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Alicia Morgans: Hi. I'm thrilled to have here with me today Dr. Tanya Dorff who is an Associate Professor of Medicine at City of Hope. Thank you so much for being here.

Tanya Dorff: Thanks for having me.

Alicia Morgans: Of course, I am really enthusiastic about this conversation because you had the great honor of being the discussant of the ENZAMET trial at ASCO, and what a fabulous job you did. Really, I think, brought home some of the really important points and helped to clarify what has become a very crowded landscape. Can you tell us a little bit about the ENZAMET study, just to remind everybody and get us all on the same page. And then we'll go through some of the key messages from what you discussed. 

Tanya Dorff: Sure. The ENZAMET study was a study of metastatic hormone-sensitive prostate cancer patients, so newly diagnosed, starting ADT, and the clinical question was whether adding enzalutamide upfront versus standard androgen receptor therapy, such as bicalutamide or flutamide or nilutamide would improve overall survival. 

Now because the CHAARTED study had reported out early enough in the trial's conception and design, patients were allowed to get upfront docetaxel as per the CHAARTED and STAMPEDE data sets, and then do the enzalutamide on top of that. 

Alicia Morgans: Great. And so patients in the control arm had standard LHRH agonist or antagonist therapy or bilateral orchiectomy. So standard ADT plus nilutamide, flutamide or bicalutamide, so really kind of a combined androgen blockade, which is a really powerful control, or at least the most powerful control that I've seen in any of the metastatic hormone-sensitive studies. 

Tanya Dorff: Right. That's something that distinguishes ENZAMET from LATITUDE and STAMPEDE. All those were placebo-controlled and here men got what would be considered more active therapy. 

Alicia Morgans: Absolutely. And then the therapeutic arm also had this LHRH agonist, antagonist, orchiectomy, plus enzalutamide, and in both arms, patients could also receive docetaxel chemotherapy. 

Tanya Dorff: Exactly. 

Alicia Morgans: Great. And so what was the overarching conclusion or the primary endpoint that was discussed? 

Tanya Dorff: The big headline and the primary endpoint of the study is that adding enzalutamide upfront did significantly increase overall survival. The other major point that makes this trial so important is that a majority of patients did receive docetaxel, so we can start to look at the question of whether triple therapy is appropriate, whether we should give docetaxel, and then also give a next-generation androgen receptor antagonist. 

None of the other trials have as big a proportion, and so they can't speak to that question. This was also a pre-specified subset analysis which gives it some statistical validity, although it wasn't the primary endpoint. 

But importantly, it looks like there is less benefit of adding enzalutamide if you gave docetaxel. Also, there is less benefit in the high volume patients, and I presume that's because the majority of those were patients who got docetaxel, compared to the low volume subset where you saw a bigger separation in the curves from the addition of enzalutamide because fewer of them received docetaxel. 

It's not that you can't use triple therapy, although Dr. Sweeney did show a little bit more toxicity with the combination that needs to be studied further, but there's not a signal of a huge advantage, and I think if we can do just as well by giving some kind of intensification upfront and not use maintenance after chemo, but waiting for progression and implementing advanced androgen-targeted therapy at that point. 

It doesn't look to me like there's a big difference, and so I think from a quality of life and a toxicity and cost standpoint, that it would make sense not to do triple therapy outside of a trial at this point. 

Alicia Morgans: That's really interesting because I think we'd all been hoping that there would be this big addition to combining the therapies, and in ENZAMET at least, it does not look like the benefit of adding enzalutamide on top of docetaxel is as substantial. Really interesting and really important. And about how many patients... what percentage of patients or approximately what percentage of patients received the docetaxel treatment in these two arms? 

Tanya Dorff: It was on the order of 60 plus percent, more on the high volume side than on the low volume. 

Alicia Morgans: Okay. And were there any conclusions that could be drawn or that Dr. Sweeney talked about related to high volume versus low volume. You alluded to it a moment ago, that adding enzalutamide may be... you really maintained that benefit signal in the low volume, as well as in the high volume, and perhaps that's in the setting of not receiving docetaxel. 

Tanya Dorff: Right. That's my speculation, but I think it is important because of the CHAARTED subsets where we didn't see as much benefit of upfront docetaxel in low volume patients, but with our androgen-targeted therapies like abiraterone, enzalutamide, apalutamide, it seems like any sort of volume of disease patient can benefit. At this point, most, if not all metastatic prostate cancer patients should be offered something beyond just LHRH or castration therapy. 

Alicia Morgans: Absolutely. What other take-home messages would you have? It sounds like really this triple therapy is probably not necessarily the way that we need to go at this point, or at least there's no compelling data to suggest that that's going to give us a better outcome at the end of the day. What else do you draw from this trial that you really want to make sure that everyone understands?

Tanya Dorff: The other big conclusion that I think is important for the community to hear is that this is now a non-corticosteroid option. And apalutamide falls into that, as well, from TITAN. Docetaxel comes with a lot of steroids, abiraterone comes with prednisone, although at the lower doses it's well tolerated, but it is nice for those patients in whom corticosteroids are not a great choice or who aren't good candidates for abiraterone for one reason or another to have this third option. 

Alicia Morgans: I totally agree. And now that you brought it up and since you have seen all the data, too... and I've really thought about this in the metastatic hormone-sensitive setting... that the TITAN data demonstrated that in the metastatic hormone-sensitive population, the addition of apalutamide to standard ADT-type therapy also prolongs survival and radiographic progression-free survival, which is really an exciting thing to come out of this meeting, as well. How do you sort through all of these options when you're thinking about it and you haven't seen patients, I don't think, at this point, since we've gotten all this data, but how do you think you're going to be making choices as we move forward in the future? 

Tanya Dorff: It's going to be very complicated, and I think physicians will largely choose based on their comfort level. There are a few obvious situations maybe where low volume, you're not going to use docetaxel and you'll prefer an AR-targeted therapy. Maybe someone with more aggressive features, visceral involvement, lytic bone metastases, something unusual, sometimes we have a gut feeling that chemotherapy would be a better call for those patients, although it's certainly not proven. 

And there are a few drug-drug interactions or comorbidities that might push you towards one or another. There were some seizures seen in ENZAMET. That's been a question that we've had with enzalutamide since the beginning, although the rate's very low. Someone who's had a stroke or a seizure history, that might push you away from enzalutamide. But again, there are times where you want to avoid corticosteroids or in certain cardiac comorbidities, avoiding abiraterone is favored. I think it's going to be very individualized. I think all these drugs have significant merit, and it'll be the comfort level of the physician really and a shared, informed decision-making with their patients. 

Alicia Morgans: I agree. Well, I sincerely appreciate you sharing your insights, both at ASCO certainly and then now, and I look forward to continuing these kinds of conversations because I can't imagine that this landscape is going to be less complicated. 

Tanya Dorff: I think it's only going to get more complicated. I think what's really exciting is that we see this amplification of benefit by moving drugs earlier, and I think a lot of new trials are going to be conceived in this space with new therapies that will hopefully really improve the lives of our prostate cancer patients. 

Alicia Morgans: Wonderful. Well, thank you for your time today and I appreciate all of your thoughts. 

Tanya Dorff: Thanks.