Case 2: Combination Therapy Options in Metastatic CSPC

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Jorge Garcia, MD:Oftentimes, it depends on how the practices are set up in the country. These patients come to different groups. For some of us, they come directly through urology, but they get shuffled quite quickly into medical oncology. But I would argue, then, that urologists in America aren’t capturing the bulk of these patients up front. Have you, from the urological perspective, seen a big uptake in the new oral therapy, even with docetaxel?

Kenneth Kernen, MD:We have. One of the things that’s compelling, as Neal said, is there has been an uptick in these patients that we’ve seen, unfortunately. I think the thing that I think is also crucial to talk about is ADT [androgen deprivation therapy] as monotherapy, which is not the right answer. We all live this on a daily basis, but I will tell you being both in a big group and talking to people around the country, some people still think that’s potentially the right answer. I think we’re going to talk about the nitty-gritty of all these different subtleties of good therapy and what good looks like, but I think it’s important to just get out there that monotherapy is not necessarily the right answer.

Jorge Garcia, MD:And you mean monotherapy with?

Kenneth Kernen, MD:ADT, just hormonal therapy, yeah. We see that people get referred to us, as the advanced prostate cancer guys, and they’ve been on ADT monotherapy for a while. They’ve never been talked to about some of these advanced agents, whether it’s 6 cycles of docetaxel or the new oral oncolytics.

Neal Shore, MD, FACS:I’ve recently seen some marketing data and about 70% of patients in the United States are still getting ADT monotherapy, and it’s not too dissimilar around the rest of the world. This is today.

Jorge Garcia, MD:I think that’s unacceptable with the existing data that currently stand.

Alicia Morgans, MD:I agree.

Kenneth Kernen, MD:But I think that’s the importance of something like this, to say…

Neal Shore, MD, FACS:Fully agree, but it’s quite amazing. Well, why is that happening? You give the ADT, you see the PSA [prostate-specific antigen] come down, and you declare victory. Well, that’s unacceptable because there’s now Level 1 evidence, which we’re going to review. I was at a conference recently and someone said, “But if I have somebody with high-volume disease and they’re asymptomatic, I start them on ADT. Their PSA goes to less than 1 or almost to 0. Why do I have to start combination therapy? And I said, “Because there’s Level 1 evidence.”

Jorge Garcia, MD:That’s actually right on the money. Oftentimes, when I get those calls, or even when I see patients, I actually tell my patients, “I think the state or the management of advanced disease has really changed.” I use December 2013 as the benchmark for us. In that month, or in that year, we released the results of the CHAARTED data, the ECOG data, that to me really changed the standard practice throughout the United States, at least. It was 6 months later when experts presented STAMPEDE and the CHAARTED data, at least for chemotherapy.

But since then we have CHAARTED and STAMPEDE for chemotherapy. And then in 2017, we had LATITUDE, which is high-volume disease using the biosynthesis inhibitor, abiraterone acetate. On top of that, we have the arm within STAMPEDE looking at the same biosynthesis inhibitor. Then last year, or this year, we have new data looking at not only apalutamide as a newer inhibitor but also the TITAN data, as well as ENZAMET and ARCHES looking at enzalutamide in the same space.

When you think of 5 or 6 different trials with roughly 3 or 4 different agents, how do you guys make that decision as to, “How do I pick?” And I agree with you. I think high and low volume meant a lot more before ESMO [European Society for Medical Oncology Congress] 2019. I still think volume matters for us when we’re distinguishing these agents, to some extent, especially when you’re thinking about local control for those patients who have local tumors in place. But how do you guys, Alicia, make that decision between, “Do I get chemotherapy, or do I get an oral agent?” And if you pick an oral agent, which of the agents would you pick, and why?

Alicia Morgans, MD:Again, if it’s low-volume disease, I’m going to talk to the patient about radiation of the primary. I don’t want to forget that. As a medical oncologist, sometimes I do, because I focus so much on systemic therapy. But when I am thinking about high- and low-volume status, particularly if there’s visceral disease, I think we sometimes think about chemotherapy. I also have a really in-depth conversation with my patients, trying not to overwhelm them and splitting people into chemotherapy and AR [androgen receptor]—directed therapies, or having that conversation around chemotherapy versus AR-directed.

I don’t go into all the nitty-gritty of every AR-directed therapy until we’ve at least made that decision. Chemotherapy is over relatively quickly, if they’re fit enough to tolerate it, and does not have the co-pay issues that patients can face when they’re using the AR-directed therapies. Some patients do like to kind of get that chemotherapy out of the way and continue on their injections, which is most commonly what they do for an extended period of time before they need to initiate something else, particularly because some people feel as if they may be fit for it now but may not be fit for chemotherapy later.

But there are many people who end up going into the AR-directed therapy camp, and people do sort themselves out pretty well, in my clinic at least. They say, “I can’t do chemotherapy right now because of my job.” “Because of the people who are depending on me for this or that.” “Because I just choose to live my life now, and I want to avoid the adverse effects of chemotherapy and potentially take them later.” “I don’t want to lose my hair.” These are some of the things that they think about.

Then when I try to dig into the AR-targeted agents, that’s where it gets really hard, Jorge. I think that’s exactly why you drew me into this question. So we’ll have to talk about it as a group too. I do think, and you mentioned before, that there is some fatigue associated with enzalutamide, although we do have a long length of experience with this drug. And so some people feel comfortable knowing that we at least have defined the adverse effects, and I feel as if I’ve known them for a long time. Abiraterone comes with prednisone. Some people like that because maybe they have some bone pain, and that helps to resolve some of that discomfort relatively quickly. They can get that and feel better. But other people don’t want the prednisone.

We know that apalutamide does have its own adverse effects as well—rash, maybe some hypothyroidism, and of course falls and things like that. I think that people, in my clinic at least, sort into chemotherapy versus AR-targeted, and then we get into the weeds sometimes in those conversations about which AR-targeted agent to choose. How do you have those conversations, Neal?

Neal Shore, MD, FACS:I’m actually still pretty aggressive about the docetaxel, 6 cycles, up front. The patients tend to be younger. In my experience—I’ve been doing this now for several years—they tolerate it pretty well. They’re younger. They’ve probably got a better performance status. And why I still am a bit more partial to that is because then, if they have a really good response or good response, before they become castration resistant, the real question then is, “OK, do I then add an AR-targeted therapy while they’re still hormone sensitive, to give them the best shot?” We’re in a data-free zone, right? We have some data that we can talk about. So would I, prior to September, have added abiraterone and prednisone at some point in time once they’ve gotten through their 6 cycles of docetaxel? And now you could also add apalutamide. That’s been approved. And then enzalutamide, which is not approved but certainly will be within the relatively near term. So I struggle with that.

Jorge Garcia, MD:I think you raised a great point, Neal. Either maintenance after docetaxel—immediate maintenance before you wait for castration resistance—or triple therapy, which is ADT, docetaxel, and an AR inhibitor. We have data. ARCHES included a subset of patients who actually had prior docetaxel. ENZAMET has almost half the patients who received docetaxel. And TITAN has what? I think it’s 11% or so.

My only concern with that sort of triple approach, or docetaxel followed by, is then the data that we have appear to be good for PFS [progression-free survival], but the survival data of all that sort of triple therapy or sequential therapy are still pretty immature. I’m concerned because there are trials right now for high-volume patients looking at, specifically, triple therapy against ADT and chemotherapy. If, in fact, the data that we have appears to be negative or not positive for survival, that will create a lot of pressure in that frontline space, as to the timing of when you do an AR inhibitor and when you do chemotherapy, either immediately or together.

Transcript edited for clarity.