Neal Shore: Great to be here with you.
Tanya Dorff: I have to say, your poster really caught my eye. This is an analysis from EMBARK. And thinking back, when my institution opened the PRESTO trial, which was in biochemically recurrent prostate cancer, single versus double versus triple therapy, the reason I thought it was a good trial is I thought maybe if we hit the AR pathway hard enough in this early disease state, maybe we'll get a cure. And it didn't seem to pan out. And then fast forward, now we have this analysis about exceptional responders. So tell me a little bit about the nidus of this analysis from the EMBARK trial.
Neal Shore: Yeah, thanks so much. So proud to be part of it. And my co-PI, Steve Freedland and myself, and a great group of folks to do this across the globe. 10 plus years to pull this off. And we just presented the overall survival data and published it again in New England with a hazard ratio for the combo arm versus monotherapy ADT of just slightly below 0.6. And I think that's really kind of unique in a Phase 3 prostate cancer, advanced prostate cancer study. So what we wanted to look at was these super-responders or folks who have had an excellent response to your point. And looking at PSAs of less than 0.2 to even down to 0.02, these super-responders. What we were able to see because we had an interruption cycle, if you got it nine months, you got to less than 0.2 in any of the three arms, the combination, Enza, ADT, LHRH, traditionally, that's really what we had, three month formulation versus the mono ADT, the LHRH three months versus the Enza mono by itself, which was open-label. We had an interruption or a drug holiday, some people would like to call it. So we looked at those patients and we said, "Okay, what about the ones... How long did it take for their testosterone to recover?" Some was at 175, which was a number we sort of just picked at the beginning of the study.
We looked at 250 and we also looked at their return to baseline testosterone. And what we found was is that about slightly less than 5% of the patients in the combination arm went out to nearly three years of maintaining a PSA of less than 0.2, about one and a half percent in the mono ADT and 1.5% in the Enza alone arm. Now those are small numbers, but they became essentially eugonadal. So the nice thing about that was giving up or not having the traditional toxicities of T-suppression while maintaining really low PSAs.
Tanya Dorff: So did I understand you correctly then, there were patients who recovered testosterone whose PSA stayed low, but only on the monotherapy arms, not on the combination?
Neal Shore: No, all three.
Tanya Dorff: Oh, all three arms.
Neal Shore: All three. All three. All three.
Tanya Dorff: And it was 1.5% in the mono arms?
Neal Shore: It was about roughly 1.4, 1.1% in the... Well, let me back up. In the combo arm, it was just 4.7% and it was in the mono LHRH arm and the mono Enza arm was roughly approximately 1.4% in each one of those that maintained that PSA out to three years of less than 0.2 and were all eugonadal.
Tanya Dorff: And eugonadal. Were there some patients who never recovered testosterone?
Neal Shore: There were, and it was very, very low. In all three arms, it was approximately 0.8 to 0.4%.
Tanya Dorff: So could you discern anything about these patients that might've explained why they were super-responders?
Neal Shore: Yeah, that's a great question. So we really, unfortunately, we don't have genetic signatures on those and looking at things like such as PAM50, et cetera. So other than that, we're still doing some additional analyses on that, but I don't know that we're going to have any sort of other informative marker analyses for them.
Tanya Dorff: But clinical characteristics, were they all starting at a lower PSA, a slower doubling time?
Neal Shore: Yeah, that's a great question. That's an analysis that we're doing and hope to report on as well.
Tanya Dorff: So given these fantastic data from EMBARK, which have really changed practice in the biochemically recurrent setting, how do you approach the decision of monotherapy Enzalutamide versus the doublet?
Neal Shore: So I love the question because it's caused me to have a more shared decision-making conversation with my patients. I think there's undoubtedly if a patient is saying, "Look, I just want what's going to give me the absolute best long-term clinical efficacy in terms of disease recurrence." I mean, the data clearly supports the combination arm. The trade-off with that, and that's where we see the most robust overall survival data, and also the most robust metastasis-free survival data that's sort of the basis of the AUA plenary and the ESMO plenary presentations and the survival data. But I think your point, what's embedded in it is really important is look, much of my career when I first started was looking at all these different formulations on testosterone suppression. And we all know there's no quote free lunch. There's hot flashes, there's the fatigue, there's the quasi-metabolic syndrome, clearly the sexual dysfunction, maybe even some cognitive and depressive associated aspects, bone demineralization, et cetera. So for my patients who have either been exposed to an ADT beforehand, some of the radiation patients, and they clearly are like, "Well, I just don't want to go back to that." Or they have a sort of high performance of exercise or business-related issues or their sexual function, their libido is very, very important to them. I very carefully explain to them the option for mono Enza and I've kind of morphed in terms of my...
The key to the, or the challenge of just doing mono ARPI is the clearly well-documented breast-related symptoms that happen, not only just enlargement, but there's tenderness and nipple pain. And I've learned a lot from many of our colleagues in the Nordic countries and in Northern Europe who've been using high-dose Bicalutamide. Now, we don't have that in the US, but what I've had previously looked at was prophylactic radiation, 8 to 10 gray. You can give it in a day, maybe over a couple of days. I've stopped doing that and I've completely changed my practice to using very low-dose of a SERM, Tamoxifen. It's generic, it's inexpensive. I started off with daily 10 milligrams, and this is just me doing this, and I've talked with some of our other colleagues like Nick James, and they use it twice a week. So I give Tamoxifen 10 milligrams every two to three days for my Enza mono patients. And I probably have over 30 or 40 patients now, and they just don't get any breast-related symptoms, and it's inexpensive, and I've really become really impressed by that. The PSA declination is rather impressive, and you don't get a lot of these worsening T-suppression side effects.
Tanya Dorff: Wow. Well, that's really helpful guidance. Thank you so much. And congratulations again on the study and how much it's impacting our patient care, and thanks for being here today.
Neal Shore: Thanks very much.