We presented RETAIN at GU ASCO 2023 and this was a phase II non-inferiority trial for bladder cancer patients, patients with muscle-invasive bladder cancer, where we tried to spare cystectomy or any bladder-directed therapy such as chemoradiation for patients with muscle-invasive disease by trying to select patients who have an excellent response to neoadjuvant chemotherapy.
What was the study’s design?
The study was a non-inferiority design where all patients with muscle-invasive bladder cancer T2-T3 were enrolled and were treated with neoadjuvant chemotherapy, accelerated MVAC for three cycles. While they were getting treatment, the tissue from their original biopsy was sequenced and we were particularly looking for four mutations – ATM, FANCC, ERCC2 and RB1 – which were all known to be associated with a really good response to neoadjuvant chemotherapy at the time of surgery.
After chemotherapy, if a patient had a complete response on imaging, on cystoscopy, on cytology and had one of those four mutations, they were allowed to undergo surveillance rather than surgery. So they were monitored closely with cystoscopies, with imaging, with the bloodwork but their bladder was not removed and they did not have radiation. The rest of the patients who did not have a complete response or who did not have a mutation then went on to standard of care treatment, mostly cystectomy. The patients were all followed up and the primary endpoint was the two-year metastasis-free survival for the whole population. We were looking to hit a certain bar for our point estimate of the two-year metastasis-free survival in our confidence interval to say that this approach where we are sparing cystectomies in patients is non-inferior to the standard of care.
What were the key findings?
The key results were that the two-year metastasis-free survival was around 72% and the way we designed it, the 95% one-sided confidence interval was approximately 62.5%, just slightly shy of the 64% mark that we needed to hit to meet our primary endpoint. So the trial did not meet the primary endpoint of non-inferiority and therefore that is what we reported and stated that this certainly cannot be adopted as a standard of care at this point. However, we also showed that approximately 46% of patients who went on to active surveillance have at the two-year mark been able to retain their bladder, have not developed metastatic disease, have not died. Some of them have needed to have intravesical therapy but quite a few were, again, able to keep their bladder intact which is a big positive for patients.
We learned that most patients on active surveillance who did recur with metastatic disease, of which there were ten patients, 80% of them had actually a local recurrence first. So they had either non-muscle invasive or muscle invasive recurrence first before their metastatic disease, and that’s an important consideration as we think about in the future what to do with patients in whom that occurs where we are suggesting that you need to be very aggressive in those situations and/or go immediate cystectomy. The chemotherapy was well tolerated and patients certain appreciated not having a cystectomy.
How could these results impact future bladder cancer treatments?
These results are hypothesis generating. They are one of a few trials in this space where we’re trying to spare bladder therapies. There’s another trial presented at GU ASCO by Matt Galsky who had a similar, not the same but a similar, approach. So the work will have to be put together with that trial as well as several ongoing trials to figure out how we better select patients for this bladder preservation. It will involve ctDNA, urinary biomarkers and better imaging, such as with MRIs, to really go on to the next generation of trials. So there are a few ongoing trials, there’s one by Alliance, one called RETAIN-2 at our centre, that are examining this question. So this is building a foundation for this approach.
