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Alicia Morgans: Hi, my name is Alicia Morgans. I'm a GU Medical Oncologist at Dana-Farber Cancer Institute. I'm so excited to have here with me today, Dr. Neal Shore, who is the Medical Director for the Carolina Urologic Research Center in Myrtle Beach. Thank you so much for being here with me today, Dr. Shore.

Neal Shore: Thank you. It's a pleasure, Alicia.

Alicia Morgans: Wonderful. And I'm so excited to have you here today to really dig into your AUA 2021, podium presentation, looking at ARCHES, which is, of course, a phase three trial that is looking at men with metastatic hormone-sensitive disease treated with enzalutamide. Can you tell us a little bit about the study and then what your group did to further investigate?

Neal Shore: Yeah, thanks very much. Alicia. ARCHES is a really well-done study under the leadership of Andy Armstrong, low and high volume mCSPC patients getting randomized one-to-one to monotherapy ADT versus ADT and enzalutamide. There was a compendium trial, ENZAMET, which has demonstrated radiographic progression-free survival, but also overall survival. And excitingly, we are going to be presenting the final analysis, the overall survival data at ESMO, and that's just a couple of weeks away. But for AUA, what we wanted to look at was...the standard for so many of our colleagues around the world is using, what we call, the vintage androgen receptor inhibitors, the first generation. And so still there is a lot of use of bicalutamide, nilutamide, and flutamide. And what we wanted to do in the ARCHES population in comparing the patients who received ADT and enza versus ADT and placebo, first of all, was it balanced between those who had any exposure to a vintage anti-androgen? The answer is yes. It was balanced about 25% of the patients.

And what was the impact, whether it was for a month or longer duration use of anti-androgen? Did that in any way mitigate the effect of enzalutamide? And the bottom line is no, it did not. In fact, it did not at all. So I think that is really exciting and really great data. I say that because we did other studies looking at the novel hormonal agents, the newer agents in an AR signaling inhibitor, like enzalutamide versus the vintage ones. We did this in mCRPC trials. And we, again, show that there is a clear advantage to the potency of the inhibitory effect of enzalutamide over the vintage agents. And this was once again, what we demonstrated. We did a sensitivity analysis. We looked at the overall population. We looked at the primary endpoint, was that impacted at all by prior vintage AA or anti-androgen use? We looked at the time to castration, PSA modulation, time to a new antineoplastic therapy, objective response rates.

Bottom line, everyone did better regardless of whether they received the one month or a longer duration of an anti-androgen, typically it was bicalutamide. And so we saw this in a really robust way and that's the data that we are presenting here. We have numerous KMs on rPFS, time to PSA progression, time to antineoplastic therapy, time to CRPC, PSA undetectable rate, objective response rate, everything favoring the use of ADT plus enza versus ADT placebo regardless of whether a vintage anti-androgen was used. I have to say sort of once again, driving another nail into the coffin so to speak, as to the role for anti-androgen vintage in this population, mCSPC. And I've always found that to be the case for mCRPC patients. In all fairness, I can understand if there is an accessibility issue, the use of an anti-androgen, but certainly, now ARCHES and then this analysis has undoubtedly demonstrated that starting your patients, whether it's low volume, high volume, start them on ADT and enza, and no real need to even consider a first-generation anti-androgen.

Alicia Morgans: So I appreciate that you and your team really were able to demonstrate this across numerous important endpoints, which is so critically important. What do you think is the biggest implication for your day-to-day clinical practice?

Neal Shore: Yeah, I really appreciate that question because when you still look at market data in the US and other countries, despite the robust level one or grade A evidence of combination therapy for mCSPC patients, whether it's low volume or high volume, regardless of how you even choose to define that, a bone only, soft tissue only, bone and soft tissue, visceral and bone, patients should really no longer be started on monotherapy ADT. This is the real key message.

And ADT/enza, regardless of whether patients had received an early vintage anti-androgen, all did extremely well. And it was balanced between the control placebo arm and the ADT/enza arm. So this is really the incredibly important take-home message that even though when we start ADT, we see the PSA go down, we can't declare victory. ARCHES, ENZAMET, other mCSPC studies have shown that combination therapy with an AR signaling inhibitor or ADT plus docetaxel in high volume, patients for sure are going to do better. They are going to have a delay in the progression of their disease. They are going to have enhanced survival. And so thinking well, I'm going to add an earlier generation AR inhibitor or just immunotherapy, that's really the take home. That is just not the standard of care anymore.

Alicia Morgans: Thank you so much for driving that home. I know you and others have really presented some of that real-world data that ADT alone is so commonly used. And I think the bottom line is ADT alone, or with one of these as you call them, I love it, a vintage anti-androgen is not sufficient. Choose a partner for your ADT. It needs to be something, something novel, something newer, either an AR targeted agent, or docetaxel if that's the choice in that high volume population. So thank you for really going into this data and reminding us of the ARCHES overall message. And certainly, as you mentioned, this subset analysis or this sort of post-doc analysis on all of these really important outcomes. So any final thoughts for the viewers?

Neal Shore: Yeah, again, just hammering home the concept that, yeah, the partnership is better.  A lot of times we say, is more better? Combination therapy is clearly the role for mCSPC patients. ARCHES is a remarkably successful study. And I really do not see a role anymore, unless it's an accessibility issue for an earlier generation AR inhibitor. And so that is really the key thing. We all know since 2012 that the safety profile for enzalutamide is now really well-established from mCSPC through all aspects of mCRPC.

Alicia Morgans: Great. Well, thank you for taking the time to do the work, to share your expertise. We really appreciate you.

Neal Shore: Thank you, Alicia.