Zachary Klaassen: Hi, my name is Zach Klaassen, urologic oncologist at the Georgia Cancer Center. We are at AUA 2025, in Las Vegas. I'm delighted to be joined on UroToday by Dr. Pedro Barata, who's a medical oncologist at the Seidman Cancer Center in Cleveland, Ohio. Pedro, as always, great chatting with you on UroToday.

Pedro Barata: Of course, happy to be here. Thanks for the time.

Zachary Klaassen: So we're-- the emergence of metastatic hormone sensitive prostate cancer has just taken off in the last decade. I mean, we're both not very old. But when we were in training, we were giving ADT for metastatic hormone sensitive prostate cancer. Now, it's become its own incredible field. At a very high level, we could talk for hours about this, but just give us a rundown from 2015, CHAARTED, STAMPEDE, ADT plus docetaxel to where we are today.

Pedro Barata: Sure, actually, it's funny that you bring that up because we can start there. I like to think that I'm young. I'm not young forever. You aren't either, although you look young. But I do remember we were around-- we were debating already, forever, actually, for many years, whether or not we should add first generation antiandrogen, whether or not bicalutamide, flutamide, in addition to ADT, would translate into survival gains of 3%, 4%. That was the debate in 2010.

So we've come a long way. As many other things in cancer, we have therapies that work. And see what about offering them early on and see what happens? And I think the story in hormone sensitive kind of looks like that. Chemotherapy with docetaxel was approved and is approved for patients with metastatic castration resistant disease.

The same with the ARPIs, there were abi, abiraterone and enzalutamide approved pre and post chemotherapy based on survival gains as well. So it was a natural next step to move them early on to this setting of patients who have not seen or are still sensitive to hormones, so metastatic hormone sensitive,

We still define by conventional scans. So you can have metastatic disease based on PET. But we're still going by volume and timing of metastatic disease. For the most part, it's still being done based on conventional scans, meaning CT scan and bone scan.

So when you go from ADT alone or ADT with first generation anti-androgens and you bring those docetaxel first, CHAARTED, STAMPEDE, these are all names of phase III trials, and then you bring ARPIs, ENZAMET, ARCHES, TITAN, with enzalutamide, apalutamide, and then both ARPIs and docetaxel, so called triple therapy, darolutamide, docetaxel, or abiraterone docetaxel, ARASENS, PEACE-1 you clearly see a number of things.

Number one, whether you do chemo or whether you do ARPI, you improve outcomes. Actually, radiographic progression free survival, overall survival while preserving quality of life in addition to ADT, triple therapy better than ADT with chemo. So ADT chemotherapy, which was the standard of care in 2016-17, it kind of disappeared because if you have a chemo fit patient, and perhaps we'll talk a little bit more about it, then you're going to be offering triple therapy.

So it's really an ADT ARPI plus/minus docetaxel superior to ADT? Or now we consider ADT with first generation anti-androgen similar to ADT alone. So the message out there, what has changed in the last 10 years is we no longer spend time debating is the patient on bicalutamide or flutamide. That's the same as ADT alone.

We are debating all about, OK, we need to think of layering treatments. What is the best partner with ADT? And a lot of our conversations have been around that. From the efficacy perspective, ARPIs look similar. From the safety perspective, there's absolutely differences in terms of the safety profile of the different ARPIs. And then who are the patients who can get treatment intensification? That's where we are today.

I think in the near future, we're going to have to include molecular makeup of the tumors. What happens at the molecular level? And that's why we talk so much about genetic testing. And what might happen in the future is we're going to start understanding a little bit more about who gets what of these different combination opportunities that are out there. So I guess, this is kind of how I would summarize the treatment management in this particular setting.

Zachary Klaassen: That's a great answer. I gave you a 10 hour question. You gave me a perfect 3-minute answer. So that was great. Let's just focus on the triple therapy trials just for a minute. Maybe just overall survival benefit for ARASENS and PEACE-1, just so our listeners are up to speed on what those benefits are.

Pedro Barata: Yeah, so we do have different studies. We tend to highlight two phase III trials, one trial in Europe, one international trial. The trial in Europe was actually 2 by 2 design, actually two questions in one. Karim, the group in France led those efforts called PEACE-1. Basically, asked the question about adding abiraterone to the standard of care.

At that time, the standard of care was changing from ADT alone to ADT docetaxel. So actually, while you were on the trial, then it became an ADT docetaxel plus/minus abiraterone. The second question has to do with radiation to the primary tumor. I'm not going to touch on that. So you have that trial.

And then you have the ARASENS trial, which was a pure ADT docetaxel plus/minus darolutamide. So in short, most patients that were looking at this on the ARASENS trial with darolutamide, most patients had high volume disease, newly diagnosed disease. And then on the PEACE-1, you actually have the breakdown very nicely done based on volume.

So in short, you can clearly see the benefit of the addition of docetaxel to-- or the ARPI to docetaxel, triple therapy compared to ADT docetaxel, particularly in the patients with high volume disease as well as the patients in synchronous disease, present with metastatic disease upfront.

So that plus all the other data we knew getting to that point, so remember, we were not really offering chemotherapy to everyone. We were already favoring patients with high volume disease. And we saw also people with synchronous disease benefited the most from it. So we were not doing ADT docetaxel for every single patient.

So when the standard of care changed to ADT docetaxel, the patients who would meet the criteria for the trial, providers around the world, were selecting the patients that by answering the question. Is this a patient that would be offering docetaxel? Yes or no. And then if the answer is yes, let me randomize them on study for that, or that plus ARPI, abi or daro.

Zachary Klaassen: And I think that you made this earlier, and I think just a quick take home point from that is if they are candidates for docetaxel, they should be getting triple therapy in 2025?

Pedro Barata: Yes, but not always. So the two aspects, and that's why you might get a little bit more complicated. So here's what I think about it. My docetaxel question is not the first question I'm going to answer. So if I walk through the process, just think of clinical features.

I try to answer a number of questions. Is this patient in front of me facing mortality from prostate cancer or not? If it is, that means survival or life expectancy is going to be impacted by prostate cancer. If that's the case, that means I'm going to offer the best treatment available for him.

The second question is, what's the volume? And what's the timing of disease? Does he have synchronous disease, or does he have metachronous or recurrent disease, or does he have high volume or low volume? And we still define volume by CHAARTED criteria, four spots in the bones, one outside spine and pelvis, and/or visceral disease like liver mets, lung mets.

So by answering those two questions, then you start categorizing the patients in four groups, newly diagnosed, high volume, newly diagnosed low volume, recurrent high volume, recurrent low volume. The newly diagnosed high volume tend to do the worst. The recurrent low volume tend to do the best.

We tend to reserve the triple therapy, this intensified way to treat these patients for patients with synchronous, particularly high volume disease. Why? Because they do worse. The biological explanation might lie on the fact-- the fact that, more likely, that disease-- you will have a component of the disease that's dependent on the androgen. And you have a component of the disease that might have forgotten the zip code from prostate cancer and is not dependent on androgen inhibition to grow and progress.

So by having those two components of the disease, it makes sense that we were to address the androgen component with a very potent way to do it, ARPI on top of ADT. And then you would address the other component of the disease that can be selected down the line with chemotherapy piece. And then of course, I answer the question, can actually the patient get chemotherapy?

Is the patient chemo fit? And for docetaxel, as a taxane, you got to think of things like, obviously, what are the counts? Does he have neuropathy? How old is the patient? Can he handle the side effects from it? Can he come to the center every three weeks six times.

So those aspects of the chemotherapy, that tends to be a conversation with the medical oncology, it usually, in my mind, it doesn't happen the day I meet the patient. So I do this multi-step approach. And when I'm thinking about adding the ARPI, which often happens on visit two, I'm thinking, is this a patient where I'm going to bring up the conversation about chemotherapy maybe on visit number three?

And by the way, just a reminder for our group that we don't have to do everything up front. On the trials, we also allow that. We allow some time, mostly three months, it was up to four months in some trials, where we could actually layer the treatment for these patients. So the triple therapy, to me, it's a consequence of all the other steps that we described. And I even-- I didn't even bring the genetics into it, which we can talk a little bit. But it's something that is important to be mindful from the get go. But it's a conversation might occur, two or three visits later.

Zachary Klaassen: It's a great message, great summary. When you look at these trials for triple therapy, overall survival, as you mentioned, obviously important. When I think about other data points and you're sitting with a patient, is there other key secondary endpoints, and you're also saying time to mCRPC, pain progression? What are you using from the secondary data to maybe help sell that story?

Pedro Barata: Yeah, it's a great question. So I'll try to step away or aside from the secondary endpoints of the trials, we can quote that time to chemo, or to next subsequent therapy, or time to next systemic chemotherapy, or time to castration resistant disease. Let me just step back and answer the following way.

What do we know about how patients go on treatment? Can we predict what's going to happen? So far, the earlier predictor of outcomes has been probably undetectable PSA. So that means if a PSA achieves-- if a patient achieves a PSA of less than 0.2, he's destined to do better compared to those who don't. So that's one part of the story. So I want patients to get there. So if you look at secondary endpoint, undetectable PSA rates, it's important to see that almost 2/3 of people get there. That's a good sign.

Zachary Klaassen: And patients know that number. They can see that.

Pedro Barata: Patients care about the number. Patients are not numbers, right? And they see the PSA dropping. And they're very, very happy. And a lot of times, I use that opportunity to say, listen, it's great. It's going down. But you're not a number. We're not treating your number. We're treating you.

But it is, in fact, the case that if a patient achieves an undetectable PSA, he's destined to do better than if it's not. That's one end. The other end of the spectrum is going to be you have maybe a third, depends on the different data sets, of people who might progress despite rising PSA.

So where castration resistant disease will be defined not solely by PSA progression. So you might have a patient who got a PSA undetectable. And then PSA is very low, let's say 0.1 or 0.2, and you scan them, and you will find more disease. That is extremely important.

Why? Because what we do in clinical trials, scanning these patients, usually every 9 to 12 weeks, is not reflected by what we're doing in clinical practice. Most of us don't get scans as often. So it's important message to, yes, it's great that you're looking at PSA from the PSA undetectable perspective. But it's also important that you do not forget about restaging the patients.

So when you put all that together, to me, that matters. Now, patients care about how long am I going to stay on this treatment? And the answer to that is by median time to CRPC. And as we know, these patients stay on this treatment, they can be on it for like three years. We're talking half of the people.

The other half might do actually longer than that. Which is really-- I mean, it's really good. We cannot cure those individuals. But we can have them on these therapy for a very long time. So knowing this, it's important. But here's how we can slide in the genetic information.

If I get germline and somatic testing on these patients, and I find out that they have an altered BRCA, or ATM, or another gene part of the HR family, I do expect-- I know that's a poor prognostic factor, particularly BRCA followed by non-BRCA HR compared to non-HR. Why is important?

Because whatever you do, you know those patients are destined to progress faster. So it allows you to have a conversation about prognosis, what are you expecting to see, how long are you going to expect this-- the treatment they're on to work.

And also, it's going to help you understand, this is probably a patient where I need to do scans a bit more often. I need to pay a little bit more attention. I might not believe as much on PSA. I know already what I'm going to do when these treatment stops working.

So the genetic information upfront, it's not that it's allowing you to treat-- to choose A versus B versus C versus E, but also it helps in this conversation with the patients when we are in the clinics. So when you put all that together, I care a lot about-- and patients do care about when do this treatment is going to fail?

So you can look at that by time to CRPC, or time to next systemic therapy. They care-- when am I going to have more symptoms? Doctor, when am I going to do-- be worse? When am I going to have more pain? So time to need for more opioids or more skeletal related events, those endpoints are reflection of what patients care in real life in addition to living longer. So I bring that up in our conversations with them in clinics.

Zachary Klaassen: Outstanding. Last question I want to ask you is I'm a urologist. You're a medical oncologist. There's so much multidisciplinary treatment of prostate cancer. And it's important for all the aspects we know about. Just talk a little bit about the-- let's say somebody comes to the urologist first, they get diagnosed with de novo metastatic hormone sensitive prostate cancer. Let's say they're a triple therapy candidate. Let's say that urologist doesn't give docetaxel or doesn't have those conversations.

When we're partnering with our medical oncologist and vice versa, there is occasionally pushback about losing patients or territorial discussions. You and I both work in big cancer centers. We have great relationships with our colleagues, for the most part. Just talk about the importance of multi-D And that sharing of the patient, rather than territorial sort of advantages.

Pedro Barata: Yeah, so complicated question. So there's a lot of things that can be done and are being done, perhaps, to improve that relationship or get us closer. I think the more closer we get like being here at AUA, right? I'm a medical oncologist, as you said. You're urologist. And we're here at AUA chatting.

And that's actually allowed me to build relationships, very positive relationships with my colleagues. Some of them work in Ohio area and in other areas. And so there's actually-- we just text back and forth, we call each other for questions, comments. But to answer your question at the regional level, I see this in different ways.

So patients get to metastatic hormone sensitive disease in two ways. You walk in the clinic with metastatic disease, that's a patient that either got a scan found with mets and end up getting urology involved because PSA was very high, or they go to the emergency room, get urology involved. And then they tend to-- those are the patients that I think they tend to be reached out to medical oncology faster. There's not really a huge or long relationship between the patient and the urologist because you just met them.

However, the most common case of you getting to metastatic hormone sensitive, it still is through recurrent disease, as you mentioned. The patients who end up-- underwent radical prostatectomy. And they were either lost to follow-up, or they're seeing the urologist, PSA starts to rise. We scan them. And then you find metastatic disease.

So they have recurrent metastatic disease. So on trials, actually, we tend to enroll more of the newly diagnosed disease. But in reality, we have a lot of those patients with recurrent metastatic hormone sensitive.

Zachary Klaassen: Great point.

Pedro Barata: In that group of people, actually, have a great established relationship with urology. So I think it would be horrible for us to destroy that relationship. And that speaks, again, to the partnership that you were alluding to.

So when a patient comes to me, whether it was found with metastatic disease upfront or whether it was found with recurrent disease now with visible mets, I always try to keep the relationship with urology going. Why would I not?

They trust the team there. They do a great job. So what I do there, I'm actually not interested in doing all the treatments at the cancer center where I am. I don't have a particular interest in doing ADT at my center. All I care, castration is happening the right way.

So how do I know that? Well, we check testosterone levels when the patients see us. So that can be done locally. Sometimes, the ARPI is easier if urology feels very on board with it, wants to do it, is prescribing it and doing a good job, they're doing it there as well.

Chemotherapy might be more challenging to do that. It's a case-by-case conversation. Often, patients are getting chemotherapy with us. And then they keep engaged with us to make sure we are talking with urology about are we getting scans on time? What is coming down the line? Did we do genetic testing, which sometimes we have more ability of doing the pretest counseling or access to genetic counseling, whether it's in person or remote?

Explain what that means. Opens the door to different conversations. Then we go back to urology and say, hey, we just found a PTEN loss here in this tumor. The tumor is a poor prognostic factor. So let's keep that in mind as we are handling it.

So what I'm describing is we actually-- this patient ends up keeping the relationship with the local team. And at the same time, checks with us as things move along. And we can give some inputs to enhance the conversations in a more informative manner and start preparing for the future. Because there's one thing we know, this treatment is not going to work forever.

So we always have-- so my mind, usually don't say that a bit, our mind is usually in the next systemic therapy. And remember, Zach, half of the people don't get another line of treatment. We lose patients. That's really-- treatment attrition is a reality.

So I always like to think that sequence is a reality. So what is the best next treatment when this treatment stops working? And when do I expect that? Well, that's when you go after the trial data and you look at the median time to progression, et cetera, to understand how long are you expecting the patient to be on. So that relationship is crucial.

What do we try to do? So when I moved back to Cleveland, I try to meet the team in the region, get to know them cell phones, emails. We tried to put some meetings together. And we invite our friends from the community and in the region. That allows us to do this, to get talking.

And then you understand where I'm coming from. I understand where you're coming from. And then we also understand the changes. There have been a lot of changes in this space in the last few years. And in that way, we are more aligned.

So I don't have to do that as much in the cancer center. But you would be surprised. I mean, the tumor board is always an opportunity for us to talk to each other, right? Chatting, having mutual patients, there's always an opportunity to chat to each other.

And so even in cases where you always say, Pedro, in this case, you are the quarterback. Let me know if you need me. Here and there, I still keep the urology up to be up to date of things because it's important for them to understand what's going on, even if they're not seeing them.

But even in those cases, you always want your urology with you. You're always going to have needs, whether it's going to be an obstruction, whether it's nephrostomy tubes, or scope that needs to be done, et cetera. I mean, it's always important.

So to me, I think keeping that important relationship with urology is critical. At the end of the day, I care about the expertise and the know how you have to treat the patient. We are AUA. That's absolutely an immense group of competent urologists handling this disease. If you go to a medical oncology specific meeting, there's absolutely an immense group of medical oncologists with the expertise to handle those patients.

But I don't see-- this is not specific to a specialty, the way I see it. It's more about, are you comfortable with this? Do you know what you're doing? If you don't, that's OK. We can work together to get it better. But if you do, you do. And that's amazing. And so that's where the educational opportunities come into place because you can try to address those unmet needs or those opportunities to bring everybody at the top of their level for patients' benefit.

Zachary Klaassen: Fantastic conversation, Pedro. Just so much information in that conversation that I know our listeners will be really appreciative of. So thank you for joining us on UroToday.

Pedro Barata: I appreciate it. It's always a pleasure to be here. Thank you so much for our relationship as well.