ctDNA Offers Prognostic Clarity for Bladder Preservation

In an integrated analysis of the RETAIN-1 (NCT02710734) and RETAIN-2 (NCT04506554) trials, the distinct role of circulating tumor DNA (ctDNA) in managing muscle-invasive bladder cancer (MIBC) indicate that posttreatment ctDNA clearance or negativity is associated with improved metastasis-free survival. Specifically, patients who were ctDNA-positive after neoadjuvant therapy faced a significantly higher likelihood of developing metastatic disease. Conversely, those with undetectable ctDNA after treatment demonstrated a low risk of systemic recurrence.

Findings were presented by Pooja Ghatalia, MD, during the 2026 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium.

RETAIN-2 met its primary end point by demonstrating a 70% metastasis-free survival rate at 2 years within the intention-to-treat population, suggesting a potential path to avoid life-altering cystectomy. Among the specific cohort that moved into active surveillance, the 2-year metastasis-free survival was even higher at 85%.

Overall, 68% of the patients who underwent active surveillance remained metastasis free while maintaining an intact and nonirradiated bladder. While some patients did experience recurrences, many were manageable; for instance, among the 22 patients on surveillance, 14 remained recurrence free, and those with local recurrences were often treated with salvage cystectomy or chemoradiation.

“Incorporating ctDNA into the decision-making process helps refine who can safely keep their bladder,” Ghatalia, associate professor, Department of Hematology/Oncology, at Fox Chase Cancer Center in Philadelphia, Pennsylvania, said during the presentation.

For patients who remain ctDNA-negative but show clinical evidence of local disease, the study suggests that bladder-directed therapies such as chemoradiation or intravesical Bacillus Calmette-Guérin remain viable options.

Study Design

The single-arm phase 2 trial focused on patients with clinical T2 to T4a, N0, M0 muscle-invasive bladder cancer. Participants received 3 cycles of neoadjuvant accelerated methotrexate, vinblastine, doxorubicin (Adriamycin), and cisplatin (MVAC) combined with the checkpoint inhibitor nivolumab (Opdivo).

“A critical component of the schema involved testing pretreatment tissue for mutational biomarkers associated with cisplatin response,” Ghatalia said.

Following neoadjuvant therapy, patients underwent a comprehensive restaging process that included endoscopic assessment, biopsies, CT imaging, and urine cytology. Patients who were both mutation positive and showed no residual disease were directed toward active surveillance. Conversely, patients who lacked the mutation or showed residual disease were recommended for surgical or radiation intervention, though the final path was determined through shared decision-making between the physician and the patient.

Patient Characteristics and Background

The study population included 71 evaluable patients with high-risk features, including 42% with clinical T3 disease and 32% with mixed histology.

Of 80 treated patients, 60 (75%) completed 3 cycles of MVAC with nivolumab; 7 tolerated only 1 cycle, and 2 died shortly after completing 3 cycles from treatment-related adverse events and were not evaluable for the primary end point.

The study focused on the high rate of pathologic complete response seen with neoadjuvant chemotherapy, which ranges from 35% to 60%. The goal of the RETAIN program is to capitalize on these high response rates to spare patients the morbidity of a radical cystectomy. By combining clinical restaging, mutational biomarkers, and now longitudinal ctDNA monitoring, researchers aimed to refine the selection process to ensure that only those with the lowest risk of both local and systemic recurrence defer definitive surgery.

These findings demonstrated that ctDNA was prognostic for systemic disease control with ctDNA positivity associated with a 10.7 times higher risk of inferior metastatic-free survival (P <.0001). Further, ctDNA positivity was associated with poor outcomes despite cystectomy.

DISCLOSURES: Dr Ghatalia has received research funjding from AstraZeneca (Inst), Bristol-Myers Squibb (Inst), and Merck (Inst).

REFERENCE

Ghatalia P, Ross AE, Zibelman MR, et al. Circulating tumor DNA (ctDNA) to guide response-adapted bladder preservation in muscle=invasive bladder cancer (MIBC): Integrated analysis of the RETAIN trials. J Clin Oncol. 2026;44(suppl 7):LBA632. doi:10.1200/JCO.2026.44.7_suppl.LBA632