RETAIN-2 Study Shows Promise for Bladder Cancer Preservation - Pooja Ghatalia
March 4, 2025
Pooja Ghatalia joins Ashish Kamat to discuss the RETAIN-2 study. This phase II trial for muscle invasive bladder cancer evaluates neoadjuvant dose-dense MVAC plus nivolumab, with patients achieving clinical complete response and specific mutations eligible for active surveillance. With 21.7 months median follow-up, results show a 40% ypT0 rate in patients undergoing cystectomy - significant because these represent "bad players" not selected for surveillance. Of 71 patients, 22 pursued active surveillance with 82% metastasis-free survival, while the composite ypT0 plus clinical CR rate reaches 54%. Dr. Ghatalia emphasizes these results exceed previous chemo-immunotherapy combinations and highlights the importance of bladder preservation, with plans for RETAIN-2.5 including maintenance immunotherapy for surveillance patients.
Biographies:
Pooja Ghatalia, MD, Oncologist, Fox Chase Cancer Center, Philadelphia, PA
Ashish Kamat, MD, MBBS, Professor of Urology and Wayne B. Duddleston Professor of Cancer Research, University of Texas, MD Anderson Cancer Center, Houston, TX
Biographies:
Pooja Ghatalia, MD, Oncologist, Fox Chase Cancer Center, Philadelphia, PA
Ashish Kamat, MD, MBBS, Professor of Urology and Wayne B. Duddleston Professor of Cancer Research, University of Texas, MD Anderson Cancer Center, Houston, TX
Read the Full Video Transcript
Ashish Kamat: A warm welcome to all of you from the UroToday Studios. I'm Ashish Kamat, Professor of Urologic Oncology at MD Anderson Cancer Center. And we're live in San Francisco at ASCO GU 2025. It's a pleasure to welcome to our studios Professor Pooja Ghatalia.
Pooja Ghatalia: Hello, everyone.
Ashish Kamat: —who's going to talk to us about the RETAIN-2 study. So, Pooja, take it away.
Pooja Ghatalia: Ah, yes. So RETAIN-2, as the name says, is a sequel of RETAIN-1, which was a study that was completed and reported, published actually in JCO earlier this year. RETAIN-2 is a phase II single-arm trial in patients with muscle invasive bladder cancer, where patients receive three cycles of neoadjuvant dose-dense MVAC plus nivolumab. And while patients are getting their neoadjuvant treatment, we send their tumor tissue to look for the biomarker signature that has been associated with response to chemotherapy.
After completing their neoadjuvant treatment, patients go on to getting endoscopic mapping and biopsies of their bladders, and urine cytology, and CT scans to look for any metastatic disease. And patients who are considered clinical complete response, and who have one of the mutation markers that we had tested for, have an option of going on to active surveillance.
And the active surveillance essentially comprises of close monitoring of their bladder and systemic staging. Patients who either don’t have a mutation or have residual disease in their bladder go on to receiving intervention, which could be either intravesical therapy, or chemoradiation, or cystectomy—depending on the amount of disease that they had remaining and based on patient-physician preference.
Ashish Kamat: So just to interrupt there for a quick second, the decision between a cystectomy and chemoradiation, is that based on stage, or if it’s invasive, then the patient is given the choice?
Pooja Ghatalia: Yes. If it’s invasive, then the patient is given a choice. Note that this is different from RETAIN-1, where it did not have the neoadjuvant immunotherapy component. Otherwise, the design is very similar to RETAIN-1.
And so now we have the interim analysis results. The primary endpoint of the study is two-year metastasis-free survival for all patients entering the study, which has not yet been reached. And so, at present, we have a median follow-up of 21.7 months.
Now, based on this data, I think some of the key takeaways are that when compared to RETAIN-1—even though that was not the purpose of this study—we are seeing better ypT0 rates in patients undergoing cystectomy. So we have a ypT0 rate of 40% in patients undergoing cystectomy as part of RETAIN-2.
You may think that the 40% kind of reminds you of the path CR that you may have seen with other combinations. But remember, these are patients who were selected not to go on to active surveillance. So these are zero “bad players,” if you may call them. And so we think that this number is high compared to patients—all comers—who typically receive neoadjuvant chemotherapy or chemo–I-O combinations that have so far been published.
Ashish Kamat: That’s a very important point that you bring up. So I want to highlight that. Because, again, when people see that path 0, they’re like, oh, 40%. What’s so great? But it’s the CCR-excluded patients who are recommended radical cystectomy, right? So what percentage? How many patients had CCR and went on to active surveillance?
Pooja Ghatalia: So among the 71 patients who were the intention-to-treat patient population in this study, 22 patients ended up going on to active surveillance. And the remaining 48 patients ended up getting intervention as part of this study.
The clinical CR rate that you mentioned—so another way to look at it is, if you look at the ypT0 plus clinical CR rate, which is the rate of the chance of not having any recurrence in their bladder or systemic in patients who are not undergoing cystectomy, that combination is about 54% in the study, which is also higher than what we would normally expect for any other chemo–I-O combos that we’ve seen so far.
The results are still early. So head-to-head comparison with RETAIN-1 is hard to do. But at least right now, we are seeing better data in terms of fewer recurrences among the patients undergoing active surveillance in RETAIN-2 compared to RETAIN-1.
Ashish Kamat: Yeah. Now I have to compliment you on your group with the whole RETAIN paradigm, right? Because that’s what our patients want. They want treatment, of course, but they want to be able to try and preserve their bladder.
The one thing about RETAIN-1 that struck us at recent updates is the relatively poor outcome of patients that have noninvasive recurrences in the bladder. And some of the thought process there was that, of course, there’s no prolonged treatment. In RETAIN-2, is the nivo given after getting CCR and cystectomy as well? Is there a maintenance phase, like CheckMate, for example?
Pooja Ghatalia: No, we do not have that. But we do think that it is an important component to incorporate in the future. In RETAIN-2, we also just continued to watch patients on active surveillance without giving them any systemic therapy component. And similar to RETAIN-1, we did see some patients have recurrences in their bladders that were non-muscle invasive.
But we learned from RETAIN-1 and quickly offered those patients cystectomy or chemoradiation, as opposed to intravesical therapy or just watching their bladders, because those were the patients in RETAIN-1 who were developing more metastases.
Ashish Kamat: Right. And then that’s an important point. So let me just ask you on that. So if a patient on this study elects to save their bladder and has a Ta tumor in the bladder, you’re offering cystectomy at this point, not intravesical therapy? Or are you leaving it up to the physician and the patient?
Pooja Ghatalia: So most of those patients who had clinical Ta before deciding which route to choose, they usually ended up opting for intravesical therapy. And that is still the way it happened in RETAIN-2.
Ashish Kamat: Of course. Of course. And that would make sense. So again, just to help summarize and contextualize this—I know it’s smaller numbers—but what would you say is the bladder-intact event-free survival on a patient entering RETAIN-2, at this point?
Pooja Ghatalia: So patients entering into—who went on to active surveillance—so right now, we have 60% of patients going on to active surveillance who had an intact, unrelated bladder.
Ashish Kamat: And their event-free survival at two years is what?
Pooja Ghatalia: So we are currently having it as metastasis-free survival. And metastasis-free survival for those patients was 82%.
Ashish Kamat: 82%. OK. And those that achieved an actual CR, if you bring them into this whole composite patient population, what would be the metastasis-free survival of that composite group?
Pooja Ghatalia: 75%.
Ashish Kamat: OK, excellent. Excellent results. So clearly, obviously, you’re continuing to accrue. And you’ll have expanded numbers. Where do you see the next iteration? Where are we heading next with RETAIN-3 or 4?
Pooja Ghatalia: Yeah. So right now we are planning for RETAIN-2.5 while we’re still waiting for more data to mature on the use of EV/pembro in the neoadjuvant setting. We clearly think that the use of dose-dense MVAC may have an immunogenic component in combination with a PD-1 inhibitor.
So we’re currently trying to develop a study where we are not going to have a biomarker component, which would allow us to have more patients going on to active surveillance. We would potentially add maintenance immunotherapy for the patients going on to active surveillance.
And potentially, patients who are going on to getting chemoradiation or cystectomy will also receive adjuvant immunotherapy, based on their standard of care and the amount of disease in their bladder at the time of cystectomy. So that’s what we are right now headed towards.
Ashish Kamat: OK. And that’s what we just talked about a couple minutes ago, right?
Pooja Ghatalia: Yes.
Ashish Kamat: So again, if you could help our readers sort of contextualize the results of RETAIN-2 and maybe a little bit of your knowledge of RETAIN-1 with some of the other paradigms—for example, the NIAGARA data that we have for patients who are undergoing radical cystectomy and the path CR there, then Matt Galsky’s data—where would you think that the RETAIN paradigm, whether it’s MVAC plus or minus nivo, fits in?
Pooja Ghatalia: Yeah. Path CR rates in the patients undergoing cystectomy in RETAIN-2 was 40%. In RETAIN-1, it was 15%. So definitely the addition of immunotherapy has helped there. In Matt Galsky’s trial, it was different. And it’s hard to make comparisons. But the path CR rate was around 30% in that study.
And so I think the path CR rate of this dose-dense MVAC–nivolumab combination is definitely higher than what we have seen with the other I/O combinations with chemotherapy. And I’m not sure if it’s the involvement of dose-dense MVAC because traditionally, most of the I/O chemo trials in the neoadjuvant setting have used gemcitabine–cisplatin. But I think that will need to be explored further.
Ashish Kamat: Right. In the ITT for the NIAGARA study, of course, with the GC plus durva, it was about 33% or something like that, right?
Pooja Ghatalia: Exactly.
Ashish Kamat: But I think the distinction that you made earlier is very important for our readers—that the pT0 rate, or the path CR rate, is in those patients who did not elect to go on active surveillance. And if you take that composite, it’s a lot higher, right?
Well, this was a great conversation. Any closing thoughts or messages based on your trial for our listeners?
Pooja Ghatalia: I think bladder preservation is extremely important for our patients. The theme that we have seen with RETAIN-1 and as I enroll patients into RETAIN-2 is that these are the trials that patients really are interested in—seeing how they can preserve their bladder safely. And with the new developing studies, it would be very important to keep this consideration in mind and to try to optimize the amount of treatment we give to our patients.
Ashish Kamat: Absolutely. Well, thank you so much for taking the time.
Pooja Ghatalia: Yeah. Thank you.
Ashish Kamat: A warm welcome to all of you from the UroToday Studios. I'm Ashish Kamat, Professor of Urologic Oncology at MD Anderson Cancer Center. And we're live in San Francisco at ASCO GU 2025. It's a pleasure to welcome to our studios Professor Pooja Ghatalia.
Pooja Ghatalia: Hello, everyone.
Ashish Kamat: —who's going to talk to us about the RETAIN-2 study. So, Pooja, take it away.
Pooja Ghatalia: Ah, yes. So RETAIN-2, as the name says, is a sequel of RETAIN-1, which was a study that was completed and reported, published actually in JCO earlier this year. RETAIN-2 is a phase II single-arm trial in patients with muscle invasive bladder cancer, where patients receive three cycles of neoadjuvant dose-dense MVAC plus nivolumab. And while patients are getting their neoadjuvant treatment, we send their tumor tissue to look for the biomarker signature that has been associated with response to chemotherapy.
After completing their neoadjuvant treatment, patients go on to getting endoscopic mapping and biopsies of their bladders, and urine cytology, and CT scans to look for any metastatic disease. And patients who are considered clinical complete response, and who have one of the mutation markers that we had tested for, have an option of going on to active surveillance.
And the active surveillance essentially comprises of close monitoring of their bladder and systemic staging. Patients who either don’t have a mutation or have residual disease in their bladder go on to receiving intervention, which could be either intravesical therapy, or chemoradiation, or cystectomy—depending on the amount of disease that they had remaining and based on patient-physician preference.
Ashish Kamat: So just to interrupt there for a quick second, the decision between a cystectomy and chemoradiation, is that based on stage, or if it’s invasive, then the patient is given the choice?
Pooja Ghatalia: Yes. If it’s invasive, then the patient is given a choice. Note that this is different from RETAIN-1, where it did not have the neoadjuvant immunotherapy component. Otherwise, the design is very similar to RETAIN-1.
And so now we have the interim analysis results. The primary endpoint of the study is two-year metastasis-free survival for all patients entering the study, which has not yet been reached. And so, at present, we have a median follow-up of 21.7 months.
Now, based on this data, I think some of the key takeaways are that when compared to RETAIN-1—even though that was not the purpose of this study—we are seeing better ypT0 rates in patients undergoing cystectomy. So we have a ypT0 rate of 40% in patients undergoing cystectomy as part of RETAIN-2.
You may think that the 40% kind of reminds you of the path CR that you may have seen with other combinations. But remember, these are patients who were selected not to go on to active surveillance. So these are zero “bad players,” if you may call them. And so we think that this number is high compared to patients—all comers—who typically receive neoadjuvant chemotherapy or chemo–I-O combinations that have so far been published.
Ashish Kamat: That’s a very important point that you bring up. So I want to highlight that. Because, again, when people see that path 0, they’re like, oh, 40%. What’s so great? But it’s the CCR-excluded patients who are recommended radical cystectomy, right? So what percentage? How many patients had CCR and went on to active surveillance?
Pooja Ghatalia: So among the 71 patients who were the intention-to-treat patient population in this study, 22 patients ended up going on to active surveillance. And the remaining 48 patients ended up getting intervention as part of this study.
The clinical CR rate that you mentioned—so another way to look at it is, if you look at the ypT0 plus clinical CR rate, which is the rate of the chance of not having any recurrence in their bladder or systemic in patients who are not undergoing cystectomy, that combination is about 54% in the study, which is also higher than what we would normally expect for any other chemo–I-O combos that we’ve seen so far.
The results are still early. So head-to-head comparison with RETAIN-1 is hard to do. But at least right now, we are seeing better data in terms of fewer recurrences among the patients undergoing active surveillance in RETAIN-2 compared to RETAIN-1.
Ashish Kamat: Yeah. Now I have to compliment you on your group with the whole RETAIN paradigm, right? Because that’s what our patients want. They want treatment, of course, but they want to be able to try and preserve their bladder.
The one thing about RETAIN-1 that struck us at recent updates is the relatively poor outcome of patients that have noninvasive recurrences in the bladder. And some of the thought process there was that, of course, there’s no prolonged treatment. In RETAIN-2, is the nivo given after getting CCR and cystectomy as well? Is there a maintenance phase, like CheckMate, for example?
Pooja Ghatalia: No, we do not have that. But we do think that it is an important component to incorporate in the future. In RETAIN-2, we also just continued to watch patients on active surveillance without giving them any systemic therapy component. And similar to RETAIN-1, we did see some patients have recurrences in their bladders that were non-muscle invasive.
But we learned from RETAIN-1 and quickly offered those patients cystectomy or chemoradiation, as opposed to intravesical therapy or just watching their bladders, because those were the patients in RETAIN-1 who were developing more metastases.
Ashish Kamat: Right. And then that’s an important point. So let me just ask you on that. So if a patient on this study elects to save their bladder and has a Ta tumor in the bladder, you’re offering cystectomy at this point, not intravesical therapy? Or are you leaving it up to the physician and the patient?
Pooja Ghatalia: So most of those patients who had clinical Ta before deciding which route to choose, they usually ended up opting for intravesical therapy. And that is still the way it happened in RETAIN-2.
Ashish Kamat: Of course. Of course. And that would make sense. So again, just to help summarize and contextualize this—I know it’s smaller numbers—but what would you say is the bladder-intact event-free survival on a patient entering RETAIN-2, at this point?
Pooja Ghatalia: So patients entering into—who went on to active surveillance—so right now, we have 60% of patients going on to active surveillance who had an intact, unrelated bladder.
Ashish Kamat: And their event-free survival at two years is what?
Pooja Ghatalia: So we are currently having it as metastasis-free survival. And metastasis-free survival for those patients was 82%.
Ashish Kamat: 82%. OK. And those that achieved an actual CR, if you bring them into this whole composite patient population, what would be the metastasis-free survival of that composite group?
Pooja Ghatalia: 75%.
Ashish Kamat: OK, excellent. Excellent results. So clearly, obviously, you’re continuing to accrue. And you’ll have expanded numbers. Where do you see the next iteration? Where are we heading next with RETAIN-3 or 4?
Pooja Ghatalia: Yeah. So right now we are planning for RETAIN-2.5 while we’re still waiting for more data to mature on the use of EV/pembro in the neoadjuvant setting. We clearly think that the use of dose-dense MVAC may have an immunogenic component in combination with a PD-1 inhibitor.
So we’re currently trying to develop a study where we are not going to have a biomarker component, which would allow us to have more patients going on to active surveillance. We would potentially add maintenance immunotherapy for the patients going on to active surveillance.
And potentially, patients who are going on to getting chemoradiation or cystectomy will also receive adjuvant immunotherapy, based on their standard of care and the amount of disease in their bladder at the time of cystectomy. So that’s what we are right now headed towards.
Ashish Kamat: OK. And that’s what we just talked about a couple minutes ago, right?
Pooja Ghatalia: Yes.
Ashish Kamat: So again, if you could help our readers sort of contextualize the results of RETAIN-2 and maybe a little bit of your knowledge of RETAIN-1 with some of the other paradigms—for example, the NIAGARA data that we have for patients who are undergoing radical cystectomy and the path CR there, then Matt Galsky’s data—where would you think that the RETAIN paradigm, whether it’s MVAC plus or minus nivo, fits in?
Pooja Ghatalia: Yeah. Path CR rates in the patients undergoing cystectomy in RETAIN-2 was 40%. In RETAIN-1, it was 15%. So definitely the addition of immunotherapy has helped there. In Matt Galsky’s trial, it was different. And it’s hard to make comparisons. But the path CR rate was around 30% in that study.
And so I think the path CR rate of this dose-dense MVAC–nivolumab combination is definitely higher than what we have seen with the other I/O combinations with chemotherapy. And I’m not sure if it’s the involvement of dose-dense MVAC because traditionally, most of the I/O chemo trials in the neoadjuvant setting have used gemcitabine–cisplatin. But I think that will need to be explored further.
Ashish Kamat: Right. In the ITT for the NIAGARA study, of course, with the GC plus durva, it was about 33% or something like that, right?
Pooja Ghatalia: Exactly.
Ashish Kamat: But I think the distinction that you made earlier is very important for our readers—that the pT0 rate, or the path CR rate, is in those patients who did not elect to go on active surveillance. And if you take that composite, it’s a lot higher, right?
Well, this was a great conversation. Any closing thoughts or messages based on your trial for our listeners?
Pooja Ghatalia: I think bladder preservation is extremely important for our patients. The theme that we have seen with RETAIN-1 and as I enroll patients into RETAIN-2 is that these are the trials that patients really are interested in—seeing how they can preserve their bladder safely. And with the new developing studies, it would be very important to keep this consideration in mind and to try to optimize the amount of treatment we give to our patients.
Ashish Kamat: Absolutely. Well, thank you so much for taking the time.
Pooja Ghatalia: Yeah. Thank you.