OSPREY and CONDOR Trials - Evaluating F-18 DCFPyL PSMA Imaging for Prostate Cancer - Michael J. Morris

January 19, 2021

A Step Towards Personalized Medicine: PSMA-PET Imaging in Prostate Cancer

F-18 DCFPyL PSMA Imaging for Prostate Cancer: OSPREY and CONDOR.

Independent Medical Education Initiative Supported by Progenics Pharmaceuticals, Inc. a subsidiary of Lantheus Holdings, Inc.


Michael Morris, MD, Medical Oncologist Clinical Director, Genitourinary Medical Oncology Service & Prostate Cancer Section Head, Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Neal Shore, MD, FACS, is the Medical Director of the Carolina Urologic Research Center. He practices with Atlantic Urology Clinics in Myrtle Beach, South Carolina

Phillip J. Koo, MD, FACS, Division Chief of Diagnostic Imaging at the Banner MD Anderson Cancer Center in Arizona.

Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

Read the Full Video Transcript

Alicia Morgans: Hi, my name is Alicia Morgans and I am a GU Medical Oncologist and Associate Professor of Medicine at Northwestern University. I'm so pleased to have here with me today, a friend and colleague, Dr. Michael Morris, who's going to be presenting a step towards personalized medicine, PET PSMA imaging in prostate cancer, and a specific talk on PyL PET imaging. Thank you so much for being here with us today, Dr. Morris. Dr. Morris is a Professor of Medicine at Memorial Sloan Kettering, as well as being the Prostate Cancer Section Head. Thank you, Michael.

Michael Morris: Thank you very much for that kind introduction, Alicia, and thank you for inviting me to talk about PSMA imaging and specifically in relationship to 18F PSMA imaging with the compound DCFPyL. So I think we're at a period right now in which we are seeing PSMA imaging really move from a field of data that was based on initially some really surprisingly clear images of prostate cancer disease and its distribution to then moving into retrospective studies and then subsequent to that, prospective studies with the intent of regulatory approval in the United States of these tracers. And these data that I'm about to discuss are the prospective data for an 18F radio labeled tracer known as DCFPyL, and hopefully these two trials, the OSPREY and the CONDOR studies, which are the registration studies for this will ultimately lead to FDA approval, the new drug application is in. So the hope certainly is that these two trials named after somewhat uncommonly birds, but I suppose majestic in their own way, will ultimately lead to regulatory approval and availability for patients across the country.

Here are my disclosures, and I think it's an important point to begin with is why do we image at all in prostate cancer? Really, the answer depends on where the patient is in the spectrum of disease. I've just put up the clinical state's model for prostate cancer from Prostate Cancer Working Group 3 to show how these questions pose themselves throughout the natural history of the patient, as he progresses from diagnosis, ultimately to the end stages of the disease. Certainly from a clinically localized disease in particular for high-risk patients, imaging, or accurate imaging is really important in terms of initial staging and treatment decision making for the patient. For those high-risk patients, whom in the past we really didn't know did they have strictly localized disease or did they have what was previously micro-metastatic disease or outright systemic disseminated disease?

PSMA imaging has the potential to more clearly identify the distribution of disease in those patients so we can more clearly stage them and then make decisions about their treatment, which are based on more accurate understandings of where their disease distribution is. For the rising PSA population, certainly accurate staging is crucial here because these patients could either be curable if they have a localized disease in the prostate bed or in the irradiated prostate, depending on what kind of upfront therapy they received, or it's an early appreciation of whether they have metastatic disease or a systemic disease or not and whether treatment should be focused on those areas, as opposed to receiving perhaps unnecessary local treatment to the area that the primary used to be in.

Then finally, for patients who have distant disease, imaging serves many purposes in terms of treatment prediction, response assessment, prognostication based on distribution of disease. For example, identifying visceral versus bony disease or low volume versus high volume disease. Then for drug development, identifying, targeting, and pharmacodynamic effects based on molecular imaging can be quite a useful tool. Now, all of these purposes, of course, are based right now on standard cross-sectional imaging and bone scintigraphy. As PSMA imaging is introduced into each of these contexts, the role of that imaging and the implications for treatment decisions needs to really be redefined. So we're on the cusp now of redefining really the staging of prostate cancer, the prognosis, and the risk stratification within each stage, and as well how to best treat these patients based on a newly comprehensive and accurate representation of where their disease is.

For those who may not be familiar, molecular imaging is dependent really on a few key concepts. One, the presence of a molecule on the prostate cancer cell, in this case, PSMA, that's expressed in order to target to bring in the radioligand, so that we can image. Of course, that target could be used for therapy as well, but that's a topic of a different day, I would think. But the way that the molecules work is you have a targeting agent to attach to the target, and that agent is carrying with it a payload, which in the case of PET imaging as either gallium 68 or 18F.

Now, how you target the molecule on the cell, which in this case for today is PSMA, can vary in size from molecule to molecule. So you can have antibodies, you can have minibodies, you can have just an FC component, or you could have a small molecule, like a DCFPyL and the size of these molecules and what you select to be the targeting agent can have really important implications in the value of that and the convenience of that radioligand.

So, for example, if you use an intact antibody to image PSMA, well, antibodies have a relatively long half-life. So the tumor to blood ratio is much longer and you might not get blood clearance for a week or more, and you wouldn't be able to image well, whereas a small molecule clears from the blood pool much quicker, so you can generate a good tumor to blood ratio in which the tumor really lights up on a negative background shortly after injection. Hence, the preferability for molecules, such as PyL or in the case of gallium, PSMA-11 of the small molecules. Generally, these have been developed by Marty Pomper at Johns Hopkins. They have a common core based on urea, and these are now the most commonly used molecules or the basic structure of them for PSMA-based PET imaging.

Just to remind the audience, PSMA is a transmembrane protein. It's expressed predominantly in prostate cancer. It's also expressed in normal prostate tissue as well. Although we now know much more about PSMA expression than we used to, and it turns out expression is quite complex and complicated, it is expressed generally speaking in most prostate cancer patients, whether they're castration sensitive or castration resistant, and it's expressed across a range of organ distribution as well. So it will light up lymph nodes. It will light up bone metastases. It will light up visceral metastases as well. Expression is complex and heterogeneous in many patients. That complexity does increase with a histologic grade and as well prior treatment exposure. This is one of the things that we need to sort out over the next couple of years is how to appreciate which tracer might be best for which patient based on understanding how these molecules are expressed from patient to patient, lesion to lesion, and clinical state to clinical state. PSMA expression does vary by AR signaling. So that also contributes to the heterogeneity of PSMA expression in a patient or across patients, whether that AR signaling axis is signaling or is quiescent.

So to talk a little bit about PyL itself, so the road to seeking FDA approval, I don't want the title to imply that FDA approval is secured yet, but this is at least the pathway that was outlined in order to collect the data of regulatory quality to submit for new drug application really was looking across the disease spectrum in prostate cancer, based on two studies. One is the OSPREY study, which had two cohorts, one which was looking at patients with high-grade or high-risk localized disease. The other, which was predominantly focused on patients with outright metastatic or recurrent disease. Then sandwiched between those two cohorts of OSPREY was a study called CONDOR, which focused pretty exclusively on this most difficult of clinical states, the rising PSA patient after definitive local therapy, who has otherwise no apparent disease by standard imaging technology like a CT and bone scintigraphy.

This is singularly difficult because you can't have a histologic comparator easily because, by definition, there's nothing to be seen on standard imaging and qualifying imaging tracers in this space does require usually composite endpoints as truth standard to compare with the imaging, as opposed to the patient with high-risk localized disease, who's going to undergo a prostatectomy because there, you do have a histologic comparator or the patient with metastatic disease for whom you do have pathology comparative just by biopsying the patient. So CONDOR, as all trials do in this patient population of the rising PSA patient, faced some distinctive design challenges, which were discussed extensively with the agency in order to create a trial that was informative.

So let's just move state by state here in terms of the data that support PSMA imaging with DCFPyL in the prostate cancer spectrum. So let's start with the high-risk clinically localized disease patient. These patients on cohort A of OSPREY were intended all to go to surgery and so after that surgery, there was a comparison of the pathology that was then compared to the imaging. There was a specific focus in terms of the primary endpoint on the lymph nodes, because really it's the extra prostatic disease that was considered to be the greatest asset of PSMA imaging in terms of identifying extraglandular disease in patients preoperatively who are at risk of having extraglandular disease.

So the intent of the PSMA image in this case is not specifically to identify prostate cancer in the prostate. That's really a different task establishing without a biopsy. For example, whether a patient has prostate cancer or not, or high-grade prostate cancer. The focus here is on that practical question that faces the urologist as the patient who has high-risk disease is about to go to surgery and that is in treatment planning, does this patient really have strictly localized disease or does the patient have nodal or outright M1 disease and would perhaps require a different consideration for either altering the surgical template or planning the patient for multimodality therapy, which may or may not include a prostatectomy?

So the sites, there were 10 sites, eight in the US, two in Canada. There were three central and independent PET readers, and then one separate reader who was reading the conventional scans, all blinded to the clinical information and to each other. What's important here in interpreting these data is the fact that there was a histologic gold standard of truth here. So a very high bar, and I think it's worth pointing out that in some circumstances, of course, you would never expect a PET image to perform as well as microscopy in terms of interpreting the performance data that I'm going to show you. We don't think of PET as essentially imaging microscopy. We think of PET as having some threshold of detectability that will be somewhat worse than looking at lymph node packets sent to the pathologist, sectioned, stained, and then examined under a microscope.

So there were 385 patients in OSPREY, and we're talking right now about cohort A, which involved 252 men and cohort B, which we'll get to a little bit later, had 93 men in it. Again, all of these men had traditional NCCN high or highest risk disease. If you look at the patient characteristics, then unsurprisingly, you had the majority of patients here representing Gleason 8, 9, or 10 Gleason scores with the minority of these patients having Gleason 6 or 7. Again, not surprisingly, these PSAs were at a median of 9.3. So high-grade with PSA levels that if they didn't have high-grade, would bring them into the high-risk. You can see that the range here was from 1.2 to 86.2 in terms of the range of PSAs. Many of these patients did have extracapsular extension. About a quarter of them were seminal vesicle involvement as well. Similar to NCCN, you can make your way to high-risk by a variety of criteria.

So here are the summary data of the primary endpoint, which was sensitivity and specificity, but also the secondary endpoints of positive predictive value and negative predictive value. So what we did find was that the sensitivity of the tracer was 40.3% when we looked at all lymph nodes. Of course, if you remember what sensitivity is dependent on, it's really dependent on the number of false negatives that you have, because it's the true positives divided by the sum of the true positives plus the false negatives. Why would you have false negatives when comparing PET to histology? Because you would have lesions that are so small that they wouldn't be detected by PET, but they would be detected by microscopy at the pathologist's microscope.

So what we wanted to see was, well, what would happen if we set a threshold then of removing from that the nodes that were so small that we wouldn't expect PET to pick them up at all. There, the sensitivity came up. The number of false negatives declined as well. So I think that that's an important factor to keep in mind in terms of trial design, that is, we set the bar extremely high in terms of holding the PET accountable, especially for things that you can't visualize on a PET scan.

Now, moving to the lesions that you can visualize. So specificity, which is really the patients that actually don't have disease that are reflected by a negative scan. Specificity is dependent on the formula of true negatives over true negatives plus false positives. So really, the false positives are determining this? There are very few false positives with DCFPyL. You can see that specificity is virtually 98%. Meaning generally speaking, if you see a lesion, it is going to be a lesion, and that's reflected in the positive predictive value as well, which is the number of positive scans or positive findings that turn out to actually represent disease. It's quite high. This is true positives over true positives plus false positives. So 85% or so in terms of positive predictive value and very good negative predictive value as well.

When you think about which of these numbers is really most important to us as clinicians, it's really, even though the primary endpoint here is sensitivity and specificity, but when you think about how we work and how we think, it's really positive predictive value. That's the most important number to us because we come into the patient with negative standard imaging or equivalent standard imaging in terms of distance disease, and then we take the PyL scan or the PSMA PET and then you wonder whether the positive findings that you see should change your management in terms of, can I trust that that positive finding on the scan actually represents disease? I think that the answer to that is in most cases, yes, you can. So I think that from a clinician standpoint, it's really the PPV that's most important.

Moving to the rising PSA population, we're just going to talk about the CONDOR trial for a little bit. So we're going to switch from OSPREY to CONDOR. I described what the dilemma is for most clinicians and the rising PSA population. I think all people that have treated prostate cancer have seen this dilemma. You have a rising PSA. Usually, that PSA is relatively low. You have negative or equivocal standard imaging, and you don't know what to do. You don't know whether to give the patient salvage local therapy after prostatectomy. Generally speaking, that's going to be salvage radiation therapy, or whether that patient will receive that therapy to no effect because they already have micrometastatic disease.

So the CONDOR endpoints, because these patients don't have any standard imaging, generally as a standard comparator, and it's hard to biopsy these patients. The primary endpoint is a composite endpoint that was proposed by the agency that essentially equates to positive predictive value, but with the added requirement of anatomic location matching, right? So a true positive there, let's say you had a positive finding in a left-sided rib, but the actual correlate is in the right pelvis. That shouldn't count as a true positive, right? So there has to be some synchrony between the PyL finding and whatever's going to constitute truth anatomically for the correlation. So what does constitute truth was really a composite truth standard and that composite truth standard, I've outlined on the next slide, which really is hierarchical. So the first and highest level of truth is, of course, histopathology. So if you saw something on the PyL scan that you could put a needle into, or you could verify what it was, perhaps by a pelvic lymph node dissection, then certainly that's a gold standard of truth because you have tissue correlation, but for most patients, of course, you won't necessarily have that.

So the second tier of the composite truth standard was some other combination of conventional imaging. So that could have been a standard CT or focused MRI on a specific area that perhaps the PyL was detecting, or it could be bone scintigraphy or because the FDA had approved fluciclovine and choline, it could be another type of molecular imaging as well. Then finally, if none of these would suffice to identify a lesion as a true positive, then you could irradiate that lesion if you saw 50% PSA decline, then that too would define the truth composite. So any one of these or any permutation of these could define a truth standard for a positive on the PyL scan. This trial specifically addressed the issue of positive predictive value. So only the positive lesions were counted here, so to speak and the only those positive lesions were then applied to this truth standard.

So the way that the study worked was the patient who had biochemically relapsed standard AUA or Phoenix definition would get the PyL scan. Right before that PyL scan would be performed, the clinician filled out a management questionnaire as to how he or she was planning to manage the patient. Then if the patient had a positive lesion on the PyL, then they underwent this subsequent imaging or biopsy or radiation to define the composite standard of truth. Those who had no findings on their PyL scan, they did not undergo any additional testing, but everybody got a post-imaging questionnaire as well to see whether or not the image made a difference in terms of the treatment decision.

There was a lot of blinded groups here. There was a blinded group of radiologists reading the PyL PET scan. There was a separate blinded group of independent arbiters of the composite truth standard. These groups never interacted with each other. Only the statistician would have the blinded result of the central reads and the result of the composite standard of truth, and then would match the data together. So this group of patients, as you might expect for most biochemically relapsed patients, had a median of a PSA of 0.8, relatively low. Although, as you can see from this range, there were certainly some outliers that would have, if we express this in a mean skewed the data, but some of these patients had very high PSAs, but very few up here. You can see that most of the patients in the trial had a PSA of less than two.

If you add all of these strata up 70% of these patients had a PSA less than two. So you can ignore most of the higher outliers, but the median was 0.8, where most people are struggling with this decision at those low decimal point values of making a decision as to whether to give these patients a salvage therapy or not. So here are the top line data from CONDOR. So the first thing I want to point out is this top red box. These are the three independent readers who were looking at the scans, and I've just presented the data from each reader on to himself and into a separate column. So remember that all of these patients had negative or equivalent standard scans as performed by the patient's treating physician. So of these patients, about 60% of them did have a PSMA PET finding. So you can see how much more informative a PSMA PET is than a standard CT or bone scan, generally speaking, in the sense that for seven out of 10 of these patients, you did have something positive to guide your decision-making in comparison to standard scans.

The second thing is the CLR. This is the positive predictive value with anatomic localization. You can see that that is 85% in one reader, 87 in another, and 85 in the third reader. So pretty uniformly, quite good. From a statistical standpoint, the threshold for success was defined by 20%. So this is well over the threshold that had been agreed upon with the agency for defining success. The reason for defining success at 20% is that the standard most sensitive study that has been FDA approved for detection of disease in this group of patients is Axumin®. We were looking at a PSA less than two in Axumin® and what the success rate would be for those patients and set that as the bar.

You can see that the positive predictive value here, where the CLR is pretty good no matter what the PSA stratum is from low PSA values to intermediate PSA values, to the outright, very high PSA values. So I think that the takeaway is here, even with patients with low PSAs, the data are reliable. So in terms of the change of management, 64% of these patients had to change in intended match management. What's important is that some of these changes are really important to the patient's life and outcome. So for 20% of these patients, that treatment plan changed from a systemic therapy plan, where there was a non-curative treatment intent to a curative plan. That's not to say that the patient was necessarily cured, but at least the plan changed, which changed to a treatment goal, which was cure involving salvage local therapy.

So 20% of those patients brought definitive therapy back into the therapeutic equation. On the converse, about 28% of the patients had a change in their treatment goal from salvage local therapy alone to either salvage local therapy with some systemic therapy or to systemic therapy alone. Then around 24% of patients had a change from just observation to actually initiating therapy, presumably because the target had been identified and 4% had the opposite plan treatment plan, which was changed then to just surveillance and follow-up. So of course, we don't know whether the changes that were proposed by these physicians are the best changes. We don't know whether those changes resulted in cure or not. We don't know whether they resulted in prolonging survival or not. That would be the topic of a different clinical trial, but nonetheless, you can see how people do incorporate this information.

Remember that it is primarily the positives that drive the decision-making because the patients had negatives on their plain old conventional scans to start with, so a negative on a PyL doesn't bring you any lower level of information that they would have had, but the higher level of information is the positive finding. Of course, we do need to do the future clinical trials to find out whether this decision-making is in fact the best decision-making and how molecular imaging should ideally impact the treatment decisions that clinicians make.

Then I'll just wrap things up by looking at the metastatic patients, and the reason that cohort B was added to OSPREY, so we're moving back to OSPREY for just a moment. The reason that it was added, just to get more data on the performance characteristics at identifying each type of metastatic lesion from bone to lymph node to viscera. We know that biologically, that these different areas of disease do carry with them different biologic features. We also know that they carry different prognostic implications for patients. We wanted to see how PyL performed in each of those different locations. I'll limit this to just one slide, where you can see divided by overall bone nodal disease and viscera and note that there are very few visceral soft tissue specimens as is anticipated, given that this is a prostate cancer population. You can see that both sensitivity and positive predictive value pretty much hold from organ system to organ system, from metastatic site to metastatic site.

So with that, I think we have to say that first of all, as of about two weeks ago, PSMA imaging, at least with gallium 68, PSMA-11 should no longer be considered to be investigational therapy in the United States. It was FDA approved, specifically at UCLA and UCSF. What I think is very important in regards to the label here is that PSMA-based imaging was not just approved for the purposes of detection of disease at the point of relapse, which is what currently the molecular imaging studies such as Axumin® are approved for in terms of their label, but rather it includes initial staging of patients, as you can see here at my cursor, who are potentially curable by surgery or radiation who have suspected prostate cancer metastasis.

I think that that's important to recognize also the broadness of that wording. The label does not define for you who those patients are. You just need to suspect that they may have distant disease. So I think that's a very positive movement because really, I think that it's not just the relapsed patient that can be helped by PSMA imaging, but the patient with high-risk localized disease, and this label opens that up in terms of molecular imaging for the first time, at least in the United States. The second thing that I would say is that PyL was last week awarded for priority review of the data that I just showed you for its NDA. So we're hoping, of course, that this is a positive NDA and that it will result shortly within the next several months. Hopefully, it will be approved as well. We can certainly discuss what the advantages or disadvantages of one tracer versus another might be.

There is a third NDA also in review that will also add to the armamentarium of these imaging agents if two is approved. So in the US in the next year, I would think that PSMA will really transition in full force from just an imaging modality available to those in clinical trials or those who could afford to go to other countries to get them to something that's available more ubiquitously in the United States. If PyL is approved, it won't apply to specific sites. It will be a national approval. Hopefully, for all of these tracers, these will be ubiquitously available to the prostate cancer patients who need them.

Just to wrap things up, I think that molecular imaging really is an assistive device for making good decisions in prostate cancer. It certainly should reflect the true status of the patient's disease as much as possible. I think PSMA is the closest that we've come to that. PSMA-based imaging does give reliable information about the distribution of disease, because are just the performance characteristics of these tracers and they are superior to current standards, but how we use that information, well that still has to be determined in future studies. With that, I think that will wrap things up. I thank you for your attention. 


Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU medical oncologist and Associate Professor of Medicine at Northwestern University. I am very pleased to host the post-presentation discussion where Dr. Michael Morris presented some advances in PyL-PET PSMA imaging for us, which is very exciting, really focusing on CONDOR and OSPREY. And we also have here with us today, Dr. Phillip Koo, who is a nuclear medicine physician at MD Anderson Banner Health in Phoenix, Arizona. And of course, Dr. Neal Shore, who is a urologic oncologist at the Carolina Urologic Research Center in Myrtle Beach, South Carolina. Thank you all for being here today.

Phillip Koo: Thank you.

Neal Shore: Thanks.

Michael Morris: Thank you.

Alicia Morgans: Wonderful. So, why don't we start off with Dr. Shore really having the opportunity to ask Dr. Morris some questions from a urologist's perspective, because I think that better imaging is certainly something that urologists are going to be thinking about, particularly when they're facing high-risk patients in the localized disease setting. Dr. Shore, what questions do you have for Dr. Morris?

Neal Shore: Thank you, Alicia and Michael, what a great presentation.

Michael Morris: Thank you.

Neal Shore: You know 2020, a challenging year because of the pandemic, but we shouldn't forget that wonderful work has been done clearly as you're reviewing the importance of advancements in imaging. And as you said at the very beginning, "Why do we image?". Well, we image as you state, to get accurate disease localization and the data that you've presented from both CONDOR or OSPREY inculcates on how we change our decision-making, nothing more important to a patient to get the optimal treatment, whether it's a localized therapy moving from observation to an interventional treatment, as your data demonstrates, or going from systemic to local, local to systemic, and using all the tools in front of us for multidisciplinary care. I have a couple of questions for you. Again, wonderful presentation. The data on OSPREY and CONDOR is really one of these silver linings in 2020.

So important for our colleagues to understand as imaging takes on a whole nother dimension. In the US as you also stated, we're finally catching up to getting PSMA-PET technology that many other areas in the world have had so thank you so much for what you've done. But you had the three independent readers, and I'm going to presume that these were three independent readers who had a fair amount of training and I guess my first question is, with multiparametric MRI, we've learned that there's a lot of radiologic reader interobserver variability and there has to be some education, and this is probably a question that Phil can answer as well. Now that our nuclear medicine radiologists are coming into a really vital and key role, how much training is involved to get a new site up to speed, to get the nuclear medicine radiologist to understand how to interpret 18F-PyL or a PSMA-PET scan?

Michael Morris: So I'll take a stab at that, but then I think we should hear from Phil as well, since that's really within his field. So yeah, absolutely all of the readers got training in order to bring them up to speed, to be considered as experienced readers. But there are complexities to PSMA-based imaging because PSMA isn't exclusively expressed in prostate cancer, even though the PS would suggest prostate-specific, that really isn't entirely true. First of all, PSMA is expressed in the neovasculature of pretty much every solid tumor. And then PSMA is expressed in the gut it's expressed in some neurologic tissue it's expressed in of the CNS so it does take some experience to distinguish one thing from another. And also, I would say that right now, there isn't really a threshold standard so, you know that for example, a standard PET scan might be compared to liver uptake, it might be compared to blood pool, but those thresholds don't have formal definitions yet so I think that there is some training that as with anything you need in order to become expert and delineating what's disease, what's not disease. And I'd really like to hear from Phil what his views on that are since he's one of those who would be one of those experts.

Phillip Koo: Yeah great, thank you very much. First off, I had to Google inculcates, so for helping me expand my own vocabulary, I appreciate that. I agree, I think there are nuances, but I think what the data that you've shown with CONDOR and OSPREY and what UCSF and UCLA have shown is that the inter-reader variability with regards to the interpretation of the PSMA imaging, regardless of what imaging you use, is actually pretty strong. And again, this involves a group of readers that are a little more experienced, but from my understanding, speaking with colleagues across the country, it seems like it is a little more straightforward. Not to say it's a commodity and it doesn't require training, but I think there is a little more improved inter-reader variability.

And I think what is unique about Progenics and Lantheus is what we've learned about as well, is this idea of integrating AI techniques and AI tools, assisted tools into the workflow. So I think that takes it to an even higher level of consistency and reliability for the end-user, which is the urologist or the medical oncologist, which I think takes this to another level. So, very excited about that.

Michael Morris: I do think that both the gallium and PyL have their roots in academic centers, much of PyL was really by virtue of the efforts of the group at Hopkins, but I think at post-approval those who are experienced in terms of reading these, whether it's UCLA/UCSF group or Hopkins group would probably benefit the field by spreading their knowledge of how to interpret these scans to their colleagues and getting everybody familiar with the nuances.

Neal Shore: You mentioned moving from academia into the community, which is usually the pattern of adoption. Can you comment, Michael, regarding gallium versus PyL in terms of just some practical implementation, equipment purchase, time life, shelf life for the different tracers?

Michael Morris: Sure. Let's start though first with the issue of the fallium PSMA-11 approval and feel free to chime in at any point. So although that approval is for two sites, there is an agreement that those two sites have with the agency that it would be non-exclusive. So if other sites wished to produce the gallium PSMA tracer, that using the technique that is done at UCLA and UCSF, they could and produce it at their own place after securing those approvals. One of the NDAs that currently is under review and should be resulted within the next several months is for national approval for gallium-68 PSMA with a kit made by Telix, which should make that whole production process much more automated and much easier.

The thing about gallium is that generally you do need a gallium generator, which not everybody has and so that does set some limitations in terms of the availability of gallium to be made at every site that might want to do a PSMA scan across the country. On the other hand, 18F, there's a pretty international supply of 18F just from making FDG and disseminating that. So that supply chain is pretty much available and in place right now as an infrastructure. So it may be a lot easier for an individual doc-in-the-box freestanding radiologists to order the 18F PyL because of its commercial nature, its existing infrastructure, and the ease at which the tracer could be distributed to an individual radiologist, nuclear medicine physician who wanted to do it.

From a performance characteristic standpoint, there's very little data on comparing the two. I think from a user perspective, not so much maybe in Phil's fields, but certainly Alicia, Neal, and me, we just want to get a PSMA scan and of course the logistics around that, how that's done, how that's executed is of great concern to the nuclear medicine physician but right now, for the person whose patient is in front of you, any of them would be better than none. Right?

Alicia Morgans: Oh, I completely agree and I appreciate these differences though, in the potential rollout of these agents and also appreciate how collaborative we've become now as medical oncologists, urologists, and nuclear medicine docs, really this trio, and then our radiation doctors of course, on the side. So all four of us have really come together around this. And what I think is so impressive as we roll these out, and like you said, just want to get a PSMA scan, and we'll get one now. I can see that in the near horizon is that we are already enrolling on trials that will help us understand the second piece of the issue, which is not just can we see it, but can we treat it in a way that changes the trajectory of the disease and then how do we best do that? Is it just SBRT or local therapies? Is it SBRT, local therapies plus systemic therapy? How might this be useful? Can you comment at all on the trials that you're looking forward to seeing and how your practice patterns actually may have even changed outside of clinical trials? Because I know ours have, even when we aren't enrolling patients on trials, certainly this imaging has changed what we do.

Michael Morris: Yeah, I find that I'm subject to a real hazard here because I certainly have had access to PSMA imaging for a while and I find that once you order it and you have a positive finding, you can't ignore it. So certainly outside of clinical trials, I have reacted to those and have given SBRT to oligometastatic disease. I think that from a data standpoint, you do have the results of the ORIOLE trial and those did have some PyL scanned patients. And when they irradiated those lesions that were only evident by PyL and not by standard imaging, that subset of patients did tend to have a longer failure-free survival than those patients who didn't have PyL imaging. It makes sense. The more disease you irradiate, the later it will take to relapse.

But I think you're going to need to really wait for some very large trials. STAMPEDE has an arm, which will involve irradiating oligometastatic disease. And those patients, it's not required that they have molecular imaging, but they could have molecular imaging. And there's an NRG trial that's been proposed to use molecular imaging for these patients who have molecular imaging only evident disease. So those trials are mature Phase III studies that will have enough patients to really answer those questions. But it's going to be a while to get those answers just because they're big studies, they need to accrue, the endpoints are long-term, and in the meantime, we have to be really careful not to overuse PSMA imaging and not to presume that we know what we're really doing in this circumstance, which is we're really are struggling in the dark here a little bit.

Alicia Morgans: I agree. Something that was so interesting though in ORIOLE is that if all targets identified were radiated versus not all were radiated, there was almost a dose-response. So it's so interesting to see that that suggests that we may be doing something which is just really encouraging. So I look forward to seeing the results of those studies, of course, as I'm sure we all do. So, Dr. Koo, are there other questions that you would have for Dr. Morris?

Phillip Koo: The one thing I'd like to say is for imaging studies, we've used detection rate as an endpoint so often, and we've known the weaknesses of using that, so I applaud you and the investigators for taking that to another level, using this idea of correct localization rate and this composite standard of truth, because it's so important to have a better endpoint than just detection rate, which is relatively subjective. So I guess a question I have for you is outside of a clinical trial, especially in that biochemical recurrence setting, how do you manage patients with regards to imaging results and getting tissue? Do you feel confident enough with just the imaging findings for lesions that are difficult to biopsy to act on that information or are you compelled to get tissue?

Michael Morris: So that's a great question, because for example, in the past, like the choline label says you should verify with tissue, the PSMA-11 label does not say that. And I do think that the hazards of over-interpreting a negative biopsy in the context of some tiny little lesion that you're trying to get a needle into, or a bone metastasis where you have this dense sclerotic lesion, but you don't really know where the disease is... I don't think you can walk away from a negative biopsy and presume that there's not disease there. So if you've got a positive biopsy, you would just reaffirm what the scan already was telling you and if you've got a negative biopsy, you could as easily conclude, this is really tough stuff. I'm not sure I really got a good specimen, I don't know.

So I'm not sure that in the biochemically relapsed population, I need a biopsy to verify what I see. On the other hand, NCCN guidelines now recommend getting genomic profiling on relapsed disease for future treatment decision-making. And so if you are documenting your first evidence of metastatic disease, it's perfectly acceptable to get a biopsy, but you're not necessarily verifying the scan by virtue of the biopsy. You're collecting information that you'll use for prognostication and treatment decision-making and also potentially family genetic counseling. So if I see a lesion and I can biopsy it, I'll biopsy it, but not because I don't believe a scan. Because it's not going to necessarily tell me if it's negative that I should doubt the scan.

Phillip Koo: That's a great point because one of the other values of imaging is to help in targets selected for a biopsy and I think that's another indication for PET in probably several settings. So thank you very much.

Michael Morris: The only other thing that I would say I was really struck, Alicia, when you said, "It's really nice to see us all collaborating," which is definitely true. So the next battle that we need to collaborate on is the reimbursement issue because I think all of us recognize that we spend so much time battling to get patients the tools that they need with insurers, et cetera and there's a real separation between FDA approval and then CMS' decision on reimbursement and individual insurers. And so as a collective, since we've all worked to get these data and as a collective community to work on getting the FDA approval, I think the next battle is making this technology actually accessible to the broad spectrum of society so that everybody who needs one gets one.

Alicia Morgans: I completely agree and I think there's also going to be a battle over time to really pulling those nuclear medicine docs into our diagnostic and therapeutic folds because we're certainly continuing in the direction of theranostics with all of this too. And Dr. Koo, do you have any comments on that? I know that you have worked within the society and certainly as the director of your division to try to get nuclear medicine doctors to be part of the diagnostic and treatment team in a more robust way.

Phillip Koo: Absolutely. From a society perspective, we are trying to create more involvement for nuclear medicine in that multidisciplinary team, and also in the clinical research that's occurring in this space, especially since we have that role with the therapies. In a lot of ways when it comes to GU malignancies, I think clearly nuclear medicine is becoming one of the "four pillars" and four core specialties of prostate cancer management.

Alicia Morgans: Absolutely and we'll need to continue to ensure reimbursement happens in a way that supports that continued collaboration for those docs. It's not just how many scans you read in an hour, it's really how you can then use those scans to guide management that's very important. And we'll give the last word, or at least the last question, the last word goes to Dr. Morris, but the last question to Dr. Shore. What question do you have for Dr. Morris?

Neal Shore: Thank you, Alicia. Mike, you said that we don't have an adequate amount of comparator data right now for PSMA gallium versus the PyL, and I think that's a great and fair point. I'm really excited that by the third week in May, they'll have I believe it's the PDUFA date for the 18F-PyL. And also you mentioned about IND applications for the PSMA gallium based upon the recent UCLA, UCSF approvals, kudos to those academic institutions for really championing that. My question for you regarding comparator scans, the urology community avidly embraced the use of fluciclovine, the Axumin® scan, based upon the unmet need for finding improved accuracy in high-risk newly diagnosed and also the BCR population. Given the data that you've presented today and where we are now with this next-generation imaging and assuming sometime in the second quarter of 2021, all of these scans are available, fluciclovine, 18F-PyL PSMA-PET, gallium, and cost is not an issue, big caveat there, will there be any residual role for fluciclovine, the Axumin® scan?

Michael Morris: I personally think that there will be, yes, because there still is a role for metabolic imaging. Fluciclovine is in essence, a metabolic scan and there are patients who do not have good PSMA expression. I don't think we have a great handle on who those patients are, but if I had to broadly say, certainly the patient who is post-abi, post-enza, no longer has a functional AR axis tumor growth that's being driven by non-AR axis pathways with or without a neuroendocrine component. Fluciclovine may have a really important role in those patients and not just fluciclovine as a metabolic assay, but even FDG. If you look at Mike Hofman's studies, which used a combination of PSMA and FDG for eligibility onto the TheraP trial, for example, he used the combo, the cocktail of PSMA, and metabolic imaging as a positive and negative treatment selection criteria for therapeutic radioligand therapy.

Again, we don't have a comparator to know what would happen if you didn't have the metabolic scan, but 20% of the patients were found not to be PSMA avid, but to be FDG. And so that gives me confidence that there is a role for tracers like fluciclovine, where PSMA may not be ideal, but looking at metabolism may be superior in terms of identifying response or identifying even just disease distribution.

Alicia Morgans: Great. Well, on that note, and after such a wonderful presentation and conversation, I just want to say thank you to everyone. Thank you, especially to Dr. Morris, and we appreciate all of your time. Thank you.

Michael Morris: Thank you, Alicia. Phil, Neal, it's good to see you and thank you very much for inviting me, it's a real privilege to be here.

Phillip Koo: Thank you, Michael.

Michael Morris: Thanks.