Christopher Sweeney, MBBS: When we wrote the ENZAMET study, the ANZUP [Australia and New Zealand Urogenital and Prostate Cancer Trials Group] team had a global collaboration between UK, Ireland, Canada, Australia, New Zealand, and the Commonwealth of Massachusetts with Dana-Farber Cancer Institute. We actually wrote ENZAMET in 2013 before we had the results of the addition of docetaxel à la CHAARTED.

We then rapidly amended it, and we said that our standard of care is for anyone who’s either hormone plus docetaxel, or hormone—testosterone suppression alone—depending on who you are and your physician-patient decision.

We didn’t want to prevent that. It was going to rapidly become the question, “Should we be triplet versus doublet?” We actually did a stratification, and it turns out we have about 50% of the 1100 patients, so a reasonable robust data set. A number of issues came up yesterday in the poster discussion, and I get to address that again here, which it’s important.

People say, “Well, what we saw was that there was an increase in time to clinical progression, which was pronounced. But with 3 years of follow-up at the interim analysis, we actually don’t see an OS [overall survival] benefit yet. It doesn’t seem like we’ve impacted what Chuck is going after with his study. But we need to see long-term follow-up to see if we see an OS benefit.

At this stage, there is an increased toxicity with the triplet versus doing it sequentially. Most notably, it’s an increase in fatigue and neuropathy. Somehow the potent AR [androgen receptor] inhibition is making the chemotoxicity worse, and we know this in CNS [central nervous system] penetration, something is going on there that we’ve been able to find out when we looked at the analysis, the toxicity profile.

We just presented the quality of life data, and we actually see the enzalutamide monotherapy with the enzalutamide with testosterone, without docetaxel, as having the same impact on deterioration-free survival similar to some adverse effects early. But you delay the clinical progression and the cancer symptoms when you do the confidence end point of deterioration-free survival. It looks very similar to what we see with apalutamide.

We seem to have more toxicity because of the docetaxel component. We see the fatigue in the quality-of-life domain on the deterioration-free survival—it’s overlapping between the 2. No. 1, when you look at the data sets between apalutamide and enzalutamide, that has to be taken into account.

No. 2, some people say that there’s no improvement in overall survival because there’s a drug interaction between docetaxel and enzalutamide. I’m going to address this because it’s come up a number of times.

The 2 studies were combined, and they show a 10% increase in clearance of docetaxel by enzalutamide. That’s deemed clinically insignificant given the wide individual variability.

Then we go on and look at the data set, and we see no decrease in neutropenic fever. If we did, it would suggest you had decreased exposure to docetaxel, and in fact they increased toxicity. We do see a treatment benefit with the triplet with a major improvement in clinical progression-free survival. But right now, I suspect, if we don’t see an increase in overall survival, it’s because doublet followed by ENZA [enzalutamide] is as good as the triplet all along. If, however, we do see a survival benefit of 5 years or 6 years, something happened here to augment the responsiveness to the second-line therapies. If we don’t see a survival benefit, it’s just that after you progressed on DOCE [docetaxel] and ENZA, radium and cabazitaxel don’t seem to have that much effect to be determined agnostic. I don’t know the answer here. But at this stage, in 2019, I cannot advocate the triplet.

Dan George, MD: It really gets to what other secondary exposures, we just don’t know yet. But to Chuck’s point, if this were changing the survival of these patients destined to die in the first couple years, we might have seen some...

Christopher Sweeney, MBBS: I think so.

Dan George, MD: We haven’t. I think it leaves open the door that there may need to be other targets.

Charles Ryan, MD: You can add to the scenario where we can push out the PFS [progression-free survival] and the OS of the patients who are already benefiting from enzalutamide or docetaxel in this setting. That’s good work to do, right? We should do that.

Dan George, MD: Yes.

Charles Ryan, MD: But what’s happening is there is a biological fork in the road. Some people go down this fork of nonhormone sensitivity, and they’re the 22% who are dead within 2 years after starting ADT [androgen deprivation therapy] plus abiraterone or docetaxel. About 33% are dead within 3 years. There’s some biological switch, and what we hope to do is interrogate that. I look forward to the results from CHAARTED to see what molecular events are occurring and how we might be able to integrate that into the addition of what we’ll just call a more aggressive therapeutic approach.

Transcript Edited for Clarity