Gemcitabine intravesical system plus cetrelimab or cetrelimab alone as neoadjuvant therapy in patients with MIBC: primary analysis and biomarker results of SunRISe-4

Purpose Standard of care for muscle-invasive bladder cancer (MIBC) is radical cystectomy (RC) with neoadjuvant cisplatin-based chemotherapy (NAC). However, many patients are ineligible for or refuse cisplatin. SunRISe-4 ( NCT04919512 ) is an open-label, multicenter, parallel-cohort phase II study assessing neoadjuvant gemcitabine intravesical system (TAR-200) plus cetrelimab or cetrelimab monotherapy in patients with MIBC. Patients and Methods Adults with ECOG performance status 0-1, cT2-T4a N0M0, ineligible/refusing NAC, and planned for RC were randomized 5:3, stratified by TURBT completeness (residual tumor ≤3 cm permitted) and T stage, to receive TAR-200 plus cetrelimab (Cohort 1 [C1]) or cetrelimab monotherapy (C2). The primary endpoint was pathologic complete response (pCR) at RC. Secondary endpoints included recurrence-free survival (RFS) and safety. Exploratory endpoints included pathological overall response (pOR; ≤ypT1N0) and circulating and urinary tumor DNA (ct/utDNA) molecular residual disease. Side-by-side descriptive efficacy summary was planned. Results At May 9, 2025, data cutoff, 159 patients were treated; 88 in C1 and 46 in C2 underwent RC. pCR, pOR, and 1-year RFS rates were 38%, 53%, and 77%, respectively, in C1 and28%, 44%, and 64% in C2. pCR rates were consistent across subgroups. No new safety signals were observed. Across cohorts, utDNA− status before RC (week 12) and utDNA clearance correlated with pCR ( P <10 −5 and <10 −3 , respectively). ctDNA− status at baseline and week 12 was associated with longer RFS compared with ctDNA+ status at the same timepoint ( P =.04 and .01, respectively). Conclusions TAR-200 plus cetrelimab provided higher pCR, pOR, and 1-year RFS rates compared with cetrelimab monotherapy, supporting further investigation of the neoadjuvant combination in MIBC. utDNA and ctDNA MRD results support further investigation as biomarkers for residual local and non-local disease, respectively.