ctDNA-guided immunotherapy following radical cystectomy for muscle-invasive bladder cancer: results from the TOMBOLA trial

BACKGROUND: Standard treatment of localized muscle-invasive bladder cancer (MIBC) is neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC), but ∼50% of patients relapse within 2 years. Adjuvant immunotherapy is currently administered based on pathology and clinical assessment in high-risk patients only, potentially resulting in under- and overtreatment. PATIENTS AND METHODS: TOMBOLA is a Danish, multicenter, open-label, single-arm phase II trial evaluating serial circulating tumor DNA (ctDNA) testing to guide postoperative immunotherapy. Low- and high-risk patients with MIBC (cT2-4aN0-1M0) treated with NAC and RC were monitored postoperatively with tumor-informed ctDNA assays. ctDNA-positive patients initiated atezolizumab for up to 1 year, irrespective of imaging; ctDNA-negative patients received immunotherapy only upon radiographic detection of metastases. The primary endpoint was molecular and radiographic complete response. Key secondary endpoints included recurrence-free survival and overall survival. RESULTS: In total 192 patients were enrolled, and among 178 assessable patients in the intention-to-treat population (median follow-up 34 months), 104 (58%) were ctDNA-positive within 2 years after RC, 63% within 4 months. The median lead time from ctDNA detection to imaging-confirmed recurrence was 90 days (range -61 to 961 days). Of the ctDNA-positive patients, 84 completed atezolizumab and had scanning and ctDNA analyses available for primary endpoint assessment. Some 60% (50/84) of patients achieved the primary endpoint of complete response. One-year recurrence-free survival was 97% in ctDNA-negative patients and 76% in ctDNA-positive patients. Prespecified biomarker analyses showed that ctDNA status and levels, risk stratification, and immune-related gene expression signatures were associated with both recurrence risk and response to immunotherapy. Treatment was well tolerated with no new safety concerns. CONCLUSIONS: Tumor-informed ctDNA testing after NAC and RC predicts recurrence risk and enables personalized postoperative management in MIBC. TOMBOLA demonstrates that ctDNA-positive, low-risk patients may benefit from early immunotherapy, while ctDNA-negative high-risk patients may safely avoid adjuvant treatment without compromising outcomes.