinical trial information: 2017-002379-24.