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Dr. Alicia Morgans: Hi, this is Alicia Morgans associate professor of medicine at Northwestern University where I practice GU Medical oncology. And I am thrilled to have here with me today, Dr. Earle Burgess who is an associate professor of medicine of Atrium Health, and the section chief of the GU section at the Levine Cancer Institute. Just really thrilled to have you here today to talk with us today Earle.

Dr. Earle Burgess: Wonderful. Thank you for the invitation.

Dr. Alicia Morgans: Of course. So, you've been hard at work, as you always are, and one of the things that you've been working on is really exciting and brought us together to have this conversation. You've got a Phase II trial called ENZADA, hopefully, I'm pronouncing that properly, and I'd love to hear a little bit more about that.

Dr. Earle Burgess: Sure, thanks. Yeah, we're very excited about this study. As you mentioned, it's a Phase II trial for patients with newly diagnosed metastatic castrate-sensitive prostate cancer and it is a single arm trial. It's assessing the combination of androgen deprivation therapy, or ADT, plus a docetaxel backbone, plus the second gen androgen receptor antagonist, enzalutamide.

Dr. Alicia Morgans: Great. So, you know I think this is, from my perspective, such a nice meld of the CHAARTED, STAMPEDE data with something similar to LATITUDE, an abi arm of STAMPEDE approach putting these things together. Is that how you came up with this design for this patient population?

Dr. Earle Burgess: Yeah, that's exactly right. As you referenced, we know that adding docetaxel or abiraterone to ADT backbone improves overall survival and then at secondary cancer specific endpoints but the question that remains unanswered at this point is whether or not triplicate therapy with ADT, plus docetaxel, plus a next gen endocrine agent further improves outcome over either agent alone. The trial was actually conceived after the CHAARTED results were released at ASCO a few years ago and the Phase III trials assessing these combinations were in design at that time. But we conceived of this trial at that time based on the ADT plus docetaxel backbone.

Dr. Alicia Morgans: Great. And this is really an investigator-initiated trial. So you're running this study for men with hormone-sensitive metastatic disease out of Levine Cancer Institute?

Dr. Earle Burgess: Yeah, that's right. Thank you. It's an investigator-initiated study. It's a single institution study so it's only available here at Levine currently, that's right.

Dr. Alicia Morgans: Can you tell us, who are the patients who are eligible for enrollment in this Phase II?

Earle Burgess: It's predominately patients with castrate sensitive, newly diagnosed metastatic disease. And while the inclusion criteria for the recent Phase III read out slightly different we, for the most part, mirrored the criteria from the CHAARTED study. So specifically patients who have been recently diagnosed can have received initial ADT within three months of consent. However, they have to have a measurable disease either by recist or per bone scan, radionuclide bone scan. Patients with pelvic nodal involvement only, are excluded. Any pelvic nodal involvement requires an additional site of disease. And we also are stratifying patients by volume of disease and we use the CHAARTED definition, high versus low. High volume, of course, being a presence of either visceral metastasis or four or more bone lesions with one outside of the pelvis and spine.

So the inclusion criteria, very typical for the current metastatic castrate sensitive trials. Few other points, I think, to bear in mind, patients had to have had a PSA >5 prior to enrollment or initiation of ADT. Patients who have received prior ADT in a definitive setting concurrent with radiation for up to three years are allowed provided that they've received their last curative-intent ADT dose six months before enrollment and have confirmed testosterone recovery.

We do allow patients with an ECOG of up to 2, so 0-2. And certainly, anybody who's received prior cytotoxic therapy or next-gen endocrine therapy are excluded from this study.

Dr. Alicia Morgans: What's the therapy that all patients receive? Because as you said, this is a single arm trial, which makes it kind of nice that patients don't have to feel like they're going to be randomized to get less than something. What does everyone receive on the trial?

Dr. Earle Burgess: Right. All patients receive continuous androgen deprivation therapy throughout the duration of the study. It's built upon the CHAARTED docetaxel backbone, so patients receive docetaxel at the standard 75 milligrams per meter squared dose every three weeks, up to six doses and the study intervention also includes the addition of enzalutamide at the standard approved dose of 160 milligrams daily, which they begin at enrollment on day one and continue until study completion. So, all patients receive all three drugs, ADT, docetaxel for up to six cycles, and enzalutamide until study completion.

Dr. Alicia Morgans: One of the nice things, I think about that, besides the fact that you're answering this question is that for patients who want to really throw the kitchen sink at things and we don't know if that's the right thing to do or not yet. Your study will help answer that question but this gives them an opportunity to do that when regular clinical practice, insurance coverage, and those kinds of things probably wouldn't make that happen for them. Is that true?

Dr. Earle Burgess: That's right. And I think you allude to an important point. I think many of us are tempted to extrapolate from CHAARTED, STAMPEDE and LATITUDE and use the docetaxel and abiraterone in sequence, though as you know we don't have data to justify that yet. I think once the Phase III trials ... or we have to wait until the Phase III trials read out to really understand that. So outside a clinical trial setting, at this point I wouldn't encourage that but this trial provides exactly that for patients who are motivated and clinicians feel that it's appropriate, this study allows to receive triplicate therapy.

Dr. Alicia Morgans: What are the endpoints that the team is looking for at the conclusion of this study?

Dr. Earle Burgess: So the primary endpoint is the 12 month PSA complete response rate, which we define as an undetectable PSA or PSA of 0.1 nanograms per mil. Again, based off of or powered from the historical control that was established in CHAARTED. In CHAARTED, the 12-month PSA complete response rate on the docetaxel arm was about 28% and we've designed this trial to detect an improvement from 25 to 45%. Of course I don't know if that's a surrogate for survival or not but we thought that an improvement from 25 to 45% would potentially be clinically meaningful. So the primary endpoint is 12 month PSA complete response rate.

Secondary endpoints are serologic and radiographic rates, time to progression, overall survival. We also have an exploratory biomarker endpoint. We are looking at circulating tumor cells in sequence throughout study participation. We're using the Epic Sciences platform and are measuring not only CTC counts but also AR-V7 status using their assay.  There are three time points that CTCs are measured at, study enrollment, after completion of docetaxel, and then at the time of castrate resistance.

Dr. Alicia Morgans: I love that you have the correlative data in there too and agree that 12-month PSA complete response rate isn't necessarily something that we know is associated with overall survival but if you improve over that, which we saw in CHAARTED, I think that's definitely hypothesis generating to say the least. So I think that you've chosen some smart and strong endpoints and endpoints that are achievable in a Phase II, which is really what we aim to do. So how have things gone with the study so far in terms of enrollment? And how are patients tolerating the treatment?

Dr. Earle Burgess: Right, so we enrolled our first patient last August, August of 2017. And as of earlier this month we've now enrolled our 17th patient. So we're almost halfway completed. So at this point quite pleased with our enrollment numbers. Right now, we're targeting to complete enrollment by the end of next summer, so early third quarter of 2019. The study is powered to enroll 39 patients at this point, so happy with how we're doing and certainly would like to get this enrolled as soon as we can.

Dr. Alicia Morgans: Of course. Are patients tolerating the combination of the enzalutamide and docetaxel? It sounds like they're starting simultaneously. Are they doing alright with that?

Dr. Earle Burgess: That's right, so far they are. The study is undergoing routine monitoring by our DSMC as well and at this point they've not identified any safety concerns. Anecdotally, I would tell you that as well. So at this point, no unexpected toxicities in the first 17 patients.

Dr. Alicia Morgans: Okay. Well that's always encouraging to hear too. So if patients or docs out there want to either enroll themselves or have their patients enroll in the trial, what should they do?

Dr. Earle Burgess: I've provided my contact information in the slides that will accompany this and provided both my email and my primary phone number. The trial itself is registered with clinicaltrials.gov, so interested parties are certainly happy to pull the trial reference at ct.gov for more information about it, and this provides contact within our clinical trials office.  I'm also happy to answer questions directly from either patients or interested providers. The way this study was written, unfortunately, it's only available at Levine in the Charlotte region now. It was written so that patients could receive their ADT anywhere, however, they do have to receive docetaxel from a physician at Levine and the enzalutamide obviously is provided as a part of the study. And so they would receive that at Levine as well.

Dr. Alicia Morgans: So, Earle, if a patient does decide to travel to Levine and get his treatments with you for the docetaxel, how often does he have to come back during follow up and continuation on enzalutamide?

Dr. Earle Burgess: There are three phases of the study. During the docetaxel phase, the first phase, patients have to come every three weeks as would correlate with their docetaxel infusion. After completion of docetaxel, the second phase, the enzalutamide castrate sensitive phase, the study required visits are once every two months. And then the study is written such that patients would continue enzalutamide actually until radiographic progression, not biochemical. So for patients that continue on study in the castrate-resistant phase, that is they have not yet shown radiographic progression, then the scheduled visits are on a monthly basis.

So every two months during the castrate sensitive phase, decreased to once a month during the castrate resistant phase. Which would continue until the time of radiographic progression, at which time they would come off study.

Dr. Alicia Morgans: Great. So, I really appreciate you giving us an overview of the trial, Earle. I think it's really exciting and an opportunity for patients to not only get really cutting edge care but also kind of give back or contribute to the knowledge that we have for how to best take care of these patients overall, to take care of men like them. So do you have any closing thoughts before we wrap up?

Dr. Earle Burgess: No, I just echo your comments. I thank the patients and family support who allow trials like this to happen. We're all trying desperately to answer these important clinical questions that we can ultimately improve the standard of care. So it's a pleasure to speak with you today and thank you again for allowing us to talk about the study and help get the word out.