Thank you so much for talking with me today.
Zachary Klaassen: Of course. Alicia, always good chatting with you on UroToday.
Alicia Morgans: Wonderful.
So Zach, you see these patients certainly after surgery, but of course these patients exist after radiation. How do you identify these patients? Who are they going to be? And speak to the radiation population again also, if you can too.
Zachary Klaassen: Yeah, absolutely. I mean, it's sort of the old definitions of biochemical recurrence after prostatectomy, after radiotherapy. So after prostatectomy, PSA greater than 0.2, and then reconfirmed with another PSA greater than 0.2 and then typically, the old Phoenix definition for radiotherapy, so taking the nadir as low as the PSA gets as it starts to creep up. And then that's the nadir plus PSA of 2. So that's sort of the basic way that we look at it in the clinic.
Alicia Morgans: Absolutely. And when you think about defining who the high-risk BCR patient is going to be that you might treat with a regimen like ADT and enzalutamide or enzalutamide alone per the EMBARK regimen, how are you defining that patient? And are you, in a post-op population, are you doing that after salvage radiation to the pelvic bed?
Zachary Klaassen: Yeah, great question. So the first part of that question is how do we define these patients? So in the trial, they're pretty high-risk patients. So we see biochemical recurrence all the time. That PSA doubling time may be 24 months. We're not talking about those patients, we're talking about less than or equal to 9 months. So this is the patient population that was included in EMBARK. That's what I use in my clinic to have these discussions if we need to do something.
And so the other aspect is plus or minus radiation and the trial allowed both after radical prostatectomy. So I think everybody comes here with different stories. You sort of have to figure it out. And part of that is actually calculating the PSA doubling time. I know you and Steve Freedland previously presented data that the PSA doubling time doesn't really get calculated that often, and oftentimes we over or under estimate what that is. So I think a key take home point is we have to know what that is, so that we can inform these patients on these discussions and on the possible treatment options.
Alicia Morgans: Absolutely. So when you're thinking about these patients who have that high-risk biochemical recurrence, and nine months is what was used in the trial, but in practice there's no restriction on this label-
Zachary Klaassen: Yeah.
Alicia Morgans: ... so you may have a patient who's 12 months, you may have someone who is sort of in between that may be benefiting from this approach. How do you talk to them about the use of enzalutamide with ADT or enzalutamide alone because both of these regimens were used in the trial?
Zachary Klaassen: Yeah. I think my first inclination talking to the residents is just getting a general sense, are they 24 months, 36 months. That conversation's like, "Hey, we're going to keep watching this, but we know we don't have to act on it." And that's sometimes a hard conversation because they're like, "Doc, the PSA is going up, but it's doubling every 30 months or something, really long." When you identify around one year, then we start to get a little more in the granularity, are they getting close to that nine months? And if they're in that window, then we start to have those discussions. And to your point, both enzalutamide plus ADT and enzalutamide monotherapy had MFS benefit versus leuprolide in the trial.
What's interesting in subsequent follow-up is they didn't have overall survival benefit for enza plus leuprolide. The enza mono did not have overall survival. So I think in my practice, I always kind of tended to go towards the doublet. I just felt like that was the better bang for the buck. Now, we have data to suggest, at least we have the OS data for that, now there may be a patient where there is sexual side effects that they really want to prioritize, they don't want to decrease that testosterone. They may be willing to take the, not the risk, but the MFS benefit, but not OS benefit. And they'll go on enzalutamide monotherapy, but primarily it's going to be a doublet.
Alicia Morgans: In my practice as well. And let's just emphasize that in this early setting, systemic therapy can lead to an overall survival benefit-
Zachary Klaassen: Yes.
Alicia Morgans: ... which I think is incredible when we think of all of the different therapies that people may get over time. And patients in that trial, in the EMBARK trial, got other therapies, which is really important to think about.
One other piece of the trial design that I think is critical for us to consider in this high-risk BCR population is that the trial attempted to mimic the intermittent approach to systemic therapy that we often had been using in our practices to that point. Can you talk a little bit to that?
Zachary Klaassen: Yeah. elegant trial design, honestly, because of that, at 36 weeks getting that PSA, if it's less than 0.2, then going on treatment suspension. So the people that didn't get to less than 0.2, they continued on with therapy. And then, basically looking at that population, there's a whole bunch of analysis that have come out since then. How long does it take for testosterone to come back. Most people recover their testosterone actually. But the take home for that is when do we re-initiate, and I've had some where they've been on suspension for a long time, some within a year they're going back on. The take home is for the prostatectomy population greater than 2.0, for the radiotherapy population greater than 5. And that gives patients hope. When you have these conversations, it's like, "Hey, nine months, we're going to evaluate every three months, but at that nine-month time point, if you're less than 0.2, we're giving you a break." And on the flip side, I say, "We're going to keep going if it's not quite 0.2." I think that's important too.
So setting that mindset at the start of therapy that you may or may not get it, and we're going to do it by the data.
Alicia Morgans: From a practical perspective, and this was not in the trial, do you ever use additional holidays throughout that treatment course if you get back down to that less than 0.2 or do you stick to the one holiday that was included in EMBARK?
Zachary Klaassen: It's a great point, yes. There was only one holiday in EMBARK. In real practice though, these are discussions we have. And have I? Absolutely, because it's clinical practice. The patient's tolerating it well or they're not tolerating well, these are things that are going to affect these discussions and affect whether they go on or off therapy. So yeah, I think from a purely trial design, one suspension, but in the real world, we know that there's going to be things that affect that.
Alicia Morgans: Okay. And I think your patients probably appreciate those conversations.
Zachary Klaassen: For sure.
Alicia Morgans: We do the same in my practice.
Now, one elephant in the room that affects this patient population is the PSMA PET scan. Now, obviously not around when EMBARK was designed, but clearly here and here to stay.
Zachary Klaassen: Yep.
Alicia Morgans: How do you think about PSMA PET scans as you're thinking about initiating treatment, whether it's positive or negative, it's something that you could be getting, you could be talking about-
Zachary Klaassen: Sure.
Alicia Morgans: ... thinking about. How do you incorporate that?
Zachary Klaassen: Yeah. We could almost have a separate discussion on that, but I think, and it's all the trials to date basically, data's in the conventional imaging and we have to interpret it in the context of everybody's getting a PSMA PET, there's no difference here. And so we know that when patients come to us with a PSMA PET, I tend to act on that. If somebody's got a PSA of 2.0 after a prostatectomy, I need to get a PSMA PET. If they're low-volume metastatic hormone insensitive, then we have more options.
So to answer your question, it's not easy because we're interpreting data that's obviously different than the trial, and that's just the way we live in prostate cancer. It's individual patients' considerations. I think you really have to take each one separately, but it's not an easy situation.
Alicia Morgans: It's not, but what I actually take comfort in knowing is that many of the patients in the EMBARK trial would've had a positive PSMA PET.
Zachary Klaassen: Yes.
Alicia Morgans: So I often think about using it almost as I did or actually similarly to the way I did with the non-metastatic CRPC population. I start my systemic therapy, which in this case is ADT and enzalutamide for most patients, as we talked about. And I can use metastasis-directed therapy with my radiation team and layer that on. That additional bit of therapy is not proven to have any survival advantage, but we think may shift the trajectory of disease a little bit. But the systemic therapy has a survival advantage, which is really important. And ADT and enzalutamide is also approved in metastatic hormone-sensitive disease, so I feel really comfortable with that.
Zachary Klaassen: Totally agree. And I think, and not that this is a terminology that's out there, but I think about this in my mind, is its almost like it's, you're right, most of these patients would be metastatic in the setting if they had a PET. So there's maybe a PSMA ultra low-volume mAPMN/S population. And you're right, all the drugs work in that setting. So I think it's whether we get the PET, what their PSA is when they come to me, if they've had one already, then we have to interpret it. But I totally agree with your assessment too.
Alicia Morgans: Yeah. And I wonder, for those patients who think about going on enzalutamide monotherapy, and I would just say I commend the EMBARK investigators, the trial staff, the patients, this is the only study, only registration trial where we see monotherapy ARPI. And really we get a good understanding of what that looks like, which is really helpful for my practice.
Zachary Klaassen: Sure.
Alicia Morgans: So if you have patients, who go on that treatment, how do you talk to them about side effects? Because it's not that there are no side effects or more side effects, there are just different side effects.
Zachary Klaassen: Different side effects, yeah. Yeah, absolutely, breast tenderness, gynecomastia. And honestly, my experience isn't that vast because I usually do double it. But in the few that I have it, you can give Tamoxifen, you can do prophylactic radiotherapy. I don't know if any of them work that well. It's more so just counseling the patient. And again, in that shared decision making, if they're willing to potentially have those side effects, but their testosterone level is still relatively normal, they may be okay with that. But I think it's us counseling them on what to expect.
Alicia Morgans: Yeah. And in my practice, they're actually patients who, they're not so bothered by those side effects-
Zachary Klaassen: Sure.
Alicia Morgans: ... but feel differently with the testosterone levels being detectable.
Zachary Klaassen: Yeah, absolutely.
Alicia Morgans: And so it can be really for some, a preference.
Zachary Klaassen: Yeah. And a trade-off, for sure.
Alicia Morgans: And a trade-off is exactly right.
So when you think about monitoring these patients, other than of course those holidays that we talked about, do you ever incorporate scans? What do you think about in terms of that?
Zachary Klaassen: Yeah, it's a kind of a wide open box right now.
Alicia Morgans: Yeah.
Zachary Klaassen: I tend to do one at least once a year. Now, if the PSA is not behaving or it's going up, I may intervene a little bit earlier and typically, those are with PSMA PET scans. But I think imaging in general in this sort of advanced prostate cancer space is a little heterogeneous in terms of some people will do every three months, every six months, at least once a year I think is reasonable. So in my practice, generally every 6 to 12, probably 12, unless the PSA is doing something funny.
Alicia Morgans: Yeah. And I would agree with you that it's usually going to be a PSMA PET that I do.
Zachary Klaassen: Yep.
Alicia Morgans: And I counsel patients before I do it, I probably won't see anything-
Zachary Klaassen: Right.
Alicia Morgans: ... You've got an undetectable PSA or you've got a rising PSA. We are doing this for cause-
Zachary Klaassen: Sure.
Alicia Morgans: ... and I'm expecting that we might see something, which is helpful.
Zachary Klaassen: Absolutely.
Alicia Morgans: So any other ideas, thoughts that you wanted to share on how to best take care of patients with this regimen?
Zachary Klaassen: I think it comes down to calculating the PSA doubling time because I think that can be a limitation, you guys showed that. And really not over-treating of people, but not under-treating people, really focusing in your conversation with the high-risk biochemical occurrence, PSA doubling time less than nine months, completely different conversation than that PSA doubling time of 24 or 30 months.
Alicia Morgans: Yes.
Zachary Klaassen: So understanding that not everybody needs this, but the ones that need it should get it. I think that's important. And beyond that, the trial's elegant, I think the treatment suspension is really nice. Patients will buy into it knowing there's a chance or a hope that if they get to that PSA less than 0.2, a lot of them do, and then they get a treatment suspension or a holiday.
Alicia Morgans: Absolutely. And even with that treatment suspension, with the combination of enzalutamide and ADT, they had a survival advantage-
Zachary Klaassen: That's right.
Alicia Morgans: ... even in this very early non-metastatic by conventional imaging status. So that is to me-
Zachary Klaassen: Huge.
Alicia Morgans: .. hugely compelling-
Zachary Klaassen: Absolutely.
Alicia Morgans: ... so early on in the disease.
Zachary Klaassen: No question.
Alicia Morgans: Well, thank you so much for talking this through, Zach.
Zachary Klaassen: Of course.
Alicia Morgans: I always appreciate your time.
Zachary Klaassen: Likewise, Alicia. Thank you so much.