PSMA Targeted PET Imaging of Prostate Cancer, An SNMMI Webinar - Frankis Almaguel & Michael Gorin

December 6, 2022

In this Society of Nuclear Medicine and Molecular Imaging (SNMMI) webinar Michael Gorin and Frankis Almaguel present on PSMA-targeted PET imaging of prostate cancer. Dr. Gorin kicks off the webinar by talking about the basics of PSMA targeted imaging, what the target is, where the need for molecular imaging testing in prostate cancer comes from, what led to their approval, and what agents are available. Dr. Almaguel follows with how PSMA-targeted PET imaging is being used clinically to improve the care of patients with prostate cancer and how molecular imaging is changing the m multidisciplinary approach to treating these patients.

Biographies:

Frankis Almaguel, MD, Ph.D., Director, Molecular Imaging & Therapeutics Program, Loma Linda University Health, Redlands, CA

Michael Gorin, MD, Associate Professor, Department of Urology, Icahn School of Medicine, Mount Sinai, New York City, New York


Read the Full Video Transcript

Michael Gorin: Again, my name is Michael Gorin. I'm on the faculty at the Icahn School of Medicine at Mount Sinai. I've been very fortunate that over the last two years to have participated in the Society of Nuclear Medicine and Molecular Imaging's Taskforce Committee on Prostate Cancer Outreach. Through my involvement with this committee, one of the things we've done is given educational talks like this in different forums. So, I really wanted to thank the SNMMI for organizing today's talk and for making this possible.

Today's presentation is going to be broken up into two separate talks. The first will be by myself. I'll be talking about the basics of PSMA-targeted imaging, what the target is, where does the need for having a molecular imaging test for prostate cancer come from, what are the agents that are available, what led to their approval, and so forth. Then Dr. Almaguel will pick up talking about how PSMA-targeted PET imaging is being used clinically to improve the care of patients with prostate cancer.

So because this is a CME talk, I have to start with disclosures. So relevant to this audience, I have in the past served as the consultant to Blue Earth Diagnostics, to Lantheus Medical Imaging, to Telix Pharmaceuticals. I'm newly now consultant for POINT Biopharma, which also has a PSMA-targeted imaging agent. So having been consultants for all these companies, I think you'll probably get a fair and unbiased point of view from me because I've helped all of them.

So what is the need for molecular imaging, and in particular PSMA PET imaging in prostate cancer? Well, historically, and by historically I mean not so long ago, in the last five to 10 years, we've relied on conventional imaging modalities to help image patients with prostate cancer as opposed to PET imaging, which is more commonly used with other solid malignancies.

So for imaging primary prostate cancer, we relied on multiparametric MRI. While this is a helpful tool for helping us to pick out patients who have prostate cancer, it does suffer in terms of its sensitivity and specificity overall.

In addition to that, there's a high cost associated with this, and perhaps more importantly, tremendous issues with reproducibility. For imaging the entire body, looking for the N and M staging components for a patient, we relied upon CT and bone scan. Like multiparametric MRI, however, these imaging modalities suffer in terms of their performance characteristics, in terms of low sensitivity, in particular with respect to bone scan, as well as issues with specificity and that not everything that you see that appears to be a site of disease will necessarily be one.

It's unfortunate that for prostate cancer, we've been unable to rely upon tools like FDG PET, which have been available for other solid malignancies for a long time. The reason for that is prostate cancer is unique in that it does not display anaerobic glycolysis. And so, it doesn't really take up FDG all that well, especially in the non-castrate state. And so, that has forced investigators to look for other molecular imaging targets and probes for imaging prostate cancer.

That has brought the field largely to imaging prostate-specific membrane antigen. So PSMA is a dimerized type II transmembrane glycoprotein. It does have normal function in the central nervous system, where it's responsible for hydrolyzing N-acetylaspartylglutamate to glutamate in its role through CNS signaling. That's where it was first discovered.

It's also found to function in the brush border cells of the jejunum, where it's responsible for folate uptake from our diets. But where it's had an impact on prostate cancer is the fact that it's overexpressed by prostate cancer epithelial cells. It's also expressed by normal prostate epithelial cells, but its expression goes up considerably in prostate cancer, as does the accessibility of the antigen. And so, it has served as a very good molecular imaging target.

Interestingly, PSMA is also found in the neovasculature of a number of other solid malignancies. As a urologist, I've had a strong interest in using PSMA for imaging renal cell carcinoma. Myself and my research partner Dr. Steve Rowe, who's at Hopkins, we've published a number of publications on just how helpful PSMA-targeted imaging could be for imaging that malignancy.

So, again, PSMA is highly expressed by prostate cancer. Its degree of expression seems to increase both with Gleason score ... So the more aggressive the tumor, the more PSMA it has expressed ... as well as the increasing stage of the tumor. This, to some extent, has to do with the fact that the tumors are simply larger, and that's why we see more PSMA expression. But also on a per cell basis, we see a considerable upregulation of the PSMA protein. It's estimated that approximately 95% of all primary prostate tumors will show PSMA expression.

I should note that in advanced stages of the disease where the patients have had selective pressure, with things like androgen receptor blockers, as those tumors start to transdifferentiate into the neuroendocrine phenotype, there will start to be a loss of PSMA expression. But by and large, for the majority of patients that we're going to be imaging with PSMA-targeted imaging, there will be an abundance of expression in their tumors.

So the PSMA molecule has been targeted in a handful of ways for both imaging and therapeutic applications. Here's a diagram from one of Dr. Maurer's publications in Nature Reviews Urology which looks at the three major ways that the molecule has been targeted over the years.

The first way it was targeted is using antibodies to the intracellular epitope using what's known as the 7E11 antibodies. This is actually the antibody that in the past had been labeled and used for SPECT imaging and its form name is ProstaScint. This imaging agent, however, quickly fell by the wayside because the imaging quality was quite poor being SPECT. But even more importantly, the radiotracer had a very hard time getting inside the cells to allow for clean, crisp images of blood pool activity. And so, again, this has fallen by the wayside.

There are other antibodies to PSMA. The J591 antibody binds to an extracellular epitope of the molecule. This has been explored for both imaging and therapeutic applications. However, it seems that from an imaging standpoint, it makes more sense to use small molecules because of their rapid uptake and quick clearance from the blood pool, unlike antibodies. And so, the J591 antibody is largely now being used for therapeutic applications.

So PSMA, for at least imaging purposes, is largely targeted through small molecules which bind to its active site. The most common or the most frequently used class of small molecules for targeting the active site of PSMA is what's known as the urea-based small molecules. In just a moment, I'll show you some other urea-based molecules that bind to PSMA.

This is the one that's been most widely published on in the literature, what's known as gallium PSMA-11. This has, again, a urea moiety to it which binds to the active site. Then there's a linker molecule and a portion of the molecule which is responsible for binding to gallium-68, which makes it possible to be used for PET imaging.

So in the United States currently, we have two agents which are approved for PSMA-targeted imaging. Again, we have the PSMA-11 molecule labeled with gallium-68. Both Telix Pharmaceuticals and Cardinal Health make kits for labeling this molecule with gallium. I'm sorry. Telix makes the kit for it, whereas Cardinal Health will make the radiotracer for you and deliver it to your site.

In contrast to that, we have an F-18 labeled molecule, again with a urea moiety to it, but this time labeled with F-18. This molecule what was formally known as DCFPyL now goes by Pylarify as marketed by Lantheus Medical Imaging.

There are, though, other urea-based small molecules, which you'll see in the literature, and one in particular that you'll probably start seeing in clinical use once it gets approved by the US FDA. The first of these molecules is PSMA-1007. This, again, is a urea-based small molecule that's F-18 labeled. This one does not have a commercial backing, at least yet, in the United States. But we also have rhPSMA-7.3, which is a molecule that is owned by Blue Earth.

As I understand from a press release from just a few weeks ago, a new drug application has been put into the FDA based on the results of the LIGHTHOUSE and SPOTLIGHT trials. We'll probably see this agent approved in the United States as a third commercially available agent for targeting PSMA.

So using any one of these urea-based small molecules for imaging prostate cancer, we're able to achieve really spectacular images. This is just one example from a phase II trial I was a part of evaluating DCFPyL. We have the MIP image here and then some fused axial PET/CT images where you could see these very, very small lymph nodes detected in this patient prior to radical prostatectomy that could not be seen on conventional imaging.

We're able to pick out these tiny little Virchow's lymph node right here in this patient. These are sites of disease that we never, ever in a million years would've known about on the basis of CT, MRI, or bone scan. So it's really afforded us really some spectacular images to make clinical decisions for patients.

So first I'll start with what are the important differences between the PSMA-11 and the DCFPyL molecules, and then I'll talk about the performance characteristics of these in the context of the trials that led to their approval by the US FDA.

So major differences here. So gallium-68 has a half-life of 68 minutes, where F-18 has a half-life of 110 minutes. So because of that, F-18 is more amenable to central production with distribution to distant sites because of that extra 40 minutes of half-life. In addition to that, F-18 is made with a cyclotron, so you can make up very, very large quantities of radiotracer with which to then be able to distribute from your centralized production facility.

In contrast to that, gallium-68 uses a generator. And so, a smaller amount of radiotracer could be produced at any one time. Because of the only 68-minute half-life of the radiotracer, it becomes more logistically challenging. That's not to say it's not possible, but logistically more challenging to distribute the gallium-68 labeled radiotracer. That's from a production and accessibility standpoint.

Now there are some reasons to believe that the F-18-based radiotracers, not just DCFPyL but all F-18 labeled radiotracers in general, could achieve superior imaging quality than the gallium-68-based radiotracers. And so, that has to do with some of the physical properties of F-18.

In particular, the F-18 is a lower energy radionuclide than gallium-68 by approximately three and a half-fold. And so, because of that, the average path length to annihilation is much shorter with F-18 than it is with gallium-68. And so, because of that, you get less scatter and diffusion of the imaging. The continuity of the images are much higher with F-18 because the source of the positron emission is closer to where the annihilation event occurs for PET detection.

In addition to that, there's higher positron yield with F-18 relative to gallium-68. So per 100 disintegration events, you see more positron emissions with F-18 than you do with gallium-68 by roughly about 5% to 6%.

Here's just graphically a summary of those concepts where we could see F-18 has a more narrow energy spectrum than gallium-68 does. If you look at the tracks left in terms of positron emission events, you can see they've traveled much further with gallium-68 than they do with F-18, leading to, in theory, higher resolution with F-18-based radiotracers than gallium-68.

In truth, there have never really been any head-to-head trials where the same patients are contemporaneously imaged with an F-18-based radiotracer and a gallium-68-based radiotracer against PSMA. So it's all supposition in that this would lead to improved image quality. There have been in particular two studies that were done by Dietlein and coworkers in Germany, where they looked at this question but not really within the confines of a well-done clinical trial.

There seems to be a suggestion that the F-18 radiotracer is more sensitive and leads to higher SUV max values. But there are a number of problems with those data, which I won't get into now. But I think between the physical properties and what little data there is, there probably is some truth to this.

So what are the applications of PET imaging in prostate cancer? I stated earlier on that we lack sensitivity and specificity with those conventional imaging modalities. Well, where is it in the care of patients with prostate cancer that we could potentially benefit from improved imaging modalities? So I'll go through each of those right now, and then I'll talk about the two which have been enumerated in the labels of both gallium PSMA-11 and Pylarify for use in imaging prostate cancer patients.

The other applications I have here are ones that, in theory, the PET imaging could prove useful for, but we don't have enough data yet for it to make it into the label.

So the first application is to potentially guide performance of prostate biopsy. I talked about multiparametric MRI being used for this application. Well, there has been some work, in particular the PRIMARY trial out of Australia, which has shown about a 5% to 10% improvement in the detection of prostate cancer if the patient undergoes a PET scan in addition to a multiparametric MRI.

There seems to be a utility in initial staging of patients who are thought of being risk for harboring otherwise occult metastatic disease. So your patients with high-risk, otherwise clinically localized or unfavorable intermediate risk prostate cancer, who you think have clinically localized disease but are certainly at risk for having nodal metastases or widespread disease, imaging those patients with a PET scan would be very helpful, and whether or not to direct those patients to something like a systemic therapy or systemic therapy in combination with radiation, as opposed to just simply surgical removal of their prostate.

There are applications in directing therapy upon biochemical failure following failed local therapy. There's also thought that PSMA-targeted radiotracers could be useful in confirming the extent of disease in patients who are felt to be oligometastatic and perhaps could benefit from metastasis-directed therapies rather than starting them on a systemic therapy.

There's the potential for it to be helpful in judging response to treatment. Although this is one of the areas where we probably have the least data in. Now that we have a lutetium PSMA-617 approved for therapeutic purposes, we could use PET imaging to guide patient candidacy for this type of therapy. That's going to be covered in the second portion of today's talks.

So what are the indications for use currently? Well, of that list I've given you, the indications for use present are to image patients who are suspected of having metastatic disease, who are candidates for initial definitive therapy, and for imaging patients with recurrence based on a rising PSA level. I'll show you the performance characteristics now, these imaging agents, within these two context that are on the label, and how we got them approved for that purpose. So I'll start with imaging patients suspected of having metastatic disease, who are candidates for initial definitive therapy.

So in terms of registering Pylarify, there was a trial known as the OSPREY trial, which I was fortunate enough to participate in, which was published in the Journal of Urology in 2021, which led to the approval of the imaging agent for this indication. There was also the PSMA-PRP study, which was a dual-site trial between UCSF and UCLA, led by Thomas Hope at UCSF, that led to the approval of PSMA-11 for this indication.

Recall I had said that rhPSMA-7.3 is likely to be the next up for approval, and Blue Earth has completed the LIGHTHOUSE trial. They've yet to share with the world the data on that. But judging by the fact that they submitted a new drug application just two weeks ago to get the drug approved, I suspect there were positive results from that trial.

So the OSPREY trial, how was this done? So there were two cohorts to the OSPREY trial. One of them was patients who had higher, very high-risk prostate cancer who are already scheduled to undergo radical prostatectomy and pelvic lymph node dissection. These patients, they underwent a PSMA PET scan prior to surgery. Urologists then went ahead and performed the prostatectomy and also a pelvic lymph node dissection. It was those pelvic lymph node packets that then served as the gold standard with which to compare the imaging test for calculations of sensitivity and specificity.

There was also a second cohort known as cohort B. These were patients who had metastatic disease on conventional imaging and then underwent PSMA PET scan. What we were looking there to demonstrate was that with a high degree of detection efficiency, those lesions that were found on conventional imaging and known to be metastatic were also positive on PSMA PET. We biopsied a good number of those lesions and demonstrate that that was in fact the case.

Not a terribly interesting arm of the study. It was more so just to really definitively prove that what we were imaging was prostate cancer. But not one that's terribly interesting from making gains in the care of prostate cancer patients, because these folks already have widely metastatic disease and we didn't necessarily need PSMA to know it.

So in terms of preoperative staging, these are the data from the OSPREY trial. Recall that patients who entered the OSPREY trial already had clinically localized, very high-risk disease, and were felt to be N0 at trial enrollment. Having imaged them with clarified PET, we found a sensitivity of the radiotracer for any volume of disease in the lymph node packets of 40.3%, with an outstanding specificity of 98%.

We did a post hoc analysis of these data and considered what was the sensitivity and specificity if we limited the analysis to pelvic lymph nodes that on histology measured greater than five millimeters. The reason we did this is because after the fact, we felt it was unreasonable to think that we were ever going to be able to detect the lymph node that had only one or two prostate cancer cells that the pathologist was able to see under the microscope. We were never going to be able to repeat that with PET/CT scan.

So we gave ourselves a goal with lymph nodes greater than five millimeters. Less than one centimeter or less than centimeter and a half would be demonstrable gains over CT, which normally you need lesions that size to be able to call them positive unconventional imaging. So we were able to give ourselves probably a more fair truth standard, but also demonstrate that if we go down to these small lymph nodes, we are able to detect them. What we found is that the sensitivity at that point increases to 60%, but the specificity is maintained at roughly 98%.

The same was shown by Dr. Hope and coworkers at UCLA and UCSF using gallium PSMA-11. Very, very similar trial design where patients with high-risk disease underwent radical prostatectomy, pelvic lymph node dissection, and they found a sensitivity of 40% and a specificity of 95%. So essentially the same thing that we saw in the OSPREY trial.

So the use of PSMA-targeted imaging for initial staging in terms of its utility has been studied in a trial known as the proPSMA trial, which was put on by Michael Hofman and colleagues at Peter Mac Cancer Centre and other centers in Australia. What they did is they randomized patients who are initially diagnosed with prostate cancer to undergo conventional imaging with CT, MRI, bone scan, or with PSMA PET/CT. Then they had a truth standard which incorporated some follow-up endpoints as to what the patient's true TNM stage was, and then compared the ability of conventional imaging versus PSMA PET to accurately predict what the patient's overall TNM stage was eventually declared to be.

Not surprisingly, they felt that PSMA PET had a markedly higher sensitivity for detecting any metastatic disease, nodal metastatic disease, and distant metastatic disease, so bony disease and visceral disease, as compared to conventional imaging, while both modalities had a high degree of specificity, where PSMA really shined in its added sensitivity for detecting the sites of disease in accurately determining cancer stage. By more accurately classifying a patient stage, the thought is that you could then administer to them more appropriate therapies down the line.

It is worth stating, though, at this point that there has never been a trial demonstrating that if you take patients who were assigned a clinical stage with conventional imaging mode of therapy and then assign patients on the basis of PSMA PET scan mode of therapy and then compare them for, say, benefit in terms of overall or cancer survival, that's never been done. So we don't know that the more accurate staging confers improved treatment outcomes for patients, but at least now we have a starting point where we could potentially do that in the future.

So now moving on to the second indication, imaging patients with suspected recurrence based on an elevated PSA level. What we're really talking about there is patients with what is known as so-called biochemically recurrent prostate cancer. So these are patients who have undergone definitive treatment for prostate cancer. They're being followed with their PSA levels. The PSA level now starts to rise.

In the past, we had imaged them with conventional imaging, with CT bone scan or MRI and we are unable to find sites of disease. So these are patients who pose a significant clinical conundrum. What do you do with them? Now, for the first time, we have a molecular imaging technique which helps us sort that out.

So this is why that's important, because patients with PSA persistence or biochemical recurrence, they have a myriad of treatment options available to them. This is what patients who have undergone radical prostatectomy have available to them. These are the latest treatment recommendations from the NCCN. We could see that those patients could undergo salvage treatment with external beam alone. They could undergo salvage treatment with external beam plus androgen deprivation therapy, or they could undergo no treatment at all, simply with monitoring.

If the patients have positive pelvic lymph nodes, those patients can undergo treatment with external beam and androgen deprivation, plus or minus the addition of abiraterone. In contrast, the patients who have distant metastatic disease, they're not a candidate for salvage therapy, and instead they undergo treatment purely with systemic therapy.

So knowledge of where the patient's disease is has ramifications in which one of these very different treatment approaches these patients get. It gets even more vast in terms of the treatment options for patients after failed radiation therapy. These patients can undergo just simple observation.

They could be treated systemically with androgen deprivation therapy. They could undergo salvage local therapies with brachy or cryoablation or high-intensity focused ultrasound. Alternatively, they could undergo pelvic lymph node dissection. Many options for these patients. And so, again, it would be very helpful, rather than just guessing based on clinical parameters, to have imaging evidence of where the disease is so you could best treat these patients.

So what were the registration trials that led to the approval of these imaging agents in the space of biochemical recurrence? Well, with Pylarify, it was what was known as the CONDOR trial. Again, I was fortunate enough to have participated in this trial. With gallium PSMA-11, there's data from UCLA and UCSF once again, and this trial was known as a PSMA-BCR study.

From Blue Earth Diagnostics, in terms of rhPSMA-7.3, the trial to look out for is what's known as the SPOTLIGHT trial. Some data was shared from this trial at the most recent ASCO GU. The publication is going to be forthcoming on that.

So I'll talk about the trial that I was involved with, the CONDOR study. So in the CONDOR trial, we had patients who had biochemically recurrent prostate cancer. We imaged them with DCFPyL PET/CT. Prior to imaging, we administered to the clinicians a questionnaire, asking them, "How would you manage this patient given the disease characteristics and the history that they have?" After undergoing the PSMA PET scan, the clinicians were given the results of the PET scan and perhaps new treatment decisions were made about that patient. We learned what the intended treatment was from the clinicians in a post-imaging questionnaire.

The pre and post imaging questionnaires allowed us the ability to look at how often changes in managements occurred. But the more important aspect of the study is we had a truth standard by which we then compared the actual results of the PSMA PET scan to know how often the imaging test, one, was positive and, two, how often it was positive at different sites, and how did that compare to the truth standard in terms of level of accuracy here for correctly localizing sites of disease.

The composite truth standard included things like the ability to undergo biopsy or surgery of sites of disease. We allowed for additional, more sophisticated forms of conventional imaging. So, for example, if a patient was found to have a bony metastasis on PSMA PET scan, we then allowed for, say, a tumor protocol MRI of that particular bone to be performed to then allow us to confirm the diagnosis.

We also allowed for imaging with Axumin PET, which at that time was clinically available for imaging prostate cancer. The thought was, well, Axumin is an approved modality. It's felt that things that are positive on Axumin R&D prostate cancer. So if it's positive on Axumin and PSMA, therefore it most likely is prostate cancer. So we worked that into the composite definition.

Then we also allowed patients who were undergoing radiation therapy without ADT, if they had an irradiated site of disease that was visible on PSMA PET scan, and we subsequently saw a PSA change, then it must have been a site of disease which was imaged. So, again, that was a composite truth standard.

So looking at the overall cancer detection rate using DCFPyL, we found that the detection rate varied by PSA level. Even at the lowest PSA levels, we were able to see sites of disease. So in patients with PSA levels less than 0.5, we saw an overall detection rate of 36.2%. This went all the way up to 97% in patients with PSA levels of five or greater.

Similar studies have been done by ... Sorry, this slide is out of order here. So before I get to gallium PSMA-11, just a few more comments about the CONDOR trial. So, again, we had administered pre and post-imaging questionnaires, and what we had found is that roughly 64% of patients underwent a change in their management after receiving the PSMA PET scan. These changes occur 80% of the time on the basis of a positive PET/CT and, in 21% of cases, on the basis of a negative PSMA PET scan.

What do those changes look like? Well, in 21% of cases, patients underwent a de-escalation in therapy from systemic therapy to local salvage therapy. 28% of patients underwent an escalation in therapy from local salvage treatment to systemic therapy. Additionally, we saw a fair number of patients, 23.9%, underwent an escalation from observation to any form of therapy, and in 4.4% of patients, a de-escalation from some form of therapy down to observation. So, again, a significant number of changes in management, both escalation and de-escalation of therapy, on the basis of both positive and negative scans.

The same has been shown for gallium PSMA-11. The change in management was demonstrated in 53% of cases who underwent one of those scans as part of the trials done on the west coast.

As a result of these studies, again, PSMA-11 and DCFPyL have achieved approval from the United States Food and Drug Administration and have now found their way into the latest versions of the NCCN guidelines. I don't expect you to be able to read this slide, but what I wish to show you, though, is that now there's a rather robust discussion in the NCCN guidelines about the use of PET imaging for prostate cancer, whereas at one time it was rather short and it simply said FDG exists, don't use it for prostate cancer.

We have sodium fluoride PET. Yes, it's very sensitive, but it's never been demonstrated to lead to any clinical benefits in patients, so avoid using it in place of bone scan. But now we have this really robust discussion about where PET imaging should be used in the care of prostate cancer patients.

I'll draw your attention to bullet points here. The first is that PSMA-11 or Pylarify, PET/MRI or PET/CT can be considered as an alternative to standard imaging in the initial staging or in the workup of patients with biochemically recurrent prostate cancer.

The guideline specifically states that you do not need to obtain now conventional imaging with CT or bone scan prior to ordering the PSMA PET scan because PSMA PET has been shown to be equally effective, if not more effective, frontline imaging tool for imaging these patients. So this should really now be the de facto standard of care anytime you need to image of prostate cancer patient to reach for PSMA PET, so long as they meet the labeling criteria.

The Society of Nuclear Medicine and Molecular Imaging, they've also put together appropriate use criteria, as they've done for other disease states and other imaging tests, for imaging patients with PSMA PET scan. Not surprisingly, they've given the appropriateness label to imaging patients who are newly diagnosed, as well as those who are diagnosed with biochemically recurrent disease.

There's some lower levels of appropriateness for using it for the other indications that I had outlined in my earlier slide. But I imagine this will change as additional data comes out in using PSMA PET for things like, again, prostate biopsy, judging response to therapy, and so forth.

So I had alluded to this point earlier, and that is does the improved sensitivity afforded by PSMA PET imaging lead to any tangible benefits in patients in terms of their overall cancer-specific or perhaps metastasis-free survival? We know that management is changing, but is that management leading to any benefit?

So there is a trial that's ongoing right now which is going to answer this question. In this study, patients are going to be randomized to salvage radiation therapy after biochemical recurrence from radical prostatectomy, as determined by conventional imaging and clinical parameters. So the radiation oncologist is going to decide what the radiation field is, is it the prostate only, the prostate plus the lymph nodes, and so forth, simply on the basis of the conventional imaging versus patients are randomized to an arm where salvage radiation therapy is going to be directed on the basis of the results of the PSMA PET scan. The authors are going to compare the clinical outcome of disease-free and cancer-specific survival to look to see if patients did better with PSMA-directed salvage treatment.

While the study has not yet been completed in using PSMA PET imaging, we do actually have data using Axumin, which most of the audience should be aware. Axumin is an amino acid-based analog. It's labeled with F-18. It is approved for prostate cancer PET imaging. But because it's an amino acid analog that's simply taken up by rapidly dividing cells, it lacks the level of specificity that we have with PSMA. So it's largely now been replaced by the use of PSMA.

But, anyway, this was an imaging modality that's been used for the last few years for patients with prostate cancer, and a trial of the design that I just mentioned has actually already been completed and reported out. That's what's known as the EMPIRE-1 trial.

So, again, patients were randomized to receive radiation therapy on the basis of conventional imaging and clinical parameters, whereas in the other arm, patients on the basis of the Axumin PET scan were then prescribed a radiation treatment plan.

So those patients who are found to have M1 disease, radiation therapy was aborted. They were taken out of the study and given standard of care systemic therapy. If there was no uptake on the Axumin PET scan or uptake in the prostate bed only, then those patients underwent prostate bed radiation only. If, however, patients were found to have lymph node uptake of the radiotracer, they got prostate bed radiation as well as radiation to their pelvic lymph nodes.

So these are some data from the trial showing you what the change in management looks like in the arm of patients who were randomized to PET-directed therapy. So, initially, roughly half of the patients were felt to be amenable for radiation therapy simply to the prostate bed. 43% of patients were going to get radiation to the bed and lymph nodes. Then all patients underwent a PET scan, and then the treatment was assigned based on that result, what you see is pretty significant changes in management to these patients.

One-third of all patients who were originally only going to get radiation to their bed, they now all of a sudden were going to get radiation to the bed and the lymph nodes. Four of the patients out of 34 in the prostate and lymph node group were actually thrown out and got ADT only because they were found to have more widely metastatic disease. In addition, 29.4% of patients here, their degree of radiation therapy that was delivered was actually deescalated and they only got therapy to the bed.

So, overall, in terms of the change to the radiation field, one-third of patients in this study saw a change to their field on the basis of the Axumin PET results. In terms of overall change in management, once you account for the folks who were thrown out for androgen deprivation therapy, that number goes up a few percentage points.

So what was the outcome of this? Well, the study found a significant improvement in freedom from disease progression when salvage radiation therapy was delivered on the basis of PET imaging as opposed to clinical parameters and conventional imaging.

So, again, we only have these data for Axumin, but the field suspects and has every reason to believe that the same, if not better, results are most likely going to be seen with PSMA imaging as well.

So this is one disease context in particular where not only do we know that molecular imaging leads to changes in management, but it also, at least when using Axumin, leads to improvements in patient disease-specific endpoints and will likely see the same for PSMA.

So at that, that's where I wanted to finish up, really just describing to you what the imaging agents are, their target, how they were approved by the FDA, and the clinical spaces in which they've been approved to be used. Now Dr. Almaguel is going to take it away and discuss for us some other clinical applications for the radiotracers and some data showing the benefits of them, and think also going to get into radioligand therapy, which as a urologist is not something I do much or any at all of. So thank you very much and take it away.

Frankis Almaguel: All right. I'm going to show you some cool stuff, just because today our time is running out. I'm just going to show you why we are so excited about precision oncology. All that Michael has presented, Dr. Gorin has said, is leading to this. Now we have an imaging modality that is helping us detect the disease earlier and actually help patients.

As you know, in prostate cancer, or any cancer, if you detect the cancer early, you have a better chance. I don't have time to go through this, but if your cancer is detected sooner, you have better chances.

I'm going to show you for a couple of minutes how molecular imaging, this new modality of imaging, and its applicative therapy is changing the way we interact as a molecular imager with the pillars of oncology, radiation oncology, surgery, and medical oncology, and radiation oncology.

Now that you can see the pathology, I mean you can see what the disease is, you can make a lot better decisions. So I'm going to show you, this is a patient of mine, came in, have PSMA imaging as a clinical trial. Came to me after I sent him to get this imaging and we worked together with the radiation oncologist and he had a PSMA-guided radiation, and the results are pretty convincing. This patient had done really well.

I can tell you it is working. What Dr. Gorin has shown, this is an example. This is working for real people, and this has been shown in the past. If you are able to target those metastasis, you have better outcomes. I don't want to go through this because ... I won't show you a little bit more, but the idea is this is not something that has just come out of magic. This is a lot of work through the years, a lot of collaboration.

Probably this slide is very important at a radiation oncology point of view. Sometimes preventing the patient from an unnecessary procedure is key. So this imaging modality not only helped for better decision, but also when not to treat the patients.

So with surgery, I mean Dr. Gorin is a urologist, and I know he'll appreciate having a target. There are a bunch of options for urology to proceed. But having that modality that tells you and helps you predict what is going to happen, this is unique.

In this study, basically you can see here that the Gleason score, of course with the higher Gleason score you have, the lower prognosis. But not only that, once you have the higher uptake of that lesion also makes you think how much this patient needs an intervention and things that you have to change.

So not only we have an imaging modality guiding you what could you do, also you have a modality that is guiding you to see what extra step you have. Also preventing when not to do something is really key. From these studies, you can see if you combine an MRI and a PET CT, like Dr. Gorin mentioned, you have even higher negative value. Some of these research is saying maybe you don't even need a biopsy.

So we'll say there's a lot of research, a lot of things going on, but I can tell you that we are becoming more and more specific. Actually, we have more help.

I will go fast through this, but I can tell you now that you have these modalities, you want to make sure ... Now you have this vision, you have to make sure how do I change my practice? How do I do things different? Instead of blind radiation and also chemotherapy, or having the patients wait, now you can make sure that you have the right therapy for the right patient at the right time. This this is when theranostics comes out.

We don't have that much time, but I can tell you that the principle is that same imaging molecule that you have just seen done wonders for diagnostics, now you can exchange the isotope and now this becomes a paired therapeutic agent. This is basically saying that you are sending this radioactive therapeutic isotope to where you saw those metastasis. This is significantly affecting the way which we treat prostate cancer in the future. As of today, I can tell you that there is a great satisfaction when you can see what you're treating and you can treat what you see.

We don't have time to go through all these trials, but this I want to stress. This has been a lot of work. Randomized clinical trials, first with the therapy trial showing the difference between the lutetium PSMA and cabazitaxel, and significant, really good responses. The VISION trial, of course, changed everything that we have done.

Time is running out, but I wanted to get through to what you're really here for. What is this doing to your patients? We have great trials. You can see this trial is showing that it's not only treating the pictures, it actually increasing life and increasing quality of life. One of the quotes from the interviews after the approval, this is showing that these steps are changing patients' lives. This approval was evidence of all this hard work and showing it in clinical trials.

I'm going to tell you a story about my patient. This is somebody that came with a lot of disease. I mean he had significant side effects, especially metastasis in the vertebral C3. He really had issues that they told him, "Maybe you walk, but walk really careful. That breaks and you'll be a paraplegic."

Now after three rounds of PSMA radioligand therapy, he's been keeping this and this is negative scans for the last two years. This is now evidence that we're not photoshopping the pictures here. This patient now is keen on doing other things.

So I can tell you that there is hope. The good thing is the side effect profile, very low side effect profiles. This is evident because you have a more targeted approach. Of course you're going to have less side effects.

Time is really hurrying now, but I will show you that this is not only one case. This is another of my patients with significant advanced prostate cancer. With this modality, this is changing the way patients do. This is not only a great diagnosis, we have a therapeutic component with this.

This is another of my patient with localized ... I mean with lymph nodes in the pelvis. You don't need to get to advance disease like this, like it has been shown the literature. We need to make sure that we caught this disease earlier and change the way we do things.

At the end of the day, we have to change our thoughts, we have to change the way we do things and, together, make a plan where we all are moving the field forward together.

I'm going to tell you, and I want to end with this, this is just the beginning. There are going to be many theranostic agents coming for multiple cancers. This is going to affect the way we practice oncology.

One thing I can tell is together as physicians and patients, we are in this new era where information is changing the way we do things. If you see how a urologist and a nuclear physician are working together, not only from the imaging side but also from the treatment and seeing those patients and taking care of this journey where they need so much help, I can tell you there is nothing more gratifying than seeing a patient that you're able to change the way they do and to give hope.

The time has run. We'll have a follow up to this. But I can tell you if there is any questions, I would like to open the forum for questions. We have together a future where cancer is going to be treated different. You are part of this now. As physicians, as patient advocates, we can do things that in the past were only a dream.

Dr. Gorin, do you have any ... I know the time has come. We have only five to seven minutes. But I would like to see if there is any burning questions. I mean I know we went through this really fast.

Questions from Audience: Dr. Almaguel, there are questions. I don't know if you can see the chat. There are several questions that have been posted.

Frankis Almaguel: Okay. Can you read one to me?

Questions from Audience: Sure. Can you discuss the use of serial SPECT after Pluvicto?

Frankis Almaguel: Well, that is a key question. SPECT-CT is extremely valuable when you are having the opportunity, because you see lutetium PSMA has this gamma rays that are also present. You can image the therapy. You don't only see what you treat, you can actually image what the therapy is.

So I know that there are questions about dosimetry, and you want to know how much each metastasis got. That is useful, very useful. But also as a follow-up diagnostic information. For that patient, it's priceless to show him, "Hey, we treat you today and this is what your therapy is." The therapy is going to the metastasis. It's going to where it has to be.

Absolutely, we have issues, of course, because who has SPECT-CTs available to do five or multiple SPECT-CTs after the therapy? I think in the future, with faster SPECT-CT and with more infrastructure, it's going to be possible. We have patients that come from radiation therapy and they have to be there for a whole month getting treated. With the right dosimetry protocols, we can have better responses because then you know how good your therapy is working.

But that's a topic on itself for another time. There's a lot of information on this. I can tell you that at least if we say a SPECT CT is available and would you do it, I'd say yes.

Questions from Audience: Okay, great.

Frankis Almaguel: At this point.

Questions from Audience: Okay, great. We have a lot of questions coming in now. In BCR, at no prostate bed uptake on PSMA scan, do we still have to radiate prostate bed always? Why?

Michael Gorin: Yeah. So the data has shown that ... Excuse me, sorry. I was just choking on something. Yeah, so in those patients, you want to radiate the bed. Reason being that the sensitivity, as I showed in the data from the OSPREY trial, is on the lower side of things for very small sites of disease. And so, when the PSA is rising like that, the PSMA scan doesn't rule out the presence of disease, it just simply tells you ... It lets you know when something is present outside of the prostate bed.

Folks have looked at the benefits of salvage radiation therapy by PSA cut point. The earlier salvage radiation is delivered in a patient's course, the better the outcome for them. And so, we operate under the presumption that there's cancer there in the bed and we go ahead and treat it with a negative PSMA PET scan for those reasons.

Frankis Almaguel: You have to understand that for us to see a metastasis, we need around 500,000 cells. Every cell has 20,000 resection for PSMA. So once there is disease outside the prostate, it's really tough. The data is clear that if you radiate that bed after, even if you don't see the uptake, they especially have longer progression-free survivals.

We can talk more about this, but I can tell you this, that the next question about a neuroendocrine transformation of prostate cancer, when that happens is when this patient has had multiple treatment for multiple modalities and now the cancer differentiate and then it doesn't express PSMA, express something else. We're working currently in actually my laboratory looking at other markers that we could use for all this. The data is coming. We're going to have a lot more options in the future.

So I can tell you that it is not that simple, but if you have an endocrine differentiation, it's a tough spot. But there's going to be hope coming in the future. Does Prostate PET replace MRI is...

Michael Gorin: Yeah, they're used in different context. I assume the question's referring to multiparametric MRI. Multiparametric MRI is used prior to a diagnosis of prostate cancer even being made, when the patient has the elevated PSA level. So the point in time in which you use them is very different. In the future, maybe it will, once more data emerges. But presently, we order the PSMA PET scan after a diagnosis has been rendered, not before.

Frankis Almaguel: Yes. Also par MRI is coming to actually combine both of them. So they're complimentary. Any other questions that we have here?

Questions from Audience: So someone is asking whether gallium-68, PSMA-11 rather than F-18 PYL is required prior to treatment with Pluvicto. Is either one acceptable prior to treatment? I'm guessing this is related to a reimbursement question.

Frankis Almaguel: Yeah. It's a complicated question, but both tracers have the same moiety. They really work together. I mean they're basically the same accuracy, but there are some loopholes that are ... But we're fixing that as a society. So I think at this point, yes, there have been some issues with reimbursement, saying that you need a gallium-68 because it's in the actual script of the Pluvicto. But we're working on that.

Michael Gorin: Putting aside the billing question and the labeling question, from just the standpoint of does the scans tell you the correct information to proceed with radioligand therapy, this question has been looked at ... And the radiotracer distribution, the relative uptake in lesions versus normal organs and so forth, is comparable between the two radiotracers. And so, there's no reason why you can't use a Pylarify PET scan in place of a gallium PSMA-11 PET scan prior to administering Pluvicto.

As I understand it, the SNMMI has already, or if they haven't already, very soon, will be putting out a statement stating that medically it's acceptable to do so. Whether or not the insurers think that's the case is a different story.

Frankis Almaguel: Yeah, but I think-

Questions from Audience: Go ahead.

Frankis Almaguel: No, I think that this is where physicians and patient advocates come together and say, "Let's educate our regulators. This is good for patients." We need the F-18 PSMA, is getting this imaging available in places that it wasn't available before. It's convenient for patients. So it's something that we should be able to fix.

Questions from Audience: All right. One last question. Have either of you noticed a preference in PSMA imaging agents among physicians? If so, any ideas as to why?

Frankis Almaguel: I think Dr. Gorin already showed F-18 is a little cheaper. But I think the message is you have to use what you have available. It is better to have ... I'm telling you this. Do not wait to get a PSMA scan just because one or the other is ... What is available for you, you have to ... I mean I personally don't have a preference. I can get the job done regardless of which is ... I mean I can tell you, yes, everything is an optimal radioisotope, but they're both compatible.

Michael Gorin: Yeah, I'm not sure how much of a role physicians actually play in choosing the radiotracer. A lot of times it's the administrators look at how much the two radiotracers cost, availability, things like that, which is more convenient to the way that a PET center could be run and so forth. Oftentimes the decision is made for us.

With that said, I definitely see more Pylarify going on, imaging will Pylarify, than gallium PSMA011. The F-18 labeled agent, in theory, could be distributed more widely and, in theory, has slightly better picture quality, but then you get into logistics of things.

For instance, if you're going to get your doses of F-18, they're going to be delivered one time after the cyclotron run. Then if you have another patient later on that day, you may not have ordered enough radiotracer. Whereas because gallium PSMA-11 is made on a generator, you could get doses more on demand as long as you have an existing relationship with Cardinal and so forth. So sometimes the center may want to do that because they could get in more PET scans in a day than you can if you're just using Pylarify.

So I've heard all different sorts of things out there, and a lot of it just has to do with more these logistical issues as opposed to physician preference for one tracer over the other.

Questions from Audience: Wonderful.

Frankis Almaguel: Absolutely.

Questions from Audience: I am going to sneak in one more question before we wrap up. Does PSMA uptake in local recurrence obviate the need for a biopsy?

Michael Gorin: So it depends on your question. After radiation therapy, I mean I still think you should do a biopsy. But after prostatectomy, we never biopsy recurrent sites. I mean we see disease in the correct clinical location, we believe it's real and we go with it.

I don't know why we don't widely apply the same logic to radiation recurrence. But it's my practice, though, to perform targeted biopsy of any PSMA hotspots after radiation therapy in the gland. Stuff outside the gland, we just trust is real.

Frankis Almaguel: I mean I agree with you. If the imaging looks the right way, I mean high uptake and focal, I mean this is almost a fact. If it's in the right place. But in the question, if you say local recurrence in the ... It depends, after prostatectomy or after radiation will be different. But in the future, things might change.

Michael Gorin: Yeah. I guess just don't feel comfortable administering a salvage. So I do a lot of salvage cryo. I don't know, it's just been ingrained in me that before I do a surgery to have tissue. So I think I just have stuck with that practice. But I think I'd feel comfortable doing it without it.

Frankis Almaguel: Well, you see, there is ... I mean we don't have time to talk about this, but there's a study in Germany where they did a-

Michael Gorin: Yeah, I saw that.

Frankis Almaguel: It was 20 patient prostatectomy without biopsy. I mean it was like ... I mean I think it's a little too ... I mean I don't know what the future would help, but I think, as of today, I would like to have pathologic proof before I do at least a prostatectomy.

Michael Gorin: I mean the side effects of primary local therapy are so severe that even ... The specificity is imperfect. It's pretty darn good at like 97%. But there's no room for error when the side effects are that severe. So I couldn't imagine delivering a primary local therapy without a biopsy.

Frankis Almaguel: I do think that if you have a target where you can biopsy the PSMA avid lesion in the prostate, maybe you can do less passes. I mean that could be the other thing. But the bottom line is it would be less as a chance. But at this moment, I don't think that you can say let's do away with biopsy.

Well, Michael, I have enjoyed this. It's really interesting. We had to run a little bit over the minutes, but I can tell you I learned myself and enjoy answering these questions.

All right. We thank the society for providing this, and Cardinal for all the ... I mean all the team that made this possible. We'll just take it to the next level.

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