Neeraj Agarwal: Hello. Welcome to UroToday. Today I have Dr. Pedro Barata, associate professor and endowed chair in oncology in Case Western University in Cleveland, Ohio. He is going to talk to us about the recent advancements in metastatic hormone-sensitive prostate cancer, and will describe an interesting case he recently saw in his clinic. So, Pedro, welcome and thanks for taking the time to share the recent updates in metastatic mHSPC setting with us today.

Pedro Barata: Absolutely. Neeraj, thank you for having me. And we just quickly put a case together of a patient that actually came as a second opinion, and got treated as a standard of care and happy to share that with you. And then we're happy to have a conversation around this disease setting. So again, thank you Neeraj so much. So this is a 54-year-old man, young, young man. Good performance status. He did have, however, metabolic syndrome. Diabetes controlled-ish A1c 7.5.

He had metabolic syndrome diagnosed diabetes AFib. He actually was on anticoagulation. And when he was seen by the team last year, they were thinking about the workup. And he ended up having workup done in the context of these lower tract urinary symptoms, some pelvic discomfort, and PSA was elevated at 16. So he ended up getting scans.

Showed an enlarged prostate, some borderline nodes around 1 to 1.5 centimeter. He was found with a few spots in the bones. And so at that time there was a suspected prostate cancer. He ended up getting a biopsy to prove it, ended up being diagnosed with Gleason grade group 5. Poorly differentiated carcinoma of the prostate.

So patient was staged at this time was considered to have newly diagnosed low-volume by conventional scans. And because of these past medical history of these concomitant medication at the time the team was defining what would be the ARPI to go with and decided to go with darolutamide. And that's how we did. He went on he embarked on ADT along with darolutamide.

He got actually very nicely PSA response on treatment quickly a few three months later or so. PSA went quickly to 0.4 and then actually to lower and lower than 0.2. He also was offered a radiation to the primary tumor. And at that time germline and somatic testing came back. Actually, no targeted alterations were observed there.

And so the patient has been on the combination therapy of darolutamide ADT for now a little bit over a year. Doing quite well. No symptoms is on cruise control. He's actually about to get scans. He transitioned his care to us. But I felt it was interesting because the doctors, which wasn't me. I don't take credit for it. But I think it was a thoughtful process of them going through the drug-drug interactions, wanted to avoid the steroids in the context of that A1c. And to me, the decision to go with this combination made all the sense. And so this is a good example, where we are able to control the disease and patient is doing great thus far.

Neeraj Agarwal: You did share with me that the decision to start on darolutamide was based on multiple factors. First of all, patient was not considered for chemotherapy likely because of underlying diabetes for a long time. Patient is likely very predisposed to have neuropathy with docetaxel although we can argue this is low-volume de novo metastatic prostate cancer, but this is de novo metastatic prostate cancer. So docetaxel can technically be considered. But I agree with you underlying diabetes and other comorbidities likely not a very good candidate for docetaxel.

And I think you may have chosen this ARPI among many other excellent ARPIs. And I'm going to ask you a question on that in a second. But looks like dabigatran treatment may have swayed you towards using darolutamide here. Is that correct?

Pedro Barata: That's absolutely the case. And again, I won't take credit. So he came to me after this was made, and I kept him on the same regimen. But that's correct. The fact that he was on these oral anticoagulation we know how does that change. The metabolism is impacted by the ARPI we bring them on. It was a factor to consider darolutamide. The colleagues were actually aware of the different profile of the ARPIs and the darolutamide, apalutamide, abiraterone, and darolutamide.

And so they decided whether to go with the darolutamide because of that. And in regards to the chemotherapy, chemotherapy was considered. But to your point, he was not considered the best candidate. Also he was not super thrilled about it. The data was shown to him. But my understanding he actually came to see us with the understanding that chemotherapy was discussed at that time was decided not to pursue docetaxel. And so he was a conversation between ARASENS and ARANOTE.

The addition of the darolutamide to docetaxel yes or no. And then darolutamide with ADT by itself. And so you're absolutely spot on. And so the decision was to proceed with ADT darolutamide. At the same time he got engaged with a primary care doctor a little bit better to control, try to bring that A1c down. He's now under 7, which is a good thing. So from that perspective he is trying to control his risk factors for metabolic syndrome, but also cardiovascular risk factors. So that has been a conversation when he comes to clinic for us to try to make sure those factors-- high blood pressure, high glycemia, and bone health are being addressed when he comes to see us.

Neeraj Agarwal: And these patients I really emphasize exercise. This patient has achieved a PSA level of less than 0.2 nanograms per milliliter, which is a very good sign. He is one of those patients who is going to do very well for long periods of time on ADT plus ARPI combination darolutamide in this case. And these are the patients who are ideal candidates for exercise programs, enrollment in exercise programs.

Now just for the sake of completeness, Pedro, thanks for sharing this case and your clinical experience with this. Can we go through the data on metastatic hormone sensitive prostate cancer and look at the data from other treatment options available and what is coming up in the near future.

Pedro Barata: Wonderful. Sure. Neeraj, we can do that absolutely. So just a reminder to your point, we're looking at timing of metastatic disease matters, amount of disease tumor burden or disease volume matters. We have those two factors. You basically have four categories. Newly diagnosed high volume disease. Newly diagnosed low volume disease. Recurrent high volume recurrent low volume. You can see here. I know you're very well aware of these data. It does impact prognosis. Patients-- the worst actors newly diagnosed high volume. The best actors recurrent low volume.

So our patient was here in the middle, newly diagnosed and low volume disease. So just a reminder that he is facing as a young guy-- so he is facing mortality from prostate cancer. That's the expectation. So we want to do everything we can to prolong his survival and preserve quality of life as much as possible. In real world as we know, and there's different data sets. You have published a lot on that as well, and many others. But bottom line is a reminder that the use of combination strategies are under utilized today.

And it's interesting to see that there's about probably less than 20% of patients getting chemotherapy. Maybe half of the patients are getting ARPI in addition to ADT. ADT continues to be used in real world. But really we have a number of phase III trials supporting the combination treatments to be superior to ADT or ADT and first generation anti-androgens.

Today we do consider the addition of bicalutamide or flutamide. This is similar to ADT alone. And so from that perspective we came from showing that docetaxel plus ADT better than ADT alone. Then the addition of abiraterone better than the ADT alone. And then enzalutamide and APA better than ADT alone.

Neeraj Agarwal: Thank you for sharing this really nice picture showing the efficacy data from so many different trials. It takes a long time to prepare these or dig them out from the literature. But it's so striking to see that almost all ADT plus ARPI combinations are associated with a significant overall survival benefit with a hazard ratio, which is so similar, favoring the combination at about 0.66, 0.70, 0.60. And as you said, Pedro, it is so unfortunate that many of our patients are still not getting these combinations. So I just wanted to interrupt you and emphasize that.

Pedro Barata: I couldn't agree with you more, Neeraj. And since you're on that point, it just maybe a highlight for the audience, the delta, the benefit, the addition benefit of bringing the ARPI in this setting. Look at that over a year. Well, over a year in many cases is way bigger than the delta that we are used to "later on in the metastatic CRPC setting." So bringing these agents early are really able to allow us to play the game of many more years in terms of overall survival.

So it's a huge significance. So this is a call out to say do not save these therapies for later because the ability to control the disease in the long run you get a lot more from doing it early on, and actually waiting from later on. Because remember you will have PSA responses. Your PSA is very likely going to come down. The ADT works, but this is not the game you're playing. You don't want to play a game of three or four years. You want to play the game, hope, for a much longer time of that. And I think these data whether chemo, which we won't do anymore by itself, whether it's ARPI with or without chemotherapy, that's really what we should be talking about today.

Neeraj Agarwal: Pedro, how the future is looking like in metastatic hormone-sensitive prostate cancer?

Pedro Barata: Yeah, I'm actually happy. So let me show you the most recent data actually supports the decision for darolutamide in this particular patient without docetaxel. We had data from darolutamide on top of the stacks ADT on the ARASENS trial. To be fair and to be comprehensive, we also had that data for abiraterone. But more recently we saw data from ARANOTE, which by the way was ex US study. It was a big actually international effort. Here's the representation of all the sites around the world.

At this time patients were randomized 2 to 1 to darolutamide or placebo with ADT. Just, again, enroll in other areas of the world where access to therapies is not the same as it has been in the US in the recent past. This is really patients that we really, really what we see in clinic about interesting all the trials that I've shown, about over 2/3 of patients have high volume disease. And that's something we've seen that. And also is also true as far as newly diagnosed disease first recurrence.

So on these trials we have enrolled more patients with newly diagnosed disease as well as high volume disease, which not necessarily what we see in real world because we have a lot of those patients in real world come to us with recurrent, and a lot of times PET scanning showing low volume metastatic disease. But that's the characteristics of the patients we're looking at. We know that the addition of darolutamide is able to significantly prolong tumor control measured by radiographic progression-free survival. You see here a delta of almost 20% absolute delta two years.

And then the good news is with two years a little bit shy from two years of follow up you can see that no matter the pre-specified subgroup you look at you do see the benefit of the addition of the ARPI darolutamide on top of ADT. Again our colleagues from another institution were very well aware of this benefit, and that's why they consider this for this particular patient. In this case I'm highlighting the volume of the disease, which is important. The fact that you see two or three spots in the bones or just no disease, please do not use that argument not to treat intensify particularly in the newly diagnosed disease.

And finally, other endpoints that matter to patients. Patients will ask you in clinic, doctor, for how long is this going to work? When do I have to go and embark on a new line of treatment? When do I have more symptoms from my cancer? Those are very meaningful questions in clinical practice. And so those secondary endpoints are important for us to educate our conversations in our clinics. And as you can see the benefit here is throughout.

My comment about survival-- I'm just going to say it's immature. It's not really surprising because as we go through the data two years is not enough to appreciate the difference in survival of patients treated with ADT ARPI versus ADT alone. And that's a good problem because these patients live longer than that. We know that. So the 2-year mark or the 20-month mark is fairly short to assess, to have the events. So we want these patients to live long. So my anticipation is as we get longer follow-up, we will see how these two groups of patients will perform over time.

But we really got to wait longer to see a benefit in terms of overall survival because this is a short follow-up for that specific endpoint of interest. And so to answer your question, Neeraj, what is coming, I mean, the future from the intensification strategy includes ARPI's backbone and includes precision medicine. We have examples that you and others were also were involved. Whether you're looking for PSMA expression, your data like lutetium PSMA, with a PSMAddition is looking to that. If you have PTEN deficient, you're going to see data from CAPItello trial, which there's a press-release that's positive.

So we'll learn how to deal with that when the time comes, which will be soon. We're going to have data show or presented very, very soon on amplitude with a PARP inhibitor in addition to abiraterone for HR-positive disease. So this is really precision oncology advances. I have not included in here, but I should say on another angle we are getting a little bit smarter understanding who might be safely-- where a strategy of the intensified treatment might be a right approach.

You and others have been working on that really hard. And so it is very possible that in the future we'll understand who are the patients, where we are safely going to deintensify treatment because we have tumor under control, and allowing them perhaps better quality of lives, et cetera, metrics. So from that perspective, that's what I think the future is going to look like for us as we have advances in this field.

Neeraj Agarwal: Thank you very much. That was such a wonderful presentation, Pedro, very nice case. And then recent advancements talking about the ARPIs in general talking about ARANOTE trial, talking about upcoming trials such as amplitude TALAPRO-3, PSMAddition, CAPItello and hopefully many more in the coming near future. So thank you very much for sharing your time and wisdom as always.

Pedro Barata: Thank you so much for the opportunity, Neeraj. It's always pleasure to sit down and go over these important disease and this important setting. So congratulations and thank you for having me.