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Alicia Morgans: Hi, my name is Alicia Morgans and I am a GU Medical Oncologist and an Associate Professor of Medicine at Northwestern University. I'm so delighted to have here with me today, a friend and colleague Dr. Michael Morris, who is the Prostate Cancer Section Head and a GU Medical Oncologist at Memorial Sloan Kettering in New York. Thank you so much for being here with me today, Michael.

Michael Morris: Thank you very much for having me, Alicia. It's always a pleasure to be hosted here.

Alicia Morgans: Well, always a pleasure to talk to you too, especially about radiopharmaceuticals because we are really entering an era where there is a lot of hustle and bustle. There is a lot of development. We've recently heard the VISION data, and of course, we've had radium-223 and have been using it for years, and there is ongoing research looking into new and different molecules as well. So I'm wondering from your perspective, how do we think about radium in the context of these newer radiopharmaceuticals? Where does it fit in and how do we think about taking it and others into the future?

Michael Morris: Well, it's a good problem to have, which is as we come into the future as radioligand therapy or tumor-directed radioligand therapy comes onto the stage as a treatment option for patients. The good problem is we have an abundance of various radiopharmaceutical tools, all of which prolong life for patients. And one is a bone-directed alpha emitter with lutetium, which will get a tumor-directed beta emitter, there will be more to follow as well. There will be tumor-directed alpha emitters coming onto the stage in the future, which will further increase the number of drugs in this class for prostate cancer.

And we have to remember that these are not the same drugs. So some, obviously radium doesn't target the tumor, it targets bone, and it releases an alpha particle. And amongst the radioligand therapies, they are not all the same either. Even though they may not have all the same PSMA targets, there are new targets being developed, and there is a difference in the behavior and the side effect profile and therapeutic index of the alphas and betas, and of the antibodies versus the small molecules.

So we're probably looking at, as the future unfolds, various niches that each drug class and drug type within that class will fill. There are patients who may have high volume versus low volume disease. There are patients who may have impaired bone marrow for which one drug class and drug type might be superior to another. The salivary gland toxicity, especially the alphas that are conjugated to small molecules, needs to be accounted for. There probably will be a place for each of these therapies as we mature in the field, and figure out which patient is going to benefit most from which type of therapy.

These also are not one-shot deals in terms of decisions. You can get lutetium after radium. You could probably get an alpha after a beta. In fact, that's being explored now as salvage therapy after treatment failure, after beta tumor-directed therapy. So these may be sequenced as opposed to one being the exclusive player on the field at a given patient's time in its history.

There are combinations. You can't combine all of these therapies equally. We know that, for example, radium and abiraterone had an untoward side effect in terms of bone fractures, but we may find that combinations with radioligand therapy have equally unexpected combinatorial results that point away from those combinations, that point towards combinations with other therapies. So there is a lot to explore here. And I wouldn't say that we have all those answers yet, but certainly, an interesting world that we are coming into.

Alicia Morgans: I agree. And just to pick up on some of those threads, really what you're saying is these are distinct approaches, even though things like lutetium and radium may be radiopharmaceuticals. So these are using radioactivity to sort of get some cancer control. They are very different and they are not mutually exclusive in terms of patient exposure. I think importantly, for people who are just learning the results of VISION, for example, there were a number of patients who were in that trial who had had previous radium. They certainly couldn't have had it within the six months preceding their enrollment, but they could have had it before that. And as you said, that is certainly targeting the bone versus a PSMA-targeted radiopharmaceutical, an alpha versus a beta. So these are very different. And my hope as a clinician is that patients can actually get every single option available over time, as long as that is safe. And hopefully, it will be effective because that allows us to get the maximum benefit, I think, for the patients at the end of the day. What are your thoughts?

Michael Morris: I entirely agree with what you just said. If you think of these drugs as, again, not precluding each other, but having a tiered approach, like for example, we're currently exploring the role of radium and docetaxel in the DORA trial. If that study is positive, then chemotherapy may well be given with radium as a standard at some point in the future. But that doesn't mean that the patient down the line, after progressing on that regimen, couldn't then receive lutetium PSMA or alpha or something directed against another target. So each of these will have an evolving role in the landscape of metastatic CRPC.

And given the significant differences in the side effect profiles of each of these agents as well, we'll find that certain patients may be geared towards one therapy versus another as well. A person who, for example, already has issues in terms of salivary glands, maybe they had neck cancer or something like that, well, that's something to really consider as you think about a PSMA-directed small molecule, whereas a person with impaired bone marrow, that may be more of a role where you might want either a small molecule instead of an antibody, or you might want radium as opposed to a tumor-directed radioligand therapy. So again, we're going to have to figure out the answers to all of those questions in ways that right now we're only beginning to entertain. But there will be a lot for investigators to study over the course of the next several years as to how to sort this out.

And that's not to mention as we move all of these therapies earlier, and I think most people are thinking of the whole field, ultimately moving earlier than metastatic CRPC, which of these will have the sort of most favorable long-term toxicity side effect profile, because that's really important from a survivorship standpoint and from a long-term tox standpoint. If you're going to move anything earlier, you have to really be cautious about what the side effect profile is, and we will have to see which of those has the most favorable side effect profile from a long-term tox basis.

Alicia Morgans: I agree. And I think sort of to that end, certainly radium can be used prior to chemotherapy. We do it routinely here, often based on patient preferences for that approach. Lutetium is being studied in earlier areas, as well, you are participating in some of that work. And then things like DORA, these combination trials, are I think going to move, really disrupt the entire landscape as we know it. And as we start giving these agents in combination, we are probably not going to reuse the same mechanism of action repeatedly, we will have other things kind of filling in behind. So it is incredibly exciting. Before we wrap up, can you just tell us a little bit more about the DORA trial, just for those who are interested in looking for options for their patients? I think that this has been going on for a couple of years at this point, and is a really exciting trial. I'm looking forward to the results.

Michael Morris: Sure. For those who may not know, DORA is an international, randomized, phase three study for men who are chemotherapy eligible with metastatic CRPC, who've progressed on some androgen receptor pathway inhibitors, such as abiraterone or enzalutamide. These men do need to have the bone dominant disease, but certainly, low volume nodal or visceral disease is permissible because everyone does get chemotherapy. And the randomization is to either docetaxel as monotherapy or docetaxel in combination with radium-223. The primary endpoint is overall survival. And I would say that for anyone who is thinking of participating, we try as much as we can because these are two FDA-approved, life-prolonging therapies. There is no downside to the control arm and no downside to the investigational arm because it's quite safe in terms of the combination. But we've tried to make the trial as user-friendly as possible from both a patient and investigator perspective.

So basically the chemotherapy is every three weeks. The radium is given every other chemotherapy cycle on the combination arms to avoid extra visits if we gave it monthly. So we are giving it every six weeks so that patients can get just every three-week visits. And we try not to pack any additional visits in between those three weeks so that patients really are on a standard and routine chemotherapy schedule. So I think it's a patient-friendly and investigator-friendly study, and we have centers across the US, as well as in Europe. So if anyone has any difficulty from a patient perspective or an investigator's perspective finding a site near them, then they can just contact the PCCTC, which is the sponsor of the study. That is The Prostate Cancer Clinical Consortium.

Alicia Morgans: Great, thank you. And like you said, chemotherapy works, radium works. There is no downside. And I know you and your team have actually done the safety data to look at that combination. The chemotherapy is slightly reduced in terms of dose. It's not 75, I believe it's 60.

Michael Morris: Correct.

Alicia Morgans: So safety first and patients seem to be tolerating it. And I really do look forward to this. We would love to think of prostate cancer, as some of my colleagues say, as almost like testicular cancer. If we can put things together that have different mechanisms of action and really get, not just additive effects but even synergistic effects, that would be a phenomenal, phenomenal advantage for our patients.

Michael Morris: It really would, Yeah. We are really looking forward to seeing if we can't leverage some of the existing therapies' potential with the radium irradiating the boning compartment and the docetaxel addressing the tumor compartment. See if we can prolong life even more than either agent does already alone.

Alicia Morgans: Fantastic. Well, as we wrap up, we'd love to hear your final thoughts on this evolving landscape, where radium fits in, and any words of hope and thought for the patients and clinicians who are listening.

Michael Morris: Sure. I guess my final thought is that with the introduction of radioligand therapy onto the prostate cancer stage, presuming that the FDA approves it, I think that the place for radium is going to be pretty variable. It really depends. The lutetium will probably displace radium to either before or after or in lieu of in some patients. I don't think we have that answer yet, to be honest.

There are a number of studies that are ongoing exploring radium in combination, DORA being one of them. There is also an upcoming SBRT with radium study that's opening. So the role of radium in this new era will continue to be defined. We all hope that it will end up in a place that's most beneficial to patients so that these two therapies, one bone-directed and one tumor-directed, will each be used to the optimal benefit of the patients. There are lots of combinations for each that could be explored. And as the data unfolds, it's what keeps the field exciting and gives hope to patients that folks like you and me are continuing to work to their benefit and find new ways to apply these both old drugs and brand new drugs.

Alicia Morgans: I could not agree more. And I do encourage clinicians, I encourage patients, each new addition to our armamentarium does not mean something else has to leave. It just means we need to think about the order and find the right sequence for the right individual person. Engaging patients, I think will help us find the way. Thank you so much for your time today.

Michael Morris: Thank you, Alicia. It's been a pleasure.