Alicia Morgans: Hi, I'm so excited to have here with me today, a GU medical oncologist and friend Dr. Michael Morris, who is the Prostate Cancer Section Head at Memorial Sloan Kettering Cancer Center in New York. Thank you so much for being here.

Michael Morris: Oh, it's a pleasure, Alicia. Thanks for having me.

Alicia Morgans: Wonderful. So today I really want to talk about the novel radiopharmaceuticals that are really on the horizon. They're making their way into clinical trials and we are all really excited about where these agents are going to go in advanced prostate cancer and perhaps moving even earlier on.

Michael Morris: This is a very exciting time.

Alicia Morgans: But I would love to hear your thoughts. What are the agents, what are their unique properties, what are the special things that we need to understand about them if we're using them, and where are they going?

Michael Morris: Sure. Well, historically the radiopharmaceuticals have been bone-targeted and primarily the one that probably most clinicians are used to or familiar with is radium-223, but what's exciting now is that there are a whole host of tumor-directed radiopharmaceuticals that are coming into clinical trials or just having finished definitive clinical trials. And that really is an exciting wave of new drug development in prostate cancer for right now the advanced prostate cancer population, but as you alluded to, there's really quite a bit of potential for the early phases of the disease as well. What is most mature are the beta-emitting radiopharmaceuticals. These emit a somewhat lesser energized particle but have deeper tissue penetration. Those characteristics distinguish it from the alpha emitters, which are higher energy release, but a much shorter depth of tissue penetration. The betas right now are primarily represented by lutetium-177. The lead product is something called PSMA-617 and that just completed its definitive Phase III study.

It was the standard of care plus or minus lutetium-177, PSMA-617 with a co-primary endpoint of RPFS and OS. It's completed accrual. We're just waiting for events. We're really hopeful, those of us who have worked in this field for a long time, that this is a positive study. Certainly, the preliminary data looked good and that is the first probably that will be approved if it's positive. But that's really the leading edge of a much larger wave of other radiopharmaceuticals. Some of those PSMA-targeted, but there's the potential for other targets as well. And that includes both the betas and the alphas.

Alicia Morgans: So when you think about agents that are on the horizon and there are multiple, so just narrow down to some of the ones that either you have the most experience with or that you think are closest to getting into clinical trials. What are these agents, beta or alpha? Tell us a little bit about them.

Michael Morris: Sure. So these drugs really have two components. One is the targeting agent, one is the payload. The targeting agent is what can target PSMA and is very important in terms of determining the behavior of the molecule and its therapeutic index. The smaller molecules such as PSMA-617, they target extremely well. They have a very short half-life in the blood. They do target the salivary glands. So that can be a concern in terms of the therapeutic index, especially with the alphas. There are some newer small molecules that target PSMA as well that look like they may have a lesser degree of uptake in the salivary glands. And then there are antibodies that target PSMA, which are larger molecules, have a longer half-life but seem to spare the salivary gland. So the targeting agent's quite important.

There are some new targets as well. There's a new target called HK2 which is a human kallikrein is on prostate cancer cells, and then there's a new target for prostate cancer as well that's called FAP, fibroblast activating protein and another one called STEEP. So there are a whole family of potential targets in prostate cancer. Then the payload of course, as we're saluting to the alphas that are very different than the betas and they have different side effect profiles, different levels of energy, and between the permutations of the targets, the targeting agents and the payloads if you just think of all of those treatment possibilities, both alone in combination with each other and in combination with other systemic therapies. There's really a plethora of possibilities here in terms of offering patients different treatment modalities depending on the phenotype of their disease and the stage of their disease.

Alicia Morgans: So let's talk for a minute about alpha particles. So you alluded to this, but just to reiterate, what are the other benefits potentially of alphas and what are the challenges in terms of actually if you're in clinical practice at some point delivering these?

Michael Morris: So it's not the alpha particle itself that's targeting the salivary glands, it's the targeting molecule. But you're right in a sense that once the alpha is in the salivary gland, it tends to be more destructive of the salivary gland tissue than a beta would. On the other hand, as you alluded to, the alphas deliver a lot of radiation but of are very, very small distance and so you can get a lot of radiation once you attach it to a prostate cancer cell, wherever it might be, and do extremely little tissue damage to the surrounding area, which really gives you quite a bit of therapeutic potential to treat patients with a minimum of toxicity. In Germany, they've started using alpha directed therapy as sort of a salvage strategy after betas may have been tried and not worked so well or the patient's beginning to relapse.

There's also a role for using alphas upfront. Those Phase I studies with alphas are just beginning to be rolled out and in terms of formal dose-escalation studies, but the nice thing about alphas is that there's really a potential to move the alphas from the advanced disease state into the minimal disease state, into even high-risk localized disease because they can attach to the prostate cancer cell and really kill that cell very effectively. So in the micrometastatic state, it offers the potential for a curative paradigm where you, let's say you had a high-risk localized patient where there's a microscopic circulating disease that we can't appreciate even on PSMA imaging. We think of the alpha as the potential to eradicate that circulating unseen component of the disease.

In addition, when you think of the DNA damage that an alpha can inflict, when you have a patient population that has a DNA repair defect, we hypothesize that those patients will be exquisitely sensitive in terms of really their prostate cancers because you have a DNA damaging agent in a DNA deficient repair system. Not only that but the alphas we think of as a potential for PARP inhibitors to be effective even in an unselected patient population because you take a DNA damaging agent like an alpha and combine it with an inhibitor of DNA repair and perhaps then you could take in unselected patients a strategy that really would be an effective method of killing prostate cancer cells, especially in combination with the PARP inhibitors.

Alicia Morgans: Absolutely. So that I think especially as we anticipate that some of the PARP inhibitors, maybe two actually may be approved for metastatic CRPC in the relatively near future, I think this combination might be a really interesting one to explore.

Michael Morris: Oh absolutely. I think that the alphas really offer a potential across the spectrum of disease and as combinations with novel agents that is really quite provocative and exciting.

Alicia Morgans: Wonderful. So as we wrap up, do you have any recommendations really more back on a basic clinical level for how clinicians can really engage? Because this takes a partnership between nuclear medicine physicians and medical oncologists, perhaps urologists, but probably medical oncologists to really get patients to the place where they need to be and to care for them adequately. So any suggestions from your experience?

Michael Morris: In some communities, that relationship will be with nuclear medicine in others with radiation oncology and it will depend on the community of an individual practitioner as to who he will partner with. But these partnerships are really necessary so that you could have mutual stakeholders invested in the patient's care. It will probably vary from practice to practice as to who the primary caretaker of the patient will be. So for example, in some practices, it might be the medical oncologist that's taking care of the patient as a whole or it could be, for example, the radiation oncologist that assumes the care longitudinally. Usually, these drugs are given over four to six cycles. So for that period of time, somebody does have to assume control of the patient. It's an exciting time to think about how those collaborations can be creatively conceived and executed. They probably will be individual to institutions and practices, but I think that taking care of prostate cancer patients has always been a team sport and now more so than ever.

Alicia Morgans: Absolutely and probably organizations can build on relationships that they've built with radium, taking them maybe to the next level in certain ways of monitoring and drug delivery and all of that. But at least this is not entirely new to the world of folks taking care of prostate cancer.

Michael Morris: Those same new relationships will be on the drug discovery end as well. To date, the investigations and development of these drugs have been limited to a couple of centers across the world. And I think that you're going to see much more interest by investigators, by pharmaceutical companies who see the potential for these drugs and engage more and more investigators and prostate community stakeholders as well.

Alicia Morgans: Absolutely. Well, thank you so much for sharing your expertise in this rapidly evolving realm of prostate cancer treatment. Even though some of these agents are not here today, they are certainly on the horizon. The wave is coming.

Michael Morris: It sure is. It's a very exciting time and thanks for having me, Alicia.

Alicia Morgans: Thank you so much.

Michael Morris: Thank you.