Response-Adapted Bladder Preservation in Muscle-Invasive Bladder Cancer: Results of the Phase II RETAIN-2 Trial and Analysis of ctDNA Dynamics
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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 RETAIN-2 trial together with a retrospective circulating tumor DNA (ctDNA) analysis of the RETAIN-1 and RETAIN-2 studies.
Patients and Methods
RETAIN-2 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 RETAIN-2. 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 RETAIN-1 and RETAIN-2. 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.
