Charles Ryan: Hello everybody. We have exciting news in the area of prostate cancer. There has just been an FDA approval of Gallium-68 PSMA PET scans for prostate cancer. And I'm joined by two experts in nuclear medicine, Phil Koo from Banner MD Anderson in Phoenix, Arizona, and Tom Hope from the University Of California, San Francisco, and the San Francisco VA hospital. Dr. Hope led the studies that led to the FDA approval of this in collaboration with colleagues at UCLA. And welcome both of you. Tom, tell us, this is really exciting. What is this FDA approval exactly for?

Thomas Hope: So the FDA approved Gallium 68 PSMA-11, a radiopharmaceutical, and the approval is in two indications. One is in patients at risk for metastatic disease at time of initial staging prior to definitive therapy and then the second indication is at time of biochemical recurrence after definitive therapy, as indicated by a rising or persistent PSA. So those were the two approvals of this imaging agent. I think the unique thing is it was approved only at UCSF and UCLA, and I'm sure we can get into what that means in terms of the availability over time.

Phillip Koo: So Tom, first off, thank you. I think a big congratulations and a big thank you on behalf of all the prostate cancer patients and people in the community who work on this because I think this is a monumental step forward. Can you sort of tell us a little bit about some of the misconceptions that we're seeing in social media about the availability of this new radiopharmaceutical?

Thomas Hope: Well, they're probably not fully misconceptions. So the approval is right now only at UCSF and UCLA. So the FDA, when they approve a new drug application, they approve it at a manufacturing facility and the manufacturing facilities, or the cyclotron facilities at UCSF and UCLA. Neither of the two institutions of our institutions paid for exclusivity. So it's a non-proprietary approval and anyone else can now submit an ANDA or other paperwork to make it at their facility. So we don't distribute it, we can't distribute it legally. We can only use it at our own institutions. But that being said, it opens the door and paves the way for other companies to now reference our NDA. So if you're a company that makes a kit, that's a PSMA-11 kit, and you want to sell that, you don't need any clinical data, you don't need any toxicology data, or anything like that, you just need chemistry data that you submit to the FDA and reference our ANDA.

So there are multiple companies out there already that have these kits that are submitting ANDAs or CNDAs, as they're called, and then other academic institutions can obviously submit ANDAs. And I think the way it will get out also most quickly is radiopharmaceutical distributors. So now, if you're a SOFIE, which makes radiopharmaceuticals around the country, they get one ANDA applied through their network, and then it can become widely available. But that process, the paperwork process will take about a year.

Charles Ryan: Oh wow. So at our own facilities, academic facilities, should we be contacting our business development associates in the enterprise to have them begin this process? Or are we not ready for that yet?

Thomas Hope: Yeah. So let's take the University Of Minnesota. What you would do if you're the University of Minnesota, you don't have PSMA PET. I want to make it available tomorrow. What's the fastest way to making that happen? So there's a couple of paths. Well, they're all sort of merged together. So first of all, you can start what's called an expanded access protocol. So you can get a gallium generator, label it and submit to the FDA an expanded access protocol, which will now get approved because there's an approved drug and it's not available in your region. So it's very easy to get that approval from the FDA and you can use cost recovery and charge for the drug itself. And now the nice thing is with this approval, Medicare will now be covering PET imaging and initial staging of prostate cancer, which they did not before this approval. So you can actually get paid for the technical component, both at initial staging and a biochemical recurrence for the use of the drug. So that's sort of the short term.

The longer-term is not... And this is where I think it's unclear how sites want to do this. So there were two NDAs submitted in September of this year. Which was Telix pharmaceuticals submitted a kit actually on PSMA-11. I'm not actually so sure in all honesty how the FDA handles an NDA now that the drug's already approved, if Telix we'll be converting it into an ANDA that's not actually clear. And then there was also DCFPYL. So one option would be, you wait for the kit or DCFPYL to be approved and use that in the fall of next year or you submit an ANDA as well, and you can make it in-house, but that will take you over a year to get that approved if that makes sense. There's a backlog of ANDA reviews at the FDA. So it's not going to be immediately available... You won't get it immediately approved like you would an expanded access protocol. There are some benefits of having your own ANDA because then you can bring revenue into your cyclotron facility. Instead of paying some random company a lot of money per dose, you can buy it off of your own institution, which will support research services at your sites.

Phillip Koo: Great. So Tom, you mentioned the initial staging piece, and this is the first time I believe a PET agent has been approved for use at initial staging. The approval is based on some of the data you presented at ASCO this year. Can you talk a little bit about that data, how you see this being utilized in that space?

Thomas Hope: Yeah, I think that's a really good question. So we were surprised in all honesty to get initial staging on our label. And why are we surprised? We were surprised because we did not meet our statistical endpoint from our trial. We were modeling our statistical plan after a paper that came out of the Technical University Of Munich. The first real paper was a very well done paper, 130 patients, PSMA PET compared to lymph node dissection and prostatectomy. And they reported a sensitivity of 67%. In the last year and a half, a bunch of papers have come out with sensitivity is more like 40% and not 67%. And what we published was 40%. And there's probably a couple of reasons for that, the difference in sensitivities, but it's probably because ours was prospective blinded readers. It was majority rule reads, so two of the three readers had to agree with each other in order for it to be determined a true read as compared to a single reader from the site where the path was done who might be able to see the results of the pathology, et cetera, or know the case because they probably read it out three months before all of our readers for external from our site. But anyway, so we ended up with a sensitivity of 40% in our population compared to pathology. Now that being said, that's much better than conventional imaging, which would have been negative in those patients. So it's a marked improvement.

I think that one of the take-home points and we... This paper is under review. Anyone listening to this, reviewing our paper give it a good comment. That's probably against the law to say that, I'm not sure, but when we were writing the paper, I think the thing that came out in the discussion, a lot of it was that if you have a negative PSMA PET, that does not mean you don't have nodal metastasis. So it's really important for surgeons for example to note that if you're going to do a prostatectomy on a negative PSMA PET patient, but they're high risk, maybe Gleason 4+5 high, but whatever it might be that patient probably still deserves a nodal dissection, even though the PSMA PET was negative. On the other hand, if it's positive, the PSMA PET specificity is very high. So if you do see nodal metastases, that's real. So I think that's a really important distinction in the way that this test is used clinically it's for detecting disease, more so than ruling out disease at initial staging. Does that make sense?

Charles Ryan: Yeah. And I think one of the things that I've come across with these scans is that you have these very rare cases or not even very rare but rare cases where people have mediastinal nodes or very high retroperitoneal nodes, things like that in a place you wouldn't expect it now I'm not the urologist making the decision about doing this surgery, but how much of that do we see? This is really sort of a natural history of prostate cancer kind of question. How often is it likely to maybe make the urologist say just say, "Well, I'm not going to operate because there's out of template nodes here."

Thomas Hope: Yeah. So there's definitely a good percentage of patients where the disease is out of template and would make you not do surgery. Now our study, we didn't do change in management analysis of our study. So we didn't track that as a change in management. But if you were to look at our patient population retrospectively, we had slightly more than half didn't undergo prostatectomy. And the majority of those patients underwent radiation therapy. And if you look at the incidence of metastasis in those patients is much higher. So the rate of pelvic nodal metastasis is like 55% or something in the patients who went underwent radiation therapy or systemic therapy. So there was clearly based on the results of the imaging study, people were changing their minds about what they wanted to do in terms of therapy.

I don't have that exact number of "we found this many lesions that changed the management of the patient". There are also some patients who still underwent prostatectomy, even though they had disease outside of the pelvis. So I don't think we have a really perfect idea of how you manage these patients. If you do have disease up here, does that mean the patient just goes straight to ADT?

Charles Ryan: Yeah.

Thomas Hope: We don't know the answer to that question, especially you could sort of extrapolate from maybe the STAMPEDE trial data, which suggested that in low volume metastatic disease, maybe radiation therapy to the prostate can be beneficial. I don't know if that can be extrapolated to prostatectomy. It hasn't been done obviously, but those are the discussions that we might be considering now that we're starting to see much lower volume disease outside of the pelvis.

Charles Ryan: And you also have data on serologic relapse, which may inform this conversation as well. In terms of whether ADT is the appropriate thing to do and which patients with serologic relapse can be treated with salvage radiation therapy and Phil, I wonder what your thoughts are on those analyses?

Phillip Koo: It was interesting in your study time, I think 87% of patients with a positive PSMA PET had rapid biochemical recurrence?

Thomas Hope: Well, rapid is a strong term. So we want to distinguish between biochemical persistence and recurrence.

Phillip Koo: Sure.

Thomas Hope: So a very high percentage of them had persistence.

Phillip Koo: Persistence.

Thomas Hope: Rapid indicates this aggressiveness, which is persistence, just to be clear.

Phillip Koo: All right. Yeah. I think this does raise a lot of questions and I think it's sort of a kickoff and I've always thought of the approval of PSMA as a kickoff, for now, many more studies that can be performed using these no longer novel technologies, using FDA approved technologies to really answer some of the questions that you pose. Charles?

Charles Ryan: Yeah. I'm looking forward to participating in those studies and Tom, what is this going to do, do you think, for the development of the therapy angle on PSMA, do you think it's going to affect it or make it easier for these therapies to be rolled out or no effect?

Thomas Hope: Yeah, so we have the VISION trial, it finished enrollment sometime last year and we still don't have results. So hopefully knock on wood we get some results from that trial sometime soon, maybe COVID delayed it, we don't really know, but it would be nice to see results. The approval of that drug does not, I don't think, depend on the approval of PSMA-11 PET. Maybe it did, I'm not sure, but I don't think that it would require that, I mean, they haven't submitted their NDA yet. So it's unclear if the FDA would have required that, maybe they're waiting to submit it, and tomorrow they'll submit it. Now that we're approved. Now, when it comes into practice, separate from the approval, you are going to need a PET imaging agent to select patients. Now, I don't think it makes a difference if it's PSMA-11, DCFPYL, RHP, SMA 7, and others, the whole family of all of these different PSMA targeted radiopharmaceuticals. I think the actual rate of pharmaceuticals sort of not germane to whether or not the therapy itself can be used, but you will need to have that available.

So having these types of retraces approval, once it becomes clinical becomes important, but the availability of lutetium PSMA radioligand therapy is well over a year from now, given that no NDA has been submitted yet.

Charles Ryan: Wow. Okay. All right. So not necessarily interdependent processes, but certainly they will be useful hand-in-hand I think over time. As an oncologist, I think about CRPC and the data that really struck me was the data with the non-metastatic CRPC patients in the SPARTAN trial. I've seen that data where those who had PSMA PET, almost all of them had in many cases, widespread metastatic disease by PSMA PET, but they were negative on the basis of standard PETs. Do you think we will get expanded approvals based on studies like that? Or is this just going to be out there now for us to use, and it will be an important academic question and drive therapy decisions perhaps, but not necessarily... We won't necessarily require expanded approval of the imaging?

Thomas Hope: So using imaging in a CRPC setting?

Charles Ryan: Right. Do we need to get expanded approval for that? 

Thomas Hope: I would say no. Now, so to be clear the approval by the FDA... And I don't know if this is intentional or not on their part, does not necessitate castration sensitive versus castration-resistant disease, it simply said biochemical recurrence is indicated by an elevated PSA.

Charles Ryan: That's a key clarifier.

Thomas Hope: Correct. Now there's a difference between private insurers and Medicare. So private insurers might fight you on it. I don't know what each private insurer will... Well, they're going to fight you on everything tooth and nail, no matter what the indication actually is, but Medicare, the way Medicare reimbursement works for PET radiotracers is that really there's a modifier. I don't know if you've ever coded Medicare plans, but if you do, there's a modifier and the modified, or the stage of disease, either 1 or 2, one being initial staging and two being management post initial treatment in essence, so re-staging. So you get staging or re-staging, and that's the only two things Medicare can know about a patient from the coding. And so the key here is that we've now taken fluciclovine, which was a 2, and added 1 to it by getting initial staging. So in essence, from a Medicare perspective, now the entire spectrum of disease with prostate cancer is actually technically covered from this approval, which is nice.

Charles Ryan: So PSMA PET is covered because fluciclovine was their first in 2?

Thomas Hope: That's a difference. So no. So it is a weird loophole. It's not a loophole, exactly. But so when FDG PET got covered way back in the day, in essence, oncologic PET got a national coverage decision. Oncologic PET didn't end up being radiotracer specific. So new PET radiotracers for imaging of cancers have in essence, been grandfathered into the FDG PET approval. So dotatate for neuroendocrine tumor? Covered. Fluciclovine, prostate cancer? Covered. PSMA PET will be covered. You don't have to go to CMS and have long-standing battles with the U.S. PSTF taskforce to try to convince them to do it. And that's in very contradistinction to like amyloid radiotracers, which I know Chuck, you're very interested in side effects of ADT and these agents in the brain. But if you think about amyloid for Alzheimer's disease, not covered by Medicare, right? And no matter how much data they can give them there, they have not been able to give us Medicare for now nearly 10 years to cover amyloid PET. But that's this weird loophole with oncologic imaging.

Phillip Koo: You know, the topic of reimbursement in PET is very hot topic in our field right now, Humana is now limiting coverage for PET. And it's something that I think we need to explore more and we're going to need the help of all of the different disciplines that are taking care of prostate cancers to really advocate on behalf of patients to get coverage for these important tools that will allow all of us to do our jobs at the top of our ability. So just want to thank you, Tom, again, for sharing your knowledge and really spending your time with us to educate all of us about this great advancement.

Charles Ryan: Yeah. I'm really proud to know you and congratulations. And that yeah, I recall conversation years ago on how is this going to be made standard? How is it going to get out there? And one of the challenges was there wasn't really sort of a company that was going to go do this. And so I think you've taught us all a really important lesson that sometimes you just got to do it yourself, which is what you did. And that's great.

Thomas Hope: Not myself, I need to correct that with UCLA. So without Johannes Czernin and Jeremie Calais, Matthias Eiber, Wolfgang Fendler, and then obviously everyone else at UCSF, but yes, academia can do it. 

Charles Ryan: That's what I meant, but yes, kudos to all of them and the wonderful collaborators and a real victory for the University of California. Let's put it that way.

Thomas Hope: Yeah.

Charles Ryan: So thank you.

Phillip Koo: Thank you.