Molecular Imaging for Prostate Cancer Salvage Radiotherapy Planning - Jeremie Calais

Lead investigator, Jeremie Calais, discusses the results of a head-to-head comparative trial of 18F-fluciclovine and 68Ga-PSMA-11 PET/CT for localization of prostate cancer biochemical recurrence after primary prostatectomy. He also discusses a currently enrolling randomized trial of PSMA PET/CT based salvage prostate radiotherapy.  The purpose of this research study is to determine whether 68Ga-PSMA-11 PET/CT can increase the success rate of salvage prostate radiotherapy.

Biographies:

Jeremie Calais, MD, MSc Assistant Professor at the Ahmanson Translational Imaging Division of the Department of Molecular and Medical Pharmacology at University of California, Los Angeles (UCLA), Los Angeles, CA

Sumanta (Monty) Kumar Pal, MD Associate Professor, Department of Medical Oncology & Therapeutics Research; Co-Director, Kidney Cancer Program, City of Hope

Read the Full Video Transcript

Monty Pal: Welcome to UroToday. It's a real delight to have with me Jeremie Calais, who's a superstar nuclear medicine researcher at the Ahmanson Center for Translational Imaging at the UCLA Urology Oncology Institute. UCLA plays very near and dear to my heart, Jeremie, I trained there. Lots of fond memories. And you do this really amazing imaging work, so tell me a little bit about what you're focused on, and in particular, maybe start with a little background on PSMA PET, if you will.

Jeremie Calais: So, yes. At UCLA we have developed this PSMA Theranostic Clinical Research Program. So, it's currently mostly focused on prostate cancer. PSMA is a protein that is overexpressed at the surface of the prostate cancer cell. Now we have new molecules that can bind to this protein and with this, you can do either imaging if you put the imaging probes, which has gallium for PET/CT imaging. Or you can also do treatment, for example with lutetium and with better targeting. So we have developed this whole clinical research program around PSMA for broad indications of prostate cancer. You can do it for initial staging, so then you'll have the primary tumor and you want to detect if the disease has spread out of the prostate or not. You also have another indication that is the recurrence. Patient has been treated once for their prostate cancer, either by surgery or radiation therapy. We monitor them with the PSA, PSA is rising up again, and we do this imaging scan with this PSMA protein detection to try to find out where the disease is recurring. 

Monty Pal: Got it. And with the clinic, the other big competitor that I've heard of is Axumin®.

Jeremie Calais: So currently in the U.S., PSMA has been developed really mainly in Germany before. Like a little bit... A decade ago. In the U.S, on the market you have this Axumin® PET/CT probes, so it's fluciclovine, it means this time it's not a protein that you target, it's a metabolic tracer. It means that we look for amino acid metabolic activity. It's known that prostate cancer cells have increased amino acid metabolism and so with this probe you can target this increased metabolism. 

Monty Pal: Very interesting. So now I guess the big question is, which is better, right? PSMA PET, Axumin®? You actually have a little bit of data here at ASCO GU 2019, about that. Tell us about that.

Jeremie Calais: Yes, let me tell you a little bit of a story about that. I came here in 2016, we were developing the PSMA research program, writing the protocols to submit to the FDA to be able to do it. At the same time, 2016, the company who is selling this Axumin® PET/CT PET probe Blue Earth, just got the approval to sell it and use it in the U.S. It was the end of 2016. Because at this time there was no real other technique, PET/CT imaging technique to detect the prostate cancer recurrence, there was no real good technique. There is the choline scan, but it was not very widely available. So, they were able to get it approved and it became the standard of care PET/CT imaging technique for detected the recurrence of prostate cancer.

And by the same time, we were like developing this PSMA research program. We enrolled many patients for the recurrent setting and for some of them, they were arriving with an already done Axumin® scan. And we said, "Oh, that's funny. We can compare the Axumin® scan." And each time, it was the same finding. "Wow, this patient has an Axumin® scan, but look what we can see on the PSMA PET/CT. That's really impressive, this difference."

So, then we had the idea to design a very strict, robust scientific protocol with 50 patients who has both scans at the same time to be able to compare the two imaging techniques.

Monty Pal: That's very interesting.

Jeremie Calais: In this indication.

Monty Pal: And tell me, what was sort of the bottom line finding from that trial?

Jeremie Calais: So, all these patients were recurring after surgery, the PSA was still pretty low, so below two, which is considered still a curative stage. So depending on where you find the disease, where you detect the spots of the disease, you can treat on that. So, we talk about detection rate here, it means the present stage of the patients who has a positive scan, in which we are able to detect some disease. Because in some case, the scan is still negative. And so the detection rate where about something like 60 percent for the PSMA, versus 30 percent for the Axumin®. So almost double the detection rate, in favor of PSMA PET/CT.

Monty Pal: That's a huge difference. You know, you gave us a great background in some of the interviews we've done previously on PSMA PET and Axumin®, and I won't reinvent the wheel here, it sounded as though the bottom line was that PSMA PET seemed to, sort of, outweigh Axumin® in the setting of PSA recurrent or biochemically recurring prostate cancer, but do you have any sense of how we can potentially test this prospectively? It seems like you're working on something related to this, right?

Jeremie Calais: Yes. So here we're talking about an imaging technique that can detect where the prostate cancer is. So that's good. You can show where the disease is through the body, that's a good thing. You can prospectively study the PET/CT performance accuracy, you're having sensitivity, specificity. And all those kind of parameters, which is good for PET/CT imaging technique description. You can compare it to other radiology or any kind of test, but the true question is: Does it really make a difference at the end for patients? Because if we see more of the disease, better the disease, does it really improve the treatment outcome? Does it really cure patients better? This we don't know. 

There was, I think, at least in prostate cancer for sure, there was no PET/CT imaging trial designed and powered for the outcome. So we wanted to find out an answer to this question. The setting here is pretty simple, it's the setting in which PSMA PET/CT performed the best. Detecting where the recurrence is after the first treatment, such as surgery. In these types of patients, when the PSA goes up after surgery, usually the standard of care treatment is radiation therapy to the prostate bed, the prostate fossa, the area where the prostate was before and it has been removed. Prostate cancer is supposed to be gone, but the PSA is rising and usually, it's because some prostate cancer were left there. So, the standard of care treatment for that is to irradiate with radiation therapy, this area.

That works already pretty well, I think it's in more of half of the cases, the patient can be cured with this technique, but in the other half, it can still fail. And then we have this imaging technique that can show where the disease is, either in this area, the prostate fossa, or outside, which was probably one of the reasons of their failure in that case. 

And now we have designed this randomized Phase 3 trial, randomized with two arms. One is the standard of care arm, the patient gets a standard of care, salvage radiation therapy, and the other arm is PSMA PET/CT arm. In this one, we offer the scan for free to patients, of course, it's a randomized trial. They come at UCLA just to receive the scan, then they go back to their radiation therapy center, get the treatments, and the PSMA PET/CT may or may not influence the radiation therapy planning. And then we follow the patient for five years, mainly based on the PSA, and what we see at the end. Does the patients who receive a PSMA PET scan before, actually does better than the one who just gets the standard of care salvage radiation therapy. That's the design of the trial.

Monty Pal: It's a brilliant design, it really seems like sort of a count for that key question related to clinical outcome. Are you guys gonna be looking at toxicities and so forth associated in therapy?

Jeremie Calais: Toxicities is part of the trial as a secondary endpoint. The toxicity of radiation therapy is clearly existing, but here's it's not the main problem. That is true, you can imagine that because you know better where the disease is, you can then focus better the radiation therapy and then decrease the surrounding radiation dose and toxicity to the surrounding healthy organ, that is true. But that's just a secondary endpoint. We are really focusing on: You take the disease, you target this disease, and at the end, it really worked, the PSA stays low forever, hopefully.

Monty Pal: Got it. Do you think you'll have an opportunity there to look at metastasis-free, survival, overall survival?

Jeremie Calais: This is also... So the primary endpoint is the PSA. We monitor the PSA and we compare the two groups, the one group with the PSA that stays as low as long as possible will be the winning group, of course. And then in secondary endpoints, we have put the toxicity, that is true. We'll look also at the metastasis-free survival, that's for sure. These are all the other things we will look at. And it may have a major impact as well.

Monty Pal: And far into the study are you at this point?

Jeremie Calais: So, we have opened in September 2018, so pretty recently. Six months from now, we are at patient 45 or 46 as of today, I think. We have an issue here because one day one PSMA PET probe will be approved by the FDA. It may be pretty soon, in fact, like maybe twelve, eighteen, or twenty-four months from now. In that case, when PSMA will become available, the standard of care approved by the FDA, we'll not be able to randomize patient to the standard arm, of course, who will be willing to receive the scan, whereas he can have it as the standard of care. So we have this short timeframe window in which we need to enroll patients as much as we can and as soon as we can before we reach this limit.

Monty Pal: Absolutely, and if listeners to UroToday, if the folks viewing the program are interested in referring patients, any ideas where they might be able to access the trial?

Jeremie Calais: So yes, the trial is, of course, registered on clinicaltrials.gov, for sure. I think we can put the link in the video to click on it. There we have all the contacts. The workflow is pretty straightforward. The interesting thing we did, one interesting thing we did in this trial design is to be able to consent the patients remotely. So how do we do that? Because we are not including patients who are treated at UCLA only. We're including patients from everywhere. They just come to UCLA only if they are randomized to the PSMA PET/CT arm. To avoid patients coming for nothing, if they are randomized to the standard of care arm, we consent them before by phone, and then we explain the trial design. 

We try to answer all the questions they may have and at the end, we send them the consent form that they can sign and send it back to us, either by fax or email. Then they are enrolled, we randomize them through a software algorithm, and then we communicate with them the assigned randomization arm and if they are to... Randomized to the standard arm, they just go to their radiation therapy center as initially planned. They can start the treatment as soon as they want. And if they are randomized to the PSMA PET/CT arm, then we call them to schedule an appointment to get the scan. Of course, the scan is offered for free, and then after that, they go back to their radiation/oncology center to get the radiation therapy treatment.

Monty Pal: That's a brilliant design, very pragmatic. I've heard about telephonic consent.

Jeremie Calais: Very pragmatic. Yeah, so I do a lot of phone consultation now, it's an interesting exercise.

Monty Pal: Yeah. Yeah, I gotta try that.

Jeremie Calais: Especially with my French accent. Some patients have a hard time to understand me, but in the end, we make some progress.

Monty Pal: Well you made some very understandable, very intelligent points today. We're all looking forward to seeing your study progress along. Best of luck to you, and from UroToday, thanks so much for watching.

Jeremie Calais: Thank you very much.
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