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Alicia Morgans: Hi, my name is Alicia Morgans, and I am an Associate Professor of Medicine and a GU Medical Oncologist at Northwestern University. I'm so excited to have here with me today, a friend and colleague, Dr. William Oh, who is the Chief Medical Science Officer at Sema4, and also a Clinical Professor in Medicine and a GU Medical Oncologist at Mount Sinai. Thank you so much for being here with me today, Dr. Oh.

William Oh: Hi Alicia. It's my pleasure. Nice to see you again.

Alicia Morgans: Nice to see You too. So I wanted to talk with you a little bit about your thinking about radium, how we choose the optimal patient for it, the use of radium, timing, and of course, supportive management around radium use and really putting on your clinical hat to help us think through some of that. When you think about radium, I guess the broadest question I could ask is, who is the right patient for that approach to treatment?

William Oh: Well, it's interesting, it's hard to believe that radium has been around for over a decade. It's really mind-boggling. And when it first came out, of course, we were very excited about it because it was another treatment that improved overall survival. We had a run there with AR targeted therapy, chemotherapy, and Sip-T. So there were four different classes of drugs, but I think over the last 10, 11 years, we've learned a lot about who should get which treatment at what time, but not because of randomized trials. We've struggled to understand the sequencing of therapies because the treatments all came out around the same time. So to answer your question, basically, my feeling about radium is that it is probably underutilized. I'd say about a third to half of my patients wind up getting it at some point in their natural history.

Why do they not get it? Well, of course, if they have a lot of visceral diseases or if they have a very rapidly progressive cancer where I am worried that radium may not be able to control their burden of disease, I may start with other treatments. And usually, like most oncologists in this space, I'm starting with an AR-targeted therapy. Now what's interesting is because of all the new uses of AR targeted therapy in metastatic hormone-sensitive disease and nonmetastatic hormone castration-resistant disease, we are using these drugs, the AR therapies much earlier. So by the time patients get to mCRPC, they have often already received at least one other therapy and sometimes more than one other therapy, sometimes chemotherapy. So generally speaking, I would say that I'm using radium in the second or third line in most of my patients after AR targeted therapy and sometimes after drugs like chemotherapy. And again, only a subset of patients wind up being eligible. But when they are, when their cancers are not progressing rapidly, when they have the bone predominant disease, I will try to fit it into their course.

Alicia Morgans: And how do you think about bone pain or symptoms in terms of that selection? Because I have, as you do too still I'm sure, we teach fellows and they always say, "Well, we can't use radium until patients have really bad bone pain." And that's actually not necessarily the symptom that I'm looking for when I am choosing it. And there is some evidence that patients who have less pain, who have a better performance status even, may get even more bang for their buck when they use radium. So I'm just curious, how do you think about symptomatology and it in your choice of treatment with radium?

William Oh: Yeah, I know it's in the label and probably, I shouldn't say this, but it hardly crosses my mind. To me, I think symptoms are important, but I think if the patient has tons of symptoms and it may be too late to use a drug like radium and get the maximum benefit. So like you, I agree it's what's on the label, but I have a very, very, very low threshold to assess symptoms from cancer in the bone. That could be a pain in the bone, it could be minor amounts of pain. It could be symptoms like fatigue or weakness, which I attribute to bone metastases.

So I think that for me, that's not a big driver. It is really more about timing in terms of what other therapies the patients received. When I can give them the treatment because it's of course, six cycles, six-monthly treatments, and I'm trying to make sure that they are not worried about their PSA rising because as you know, their PSA's may rise on treatment. And I'm trying to fit it in with the other therapies I know that they may have to go to after I'm done.

Alicia Morgans: Yeah, I agree. And I find myself using fatigue and even mild bone pain as, or mild pain of any kind as really the symptom that we're using when I use the drug. There is a difference between completely asymptomatic patients and then these mild symptoms which I agree, I attribute to their cancer. And in that case, I think radium is completely reasonable and helpful.  To the point about the PSA, how do you counsel patients on that? And of course, if we get a scan, sometimes there can be a flare effect in a bone scan related to treatment. How do you explain that to patients? Or is it something that you hope they don't ask about?

William Oh: No, I always warn them because if you don't warn them in advance, you will get a call later. Because as we know most of the time, the PSA's do not go down, and I think that what I explain to them is, that it is really targeting the bone and protecting the bone. I sometimes use words like bone glue to give them a sense that this is protecting their bones. And that in and of itself has value, men live longer in a randomized trial. So it's a little like Sip-T in that you're trying to emphasize the overall benefits of the drug. They don't get as many fractures, they live longer and they have to get through that six-month period in order to get the maximum benefit. And I, for the most part, am able to get most patients through.

I'm usually the one deciding that it is not the right treatment. Let's say halfway through and if they are truly progressing, or if they have more soft tissue metastases, or if I'm worried that let's say the PSA rise is particularly fast and I'm looking for other sites of disease, so most of the time I prep them, if the PSA is rising slowly and they tolerate it. Sometimes we'll think about adding an AR-targeted therapy just to try to keep the patient and us saying, as we understand, that combination which people were worried about in the past is probably safe as long as you have bone protective agents like zoledronic acid or denosumab on board.

Alicia Morgans: So let's talk about that just a little bit because I think the ERA 223 trial where patients were receiving radium and abiraterone at the same time, did suggest that there might be a higher rate with that combination of fragility fractures, in particular. But it was interesting because of a similar study that combined radium and enzalutamide, the PEACE III trial. When patients were actually mandated within the trial to use a bone health agent, as you mentioned, the rate of these fractures went down to basically zero, which was incredibly impressive. And really, I think taught a lesson to me that if you are going to use these agents, and actually even if you're going to use an AR-targeted agent without radium, we should still be thinking about bone health and metastatic CRPC. We should still be using these drugs to support bone health and prevent fractures. What are your thoughts? Do you have a lead-in period before you use these bone health agents? Do you just make sure that they are on it before you start radium or a combination? How do you think through that?

William Oh: Well, the PEACE III presentation really scared me, and it scared me in that I probably wasn't using enough bone-protecting agents. I wasn't doing enough osteoporosis testing, looking for, doing DEXA scans to look osteoporosis. And even without radium, just with AR-targeted therapy, as you point out, we are seeing quite a lot of these fragility fractures. And I think that quantified it in a way that made sense to me. And as you said, you abrogated that effect for the most part if you had the patient on a bone protecting agent. So I've been much more aggressive about looking for osteopenia or osteoporosis and treating it in advance of adding a drug like radium and certainly of combining radium with a drug like enzalutamide. But there is more data that has come out since, that the combination is fairly safe in terms of these fragility fractures as long as you have a bone-protecting agent on board.

So that's my approach, I make sure that they have a bone-protecting agent. And if I feel like the patient is better served with the combination, let's say of enzalutamide and radium, I'm not afraid to combine them. I understand why some doctors maybe, but it makes sense to me that it's really a bone protection issue from undiagnosed osteoporosis.

Alicia Morgans: Yeah. I think that makes a lot of sense. And anytime I use radium, anytime we hit mCRPC, I am really, like you said, trying to make sure that I'm using those bone health agents or bone protective agents to really provide optimal care because this is a standard of care that has been going on, but we as clinicians, I think sometimes forget. Or we just are thinking, so focused on disease control that sometimes these supportive measures go by the wayside. And so this was a really nice wake-up call.

So the last question for you, trying to think about not just who is the right patient but dig into timing a little bit. Do you usually use radium after chemotherapy? You mentioned that doesn't seem to always happen. I'm just curious about how do you work it into the sequence? Is this your decision, a patient's decision? What are you thinking about when you are choosing?

William Oh: Well, as you know, there are patients who are still very averse to chemo. We know that they just do not want it, or they have to be convinced. And in most settings, I will use it.  I would try to use it before chemo. And I think you pointed out that there is some suggestion that using it earlier will actually have some longer-term benefits, although that is not randomized data. That said, chemotherapy is also a very good treatment for prostate cancer. So if a patient is having more rapid progression, I will always default to chemo after an AR targeted therapy or sometimes before an AR targeted therapy. So typically I'm going to use radium as a second-line after an AR therapy or the third-line after an AR and chemotherapy. Of course, the wrinkle in this is the advent of some data with second-line chemo, cabazitaxel, and also with the use of PARP inhibitors.

So I'm always testing to make sure that the patient doesn't have an HRR mutation, if they do then, of course, I'm going to start with the PARP inhibitor after an AR targeted therapy. But that said, I think that the main decision is usually the pace of their cancer progression and the sites of their metastasis. The ideal candidate for radium is progressing a little more slowly, not explosively, certainly has no visceral metastases. They can have a couple of lymph node metastasis, and maybe they are a little averse to chemo, but even if they're not, I'm going to try to get both treatments in, chemo and radium.

Alicia Morgans: Yeah. I would agree with that. I think at the end of a patient's journey through all of these different therapies, I really take comfort in knowing that we tried to get every available therapy to that patient, or at least offer that treatment. And sometimes, as you said, if patients have very, very few lymph nodes, this may be an opportunity to, and then multiple bone metastases, this may be an opportunity to get radium in before the disease alters its course a little bit, may have more lymph node disease, may have more visceral disease in the future, in which case, of course, radium will then be off the table. So we'll lose the opportunity for that benefit.

But I think about things very much the way you do, and certainly, engage the patient in those choices. Because like you said, patients may have some thoughts already about chemotherapy or other treatments and want to really play a role in that decision. So for certain individuals who like to be more engaged and others will really defer. So this is great, I really appreciate picking your brain about these therapies. The landscape is incredibly complicated. As we wrap up, what would your closing remarks be or your final thoughts on choosing patients for radium?

William Oh: Well, I think that the future may show more combinations. So I think we should look out for those combos of radium with immunotherapy or PARP inhibitors. We may see more combos in the future, but for now, I'd say, don't forget to use what is an active drug that improves survival, try to give your patient, as you said, Alicia, very nicely, every advantage to survive. That's what our patients want. So that is my perspective on every single patient that I see, and I don't want to hurt them, but many times the patients tolerate radium quite well. So I think it's a very good option in our armamentarium.

Alicia Morgans: I completely agree. Well, thank you so much for taking the time today and for sharing your thoughts. I really appreciate it.

William Oh: Thank you, Alicia. It was great talking to you.