Dan George, MD: One of the nice things about this particular disease state is that we have seen that. Maybe it’s because the disease state is so homogenous in how it’s defined because of these doctoring effects leading up to it.

Charles Ryan, MD: This is also a consistent theme across other clinical states, right? Your work in the hormone-sensitive setting. The STAMPEDE studies all suggest that agents that work in CRPC [castration-resistant prostate cancer] when given earlier are beneficial. In the CRPC studies with enzalutamide and abiraterone that are now several years old, we know that the patients with lower volume of disease in earlier points along that spectrum benefited more from the therapies. They not just lived longer but got a greater benefit from the therapy. I want to go back to my analogy of the patient with a PSA [prostate-specific antigen] of 2 and say, the data probably do suggest that we should start darolutamide-apalutamide-enzalutamide at that point. But I wonder how many of us are jumping on it right at that time, or if we’re giving the PSA doubling time to mature, so that we can say, “OK, now you’re at the sweet spot where the PSA is 9 and the doubling time is 4.4, which is exactly what the patients on the study were.”

Dan George, MD: Although there was probably 30% or 40% of patients that screen failed because we waited to that point and they already had metastatic disease. Yes, some patients can wait to 8 or 12 PSA, but some patients may develop metastases sooner. I think if you know they’re on that continuum and you’re confident of it, I’m not sure how much you gain by putting that off.

Charles Ryan, MD: We all see a lot of men with prostate cancer, so I think we can tell intuitively. It’s the PSA doubling time. It’s looking at the effects of the primary tumor. It’s the shorter duration of response to ADT [androgen deprivation therapy]. It’s the shorter duration of time from primary therapy to relapse and things like that. All those factors fit in and feed into our clinical intuition.

Dan George, MD: To what Chris said, if it’s a frail patient, if it’s an older patient, you may delay it a little longer. If it’s a 55-year-old patient, you’re probably going to jump sooner for a healthy 55-year-old.

Bertrand Tombal, MD, PhD: I used to say that this is very important for us physicians, because it means there’s very little chance we’re going to be replaced by computers soon. In a discussion like this, we would like to provide the perfect picture of the patient that we start on hormone. But actually if you see these patients on a regular basis, if you see a lot of these patients, that’s absolutely easy to decide we need treatment.

This is because of that complexity versus a clinical trial, where you’re on that steering committee, and the company is forcing you to come with a combination or 2 or 3 inclusion criteria, which we know never describe the population well. It’s like the high and low volume. There are so many things beside that. But I think physicians should be reassured if they use the ... responsibility well, they know their job and they can tell you who is good and who is bad. The message is, if you believe the guy is bad, stop the treatment right now. I would say that.

Dan George, MD: Fair enough. I think that’s great.

Christopher Sweeney, MBBS: One closing point. I would say that biology is destiny, and the AR [androgen receptor] target is relevant. All of this is clinically relevant, but it’s also very biologically plausible. The other notion that is also biologically plausible is that a little cancer is probably more sensitive than big cancer So it’s consistent.

Charles Ryan, MD: Where are we along the spectrum of AR amplification and all those factors? We have no idea because we’re studying a disease. When we’re talking about nonmetastatic disease, we’re studying an entity that we, by definition, cannot quantify biologically. But we do know, for example, that enzalutamide was developed for the sole purpose of targeting AR amplification. It’s actually remarkable or notable that we’re seeing benefits in the hormone-sensitive setting with these drugs, when theoretically, there should not be AR amplification. Which gets to the question that seems obvious, but it wasn’t intuitive that these drugs would be beneficial in the non—AR-amplified setting, as well as in the AR-amplified setting.

Dan George, MD: Well, let’s get to that because I think that’s the other really big thing. That’s the disease state we haven’t created. That’s the tumor biology that happens naturally, and that’s this metastatic hormone-sensitive initial presentation, in some cases following local therapy. We’ll talk a little about the differences between those. But this is the disease state now that is really emerging for a greater use of our androgen receptor—targeted therapies. I appreciate the underlying biology that you just brought up, and we should get back to that.

Transcript Edited for Clarity