ctDNA-Guided Immunotherapy following Radical Cystectomy for Muscle-Invasive Bladder Cancer: Results from the TOMBOLA Trial

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

doi:10.1016/j.annonc.2025.12.018

ctDNA-Guided Immunotherapy following Radical Cystectomy for Muscle-Invasive Bladder Cancer: Results from the TOMBOLA Trial

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 HoltN V Jensen, M Agerbæk, J B Jensen

^*Corresponding author for this work

4 Citations (Scopus)

Abstract

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 (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.

RESULTS: 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.

CONCLUSIONS: 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.

CLINICAL TRIAL REGISTRATION NUMBER: NCT04138628.

Original language	English
Journal	Annals of Oncology
Volume	37
Issue number	5
Pages (from-to)	712-724
Number of pages	13
ISSN	0923-7534
DOIs	https://doi.org/10.1016/j.annonc.2025.12.018
Publication status	Published - May 2026

Keywords

adjuvant
bladder cancer
ctDNA
immunotherapy
liquid biopsy

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Dyrskjøt, L., Birkenkamp-Demtröder, K., Nordentoft, I., Strandgaard, T., Lindskrog, S. V., Milling, R. V., Körner, S. K., Brandt, S. B., Knudsen, M., Andreasen, T. G., Hansen, C. F., Lamy, P., Lam, G., Dohn, L. H., Fabrin, K., Carus, A., Petersen, A. C., Joensen, U. N., Pappot, H., ... Jensen, J. B. (2026). ctDNA-Guided Immunotherapy following Radical Cystectomy for Muscle-Invasive Bladder Cancer: Results from the TOMBOLA Trial. Annals of Oncology, 37(5), 712-724. https://doi.org/10.1016/j.annonc.2025.12.018

Dyrskjøt, L, Birkenkamp-Demtröder, K, Nordentoft, I, Strandgaard, T, Lindskrog, SV, Milling, RV, Körner, SK, Brandt, SB, Knudsen, M, Andreasen, TG, Hansen, CF, Lamy, P, Lam, G , Dohn, LH, Fabrin, K, Carus, A, Petersen, AC, Joensen, UN , Pappot, H, Holt, PS, Jensen, NV, Agerbæk, M & Jensen, JB 2026, 'ctDNA-Guided Immunotherapy following Radical Cystectomy for Muscle-Invasive Bladder Cancer: Results from the TOMBOLA Trial', Annals of Oncology, vol. 37, no. 5, pp. 712-724. https://doi.org/10.1016/j.annonc.2025.12.018

@article{911ea24bdefb4f9396fe5058c140a4e3,

title = "ctDNA-Guided Immunotherapy following Radical Cystectomy for Muscle-Invasive Bladder Cancer: Results from the TOMBOLA Trial",

abstract = "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 (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.RESULTS: 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.CONCLUSIONS: 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.CLINICAL TRIAL REGISTRATION NUMBER: NCT04138628.",

keywords = "adjuvant, bladder cancer, ctDNA, immunotherapy, liquid biopsy",

author = "L Dyrskj{\o}t and K Birkenkamp-Demtr{\"o}der and I Nordentoft and T Strandgaard and Lindskrog, \{S V\} and Milling, \{R V\} and K{\"o}rner, \{S K\} and Brandt, \{S B\} and M Knudsen and Andreasen, \{T G\} and Hansen, \{C F\} and P Lamy and G Lam and Dohn, \{L H\} and K Fabrin and A Carus and Petersen, \{A C\} and Joensen, \{U N\} and H Pappot and Holt, \{P S\} and Jensen, \{N V\} and M Agerb{\ae}k and Jensen, \{J B\}",

year = "2026",

month = may,

doi = "10.1016/j.annonc.2025.12.018",

language = "English",

volume = "37",

pages = "712--724",

journal = "Annals of Oncology",

issn = "0923-7534",

publisher = "Elsevier Limited",

number = "5",

}

TY - JOUR

T1 - ctDNA-Guided Immunotherapy following Radical Cystectomy for Muscle-Invasive Bladder Cancer

T2 - Results from the TOMBOLA Trial

AU - Dyrskjøt, L

AU - Birkenkamp-Demtröder, K

AU - Nordentoft, I

AU - Strandgaard, T

AU - Lindskrog, S V

AU - Milling, R V

AU - Körner, S K

AU - Brandt, S B

AU - Knudsen, M

AU - Andreasen, T G

AU - Hansen, C F

AU - Lamy, P

AU - Lam, G

AU - Dohn, L H

AU - Fabrin, K

AU - Carus, A

AU - Petersen, A C

AU - Joensen, U N

AU - Pappot, H

AU - Holt, P S

AU - Jensen, N V

AU - Agerbæk, M

AU - Jensen, J B

PY - 2026/5

Y1 - 2026/5

N2 - 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 (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.RESULTS: 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.CONCLUSIONS: 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.CLINICAL TRIAL REGISTRATION NUMBER: NCT04138628.

AB - 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 (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.RESULTS: 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.CONCLUSIONS: 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.CLINICAL TRIAL REGISTRATION NUMBER: NCT04138628.

KW - adjuvant

KW - bladder cancer

KW - ctDNA

KW - immunotherapy

KW - liquid biopsy

UR - https://www.scopus.com/pages/publications/105030366629

U2 - 10.1016/j.annonc.2025.12.018

DO - 10.1016/j.annonc.2025.12.018

M3 - Journal article

C2 - 41544704

SN - 0923-7534

VL - 37

SP - 712

EP - 724

JO - Annals of Oncology

JF - Annals of Oncology

IS - 5

ER -

ctDNA-Guided Immunotherapy following Radical Cystectomy for Muscle-Invasive Bladder Cancer: Results from the TOMBOLA Trial

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