In a groundbreaking advancement for muscle-invasive bladder cancer (MIBC) treatment, researchers from Fox Chase Cancer Center have unveiled compelling results from the phase 2 RETAIN-2 clinical trial, which signal a paradigm shift in bladder preservation strategies. This study highlights the transformative potential of circulating tumor DNA (ctDNA) as a predictive biomarker for metastatic risk and underscores a novel neoadjuvant chemoimmunotherapy approach that allows selective bladder-sparing treatment.
Muscle-invasive bladder cancer historically necessitated radical cystectomy, the surgical removal of the bladder, as the standard of care; however, this procedure is not without profound consequences, including lifelong dependence on urinary diversion devices and a substantial decline in quality of life due to complications. The pursuit of bladder-sparing protocols has therefore become a crucial focus of oncologic innovation, aiming to maintain organ function while effectively controlling tumor progression.
Circulating tumor DNA comprises short fragments of DNA shed into the bloodstream by apoptotic or necrotic cancer cells, providing a non-invasive window into tumor dynamics. The Fox Chase team rigorously evaluated ctDNA as a surrogate marker for treatment response and disease recurrence in patients undergoing bladder preservation through a combination of chemotherapy and immunotherapy. The incorporation of immunotherapeutic agents, particularly nivolumab, represents a cutting-edge advancement, targeting immune checkpoint pathways that tumors exploit to evade immune surveillance.
In the RETAIN-2 trial, over seventy patients with MIBC were administered induction chemotherapy concurrent with nivolumab, followed by maintenance immunotherapy. This strategic combination aims to elicit robust tumor regression while fostering durable systemic immunity. Patients who demonstrated a pathologic complete response were spared immediate cystectomy, instead entering a vigilant surveillance protocol. Impressively, approximately 80% of these patients remained free from metastatic disease after a two-year follow-up period, affirming the efficacy of this approach.
A meticulous analysis of serial blood samples revealed that the presence of ctDNA following treatment was strongly correlated with the eventual development of distant metastases, making ctDNA a powerful prognostic tool for systemic disease risk. Importantly, patients who were ctDNA-negative post-treatment exhibited favorable clinical outcomes regardless of whether bladder removal was performed, emphasizing ctDNA’s potential to inform personalized therapeutic decisions.
Contrary to its utility in predicting metastasis, ctDNA did not reliably signal local tumor recurrence within the bladder. While a considerable subset of patients developed intravesical recurrences during surveillance, the majority did not exhibit ctDNA elevation prior to detection, highlighting a significant limitation in ctDNA’s sensitivity for local disease monitoring. This finding underscores the necessity for adjunctive biomarkers or imaging modalities capable of early identification of bladder-localized recurrence to complement ctDNA profiling.
This nuanced understanding of ctDNA’s capabilities enables oncologists to refine patient selection for bladder preservation strategies more safely and effectively. Incorporating ctDNA analysis into clinical decision-making facilitates a response-adapted framework whereby patients with undetectable ctDNA can be considered for organ-sparing treatment without compromising oncologic control. Conversely, ctDNA positivity may prompt more aggressive interventions or closer monitoring to preclude metastatic progression.
The implications of these findings extend beyond immediate clinical utility, illuminating pathways for future research and trial design. The Fox Chase investigators are poised to embark on the RETAIN-3 clinical trial, aimed at prospectively validating ctDNA as a biomarker to tailor neoadjuvant and adjuvant treatment regimens with heightened precision. Such biomarker-driven approaches epitomize the evolution toward personalized oncology, reducing overtreatment and enhancing patient quality of life.
Further longitudinal follow-up from RETAIN-2 participants will elucidate the long-term durability of bladder preservation and metastasis-free survival afforded by this innovative combination therapy. It will also provide critical insights into the kinetics of ctDNA and its relationship to treatment resistance and disease relapse.
The integration of ctDNA testing into the clinical management of MIBC represents a compelling evolution in bladder cancer care, enabling a more nuanced balance between effective oncologic control and organ preservation. This biomarker-driven strategy directly addresses patient-centered concerns about the functional and psychological burdens of radical cystectomy.
Dr. Pooja Ghatalia, the study’s lead author and Associate Professor at Fox Chase, emphasized the transformative potential of these findings: “Our data suggest that ctDNA can be a pivotal factor in clinical decision-making, guiding who may safely continue with bladder preservation and who requires more aggressive treatment. Nevertheless, we must continue to identify complementary biomarkers to effectively detect bladder-local recurrence early.”
Presented at the 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium in San Francisco, these findings underscore the integration of tumor biology insights with immunotherapy advances to tailor bladder cancer treatment. This pioneering work may soon change the therapeutic landscape for thousands of patients with MIBC worldwide.
As bladder cancer research progresses, the convergence of molecular diagnostics such as ctDNA with evolving systemic therapies heralds a new era of precision medicine, optimizing survival outcomes while preserving patient autonomy and quality of life.
Subject of Research: Muscle-invasive bladder cancer and circulating tumor DNA as a biomarker for bladder-preserving treatment strategies.
Article Title: Induction enfortumab vedotin plus pembrolizumab followed by maintenance pembrolizumab in first-line metastatic urothelial carcinoma (IMPROEV).
News Publication Date: 27-Feb-2026
Web References: http://dx.doi.org/10.1200/JCO.2026.44.7_suppl.TPS893
Image Credits: Fox Chase Cancer Center
Keywords: Muscle-invasive bladder cancer, circulating tumor DNA, ctDNA, bladder preservation, neoadjuvant chemoimmunotherapy, nivolumab, metastatic risk, bladder-sparing treatment, RETAIN-2 clinical trial, immunotherapy, biomarkers, tumor recurrence
