At the 2023 ASCO Genitourinary Cancers Symposium, Daniel Geynisman, MD, Fox Chase Cancer Center, Boston, MA, shares results from the phase 2 RETAIN trial, evaluating a risk-adapted approach for patients with muscle-invasive bladder cancer. Following neoadjuvant chemotherapy with accelerated MVAC, patients who were found to have at least 1 mutation (ATM, ERCC2, FANCC, or RB1) and no clinical evidence of disease (per restaging transurethral resection, urine cytology, and imaging) were put on pre-defined active surveillance.

The metastasis-free survival rate of the patients treated with the risk-adapted approach did not meet the pre-specified condition for non-inferiority. Dr Geynisman noted while “48% of patients who went on active surveillance at 2 years have continued to keep their bladder in place, have no metastatic disease, and are alive… almost 70% of patients altogether in the active surveillance group have had some form of recurrence.”

Transcript:

My name is Dan Geynisman. I'm a genitourinary medical oncologist at Fox Chase Cancer Center in Philadelphia. And we presented the results of RETAIN at the 2023 ASCO Genitourinary Cancers Symposium. RETAIN is a bladder-sparing trial. We ask the question of whether or not patients with muscle-invasive bladder cancer, who have a great response to neoadjuvant chemotherapy, can actually retain their bladder, not have any bladder-directed therapy, such as a cystectomy or chemoradiation.

We selected patients with T2 or T3 muscle-invasive bladder cancer. They received 3 cycles of accelerated MVAC as neoadjuvant chemotherapy. And while that was happening, their tissue from their TURBT was sequenced. And we particularly looked at 4 mutations, ATM, RB1, FANCC, and ERCC2. These are DNA damage repair mutations, or nucleotide excision repair pathway mutation for ERCC2, that have been associated with ypT0 response at surgery and good long-term disease specific and overall specific survival.

If a patient had one of those mutations, and at the end of their neoadjuvant chemotherapy had a complete clinical response, meaning no disease on cystoscopy or TURBT, no disease on imaging, negative cytology, they were allowed to go on active surveillance. And active surveillance meant cystoscopies, labs, imaging, very frequently, every 3 months in the first year, every 4 months year 2 and 3, and so on. If you didn't have a complete response, or you did not have one of the mutations, then you went on to some sort of normal bladder-directed therapy, such as a cystectomy or chemoradiation or, in cases of non-muscle invasive disease, could select intravesical therapy.

We enrolled 70 patients. This was a non-inferiority trial where we're looking at the whole 70 patients, and looking at the 2-year metastasis-free survival as our end point. And we were looking to see if that point estimate was within a reasonable range to what we would expect, historically, for a population like that. And if it was, then we would say, "Gosh, we could actually preserve bladders and spare patients a cystectomy."

Our point estimate for metastases-free survival for the entire population at 2 years, a landmark analysis was around 72%. The 95% confidence interval, the lower bound of it, was around 62.5%. And to declare this study positive, in other words, to approach non-inferior, it would have to have been greater than 64%. We just missed our primary endpoint, non-inferiority, so we could not call the trial positive. However, 48% of patients who went on active surveillance at 2 years have continued to keep their bladder in place, have no metastatic disease, and be alive.

On the flip side, almost 70% of patients altogether in active surveillance group have had some form of recurrence, whether it's non-muscle invasive bladder cancer recurrence that have been treated with intravesical approaches, or muscle-invasive diseases should have been treated with a cystectomy or radiation. And, unfortunately, 10 patients did have metastatic disease, of which 3 have died. And we're looking closely at that group. What we've noticed it's that almost all patients, 80% who have had metastatic disease in the surveillance group, recurred with localized disease first. It's very important to be quite aggressive if somebody recurs with localized disease, and immediately proceed to something like a cystectomy, rather than probably intravesical therapy.

We have looked at associations of those mutations with response and haven't seen that. We have to actively look at circulating tumor DNA and urinary DNA to see if we can better select patients for active surveillance. There is a trial called RETAIN-2, which is combining MVAC with nivolumab in the neoadjuvant setting as the next iteration of this. And then, we're planning follow-up studies as well that, again, select patients probably a little bit better using urinary biomarkers and circulating tumor DNA.

This is not a standard-of-care approach at this point. There are patients who have clearly benefited and have never had to have a cystectomy or radiation and are doing well. And this adds to the body of literature for this approach. There was another trial, a Hoosier Oncology Group trial, presented by Dr [Matthew] Galsky, [MD, Tisch Cancer Institute, New York, NY] that tried to do something similar and also had encouraging results, so I'd encourage you to take a look at that.

And that was our trial.

Source:

Geynisman DM, Abbosh P, Ross EA, et al. A phase II trial of risk-enabled therapy after initiating neoadjuvant chemotherapy for bladder cancer (RETAIN). Presented at 2023 ASCO Genitourinary Cancers Symposium; February 17-19; San Francisco, CA. Abstract 438