GU Cancers 2026 | RETAIN: ctDNA to guide response-adapted bladder preservation in MIBC

We will be presenting the results of RETAIN-2, the primary endpoint results of RETAIN-2. RETAIN-2 is a single-arm phase 2 investigator-initiated clinical trial where patients receive neoadjuvant accelerated MVAC plus nivolumab. And following neoadjuvant therapy, patients received clinical staging, which included assessment of the bladder with cystoscopy, as well as cytology and CT scans. Patients also received neoadjuvant testing of their tumor tissue to look for mutations in specific biomarkers that have been shown to be predictive of response to chemotherapy. And after completing clinical staging based on the presence of residual tumor in the bladder, as well as the mutational status, patients either get active surveillance, which is where patients don’t get their bladder out, but they continue to be monitored with cystoscopies and staging. And patients who have either not the mutation or who have residual disease in the bladder go on to receiving an intervention. So this is the general scheme of the study. We are going to be presenting the final results and RETAIN-2 met the primary endpoint of two-year metastasis-free survival. And also, this is exploratory, but in comparison to RETAIN 1, which did not include the nivolumab component, it was just neoadjuvant MVAC, we found that fewer patients had local recurrence and fewer patients had metastasis compared to RETAIN 1 in RETAIN 2. And also, a higher percentage of patients were able to stay metastasis-free with an intact non-irradiated bladder in RETAIN-2 as compared to RETAIN-1. So those are the main results of the study itself. We had also embedded circulating tumor DNA in RETAIN-1 and RETAIN-2, and I’ll be presenting the integrated analysis. So we have a complete data set of RETAIN-1 and RETAIN-2 trial patients where ctDNA was incorporated, mainly at baseline and post-neoadjuvant therapy. And some of the main findings are, number one, ctDNA is a very powerful prognostic indicator of metastases, especially at baseline as well as in the post neoadjuvant therapy setting. Also, ctDNA positive patients did really poorly in terms of overall survival. The second key take home from the study is that ctDNA can also be integrated in bladder preservation strategies. So for example, we saw that patients who were ctDNA positive who underwent cystectomy, they did quite poorly. But patients who were ctDNA negative who underwent cystectomy had outcomes that were very similar to patients who were ctDNA negative and went on to active surveillance, which is a provocative question that leads us to consider possibly considering ctDNA negativity in patients who we are possibly offering active surveillance to in combination with clinical staging, of course. Additionally, we saw that patients who were ctDNA positive who underwent cystectomy had really poor outcomes, and those are patients who we may want to consider some additional therapies for, as opposed to offering them radical cystectomy as an option. And finally, one of the important findings was that ctDNA is really predicting systemic recurrence, but is not a good predictor of residual disease in the bladder or local recurrence. So among the patients who underwent cystectomy, if you look at their post neoadjuvant therapy ctDNA status, the positive predictive value was 90%. So positive ctDNA correlates with residual disease. But the negative predictive value of ctDNA alone was just 32%. So a lot of patients who had clinical macroscopic disease that was found at the time of cystectomy were ctDNA negative. And this is a limitation to bear in mind as we design future bladder preservation trials where we may want to incorporate definitely clinical staging in terms of endoscopic assessment, but also maybe urinary biomarkers or other biomarkers that can help us better monitor local recurrence.

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