Alpha vs Beta Emitters in Prostate Cancer Radiopharmaceuticals: Energy, Range, and Cytotoxicity - Alan Bryce

March 5, 2024

Alicia Morgans interviews Alan Bryce about his session on radiopharmaceutical therapies for mCRPC with bone metastases, focusing on the decision-making between radium-223 and lutetium-177. Dr. Bryce explains the session aimed at practical clinical decision-making, emphasizing the underlying science of radiopharmaceuticals, including the distinctions between alpha and beta emitters and their targeting mechanisms. The discussion highlights the differences in cellular impact between alpha and beta particles, including their energy transfer and travel distance, affecting dose delivery and toxicity. Dr. Bryce also touches on the targeting mechanisms, comparing radium-223's affinity for bone due to its similarity to calcium, against targeted approaches like lutetium-177 PSMA. He speculates on the future of treating micrometastatic disease, possibly with alpha emitters targeting cancer cells directly, and encourages attention to this evolving field for upcoming developments in prostate cancer treatment.


Alan Bryce, MD, Chief Clinical Officer, City of Hope Cancer Center Pheonix, Phoenix, Arizona

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts

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Alicia Morgans: Hi. I'm so excited to be here at ASCO GU 2024, where I am speaking with Dr. Alan Bryce, who is the Chief Clinical Officer of City of Hope, Arizona, which is the new clinic that's been developed outside of Phoenix. Thank you so much for being here with me today.

Alan Bryce: Pleasure to be back. Nice to see you.

Alicia Morgans: Nice to see you too, and congratulations on a fantastic educational session at GU ASCO, where you really helped us think through radiopharmaceutical therapies and how they've evolved over time, where they might go in the future, and how we can use them in clinic today. Tell me a little bit about what you discussed.

Alan Bryce: Yeah, so yesterday's session was one of the educational sessions where we start with a clinical case and think about the various treatment options. It's a very practical question that the treating clinician is facing in clinic. My task was to help discuss the decision-making around either using radium-223 or lutetium-177 in the patient who has mCRPC and bone metastases.

In these sessions, of course, we're not presenting new data, rather we're trying to help people think through the issues, so I felt that the best way to have this discussion is to try to think about the underlying science. What are the driving principles that guide the way we think about radioligand therapy or radiopharmaceuticals in general? Of course, radium-223 is not a radioligand. It's an isotope. I think that the key principles for the existing approved drugs and for all the others in development is a combination of two major factors, which is to say, what kind of isotope are we using? Is it an alpha emitter or a beta emitter? In this case, of course, radium's an alpha emitter, and lutetium-177 PSMA is a beta emitter. Then the second aspect is what is the targeting mechanism for the drug?

When you think through those details, I think then the clinical logic and the clinical framework start to fall into place, at least on a theoretical basis. Those are the principles that I think we can apply in clinic and also the principles that we start to think through when we're trying to design clinical trials and say what's the optimal application of each drug.

Alicia Morgans: I think that's such a great way to think about it. That's what I have tried to do since talking to people like yourself and Oliver Sartor, Michael Morris. They're the group, including you, who help us kind of make sense of all of these different things. It's a little bit new to us. But one of the key things that you talked about was really the difference between an alpha particle, the energy delivered, and how that causes damage, and a beta particle, and the same things.

Alan Bryce: Absolutely.

Alicia Morgans: These are two very different approaches, and it's not just because one makes you radioactive out in public where the other one does not. Tell us how these differ really on a cellular level.

Alan Bryce: Yeah, yeah. These are very different particles. An alpha particle is essentially two protons, two neutrons. It's massive compared to a beta particle, which is essentially an electron, so the relative mass is 7,000-fold bigger, over 7,000-fold bigger, for an alpha particle compared to a beta. The alpha particle has much higher energy. In the radiopharmaceutical world, they talk about linear energy transfer, which is how much energy is that particle going to impart to the target cell? The impact of the much higher energy of an alpha particle is that it really only requires as few as one, maybe 10 hits from an alpha particle in order to kill a cancer cell. Whereas with a beta particle, you really need at least 100 or maybe a few thousand hits in order to kill a cancer cell. That has significant implications then when you start thinking about how do you get enough dose delivery. I mean, that's really what we're talking about. Dose delivery to an individual cancer cell to achieve cell kill.

Then the second piece that plays into that is with each of the particles, how far does it travel before it loses its energy? With alpha particles, we say rule of thumb, maybe 10 cell diameters is as far as it goes before it's no longer energetic enough to do anything, so really a very small diameter. With beta, then it could be 50-fold higher, so you get much higher spread. You think about those two aspects, and with alpha, you'd say, well, you don't need a lot of delivery of the drug to get cell kill. One particle may be enough. With beta, the advantage then is to say if you have a heterogeneous tumor where drug penetration or drug concentration may be unequal throughout the tumor, then the idea that it spreads farther gives you a better chance of getting enough coverage to achieve cell kill.

Just imagine a tumor where, for example, we think about lytic bone metastases with radium. Since radium targets by collecting in cortical bone, if there's no cortical bone in the center of a tumor, radium doesn't affect it. That's why soft tissue disease is unaffected by radium. Whereas if you had a beta emitter, then the ability of that beta to traverse across the tumor is much higher. It's a trade-off between the breadth of spread of the energy versus the number of particles necessary to achieve cell kill.

But that same trade-off then has implications for toxicity. Alpha, as we know, it doesn't spread as far, is less toxic to healthy tissue, beta much higher. That's the first thing we talked about, difference between alpha and beta in terms of their energy and their distribution, how far they'll travel. Then the second piece is to start to get into, okay, you've got the different particles, what about the target? How are you delivering the drug to the site?

Alicia Morgans: Tell me a little bit more about that because there are so many ways. There's antibodies, there's small molecules. We're always thinking of new things, so please, how do you think that through?

Alan Bryce: The two examples specifically with radium, of course, this is not targeted per se, it's pure inorganic chemistry. Radium is an alkaline earth metal, in the same column on the periodic table as calcium. We go back to our chemistry days. Really when it's absorbed in the body or otherwise present in the body, it's treated much the same as calcium, which is to say it's really uptaken into newly-forming or areas of high bone turnover and incorporated into hydroxyapatite crystals. All the radium you ingest is essentially concentrated in bone. That's why this is a bone targeting agent, and that's why it's particularly effective in osteoblastic metastases because in osteoblastic disease, and you're looking in the microscope, the cancer cells are really spreading. They're not grouping, but rather they're spreading along the cortical bone. That limitation of the energy only traveling 10 cell diameters is okay, because really the cancer cells are kind of lining the bone.

On the other hand, you have the radioligand drugs where there's a targeting molecule. In the case of lutetium PSMA, it's a PSMA targeting ligand, so PSMA-617. In principle, with radioligand therapies with the targeting component, it's just a matter of finding a target that's overexpressed on the cell of interest. In this case, it's PSMA on the surface of prostate cancer cells. The important thing is to get a target that's not expressed very abundantly on healthy tissue. As we know, in the case of lutetium PSMA, the major sites of overexpression on healthy tissue are salivary glands and lacrimal glands, and that's why we have dry eyes and dry mouth. Of course, because of that property of targeting the cancer cell itself, lutetium can in theory achieve cytotoxicity in any tissue. It's not limited to bone the way radium is.

As I say, radium is indirectly targeting the cancer cell by targeting the microenvironment; that is, the bony compartment. Lutetium PSMA is directly targeting the cancer cell itself. These are the components that we combine in the logic of these drugs then. The alpha emitter versus the beta emitter, and then what is your targeting mechanism.

Alicia Morgans: Great. Let's think about this in terms of one particular sort of aspect of the disease or stage of the disease. We've talked a little bit about how certain osteoblastic metastases might line that bone matrix. We've talked about some other things, but when we think about micrometastatic disease in particular, I think that this is an area where our field can really kind of come together with the nuclear medicine field and have an aha moment. Tell us what you taught us about micrometastatic disease and how we might think through really rationally targeting that.

Alan Bryce: Yeah, yeah. Of course, any time we develop new drugs, we usually start at advanced disease. In the normal course of drug development, we start marching it forward, and then at some point we start talking about adjuvant therapy. In adjuvant therapy, of course, in concept, what we're doing is we're targeting micrometastatic disease. Can we affect the disease we can't see? Of course, in modern prostate cancer with PSMA PET imaging, we can see very small deposits.

When we talk specifically about radioligand therapy or radiopharmaceuticals of any sort, this issue of how many hits you need on a cell to achieve cytotoxicity is very important to the considerations of micrometastatic disease because, to bring it all together, one alpha particle in proximity to a micro-deposit of prostate cancer could be enough to kill that prostate cancer cell. But with beta particles, because you need so many hits, the 100 or a few thousand hits necessary to kill the cell, there's a limitation on the size of the micrometastatic deposit necessary to lead to enough accumulation of the beta emitter to achieve cytotoxicity.

With lutetium PSMA, for example, the amount of drug delivery to a particular metastatic deposit is going to be a function of the density of PSMA coverage, which is essentially the SUV being an expression of the PSMA expression, and then the size of the deposit. How many cancer cells are there expressing how many PSMA molecules? Because of that, there really is a theoretical limit on the minimum size of a metastatic deposit necessary for a beta emitter to be effective.

What I was saying in the session was in theory, just because of the physical properties, the best drug for treatment of micrometastatic disease would probably be an alpha emitter that targets the prostate cancer cell. Neither radium, which targets the microenvironment, nor perhaps lutetium PSMA, which targets the prostate cancer cell with a beta emitter. Probably a combination of the two.

I think the good news with that is drugs like that are certainly in development. As we all know, there are a lot of alpha emitters being developed. There are also other targets in prostate cancer cells. It's not just PSMA. I really fully expect over the next decade we're going to see a lot of mixing and matching. Different emitters, different targets to try to optimize the balance of toxicity and efficacy. Try to get to this idea of treating micrometastatic disease. I think this is going to be an exciting space in prostate cancer for many years to come. I mean, we can anticipate a constant stream of new data as we refine as a field how we're going to approach radioligand therapy. Pay attention to this space. I think we're going to see a lot of developments for a long time to come. If you're a young fellow or oncologist looking at this, it's a great space to get into if you want to develop a career moving forward.

Alicia Morgans: I couldn't agree more, and I think it will be so fascinating too, as we start to mix and match alphas and betas, alternating treatments perhaps, ensuring patients are safe, of course, but doing that alternating approach and then also thinking about how do we combine them with different drugs that might increase the expression of our target on our cancer cells. There's so much to learn and so much to do. If you had to give a final message to folks who are listening, what would that be about our radiopharmaceuticals, where we are, and where we're going?

Alan Bryce: Well, these are fantastic drugs. It's a fantastic platform as well. Radioligand therapy is really, I think, highly amenable to rapid development of new approaches, to new molecules. I think there's every reason to be very optimistic about what the future of this looks like. For the clinician treating a patient in the clinic tomorrow, the key things to think about, of course, are the management of the bone marrow reserve, the myelosuppression. I think that's probably the most important cycle by cycle management issue. Certainly, the dry eyes and dry mouth matter, but I think the marrow reserve is probably even more critical. But that's something familiar to treating oncologists. We know how to do that.

Also, we always like to remind people, for the patients with bone metastases, please use antiresorptive therapy. There are a lot of data sets showing that they're underutilized out in the community. That was just a bit of a public service announcement we added to the end of the talk yesterday and something to keep in mind, repeat here today.

Alicia Morgans: Well, again, I could not agree more. Bone health agents absolutely need to be incorporated. These are patients with mCRPC in large part, so this is something we need to do and a way that we can improve outcomes, reduce complications, and even mortality for our patients. Thank you so much for taking the time and for sharing these insights. I think this area, as you said, is one that continues to evolve and will maintain our interest for many years to come. I appreciate your expertise.

Alan Bryce: Thank you.