Charles Ryan: Hello from EAU 2019 in Barcelona. I'm joined by Alicia Morgans, Associate Professor of Medicine and a medical oncologist at the Northwestern University Feinberg School of Medicine. Thank you for joining me for a conversation about your topic at EAU, which is attributive hormone-naïve metastatic prostate cancer. So we now have more than two options really for patients with hormone-sensitive metastatic prostate cancer, what's your approach and what's your talk going to cover?

Alicia Morgans: I think we're gonna focus on three main areas, the first being systemic therapies and the questions that still remain there because there are actually multiple ongoing clinical trials that add to the questions as well as answer some questions in the systemic therapy arena. Then I'm going to talk about treatment of the primary, which I think is really become a hot topic since the STAMPEDE data came out and even before that, but we finally had some data to sort of fuel the fire, particularly in the setting of the ongoing SWOG study that's looking at that. And I'll wrap up by very briefly mentioning metastasis-directed therapy which is really kind of an oligometastatic disease.

Charles Ryan: It seems like in those three groups that you mentioned, the high volume, how to start treatment, type of patient, should we treat the primary patient and should we treat the metastasis patient, that there's three different kind of goals of therapy there, aren't there? And how would you break that out? I mean, in one way looking to prolong time to progression and others we might be looking to cure patients.

Alicia Morgans: Yeah, I think particularly in the metastasis-directed setting we're really looking potentially to cure patients. I would argue that we probably need to treat the primary if we're going to cure a patient with metastatic disease, too. So there's some overlap in those two populations, but the purpose I think of those trials will ultimately go in that direction. Now the metastasis-directed therapy study that's already been reported, Piet Ost, who actually has recorded some interviews actually I think here, and who gave some talks at EAU really were looking to delay the time to initiation of systemic therapy.

And I think that's a valuable endpoint particularly as far as patients are concerned, but I think that for us to really move the field, we're going to need to do something, or have an endpoint that's a little bit more clinically compelling to clinicians as well as to patients. Things like better disease control, can we change the trajectory of progression and potentially even cure people.

Charles Ryan: So what's your approach? What are your recommendations for the patients who are receiving ADT plus something else for metastatic hormone-sensitive disease?

Alicia Morgans: My first would be that I don't think ADT alone is really the standard for anyone anymore, ADT plus either docetaxel or abiraterone should be the standard. There are patients who either are very elderly and maybe have dementia or who have an exceedingly short expected life expectancy because of other reasons, who perhaps for those patients, ADT alone is reasonable. And there are reasons and those people do exist, but for the majority of people, I think ADT plus something needs to be on the table. When I think about which of these options to choose, I usually think about whether one is a candidate for chemotherapy because if they're not then certainly docetaxel would be removed from the table.

And if they are candidates before both chemotherapy and abiraterone, I think about whether they have high volume disease or low volume disease, and then really have a conversation with patients about what their preferences are regarding the duration of treatment, the type of treatment. Whether you want it to have six cycles of docetaxel now and have maybe a more robust response to that therapy than you would if you had 10 cycles in the mCRPC setting for example. Or if you're already somewhat elderly, maybe somewhat frail, and you need to avoid the potential toxicity of docetaxel now and are willing to pay to take that later.

Charles Ryan: Yeah, I think we may oversell the toxicity of docetaxel in this treatment decision making because really the vast majority of patients do quite well with docetaxel. And it's remarkable to me honestly that six doses of a drug can have a prolonged survival benefit for patients compared to what would be enzalutamide or abiraterone on the other hand, which is chronic therapy which can extend for years. And when you think about the cost and the potential treatment burden down the road, I think there's a case to be made for recommending docetaxel to people, and I think we might obsess a little bit too much on the toxicity of docetaxel, especially in young healthy patients.

Alicia Morgans: Well, I think it depends on who you talk to. I actually give a lot of my patients docetaxel in the hormone-sensitive setting. I think that there is something to be said for not being on treatment other than ADT for a prolonged period of time. We had some nice data presented at ESMO that demonstrated, it was really a comparison about 560 patients who were simultaneously enrolled in the docetaxel arm versus the abiraterone arm in STAMPEDE, and there was a comparison that was not a preplanned or formal comparison.

But they did find that in terms of survival, there was no difference between these arms treated with docetaxel or abiraterone in the metastatic hormone-sensitive setting. What's important to acknowledge I think is that there was better control of the PSA, so longer progression-free survival in those patients treated with abiraterone but they did have continuous suppression of androgen receptor during that entire period. So that all makes sense but didn't actually translate into any difference then in survival.

Charles Ryan: Right, very good point. Well, the other thing and I think it's important to talk about is, we talk about how we incrementally improve the survival and the PFS from ADT alone to do something better with ADT plus docetaxel or ADT plus abiraterone. But there's still a lot of people, if you look at the LATITUDE data, a lot of people who develop early progression and death, 22% by two years and 33% by three years, which is really remarkable because for years, when I would start somebody on hormonal therapy for prostate cancer for metastatic disease, I would typically quote to them that they were going to have a few years of control with hormones, and that's just not the case. So we need to be thinking about that 22% and that 33% and asking the question about where we go next in terms of that ADT + A, maybe ADT + A + B or something like that.

Alicia Morgans: Yeah, I would definitely agree with that. I think we're trying to do that just like in other cancers where, testicular cancer, it takes an army of multidrug cocktail, and people have made that comparison before. I think that we're doing that. So clinical trials have been working on that. The ARASENS trial is looking at patients, everyone received docetaxel chemotherapy and then they either received placebo or received or enzalutamide for example. So really trying to pile that on.

The PEACE1 trial, for example, is also looking at a combination of several systemic therapeutic approaches and then plus or minus radiation. So these things are going to be determined I think, and it may be that we treat the primary, use optimal systemic therapy which actually may be a combination of therapies. And then who knows what, maybe there is also another population where we'd give a PARP inhibitor for example, but I think it's going to take a combination. It seems that the earlier we can start this, the better we might do, so in the low volume metastatic or even oligometastatic sort of setting, maybe we can do even better.

Charles Ryan: Well, we're about to launch a trial. I think you might even be participating in it of a cabazitaxel plus carboplatin followed by abiraterone in patients with high-risk disease.

Alicia Morgans: Yes.

Charles Ryan: And I've long held that platinum has a place in the treatment of this disease, in particular in the high-grade patient but we've only used it very late in the disease course, so I'm hoping we can show that it has some benefits in this really high-risk group of patients. And we wrote this trial with the cabazitaxel and carboplatin with those 22% and that 33% in mind. We really want to identify those patients at risk for early treatment failure, early disease progression, and early death, and we want to do what we can take to initially treat the patient with highly aggressive therapy to mass and a highly aggressive disease.

Alicia Morgans: Yeah. And it's important in all of these studies, including that one, to really get molecular characterization on those patients who respond versus don't respond because we need to personalize the treatment. Because we can't just say, it's 33% of the patients who need this extra treatment or who are those patients and that's going to be a really critical part of the whole thing. And I look forward to working with you on that project.

Charles Ryan: Finally, treatment of the metastases, which metastases? When do you treat them? How do you treat them?

Alicia Morgans: Yes, all of those questions.

Charles Ryan: What's the deal?

Alicia Morgans: I don't know the deal yet, I don't think anyone does. I think this is the piece of the talk that I'm giving and the piece of my thought process that's still really less data-rich, but is in the formative sort of area. I would say it's interesting in practice, particularly where I practice now, which is different than where I practiced previously at Vanderbilt, at Northwestern, there is a fair amount of SBRT being delivered to metastatic sites and I know that they do this at the Farber, I've talked to Chris Sweeney about this and there are lots of sites where the radiation oncologists are doing this. Traditionally we had thought that we will only really radiate metastatic sites in a setting of the need for palliation of pain or symptoms, that's not how things are happening anymore.

Given the interest in the field and doing this and the ability, I mean the technology has advanced to the point where this is not toxic to the patients, they're able to do this knowing that they will be able to do further treatments in the future, then we're not going to cause major cytopenias or fractures. Can we integrate this into a trial and study it more robustly and there are multiple trials. There's an ECOG trial looking at this but there are multiple trials that are looking at it, and the data right now I would say is in its infancy, but we're going in the right direction. How many metastases can we treat? Should they be lymph nodes in the pelvis or maybe bone metastases? Where can we do this most effectively? And what is the systemic therapy, the layer on top of all that?

Charles Ryan: Yeah. Well, I really like what you've done with this topic, which is to say, we've got topic A which is, which therapy to add the ADT in metastatic disease, topic B which is, should we treat the primary when and how, and topic C which is, should we treat the metastases. It's incredible that we're thinking about all these different things when, not five years ago perhaps, we would simply start a patient on ADT and sort of think, well, they'll just be on this for a while and then when they get the CRPC, we've got all these options.

And now it's completely shifting because, now CRPC is becoming actually really kind of hard because, not that it was easy before, but becoming harder in a way because you use some of these new therapies upfront and CRPC may become a more aggressive sort of a setting. But I look forward to your comments at EAU and really like the organization of this topic. I'm sure you're the best person in the world delivering this address tomorrow.

Alicia Morgans: Oh, thank you. And just to commend you and the other researchers and certainly the patients that we've become brave enough to put these patients on trials and to push the envelope.

Charles Ryan: Yeah.

Alicia Morgans: It was very hard to enroll patients in CHAARTED because we were given chemotherapy when we had an effective ADT alone option, and we're really pushing ourselves and pushing our patients and they're pushing us to do better.

Charles Ryan: Yeah, I agree.

Alicia Morgans: So thank you.

Charles Ryan: You're welcome. So it's been a pleasure. Thank you, Alicia.

Alicia Morgans: Thanks.