PSMA PET's Influence on Prostate Cancer Studies - Jeremie Calais
June 21, 2023
Phillip Koo talks with Jeremie Calais about the EMBARK trial and the impact of PSMA PET on patient population characterization. The discussion explores how the EMBARK trial began back in 2015 before the existence of PSMA PET and how its introduction has affected the understanding and definition of patient populations in prostate cancer studies. Calais explains how their team retrospectively looked at what the EMBARK patient population would look like using PSMA PET. It is noted that up to 45% of patients presented with metastatic disease, with more than five lesions in about 10% of the patients. The conversation also touches on the challenges of interpreting PSMA PET results, the need for further clinical trials, and how the introduction of this new technology has led to a stage migration effect. They also discuss the future role of PSMA PET in upcoming trials and its impact on treatment strategies.
Biographies:
Jeremie Calais, MD, MSc, Associate Professor, Nuclear Medicine and Theranostics, Director, Clinical Research Program of the Ahmanson Translational Theranostics Division, University of California, Los Angeles, Los Angeles, CA
Phillip J. Koo, MD, Division Chief of Diagnostic Imaging at the Banner MD Anderson Cancer Center in Arizona
Biographies:
Jeremie Calais, MD, MSc, Associate Professor, Nuclear Medicine and Theranostics, Director, Clinical Research Program of the Ahmanson Translational Theranostics Division, University of California, Los Angeles, Los Angeles, CA
Phillip J. Koo, MD, Division Chief of Diagnostic Imaging at the Banner MD Anderson Cancer Center in Arizona
Read the Full Video Transcript
Phillip Koo: Hi, my name is Phillip Koo, and welcome to UroToday's coverage of ASCO 2023. Today, we're fortunate to have with us Jeremie Calais, who's going to speak to us about the EMBARK trial and what the patient population would look like with PSMA PET. So before we dive into it, I'd like to refer the listeners to go watch the video with Alicia and Neal Shore that talks about the EMBARK trial that was first presented at AUA 2023, which is a link that we'll have below.
It's interesting. When EMBARK was started, I believe the first patient was recruited in 2015, which is eight years ago. So clearly, a lot of things have changed and the biggest one is PSMA PET. So can you talk to us about how that patient population would've been characterized had PSMA PET been performed?
Jeremie Calais: Yeah, sure. Thank you so much for inviting me. My pleasure to be here, giving me the opportunity to present this work and others that we presented. This work, the EMBARK-like study, was run by Wesley Armstrong who is our MD/PhD student and so I really thank you, thank him, and speak on his behalf. And then we have other projects from the UCLA team that we presented that go more or less in line in this topic, which is the stage migration and how we use the new information based on PSMA PET and all the questions that arise coming from a new technique and a new method and a new finding. So for the EMBARK, you're right. In 2015, PSMA PET was not existing, so it's not part of any screening.
But then now, the data is mature. They're putting out their data, but everybody's using PSMA PET now. So how do you interpret these results with PSMA PET? And this question, we have it for every trials, right? We had it for the SPARTAN population. There is another abstract that is presented there. Basically, all the trials that are using the metastatic setup based on conventional imaging, you have to redefine that. So we look back, retrospectively, to just see what an EMBARK-like population would look like on PSMA PET scan. We're about to find 200 patients that were the EMBARK like characteristics, so BCR high-risk, PSMA must be at least one or both after surgery. So it's not the salvage radiation therapy one. It's more the above that or two after above the nadir with the PHOENIX criteria for radiation therapy recurrence and the doubling time of less than nine months. So aggressive high risk, steep curve of the PSA incline.
And in that series, we detected metastatic disease in up to 45% of the patients. And it was polymetastatic, more than five lesions in about 10% of the patients. So what we do with that, we're not sure this work is just a first attempt to describe in the patient that was BCR, pure BCR. So the disease that we know is just based on the blood test, nothing that we visualize. Now we see it. So it doesn't tell you what we'll do with that. And I think it's good to know because we'll have that. We'll have a label that will say something and then the patient will have the scan, will have these findings. Where do they fit? Would they still benefit from the drug or not? That will be something.
But we have that for many other settings, so for the CRPC population, for example. Non-metastatic CRPC and so here, it was really saying non-metastatic. We are identifying half of the patients, again, metastatic disease by PSMA PET. So you have really this stage migration and this study, there is one that we studied with many other groups. We had the multicenter retrospective study that was led with our German colleagues and that was presented here again. And we did the first study few years ago showing exactly like the same thing with the EMBARK, very descriptive, single time point. This is how it looks on a PSMA PET scan.
And now, this year at ASCO, was presented the follow-up study looking at overall survival to see what the PSMA PET scan findings were predictive of or prognostic of in that patient population. You can see that when metastatic disease was discovered, many patients were switched to systemic therapy as a main result. But many got, still, some kind of radiation therapy, so it was real world data, so there were various types of management. And at the end, again, as always, the more lesions you see on the PSMA PET scan, the worse the outcome gets.
Phillip Koo: Sure. So it's interesting. You talked about it with PROSPER, SPARTAN, ARAMIS, those trials that were looking at the non-metastatic CRPC population and that was all based on conventional imaging. And now, we're seeing something very similar now in patients with now high-risk biochemical recurrence. We've talked about this before, but really, this idea of non-metastatic, we really need to somehow indicate whether it's with conventional imaging or whether it's with PSMA.
What advice do you have for, let's say, the urologist or radiation oncologist or medical oncologist who's managing that patient with high-risk biochemical recurrence, their approach to getting PSMA and interpreting those results now that we have the EMBARK data.
Jeremie Calais: So if your intent was to use a systemic therapy approach, I think this should not be changed based on the PSMA PET findings. You rely on the data. These are the same patients. Now, on a short term basis, before we can harvest more mature data on how to use the PSMA PET findings with the defined management, I would say that maybe you can consider irradiate the lesions that you see, that that's a possibility. In very rare cases, maybe the volume of disease would be so high that you would maybe try to intensify with a combination or doublet therapy or almost in a CRPC-like setting. That would be the first insight I could guess that you can do in that patient population in which you would already intend to use a systemic therapy agent.
And if you don't see any disease, I don't think you should avoid any therapy. I think deescalation based on PSMA PET scan findings is really not possible. In another study we show that even when you don't see the recurrence and you irrigate that location such as the prostate beds or the pelvic lymph nodes, patient do better, even when it's negative on the scan. So you cannot use only what you see on the scan to not treat.
Now, in the systemic therapy indication, we don't have a good answer. And what I'm very happy is that we have now many ongoing clinical trials that try to answer these questions that are randomizing patients based on specific PSMA PET patterns and specific management. So if you have a positive PSMA PET scan, you would do that treatment versus that treatment. If you have a negative PSMA PET scan, you do that treatment and that treatment and there, we will be able to answer some of these questions.
For now, we were really in an interesting paradigm. Like you say, it's about the time. You say in 2015, here was a trial design. Time goes and then new things come and then you end up with the rules that you set up before, conventional imaging rules, for example, that work. It's reliable. We know the outcomes. And then you have a new technology that clearly show it's better than the conventional imaging, but we have no guiding book, no rules, no cooking recipe on how to use these new findings. So how you deal with that?
You cannot ignore what you see on the scan, but you don't have the best proven way to use this new findings and the value of it. Of course, this disease you see on the PSMA PET scan is usually of not as bad prognosis as what you see in conventional imaging. Like a metastasis that you don't see in conventional imaging and you see on PSMA PET is probably not as bad. And there are some studies that now show that the over-survival of patient with metastatic disease seen only by PETS, they do much better than the one with metastatic disease seen by conventional imaging and PET. So they're not the same value.
So we just have to run new trials, know how to try to understand how to use better this information and the stage migration effect. But we are on that zone, where based on the, I would say, almost the sensitivity of each physician and patient, they would say, "Okay, I don't know how to use it. I prefer the old data that I know" or say, "Okay, look, the disease is there, we have to act on it, and we'll try that." And you will have these two approaches. I don't know what's the best idea.
Phillip Koo: Sure. So I would agree, I think in order to get those results we should stick to the EMBARK trial as close as possible and use conventional imaging. And with PSMA PET, exactly, we have that stage migration. We have the potential for the Will Rogers effect, which we have to sort out. But I think in the long term, having PSMA PET and being able to stratify those patients a little better and more accurately will hopefully, and I believe it will, lead to better outcomes, but it obviously needs to be studied.
Anything else that you're working on that is going to help us, let's say, in the next one or two years sort of navigate a lot of these unclear, murky waters that we're now sort of seeing more and more often with the wider use of PSMA PET?
Jeremie Calais: So again, I think we had this retrospective analysis on patients that got their PSMA PET scan since 2016 at UCLA. We started early compared to other United States sites and we're collecting the data and see how this impacted their outcomes and management. And it's all kinds of management. So very different. So people really use that new information very differently and it will still be the case because we have no guiding book. So I think now, the next trials, and what I'm really happy about is that everybody agree now that when you design a trial, you insert PSMA PET in your study design and you will be able to sort out, but we will not have the answers right now. It'll take years and years and until then, people will be free to use information as they want and we don't know really what's the best answer.
So at UCLA, we try a lot on leveraging the fact that we are starting early PSMA PET, so we have a little bit more outcome data than other centers that we can harvest now with at 5, 6, 7 years for some patients. So we're working hard on that with other sites, UCSF, of course, to merge data and try to get this outcomes data. Then there are, and then I think the next thing is how to... it's not PSMA imaging, per se. It's more the PSMA-targeted therapy, how to use imaging for better selection, maybe for PSMA-targeted therapy, how to refine the use of PSMA-targeted therapy, the stage and treatment sequencing, number of cycles. So we can really refine the use of PSMA PET and the use of PSMA-targeted therapy.
And then, there is all the new targets, the new radionuclides, the new techniques. You have new tracers coming. Some are targeting PSMA with copper. We have just a new FDA approval for a new PSMA PET tracer from Blue Earth. You have all the new treatments, so many radiopharmaceutical-based imaging and therapy techniques coming for prostate cancer patients.
Phillip Koo: That's great. So I think right now, what I'm hearing is it's going to be a little bit more art than signs and hopefully, the signs is going to follow, which I'm sure it will now that we have all these trials that are incorporating PSMA PET, so very exciting time and we'll have a lot more answers in the years to come.
So thank you very much for joining us, Jeremie.
Jeremie Calais: Pleasure.
Phillip Koo: And we look forward to talking to you again.
Jeremie Calais: Yep, always a pleasure.
Phillip Koo: Hi, my name is Phillip Koo, and welcome to UroToday's coverage of ASCO 2023. Today, we're fortunate to have with us Jeremie Calais, who's going to speak to us about the EMBARK trial and what the patient population would look like with PSMA PET. So before we dive into it, I'd like to refer the listeners to go watch the video with Alicia and Neal Shore that talks about the EMBARK trial that was first presented at AUA 2023, which is a link that we'll have below.
It's interesting. When EMBARK was started, I believe the first patient was recruited in 2015, which is eight years ago. So clearly, a lot of things have changed and the biggest one is PSMA PET. So can you talk to us about how that patient population would've been characterized had PSMA PET been performed?
Jeremie Calais: Yeah, sure. Thank you so much for inviting me. My pleasure to be here, giving me the opportunity to present this work and others that we presented. This work, the EMBARK-like study, was run by Wesley Armstrong who is our MD/PhD student and so I really thank you, thank him, and speak on his behalf. And then we have other projects from the UCLA team that we presented that go more or less in line in this topic, which is the stage migration and how we use the new information based on PSMA PET and all the questions that arise coming from a new technique and a new method and a new finding. So for the EMBARK, you're right. In 2015, PSMA PET was not existing, so it's not part of any screening.
But then now, the data is mature. They're putting out their data, but everybody's using PSMA PET now. So how do you interpret these results with PSMA PET? And this question, we have it for every trials, right? We had it for the SPARTAN population. There is another abstract that is presented there. Basically, all the trials that are using the metastatic setup based on conventional imaging, you have to redefine that. So we look back, retrospectively, to just see what an EMBARK-like population would look like on PSMA PET scan. We're about to find 200 patients that were the EMBARK like characteristics, so BCR high-risk, PSMA must be at least one or both after surgery. So it's not the salvage radiation therapy one. It's more the above that or two after above the nadir with the PHOENIX criteria for radiation therapy recurrence and the doubling time of less than nine months. So aggressive high risk, steep curve of the PSA incline.
And in that series, we detected metastatic disease in up to 45% of the patients. And it was polymetastatic, more than five lesions in about 10% of the patients. So what we do with that, we're not sure this work is just a first attempt to describe in the patient that was BCR, pure BCR. So the disease that we know is just based on the blood test, nothing that we visualize. Now we see it. So it doesn't tell you what we'll do with that. And I think it's good to know because we'll have that. We'll have a label that will say something and then the patient will have the scan, will have these findings. Where do they fit? Would they still benefit from the drug or not? That will be something.
But we have that for many other settings, so for the CRPC population, for example. Non-metastatic CRPC and so here, it was really saying non-metastatic. We are identifying half of the patients, again, metastatic disease by PSMA PET. So you have really this stage migration and this study, there is one that we studied with many other groups. We had the multicenter retrospective study that was led with our German colleagues and that was presented here again. And we did the first study few years ago showing exactly like the same thing with the EMBARK, very descriptive, single time point. This is how it looks on a PSMA PET scan.
And now, this year at ASCO, was presented the follow-up study looking at overall survival to see what the PSMA PET scan findings were predictive of or prognostic of in that patient population. You can see that when metastatic disease was discovered, many patients were switched to systemic therapy as a main result. But many got, still, some kind of radiation therapy, so it was real world data, so there were various types of management. And at the end, again, as always, the more lesions you see on the PSMA PET scan, the worse the outcome gets.
Phillip Koo: Sure. So it's interesting. You talked about it with PROSPER, SPARTAN, ARAMIS, those trials that were looking at the non-metastatic CRPC population and that was all based on conventional imaging. And now, we're seeing something very similar now in patients with now high-risk biochemical recurrence. We've talked about this before, but really, this idea of non-metastatic, we really need to somehow indicate whether it's with conventional imaging or whether it's with PSMA.
What advice do you have for, let's say, the urologist or radiation oncologist or medical oncologist who's managing that patient with high-risk biochemical recurrence, their approach to getting PSMA and interpreting those results now that we have the EMBARK data.
Jeremie Calais: So if your intent was to use a systemic therapy approach, I think this should not be changed based on the PSMA PET findings. You rely on the data. These are the same patients. Now, on a short term basis, before we can harvest more mature data on how to use the PSMA PET findings with the defined management, I would say that maybe you can consider irradiate the lesions that you see, that that's a possibility. In very rare cases, maybe the volume of disease would be so high that you would maybe try to intensify with a combination or doublet therapy or almost in a CRPC-like setting. That would be the first insight I could guess that you can do in that patient population in which you would already intend to use a systemic therapy agent.
And if you don't see any disease, I don't think you should avoid any therapy. I think deescalation based on PSMA PET scan findings is really not possible. In another study we show that even when you don't see the recurrence and you irrigate that location such as the prostate beds or the pelvic lymph nodes, patient do better, even when it's negative on the scan. So you cannot use only what you see on the scan to not treat.
Now, in the systemic therapy indication, we don't have a good answer. And what I'm very happy is that we have now many ongoing clinical trials that try to answer these questions that are randomizing patients based on specific PSMA PET patterns and specific management. So if you have a positive PSMA PET scan, you would do that treatment versus that treatment. If you have a negative PSMA PET scan, you do that treatment and that treatment and there, we will be able to answer some of these questions.
For now, we were really in an interesting paradigm. Like you say, it's about the time. You say in 2015, here was a trial design. Time goes and then new things come and then you end up with the rules that you set up before, conventional imaging rules, for example, that work. It's reliable. We know the outcomes. And then you have a new technology that clearly show it's better than the conventional imaging, but we have no guiding book, no rules, no cooking recipe on how to use these new findings. So how you deal with that?
You cannot ignore what you see on the scan, but you don't have the best proven way to use this new findings and the value of it. Of course, this disease you see on the PSMA PET scan is usually of not as bad prognosis as what you see in conventional imaging. Like a metastasis that you don't see in conventional imaging and you see on PSMA PET is probably not as bad. And there are some studies that now show that the over-survival of patient with metastatic disease seen only by PETS, they do much better than the one with metastatic disease seen by conventional imaging and PET. So they're not the same value.
So we just have to run new trials, know how to try to understand how to use better this information and the stage migration effect. But we are on that zone, where based on the, I would say, almost the sensitivity of each physician and patient, they would say, "Okay, I don't know how to use it. I prefer the old data that I know" or say, "Okay, look, the disease is there, we have to act on it, and we'll try that." And you will have these two approaches. I don't know what's the best idea.
Phillip Koo: Sure. So I would agree, I think in order to get those results we should stick to the EMBARK trial as close as possible and use conventional imaging. And with PSMA PET, exactly, we have that stage migration. We have the potential for the Will Rogers effect, which we have to sort out. But I think in the long term, having PSMA PET and being able to stratify those patients a little better and more accurately will hopefully, and I believe it will, lead to better outcomes, but it obviously needs to be studied.
Anything else that you're working on that is going to help us, let's say, in the next one or two years sort of navigate a lot of these unclear, murky waters that we're now sort of seeing more and more often with the wider use of PSMA PET?
Jeremie Calais: So again, I think we had this retrospective analysis on patients that got their PSMA PET scan since 2016 at UCLA. We started early compared to other United States sites and we're collecting the data and see how this impacted their outcomes and management. And it's all kinds of management. So very different. So people really use that new information very differently and it will still be the case because we have no guiding book. So I think now, the next trials, and what I'm really happy about is that everybody agree now that when you design a trial, you insert PSMA PET in your study design and you will be able to sort out, but we will not have the answers right now. It'll take years and years and until then, people will be free to use information as they want and we don't know really what's the best answer.
So at UCLA, we try a lot on leveraging the fact that we are starting early PSMA PET, so we have a little bit more outcome data than other centers that we can harvest now with at 5, 6, 7 years for some patients. So we're working hard on that with other sites, UCSF, of course, to merge data and try to get this outcomes data. Then there are, and then I think the next thing is how to... it's not PSMA imaging, per se. It's more the PSMA-targeted therapy, how to use imaging for better selection, maybe for PSMA-targeted therapy, how to refine the use of PSMA-targeted therapy, the stage and treatment sequencing, number of cycles. So we can really refine the use of PSMA PET and the use of PSMA-targeted therapy.
And then, there is all the new targets, the new radionuclides, the new techniques. You have new tracers coming. Some are targeting PSMA with copper. We have just a new FDA approval for a new PSMA PET tracer from Blue Earth. You have all the new treatments, so many radiopharmaceutical-based imaging and therapy techniques coming for prostate cancer patients.
Phillip Koo: That's great. So I think right now, what I'm hearing is it's going to be a little bit more art than signs and hopefully, the signs is going to follow, which I'm sure it will now that we have all these trials that are incorporating PSMA PET, so very exciting time and we'll have a lot more answers in the years to come.
So thank you very much for joining us, Jeremie.
Jeremie Calais: Pleasure.
Phillip Koo: And we look forward to talking to you again.
Jeremie Calais: Yep, always a pleasure.