Zachary Klaassen: Hello UroToday. My name is Zach Klaassen, urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm really pleased to be joined on UroToday by Dr. Jackie Brown, who is a medical oncologist at Emory University in Atlanta, Georgia. Jackie, thanks for joining us on UroToday.

Jacqueline Brown: Thanks so much for having me, Zach.

Zachary Klaassen: So today we're going to talk about a case you put together looking at treatment selection and metastatic hormone sensitive prostate cancer. And really putting into context ARANOTE, which has been presented just under a year ago at ESMO, and then we've seen some subsequent sort of subgroup analyses. So let's roll through your case. So this is a 77-year-old male presented to his PCP with nocturia. Unfortunately, PSA at that point was more than 1,000. He had a CT scan, showed a large prostate, pelvic and retroperitoneal lymphadenopathy, a left iliac crest sclerotic bone lesion. He then saw a urologist, had a prostate biopsy, predominantly Gleason 4+5 prostate cancer.

Then he had a PSMA PET scan, showed PSMA avid lesions in the rib, clavicle, vertebral body, acetabulum, and the iliac crest, as well as the aforementioned lymph node disease. Tim has some comorbidities. Chronic systolic heart failure, ejection fraction of around 45%, hypertension on Losartan, as well as paroxysmal atrial fibrillation on Apixaban. And social history, he's also a caregiver for his wife who has dementia. So this is a very common patient we see in our practices. You and I practice in the same context in Georgia. Unfortunately, this is not uncommon. So Tim has several decision points in terms of what therapy, and maybe roll through some of the considerations you had for Tim.

Jacqueline Brown: Yeah. So taking it from the top, I think it's important that he initially gets his conventional imaging, which shows pretty low-volume disease. He had some nodal disease. He has his primary. He has the one bone lesion. So the way that we have defined it in CHAARTED, and the way that we have applied it in our triplet therapy studies with regard to high volume and low volume, those definitions came from conventional imaging. So he then gets the PSMA PET scan, which I would argue upstages him to some degree. He now has multiple bone lesions.

Now is this high volume? I don't think it's the high volume that's defined by CHAARTED because that wasn't with a PSMA PET. But certainly I'm trying to think about whether he warrants a doublet or whether he warrants a triplet therapy. And there's a lot of things that go into that decision. And honestly, for me, a really big part is patient preference. And we'll get into that at a later point. As we're thinking about—we know at least he needs a doublet. Everyone needs a doublet; ADT monotherapy is out, has been for a while. So I'm meeting him, I'm thinking about him, which doublet should we choose? He is this primary caregiver for his wife. That's a huge job.

You're exactly right. A lot of our patients are older. A lot of our patients have stuff going on in their lives other than coming back and forth to an infusion center, other than coming back and forth and trying to see me and navigate Atlanta traffic and all of these things. And so it matters the impact on his life that therapy is going to make. I need it to be tolerable. I need to not take too much of his time with treatment because he has other things going on. I'm thinking about his cardiac history. He has this history of mild systolic chronic heart failure. He's on Apixaban. I'm thinking about med-med interactions with Apixaban as well and what I might choose there.

I think one branch point here is we have two classes of drugs. We have second-generation AR inhibitors. So that's our enzalutamide, our apalutamide and our darolutamide. And then we have our abiraterone. I've been admittedly really mulling over the STOPCAP data from ASCO GU. And a quick summary of that is it was a meta-analysis of major trials looking at these secondary agents—enzalutamide and apalutamide and abiraterone. And essentially what we know is that prostate-specific survival is approved across the board when a secondary agent is added.

I thought it was really interesting in the patients over 75. We see an improvement in prostate-specific survival in the patients who received abiraterone with prednisone. But then that overall survival benefit really goes away in those older patients, whereas we see an overall survival benefit when we're thinking about the second-generation AR antagonists. So I use abiraterone. I'm pretty adept at using it, but I also have a lot of 80-year-old patients where I'm thinking about their comorbidities, and their heart failure, and what that 5 milligrams once a day of prednisone might do to them chronically.

And STOPCAP wasn't a randomized controlled trial, but as we are trying to decide between secondary agents, things like meta-analysis and real-world data, that might be the best that I get. And so I've just been thinking about that. I may not choose that for him, given his cardiac comorbidities and his age. Perhaps I'll choose a second-generation AR inhibitor. And then which one? Drug-drug interactions—I think it's reasonable to think that there's potentially slightly less with darolutamide compared to enzalutamide and apalutamide. And so that will come into play in my mind.

And I'm thinking about the fatigue and the brain fog that can be incurred. And I think that that's a little bit less with darolutamide compared to some of the other drugs as well. I use them all, but in his particular case, I'm thinking about using darolutamide. Now that's separate from am I going to be able to get it paid for and all of those things, given that it's a newer drug and it doesn't have category 1 data in NCCN yet. But I think if I'm trying to choose the most tolerable drug for him that's going to have efficacy, I think darolutamide would be a good choice.

So once I've chosen his doublet, I'm thinking about whether he needs a triplet. I have to admit to you, the guy who comes into my office who has lost 20 pounds, who can't fully sit up off the exam table because he is so impacted by his bone pain, who was a normal guy 6 months ago and now is really struggling to function—he needs chemotherapy. He needs chemotherapy yesterday because we can bring him back from the brink extremely quickly. That's very clear-cut to me. The person who has a low PSA with viscerally inclined disease—he needs chemotherapy because he's going to progress to hormone resistance quicker.

When I'm thinking about Tim, he has low-volume disease on conventional imaging. He has reasons that getting back and forth to an infusion center even just six times can be problematic. And I just don't know that I get all that much bang for my buck with him. And I think I always tell my patients, if they ask me, “Well, doc, I'll do whatever you say. So will this help me live longer?” I really can't tell him that because the comparator arms in ARASENS, and in PEACE-1 that looked at abiraterone, was chemotherapy plus ADT. So for him this is a pretty clear decision that he should get a doublet, and I'm likely not going to intensify with triplet therapy in him. So those are the things that I think about.

Zachary Klaassen: That's great breakdown. And I think going through that, how you did is exactly what's great for our listeners, just really taking it step by step and layering what your decisions are.

Jacqueline Brown: And then just to prove that we're not just going on vibes, we have some data to back us up. Let's just review the ARANOTE design. So we have about 700 patients—a little less than that—hormone sensitive metastatic prostate cancer. ECOG 0 to 2 included, so more reflective of my actual real-world population, as you mentioned in Georgia, Zach. And they are randomized 2 to 1 to darolutamide versus placebo. Obviously both arms had an ADT backbone.

Important to point out that the primary endpoint here was radiographic progression-free survival. Overall survival is a secondary endpoint along with a lot of other important clinical endpoints. So in terms of that primary endpoint, you already alluded to the ESMO data, but we heard and saw and now know that darolutamide improved the radiographic progression-free survival over ADT monotherapy. That hazard ratio was 0.54 with an undetectable p-value. And we look at that two-year landmark analysis, 70.3% of patients who got the darolutamide did not have progression, compared to about half of the patients with ADT monotherapy.

This is maybe, I don't want to say a more important slide, but as we are thinking about—we have a menu of great options—and so as I'm actually thinking about what I'm going to choose and how I'm going to choose between agents, this slide is arguably more important than the first. I almost take it for granted that the first is positive, which I shouldn't do, but the tolerability is pretty key here. So as you can see, whether we're looking at fatigue, that first line, we see the incidence 5.6 in the darolutamide arm compared to about 8% in the placebo arm. Now, I had a colleague tell me there was less fatigue in the darolutamide arm. I have my doubts about that. I don't think it's going to be a magical pill that takes away fatigue, but I am thrilled to see that it didn't significantly add to it.

That brain fog our patients complain about is minimally elevated compared to placebo and then falls. Particularly in our older patients, I'm not seeing that huge jump up that I see with some of the other AR antagonists. And then particular to Tim with his cardiac history, thinking about hypertension, arrhythmias, coronary artery disease and heart failure, we know that ADT increases those. And I think it's important to see that these are relatively similar between darolutamide and placebo. It's maybe slightly elevated coronary artery disorders right there, elevated cardiac arrhythmias, but pretty similar in terms of heart failure incidence and hypertension. So that's encouraging to me as well.

And then this whole high volume, low volume triplet therapy debate—I appreciate this slide. It broke down the primary endpoint by high volume and low volume based on conventional imaging. And what you can see is that darolutamide had a benefit in progression-free survival improvement, regardless of the volume of disease.

Busy slide, lots of schema—bear with me. I think the take-home here is that whether we're looking at TITAN, which looked at apalutamide, ARCHES and ENZAMET, which looked at enzalutamide, and then ARASENS, which I referenced earlier, which was triplet therapy with darolutamide compared to docetaxel and ADT—overall survival was the primary endpoint across these trials, whereas when we're looking at ARANOTE, progression-free survival radiographically was the primary endpoint. It's a much smaller study. It has a category 2B recommendation on NCCN because we don't have that overall survival data based on a randomized clinical trial. Honestly at the interim analysis we don't see that that's significant yet. I think that it will be. But even if it isn't, right, it wasn't powered for that. So I don't know that my practice will change based on that. I'll be interested to see how other people take that, but I just recognize the difference in the trial design.

And so, I have Tim as an actual patient, and I have patients like Tim every day. For him, I would initiate LHRH antagonist therapy. And I tend to do things in a very sequenced way—let's do one thing at a time, see how you tolerate it, make sure all hell doesn't break loose, and then add the next thing. So I usually have people back four or five, six weeks later, after starting ADT, and then I add the secondary agent at that time, and that's what I did for him. He is tolerating well. He's had some mild fatigue and his blood pressure did increase slightly, but that was pretty manageable with his regimen of antihypertensives.

As I mentioned before, I don't think we should have added chemotherapy for Tim. He agreed with me and ultimately, we decided together that we wouldn't add it. And he's had this really nice and precipitous PSA drop on therapy to PSA 0.02 by 18 weeks of therapy, which is important, and I can tell him that that's a good marker for us going forward. And so with that, thanks for going through the case with me and let's talk about it.

Zachary Klaassen: Yeah, fantastic case. And again, something we see every day and something I know our listeners see all the time as well. I think we're not pharmacists, but we see these patients on multiple medications. This patient is on Apixaban and Losartan. In terms of obviously efficacy, tolerability, cost, all those things, where does DDI sort of play into it? You alluded to it a little bit in your case. Maybe just expand on that in terms of what level we should be aware of it, how much we should be concerned by it.

Jacqueline Brown: I think certainly there are those drugs where if someone is on amiodarone or someone is on rifampin or somebody is on some anti-seizure medicine that I don't encounter that much, I am so privileged to be able to turn around and talk to my pharmacist and say, Sarah, can you help me out? What do you think about this regimen for him? So I think it's always important when available to partner with a pharmacist for making those decisions.

With that said, a lot of potential drug-drug interactions have not borne out in trials. I think there have been lots of post-hoc studies of big trials of inhibitors, where in fact, we haven't seen that although there is a potential interaction between darolutamide and Apixaban, for example, we are not seeing an increase in clots in those patients who take both. So I think for so many drugs there's a potential interaction, but clinically, we're not seeing that.

And if I'm meeting a patient who takes Apixaban and I want to start darolutamide, I am not saying that we need to change to some other anticoagulant. I'm not going to put them through that. Honestly, I think changing up their regimen increases their risk that they're not going to take it right, and then they'll have a clot because of that, not really because of the drug interaction with the darolutamide. So I'm aware of it. But I think there's a difference between the theoretical interaction and the actual clinical impact of that interaction. And for the most part, for a lot of these drugs, the clinical impact is pretty minimal.

Zachary Klaassen: Yeah, no, I agree, I think we see that in our practice. I think Neal Shore as well did a very nice post-hoc analysis of ARAMIS looking at darolutamide in the nmCRPC setting and looking at patients on statins, not on statins, versus anticoagulants, not on anticoagulants. No difference in those, at least in that trial. So that's something I always come back to as well.

Jacqueline Brown: And that's like thousands of guys. This is not, “Hey, we did a retrospective at our institution of 40 people.” I mean, this is a lot of patients and a lot of data. I agree.

Zachary Klaassen: Last question, I think you mentioned the PSA of 0.02 at 18 weeks, coming from over 1,000 to 0.02. Phenomenal results for your patient. Fred Saad has recently presented some importance of 0.02 or less and really shifting our mindset as urologists and medical oncologists that we're not looking for a decrease to one or five or 0.5, we're really looking to drive this down. Just talk to how you speak to patients about those results when you see them back at that three-month, six-month time frame.

Jacqueline Brown: Yeah, I mean, I think when you meet a patient in your clinic—and you and I both see these patients—you meet them in your clinic for the first time, and a lot of our patients are understandably anxious. They're starting this regimen, they've googled their median overall survival. And they're saying, “Well, what's my number?” And I say, look, first of all, I can't give you that number. I'm a human being. But we're going to collect data points as we go. And those data points will help us to clarify what that number might be for you. One of those data points is that deep PSA response early on. And that's that threshold you mentioned, Zach, less than 0.02.

And we know that if this deep PSA response can be achieved, then there's a longer time to progression of castration-resistant disease. There's a longer overall survival for those patients. So for me, when I meet somebody, I say my goal is to get this PSA to 0. Is it necessarily going to happen? No, but if it does, that will tell us that your disease was really hormone responsive and we can take a deep breath and know that we've chosen a great regimen, it's working for you, and it will be more time, most likely, until we have to make another decision on therapy. So I think it's just another data point in prognosticating for patients that is better than what they've read as they come into my office.

Zachary Klaassen: Yeah, absolutely. Great case Jackie, always great chatting about prostate cancer. Such a high-level discussion. I know our listeners will enjoy this. And thank you so much for taking time out of your busy day to join us on UroToday.

Jacqueline Brown: Thank you, Zach.