Pedro Barata: Thank you so much. It's a pleasure to be here, as always.
Zachary Klaassen: We've had just a plethora of options in the last decade or so. And as you're going through and selecting options, whether it be doubled or triple therapy, what are the patient-related and disease-related characteristics you're looking at for these selections?
Pedro Barata: It's a great question. I think as we rolled out, and there's a lot of learning coming out from all the trials we conducted in this space that ultimately provided the evidence for us to make recommendations to the patients who come to see us. As you know, they come to see us in one or two ways, either with recurrent disease, meaning they got treatment for prostate cancer before and then unfortunately recurred, and now we're found with advanced disease or stage-four disease, as well as those patients who unfortunately are found first time with stage-four disease. We call that timing of metastatic disease, synchronous versus metachronous disease. And the other aspect, which basically is based on scans that patients got, more and more we get patients with PET scans, but you can also get those patients who came with CT scans and bone scans for staging. We still use the conventional designation of tumor volume based on one of the initial trials that we ran called CHAARTED, and basically looking at number of bone metastases as well as visceral disease to define low and high volume. Those are the factors that we use on the disease piece. Again, we're talking most patients harbor adenocarcinoma of the prostate.
We call that bread and butter prostate cancer. That's a conventional prostate cancer, meaning no neuroendocrine or small cell features. Then on top of that, I am for now not talking about the genetic profile of those tumors. As you know, also plays a role, is playing an important role for prognostic reasons, but also predictive, if you will, to target therapies. That's objective. Then when we meet the patient, we look at their clinical status, their clinical functionality. And that includes how fit are you and also life expectancy from two angles. One, how are you doing from the prostate cancer perspective? Are you symptomatic? Do you have pain? Do you have lower tract urinary symptoms? That's one angle. The other angle is do you have other health related issues that would give you a limited life expectancy? And all of that put together allows you to then think what is going to be a treatment strategy for that patient. Backbone of treatment still is ADT-based strategies, meaning lowering testosterone also known as castration. I'm now using the new designation, PCW group four. And then you layer an ARPI, meaning optimized way of blocking the androgen-signaling pathway. And you know by doing so, you're improving outcomes, and outcomes that go from PSA progression to time to castration-resistant disease to overall survival, but includes other important endpoints, time to chemo, time to next line of treatment, symptomatic skeletal events, or skeletal-related events. All those are endpoints that we care, patients do care. And you want to prevent those events as much as you can.
With the life expectancy, with the tumor burden, with the timing of metastatic disease, and then the genetic profile of those tumors, you can put together a plan and discuss that plan with the patient and come up with an agreement in regards to how you're going to execute that.
Zachary Klaassen: Great background and awesome overview of how you go through that thought process. Because we've done so well, we have survival benefits, we have time to mCRPC benefit, we're now looping in patient goals, quality of life, tolerability, so when you're sitting with the patient, you have an idea of what you want to propose to them. How are you integrating those discussions with the patient?
Pedro Barata: I will just say the more we talk about metastatic hormone-sensitive, it allows us to reflect a lot on that topic and appreciate the priorities for patients which are not exactly all the same. But if I were to summarize some of them, what I find being a common topic is the sense of urgency and, quite frankly, the sense of scare and concern for the first time you hear you have stage-four disease. In that moment, when they come to see us, many times patients are scared. They are very concerned and very worried. There's this perception that stage-four disease means mortality, is associated with mortality and fast, and that means chemotherapy, that means intensive treatments, being sick. All of that, we have to break it down and explain what those treatments do. Some people care more about that. Basically, in other words, they say, "Doc, I'm happy to walk through this with you, but don't give me too much details, but I want you to do whatever you would do if it was you in my seat, or if it was your significant other seated where I am." Others will tell you, "I want to understand all the options I have available, and then I want to be able to make the decision." But I always get the sense that at the beginning, before they start on any treatment, more often than not, there's a big openness for whatever we will recommend, it will be appreciated and adopted moving forward.
That's particularly true for the triple therapy component. When you mention chemotherapy, you mention ARPI and ADT, there's a highest chance of being compliant with that strategy in the beginning. And as time goes by, and as you see the effectiveness of the treatment, particularly [inaudible 00:06:16] combination, the thought process around the bringing the chemotherapy piece into it, as an example, can change because now you're getting on cruise control, so to speak. You're making the cancer a chronic disease, it's not gone, but you can go in remission from that perspective. Often, almost two thirds, PSA becomes undetectable, scans are stable, patient found their new way of living their life, hopefully as normal as possible. And then the conversations around treatment intensification, de-intensification, what to do if things change, how long are you expecting to have tumor control, why you keep looking at bone health, why you keep looking at mental health, continue to focus on cardio-oncology, continue to focus on multifactorial reasons for you to be on multiple number of treatments beyond prostate cancer related treatments, those conversations need to be revisited every visit. It is, as I call it, a multi-step process. Doing everything at once, it's very likely very overwhelming, and we have to have a strategy to address this in a way that we are being comprehensive, but at the same time we're not overwhelming the patient with all that information at the same time.
Zachary Klaassen: Phenomenal explanation. I think as you're going through that therapy discussion, even when they're on therapy subsequently, how does the conversation get revisited? How do you evaluate these patient goals and quality of life assessments? Because we know the PSA is coming down, as you mentioned. What sort of thought process from at that three month visit, the six month, the nine month, how are you coming back to the patient goals and the tolerability?
Pedro Barata: Most patients do well because they learn how to live with low testosterone levels from one angle. We call it menopause in men, which is not the same as you having normal levels of testosterone. And some people have a different perception of how that's impacting their lives. The long list of clearly relevant adverse events to patients are perceived, they leave those side effects in many different ways. We do our best to address them, to ask for them, and that goes from sexual-related adverse events all the way to mental or emotional-related adverse events, including, of course, fatigue, hot flashes, et cetera. Then you also need to bring up things that are not necessarily symptomatic but matter, for example, cardiovascular health.
Zachary Klaassen: Right. Very important.
Pedro Barata: Not necessarily they will see the risk, not necessarily they'll understand the metabolic syndrome, but it's extremely important to make sure the cardiovascular risk factors are under control. Then you need to bring up also another thing that's not necessarily symptomatic until something happens. I'm talking about bone health. These patients are at risk for osteopenia and osteoporosis. You need to remind them of bone health, you remind them of calcium, vitamin D supplementation. You need to do the DEXA scans. You need to think whether or not there's an increased risk for osteoporosis-related events like fractures. Not all of this matters, right?
Zachary Klaassen: Yeah.
Pedro Barata: Sometimes some of what we're doing is preventing problems, not necessarily addressing the problems already there. So you are addressing side effects from the medications you're giving, and I just mentioned ADT. Of course, when you bring an ARPI on top of ADT, it's very different for you to be on a medication that requires a prednisone, even if it's a low dose every day, versus a medication that does not require fasting, you take it with or without food, that doesn't have as many drug-drug interactions. Those things matter. We have several ARPIs available. Also, the thought process around how do you take that medication? Are you changing your life to do that? Is there certain parts of the day that you're more comfortable doing that? Do you have to change the other medication you're on? Are you on anticoagulation? Are you on statins? Do you have to think of that? How are you going to do that? Are you going to reach out to the primary care doctor? Are you going to reach out to cardiologists? Or are you going to be doing the change yourself?
Those questions are not necessarily perceived as symptomatic, but they do affect, patient will be worried. Patient is worried. If you start him on a medication, his question likely will be, "Doc, are you sure this is not going to impact the other things that I take? And how are you going to communicate with my other team that doesn't work here, that works an hour away?" Those things, sometimes we don't appreciate them as much, but it's always important to keep that in mind as we see them. Yes, it's super important to talk about the disease and the outcomes that we're expecting, but at the same time, keeping in mind, all of us, including myself, I do the effort to keep that in mind, to bring those topics up because it's extremely important as we address these as a chronic disease, if you will.
Zachary Klaassen: Fantastic discussion. As always, Pedro, high level, fun. Any take-home messages for our listeners? Anything to take with them to the clinic tomorrow?
Pedro Barata: I would say this space is evolving and it requires a comprehensive approach. I call it a multi-step approach. I say that to my patients. I have a strategy in my mind how to address these things. I might prioritize certain things in the beginning and then bring those up as things go on. I really think as we think of the disease, think of life expectancy, think of the benefit of bringing an ARPI on top of ADT, think of the role of triple therapy, particularly high-volume, high-risk patients, those patients who present with newly diagnosed disease, high-volume disease, symptomatic disease. At the same time, don't forget bone health, don't forget cardiovascular disease, and always have a plan, and have a plan when these treatments stop doing the job they have been doing. And it's important to have a plan so you start strategizing what's coming, what options are available, and do not forget genetic testing, because that does open the door to other opportunities for those patients.
Zachary Klaassen: Well said. Pedro, thanks for joining us again on UroToday.
Pedro Barata: Thank you very much for having me.