Enzalutamide With or Without Vaccine Therapy for Advanced Prostate Cancer – Ravi Madan
October 15, 2021
Ravi A. Madan, MD, Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States of America
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts
Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist at Dana-Farber Cancer Institute. I'm so excited to have here with me today, a good friend and colleague, Dr. Ravi Madan, who is the Clinical Director of the GU Malignancies branch of the Center for Cancer Research, National Cancer Institute in Bethesda. Thank you so much for being here with me today, Dr. Madan.
Ravi Madan: Thank you, Dr. Morgans, for that kind introduction.
Alicia Morgans: Of course. Ravi, I wanted to talk with you about some work that you and the team presented at ESMO 2021, really looking into sodium fluoride PET imaging in patients who were getting enzalutamide and PROSTVAC. Can you tell us a little bit about this study and what you presented?
Ravi Madan: Sure. The study was launched in 2013, and sodium fluoride was kind of emerging as an interesting PET platform that we were trying to understand. So as part of the trial, which evaluated a randomization of enzalutamide, with or without a therapeutic cancer vaccine, we incorporated, in a subset of patients, serial PET imaging. Now, ultimately, the addition of PROSTVAC did not yield a clinical difference, but it allowed us an opportunity to evaluate the impact of enzalutamide alone on this population that was basically first-line metastatic castration-resistant prostate cancer, and in that context, look at serial sodium fluoride PET imaging.
Alicia Morgans: I think that's really such an interesting concept, and even might be something that we would love to hear about just in terms of general PET imaging, because that's not something that we have typically for our patients with prostate cancer. Can you tell us a little bit about what you found and what you're thinking about the data?
Ravi Madan: Right. The backdrop of this is we really encourage patients to stay on until radiographic progression on conventional imaging. The interesting tidbit that came out of that, which isn't too surprising to yourself, I'm sure, and other GU medical oncologists, is that we saw initial PSA rises at a median of 6 months in these patients, but in the patients that continued on, which was the vast majority, until radiographic progression on conventional CT scan or technetium, that didn't occur until about 23 months. So that provides some insight into how important it is to leave patients on until radiographic progression, because it provided substantially greater clinical benefit. And there was not more than one patient who had substantial clinical symptoms at progression either.
Ravi Madan: So in that context, it gave us an opportunity to evaluate, in a serial fashion, what was going on on the sodium fluoride PET imaging. What we found when we looked at the sodium fluoride PET imaging, was that there were a lot of dynamic changes. And what we found is that in the 18 patients, and 14 of them ultimately had radiographic progression during the course of the trial, there were nearly 400 new lesions across all the patients, and 28% of those lesions actually resolved over time. So I think in one fashion, it highlights that if you are using PET imaging to evaluate for progression, we really don't know how to do that, especially in the context when lesions seem to appear and disappear, although the standard imaging in the patients remained stable. Those changes occurred in 14 of the 18 patients.
Alicia Morgans: To that point, I think it's really important that we take a step back and emphasize what kind of imaging technology PET imaging is. This is, of course, functional imaging. Looking at changes in the biology, changes in some sort of cellular mechanics that are going on at that time. So changes don't necessarily always equate with progression of cancer, there could simply be changes, which is what it sounds like you were finding, and is certainly something for us to think about as we're thinking about all of the PET imaging that we are planning to integrate into our algorithms and future care.
Ravi Madan: That's exactly right. I think it's important to acknowledge that sodium fluoride probably is more of an evaluation of inflammation, and so you can see how that could happen. But I think that as we move forward into the age of PSMA PET imaging, we should do so with our eyes open and not with presumptions, because as you alluded to, there could be biologic changes that occur that we don't fully understand and may not truly represent treatment failure. And when we're talking about first-line therapy with a drug like abiraterone, or in this case enzalutamide, that are well tolerated, I think it's important to maximize patient exposure.
Alicia Morgans: Can you tell us, Dr. Madan, how did these changes correlate with PSA? Or do you have that information?
Ravi Madan: They did often happen during a rise in the PSA. It seems to be both during the decline and during the rise. And I think that's important, because it could provide a false signal, again, of treatment failure and ultimately lead to discontinuation of effective therapy prematurely.
Alicia Morgans: Well, I think this is really highly important clinically relevant data, even if it is on a technology that we're not using as widely as we may have in the past, especially with the admin of some new imaging. What would your bottom line recommendation or guidance be to clinicians who are trying to think about their practices and how to move forward, given the data and your findings from this trial?
Ravi Madan: Right. I think it is important to acknowledge that this is a little bit older technology, but we need to, again, be aware that with new technology that we're going to be using with PSMA comes great responsibility, and we shouldn't be presumptuous in how we use it. We have to remember that agents like enzalutamide were developed using conventional imaging and we shouldn't presume that changes on PET imaging demonstrate treatment failure.
Ravi Madan: The other thing that I think is important that this data highlights that wasn't a pure focus of the abstract, but is clearly a result of the analysis, is that it appears as though, even when patients are having radiographic progression over time, it's occurring in kind of a heterogeneous fashion, in that there are lesions that are still responding to enzalutamide when they meet criteria for progression. And so I think that, potentially, could be one of the more interesting findings here, because it could highlight that even though we're seeing progression on even conventional imaging with a treatment like enzalutamide, we're actually seeing oligo progression, and that perhaps a large amount of the cancer is being held in check even though we're getting a clear signal that there are new lesions. And I think we're working here with my team to incorporate that in the future studies, and I'm hoping to get this data out there so other people can do that as well.
Alicia Morgans: Well, I hope that others really take this into account as well, and that future studies, not just with your institution, but across the US, and of course we're all of this is happening, in Australia, Germany, and through Europe, et cetera, I hope that we all can think about this and integrate it into our prospective trials as a way to understand the treatments that we are now investigating, in the context of this new imaging, especially given your findings, just very fascinating and also leaves a lot of questions for us still to answer. I think that's some of the best science. That science, that raises more questions than it necessarily answers.
Alicia Morgans: So thank you so much for this great work and for bringing us something new, even in the setting of things like PROSTVAC, that don't necessarily give us new treatments, but absolutely inform the way that we care for men who have this disease. I appreciate your time and expertise, as always.
Ravi Madan: Great. It was great talking to you about this, and good seeing you again.