Neal Shore, MD, FACS: Let me jump to this question, because I’d like you to review it if you wouldn’t mind, Pedro. We talked early on about historically using monotherapy, testosterone suppression, agonists, antagonists, and bilateral orchiectomy. In the last few years we’ve seen this explosion of couplet therapies: docetaxel, enzalutamide, apalutamide, abiraterone. Can you review some of those data?

Pedro C. Barata, MD, MSc: It’s quite an interesting story. These are actually exciting times. Things changed dramatically, I would argue, in 2017 when we started seeing the data. Initially, the American study, CHAARTED, would basically compare the treatment intensification with 6 cycles of docetaxel on top of a backbone of ADT [androgen deprivation therapy] versus ADT alone. It showed a survival benefit regardless of volume at that time. The study was positive. But then the French study, which was a negative study, asked the same question about the addition of chemotherapy to ADT. We actually did up to 9 cycles in that study. We start discussing, is chemotherapy helpful for everybody? Then we start discussing the concept of volume of disease. Today we still use the CHAARTED definition, which includes 4 or more bone lesions with at least 1 outside the spine and pelvis and/or visceral disease.

We start understanding that using a drug that improves survival in the castration-resistant setting, docetaxel, also improves survival if you use it early on. It was obvious for us to use other therapies out there, very powerful agents such as abiraterone and enzalutamide and apalutamide, and test them in the metastatic castration-sensitive setting and ask the same question. Does treatment intensification make people live longer? And do they live better? We now have data from STAMPEDE, CHAARTED, and LATITUDE for docetaxel and abiraterone; we have ENZAMET and ARCHES for enzalutamide; and we have TITAN for apalutamide.

We can spend an hour just talking about all the details of those data, but I think the take-home points from all those data are that the new standard of care for most men with metastatic castration-naїve or castration-sensitive prostate cancer should indeed be treatment intensification. In other words, hormones or hormones plus bicalutamide is not enough. The second question that some of us can weigh in on is in terms of quality of life. By doing that, we allow them to live longer but also better. We delay a lot of symptoms in relation to the disease that they develop over time. We know these treatments for the most part are not curative, but they did dramatically change the way we manage these patients. It brought us another set of questions such as, how are we going to sequence all these treatments? If we start using them up front, what’s going to happen once they fail?

It’s an exciting time. At the same time, we’ll start seeing the development of new molecules. We will start having these studies that ask the question, what actually is the right timing for therapies, after we start using these agents that you just mentioned, early on in the course of the disease?

Neal Shore, MD, FACS: Wonderful summary of an enormous amount of work that’s been done. Let me ask the panel: we have this proverbial embarrassment of riches, right? Prior to just a couple of years ago, we had monotherapy ADT or a clinical trial. Let’s exclude clinical trials, because we all have some really interesting clinical trials still ongoing in this space, which is so exciting. You now have ADT plus abiraterone, ADT plus enzalutamide, ADT plus apalutamide, or ADT plus docetaxel. I’d like to ask you, how has your decision making evolved with all these new agents out there? I think it’s unique for the United States, right? Because in the United States we have, as a general rule, access to all these. In the rest of the world, it’s still a little bit of a challenge, with the exception of ADT and docetaxel. Nancy, has it evolved? Has it changed for you when you discuss treatment with someone who has low-volume, high-volume, or newly presenting disease?

Nancy Ann Dawson, MD: Absolutely. I look at these studies and, as you said, when CHAARTED and STAMPEDE came out, they both showed the benefit of docetaxel, but the CHAARTED trial showed that the patients with low-volume disease did not benefit. Only the patients with high-volume disease seemed to have the survival benefit. I take into effect the volume. If it’s a patient with low-volume disease, I’m probably not thinking docetaxel. In fact, if you look at our NCCN [National Comprehensive Cancer Network] Guidelines, they actually tell you that they do not think you should give docetaxel to the patients with low-volume disease. Apalutamide and enzalutamide work in both high- and low-volume disease. Abiraterone, of course, works probably in high- and low-volume disease, but they didn’t really break it out quite the same way.

If you look at the STAMPEDE trial, they showed benefit of abiraterone in patients who just have high-risk localized disease with nodes that are involved. I do now have to look at not only the volume of disease but also where the disease is. I have to look at the patient’s preference, of course. It’s a much longer conversation than it used to be. I look at other reasons not to give a patient something. If a patient has an ejection fraction that’s under 50%, I’m not going to want to give them abiraterone.

If a patient is on some of our anticoagulation drugs—Eliquis [apixaban], drugs such as that—that’s going to have an interaction with enzalutamide or apalutamide, so I’m going to have to try to figure that out and change their medications if I want to do that. I do take those things into account: where the disease is, what their heart function is, and what their preference is. I’m surprised sometimes how patients will say, “Well, I’d like to get the chemotherapy—I don’t want the oral drug because I’ll be on it for years,” if they’re lucky, as opposed to 6 cycles of chemotherapy and they’re done.

Neal Shore, MD, FACS: That’s a really good summary. William, for the audience, when you have patients come in, is there ever a role now for not using some form of couplet therapy? Would you just give monotherapy ADT?

William Oh, MD: I don’t think so. If you look at the survival benefit of these combinations, whichever 1 you choose, it’s just so dramatic. You’re really keeping these patients alive years longer with the second therapy than with ADT alone. We’re all taking care of patients with lots of comorbidities, lots of other issues. But in the end, they all want to live, and we want them to live. In my mind, there’s almost no situation where I can’t offer 1 of these 4 options. I think the biggest challenge is which 1 do we choose and why? There’s a lot of variability, as you heard. But for the most part, I don’t think there’s really any person who I wouldn’t try to get a second therapy into.

Neal Shore, MD, FACS: Agreed. Alicia, any other contrarian thought to that?

Alicia K. Morgans, MD, MPH: I have seen some patients with pretty advanced dementia, in which I know that dementia—I talk to the neurologist—is probably going to be an issue for them and probably cause their death within the next 12 months. Sometimes chemotherapy is not really ideal in that patient population because of the potential risks of complications that they or may not be able to cope with. And then there can be other problems. I have given some of them or tried to give some of them oral agents, because I completely agree with William that if there is any way to get a second agent and really intensify it, I will always try to do that. But sometimes for people with severe dementia, they can forget to take their pills. I certainly don’t want to put anyone in a position where he’s taking abiraterone without his prednisone because I don’t want him to have hypertension and a stroke.

There are those kinds of situations. I could imagine if somebody had such severe heart failure, the life expectancy could be within a year, based on the cardiologist assessment. But it is a very small minority of patients. I have to say it is concerning sometimes when we are in meetings and talk to people and they say, “Well, I like to give the ADT, whatever that GnRH or antagonist is, and I see how low the PSA [prostate-specific antigen] goes. And then if it goes really low, I don’t add another agent.” In reality, that’s not how the studies were designed. The studies were not considering how low that PSA went, and that should not be a consideration of ours.

Neal Shore, MD, FACS: That’s a great point, Alicia. I really appreciate you saying that. I’ve been asked that, too, and you’re right, the studies weren’t designed that way. Market data that I’ve seen—maybe you’ve seen otherwise—show that in 2019, there’s still an enormous amount of monotherapy that’s occurring.

Alicia K. Morgans, MD, MPH: Yes.

Neal Shore, MD, FACS: I think that there is still a great educational need for many community medical oncologists and uro-oncologists. I think this was a great discussion.

Transcript Edited for Clarity