Response-Adapted Bladder Preservation in Muscle-Invasive Bladder Cancer: Results of the Phase II RETAIN-2 Trial and Analysis of ctDNA Dynamics

Purpose: Response-adapted bladder preservation has emerged as a potential alternative to immediate radical cystectomy for selected patients with muscle-invasive bladder cancer (MIBC), but biomarkers to guide treatment de-escalation are lacking. We report the clinical outcomes of the phase II RETAIN2 trial together with a retrospective circulating tumor DNA (ctDNA) analysis of the RETAIN1 and RETAIN2 studies. Patients and Methods: RETAIN2 prospectively evaluated neoadjuvant accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) plus nivolumab followed by response-adapted management based on clinical restaging. A retrospective tumor-informed ctDNA analysis evaluated longitudinal ctDNA dynamics and associations with clinical outcomes. Results: Seventy one evaluable patients were enrolled in RETAIN2. The trial met its primary endpoint, with a 2 year metastasis free rate of 77.5% after a median follow-up of 34.7 months. Among 22 patients managed with active surveillance, 15 (68.2%) remained metastasis free with an intact, non irradiated bladder and 3 (13.6%) developed metastatic disease. In a sensitivity analysis using time to metastasis, the Kaplan Meier estimated 2 year metastasis free probability was 83.7% overall and 85.5% with active surveillance. Retrospective ctDNA analyses were performed in 111 patients from RETAIN1 and RETAIN2. Baseline and post-treatment ctDNA positivity were associated with metastatic progression and inferior overall survival. Among patients managed with active surveillance who were ctDNA-negative after treatment, the 2 year Kaplan Meier estimated metastasis free probability and overall survival were 91% and 97%, respectively. Plasma ctDNA predicted metastatic progression but not intravesical recurrence. Conclusion: Response adapted bladder preservation after neoadjuvant AMVAC plus nivolumab achieved encouraging long term outcomes in selected patients with MIBC. Retrospective ctDNA analyses suggest that plasma ctDNA reflects occult systemic disease rather than bladder confined recurrence and may refine patient selection for bladder preservation. These findings support prospective evaluation of ctDNA guided strategies while emphasizing the continued need for bladder directed surveillance and complementary urinary biomarkers.