Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU medical oncologist at Northwestern University. I'm excited to bring to you today, "A Step Towards Personalized Medicine: PSMA PET Imaging in Prostate Cancer". Our talk now is by Dr. Ken Pienta, a Professor of Urology and Medical Oncology at Johns Hopkins University and he'll be talking with us about the biology of PSMA PET and taking that into the future. Thank you so much for joining us today, Dr. Pienta.

Kenneth Pienta: Thank you, Alicia. It's such a pleasure to be here and really talk about this extremely important topic that is going to be changing the way urologists and medical oncologists approach the treatment of prostate cancer and now in the very near future as we see some approvals of this imaging agent just recently as well as in the coming year. Let me share my screen and dive right into this topic. I'm specifically going to be talking about the biology of prostate cancer metastasis and what PSMA imaging is teaching us. If you think about how prostate cancer spreads and metastasizes, you have to think about the highways it takes out of the prostate. Prostate cancer cells can leave the prostate through the lymphatics, through potentially nerves that then lead to the lymphatics straight into the venous circulation, but all of those highways lead to the venous blood supply. The venous blood supply then has to go through the heart, through the lungs to go into the arterial blood supply, and then you eventually get to distant metastatic sites like the bone.

So for many years, we thought about prostate cancer because everybody who dies of prostate cancer pretty much ends up with metastatic disease to the bone. We never knew how many cells dropped right into the circulation and went right to the bone versus how many were going up the lymph nodes. And so understanding these pathways has really been something that has been a conundrum to physicians and scientists thinking about prostate cancer metastasis. If you really do think about metastasis staging, PSMA is going to continue to be very important in helping us understand this better and understanding these pathways. So, just to review very quickly, N0 is no regional nodes, N1 is regional nodes in the pelvis, but once you leave that pelvic brim you're into the retroperitoneum and that's actually considered metastatic disease.

So thinking about how patients present, especially in the biochemical recurrence status stage and in the high-risk prostate cancer stage, these ideas of how PSMA is going to help us are really important. Just to remind everyone, PSMA PET, we know already from all the studies that have been published around the world that it localizes prostate cancer with high sensitivity and specificity. Prostate-specific membrane antigen is a transmembrane glycoprotein that is highly retroperitoneum in prostate cancer, primary tumors, and mets. Its expression is further increased in advanced stages in metastatic castrate-resistant disease making it an important potentially theranostic in metastatic castrate-resistant disease, but what we really want to focus on this morning is what is it doing for us in localized and local-regional disease in the BCR space, diseases that urologists and radiation oncologists are thinking a lot about.

The beauty of PSMA is that it does contain this large extracellular domain which can be targeted by multiple types of ligands for imaging and treatment purposes in gallium PSMA PET, as well as ¹⁸F-PSMA PET, have demonstrated to have sensitivities and specificities of about 0.74 and 0.96 respectively for the detection of prostate cancer, but we're going to dive into that a little better to understand where those numbers come from.

So this, for example, is a representative ¹⁸F-DCFPyL PET imaging finding in a patient with biochemical recurrence that we did here at Hopkins. You can see that the background is really clean in these PET CTs, and you really can localize prostate cancer that's very tiny. But one of the questions is how tiny? What's really the size of those lymph nodes? One of the problems with CT scans and the black-white gray images is that you can find lymph nodes that are five millimeters in size but you don't know if that's cancer or not, and certainly, we use the one-centimeter cutoff to worry about something being pathologically cancer.

So what is PSMA bias? Well, we can sort of do a math calculation of the number of cells versus the volume assuming, let's just for argument's sake assume that a cancer volume is pure cancer cells. Well, how do you calculate volume? 4/3πr³ if you go back to grade school. One cell has about 10 microns around so the volume is about 500 um³. So, if you get into the two-millimeter to three-millimeter tumor size, that volume is equal to about eight million cells if you're two millimeters, 27 million, three millimeters and look at the numbers there, 10-millimeter tumor, one-centimeter tumor, is actually where we get that billion cells per volume that many people talk about that if you have a centimeter tumor it's a billion cells. So PSMA detection is about eight to 20, 30 million cells. That's what we're buying with PSMA detection. And it's really important to note that even though that spot looks really bright, we're talking about something that's on the order of two millimeters in size and that's the sensitive limit of detection.

So what do we know about PSMA imaging in men with high-risk prostate cancer? Well, across a variety of studies and multiple institutions, studies reveal that about 40% of men will have disease detected outside the prostate and about five to 10% of those are detected in the bone. The real percentage of men with disease outside the prostate is going to be even higher because of the limitations of detection. So if you have a millimeter of cancer in a lymph node at the time of prostatectomy, we're not going to see it with PSMA. And that's where that sensitivity of about 75% or 0.75 comes from, is that in the studies where men with high-risk disease were subjected to PSMA prior to surgery, PSMA only found cancer outside the prostate about 70% of the time because the other disease was outside the limit of detection. So the real question and the real challenge for the field going forward in the next couple of years, how will urology respond to knowing? We're going to all of a sudden find more patients that have disease outside the prostate. Are we going to do better RPLNDs? Are more patients going to receive primary radiation therapy? What other multidisciplinary approaches are we going to take?

This is going to be a crisis in the urology field. It's got to be addressed proactively and thoughtfully and I don't know those answers, I don't pretend to know those answers, but it really is going to be important. We as a field, have to respond to knowing. Let me help you a little bit in understanding what we've seen, where do we detect disease by PSMA imaging in patients with biochemical recurrences. We're talking about generally in the field for urology, the prostate's been removed. So we're going to ask to sort of restage people with that prostate out in some, at least some lymph nodes that were removed at the time of surgery. So where do we find the cancer in the BCR state?

Well, we've done several studies here at Hopkins about this and participated in other studies with the NCI, as well as our colleagues in China and we were very much aware of the studies that have been done around the world and I'm just going to give you some examples of some sort of rules of thumb that we've seen that have held up across multiple studies, although I'm going to use some of our specific examples. So if we look across several hundred men and we look at who is in the BCR state, BCR right now means negative CT scan, negative bone scan, or negative MRI, and a recurrence of the PSA.

So the first thing you need to know is what are you going to find? Are you going to find something? And when should you look? Well, if you look at these PSA values and what we see with on PSMA imaging, whether it's gallium or ¹⁸F, if you look at a PSA of 0.2 to 0.49, about 30% of those scans will be positive, 70% negative at 0.5 to 0.99, it's 60% positive, about 30% negative, 60 to 70% positive over one to four, you get 80% positive, 20% negative, and over four we're pretty much going to find the disease. So I personally have been using a cutoff of 0.5 before I pull a trigger on getting a scan on some PSMA scan on somebody who is in the biochemical recurrence state to optimize our chances of finding the disease.

Where do we find disease? Well, what you can see here on the Y-axis is the percentage of patients that were negative or positive in those different ranges. This is from about a hundred patients here at Hopkins and you can see that for the first time which was a very big surprise to me the first time I saw it, literally across the spectrum in that 0.5 to 4 range, about 20 to 30% of patients actually have prostate bed recurrences. We find disease in their prostate bed, and that's independent of whether they had a positive margin at the time or not. And so the biology of how they got a recurrence in the prostate bed is really interesting and a topic for another day, but then you see, again a significant percentage of men have lymph node disease or prostate bed plus lymph node in blue. Some men have lymph node plus bone, and then there's this special group of about 10% of men who have bone-only disease and we're going to talk about that.

The other thing that starts to become a little predictive is will you see one spot or more than one spot? In other words, a single lymph node or multiple lymph nodes? And again, in general, as PSA goes up you are going to see more spots light up but in the critical setting where the PSA is less than one and we're doing a scan in the realm of biochemical recurrence, most of those men are lighting up with a single spot of disease on oligo disease, so to speak, and how again will we address that? When do we detect disease? Again, we've done a lot of plots of PSA value versus years from radical prostatectomy and it's pretty flat, we can see a lot of men failing in the first couple of years, but we also see very late failures also in this setting. We also start to see, when do you see a local recurrence? We tend to see those earlier. So this is prostate bed only prostate bed and lymph node. You can see that most of the failures we've been seeing are within the first couple of years, post radical prostatectomy.

And this is sort of another interesting point that I'd like to make that's very interesting for us is trying to figure out that pathway is again, PSA on the Y-axis, years from radical prostatectomy on the X-axis. Notice that in green you see the lymph node only patients and you see many of them all the way out to even 12, 15 years, and then the lymph node and bone in orange. Again, we're seeing those a little within the first five years, but what we've seen across multiple studies is that if you're going to have a low PSA and present with bone-only disease it's going to happen in the first couple of years which you see in brown there meaning that you had a cancer cell that escaped the prostate prior to prostatectomy. And if you're going to present with bone disease, you're going to do it early. We have not seen bone-only disease present after five years, even after three years, it's a different biology of disease that we're talking about there. And so this is really helping drive the way we're thinking about when is it safe to think about somebody maybe just having a local regional recurrence versus a distant recurrence.

This is a bit of a complicated slide and I'm going to walk you through it but it really is a summary of data. Again, we had a hundred patients that had undergone radical prostatectomy and we really traced where their disease occurred and when. So, first of all, again, across multiple studies, multiple countries, we're seeing a 20% recurrence in prostate bed after radical prostatectomy. That can be with or without lymph node recurrence but 20% prostate bed.

We then have a series of men circled with the seven on the right that you can see, recur very early in the pelvis and three patients who recurred very early in red had pelvic bone recurrences. Again, notice how quickly that happened. We then have a series of men on the left-hand side, nine of them who have a recurrence in the pelvic area but very sort of late five years out, all the way out to 17 years out and they seem to have oligometastatic disease, slow-growing. An interesting question is what do you do with the guy that's 17 years out from a prostatectomy lights up because his PSA is now 0.5 and he has a single lymph node. Does he really need that treated, or maybe that's something up for a discussion? But we do see prostate cancer marching up from the pelvis to the retroperitoneum all the way up to the mediastinum, and again, a scattering of bone mets in the ribs in the sternum, in the pelvis, but all very early.

Another thing that we've been trying to do is link PSA with PSMA imaging and PSA doubling time. We know that in the BCR space if you have a PSA doubling time less than nine months, you tend to have more aggressive disease, and more than 12 months may be more indolent disease. And what we're really seeing here on the again, left upper in A, is PSMA result percent positive with the different levels of PSA as I've talked about here, breaking it down to 0.5 to 2.0, you saw that we had 80% of the folks with a positive PSMA scan. This is combining about 300 patients from Hopkins and the NCI and again very few negative scans once you got over two. If you break in B, PSMA result by PSA doubling time, you can see it's a pretty flat curve that it didn't really add much to tell us. Once you have a positive scan, the PSA doubling time didn't seem to help.

If we look at pelvis confirmed disease and see again, PSA helped us determine where disease was, but not significant, really very significant unless you were looking at very low PSA values versus very higher PSA values. I don't think it's a real helpful measurement, but PSA doubling time does seem to help predict pelvic disease only. If you have doubling times that are certainly shorter than nine months versus longer. So this is still an area that's under active investigation and I think is going to be very interesting going forward but so far we haven't been able to make a firm link between PSA doubling time, PSA total value, and PSMA imaging. So where this has left us is that I think what PSMA imaging is telling us is that the majority of prostate cancer leaves the prostate and goes up, whether it's by nerves or lymphatics they've gone to lymph nodes. And they're climbing from the pelvic nodes to the retroperitoneal nodes and above.

There is about 10% of patients that have presented with bone-only disease and don't have lymph node disease and that may be because they dropped right into the blood and it may be that they just transited through the whole lymphatic system very quickly. So we're using this sort of as a new paradigm. I used to believe as somebody who's studied prostate cancer metastasis for 30 years, that the majority of prostate cancers were spilling right into the venous blood and contaminating the bone and now I no longer believe that. I believe that just like most solid tumors, cancer goes up lymph nodes and then gets to the bone. And again, I want to remind you in the setting of BCR, 20% of patients are going to have a recurrence in the prostate bed and that's a different kind of biology than what we're talking about here.

So in conclusion there's significant added value for the detection of lesions compatible with sites of prostate cancer over conventional imaging, even at low serum levels of PSA by PSMA PET imaging, whether it be gallium or ¹⁸F. Several clinical definitions may soon need to be modified, including oligometastatic disease, because oligometastasis is in the eyes of the imaging agent BCR itself, et cetera. A PSA less than 0.5 can be significant for predicting pelvic only disease PSMA 0.5 to 2. We really needed to define who has pelvic only versus extra pelvic disease, of course, for me the underlying potential biology needs to be further studied and validated. But I would say to all my colleagues in urology and radiation oncology and medical oncology, watch out, we're going to know things we didn't know before and we have to be ready to react to it. Thank you so much and I'm looking forward to discussing this.

Discussion

Alicia Morgans: Hi, my name is Alicia Morgans. I'm a GU medical oncologist at Northwestern University. So excited to talk with Dr. Ken Pienta, who is a Professor of Urology and Medical Oncology at Johns Hopkins, who just gave us a wonderful talk about the biology of PSMA and PET imaging. Also here today, urologist, Dr. Neal Shore, who is the Director of the Carolina Urologic Research Center in South Carolina, and Dr. Phil Koo, who is a nuclear medicine physician and the Director of Diagnostic Imaging at Banner Health MD Anderson Cancer Center in Phoenix.

Thank you all for being here and Dr. Pienta, I have the honor of asking you the first question. Thank you again for your talk, which was fantastic. I just wanted to learn a little bit more about your thoughts on this new understanding of mechanism of spread, or pathways of spread rather, that we seem to be understanding and defining with this novel PSMA imaging, really is seeming to upset our prior understanding of the way that cancers get out of the prostate and move.

Do you see this as having implications for therapy, for treatment? Thinking about salvage treatment, for example, if we have 20% of patients who have had a prostatectomy actually reoccurring in the prostate bed, and then this thought that perhaps a lot more of our patients may be having spread through lymphatics, rather than directly to bone, what are your thoughts there?

Kenneth Pienta: Well, thanks, Alicia. And again, it's just been a real pleasure to be here today. So there are two things going on in my brain here that are really exciting. Number one, I'm really encouraged to see that most of the failures that we see in the biochemical recurrent state are really local regional. The vast majority, if we really look with a PSA in less than two, and certainly in less than one, are going to be either in the prostate bed or in the pelvic lymph nodes.

And I think we have to, number one, figure out that biology of how does that prostate bed recurrence happen? And I think we'll learn more about thinking about positive margins versus negative margins. But remember, all of the patients I showed you did not have salvage radiation, did not need it, or adjuvant radiation, they had undetectable PSAs and mostly negative margins at the time of surgery. So, was that a cell that dropped out? I don't know, versus got left behind.

It also tells us, again, this stresses the importance of what PSMA imaging is going to be doing for the high-risk population. Again, what we're finding is that there is 10% of guys that probably have bone disease, and we have to figure out how to find them, we have no idea. Because they have that bone disease, they have a cell up there in a bone, probably at the time of prostatectomy, who are those guys?

But again, what are we going to do for the patients who do have positive lymph nodes now known at the time of surgery? And I leave that for Neal to address during this panel. But I also, again, want to point out that if you look at the big studies from Australia and by Nickols about failure after salvage radiation, you see the 50% of people fail, have disease that they can see by PSMA in retrospect that was outside that pelvic field. So, we have to use PSMA imaging to define where salvage radiation is going to be given, and primary radiation when the time comes.

Alicia Morgans: Absolutely. And I think certainly to think about our high-risk patients, as we're planning for surgery too, and try to understand better whether they may already have that metastatic disease in bone, as you've mentioned. I'll give the next question to Neal, to ask of you, he's thrown several your way already, Dr. Shore, if you want to answer any of those, and then, of course, ask Dr. Pienta any questions?

Neal Shore: Thank you very much, Ken. That was a brilliant talk as always. I love the way you're able to distill very complex concepts and make them very interpretable. And you began your presentation by talking about the personalized nature, which we've all talked about for decades. The heterogeneity of the biology of prostate cancer. We enter this era now of genomic molecular profiling, and now we see how that can create personalized tailored therapy.

Clearly, your message is with PSMA PET scanning, this will further lead to personalized better uses of our decision-making, rather than just saying, "okay, radiate the pelvis," or "radiate the prostatic bed," or think about taking out the prostate. So, these are really important decisions that you've now brought up, so really, thank you for that. I think in 2021, based upon what you're telling us, if you're running a busy clinic, academic or community, urology, medical oncology, radiation oncology, get ready because PSMA PET is going to be a proverbial dramatic game-changer.

I'm curious about your thoughts, Ken, on the OSPREY trial, and this concept about correct localization rate, which I think, really, at least from my interpretation, dovetails on everything that you're saying, a more tailored approach to understanding what to do in high-risk localized disease, in biochemical relapse, or additional trials in the nmCRPC arena that everyone's very excited about, and how we best figure this forward. Clearly, in my mind, it's all about multidisciplinary treatment now and cares approach. You can't go this alone anymore.

Kenneth Pienta: Yeah. I agree with that so much. And in the metastatic space that medical oncology lives in, there's no question that PSMA imaging, as part of theranostics PSMA treatment, is going to be critically important for therapeutics.

The other place that PSMA imaging is already, for those of us who've had the opportunity to use it a lot already because of trials and things, is that we're redefining oligometastatic disease. So, all of a sudden we'll have a patient who's been on hormones for years, we do a PSMA scan because they're now castrate-resistant biochemical recurrent. We see a single oligomet and we play whack-a-mole, we radiate that met. I mean, that paradigm didn't exist just a few years ago, and that's going to become a widely used paradigm by radiation oncology, urology, and medical oncology, in the very near future.

Whether that should be done is another question. But we're docs, if we see it, we want to kill it. So, whether that's a smart play or not, again, we're going to need multiple studies to do, and it may be hard to do them because once this technology is out and available, I certainly if I'm a patient, I want to get treated when I see something. In the setting of the OSPREY trial, the OSPREY trial for those of you who don't know is a study where we looked at men with high-risk prostate cancer, did PSMA imaging, and then very standardized lymph node dissections to see what the sensitivity and specificity were for detecting disease.

The trial actually didn't reach its primary endpoint and therefore is not being used for "registration", because it didn't meet it's sensitivity goals, in that there's a limit to detection, we can detect two millimeters of disease in the lymph node, we can't detect one millimeter. And what we found when we did these very nice packeted lymph node dissections templated, we found prostate cancers hiding in lymph nodes frequently. Ten cells can be found by a pathologist, can't find that by any known imaging agent. But if we did see it, specificity was way over 95%. If you light up by PSMA, it's cancer, it's not infection, it's not some strange metabolism thing going on, it's cancer, so specificity, really good.

And again, I would turn it back to you, Neal, what are you going to do, and now you have a scan in a glycinate guy who, by every other measure, you thought was negative, but now by PSMA you know he has three positive lymph nodes?

Neal Shore: Yeah. And it's a great question. And there's a lot of different approaches that are going on. As you mentioned earlier, will it move us towards a much more extended field of pelvic and retroperitoneal extirpation of the nodes? I don't think there's any doubt about that if we're taking a surgical approach. There are ongoing trials, which we're all very familiar with, looking at aggressive neoadjuvant hormonal strategies, and even adjuvant strategies, combining AR signaling inhibitors and going back to testosterone suppression.

And then even the concepts of subsequent pelvic whole field radiation, these are all up for discussion and review and clinical trials that we need to enroll to. I think one of the things that's particularly interesting to me is, can we use 18 F-PyL PSMA PET imaging to do a better job of our active treatments, and somehow, ultimately avoid testosterone suppression, which is really something that all patients and most clinicians recognize would be very important?

Kenneth Pienta: Yeah. And so, I certainly agree with that and I will admit, anecdotally, I've had patients travel out of the country to receive PSMA lutetium to avoid castration when they have early disease. And we have also seen from studies like the ORIOLE study, that Phuoc Tran ran, that you can use PSMA imaging to treat oligometastatic disease and significantly delay the need for castration therapy. So, this is a game-changer in early disease, there's no question about it.

Alicia Morgans: And I'd like to turn it over with the next question now to Dr. Koo because as a nuclear medicine physician, a lot of the onus of reading these scans certainly falls on you. And I know that you will have some really interesting questions, I think, for Dr. Pienta. So go ahead, Dr. Koo.

Phillip Koo: Thank you very much. And thank you, Ken, for that wonderful talk. I think it clearly solidifies the fact that biology is important, and rethinking biology is even more important now that we have this disruptive technology available. So, I think your talks are always so thought-provoking and really challenge all of us to really think about this space.

When we think about nuclear medicine and PET imaging, one thing that's interesting is, we've always treated how we interpret the images as binary, either it's negative or it's positive. And one of the strengths of PET imaging is the fact that it's a semi-quantitative technology where you could actually maybe assign a number to the amount of activity, the expression of the receptor.

What are your thoughts on perhaps what that might mean for these patients in biochemical recurrence? Do you think there's a role for looking at the SUV of PSMA uptake or lack of uptake, and maybe how that might impact how we make decisions down the road?

Kenneth Pienta: Well, that's a great question. One of the things that I like about PSMA a lot versus sort of standard PET is that, again, it's so specific to prostate cancer. And maybe you want to comment on it. It's not prostate... Prostate PSMA not only lights up with prostate cancer because of the PSMA on cancer cells, but it also can detect other cancers because of PSMA being an enzyme by another name that is on the endothelium of things like kidney cancers and other cancers. And there are several studies ongoing to see if PSMA can be used for those.

We've actually found several patients with thyroid cancer, for example, that was unknown because they lit up. And of course, we now know, we have a new organ in our nose based on PSMA. But except for where you see the sort of uptake in the salivary glands and et cetera, PSMA SUV's are pretty bright, as you know, and there's really... The specificity is so high because we don't get inflammation lighting up, and other non-cancer entities lighting up. And I think the amount of SUV is related to the amount of cancer that's there, the higher the SUV, the more cancer. And how we'll put that into practice is interesting.

So, for example, if you've got a guy who's 10 years from his prostatectomy, he's now 80, and he has a low bright lesion in the retroperitoneum. Maybe we could just leave that alone. Will we have the fortitude to leave it alone? I don't know, but that's probably somebody who we could leave alone versus somebody who might have an SUV of 10. So, I think that's going to be great and fascinating to figure out, and it's going to be a challenge for us to figure out. And maybe we'll be able to relate that to PSA DT, total PSA, where it is, lots of questions there that are really exciting to think about in the future.

Phillip Koo: Thank you.

Alicia Morgans: Great. So, Ken, I have another question. I just wanted to ask, because as a medical oncologist, which you are too, of course, I always want to try to walk this line where I balance benefits of my systemic therapies versus, of course, their harms. And we all recognize the significant harm of hormonal therapy, we've talked about that for sure.

I wonder what your thoughts are on using PSMA, this really exciting disruptive technology, as we try to think about some of the systemic therapies that we have for M0 CRPC, for example, so this "non-metastatic" setting where we know there's metastatic disease. We can see it, we know from analyses of SPARTAN, 98% of these patients, if scanned with PSMA, are going to have PSMA positive disease, we know that's true. But we also know if we treat people who fit those criteria with these intensified systemic therapy strategies, we not only delay time to metastatic disease, which is helpful in many ways but we also now know that we help them live longer. So there's a pretty significant survival benefit for that earlier intensification.

How do you see this technology, the thought that we're going to radiate different areas with SBRT, or whatever it is, or maybe we'll use surgical approach, how do you see that kind of an approach, using PSMA, melding with our understanding of the benefits of systemic therapies? And certainly, this is something that needs to be studied so I'm not asking for you to tell us the truth and the best way forward, but what are your thoughts on that?

Kenneth Pienta: Well, of course, I know the way forward.

Alicia Morgans: Of course you do, that's why we have you here, Dr. Pienta. Go ahead.

Kenneth Pienta: Well, so first and foremost, again, I think we're all going to struggle with redefining what M0 is. And again, I think five years from now, our future, the trainees that are now coming to the fore, will never know a non-PSMA world. And so for them, M0 is going to be defined in a totally different way.

My current approach in any patient, anecdotally, if we can have the power of a PSMA scan, or even right now, an Axumin® scan, that allows us to... Because their PSA is rising, we do one of those scans and see oligometastatic disease. I try to play whack-a-mole with that, look what their PSA does in that setting, and if it does not go away completely, then I go to those aggressive systemic approaches that we know increases life. So, I'm sort of melding the two already, recognizing that that's an anecdotal approach, but it's one that certainly my patients are very comfortable with, and certainly something I'm very comfortable with.

Alicia Morgans: I appreciate that. I think that's what a lot of us are actually doing. But as you said, it's going to be really difficult to study the best approach so we'll have to be creative and think about how to make sure that we can get that done. I'll throw out to Dr. Shore and then to Dr. Koo, one more question each as we start to wrap up. Dr. Shore?

Neal Shore: Yes. Thank you. Ken, in thinking about 2021, which is really around the corner, I think it's fair to say that technetium bone scan will become obsolete, relegated to oblivion. And thanks to the work that you're doing and others, 18 F-PyL, which we'll hopefully see an FDA approval by the end of May, early June, this will give our colleagues in the US access to this technology which has actually been around, and with the great accessibility, in many other countries throughout the world. There's a sort of an interesting disconnect that we have in the US, we have accessibility to advanced therapeutics, but we've really been behind in next-generation imaging. So, I get it, and I really appreciate the great presentation that our colleagues should benefit from how you've distilled this.

I also really appreciate the way you're thinking about this. So you've spent your whole career thinking about this, the homeland to host land concepts, which you've talked about before, which I think is a brilliant way of thinking about it. And now these highways that you described, and we're still learning, thinking, venous versus lymphovascular landing zones.

So, I guess my final question for you would be if I'm out in the community right now, and I have an advanced prostate cancer clinic, and I'm a radiation oncologist, I'm a urologist, a medical oncologist, how should I be thinking about this recent approval by the FDA for UCLA and UCSF getting their PSMA PETs approved, and how can we start to prepare for 2021 and accessibility to this really important technology?

Kenneth Pienta: So, it's a great question. And I appreciate the California folks got those approvals to help continue to use this scan for people that can access them in California and can afford to travel and things like that. And eventually, we'll probably see further approval of the use of gallium based PSMA imaging, it'll spread, it'll probably get approved down the line. But I think it's important to recognize that the number of scans that you can do, gallium based scans, and Dr. Koo can help us here understand this better, but you're limited in how many scans you can do in a day. Whereas with F18, hospitals almost are unlimited in their ability to use F18 PET scanning, and now F18 PSMA scanning.

So, once PSMA PyL is approved, I think it will become the standard because it's easy to make and it's easy to travel because it's based on current PET technology, and gallium is just tough to make enough of and get it out. And I think Phil can help us with that.

Phillip Koo: I think that's a great point. And right now, the gallium-68 supply is something that's being questioned, given the high use for GI malignancies and now potentially for prostate cancer applications. So, that's something that needs to be worked out, but you're right, F18 can be produced by cyclotrons that are now distributed throughout the country widely, which makes the supply of F18 pretty much a non-issue. And with the fact that the half-life is twice as long as gallium, I think the distribution and commercialization aspects really make this probably the ideal rate of pharmaceutical that could be distributed nationwide as fast as possible once approved.

I think the biggest concern right now is, I'm not too concerned about approval. I think the coverage, to me, really concerns me. Getting the payers to say, "This is valuable and we need to cover it." to me, is an even higher concern and I think it's something where we can all work together to then make sure our patients have access to this wonderful technology.

Just a quick question that I had was, what's your experience with non-PSMA expressing prostate cancer cells, and any thoughts on that with regards to biology?

Kenneth Pienta: So, I haven't figured out that biology. What I do think is important is that in primary disease and early castrate sensitive disease, the number of cells that are non-PSMA positive is not big. For example, when we do stating by immunohistochemistry for patients with small amounts of cancer that we missed by imaging, you don't see that it's PSMA negative. What we do see is that in patients who are more castrate and as cancer evolves, there are patients that have a mix of PSMA positive and PSMA negative disease. And it's actually fascinating that if you look at the Australian groups when they treat with PSMA lutetium, they actually get both scans, they get a PSMA PET and they get a regular PET. And if there's any disconnect between the PSMA positive disease versus the standard glucose PET F18 disease, they don't treat, you have to have matched disease. So that's a whole great story right there. But I think it's important that, at least for the high-risk in BCR states, that's not going to be a big issue.

Alicia Morgans: Great. Well, I sincerely appreciate your time today, Dr. Pienta, and of course, appreciate your time, colleagues here on this webinar. And I just want to congratulate you too, Ken, on all of the work that you've done with ORIOLE, with other studies where you really helped us to understand the basic biology, and also, to help us see how we really need to think again about the paradigm of metastatic spread and how we can tackle it more appropriately. So, thank you for being a groundbreaker, for being a great teacher to all of us, and we appreciate your time.

Kenneth Pienta: Yeah. Well, thank you again for having me. Anytime I can come back and talk about this fun topic that's going to change our professional worlds, I'm happy to do so.

Alicia Morgans: Wonderful.