Robert Flavell: So it's my pleasure today to welcome you all to join us today for this Prostate Cancer Outreach Webinar. This webinar has been organized in collaboration with the Society of Nuclear Medicine and Molecular Imaging's Prostate Cancer Outreach Working Group together with faculty from the University of California in San Francisco. And the topic of the webinar today is on changing the standard of care in prostate cancer with advances in nuclear medicine, PET, and theranostics.

And so I'll briefly introduce myself to start. So I'm Rob Flavell, I'm an Assistant Professor in the Department of Radiology and Biomedical Imaging at UCSF. Also, the Section Chief for Molecular Imaging and Therapeutics. Today, we have a great selection of speakers, including both nuclear medicine physicians, as well as clinicians of various different types involved in prostate cancer care. So really clinicians and imagers spanning the spectrum of clinical care in prostate cancer.

Maybe if we can have all the speakers turn on their cameras and then unmute when they want to speak. Linda has been passing me some questions. There have been some technical issues with the Q&A box and the chatbox, but I do have some that have been passed to me, so let's start with those.

So the first one that comes up is maybe for Tom, which is, PSMA is not universally available, and there are other radiotracers in addition to Axumin® that are out there. Do you see a future role or can you comment on the use of sodium fluoride or FDG in prostate cancer? Is there a future role there?

Thomas Hope: Yeah, so that's a great question. So first, I guess I should clarify something that's really important, is that fluciclovine currently is the best widely available radiotracer for the staging of patients with prostate cancer. I think I didn't state that strongly enough in my talk and that should be clarified.

In the era of when PSMA PET becomes widely available, which it is not currently yet, let's say two years from now it's widely available, in that setting then there in my view is very little to no role for fluciclovine or sodium fluoride. FDG PET's a different story. FDG PET I would say currently has a limited role. There are a few institutions in the country that use FDG PET, but it's much more in the castration-resistant area where you're not really using it for detection, but for characterization of aggressiveness of disease. And the Peter Mac data that Rahul had mentioned where you're looking at PSMA PET and FDG to characterize whether or not there's PSMA negative FDG positive disease, then maybe as we move forward in the setting of PSMA and radioligand therapy. But currently, the role of FDG is somewhat limited.

Robert Flavell: Great. The next question, any of the speakers could take this one. Which is, since the targets are new and much of the data is quite recent, how well do current guidelines reflect the role of PET or SPECT imaging in prostate cancer?

Thomas Hope: I'll go for that one. So it's a big issue, guidelines. So I would say that currently, the NCCN guidelines are really the most commonly followed guidelines, particularly for insurance coverage and Medicare coverage. Fluciclovine was really the first radiotracer to be approved in the setting of prostate cancer and from Medicare reimbursement at the base only in the re-staging setting. So currently you can really only get paid repetitively in our re-staging setting, which sort of mirrors that of fluciclovine.

So hopefully moving forward, one of the big goals of PSMA PET or other radiotracers to get approval in initial staging settings so that we can get coverage from Medicare and other private insurers at initial stage in which it currently is not.

Robert Flavell: Okay, great. The next question on the list is, so I think it was well covered the role of PSMA PET and other next generation imaging agents in newly diagnosed high-risk prostate cancer and in biochemical recurrence. What about other clinical settings in terms of expansion? For example, is there a future role for PSMA PET in active surveillance patients or other types of prostate cancer? Do we think it's effective for monitoring response in oligometastatic disease?

Felix Feng: You know, I'll jump in with part of that. Maybe Hao can jump in on the active surveillance. With regards to response monitoring, I think the answer is, we don't know. Certainly, I think it's an area that should be tested in ongoing studies. I know it's one of Tom's primary interests is to get PSMA PET as the patient's responding to look for response resistance. But if you extrapolate from other disease settings outside of prostate cancer, early PET scanning is a predictor of response to therapy and I don't see why it wouldn't be true in prostate cancer, but I would say that it's not well established yet. With regards to active surveillance, Hao, I'll pass that one to you.

Hao Nguyen: We had a Phase III trial looking at MIP-1404 PSMA PET scan in active surveillance patients and the data didn't meet the primary endpoint, which is detecting of high-grade cancer sensitive enough above 40%. So it was at 40%, so the trial was not a positive trial, but I think it could be the agent. I think that it may have a role if the technology improved in terms of if we identified better agents to augment the expression of PSMA in the patient who has a low rate of disease or a very small amount of high-grade disease that is not detectable by the traditional imaging that we use, mainly MRI. So I think in the future, we would like to expand this into the active surveillance cohort. Because currently, the main thing to monitor active surveillance any chance of any sign of progression is mainly biopsy. So we typically biopsy them every two years or every one year. I think I do the majority of these biopsy for the practice, and that's a lot for these patients.

So if we have a better imaging modality that can detect a small amount of high-grade cancer that is not visible by MRI, that would be better. I think we have a few. I think Rob is involved in one of them using pH or lactate, the various modalities that we're going to be integrating in the future, I think. I think it does happen.

Felix Feng: I'm going to jump in behind you, Hao. I'm interested in what Tom has to say about this event and Rob as well, but I suspect it might be harder, and this is only a suspicion, harder to get PSMA PET approved in the active surveillance setting just because of the number of patients that you would need to scan for one positive finding. And so from an insurance perspective, I'm not sure what the metric will be for them to reimburse for that. Tom, do you have any idea about that?

Thomas Hope: I think it's a really good question. The reimbursement coverage in active surveillance sessions gets a little set and gets a little complicated. So Medicare doesn't have the ability to differentiate between low-grade and high-grade disease in the initial staging setting. So actually technically once it becomes approved by the FDA in initial staging, it gets covered by Medicare in the setting of initial staging, it actually automatically will be covered, unfortunately, in the active surveillance setting which will lead to a lot of inappropriate use of PSMA PET, which is likely to happen. I think one of the issues of PSMA PET from what I can tell of our experience, is that the uptake on PSMA PET doesn't very well distinguish high and low-grade disease. But it is fairly good for detecting between Gleason 3+3 and greater than 3+3, so maybe in clinically significant cancer.

So it's never going to replace biopsy or biopsy [inaudible 00:08:17]. It's going to be another adjunct to biopsy to tell you where it's cyclical in the end. So whether or not it will ever play a role stronger or greater than that of MRI, is a [inaudible 00:08:29] where people put needles or TRUS biopsies. I think it was a long way to go. Insurance is a little bit muddier simply because of the way Medicare coding works.

Robert Flavell: And since we're on the topic of insurance reimbursements and coding, what do you guys think about the cost-effectiveness of PSMA PET or other next-generation imaging? Is this something that society is willing to pay for? And if so, how frequently?

Hao Nguyen: I think PSMA for high-risk disease, I think that we should get these on everyone with high-risk disease so we don't under treat the cancer or over-treat it. And I think Medicare or the payer should invest in that. In the longterm, it does reduce the burden of treatment or the costs associated with it. So I do believe that for high-risk patients, everyone should get a PMSA PET scan.

Thomas Hope: I'll just point out that that was not a nuclear medicine physician speaking right there.

Money is a funny one in our system, right? We don't actually make decisions based on whether or not they're cost-effective and that's particularly true in a Medicare population. So whether or not it's cost-effective, that's a whole different discussion. And how we determine costs varies over time. But I think it's clear that there's a clinical benefit and it is the best way to stage patients with prostate cancer. I don't think right now anything ever actually goes through a cost-benefit analysis effectively in how it's used, except for maybe in a USPTS screening guideline.

Robert Flavell: I guess a question maybe for Felix is, are there trials either ongoing or planned with the use of PSMA PET to help guide oligometastatic disease therapy and correlating the results with outcomes?

Felix Feng: So in one of my other roles I didn't mention, I chair the Genital Urinary Cancer Committee for NRG Oncology, which is a national international clinical trials group. And so we have a randomized study using PET imaging. We didn't specify to identify patients with oligometastatic disease, which we're then randomizing to radiation with upfront systemic anti-androgen therapy or radiation with delayed anti-androgen therapy. Tom actually is the imaging lead on that particular trial. And so we're trying to push that one through, but also in the biochemical recurrence setting, we are trying to start a STAMPEDE-like trial, which is STAMPEDE is a multi-armed trial that was led by Nick James out of the United Kingdom and is still ongoing in the space of metastatic hormone-sensitive prostate cancer.

We're trying to accomplish the same thing in the context of PSA recurrence, where we want patients to undergo both PET imaging, ideally with PSMA PET, but actually for whatever they can get reimbursed for, and genomic tests. And using the combination of genomics and imaging to risk-stratify patients, and then offering them a multi-armed randomization. And some of the randomizations will be based on de-escalating therapy based on where the PSMA PET does not show a lesion. So for example, in patients with PSA recurrences after surgery, if they're shown to have positive lymph nodes, but they have no disease in the surgical bed and they have negative surgical margins, one of the arms is proposing to radiate to a less dose from 70 grade to 50 grade.

And so there are a number of concepts out there. I think with the pending FDA approval of PSMA PET, our therapeutic landscape is changing. I think a lot of people are going to be running trials with it just because now that you have the data, what do you do with it? So I think that's going to be the bigger issue that we're going to spend the next five, 10 years trying to answer.

Robert Flavell: Great. One other question just typed into the chat is, there's some interest in using focal therapy for treating prostate cancer, like focused ultrasound or gland cryoablation. Is there a role for PSMA in assessing patients for focal therapy to the prostate?

Hao Nguyen: Yeah, so I'll take that one. So yes. So focal therapy is definitely a good option for some patients with just one area of cancer that is away from vital structures and they want to minimize the side effects from erection issues or urinary incontinence associated with surgery or a more definitive treatment. So right now we use it to determine if we miss any high-grade cancer that we potentially we could miss on focal therapy. We use MRI template mapping of the prostate by systematic biopsy and MRI. So we use a biopsy 1820 sample in this patient. Totally, if we have the ability to accurately detect high-grade cancer elsewhere in the prostate with PET, that would be better.

Currently, there's no trial for that yet, but these patients are patients with low-grade to high intermediate-grade lesions, six or seven. Those are candidates for focal ablation. We don't have an indication to use the PSMA PET in those patients yet, but I think once you get FDA approval using it to guide treatment decisions for these patients, I do think it's going to play a future role in our selection for patients who desire focal therapy.

Robert Flavell: Great. I think this next question is maybe better for Rahul. Which is, it seemed like the data that you've presented on the use of lutetium PSMA were focused more in late-stage patients who had received prior taxane therapies. Given that the rate of PSMA positivity seems to go down in these late-stage patients, do you think that lutetium PSMA, for example, might be better positioned to be moved earlier on in a patient's treatment course?

Rahul Aggarwal: Yeah, I think that's a great question. I think that in terms of the initial design of vision and some of the post-chemotherapy trials, this is I think more a by-product of drug development and trying to get timelines, and a readout, and what are you trying to compare lutetium to? So I think you can use VISION as sort of the first foray where you could see the comparator was really retreatment with AR targeted therapy. Really little in the way of active treatments. I think an important trial in a way of a proof of concept, but I absolutely agree that biologically perhaps it makes sense to move earlier in a setting where you may have more homogeneity. Although I will point out, I think even in earlier CRPC settings, the patients were all, and the cancers were all, still castration-resistant and so I think you may have heterogeneity in that setting.

I think ultimately it will be borne out by the data. I think as you move earlier, of course, your comparator arm changes. You'd have to see how good lutetium stacks up. I think that I would want to see the data personally before I decided to treat a patient with lutetium ahead of some of the more standard of care therapies knowing that patients respond but the response duration can be relatively short. I think it's going to be important to see the survival outcomes from those trials.

Robert Flavell: Okay, great. Well, I think we're about at the time here. I'd like to thank all of our panelists for outstanding lectures and the lively discussion on the use of next-generation PET imaging and theranostic agents. And thanks again for your attention and for attending.