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.
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 (ctDNA+) patients initiated atezolizumab for up to 1 year, irrespective of imaging; ctDNA-negative (ctDNA-) 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.
In total 192 patients were enrolled, and among 178 evaluable patients in the intention-to-treat population (median follow-up 34 months), 104 (58%) were ctDNA+ 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). Of the ctDNA+ patients, 84 completed atezolizumab and had scanning and ctDNA analyses available for primary endpoint assessment. 60% (50/84) of patients achieved the primary endpoint of complete response. One-year recurrence-free survival was 97% in ctDNA- patients and 76% in ctDNA+ 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.
Tumor-informed ctDNA testing after NAC and RC predicts recurrence risk and enables personalized postoperative management in MIBC. TOMBOLA demonstrates that ctDNA+, low-risk patients may benefit from early immunotherapy, while ctDNA- high-risk patients may safely avoid adjuvant treatment without compromising outcomes.
NCT04138628.
Annals of oncology : official journal of the European Society for Medical Oncology. 2026 Jan 14 [Epub ahead of print]
L Dyrskjøt, K Birkenkamp-Demtröder, I Nordentoft, T Strandgaard, S V Lindskrog, R V Milling, S K Körner, S B Brandt, M Knudsen, T G Andreasen, C F Hansen, P Lamy, G Lam, L H Dohn, K Fabrin, A Carus, A C Petersen, U N Joensen, H Pappot, P S Holt, N V Jensen, M Agerbæk, J B Jensen
Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark. Electronic address: ., Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark., Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Urology, Aarhus University Hospital, Aarhus, Denmark., Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark., Department of Urology, Herlev Hospital, Herlev, Denmark., Department of Oncology, Herlev Hospital, Herlev, Denmark., Department of Urology, Aalborg University Hospital, Aalborg, Denmark., Department of Oncology, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark., Department of Pathology, Aalborg University Hospital, Aalborg, Denmark., Department of Urology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, University of Copenhagen, Denmark., Department of Oncology, Rigshospitalet, Copenhagen, Denmark., Department of Urology, Odense University Hospital, Odense, Denmark., Department of Oncology, Odense University Hospital, Odense, Denmark., Department of Oncology, Aarhus University Hospital, Aarhus, Denmark.