Zachary Klaassen: Hi, my name is Zach Klaassen, urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted, as always, to be joined on UroToday by Dr. Pedro Barata, who is a medical oncologist at the Seidman Cancer Institute in Cleveland, Ohio. Pedro, thanks for joining us on UroToday.

Pedro Barata: Of course. Always a pleasure to be here with you. A fantastic interview that you are able to do.

Zachary Klaassen: No, I appreciate it. And likewise, you as well. You host some great discussions too. So today, we're going to be talking about chemo hormonal therapy and treatment intensification for metastatic hormone sensitive prostate cancer. So there's been a lot of work in mHSPC over the last decade or so. Maybe just start at the beginning and give just a quick overview of the early chemo hormonal treatment intensification that happened about 10 years ago.

Pedro Barata: Yeah, great question. Indeed, the field has changed quite significantly. I believe you're referring to 2015, '14 when we learned, really, the addition of docetaxel to backbone ADT improved outcomes. And you have an American study called CHAARTED, and very important study.

At that time, it was a positive trial. The addition of six cycles of docetaxel to ADT improved outcomes versus ADT alone. What's interesting at that time-- the data was stratified by volume. At that time, volume was defined based on data at that point. The patients with high volume disease do the worse.

And so there was this concept that volume probably would matter. And so that's what happened. Despite the trial being overall positive, when you also saw the data break down by volume-- high volume versus low volume, defined by four or more lesions in the bone outside spine and pelvis-- at least one of them-- and/or visceral disease.

So what's interesting is, overall, the study is positive, but then the high volume is positive, and you don't see much in the low volume disease. And so everybody start talking-- the addition of chemo is a good idea. But should we actually learn a little bit better who are the patients who tend to benefit from that?

So that's that. And then at the same time, I don't know if you remember, but they get to the European-- or the French co-operative group, as we call it-- kind of did a similar effort up to 9 cycles. At that time, they did not appreciate a benefit. And perhaps in retrospect, one of the reasons is they included a significant number of patients with low volume disease.

So that was the conversation we had back then. And then we end up confirming the results with the STAMPEDE study with the docetaxel data, basically, again demonstrating a benefit of the addition of chemotherapy. So this was really the beginning of what we today call treatment intensification or combination therapies that have shown superiority in terms of controlling disease and by virtue of time to castration resistant disease, controlling disease in terms of delaying more cancer in the scans, as well as overall survival. And so, in short, that's what we've learned from those important trials.

Zachary Klaassen: Yeah, and it's a great summary of where we started with treatment intensification. Let's fast-forward about eight years now, to where now we have triplet therapy with chemo and ADT as the backbone. Maybe walk us through those studies that have really changed from-- basically giving doublet versus giving triplet to certain patients.

Pedro Barata: Yeah, so at that time we learned adding chemo to ADT was a good idea. Then the next logical step was to try and do the same with an ARPI, first with abiraterone. We saw a number of studies, including STAMPEDE for abiraterone as well as LATITUDE. And then we saw that with the antiandrogens, and with enzalutamide, and apalutamide.

We saw that with the TITAN trial, ENZAMET, and ARCHES. They've all shown the same thing. Bringing these agents early on also improved outcomes. The difference is it appeared that the benefit of the addition of the ARPI was present irrespective of volume. In other words, low volume patients benefit, high volume patients benefit.

So at that point, for a while, there was this conversation about what should we do? Should we do docetaxel? Should we do ARPI, or should we actually combine them all? And this last portion of the conversation was answered with another two trials, one called PEACE-1, which is actually a 2 by 2 design. And the other one is called ARASENS adding darolutamide to docetaxel.

And basically, they were both shown superiority, at least in the high volume disease, to ADT docetaxel. So we are left with a question-- is the triplet better or equivalent or perhaps than the doublets with an ARPI. We don't know that yet. So today, you can say that standard of care for patients who are facing mortality from prostate cancer is a combination treatment.

We can also say that ADT docetaxel by itself is no longer standard of care, because if you want to do docetaxel, you're going to do a triplet. Some patients might not need it, and that's going to be a doublet with an ARPI. So that's where we are right now. And I think in the future, we might have some-- we might have a path forward in terms of who might benefit from the triplets, who might benefit from the doublets, who might actually not need any of that. I don't think we're there yet, but we also need to do-- to get some progress to understand who might deserve from treatment deintensification.

Zachary Klaassen: Great points. And I think you highlighted something really important, and the NCCN guidelines reflects this. Now if somebody chemotherapy fit and deemed needing chemotherapy, that should be a triplet therapy patient, not the ADT plus chemo, because that was the control arm in ARASENS. So I think that's a very good point, that if you're going for chemo, give the triplet.

When we look at our practices, it's always deciding what to give. We don't have any head-to-head studies. Let's talk about the chemotherapy patients in your practice. How do you decide that I'm going to give triplet therapy with chemotherapy to a patient?

Pedro Barata: Yeah, so I care about timing of metastatic disease. I do favor triplet therapy-- that includes chemotherapy for patients with synchronous disease, particularly those with high volume disease. So to me, the high volume synchronous disease is the group of patients where I do think of triplet, whether or not there is reasonable to do.

The second question is, when do I do it? I never do it on day 0 or the first time I meet the patients. I tend to make the decision-- the first ADT. The second point will be addition of an ARPI, and the third would be the potential addition of docetaxel. So I break it down through two or three visits as we talk about the other things, including genetic testing, et cetera, PSA as an early predictor of outcomes, et cetera.

So to me, the question comes up usually at week 8, week 9, week 12. Not really on week 1. So that. I think there's a standard or universal features for chemotherapy for you to be considered fit. Whether or not you have significant comorbidities, whether or not you have neuropathy, whether or not you take some medication, what's the distance from the cancer center, are you open to it, do you understand what it is?

So there's a number of factors that are related to the provider, but also related to the patient that we should take into consideration. Symptoms of the disease might matter. As you start these treatments, sometimes the patient gets better by the time you're deciding actually chemo or chemo. And sometimes performance status can change from the first time you met the patient compared to about two months later.

And so sometimes what you're thinking in the beginning might change a bit when you actually bring in docetaxel on board. With that said, in US today, chemotherapy is estimated to be used around 10% of the time. So only one out of 10 patients or so seem to be receiving docetaxel in this setting.

Zachary Klaassen: Yeah, great summary. When you've decided, from a medical oncology background, we're going to give chemotherapy, how do you explain docetaxel in this setting? What are the side effects, how many treatments? What are your messages to the patient?

Pedro Barata: Yeah, that's a great point. So we are used to taxanes. So docetaxel is a taxane, is a microtubule inhibitor. So we do expect a couple of things-- cytopenias are to expect, some GI alterations. But neuropathy is something that we bring up as potentially as relevant to patients, of course. Alopecia can happen. Toxicity in the nails can happen.

Sometimes eye alterations, like dry eye, can happen. And very rare you can get lung toxicity. That's very rare. So we are used to med oncs used to giving taxanes to patients. So we tend-- I'm not going to say simplify the conversation around it, but it's not something that we are very particularly concerned.

Many patients in their 80s can receive docetaxel doing well-- with a good tolerability profile. I would say in this case, it's a finite number of cycles. We do six cycles. It doesn't matter how patients are doing in terms of PSA response and how symptomatically whether you don't continue.

So that's different from the castration resistant setting. We don't do prophylactic neutropenia treatments unless it's required. And dose adjustments can be done, but they're not super common. I think most of us would probably be starting at 75 milligrams meter square every three weeks.

Zachary Klaassen: No, that's great. I think as we move into just a very busy space, it's important to always talk about chemotherapy because we have some great data. I mean, that ARASENS trial, the study design is excellent. PEACE-1 also showing us great data as well. So any take home messages for our listeners based on chemo hormonal treatment intensification?

Pedro Barata: Yeah, I think philosophically speaking, every time you're looking at a patient who is destined not to do as well as others-- those are synchronous patients with synchronous disease, high volume disease, visceral disease particularly, maybe symptomatic-- and you're thinking that there might be a component of the tumor that might be less responsive to androgen signaling pathway inhibition, bringing the chemotherapy on board-- that's just what I do in my clinic-- has shown to be of value, has shown to improve outcomes. And that's why I do it.

In my clinics, I save it to about 10% to 20%, maybe 15% of the patients I see. So I think it's about that. It's not for everybody. And the decision about bringing the chemo can happen a few weeks later. You don't need to commit to anything day one. You can think about the triplet-- the chemo component of the triplet therapy-- a little bit later on-- see how the patient does on castration, see how he does on ARPI.

And he's also going to be overwhelmed with so much information you're sharing. So it's OK to break it down and bring it a little bit later as you are addressing this disease. And this game is a game of many years, fortunately. And so this is not a sprint. It's a marathon. And so doing the chemotherapy with that intent of thinking what's going to happen four or five years down the line.

Zachary Klaassen: Great points. Always a high level, thoughtful discussion with you, Pedro. Thanks so much for joining us on UroToday.

Pedro Barata: I appreciate it. As always, great to see you, Zach. And great number of questions, and I hope this was helpful.

Zachary Klaassen: Absolutely. Thank you.