Dan George, MD: Patient choice. Absolutely. Let’s not forget that at the end of the day, that’s a huge issue, because there are very different consequences to doubling-down chronic hormonal therapy versus a shorter but more intensive course of chemotherapy. It’s very important to consider that factor. What we need to fill in somehow is biology here. Is this because this is just really a burden issue? The same biology, just slowly building and burden. Or are we seeing really different biology in these patients who present as de novo with high volume, versus these patients who slowly build up to that point? As you said, there’s more of a continuum with some of these, and other ones really seem to be biologically very different. So that’ll be.

Christopher Sweeney, MBBS: We have the STAMPEDE study with abiraterone and docetaxel front and center, ENZAMET, and CHAARTED. We have all aligned, and we are analyzing samples, and we’re all going to do gene expression profiling using the same platform with.... They’ve kicked in, and they’re doing it with some kind support as a team sport. We’re all going to do whole exome sequencing, and we’re planning to do germline DNA. The other beauty with this is that we’ve annotated our patients the same way. We’ll be able to do thousands of patients with the proper annotation with the leading technology platforms to actually characterize the biology of these patients, tied to prospective clinical data. We have a plan for that.

Dan George, MD: Fantastic. That’s really inspiring to know that that data are coming. These studies are continuing to mature for overall survival more and more events, that meta-analysis is really going to be a huge knowledge gap filled. Maybe not completely. Maybe there will be other tests we’ll need, but a huge step forward in insight. That’s great, thanks for sharing.

Other thoughts on this, Chuck? When you’re dealing with a patient now who’s presenting with metastatic, say de novo high-volume disease, how do you counsel a patient between docetaxel chemotherapy or novel hormonal therapy? We talked about patient preference. A lot of this is how we frame these things. How do you do that?

Charles Ryan, MD: Yeah. I really liked Chris’s analogy, or analysis rather.

I appreciate your work, and it needs to continue. It’s vitally important. But let me give you an alternative perspective, which is that this analysis that you’re doing, as important as it is, it’s still focusing on the delta between no ADT [androgen deprivation therapy] with no additional treatment, and ADT with some additional treatment—whether it’s enzalutamide, abiraterone, docetaxel, and so forth.

But I like to look at those curves, and I think I look at the curve from LATITUDE, for example. The curve from CHAARTED is very similar. About 20% of patients who present with high volume with de novo metastatic disease are relapsing within a year, only 22% survive up to 2 years and only 33% survive up to 3 years.

While we need to continue to work on this issue of which is the best drug, somebody needs to be thinking about, “How could we do better?” And I have a plan for that.

This is an area in which we need to integrate some novel therapies and some other approaches. At my center, and through our prostate cancer consortium in the United States, we’re actually testing a combination with platinum and taxane in the high-volume setting. This is because what we’re hypothesizing is that some patients have occult small cell or neuroendocrine, and that those are the situations where the relapse is coming from. Hormone sensitivity is important. Taxane sensitivity is important. But when you get to the end of all this analysis—we figured out that we need better hormonal therapies and we’re using them, and we need to have taxanes—we are still losing a high number of patients.

What I’m hoping we can do as a field is to try to think about that top of the curve, right? We need to think about those people who are not doing so much better with these additional approaches and how can we address that concern.

Dan George, MD: I think that’s brilliant. It brings up some studies now that are complete. ARASENS is 1 in which we’re combining docetaxel and AR [androgen receptor]—targeted therapies, not platinum yet, but what we learned from your study may ultimately go into even a greater combination. Again, you’re not going to do this in everybody. But in the patients, as you said, as best we can know from our prognostic factors, they are at risk for falling in that top of the curve early death from disease. In patients we can justify these greater and greater combination approaches.

Transcript Edited for Clarity