Circulating tumor DNA (ctDNA)-guided adjuvant therapy for muscle-invasive bladder cancer (MIBC): ready for primetime?

Bladder cancer is the 7^th most prevalent cancer worldwide (1), and the treatment of muscle-invasive bladder cancer (MIBC) has dramatically changed over the last several years. MIBC remains an aggressive malignancy and makes up a quarter of all bladder cancer presentations. Although surgery alone is curative for a subset of patients, disease recurrence occurs in up to 50% of cases and is associated with poor long-term survival (2,3), hence the need for multimodality treatment with radical cystectomy (RC), as well as neoadjuvant and adjuvant therapy. Despite these interventions, nearly 50% of patients with non-metastatic MIBC who undergo curative-intent local cystectomy or chemoradiation treatment will eventually experience disease progression or develop metastatic disease within 2 years (1). While several trials have demonstrated improvements in disease-free survival (DFS), including adjuvant immunotherapy with nivolumab in the CheckMate 274 trial (4) and adjuvant pembrolizumab in the AMBASSADOR trial (5), consistent overall survival (OS) benefit has remained elusive. AMBASSADOR had dual primary endpoints with median DFS met at 29.6 months [95% confidence interval (CI): 20.0–40.7] with pembrolizumab compared to 14.2 months (95% CI: 11.0–20.2) with observation [hazard ratio (HR) 0.73; 95% CI: 0.59–0.90; two-sided P=0.003]. While median OS (mOS) was 50.9 months (95% CI: 43.9 to not evaluable) for pembrolizumab compared to observation of 55.8 months (95% CI: 53.3 to not evaluable) (5). On the other hand, updated CheckMate 274 trial did show improvement in the primary endpoint of 21.9 months (95% CI: 18.8–36.9 months) with nivolumab compared to 11.0 months (95% CI: 8.3–16.6 months) with placebo in all randomized patients (HR 0.74, 95% CI: 0.61–0.90) but the HR for OS with nivolumab versus placebo at 0.76 (95% CI: 0.61–0.96) in the intent-to-treat (ITT) population and 0.56 (95% CI: 0.36–0.86) in the programmed death ligand-1 (PD-L1) ≥1 population (6), suggesting trends towards OS upon longer follow-up. The 5-year efficacy results recently published showed updated mOS of 75.0 months (95% CI: 56.7 months to not estimable) with nivolumab compared to 50.1 months (95% CI: 38.0–72.1 months) with placebo but with an HR crossing 1 (HR 0.83, 95% CI: 0.67–1.02) (7). Conversely, the IMvigor010 that utilized adjuvant atezolizumab did not meet its primary endpoint (8), although its accompanying circulating tumor DNA (ctDNA) results showed that patients who are ctDNA-positive (ctDNA+) and have high tumor mutational burden (TMB) may derive benefit from adjuvant atezolizumab (9). Therefore, this has raised an important clinical question of how to identify patients with residual disease that are most likely to benefit from adjuvant therapy while sparing those already cured from unnecessary overtreatment.

ctDNA testing is emerging as a prognostic biomarker, helping to detect molecular residual disease and guide adjuvant therapy decisions. Across multiple solid tumors, ctDNA positivity after surgery has been shown to correlate strongly with recurrence risk and to precede radiographic relapse by months (10-12). In urothelial carcinoma, retrospective analyses and exploratory studies have consistently demonstrated the prognostic value of ctDNA after cystectomy (13-15). However, whether ctDNA could be used to guide adjuvant treatment decisions, and thereby improve clinically meaningful outcomes, has remained unclear.

The phase III IMvigor011 trial directly addresses this question by evaluating a ctDNA-guided adjuvant treatment strategy in patients with MIBC following cystectomy. IMvigor011 is a phase 3, international, double-blind, randomized trial which evaluated the efficacy and safety of adjuvant atezolizumab versus placebo in MIBC patients who were ctDNA-positive within one year after cystectomy (16). The trial employed serial ctDNA surveillance to identify patients with molecular evidence of residual disease and randomized only ctDNA-positive patients to receive adjuvant atezolizumab or placebo. Patients who remained persistently ctDNA-negative did not receive adjuvant therapy and were followed clinically, a shift from traditional adjuvant strategies that rely primarily on clinicopathologic features. The primary endpoint was DFS from randomization to recurrence or death, while secondary endpoint was OS, distant metastasis-free survival, disease-specific survival, ctDNA clearance, and patient-reported outcomes. There were other exploratory endpoints such as DFS and OS in persistently ctDNA-negative patients. Among the 761 patients enrolled in the surveillance phase, 250 who tested ctDNA-positive were randomized (167 to atezolizumab, 83 to placebo) while 357 patients remained ctDNA-negative. In this ctDNA-positive patient population, adjuvant atezolizumab significantly improved investigator-assessed DFS compared with placebo (median 9.9 vs. 4.8 months; HR 0.64), and notably also demonstrated a statistically significant OS benefit [median 32.8 vs. 21.1 months; HR 0.59 (95% CI: 0.39–0.90)]. Benefits were consistent across subgroups, including those with different PD-L1 status and timing of ctDNA positivity. ctDNA clearance was higher in the atezolizumab group, especially among those with high baseline ctDNA levels. 4% of patients died during follow-up. Safety of adjuvant atezolizumab is as expected with other trials on adjuvant therapy including grade 3 or 4 adverse events which were more frequent with atezolizumab (28% vs. 22%), but fatal events were rare and similar between groups (3% and 2% of the patients, for atezolizumab versus placebo, respectively. In addition, immune-mediated adverse events were more common with atezolizumab, not surprisingly. Immune-mediated adverse events occurred in 39% of the patients in the atezolizumab group and in 12% of those in the placebo group; immune-mediated events of grade 3 or 4 occurred in 5% and 1% of the patients, respectively. Most common side effects included urinary tract infection and pruritus.

The trial demonstrated significant improvements in DFS and OS with adjuvant atezolizumab particularly in ctDNA-positive patients. The OS observed in IMvigor011 is particularly noteworthy when contrasted with prior adjuvant immunotherapy trials in urothelial carcinoma. Large all-comer studies such as CheckMate 274 and AMBASSADOR demonstrated DFS improvement but not clear and consistent OS benefit yet in unselected patient populations, especially with adjuvant pembrolizumab. By focusing on patients with molecular residual disease, IMvigor011 may have preferentially identified individuals with biologically active micrometastatic disease who would benefit most from early systemic intervention. In addition, the persistently ctDNA-negative patients were observed to have excellent outcomes, with 95% DFS at 1 year and 88% at 2 years. These findings suggest that ctDNA negativity identifies a population with a favorable prognosis in whom adjuvant immunotherapy can be deferred. Here, ctDNA functions not only as a trigger for treatment escalation, but also as a basis for de-escalation given the increasingly important consideration for the potential for the impact on quality of life, financial burden, and adverse effects associated with checkpoint inhibitors.

Beyond binary ctDNA status, IMvigor011 also provides insight into ctDNA kinetics. Clearance of ctDNA was more frequently observed in patients treated with atezolizumab, and clearance of higher baseline ctDNA levels occurred more predominantly in the treatment arm (16). In contrast, ctDNA clearance in the placebo arm was largely found in patients with low baseline ctDNA levels, raising the possibility that some clearance events may reflect assay variability near the limit of detection rather than true biological elimination of disease (17,18). These observations highlight the need for future studies to move beyond dichotomous ctDNA classification toward quantitative and longitudinal modeling of ctDNA dynamics, although whether quantitative ctDNA levels may also predict for outcomes remain unknown (19).

Nevertheless, several limitations merit careful consideration. First, while the trial strongly supports the prognostic value of ctDNA, it does not serve as a companion diagnostic. The extent to which ctDNA is truly predictive of immunotherapy benefit remains an area for further investigation. It is possible that ctDNA positivity simply identifies patients with aggressive disease biology who would fare poorly regardless of intervention. Although the randomized design and OS benefit argue against this interpretation, formal biomarker-treatment interaction analyses and longer follow-up would be informative (20). It will be worth noting that given the continuously ctDNA− patient population received no adjuvant treatment, the IMvigor011 trial design assumed that ctDNA was both prognostic and predictive for benefit of atezolizumab. However, in order to prove that ctDNA is truly predictive, a formal biomarker-by-treatment interaction assessment across both biomarker stratification (ctDNA+ and ctDNA−) with randomization in both groups could have been done rather than an enrichment biomarker study alone. Second, false-negative ctDNA results remain clinically relevant. A minority of patients with persistent ctDNA negativity still experienced disease recurrence, highlighting that ctDNA should not be used in isolation (21). Third, assay-specific considerations limit generalizability. IMvigor011 employed tumor-informed ctDNA assays with high analytical sensitivity, and results cannot be expanded to all commercially available platforms (22,23). Similarly, the IMvigor011 trial utilized the BGI platform in China but Signatera platform for the rest of the world in applicable sites. Standardization, cross-platform validation, and performance studies will be vital before ctDNA-guided strategies can be broadly implemented. In addition, the lack of central radiology review for DFS assessment in IMvigor011 could have a potential impact on endpoint robustness. Furthermore, additional practical questions remain regarding optimal testing intervals, duration of surveillance, and cost-effectiveness, especially since existing cost-effectiveness modeling studies for ctDNA surveillance in other solid tumors have not been unanimously shown to be cost-effective (24). Serial ctDNA monitoring introduces logistical complexity and potential patient anxiety, and the implications of adoption must be weighed against the potential savings from avoiding overtreatment (25).

ctDNA-guided therapy allows for more precise treatment, sparing ctDNA-negative patients from unnecessary toxicity and cost. The findings support the use of ctDNA-based testing to guide adjuvant therapy decisions in bladder cancer and potentially other solid tumors.

The IMvigor011 trial is one of the prospective trials that provides strong evidence that ctDNA-guided adjuvant immunotherapy improves outcomes for MIBC patients with molecular residual disease, while those who remain ctDNA-negative after surgery have excellent prognosis without additional therapy. This approach may redefine post-surgical management in bladder cancer and other cancers. Recent publication of a similar prospective ctDNA-guided trial called TOMBOLA is worthy of mention. TOMBOLA is a Danish, multicenter, open-label, single-arm phase II trial evaluating serial ctDNA testing to guide postoperative immunotherapy using atezolizumab (26). In this trial, ctDNA monitoring was performed at fixed intervals and within two years after RC in an ITT manner, 58% (104/178) were shown to have ctDNA-positive results and in 63% of cases, ctDNA-positive conversion occurred within four months after RC. Of the 58% who converted to ctDNA+ results, 84 patients received atezolizumab, with 60% (50/84) achieving a complete response, while the 1-year RFS for ctDNA+ patients was 76%. The trial is similar to IMvigor011 although with fewer patients at 95 who initiated adjuvant atezolizumab (see Table 1 for similarities and differences). The results revealed RFS at 97% in ctDNA-negative patients and 76% in ctDNA-positive patients at the end of 12 months after RC with 1-year OS of 100% for ctDNA-negative patients and 88% for ctDNA-positive patients. The median lead time from ctDNA detection to imaging-confirmed recurrence was 90 days which is concordant with different ctDNA studies (27). Low- and high-risk patients with MIBC (cT2–4aN0–1M0) treated with neoadjuvant chemotherapy (NAC) and RC were monitored postoperatively with tumor-informed ctDNA assays.

Collectively, trials such as IMvigor011 and TOMBOLA provide compelling evidence to date supporting ctDNA-guided adjuvant immunotherapy in MIBC. By selectively treating patients with molecular residual disease while sparing those with persistently negative ctDNA, this approach moves the field closer to biologically informed postoperative management. Broader validation, longer follow-up, and careful consideration of implementation challenges are required before ctDNA-guided adjuvant therapy can be universally adopted. Furthermore, the 6-week frequency and cadence employed in IMvigor011 may prove to be overly resource-intensive and impractical in alternative contexts or in other resource-challenged countries. As with other emerging risk-stratification tools, ctDNA appears very promising but viewed as a complementary tool that augments, rather than replaces, established clinicopathologic and radiographic assessment. Conversely, it is yet to be determined whether ctDNA-guided administration of adjuvant therapy is universally applicable to all forms of adjuvant therapy, rather than being limited to adjuvant atezolizumab as observed in both the IMvigor011 and TOMBOLA trials. For instance, the NIAGARA trial using NAC with durvalumab already showed correlative ctDNA findings and ctDNA+ results showed a high likelihood of non-pathologic complete response (non-pCR) in 97% of patients. On the other hand, finding ctDNA− results does not guarantee a pCR either which occurred in only 51% of patients. Other challenges include applicability of ctDNA-guide therapy with other agents like enfortumab vedotin (EV) and pembrolizumab used as neoadjuvant treatment as seen in the Keynote-905/EV-303 trial (28) and Keynote B15/EV-304 trial (29). The CheckMate 274 trial looking at adjuvant nivolumab versus placebo also reported the ctDNA results showing benefits in those who test ctDNA+ in whom the median DFS HR was 0.35 (95% CI: 0.18–0.66), although HR was 0.99 (95% CI: 0.51–1.93) in those who are ctDNA−, suggesting lack of benefit of using adjuvant nivolumab in those who test ctDNA− (7). The quest for the ideal biomarker is at hand, and while the use of ctDNA has vastly improved the goal of precision medicine in the adjuvant therapeutic decision-making, there remains a need for ongoing phase III validation trials in PD-L1-low subgroups and integration with NAC response to fully address generalizability before universal adoption.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Translational Medicine. The article has undergone external peer review.

Peer Review File: Available at https://atm.amegroups.com/article/view/10.21037/atm-2026-1-0015/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-2026-1-0015/coif). J.B.A.C serves as an unpaid editorial board member of Annals of Translational Medicine from June 2025 to June 2027. J.B.A.C. reports Advisory and consulting fees from Merck KgA, BMS, EMD Serono, Pfizer, Astellas but no relationship to disclose as part of this manuscript. No conflicts of interest is identified for all authors regarding work for this manuscript. The other author has no conflicts of interest to declare.

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