Oliver Sartor: Hi, I am Dr. Oliver Sartor. I'm with UroToday, and it's really a pleasure for me to be able to introduce someone who's very well known in the urologic field, Dr. Neal Shore. Welcome, Neal.

Neal Shore: Thanks, Oliver. Great to talk with you today.

Oliver Sartor: We have an interesting topic. We're going to be talking about the development and the implementation of radioligand therapies within the context of community practices. Since you're a urologist, you're a rather unique urologist. I don't know anybody else quite like you. That's a compliment, not a detriment, that's a compliment. Neal, you're giving the radioligands in your practice. You're in Myrtle Beach, South Carolina. Can you tell us a little bit about your journey, about how you began to think about creating the opportunity for radioligand therapies for your patients and actually began to implement it? Go back to the beginning, because I would like to hear, and I think our listeners would like to hear how you managed to think about it and get things started.

Neal Shore: Well, I actually was very much influenced by you, and the first time we met was when Algeta was developing radium-223, before it was acquired by Bayer, or as our overseas colleagues say, Bayer Pharmaceuticals. And I loved your passion for radiopharmaceuticals and particularly the role for radium-223. So after the expanded access program, we actually gave the first dose in our clinic after the EAP and the FDA approval. We were proud of that. So that was, gosh, I think 12 years ago.

Oliver Sartor: Gosh, I was about to say that. That's probably 2013, so well over a decade ago. That's amazing. I didn't realize that, Neal. I didn't realize that I was influencing you, but I'll simply say you've taken it and run pretty nicely.

Neal Shore: Well, you were awesome. ALSYMPCA was a great study, a great trial. It was cutting-edge for the period that it was. If we fast-forward now, geez, we have the proverbial embarrassment of riches now with lutetium PSMA-617 and many other products that are coming into play. So lutetium is a beta-emitting particle, but there are going to be alpha-emitting particles for sure in the form of actinium-225 and others and other moieties, and it's so interesting to think about the development pathway of just lutetium and the VISION trial, which was brilliantly led by you. You've also been involved in PSMAfore, which is pre-chemotherapy mCRPC. I was on that steering committee with you. And then PSMAddition, which is now a positive study in mHSPC. We both talked about it over a meal at ESMO just a couple of weeks ago. So I love the leadership that you've shown and many of our other colleagues, and it just expands what we do in systemic therapies. Because unfortunately we don't cure everybody with prostatectomy or with radiation or other forms of ablative strategies, and unfortunately too many of our patients present with metastatic disease.

So I really got so interested, Oliver, back over a decade ago, recognizing here are unique mechanisms of action on top of taxane-based therapies, on top of other immunotherapeutics, on top of ARPI strategies, PARP inhibitor strategies. We now have so many other things in the pipeline, but the radiopharmaceuticals or the theranostics really lend themselves—as you were really demonstrating that radiopharmaceuticals lend themselves brilliantly, as the ALSYMPCA was designed with your vision—to combinations, and there's even arguably an opportunity for radiopharmaceutical strategies to obviate testosterone suppression for a time in certain patients. And these therapies require a multidisciplinary team. I've always been an enormous proponent of that, whether it's for a radiopharmaceutical or a taxane-based therapy or now with antibody-drug conjugates and T-cell engagers. But the radiopharmaceuticals, and I know that's what we're talking about, radioligand therapy, really should be part and parcel of any well-described, well-designed center of excellence, academic or in the community, so that patients can have an opportunity to benefit.

Oliver Sartor: Neal, let's drill down on some of the practicalities. It takes things like a radiation safety officer. You have to be able to store radioactive waste. You have to be able to accept delivery through your door and have an authorized user for somebody to administer the isotope. That's very daunting. If you were to advise someone today to begin getting into the practice, to go from step zero, which is nowhere, to step one, which is actually being able to implement some of these therapies like lutetium PSMA-617, what would you tell an interested investigator today about how to begin the process?

Neal Shore: Yeah, it's a super important question and something that all medical oncology practices and uro-oncology practices and radiation oncology practices and certainly our nuclear medicine colleagues are addressing, whether you're in academia or in the community in the US or outside the US. So you're absolutely right, there's different licensure. You need to understand what it means to be an authorized user who can administer these therapies, who's qualified to handle them. In the US we have what's known as a radioactive materials license or a RAM license. There are different ones for whether it's a beta-emitting versus an alpha-emitting particle, and it can also vary on a state-by-state basis. This is not daunting. This can all be accomplished. One needs to have an understanding of the Nuclear Regulatory Commission parameters within your state. You need a radiation safety officer. You are ultimately, much like with radiation and linear accelerators, going to have a physicist who's going to help you, especially if you've been having an active brachytherapy program.

There are some really important issues regarding shielding. It's not particularly capital-intensive. There are important issues about having certain not-expensive startup pieces of equipment, calibrators, and what to do with your storage, but also the waste and some level of shielding. None of this is impossible to do. It doesn't require an enormous amount of space. You do have to have some thoughtful planning around how you set up your therapy and your uptake rooms as well as bathrooms for patients. And of course the ever-present issue of how do you bill for these things. But it's not insurmountable. It's a team approach, a team sport, so to speak. These resources are all available, and ultimately I would say the startup to do all this involves understanding the scope of the needs—I just mentioned them very briefly and very succinctly—but what the deliverables are, how you can approach it, who has different roles and responsibilities, the regulatory requirements.

Not too dissimilar, but specific and unique in certain aspects from setting up a radiation center or setting up an infusion center. It does take a multidisciplinary team, and there's no doubt about it. And I think that's one of the big lessons I've learned over the arc of my career: it's really pretty impossible to do any of these things totally on your own. But I think our patients demand that they get this sort of integrative care, and it's great because it not only will provide state-of-the-art care in the US. We have the good fortune now of having lutetium PSMA-617 approved in both pre- and post-chemotherapy mCRPC. I'm optimistic that the PSMAddition study, which you are a key leader on, will also get approval. I hope that's the case.

And there are many other radiopharmaceuticals in the theranostic world as opposed to the diagnostic that'll be moving forward. So many of our colleagues now globally have PSMA PET technologies, and that PSMA PET/CT is really now somewhat of the undisputed champion. I mean, there's still some smaller role for conventional imaging, but when you take that PSMA-targeted approach towards diagnostics and then you put in a payload with the appropriate linker, which you've been pioneering, and there are many other ones to follow lutetium, I think it's not about if you're going to do it. It's really when are you going to get started and putting in the team to do it. The capital expenditure is not that formidable, nowhere near what it would cost to really set up and buy a linear accelerator in a radiation center or an ambulatory surgery center.

Oliver Sartor: Neal, let me ask a little bit about the PET imaging. Is that something you've incorporated into your larger practice? Do you have a liaison, a relationship with an outside nuclear medicine facility or a hospital? How does the PET imaging work in your facility?

Neal Shore: Yeah, we brought in a consultant. We're actually on our second consultant. I don't want to necessarily go into the reasons why we went from one to another, but you learn. Certain consulting services are more appealing for different practices versus others. We have our own full-time capability for PSMA PET. We're able to use fluorinated products. We have the gallium products. Soon coming to market, almost assuredly, there'll be copper products. And I think it's an incredibly exciting time. I mean, I think it's not too exaggerated to say that this is the state-of-the-art, most accurate way to test for the lower-volume disease that we were missing with biochemical recurrence or with non-metastatic castration-resistant prostate cancer. So what's exciting about that is it gives us greater accuracy, and there's a whole landscape of clinical trials looking at radiation approaches to these patients who are conventional imaging-negative, but PSMA PET-positive.

And thanks to your leadership and others, we're trying to put some homogenization to the nomenclature of how we decide what's low-volume, what's intermediate-volume, what's high-volume on PSMA PET. How much of the verbiage needs to be consistent. And it continues to be an area of fun discussion and controversy, but it's here and it's not going away. That's just on the diagnostic PSMA PET side. Within the broader US urology community practices, the PSMA PET model, the business model has taken off pretty much like wildfire, in keeping with what happened years ago when CT scans first came into clinical practice. Everybody was like, "Wait a minute, how could you have a CT scanner?" And the next thing you knew, all urology practices and medical oncology practices had multiple CT scanners. And that technology has evolved over time, as is now PSMA PET.

Oliver Sartor: Neal, are you able to do clinical trials within your group? Is that part of your bandwidth?

Neal Shore: It is, and honestly, that's what I find most enjoyable, doing both the diagnostic and the theranostic trials. I mean, we have a bunch of really fascinating studies both on diagnostic and theranostic sides. I've always liked to say clinical trials are a standard of care. I mean, ASCO says that. I think AUA does as well. And honestly, given the challenge that everyone has in being overburdened with regulatory and compliance issues and being tested constantly every time you turn around, whether it's your clinic, or your hospital system, being involved in clinical trials is inspiring, and intellectually it has vigor and it creates—I think it's really the perfect antidote to burnout. We never heard about that before, but yes, I love doing the trials on both the diagnostic and the theranostic sides.

Oliver Sartor: Neal, we're going to need to wrap up here in just a moment, but I wonder if you might have a relatively simple message to some of your listeners who may be contemplating a diagnostic or theranostic site using the radionuclides?

Neal Shore: Yeah, thanks, Oliver. You and I, with Dan George, we published a paper about four or five years ago where we showed that in Canada and the US, like 77% of patients who died of prostate cancer-specific mortality only received one life-prolonging therapy, and 38% received two, and 18% received three. There are so many life-prolonging therapies, FDA-approved with level I evidence—it makes me sad when I repeat those findings. Now, I'm hoping it's better. We need to look at a little bit more contemporaneous data, but it wasn't that long ago that we published that in Canadian Urological Association Journal.

But my takeaway would be based upon that comment that radioligand therapies are really redefining not only prostate cancer care, but other solid tumors as well. There's really some novel work going on in kidney and soon to be in bladder and also in breast and colorectal and lung. There are trials that span from late-stage to frontline therapies. There's personalization and there's a need for better understanding of the dosimetry, and working together in a multidisciplinary team, I think we're going to be able to become more precise in how we think about utilizing these therapies. For my colleagues out there who haven't embarked yet or initiated a program, you need to be addressing this now. The time is now. And it's a really exciting time for advancements from both systemic stage IV disease to even some high-risk localized disease. So that would be the take-home message.

Oliver Sartor: Right. Well, Neal, to be honest with you, you're an inspiration for many because you've been able to lead so many trials yourself. You've been able to create multidisciplinary care. You've been able to create the type of environment where your patients can come and know that they're going to have the very best of therapies available to them, both standard of care and clinical trials. Hats off to you for being a leader in the field. Hats off to you for being able to incorporate these radiotheranostics into the practice, and I'll simply say thank you, Neal, thank you for being here today.

Neal Shore: Great pleasure, always, Oliver. Thank you.