Alicia Morgans: Hi this is Alicia Morgans, Associate Professor of Medicine and GU medical oncologist at Northwestern University. I am so excited to have here with me today a friend and colleague, Dr. Evan Yu, who is a Professor of Medicine at the University of Washington, where he's also a GU medical oncologist. Thanks so much for coming to speak with me today, Evan.

Evan Yu: Yeah, thanks for having me on. It's always a good time.

Alicia Morgans: It is. All right, well I wanted to talk with you today about how you think about sequencing drugs in the metastatic castration-resistant prostate cancer setting because this is an area where we certainly have multiple options for treatment and we continue to have more data that helps to guide us in terms of things that we maybe should or should not do. What are some of the things that you're thinking about as you're moving a patient through the different phases of mCRPC, in terms of treatment?

Evan Yu: Yeah. I think when I have a patient with metastatic castration-resistant prostate cancer there are multiple questions. One of the questions is what do you do with your novel hormonal agents? I think most people will use either abiraterone or enzalutamide quite early. Occasionally patients will get sipuleucel-T, but if not usually the next drug people will use is either abiraterone or an enzalutamide. When a patient progresses on that what's the next best thing to do?

I think for ease and simplicity if a patient is not symptomatic, a lot of providers want to just go to another hormonal agent but I think there's quite a bit of growing data that shows that that strategy is not leading to a lot of benefits. There are retrospective data that shows that PSA response rates might be as low as in the 20/30% range with enzalutamide after abiraterone. With abiraterone after enzalutamide, it's even worse. There are prospective data from the PLATO trial that shows abiraterone after enzalutamide is a 2.5% PSA response rate. There's data from the University of British Columbia also that shows the time to PSA progression seems to be better if you go abiraterone/enzalutamide versus enzalutamide/abiraterone, but the response to the second agent is generally not good. So my strategy is really to change the mechanism of action and to go away from back to back sequencing of these novel hormonal agents.

So that brings the next question, which is well what do you change to? Really you have a couple of options. Your options are either docetaxel chemotherapy or radium-223 in that situation. Now the challenge is radium-223 does require symptomatic bone metastases and no visceral metastases, but in my philosophy, I try to use radium-223 when possible. I have a lot of rationale for that but my greatest rationale, I would say, is really pragmatic. That comes down to the fact that we have a lot of flexibility as providers to use docetaxel, use cytotoxic chemotherapy when we feel the risk/benefit ratio is in our favor. There is not a lot of regulation over when to use docetaxel, or how to use docetaxel, or who you can or can't use it in. As long as you have somebody with metastatic castration-resistant prostate cancer you can use it. If somebody's platelet count is 98,000 or even 44,000 I can use it, even if I think that the patient might benefit.

With radium-223 that is obviously a higher cost medication, but insurance companies will then keep a close watch on that and they care a lot about the absolute neutrophil count, the platelet count, the hemoglobin level. These have to be above a certain criteria. As you follow patients out with metastatic castration-resistant prostate cancer the later you go the more likely there is to be marrow involvement in the disease, the more likely there is for the patient to be heavily pretreated and to have cytopenias in which case then I might not be able to use radium-223. So my goal is always, and I've said this before on some recordings, is to get my patients as many life-prolonging therapies as possible. And if that's my goal then it probably makes more sense, for if and when I can, to give radium-223 and then docetaxel next.

Alicia Morgans: I think about it in a very similar way. I don't necessarily think about chemo first, radium first, how I do that. Except that I try to give the radium early enough, exactly as you said, that I don't have refractory cytopenias or just cytopenias in general that make it either challenging for me to get approval, though that's not usually an issue in my setting. It's more that the nuclear medicine docs say, "Hey, this person's got a pretty persistent anemia or maybe a thrombocytopenia and I don't feel comfortable giving a treatment." Certainly, I would never be able to or want to twist somebody's arm to do something that he or she doesn't feel comfortable with.

So giving it earlier does provide that marrow reserve, I think, and enables us to get more cycles of radium in too. Because that's the other thing if I give radium, or when I give radium, which I give pretty regularly, I try to get in at least five to six cycles if I can. Because we do know that there seems to be more of a benefit for patients who receive more cycles.

Evan Yu: Yep. I agree with that completely. I think it matters. If you give radium as your last-line therapy, like most last-line therapies, good luck getting more than two or three cycles in, right?

Alicia Morgans: Exactly.

Evan Yu: So it makes more pragmatic sense, I think, to try to give it earlier rather than later.

Alicia Morgans: What do you think about the symptomatic part of this, because I have to say I'm actually pretty flexible on what a symptom is in this setting. Because I typically give radium not for pain relief. I use a fair amount of external beam radiation for pain relief. Though, of course, radium does have that effect, that patients can have a reduction of bone pain, but I give the radium because I know it's a life-prolonging therapy or so it demonstrated in a Phase III trial. So what are your thoughts about the definition of symptomatic and the use of radium?

Evan Yu: Yeah, absolutely. I'm pretty loose on that as well. Certainly, I think that there's theoretically ... As long as you have bone metastases I would think that radium would probably work. I think that's in the reason that's in the label is just because that's how the clinical trial was designed, but you have to look at the clinical trial data and recognize that around 40% of the patients on the trial, their definition of symptomatic was pretty minimally symptomatic. They weren't patients that were on lots of narcotics. I think around 40% of the patients were on zero narcotics. They either were on Tylenol® or ibuprofen or pointing to a site where they had a known bone metastasis and says, "It kind of hurts." So, even if you look at the clinical trial data, one could argue a lot of the patients were not very symptomatic and they still garnered benefits there. I think it's okay to be loose on that criteria. Of course, they do require some symptoms but they don't have to be incredibly symptomatic.

Honestly, I agree with you. I think radium is not my number one choice to improve patients' symptoms of pain. Certainly, I've seen patients with pain resolve over time. It's not an immediate pain relief. If you really need pain relief, external beam radiation is going to get you there a lot faster. You can do external beam radiation with radium-223 or do the radium-223 after that as well. I mean and that was ... There were patients that had that happen on the clinical trial.

Alicia Morgans: Yeah, absolutely. That's a great point. I have definitely ... And there were patients on the trial who received, essentially, radium and concurrent external beam radiation. That is not contraindicated. I have had folks question that. And, of course, as I was first using the drug I questioned it myself, of my radiation oncologist. We both looked into it, reviewed the data, and it is safe and it is something for all of us to be aware of.

So as you're thinking about sequencing it sounds like the points that you're really driving home are get every life-prolonging therapy into a patient that we possibly can, because we know this isn't curable and we want to give them every opportunity to live better and to live longer. And too, really switching mechanism of action seems to be the way to go, in terms of getting a meaningful benefit for our patients rather than, potentially, kind of wasting time with an ineffective therapy.

Are there other overarching themes or concluding thoughts that you want to just share with the listeners as we wrap up?

Evan Yu: I will just add one thing. I think the treatment landscape is changing. I'll give you an example, is I first approached this saying, okay, first-line therapy, most people are either going to give sipuleucel-T, or abiraterone, or an enzalutamide for metastatic castration-resistant prostate cancer but there is another pathway. That other pathway is for patients that have M0 castration-resistant prostate cancer that are getting an AR antagonist early. That can be enzalutamide, apalutamide, or darolutamide and when they progress I think most people realize that it's not a great option to then give abiraterone in that setting when they do progress to mCRPC.

There are multiple people entering from different pathways and so it's really an unmet need opportunity, I think, to develop new agents for metastatic castration-resistant prostate cancer first-line. But if you really think about it, with more and more people entering from different alternative pathways coming through maybe M0 CRPC to mCRPC, maybe that first-line therapy could be radium-223 versus docetaxel and this conversation that we just had could be applicable to the first-line patient with mCRPC.

Alicia Morgans: I completely agree. Of course, there are those patients who receive an AR targeted agent in the hormone-sensitive setting as well, the metastatic hormone-sensitive setting. So always something to consider. I think always a great opportunity to have a conversation with patients about their preferences as well and thinking about all of the things that come with a given treatment so that patients can really engage in that choice, and help guide their therapy and the way things could go for them.

So thank you so much for your time and for sharing your expertise today.

Evan Yu: Thank you.