Daniel J. George, MD: Ben, do you have any thoughts on the real-world experiences? I’m sensitive to what Eleni says, because I think about my own practice, and we use a lot of these drugs in this setting. But I realize that Duke Cancer Center doesn’t necessarily represent the real world. The patients we’re seeing in the academic centers aren’t necessarily the populations you’re treating out there in community settings. Do you want to speak to that a little?
Benjamin H. Lowentritt, MD, FACS: It is a great point, and for the most part, where we’re falling short is in the de novo patient, which arguably is the highest-risk patient, who shows up metastatic. For a long time, the standard has been to get them on ADT [androgen deprivation therapy] and watch them, and we’ve had enough time to adjust. Many of us have. The first 2 agents, abiraterone and docetaxel, came with potentially a bit more baggage. I don’t want to disparage docetaxel. It’s a very tolerable drug, but it may have scared a few people off. I’m speaking very much in conjecture.
The discussion that I have now with my colleagues is that we have many options for better hormonal therapies, and you shouldn’t think of this as anything other than that. In many ways, this goes back to what we had before with total androgen blockade. It wasn’t really adhered to then, when we had data that there was some advantage to adding agents. Now we have better data and more agents. For many of my colleagues who are so used to having these patients in their practice, they’ve either embraced this or they haven’t.
For those who haven’t, they’ve created their referral patterns, hopefully. It’s all a bias on the part of the provider. A patient will go where they want, where they’re directed, when they have a clear direction to do so. Many providers are still getting onboard with the real level of difference that Eleni and Chuck referenced between early and late. To get this done earlier is such a differentiator that there is no excuse, and we’re going to keep working toward getting better.
I do think there is a real question about whether you go to cytotoxic chemotherapy or an oral. Is there ever a patient where there’s a clear right or wrong answer? That is still being discussed. I think the high-volume patient with bone metastasis is the 1 that I make sure gets a discussion about chemotherapy, without question. There is further discussion about some of the lower-volume metastases and then certainly visceral metastases. I’m curious if anyone else has any input on that part of it.
Daniel J. George, MD: It’s a great question. Tanya, I wonder if you could address that for us, and also the idea that perhaps it isn’t always an either-or. Maybe there’s a rationale for either a combination of docetaxel and AR [androgen receptor]–targeted agents or a sequence of these before disease progression. Any comment from the clinical trial data we have? I think there is an ongoing study asking that question.
Tanya Dorff, MD: From ENZAMET, which was the up-front enzalutamide study, about half the patients got docetaxel and then either enzalutamide or placebo. What we saw in that trial was that it did not look as though there was added benefit, so maybe 1 agent to intensify up front is enough. But it wasn’t a study that was formally designed to answer that question. In the ARASENS trial, which is ongoing with darolutamide, everyone is going to get the chemotherapy, and then there’s the randomization between darolutamide or placebo.
I think that’s going to give us more definitive evidence. But right now, based on the evidence we have available, I tend to pick just 1 drug. I agree with Eleni that the real battle is getting providers in the community to adopt that. There’s been this mentality of “Let’s save an arrow in our quiver. Let’s wait.” I find that the patients also talk about it that way, and I really have to emphasize that most people on the placebo arm crossed over and got these life-extending therapies after they progressed. We saw this very dramatic difference, so there is something about intensifying and getting a better remission by killing more cancer right up front.
The neoadjuvant studies presented at ASCO [American Society of Clinical Oncology Annual Meeting] this year by Rana McKay and others really speak to the fact that we kill more cancer when we add abiraterone, for instance, in the neoadjuvant setting. We can look when we pull out the prostate. Some men have no cancer left. We don’t achieve that with the ADT-alone standard. I talk about it in those terms with patients. We know we kill more cancer with these drugs, and that’s going to keep you well longer. It’s going to delay the time to you having pain or feeling sick from your cancer or needing chemotherapy if we’re starting with a hormone agent.
Those are some ways around that conversation that can be helpful. There is that financial cost, and there is some concern about whether that intensified hormone therapy will lead to more toxicity over such a long period of time. But at the end of the day, the survival is markedly better. There’s a delay in skeletal morbidity. These are very meaningful clinical end points. More education and more communication with all our colleagues is necessary to really emphasize this. Then we’ll learn whether we want to choose both chemotherapy and an AR-targeted agent when we get the ARASENS data.
Daniel J. George, MD: That’s really good advice about recognizing the need to follow that clinical data. That’s where the survival benefits are.
Charles Ryan, MD: May I make a quick point on this, Dan? It’s such an important point. Tanya nicely addressed the issue of the clinical data, the crossover, and this change our mentality from “Let’s do the easy thing first and the hard thing later.” But the other piece that is happening is that in our literature, our knowledge of the biology of castration-resistant prostate cancer [CRPC] is exploding. What we’re finding out is that that is a disease that is much more complex, much more heterogeneous, and associated with many more lethal mutations than the earlier-stage untreated disease.
We’ve seen this with data on loss of RB [protein]. There was a whole oral presentation at ASCO on methylation, CRPC, and neuroendocrine small cell cancer. That conversation with the patient shouldn’t be about just what’s the easier therapy. It has to be that we’re trying to prevent or treat when you have a low-volume, less complicated disease rather than wait to have a higher volume, more complicated disease when things become really challenging.
Daniel J. George, MD: There is a practical problem that happens. Everyone gets on their injection first. They get on their ADT first, and if you haven’t had the conversation almost right then, what ends up happening? At the next visit, they get a PSA [prostate-specific antigen] that shows that they had a great response. Then the patient says, “Well, why do I need another therapy?” The enemy is that PSA, and it’s why you have to plant the seed very early.
It speaks to the need for early referral if you’re not doing it yourself, or certainly incorporating that into the very first discussion. I’d say that, associated with the financial cost, ends up being the big hurdle, because they say, “What’s the differential? My PSA can’t go any lower; it’s down from 83 ng/mL to 1 ng/mL.” That’s the issue.
Charles Ryan, MD: Any oncologist out there who treats triple-negative breast cancer is going to know the model for how this works. You identify an aggressive biology. You have an aggressive treatment that has multimodal therapy associated with it, and you improve outcomes. No one would ever dream of starting with something easy in that setting and allowing the disease to evolve, so we need to shift our mentality. I think we are shifting our mentality in prostate cancer.
Eleni Efstathiou, MD, PhD: This is an important point that you brought up, Chuck and Tanya. It has been my passion, as you know, to actually be able to characterize that disease. Where we’re stuck is, unfortunately, we have these options, and we don’t really know how to best guide and how to provide the sequence. We don’t know if it would be chemotherapy. We know that volume and risk are more like the low-hanging fruit that we use as a surrogate for the biology we’re looking for, but the bottom line is that everyone needs to understand that there is progress.
There’s no perfection. It’s just progress, and I want to tie something in here. We have clear guidelines that all men who walk in with de novo metastatic disease, or even any metastatic disease, should be offered germline testing. We’re probably going to get to that a little later. You get a lot of second opinions because of your position and where you are. I can tell you that maybe 1 of 20 of my second opinions have received community germline assessment mutation.
You may not be able to act on it, but just the sheer knowledge is valuable, especially with what’s happening. Most practices would be advised to at least have this type of algorithm where they’re trying to maximize benefit up front, when the patient is also in a better performance status. Get a hold, and actually account for all comorbidities and make these decisions. Then maybe it’s a little harder for urology practices, but they can pair up with either oncology or even involve internal medicine when it comes to these interactions.
Benjamin H. Lowentritt, MD, FACS: Germline testing and better risk stratification should already be in the discussion for some patients with presumed localized disease. It’s not something that’s solely for the metastatic world, and I think it’s just another of those things that we have to get better at quickly. That’s true across all of what we’re doing in all cancers and all specialties. Understanding what we understand now: That’s the challenge.
Transcript Edited for Clarity