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Alicia Morgans: Hi, my name is Alicia Morgans and I am a GU medical oncologist and Associate Professor of Medicine at Northwestern University. I'm so excited to have here with me today two coauthors for the ACIS trial, Dr. Dana Rathkopf who is the Associate Vice Chair of Faculty Development and is a GU medical oncologist and Associate Professor in the Department of Medicine at Memorial Sloan Kettering Cancer Center in New York. As well as Dr. Fred Saad, who is the Professor and Chairman of Urology and the director of GU Oncology at the University of Montreal Hospital Center. Thank you both for being here today.

Fred Saad: Our pleasure.

Dana Rathkopf: Thanks, Alicia.

Alicia Morgans: Wonderful. So why don't we start with you, Dr. Rathkopf, can you tell us a little bit about why you did the ACIS trial?

Dana Rathkopf: So, the ACIS trial was designed based on the hypothesis that targeting both ARi pathways at the same time would improve outcomes for patients. Currently, the standard of care is of course targeting the androgen receptor pathway, but there are different ways to target the androgen receptor pathway. One way is to block the androgen receptor itself through an antagonistic mechanism. The other is to actually shut down additional pathways of testosterone synthesis through drugs like abiraterone. And this trial was designed specifically to look at whether combining these two pathways together, what we call androgen annihilation would be better than blocking one pathway alone.

Alicia Morgans: Thank you. And I think that's a really exciting way to think about it and certainly something that our patients need if we can get that kind of approach to work. Dr. Saad, can you tell us what was the schema? Who were the patients and how were they treated in the trial?

Fred Saad: Yeah, so the study was a little bit less than a thousand patients randomized to getting either abiraterone and prednisone, which is pretty much considered one of the standards of care treatments for metastatic CRPC. And this was compared one-to-one with the combination of abiraterone, prednisone, and apalutamide. And these patients were metastatic CRPC, could not have been treated prior with either chemotherapy or one of these agents. And basically, all comers. Patients could have this role metastasis, which was different than the pivotal abiraterone study that was done several years ago.

Alicia Morgans: Great. Thank you. Dr. Rathkopf, what did you find?

Dana Rathkopf: So when we looked at the abiraterone and prednisone arm versus the androgen annihilation arm with abiraterone and apalutamide, what we found was there was actually a pretty significant improvement in radiographic progression-free survival, favoring the androgen annihilation arm of six months at the planned primary endpoint interim analysis. And then when we looked again at the final analysis, it was actually even longer, at 7.4 months.

Alicia Morgans: So was their central review of this radiographic progression?  Or was this all driven by the investigators treating the patients? How was that done?

Dana Rathkopf: So, the review for this study was driven by the investigators. As you know, there have been other studies similar to this where there has been a great correlation between investigator review and centrally-blinded review. And so here we found something similar. This was actually the primary endpoint that was met, with an investigator review, but we also looked back through a retrospective, centrally-blinded review, and there were similar outcomes.

Alicia Morgans: That's fantastic and really strengthens that difference, which is quite striking. But was there a difference, Dr. Saad, in the overall survival when that was analyzed at this point in time at least?

Fred Saad: So, that is a great question. So, clearly, I just want to put things into perspective. This was 980 patients. When we look back at 302 against a pure placebo and prednisone, it was over a thousand patients. And with PREVAIL, there were actually 1700 patients to compare enzalutamide to a pure placebo. So here, the primary endpoint was clearly rPFS. Really, there was not much hope to be looking at an overall survival endpoint with so few patients, and then [inaudible]  to use the standard of care in terms of clinical trials has tended towards rPFS as a surrogate. So, as expected, we didn't see an overall survival advantage that was statistically significant, even though there was a 2.5-month improvement in overall survival. And what is really striking is when you look at the data 302 to this data, the abiraterone arm was almost identical to what we saw in the era of the 302 study in terms of rPFS and even in terms of OS.

Alicia Morgans: Well, thank you so much for putting that into context, Dr. Saad, because I think sometimes we look at the results, but we don't really understand, one, that this was not powered to necessarily find that obviously, it was not the primary endpoint. And two, just thinking about the differences in numbers and the numbers, of course, that would be required to find that OS difference is really, really helpful. It's also really important and helpful for us to know that there is consistency with prior trials, with 302, to recognize that this is not an aberrant signal or it doesn't seem to be. So that is really very, very helpful.

Alicia Morgans: One of the things of course, that we think about as we are trying to combine these agents potentially in this setting would be the side effect profile. Dr. Rathkopf, can you tell us a little bit about what that showed?

Dana Rathkopf: Sure. So, the toxicities of abiraterone and apalutamide are well-known by themselves individually. And when we combine these two drugs together, we really didn't find any new signals or increased signals when you add them together that were enhanced. So, as expected, when you look at the two arms, the arm that got the apalutamide had a higher incidence of rash, hypertension, things that we typically associate with apalutamide, but generally speaking, the quality of life for these patients was preserved in both arms as they continued on the trial. So, there wasn't really any increased signal of toxicity with the combination for this trial, which was certainly supportive and rewarding to see.

Alicia Morgans: Definitely that is important. One of the things that I think about when I'm talking with patients, of course, is if I'm going to use more therapies, particularly if they are oral, there can be some financial toxicity. And I'm just curious, how do you see this combination? These are approved agents, not necessarily, obviously in combination in this setting, particularly apalutamide, but how do you see this potentially being incorporated into the standard of care? Do you, and do you have a sense of whether there may be barriers in terms of patients actually accessing these drugs with the co-pays that they wouldn't face hopefully, in Canada, but might face in the U.S., Dr. Rathkopf?

Dana Rathkopf: Yeah, absolutely. I think that we definitely have to think about the financial toxicity. So thank you for bringing that up, Alicia, I think that this combination should be considered for patients. I don't think it needs to be used in every patient. Certainly, there was a signal that for patients that are older than 75, patients with visceral metastasis, there may be a better benefit. And we are also looking at molecular studies to understand better which patients might benefit more from this combination of therapy.

Dana Rathkopf: And so, I think that financial toxicity is just as important in some ways, as the physical toxicity of the agents. And so we really have to be judicious when we choose this therapy and select the patients that we're going to give this combination to.

Alicia Morgans: I appreciate that. Thank you. And, Dr. Saad, I'm curious too, the landscape for the metastatic hormone-sensitive disease has really changed. And of course, we have this nonmetastatic CRPC entity as well. And in those cases, we are often intensifying therapy sometimes using chemotherapy, sometimes using an AR-targeted agent in those earlier settings. How do you envision this work really being integrated into our minds, into the landscape that exists now, which is very different than when ACIS started?

Fred Saad: Actually, that's really the bottom line of what we are dealing with.  As patients come to see us in different states and also different ages, different plans in terms of what will come after, so I think what we are looking for is to do the very best we can upfront, try to control the disease as long as possible because we know many of our patients that are elderly and Dana brought this up, which is very important. For patients over 75, many of them, we clearly won't consider chemotherapy as subsequent therapy. And so we have to do the very best we can upfront. And it was very reassuring that in almost about 350 patients, it was actually statistically significant, the improvement in overall survival in that subgroup. Probably because they are less likely to get subsequent therapy once they progress because of their age, their comorbidities, and all the rest. So, it is something that we need to consider, both in the non-metastatic CRPC and early CRPC setting, where we might see better upfront responses and longer time without progression, which is very important for patients.

Alicia Morgans: I completely agree. And I think it's interesting, we in academic centers often talk about trying to intensify and I think that as a field, we are all trying to do that. But the fact remains that maybe half of the patients do not receive intensified therapy in either the metastatic hormone-sensitive setting or probably the non-metastatic CRPC setting, which is for some people sort of more difficult to even identify if we don't have access to the right imaging. So, I really do see that this has a clear role and certainly applies to patients who are reaching us without having those intensified approaches in their first-line mCRPC setting. So, I really appreciate that.

Alicia Morgans: Dr. Rathkopf, I know you are a member of the Alliance group. You contribute a lot of intellectual knowledge there and do a lot of work there. And I was just wondering if you have any comments on how this may be similar or different from one of the previously-published Alliance trials, it was A031201. Dr. Morris really led that study in the metastatic CRPC setting.

Dana Rathkopf: Yeah. Thanks, Alicia. I'm happy to bring that study up because I think that there is a natural comparison between these trials in that Dr. Morris and the Alliance group also looked at a combination of androgen annihilation. In this study, it was a little bit different because the control arm was actually an AR antagonist enzalutamide, as opposed to our study, which was abiraterone. And the combination, of course, was enzalutamide and abiraterone. And for the Alliance trial, it was interesting because this trial also showed a radiographic progression throughout the trial. This was the secondary endpoint for the trial. That was the way it had been designed, but it also showed that there was a benefit to some patients with the androgen annihilation arm. And it was actually a statistically significant benefit despite being a secondary endpoint.

Dana Rathkopf: Now, that study did not meet its primary endpoint, which was overall survival, but there were some differences between the trials as well. Despite the androgen annihilation arm, of course, the enzalutamide comparator was different, but also that study was not blinded. Patients needed to actually pay for the drug themselves, the abiraterone. And so some patients actually couldn't be enrolled on trial because of their insurance companies or they couldn't afford, of course, the abiraterone arm and that added some color to the trial, of course, in terms of what the end analysis was.

Dana Rathkopf: The other issue of course was geography. This was not an international trial either. So, I think that there are some differences that we can parse through, but the similarity of this is clear, that there was a radiographic progression-free survival benefit to the combination relative to monotherapy.

Alicia Morgans: Great. Well, thank you for putting that into context too, because I think as we are all trying to get these studies or keep them straight in our minds, it's really helpful to just have a reminder, even if something was published a few years ago. So as we close, I would love a summary from each of you on what your message would be to clinicians, to patients about the results of the ACIS trial. We'll give the first summary opportunity to Dr. Saad.

Fred Saad: Okay so, I think that the basic message is, we can do better than what we are doing right now. And there makes biological sense of attacking the androgen receptor and the production of androgens. And we did meet, this is the first study to actually meet its primary endpoint of radiographic progression-free survival in patients with the metastatic castration-resistant disease. So, I think we should be very happy that we are moving in the right direction. We did not see an overall survival, even though we had more survival in patients with combination, but I think it is important then to look at subgroups and patients that are unlikely to get subsequent aggressive therapy. This is something that I think should be considered in the future.

Alicia Morgans: Thank you, Dr. Saad. And Dr. Rathkopf?

Dana Rathkopf: I think when we do these clinical trials, it's important to realize that although we have primary endpoints and secondary endpoints, that it is not one size fits all. And so for the clinicians, what I would say about this trial is that it just adds an opportunity or a treatment option to our armamentarium. There is clearly, I feel, some benefit to the combination for some populations of patients. This has been shown as a primary endpoint in this trial, and of course, as a secondary endpoint in Alliance with the trend towards improvement in radiographic progression-free survival.

Dana Rathkopf: What that ultimately means in terms of overall survival, presently, this study did not show an overall survival benefit. But there are benefits that can be present, that isn't just overall survival, that you can find in a long time to radiographic progression or seeing a greater decline in PSA. And maybe, when you treat upfront, patients have a better quality of life early. It's hard to know which patients will be best served by this at present, but I think that we are doing studies to better understand that and that I would take away from this trial that it is just another option to consider when you are speaking to your patients in the clinic.

Alicia Morgans: I appreciate that. And I also encourage everyone to be on the lookout for the other data that you'll be presenting I'm sure. I'm sure you are doing molecular analysis as you mentioned. And for us all to consider, for patients, especially those who may not receive subsequent therapies, for whatever that reason is, particularly maybe these patients over 75, those patients with visceral metastasis, this may be an option to give them an opportunity to have a better outcome early when they need it now. And so I think it is something for us to consider. I sincerely appreciate the time that you've both taken to go over this and congratulations on another fantastic trial and for contributing to the field and the care of men with mCRPC. Thank you both.

Dana Rathkopf: Thank you.

Fred Saad: Thank you.