Kristine Lacuna: Absolutely. I'm really excited to be here. And I think it's a really exciting time to be looking at metastatic hormone-sensitive prostate cancer, because really so much has changed.
Zachary Klaassen: It really has.
Kristine Lacuna: And so, I just want to put in a plug for Prostate Cancer Working Group 4, because the nomenclature will be changing. I'll use MHSPC today, but we're going to be transitioning to APMS.
Zachary Klaassen: Excellent. Great plug.
Kristine Lacuna: Yes.
Zachary Klaassen: You just mentioned, the last decade's been unbelievable since we've come from CHAARTED, STAMPEDE literally 10 years ago. And now, we have had such good success with a lot of the combinations, doublets, triplets that sort of talk about quality-of-life assessments, how this could be a treatment success metric. How did we get to this point?
Kristine Lacuna: Absolutely. So I think that we have to take a step back and look at the last 10 to 15 years.
Zachary Klaassen: Right.
Kristine Lacuna: 15 years ago, we only had ADT for these patients. And it was the first time that we were asking ourselves, "What about escalation of therapy?" And really, that brought together exactly what you said, CHAARTED and STAMPEDE where we were for the first time escalating therapy with chemotherapy. And that was the first, as you will, OG doublet therapy where we were seeing a survival benefit where we were adding docetaxel to ADT. Fast-forward to 2015, 2016, more of the questions come in, "What about using these ARPIs that we use in the later-line setting and bringing them forward?" And what we saw was a slew of studies looking at abiraterone, enzalutamide, apalutamide, which also resulted in overall survival benefit. Again, fast-forward to the 2020s where we're again being asked the question, "What about even more escalation of therapy with triplet therapies?" And again, with PEACE-1 as well as ARASENS, we're seeing a survival benefit. And even last year when we're thinking about data that is kind of being presented in the current state, we also see the possibility for lutetium. We also see the possibility for PARP inhibitors, possibly AKT inhibitors.
Those don't have an OS benefit potentially yet, but those are in the pipeline. And so, when we think about the last decade, the last 10, 15 years, we have a bunch of treatments that we can offer our patients that show an overall survival benefit. But the important question is, what does that overall survival benefit mean for the patient? And what does that mean in the context of choosing a treatment that will control their disease that we think will be the best for them, but also making sure that that treatment is not worse than the disease itself?
Zachary Klaassen: That's great. That's a phenomenal summary of the last decade in one minute. Going off of that, we just talked about doublet, triplets. When you're talking to a patient with MHSPC, are you changing your conversation in terms of quality-of-life discussions, or is it just sort of generic, "We've got to get to these points and we want to preserve your quality of life?" Does it change with doublet versus triplet?
Kristine Lacuna: I think it absolutely does change, but I think it's important to take a step back and talk about the context of these triplet studies. Because as we all know, the studies were designed based on the original doublet therapy, which was ADT and docetaxel. And it was asking the question, "What is the difference or what is the efficacy when you add one of these ARPIs to that backbone of ADT plus docetaxel?" It didn't ask the question, "What if we add docetaxel to what we contemporarily use now?" which is ADT plus ARSI.
Zachary Klaassen: Right.
Kristine Lacuna: And so really, we have these studies where we have to extrapolate all of what we know about our patients and decide and make a decision with our patients of who to choose triplet therapy for. And when it comes back to the quality-of-life question, certainly I have a preconceived notion of which patients I'm thinking about for triplet therapy, right? It's going to be those younger patients who are more fit, who are able to withstand the six cycles of chemotherapy, but also those patients who have high-volume disease, visceral disease. And so, when I present that information to that pre-selected patient, I'm certainly telling them, "Look, we don't have the perfect data out there. There's data that are coming from cooperative group studies, but these are the reasons why I think maybe escalation of therapy might be important for you." And you talk about the quality of life at that point, that, "It is six cycles of chemotherapy, but maybe there is a potential, based on my own clinical opinion, that there could be a benefit clinically while also trying to maintain your quality of life." But it is certainly, absolutely a discussion because this is sort of a gray zone, and we need to have shared decision-making with our patients. And so, certainly, quality of life is discussed there.
Zachary Klaassen: Yeah. I like how you laid out the expectations of triplet. Some patients, we just know they need it, right?
Kristine Lacuna: Absolutely.
Zachary Klaassen: So it's our job to talk about it, have those conversations, mixing quality of life. I thought that was great. Let's focus on doublets. So if you're looking at an ARPI, what are you looking for in an ARPI in terms of the quality-of-life metric or the success outcome?
Kristine Lacuna: Yeah. So I think going back to the studies, the decade that we laid out earlier from today, we're seeing a lot of options. We have a lot of options as clinicians, doublet therapies, triplet therapies, things are coming in the pipeline. And so, we all know that they can improve overall survival. But it's our job to also think about the treatments that, again, we think are going to be successful for the patient from the disease standpoint, but also making sure that that treatment is, as one of my mentors said, "not worse than the disease itself."
Zachary Klaassen: That's right.
Kristine Lacuna: And so, you want to be able to choose a therapy that you think is going to do both. And when I think of treatment success, I ask myself, "Does the patient have function? Is the patient independent? Is the patient able to have social relationships? Is the patient able to have minimal pain? Is their pain controlled?" In addition to that survival benefit or that efficacy benefit that we're seeing from the ARPI. So when I think of treatment success for an ARPI, I think of a treatment that can control the disease and maybe see their PSA go to less than 0.2, but also seeing that they're able to be functional, they are able to be independent. And that is something that I think about when we choose ARPIs, right? We have some older-generation drugs, and then we have some newer ones. And I think that is a really important feature where we are thinking about this disease state.
Zachary Klaassen: Yeah, absolutely. And I think quality of life is different for everybody. So just give me a sample of some of the feedback from your patients when they're on doublet, what does quality of life mean to them?
Kristine Lacuna: Yeah. So quality of life means to them a number of things. One, I think for both of us, me as the clinician and the patient, that survival is always a piece that they want to achieve.
Zachary Klaassen: Sure.
Kristine Lacuna: But also, achieving a lower PSA and making sure that they are able to have function, able to still do the things that they like to do, able to spend time with their family, able to be independent. And so when I get the feedback of... One of the things that I think about if a patient is telling me, "I have response, treatment response," but they're telling me, "I am fatigued all the time. I cannot get out of bed. I'm mentally foggy. I'm not able to kind of do the things that I used to do." Then that to me, maybe we're achieving disease control, but we're not achieving what life is meaningful for that patient. And so, my goal of success is where we are achieving disease control, but the patient is telling me, "I'm able to golf with my family. I'm able to work. I might be a little bit limited, but I'm able to do that. I'm able to grocery shop. I'm able to still work." And so, that to me is something that I hear. So when I'm hearing a disconnect between those two avenues, then I kind of have to take a step back as a clinician and say, "Maybe we don't have the right treatment, although it's treating their disease. Maybe we have to think about other treatments that are more focused to improving their quality."
Zachary Klaassen: Yeah. So it's a great discussion. I think some awesome insights there. We have so many good drugs. A lot of them work in a lot of patients, but we have to really think about quality of life. And I think you highlighted that beautifully. Anything we didn't hit on? Any concluding statements for our listeners before we wrap up?
Kristine Lacuna: No, I think that this is a really exciting time to be an APMS. And so, when we're thinking about treatments that are coming down the pipeline, I think it's always important to talk about, not only their efficacy and the overall survival, as well as progression-free survival, but I think that quality of life is something that we have to always be thinking about for our patients. Because it's the life that they're living. We might be extending their survival, but what does that survival mean for that patient? Is it a life worth living for the patient, or is it that they are a shell of themselves? And that is our job to sort that out and choose the right therapy for them.
Zachary Klaassen: Well said. Thanks so much, Kristine. Great having you.
Kristine Lacuna: Thank you. Thank you for having me.