Circulating tumor DNA informs response-adapted bladder preservation in muscle invasive bladder cancer: an integrated analysis of the RETAIN trials

Muscle-invasive bladder cancer (MIBC) is traditionally managed with neoadjuvant chemotherapy followed by radical cystectomy. Although bladder preservation offers substantial quality-of-life advantages, clinically validated biomarkers to guide organ-sparing strategies are lacking. Here, we report results from RETAIN-2, a phase II trial evaluating neoadjuvant AMVAC plus nivolumab followed by response-adapted management, alongside an integrated tumor-informed circulating tumor DNA (ctDNA) analysis spanning 111 patients across RETAIN-1 and RETAIN-2. Whereas prior ctDNA studies in MIBC have been limited to cystectomy- or chemoradiation-based paradigms and largely limited to binary assessment at discrete timepoints, this integrated analysis uniquely captures longitudinal ctDNA dynamics in patients forgoing any immediate definitive local therapy, representing the largest prospective ctDNA dataset in any bladder-preservation trial. RETAIN-2 met its primary endpoint, with 70% of patients metastasis-free at 2 years. The Kaplan–Meier analysis estimated 2-year MFS was 83.5% and 68% of active surveillance patients remained metastasis-free with intact, non-irradiated bladders. Baseline and post-treatment ctDNA positivity were strongly associated with inferior metastasis-free and overall survival. Critically, ctDNA-negative patients managed with active surveillance had outcomes comparable to those undergoing cystectomy (24-month MFS 91% vs. 84%; OS 97% vs. 89%), providing the first prospective evidence that ctDNA negativity can identify patients who safely avoid radical cystectomy without compromising metastatic control. Importantly, plasma ctDNA reflected systemic metastatic risk rather than intravesical disease burden, underscoring the need for complementary bladder-directed surveillance. These results establish ctDNA as a clinically actionable biomarker for response-adapted organ preservation in MIBC. Trial registration number: NCT02710734