Zachary Klaassen: Hi. My name is Zach Klaassen, urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. We are on UroToday at ASCO 2025, in Chicago, Illinois. I'm delighted to be joined on UroToday by Dr. Kristine Lacuna, who is a medical oncologist at Memorial Sloan Kettering Cancer Center in New York. Kristine, thanks for joining us on UroToday.

Kristine Peregrino Lacuna: Thank you so much for having me. I'm excited to talk about this changing field in the metastatic hormone sensitive space.

Zachary Klaassen: It's such a burgeoning space. And I think we go to ASCO, GU ASCO, ESMO, even AUA, EAU, we're seeing updates for new data subgroup analyses. So these conversations are so relevant.

And today, I want to focus on really where we're positioning chemo in the setting of ARASENS which we've known as a great triplet therapy based on trial published a few years ago. And now ARANOTE what you heard from Fred Saad last ESMO 2024. So maybe just before we get into some of the nuances, give our listeners a background on ARASENS and ARANOTE.

Kristine Peregrino Lacuna: Yes, for sure. So ARASENS, as we were a study, a randomized phase III study that was performed in patients with metastatic hormone sensitive prostate cancer. And they were randomized in a one-to-one fashion to receive treatment with ADT plus, docetaxel, plus the addition of darolutamide versus ADT, plus the addition of docetaxel, plus the addition of placebo. And the primary endpoint of that study was overall survival.

And in a nutshell, the study demonstrated an overall survival benefit with a hazard ratio of 0.68 and a reduction in the risk of death of about 32%. And so the important thing to note about the ARASENS study was that the investigators did several subgroup analyses looking at high-volume disease, low-volume disease, high-risk disease, low risk disease.

And just to get a sense, high-volume disease, as we all know is those with greater than or 4 bone mets or the presence of visceral disease and high-risk disease, which was taken from some earlier studies, the CHAARTED study looked at risk factors, including volume of bone mets, but also visceral disease and Gleason score.

And so the investigators looked at overall survival in that context and really saw a benefit from ARASENS ascends in the subgroup populations that had high-volume disease, high-risk and low-risk disease. And an important note of this study was that this study mainly focused or enrolled patients who had de novo metastatic disease.

And so when I'm thinking about a patient with this, what we call triplet therapy, where we're incorporating ADT plus docetaxel plus darolutamide, I really think of these subgroup analyses to guide my direction for that.

Zachary Klaassen: Absolutely. Tell us about ARANOTE.

Kristine Peregrino Lacuna: Yeah. So ARANOTE was a more recent study that was performed similar population metastatic hormone sensitive prostate cancer patients randomized one-to-one to receive treatment with-- or two to one to receive treatment with ADT plus darolutamide versus ADT alone. And the primary endpoint of this study was an rPFS. And so in a nutshell, the rPFS was met with a hazard ratio of 0.54 with a reduction in the risk of radiographic progression of 46% in the treatment arm versus the placebo arm.

And that's quite considerable. As a community, this is what we were hoping to see what we are already probably doing. And essentially one of the important things of this study is that it was really well tolerated. The side effect profile was quite manageable, and it's important to note that fatigue in the combination arm was actually slightly lower in that context.

So I think this is a really remarkable study, but also brings more options in this space and how we think about patients and choosing chemotherapy for our patients.

Zachary Klaassen: Great summary of both those trials. And I always like to think of ARASENS as the control arm was the best control arm we've ever had, ADT plus chemo. And that's why the triple therapy, the addition of darolutamide was the benefit because it was a very active control arm. So I think when we look at triple therapy and we think about triplet versus doublet, there's a lot of nuances. And so still pending FDA approval for darolutamide plus ADT.

But I think when we move forward and we have the context of OK, if this is our backbone, who do we add chemotherapy to? Because there's still going to be patients that will benefit from triplet. The young patient that I see my practice on a monthly basis, you probably see as well high volume. How are you selecting these patients? What are you going to take out of these nuances? Who's going to benefit from chemo in that upfront setting?

Kristine Peregrino Lacuna: I think that's a great question. And it's certainly something that we face every day in clinic. And so it's important to note from the ARASENS study that the comparison arm was ADT and docetaxel. It wasn't ADT plus darolutamide. So that is a nuance that we have to understand and use that and make a decision when we're seeing a patient who's coming in where the landscape has changed, where in the frontline setting we are using ADT and an ARSi now.

But when I have a patient who's coming in to me and I think of the subgroup analyses that were performed in ARASENS, the majority of patients with de novo disease who have high-volume disease, greater than or equal to 4 bone mets, or the presence of visceral disease, who are young, who are fit, who are coming in first time being diagnosed. I certainly still consider chemotherapy for those patients.

And I think that is a very different scenario than someone who is coming in who had a diagnosis of prostate cancer many years ago is now just progressing. And they're older, less fit. They have bone only disease or lymph node only disease.

I think that is a very different patient than the first patient that I described. And so I certainly think that there's still a role for chemotherapy. And I have that conversation with the patient of these different risk factors and the differences in the patients I choose for chemotherapy.

Zachary Klaassen: Yeah. Great answer. I think from a medical oncologist perspective, when we as urologists say chemo, you're going to see a medical oncologist, all sorts of alarm bells start going off. But just tell our listeners this is not chemo for life. This is not chemo until you progress. Just give us a sense of what your conversation is with the patients about docetaxel in this setting.

Kristine Peregrino Lacuna: Of course. So, in the ARASENS study, docetaxel was given every three weeks for a total of six cycles. So when I have a conversation with my patient, that patient that I had mentioned who's coming in, who's young, coming in with de novo disease, high-volume disease, visceral disease.

I have this conversation and say, your disease that I think is personally more aggressive than someone who is not in your scenario. And so the addition of chemotherapy, although for the first five to six months that you're on this regimen, you're going to have more side effects. I think that it might provide you a longevity that might have not been if we did not give chemotherapy.

And so it's a short period of time, time limited period of time where they would be on chemotherapy. And they might be able to receive a long and durable PSA response, as noted from the ARASENS study. And if we're able to get a PSA that's less than 0.2, we do that those patients do better than patients who are otherwise, less likely to be considered for chemotherapy.

And so I have these conversations. Obviously, it's going to be a bidirectional discussion, a bidirectional decision point. Whether the patient is wanting to have chemotherapy. But it's also something that I discuss. You're putting a lot of effort in now for potentially longer term outcomes. I think that that's something that would really need to be elicited to the patient. If I really think that chemotherapy is the right choice.

Zachary Klaassen: That's awesome. I think to the listeners, too, I mean, once they finish that chemo, they're on darolutamide plus ADT 2 and 1/2 times longer than ADT plus placebo. So it's at 6 cycles 4 and 1/2, 5 months, and then they're on their treatment for much longer than the control arm.

Kristine Peregrino Lacuna: Exactly.

Zachary Klaassen: Great discussion. Anything we haven't hit on any concluding statements you want to give our listeners?

Kristine Peregrino Lacuna: I think that every patient is different. We take these data and we as a clinicians, as people who the data, really have to apply that to each individual, every patient, every scenario is different. And that is something that we have to digest the data. But that's the art of medicine. And I think that we really need to be able to apply each of those points to every patient that's in front of us. And everyone is different.

Zachary Klaassen: Yeah. Every patient is a sample size of one.

Kristine Peregrino Lacuna: Exactly.

Zachary Klaassen: Thanks so much for joining us, Kristine. Great conversation UroToday.

Kristine Peregrino Lacuna: Thank you so much. Thank you for having me.