Lecture Presentation:

Neal Shore: Hello, and welcome to our program today. This is one of a series of modules and the title, subject of our series of really educational events is called "Precision Medicine, PSMA Targeted Therapies in Progressive Metastatic Prostate Cancer Educational Forum". Really pleased today to have an outstanding faculty. Dr. Oliver Sartor, who is going to discuss academic practice perspectives on integrating PSMA lutetium-177 into clinical practice, lessons learned from radium-223 and more. Dr. Sartor is a Professor of Medical Oncology at Tulane.

And then we'll have Nick Vogelzang, who is an internationally renowned expert also in prostate cancer, who will talk about the lessons learned in going from radium-223 and other radiopharmaceuticals into this newer age of radiolagand conjugates, and how it might impact a community medical oncology practice. And we're really fortunate to have Alicia Morgans, medical oncologist, and Phil Koo, nuclear medicine radiologist, to weigh in along with myself. I'm Neal Shore, urologist, and have a really interactive question and answer period after the presentation. So thanks for listening. Oliver, please take it away.

Oliver Sartor: Oh, absolutely. And thank you so much, Neal, for the opportunity to be here today. It's really intriguing to be able to incorporate new practice-changing opportunities like PSMA lutetium-177 into clinical medicine. And I'm going to be talking a little bit about that today. And some of the lessons we've learned for radium-223. It turns out-- I've got a little outline here. Initially starting to think conceptually about therapeutic pharmaceuticals, then a little bit about the lessons we've learned from radium and some of the differences between radium-223 and lutetium-177. And then a little bit about the potential path forward, which I really think is intriguing.

So first of all, talking generally about radiopharmaceuticals, especially those that have some gamma emissions such as lutetium-177, there are "buying ripe tomatoes". That's the issue that I state, we talk about short half-lives and the implications of dealing with short half-lives. And then licensing. These were radiopharmaceuticals. They are special licensing. And then facility issues that have to be dealt with. And then multidisciplinary aspects to this therapy, which is very, very, very important. So let's look at this first concept about "buying ripe tomatoes", the radioactive half-lives make a real difference to the planning.

You really have to have an understanding of the shipping sites and when they can ship, the delivery companies, and when they can deliver, the planning for the receipt of the radiopharmaceuticals and the patient visit. And all of this needs to be coordinated. It's very unlike, something like cabazitaxel or docetaxel where you've got a long shelf half-life. People also need to understand from all perspectives, the companies who are doing the shipping, the sponsors, they need to understand that local conditions can change all of this well-timed planning and result in something that doesn't work out so well. Blizzards, floods, hurricanes, you name it. There needs to be some type of refund policy. And this is something that has to be worked out from the very beginning, because you can have patients who simply cannot show up for a whole variety of reasons, including accidents. So this is really an important part of the planning when you're dealing with these radiopharmaceuticals.

Another important aspect is licensing. So if you want to be able to administer radiopharmaceuticals, you have to have a licensed facility and you have to have a licensed administering position. And the licensure requirements take planning. It's not something you do one day and then administer the drug the next. You have to have a submission of documents, typically throughout radiation safety, to ensure licensure is approved both at the local facility level, as well as state agencies. And only properly licensed and trained physicians can administer these radiopharmaceuticals, typically that's either nuclear medicine or radiation oncology. So the proper licensing applies not only to the facility, but also the physicians that are involved, very, very key.

Now the facility requirements are a little bit different when it comes to lutetium as compared to radium. Lutetium emits a pretty high energy gamma. The fact is, you can image with lutetium and it turns out that you need to be able to isolate the patients in individual rooms and also limit exposure to clinic personnel. So you need to be able to monitor, I might add, the clinic personnel, in terms of their exposure. We use dedicated rooms with an adjacent dedicated restroom. Now it's just for the day. These are not dedicated rooms for now and forevermore. But if you have a spill or you have a contamination, you're going to create a major issue and basically keep that room out of commission until you get full decay. So watching out for spills, we actually put pads down in the region. We have these isolated, dedicated rooms and the dedicated restrooms we think are important.

Now, the holding times can vary according to local regulations. And if you look at a beta-gamma emitter like iodine-131, you might have some precedent set. But you typically need to be able to monitor the amount of radioactivity that is present within these patients. Now, multidisciplinary teams - absolutely necessary for optimal care. You must have that licensed physician to administer the drug. But that's not enough. You really need to have a physician expert in the management of prostate cancer. And that could be a urologist, it could be a medical oncologist, but it has to be somebody who really understands the disease of prostate cancer, not just somebody who pushes a drug. I say it takes two to tango. It may even take three to tango because a lot of times you may end up with nuclear medicine, radiation oncology, medical oncology all working together. You also need a radiation safety specialist. We use that specialist for licensure, for spill management, for monitoring personnel exposure, et cetera. And we consult with our radiation safety specialist at multiple levels along the way. You also need to be able to measure, as I mentioned earlier, radioactive emissions. That takes some proper equipment. It's not expensive, but you need to have some type of gamma counter or something like that that you can be able to see how radioactive these patients are because that in part will govern the discharge policies.

Now, lessons learned from radium-223. If you've administered radium-223, you've already gone through the necessary licensing. You've already gone through the team building for that compound. And transitioning to a new isotope is much, much easier than starting with a new isotope. So we've been using radium for a long time, actually over a decade now, and those preparations that we utilize for radium are very essential for us being able to set up a lutetium-177. But there are some real distinctions. The gamma emissions are quite low with radium, and the lutetium has a substantial gamma emission, so the hold times are going to be different. Just emphasizing for a moment the commonalities and the distinctions between radium and lutetium. Licensure is different. You've got a different isotope, and that has to go through different regulatory approval. The radium is an alpha emitter. The lutetium, the business end, the therapeutic end, is a beta emitter, but you also have to worry about the gammas because they can expose personnel, et cetera. Radium is bone targeting. The PSMA lutetium-177 is tumor targeted. When you're talking about tumor targeting, you need to have a selection criterion, and we have a predicted biomarker in terms of PSMA PET, whole different discussion, but it's not just bone and CAT scans like you use for radium. If you're going to be using PSMA, the lutetium, you need to have a way of selecting the patients who are appropriate for that therapy.

The degree of gamma, I've mentioned, you could actually image with lutetium-177, a little bit of trick there. You can actually treat and image with the same isotope, a little bit like samarium-153. And then the degree of post-injection monitoring is a little bit the same. In terms of the path forward, so a little bit speculative because obviously, I think we're going to move forward with betas as monotherapy, but they're already looking at combinations of alpha and beta, looking at isotopes and various hormonal therapies, Alliance/NRG is an upfront trial that is being planned along with Novartis. That'll be a global trial. We're going to be looking at isotopes in patients with DNA repair defects that may be particularly radiation-sensitive. We're going to be looking at isotopes and PARP inhibitors and maybe other inhibitors in DNA repair, like ADR inhibitors. We're going to be looking at isotopes and radiosensitizers and to be able to potentially augment the effects of these isotopes and also isotopes and immunotherapy as an area that's burgeoning and filled with new clinical trials. So all in all, very exciting area, lots of lessons learned, lots of opportunities for advances. And again, thanks for the opportunity to be here today with you.


Neal Shore: So Oliver, that was fantastic. I love your energy and your enthusiasm. The path forward is really exciting. And you did a great overview of some of the accessibility implementation and licensure issues. I know we'll want to hear from Phil Koo later as well as Alicia, but maybe we turn it over now to Nick Vogelzang. And Nick, can you give us your thoughts on Oliver's presentation as well as how it will impact community medical oncology, and quite frankly, probably community urology, nuclear medicine, and radiation oncology? So a simple ask of you.

Nicholas Vogelzang: It's a pleasure again to be here. I enjoy meeting with all my colleagues in a virtual format. So Oliver and I were early users of radium-223. We both accrued to ALSYMPCA, and then when the expanded access program for radium-223 opened up, we were able to accrue well and publish that data. So subsequently we've treated in Nevada about 300 radium patients. So we have a large experience. About two-thirds of those are my patients. One third are my colleagues' patients. We've given it at two sites. We've opened up my site, which is in the Central Valley, and a peripheral site, and that's been logistically better because it allows patients to not have to travel so far. The uptake of lutetium, of course, was then an obvious next step because radium has some drawbacks, mentioned by Oliver, namely the lack of a PSA decline and a protracted period of treatment. And also some data that suggests giving it with abiraterone or the second-generation AR inhibitors may increase the risk of fractures. My policy and those of my colleagues has been to give radium with a bone agent, and we've had a fracture rate that is less than 10%. So I believe you can give radium along with a second-generation AR inhibitor safely and effectively as long as you use it on an AR agent.

That having been said, the lutetium VISION trial made a lot of sense to us because radium doesn't hit the soft tissue disease. And many times you see lymph node or lung or even worse, liver progress when you're on the radium program. And you're frustrated. You don't know whether to give chemo or to stop the radium. You want to get maximum radium effectiveness, which is six doses. So we've embarked upon the lutetium. And lutetium really is being boosted by the PSMA scan. And I would just drive everyone's attention to the CONDOR trial that was presented by Mike Morris at ASCO showing an extremely high uptake and sensitivity across all disease states, even as low as 0.5 PSA. So we're able to identify sites of disease. There's a very high correlation between radiology reviewers and what is reviewed as a possible site. And this will, of course, stimulate the use of a PSMA-linked radioisotope. And so my feeling is that lutetium has a big leg up on radium. It not only has a target that we can image, but we also have a PSA decline that is much superior to radium-223. And the two agents that are least utilized in castrate-resistant prostate cancer are sipuleucel-T and radium. And both of them do not lower the PSA, even though they extend life. So the lutetium data that was presented from Australia, and hopefully the VISION trial, will be a big, big boost.

Now, I would add one caveat, and that is that, again, these are palliative agents. They are not curative agents. I've treated a lot of lutetium patients now, and unfortunately, the duration of response is finite. Now, if we move lutetium earlier into lower-volume disease, particularly since we're picking up PSMA scans in a very early stage, it may be possible that the early use of lutetium in a PSA-only relapse patient will improve overall survival and improve our number of long-term survivors measured by two, three, four-year survivors. So my view is that lutetium will be great as long as it's known to be a palliative agent, and in the right setting, we may find that it extends the overall survival, but also improves the number of patients who are potentially cured of this disease. That's my hope for the future. It's a little optimistic, but that's the hope. The logistics of lutetium are daunting at some level. You need a higher level of radiation safety. You have to have the patients exit the building. You do have to take precautions against spills, transport issues. We are very careful with patients who are urinary or even have minor fecal incontinence and have turned patients down because of the urinary and fecal incontinence issues.

That having been said, the other minor points that Oliver addressed were the dry mouth, dry eyes. Those are real. They seem to resolve over time, but they can be annoying to the patients as we get further into the fifth, sixth cycles, again, a reason may be the potential to reduce the number of cycles to four rather than six.

Faculty Discussion:

Neal Shore: Thanks, Nick. Those were really great insights from your vast personal professional experience as well as insights as to how this will work in community medical oncology and for all community health care providers, gosh, with the complexity of prostate cancer treatment options. Let me ask you, Phil Koo, I mean, Oliver brought up some really important points about especially the multidisciplinary team aspect to getting a radiopharmaceutical, not only up and running, but transitioning it from potentially radium to new radiopharmaceutical ligands. What are your thoughts, Phil?

Phillip Koo: Yeah, I completely agree. And this idea of multidisciplinary teams, it's a theme that we've heard now in several modules, which I don't think we can emphasize enough the importance of that type of model. And I think that model is going to look different in the community setting, what Dr. Vogelzang alluded to, and Oliver in the academic setting. I think it requires just some creativity with regard to how we make it work. When it comes to nuclear medicine, even from my perspective, even if you [inaudible 00:18:26], it's kind of like one of those [inaudible 00:18:30] on how a cruise ship works. There are so many things that go on behind the scenes that people can't appreciate that really make a huge difference in terms of safety for the patient, safety for the staff, and safety for society as well. And when we're dealing with these radiation particles that are unsealed, there is a potential for some harm here. And I think it's important for us to make sure we follow all the different regulatory requirements.

The question I have... And maybe I'll ask Dr. Sartor first... is unsealed radiopharmaceuticals, they've been around for a while, but clearly we're seeing a resurgence in prostate cancer and GI malignancies and whatnot, but there seems to be a stigma associated with these radiopharmaceuticals when it comes to prostate cancer. Can you talk a little bit about that and how we could sort of get away from that and really embrace the idea that these radiopharmaceuticals [inaudible 00:19:24] clinical endpoints as opposed to just bone pain relief?

Oliver Sartor: Sure. And it's an interesting point. If you go back to the radiopharmaceuticals, you really have to start with strontium-89, the samarium-153, which were purely palliative, and the ability to provide true therapeutic benefit beyond simple pain relief has been something that was lacking until radium came by. Now, radium has its own limitations, being bone-targeted only, not really altering PSA to any substantial degree, and yes, it did prolong survival, but it was hard for patients to see that PSA decline that they often associate with an effective therapy. I think all of that's going to change with PSMA lutetium-177 because not only do you target the tumor, you change the PSA. I'm confident that we're going to show that there's true benefit in terms of radiographic progression-free survival, overall survival. And I think patients are going to endorse this because of the lack of toxicity. And I think it's going to be much preferred as compared to chemotherapy. So I think that old stigma, I think it's going to go away with these new agents.

Neal Shore: I think those are great points. Phil, I love the fact that you're emphasizing that this is not insurmountable. Collectively and based upon all of our experiences with radium, lutetium-177, as Oliver suggests, this is going to be a game-changer. And I really always bristle when I hear any of my colleagues say, "Well, there's this. There's that." Yes, we have to overcome certain barriers of implementation, but when there's clearly demonstrated efficacy, outcome benefit, and good safety profile, which we'll further discuss, then the burden is on us as healthcare providers. But Alicia Morgans, I'd love for you to weigh in. You have an enormous trial and clinical experience, but you also work a lot with the community folks too in Metro Chicago.

Alicia Morgans: Yeah. So thank you, Neal. And actually, thank you both for such outstanding presentations. I think that my question really for Nick is as a community medical oncologist, you have made these coordination processes work in administering radium and also in participating in trials like VISION. And I have been able to do that too, as have multiple community practices around us here in Chicago, though at this point, in terms of lutetium, they have sent everybody to us while that study was open. When lutetium is approved, I'm sure that you have advice or guidance for community practitioners who are trying to solidify these relationships between themselves and these other practitioners and how to make them run smoothly. What advice do you have?

Nicholas Vogelzang: Well, my view on lutetium is that it will be a better agent in earlier stage disease, particularly in the node-positive patients that we're picking up on the PSMA scans. These are low-volume disease patients, and we are currently doing external beam radiotherapy in an ORIOLE, STOMP, RAVENS-type trial design. But my feeling is that the adjuvant use of lutetium for maybe four cycles should be okay. I do worry a little bit more about lutetium and its potential for secondary malignancies because it's a beta emitter. We haven't seen that with the alpha emitter yet, hopefully never. So that would be the next step with lutetium, I think, earlier use, adjuvant use, and expecting no or minimal hematologic toxicity, which was shown in the Australian trial. So one of my concerns, of course, is that radium is a bone marrow suppressive agent, and radium, lutetium combinations either together or in sequence may have unexpected bone marrow suppression. So I would urge docs if they're going to do lutetium after radium to at least be cautious and not to get overly optimistic. But I also would suggest that lutetium should suppress or supplant radium-223 until it's approved. So I'm looking forward to the utilization of both agents because sometimes the bones are a real dominant issue, and you want to use something like radium earlier than you would normally do.

Neal Shore: Thank you very much, Nick. That was great. I appreciate the comments and for all that you've done and your presentations today. So with that, I think we all absolutely unanimously share that enthusiasm. Phil, I'd like maybe you to get the last word on your perspectives as an expert in nuclear medicine radiology. And we know that different folks around the country will be having different models, nuclear medicine key leadership, radiation oncology key leadership. Your thoughts on how to tackle developing a program? Because, as Oliver pointed out, and Nick also states, it's not a question of if, it's when. These new advances are going to happen for sure. So final comments.

Phillip Koo: I think the roadmap to success here is going to look different for each practice. I think it's important that when we start having these discussions, that we keep the patient at the center of all those discussions. How do we make it better for the patient rather than the providers? Because this idea of patient-centered care is the driving mission for our practices. So it's complicated, but it's not insurmountable. I imagine in the community setting radiation oncology will play a much larger role in the delivery of these unsealed sources of radiation, and they have the qualifications and the knowledge and the capabilities of doing this. Again, we have experience with this. For facilities that are starting a new radiopharmaceutical program from scratch, yes, it will require some capital investments, lead-lined rooms, radiation safety equipment, these wells where you could have these radiopharmaceuticals decay. But again, with some support, whether it's consultant support or whatnot, it's doable in a variety of settings.

Neal Shore: Wonderful. Thank you. Great panel. Great discussion. Thanks for all your efforts. I really appreciate it. Thank you.