Daniel George: Great to be here, Zach.
Zachary Klaassen: So success is a different term for surgeons, for radiation oncologists. For medical oncologists when we're treating metastatic disease, what does success look like for you guys?
Daniel George: Yeah. I think it really depends on the patient and meeting them where they're at. We'll have some patients where they're young, they're healthy. For them, success means no residual disease, right? Getting to CR and that's by PSA, that's by imaging. And ultimately for some of those patients, success means off therapy.
Zachary Klaassen: Sure.
Daniel George: Now, we recognize we're probably not curing these patients yet, but long-term remission and even on and off therapy can be success. So a lot of this is really about meeting the patients where they are.
Zachary Klaassen: Yeah, it's a good answer. And I think that aspect of coming off therapy, this is new to us. We have some de-escalation studies going on right now. How do you approach that subject with your patients?
Daniel George: So this is sticky because on one hand, we're really happy. The PSA is undetectable. The patient's scans are negative and we feel really good about things. But you and I both know that that patient could be on hormonal therapy for the rest of their life. And that could be 10, 15 years. The truth is that all of these big phase three studies, maybe they got five or seven years follow-up, but the FDA, nobody's requiring them to follow these patients for 20 years. So when patients ask me, "Okay, what's the best case scenario here?" I don't know. We don't know. And so one of the things I think we need in the field is really long-term registries. So we cross these people over to follow them for long-term outcomes. We need that data to know and tell people. In the meantime, if it could be indefinite like that, at some point we got to say, look, do we want to take a break?
Zachary Klaassen: Yeah.
Daniel George: And what do we lose by doing so? If we can measure this disease, we can follow it and track it. To me, it's worth doing that at least once.
Zachary Klaassen: Yeah, absolutely. I want to focus on doublet versus triplet. And when you talk about success with these patients and what the goals are, are they different whether you're choosing a doublet ARPI plus ADT or DARO plus docetaxel ADT?
Daniel George: I don't think so. When I escalate up to triplet therapy, it's for two reasons. One, it's because the patient's chemo fit. It's not a discussion if they're not chemo fit because I'm going to make them worse more than cancer. So that's the first question. And then the second thing is why are we doing it? It's because we want to cytoreduce. We want to use a cytotoxic therapy to knock this tumor burden down and really help our hormonal therapy last even longer. So those are the two objectives. And if a patient buys into that, great. But at the end of the day, it's still getting to minimal residual disease. It's still getting to chronic long-term hormonal therapy and then on or off therapy. Those are all the things that we talk about as goals depending on where the patient's comfort level is and what their goals are.
Zachary Klaassen: Awesome. When we look at the discussions around goals of therapy, you just talked about a success. We know that everybody wants to live longer. What are some of the other metrics that your patients really lean into? Is it MCRPC? Is it undetectable PSA? What is the feedback from the patient in terms of what they're also looking for?
Daniel George: Zach, it's really interesting when you think about it because even myself, when I think about, as an oncologist treating somebody, when I was in my 40s, I was much more aggressive, always focused on overall survival. Now that I'm turning 60, not that that's old, but-
Zachary Klaassen: You look great, by the way.
Daniel George: Thanks. But the truth is that now I'm seeing life through a little bit different prism. Now what I'm thinking about it's quality of life. So it's really about the next 10, 15 years and have the best quality of life for that. And I think our patients are in that range and more. So for them, it may be just the next five years quality of life. Those are the best five years they're going to have. And so for a lot of our patients, yes, they want to live long, but they don't want to sacrifice the next five years of quality of life. And that's where some of this intermittent therapy, that's where kind of meeting them where they are, plus or minus the chemotherapy, but really kind of time off treatment, if that's a goal. Many of my patients that are fit and active, they tolerate hormonal therapy really well and they'd rather stay on it.
Zachary Klaassen: Yeah.
Daniel George: It's the peace of mind-
Zachary Klaassen: Sure.
Daniel George: ...having that down and they can go and keep going through it. So that's wonderful. But for my patients who are really gaining weight, losing muscle mass, this is a real problem-
Zachary Klaassen: Yeah.
Daniel George: And the lack of motivation associated with hormonal therapy, getting them off treatment, getting that testosterone back up, even if it's briefly, it's really worth it.
Zachary Klaassen: And as we've talked about, I mean, success can have very different forms based on what the treatment goals are, what the patient's goals are. A little bit of a spinoff from the last question. We talk about overall survival, oncological efficacy. There's other things we have to balance, progression-free survival, quality of life, DDIs. How do you wrap that up in a conversation? Is there something you rely on to sort of go with?
Daniel George: Yeah. Yeah. So I think it's really important from our discussions with patients that we're kind of short-term and long-term goal-oriented.
Zachary Klaassen: Mm-hmm.
Daniel George: We say, okay, what are our short-term goals with these patients? It's disease control, right? It's minimal residual disease, it's remission and helping them see that, that we want to get to that point. And then the conversation switches a little bit. And it's sort of like, where are they with that remission? If they're feeling good and doing great, let's not rock the boat. If we're concerned that there is biology that we're not tackling. So this PTEN deficiency story that's coming out and the fact that there may be an alternative pathway that we're not seeing by PSA and the idea that we might need to do more imaging to look for disease progression, we might need to think about blocking with AKT inhibition if that's possible, looking for other alterations like BRCA and whatnot. If someone's got an MSI-high, when do you use an agent like that?
Zachary Klaassen: Right.
Daniel George: And think about it. Do you wait until progression or can you use it as sort of the consolidation? So these are all the kind of things that we can start having those conversations with patients about. And I think it's really helpful for them to kind of be participants.
Zachary Klaassen: Sure.
Daniel George: I like to think of this as the shared decision isn't me just telling them, and it's not just them getting what they want-
Zachary Klaassen: Right.
Daniel George: It's a conversation. It's listening, it's hearing back, it's educating them, it's hearing back, and then ultimately arriving on, "Okay, you know what? I think we both agree this is the way to go."
Zachary Klaassen: Yeah.
Daniel George: Those are the best meetings. So it doesn't always work that way, but when we can, that's really, I think, ideally where we want to go with these patients. And that's where things like the time off treatment or progression-free survival are duration of response and endpoints like that really matter.
Zachary Klaassen: Yeah. And I think you just mentioned there's a shared decision-making because we have so many options. We've got things moving up in the disease space. So I appreciate laying that out. And really, again, highlighting shared decision-making, always a good thing to highlight. Great conversation, high level as always, any take-home points, anything we haven't hit on?
Daniel George: Well, I think the other thing I tell patients is that the best is yet to come. I mean, if you ... Just at this meeting today at GU 25/26, I mean, just laying out all the additional targets, all the different mechanisms, the radioligand therapies, the bispecifics, the antibody-drug conjugates, I mean, you look at all this stuff and you realize, "You know what? I don't have to cure them today," because we may have that three or four years from now." And what's really going to be important is understanding how to keep them physically and functionally as well-being as possible with the minimal residual disease so that when that opportunity comes, we can pounce, they can tolerate it and it's a life worth saving. So these are the things that I kind of give me hope, give me reasons to kind of help the patients understand like, no, let's not go crazy and try and do some off study kind of treatment or wacky radiation or surgery. Let's keep you whole, let's keep this disease under control and when the time comes, we'll use our best therapies yet to come.
Zachary Klaassen: Great way to wrap it up, Dan. Thanks as always for joining us on UroToday today.
Daniel George: My pleasure. Good to see you