Editor’s Note: At the recent genitourinary oncology symposium, Dr. Pooja Ghatalia from Fox Chase Cancer Center presented the primary clinical outcomes of the RETAIN 2 trial. She also provided an integrated analysis of the RETAIN 1 and RETAIN 2 trials, focusing on the role of circulating tumor DNA (ctDNA) in guiding response-adapted bladder preservation for patients with muscle-invasive bladder cancer (MIBC).01 Background:
Clinical Need for Bladder Preservation in MIBC The standard of care for MIBC has long been neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC). However, RC is a life-altering procedure that significantly impacts patient quality of life. Clinical data indicate that 35%–60% of patients achieve a pathological complete response (pCR/ypT0) after NAC, creating a clear opportunity for response-adapted bladder preservation protocols. RETAIN 2 was designed to explore the feasibility of a biomarker-driven approach utilizing immunotherapy combined with chemotherapy.
02 RETAIN 2 Study Design:
Response-Adapted Selection Logic RETAIN 2 was a single-arm Phase II trial enrolling patients with clinical stage T2–T3N0M0 MIBC. All patients received three cycles of accelerated MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) combined with nivolumab.
- Selection Strategy: Patients were stratified based on mutational biomarkers in pre-treatment tissue (associated with cisplatin sensitivity) and clinical restaging post-NAC (including endoscopic assessment, biopsies, CT imaging, and urine cytology).
- Treatment Pathways: Patients who were mutation-positive and had no clinical residual disease proceeded to active surveillance (AS). All other patients (mutation-negative or with residual disease) were recommended for intervention (RC, chemoradiation, or intravesical BCG), decided through shared decision-making.
03 Primary Endpoint Met:
Significant 2-Year MFS Benefit The RETAIN 2 trial successfully met its primary endpoint. In the intention-to-treat (ITT) population (n=71 evaluable patients):
- 2-Year Metastasis-Free Survival (MFS): Reached 70.0%. The lower bound of the one-sided 90% confidence interval (CI) was 62.4%, well exceeding the pre-specified non-inferiority threshold of 56%.
- Active Surveillance Outcomes: Patients in the AS group (n=22) achieved a 2-year MFS of 85.0%.
- Intervention Group Analysis: Among patients who underwent RC (n=35), the ypT0 rate was 46.0%.
Overall, 68% of the AS group remained metastasis-free with an intact, non-irradiated bladder at a median follow-up of 32.3 months. Notably, all metastatic events were preceded by local recurrence, emphasizing the critical need for rigorous local monitoring.
04 Integrated ctDNA Analysis:
A Powerful Predictor of Systemic Relapse An integrated ctDNA analysis across RETAIN 1 and RETAIN 2 was performed, evaluating 275 timepoints from 111 patients using the tumor-informed Signatera assay.
- Dynamics: Baseline ctDNA positivity was 42%, dropping to 14% post-NAC, reflecting an overall ctDNA clearance rate of 73%.
- Prognostic Correlation: Both baseline and post-NAC ctDNA positivity were strongly associated with inferior MFS and overall survival (OS). Patients with persistent ctDNA positivity post-NAC faced a significantly higher risk of metastasis, with a hazard ratio (HR) of 10.7.
- Stratification Value: Patients who remained ctDNA positive had poor outcomes despite undergoing RC, suggesting this subgroup requires more intensive systemic therapy rather than localized intervention alone.
05 Limitations:
ctDNA Insensitivity to Local Bladder Recurrence While ctDNA performed exceptionally well in predicting systemic metastasis, it showed significant limitations in detecting local residual disease:
- Residual Disease Prediction: Among patients with ≥ypT2 disease at the time of RC, 67% were ctDNA negative. The negative predictive value (NPV) for detecting residual bladder disease was only 32.4%.
- Recurrence in AS Group: In the AS group, the 2-year MFS for ctDNA-negative patients was excellent; however, the 2-year recurrence-free survival (RFS) was only 51%, driven almost entirely by local bladder relapses. Of the 21 local recurrences in the AS cohort, only 2 patients were ctDNA positive.
- Conclusion: ctDNA is optimized for detecting systemic tumor burden rather than microscopic local urothelial recurrence.
06 Conclusion and Outlook:
Building a Multi-Modal Assessment Framework Dr. Pooja Ghatalia concluded that RETAIN 2 demonstrates the safety and feasibility of a biomarker-selected bladder preservation strategy following NAC plus immunotherapy. While ctDNA is a highly prognostic marker for systemic disease control, it does not reliably replace standard clinical restaging (endoscopy and biopsy) for monitoring the bladder itself. Future trials should integrate ctDNA with clinical restaging and emerging urinary biomarkers to create a multi-dimensional precision framework, optimizing quality of life without compromising oncologic safety.
