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Alicia Morgans: Hi. My name is Alicia Morgans, and I'm a GU Medical Oncologist at Dana Farber Cancer Institute. I'm so excited to have here with me today, a good friend and colleague Dr. Ana Aparicio, who is a GU Medical Oncologist and Associate Professor of Medicine at MD Anderson Cancer Center. Thank you so much for being here with me today, Dr. Aparicio.

Ana Aparicio: Of course. My pleasure. Thank you for having me.

Alicia Morgans: Wonderful. Well, I wanted to really pick your brain about a topic you have been investigating for many years at this point, androgen indifferent prostate cancer and thinking through how we define these patients, how we think about treating these patients, and where we are going in terms of future endeavors. Let's start with how we define these patients. Because I think in clinical practice, that can be one of the more challenging things that we have to do, and there are so many ways that I've seen people try to define a population that they call either androgen indifferent or anaplastic or aggressive variant. How do you think about defining this population of patients?

Ana Aparicio: I think historically we all basically thought of the purely androgen indifferent tumors that were represented by the small cell or neuroendocrine prostate cancers because a large majority of those were actually AR negative. And we knew from multiple case series and experiences that they did not respond to any androgen signaling inhibition. What has become more evident in recent times is that there is a proportion of patients that, while they may not have the small cell morphology, so under the microscope not look like a small cell prostate cancer, they behave as such. So recognizing that cancers of various morphologies, be it adenocarcinoma, poorly differentiated carcinomas without neuroendocrine differentiation, et cetera, could have this kind of androgen indifferent behavior has led to us being, I think, more aware of it in the clinic. Then, in an effort to try to enrich for this population to arrive at therapies that would be able to treat them, we have all tried to put together different elements and characteristics, and define them as far as the eligibility criteria for clinical trials in different ways.

On this slide, I've tried to summarize some of the ones that have been used most frequently, so obviously, we have the small cell morphology, that's clear, that we know is associated with a certain behavior. People have tried to use the neuroendocrine markers in the clinic. I spoke a little bit about this at ASCO, but clinical trials have suggested that the neuroendocrine markers on their own are insufficient to enrich for this, what appears to be different biology. Then as you can see, different people have come up with different criteria. Prostate cancer with more than 50% neuroendocrine marker staining or development of liver metastasis without PSA progression, staining by immunohistochemistry, it relates to progression on abiraterone or enzalutamide. We came up with a series of clinical-pathological features that are listed here under aggressive variant prostate cancer, then, later identified a molecular profile that characterizes the tumors that have these features.

Right now, I think we are in a better place than we were 10 years ago in the sense that we recognize these exist and we've developed a series of characteristics that allow us to enrich the population. But we still have a ways to go in terms of markers that uniquely identify this particular subset.

Alicia Morgans: I really appreciate that. That's why I love the way that you and your team have included at least two of the following, the TP53, RB1, PTEN alterations, that from my perspective, when I can see that on a report, I feel like I have something that is a little more concrete. Because I do worry sometimes as pathologists at different institutions are maybe subspecialized in GU cancers, maybe subspecialized in prostate cancer, but in many centers, these are pathologists who have to look at many, many types of cancers and other tissues potentially. And so having that molecular subtype to fall back on really helps me think through it. Just given the heterogeneity even of the people who would help us make those pathologic diagnoses. Do you feel like that will be something that we are going to be able to rely on in the future? And is your team doing more work to really pull out maybe other alterations or signatures that might help us when we do have this grab bag in terms of pathologists' knowledge?

Ana Aparicio: Absolutely. We're doing a lot of work to try to better define this molecular profile and also in a way that is accessible to current clinical practice and available to all. The combined tumor suppressor defects as currently defined either by immunohistochemistry or by genomic alterations, some work that we are close to completing, is looking at cutoffs. We've used 10% as a cutoff in the past and the intensities, and so on and so on, that we can give an idea to people of what the variability might be in looking at those tumor suppressors by immunohistochemistry. Then of course, what are the specific mutations, if there are specific mutations, that count more than others. Just to be clear, I think this molecular profile, again, it's an effort to enrich, right? I think that these genomic alterations in the same way that we're seeing, I think, with the DNA repair gene alterations are not perfect markers. Because obviously, the tumor microenvironment is so complex that just having a genomic alteration doesn't mean that you absolutely have that phenotype, but they do help to enrich.

Then yes, we are working to, within that enriched group, trying to define additional molecular markers that can help to pinpoint it a little bit better. And then at the same time, making a big effort to build therapies for these patients, right? Because we really do not have a lot to offer

Alicia Morgans: Thank you for clarifying that. I think everyone who is listening has at least thought about or heard about, if not seen in their practice the way that as you said, even DNA repair defect mutations, not all mutations, even of the same gene, are created equal. And so it's really something that we, as a field, are trying to define both from a biologic perspective, but then to interpret in the clinical practices that we have. It's all a work in progress, but I really appreciate how you think through this.

Now certainly, this is the biology that we see. What are your thoughts in terms of how this either develops? I think some patients actually come into the clinic with these types of alterations and androgen indifferent profiles. What are you seeing and what are your thoughts on that process?

Ana Aparicio: Actually, this is sort of another side. You are absolutely right. I think that whilst with the progression of the disease and the selective pressure of androgen deprivation and increasing AR inhibition, we see phenotypes that certainly appear to be androgen indifferent. It happens in the evolution of the disease. I agree with you. I think that this phenotype and this biology are present from the get-go in at least a subset of people.

We did a Phase 2 randomized study in men with de novo metastatic prostate cancer. We've seen that, indeed, this aggressive variant molecular profile is very much present at baseline in a subset and is highly prognostic of outcomes. So, yes, I think it is questionable. The good thing about that, well, is that we have to be thinking about two things, right? On the one hand, of course, anticipatory strategies. If we think that this is biology that is going to emerge during the evolution of the disease, but in that subset, if we can identify it early, treat them early on with therapies that are specific to their biology.

Alicia Morgans: I completely agree. As you think through this because I know you think about this quite a lot. What are your strategies? What are the trials, what are the treatment opportunities or important things that you might do to either take care of this patient from the get-go to really hit the patient hard from the beginning? Or how are you thinking about anticipatory strategies? That's not a place, I think people really would love to go there, but I haven't heard a lot of clinical trials in that direction. We'd love to hear your thoughts in both of those situations.

Ana Aparicio: To answer your first question. So I think, you know that there's not a lot of data out there. There aren't a lot of clinical trials that have, that have sort of focused specifically on this biology, but of those, we did one as you know, a randomized phase two study, where we, we sort of gathered support for the hypotheses that in men that had aggressive variant prostate cancer features, the addition of carboplatin to taxane actually was, beneficial. Right? And so what we've been doing is we've been building on that combination and adding different strategies to that. I think that the biggest, the biggest thing, and I have a slide for this too, is just, we need to learn more. And it's critical that, that we try to do that through clinical trials. And so just, I would encourage people to really search for clinical trials.

These are some that I've, that I selected a couple of months ago that is, I know, are, ongoing in this population and this variant population. And I think that it's through these trials, that we learn more about biology and that we will learn that we'll be able to come up with more effective therapies. And then in terms of anticipatory strategies, as others have done and are doing, it's a question of looking for circulating markers that can help us identify the emergence of this phenotype early on in the disease process, or before it sort of emerges full-blown. So I think there is a lot, as you know, a number of people are working on these strategies and, Himisha Beltron, for example, has done some work in, in circulating DNA methylation markers that I think are, are pretty promising. And there's the [inaudible 00:12:57] lab has published on circulating tumor cells and looking at some of the markers there and a number of other people are, are looking at circulating markers.

Alicia Morgans: Absolutely. Because if we can identify the mechanisms by which these are developing, we can use the potentially targeted agents that could prevent the development in the first place. And I just really want to make sure that the listeners are hearing that and knowing that you and others are working in that direction because these are very challenging patients to take care of this disease, when it becomes indifferent to androgen signaling, can be very, very difficult to get under control. And I know you do have a fair amount of platinum combinations here on the studies that are being done and your work certainly with cabazitaxel and carboplatin for patients in the clinic. Now, if a clinician is seeing a patient that he or she is concerned may be developing an androgen indifferent prostate cancer, what is your go-to combination that at this point, if you cannot get your patient on a clinical trial, which is very, very clearly your number one goal, what would your strategy be in terms of standard of care or approved therapy?

Ana Aparicio: So adding carboplatin to one of the taxanes has been our sort of standard approach.

Alicia Morgans: Great. And I think an approach that will continue to be investigated, certainly an approach that I've used in my clinic. And I've had actually good success in terms of tolerability and, I hope, disease control. So as, as we sort of wrap things up, what would your message be for listeners, for folks who are curious about, or facing patients who are experiencing androgen indifferent prostate cancer in their clinic?

Ana Aparicio: So a couple of things, one is, again, I think that the addition of a platinum agent really makes a difference in this disease.  One other strategy, and I'm going to say this without a shred of data, so take it as you will, but because we do not really have beyond the platinum-based combinations much in the way of systemic therapies that really work. and these aggressive variants are often associated with fairly high morbidity, so large tumor masses that can cause pain and other problems, psych-directed therapies. If you, you know, people will present with very bulky primary tumors, for example, or with sites that seem to really cause a lot of problems. And so reach out, to the radiation oncologist and, even consider some ablative mechanisms if you can't radiate, because I think that can help palliate significantly. And then again, sort of clinically learn to keep an eye out for them. And, if there is a possibility for a clinical trial, that's always the best option.

Alicia Morgans: I could not agree more. And I think that clinical trials so that we can understand the phenotype better and so that we can treat these patients more effectively are absolutely going to be the number one way to go. And because these patients may be more difficult to recognize and to identify, if you do find a patient who has one of these androgen indifferent variants, really do try to think about having that patient get to a clinical trial opportunity, both for that patient's sake, as well as to learn as a field.

So thank you so much for taking the time to go through all of this with us today, Dr. Aparicio, you are truly a pioneer in this field and we appreciate your expertise and your efforts. Thank you.

Ana Aparicio: Thank you.