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Zachary Klaassen: How are you today. My name is Zach Klaassen, I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. Delighted to be joined on UroToday by Dr. Hanan Goldberg, who is a urologic oncologist at SUNY Upstate in Syracuse, New York. Today, Dr. Goldberg is going to discuss a case today of metastatic hormone sensitive prostate cancer and really highlighting some of the new treatment options we have. Hanan, always good seeing you. Thanks for joining us on UroToday.

Hanan Goldberg: Thank you so much, Zach. It's always a pleasure to be here and with UroToday. Thanks so much. So we'll talk a little bit about metastatic hormone sensitive prostate cancer. And the data I'll present a short case that actually a patient of mine that I saw not too long ago. So he's 71 years old. He's a Caucasian male. He's got some past medical history. He's got some hypertension, some cholesterol issues. He's got not very well controlled diabetes. Hemoglobin A1C is 8.3. He does have a previous cancer history of a buccal cavity, and he had surgery and chemoradiation.

But he's considered NED by his medical oncologist. Other than that, no particular significant history. So he comes to our office with some mild lower tract symptoms, with some frequency. But he's pretty well managed with tamsulosin with good response. His urine flow PVR were normal. He was completely asymptomatic, but he had his first PSA at the age of 71, and it came back as 271, which is quite high. We, of course, repeated it to make sure there was no mistake, and it came back pretty much the same.

On physical exam, there was a clear solid nodule on the right side of the prostate, so clearly not a good thing. We sent him for an MRI, and this is just one of the images, with his permission, of course. So there's PI-RADS 5 nodule in the right posterolateral peripheral zone, extending pretty much from base to apex, so quite significant. We did a targeted and systematic fusion prostate biopsy, which as you can see, shows quite significant disease, mainly on the right, but also a little bit on the left.

We had a grade group 5 and the right apex and grade group 4 also on the right side and a little bit of grade group 3 and grade group 1 on the left side. We have pretty much transitioned to only PET PSMAs. We hardly ever do conventional imaging, and I'm sure a lot of people do the same. And just an interesting finding here, he had some pelvic lymph nodes that had some uptake. And you can see here on the sagittal view, the prostate lining up and also a pubic bone metastasis which is clearly seen both on the frontal images and on the sagittal.

Just to mention again, he's asymptomatic. This does not cause him any pain. So we also did germline and somatic mutation. This all came back negative. I always do a DEXA bone scan for these patients as a baseline. I think that's important just to get a sense of what their bones look like, and his came back normal. So he's a synchronous low volume hormone sensitive metastatic prostate cancer.

So we discussed with him the various treatment options. And we'll talk about that a little bit more later. And we told him all the various options today that are available. And we eventually went with the ADT plus darolutamide with a shared decision approach. He also received radiotherapy to his prostate based on the STAMPEDE protocol for low volume metastatic disease showing benefit. We started him on calcium and vitamin D daily.

We also recommend a very particular exercise program to do on a daily basis to help fight the adverse effects of the ADT, and I put his PSA here to show that he really responded quite well. I mean, it's really remarkable to see this, his initial PSA of 271, then one month later, 34, then 0.32 a month later and 0.0 now. And now, not too long ago, his most recent test, his PSA, is undetectable, which is quite remarkable.

And he's doing well with no significant adverse effects from the double therapy that he's receiving. So I think, Zach, if it's OK with you, we'll go over a little bit about the ARANOTE study.

Zachary Klaassen: So I just wanted before you go through some of the data, I just want to commend you on a couple of things from this case that I think are really important for our listeners. A baseline DEXA scan, easy to forget to do that. We're going to be serving these patients on double, if not triple therapy XRT, the primary tumor STAMPEDE protocol like you mentioned. And really like calcium and daily exercise. These are things that can really make a big difference, not just for bone density, lack of muscle wasting, but just overall mental health of getting through, darolutamide, ADT, whatever ARPI we're going to use in combination with ADT.
So yeah, absolutely. Great case, and I'd love for you to go through some of the data from ARANOTE.

Hanan Goldberg: Perfect. Thank you. I appreciate that Zach. So the ARANOTE trial is a global, randomized, double blind, placebo controlled study which pretty much took patients such as the case I presented, patients with metastatic hormone sensitive prostate cancer and randomized them two to one to either darolutamide plus ADT or placebo plus ADT. The primary endpoint was radiographic progression free survival, but they also looked at a lot of additional important endpoints, such as overall survival, time to mCRPC, time to additional treatment, PSA progression, undetectable PSA, and time to pain progression.

It's important to note that this study was done outside the USA. These are all the countries that were involved. And it's important also to mention some of these countries, the patients have a little bit harder time getting access to some of these medications that sometimes for us it's a little bit easier. It's important to note. These are the demographics. I'm not going to go through all of this just for the sake of time, but important to note is that majority of patients were high risk about 65% to 70%.

Majority of patients 70% were de novo metastatic disease such as the patient I presented. But they also had recurrent disease, and about 70% of patients were high volume disease and 30% were low volume disease. This is probably the most important slide of the ARANOTE trial. This is the primary endpoint, the radiographic progression free survival. So as you can see in this Kaplan-Meier curve, there's a clear benefit favoring darolutamide with hazard ratio of 0.54.

So 46% improvement, median was not reached for the darolutamide and was 25 months with the placebo. And as you can see the subgroup analysis, it's very clear to see that pretty much everything favors darolutamide whether it's the low volume, high volume, Gleason score, ECOG status, race, and age and that's important to remember. These are the other endpoints, the secondary endpoints that we looked at. So the overall survival, the time to mCRPC and PSA progression.

So darolutamide was the better choice in all of these secondary endpoints. For the overall survival, we'll talk about that a little bit more. But I think the data was still a little bit immature and the authors stated that at their presentation in multiple conferences and they're continuing to follow these patients. So hopefully we'll have more mature overall survival data at some point. But all the other endpoints, the benefit of darolutamide was quite clear.

This is the Kaplan-Meier for the overall survival. And as I said before, I think it's just a little bit immature and I think with time we're going to see a difference favoring the darolutamide arm. This is looking at two important endpoints that I think need to be looked at on a regular basis. One of our targets is, one of our goals is to delay mCRPC as much as we can. That mCRPC when it happens fast, it's usually not a good thing, leading to the ultimate outcome of death, which we want to postpone, of course.

And you can see there's a clear benefit here favoring darolutamide hazard ratio of 0.4 and also time to pain progression quality of life is also something very important. Hazard ratio of 0.72 favoring the darolutamide arm. I think this is now being talked about more and more. This PSA of less than 0.2 and sometimes less than 0.1. And there's even data of less than 0.01. And I think that has been shown to improve survival. The prognosis is better.

And as you can see in this trial, 62% of patients were with a PSA of less than 0.2 at any time during the treatment versus 18.5% in the placebo arm. And the time to PSA progression was also significantly better with the darolutamide arm, with a very impressive hazard ratio of 0.31. A little bit about adverse effects, and it's interesting to see that the fatigue was actually higher with the placebo compared to darolutamide. The rest of the adverse effects were relatively similar, maybe a little bit more cardiac arrhythmias, coronary artery disorders, but all relatively low percentages.

So it's a very well tolerated drug. And recently, I'm sure everyone has heard about this. The FDA has approved darolutamide as doublet therapy. We had our sense that FDA approved it as triplet therapy, but now we have it as doublet therapy, and this just happened 20 days ago pretty much. So now it's FDA approved treatment. And we always get asked the question of how does this compare to other treatments. So it's a very hard question to answer.

We have all these other trials that have been published before looking at all these other different treatments. Chemotherapy abiraterone, enzalutamide, apalutamide. And of course, the triplet therapies abiraterone plus docetaxel and ARASENS with darolutamide with ADT. And these are the overall survival benefit that has been shown. So ARANOTE is not here because the overall survival data is still immature. But these are all good treatments, it's very difficult to choose which one is better than the other.

And that's something I think that we'll continue to talk about in the next few years. If we look at NCCN you see all the treatment options are available. So this is crazy. I remember as a resident, we only had ADT. Nothing else was available. Now, we have a plethora of options. So it's quite amazing. They divide this to high volume versus low volume. If you look at the low volume it's even worse, all these options. So very interesting times we're living at that we have all these options for these patients, absolutely.

So maybe just a few points for discussion and then I'll let you lead with this Zach. So need for education on treatment intensification, I know that's a very important point that you've brought up many times before. I completely share that with you. I think it's critical that we talk about this. If you look at various databases, various studies, anywhere between 30% to 50% of patients are still only getting ADT in the United States. And that's really something that us as academic urologists, academic medical oncologists need to work on and improve and emphasize the education.

And it's not just in the United States. This was presented at GU ASCO 2022. This is in Great Britain, and 45% of men were not receiving treatment intensification. So that's an important point. Choosing the right treatment, we talked about that a little bit before. that's where I think the art of medicine comes into. It's something that we each learn and we each have our own habits.

These are all good treatments, but of course, there's different side effect profiles that we all need to remember. And choosing the right thing for my patient that I presented with a very uncontrolled diabetes, giving prednisone with abiraterone probably not something I would want to do. But other than that, these are all good treatments. But I think there darolutamide is kind of very safe. The data has shown that it's a very well tolerated drug and has a very good efficacy and good results.

PSA target as I mentioned before, this is becoming more important. This is from the Ironman registry that was presented at the last ASCO meeting, the big ASCO. They show that regardless of what treatment you get, if your PSA is lower than 0.1 you do better. You just significantly do better with overall survival and it doesn't matter what treatment you're on, darolutamide, apalutamide, enzalutamide, abiraterone. So the lower the PSA that you can reach this will benefit the patient.

And they also show that a PSA of above-- 12 month PSA of above 0.2 was associated with a five-fold risk of death, which is very interesting I thought when I saw that. Lastly, doublet versus triplet. Again, I'm not sure we'll be able to answer that question. It's very, very difficult to answer. This trial's being done. This is the TRIPLE-SWITCH trial which is going to randomize patients to either doublet or triplet if their PSA is above 0.2.

So I think this will be an important trial to see the results of. There's other trials looking at de-escalation of treatment as well. We won't go into that, but I think it will be important in the future to tailor the treatment be a little bit more nuanced than we are today. And I think finally, the shared decision making, which is so important, I think that's critical. There's so many things involved here patient wishes, patient comorbidities, who's taking care of the patient, access, financial toxicity.

That's why the discussion with the patient and his family, I think, is kind of critical and I can't emphasize the importance of this concept, which is from localized disease up to advanced metastatic disease, which is super critical. Perfect. That's all I have.

Zachary Klaassen: Absolutely fantastic. Just a whirlwind of great points. You and I could talk probably on each of these bullet points for 20 minutes each, which fortunately for our listeners, we won't. But I think you bring up great points. I think you mentioned all the plethora of options we have, but it's still a lack of treatment intensification. I think the PSA target is super important. Your patient hit undetectable within about five or six months, which really does bode well for staying on treatment. All those end points you talked about, overall survival time to mCRPC are all going to improve with that really deep, durable PSA response.

And I think you nailed it at the end with the shared decision making. I mean, this is all about looking at the patient's comorbidities, there are other medications that they're on, all these considerations. And in the US as well, coverage, what's being covered, what may be a little more difficult to get covered. So just great, great points and on. I want to wrap up with just a general question, just for your practice. We just had the FDA approval, like you mentioned, around roughly three weeks ago in early June 2025. In your mind, how is this doublet therapy approval shaped your practice in the last several weeks, and how do you see it over the next 6 to 12 months?

Hanan Goldberg: Yeah, I think that's a great question, Zach. Thank you. We've been using darolutamide even before that. A lot of us have been doing that. I think this FDA approval, I was not a lot of people were maybe unsure if it's going to happen. I was certain that this was going to happen. It's a good medication. The ARANOTE study showed very clear results, very clear benefit. I'm sure with time, the overall survival will show to be beneficial with the darolutamide.

And I think it's what was expected. To me, it's the natural course of things. And I'm very glad that it got approved quicker than originally anticipated.

Zachary Klaassen: Yeah, absolutely. As I mentioned, great slides. Thanks for putting time into putting those together. Any final conclusion points, anything you want to mention before we wrap up.

Hanan Goldberg: No, nothing. I think just the education piece of it. I can't stress that enough. To me, that's a personal thing that's very important. I sometimes see patients more from rural areas as well. And, for me to make sure that these patients are getting the right treatment today is really critically important. And I think us, people who work in academia who have access to this data, we need to focus on education and spreading this wealth of knowledge to everyone. So all patients get the right treatment.

Zachary Klaassen: Yeah, well said. Hanan, thanks so much for joining us, as always, and thanks for your time.

Hanan Goldberg: Thank you so much. Always a pleasure, Zack. And UroToday for having me here. Thank you.