Alicia Morgans: Hi, this is Alicia Morgans, GU medical oncologist and Associate Professor of Medicine at Northwestern University in Chicago. I am so excited to have here with me today, a friend and colleague Dr. Rana McKay, who is an Assistant Professor of Medicine at the University of California, San Diego. Thank you so much for being here with me today.

Rana McKay: Thank you so much for having me, Alicia. It's really a pleasure to celebrate Virtual ASCO with you.

Alicia Morgans: Wonderful. It is a celebration there's a lot going on, and you've contributed multiple abstracts and presentations to this year's ASCO 2020. I really wanted to talk to you about a study that you and colleagues have done looking at neoadjuvant abiraterone and apalutamide in patients prior to prostatectomy. You're really looking at what's the response rate? You could look at that pathologically after prostatectomy. I'd love to hear your thoughts on the impetus behind this trial and the outcomes of the trial, of course, itself.

Rana McKay: Great. So just to give a little background about this trial and the Genesis of it. So as we know, prostate cancer is the most common cancer in men in the U.S., and the majority of patients present with localized disease. However, of those patients who present with localized disease, approximately 15% of patients actually have high-risk features. Either a high Gleason score, high PSA, advanced stage.

When we look at the 15-year prostate or specific mortality rates for those patients, they can be upwards of 38% depending on the risk parameter. When we look at the treatment paradigm for patients with high-risk prostate cancer, it really hasn't changed over the last several decades. The platform is basically been radical prostatectomy, followed by either adjuvant, or early salvage radiation with hormones, or upfront definitive radiation with hormonal therapy.

The neoadjuvant strategy has really been the standard of care for other solid tumor malignancies like breast cancer, bladder cancer, rectal cancer, where neoadjuvant therapy has been demonstrated to improve long-term survival for patients. It downstage local disease which may facilitate surgical resection, reduces and delays post-surgery treatment, and actually also is able to provide an in vivo assessment of response. Pathologic response in those diseases: breasts, bladder, rectal has actually been associated with longterm outcomes.

However, the neoadjuvant platform in prostate cancer, it's not new. This strategy has been looked at in the early 1990s. There was a series of trials that were designed looking at LHRH agonist with or without first-generation anti-androgens. Those initial trials that were designed were really looking at the rate of positive surgical margins. They enrolled a high proportion of patients with low-risk disease. They did not integrate systematic evaluation of pathologic response. They had very limited longterm followup, and really that oppose was put by the wayside.

However, with the advent of more potent ended in signaling agents like abiraterone, enzalutamide, apalutamide, we sort of reinvigorated this paradigm, because we've seen the efficacy in the advanced setting. These drugs are moving earlier on from castration-resistant disease to hormone-sensitive disease. Really this provides an opportunity to investigate these drugs in the context of the neoadjuvant trial.

So we've conducted over the last 10 years through the work of just amazing individuals, and really Dr. Mary-Ellen Taplin, who's really spearheaded a lot of the efforts behind these neoadjuvant studies, a series of trials enrolling high-risk patients, investigating more potent hormonal agents in the neoadjuvant setting. These trials had a systematic central pathology review. Looking at response, they had longterm followup. Just to kind of give a summary acknowledging the limitations of Phase II studies, from the series of contemporary neoadjuvant studies that have been designed, we see a signal that pathologic responses are observed with more potent hormonal therapy in a subset of patients.

One of the biggest things about pathologic responses is does it correlate with longterm outcomes, and we've conducted a pooled analysis from these prior contemporary studies and from this historic analysis, demonstrated that not a single patient who actually had a path response or minimal residual disease actually had a recurrence. Now this data is being updated and we hope to present that soon, but this was the backdrop that really led to the design of our current trial which seeks to answer the question of does more potent neoadjuvant treatment with abiraterone, apalutamide, and leuprolide result in improved pathologic responses and rates of biochemical recurrence in men with localized high-risk prostate cancer?

Alicia Morgans: So, excellent question. A question that we've been thinking about for some time. We've had other studies in the mCRPC setting, for example, where we combined an AR antagonist with abiraterone, which was a little disappointing, unfortunately. But what are your thoughts in terms of this?

Rana McKay: Yeah, so kind of to segue into the trial's EMA and sort of what we learned from this study, this trial enrolled patients who had a prostate adenocarcinoma, it enrolled people with at least a 4+3 disease, PSA greater than 20 or T3 disease by MRI, pelvic lymph nodes had to be less than a 20 millimeters. Patients were randomized 1:1 to receive either abiraterone, apalutamide, prednisone, and leuprolide. Or abiraterone, prednisone, and leuprolide.

They received therapy for six months prior to radical prostatectomy and then underwent the radical prostatectomy. There is currently ongoing a part II of this study, which is a post-RP randomization to additional hormonal therapy or observation. We won't be talking about that today. That part of the study is still ongoing. We'll just be talking about the part I, the neoadjuvant component.

But just to say that post-prostatectomy, 70% of patients actually were able to be randomized onto the part II. So the primary endpoint for part I was the rate of path CR and minimal residual disease, which was defined as less than or equal to five millimeters of tumor in the radical prostatectomy specimen.

So in total, the trial actually enrolled 119 patients. When we go into the baseline characteristics of the trial, they're kind of in line with the eligibility criteria, this was a very high-risk patient population. The majority of patients had T3 disease. Ninety-four percent of patients had NCCN high-risk disease, 42% of patients had Gleason 9 and 10 disease. So really enrolling a very high-risk patient population.

Interestingly, when we look at the PSA responses, kind of in line with what we saw in our other contemporary trials that PSAs dramatically declined early in both arms. The pre-PSA medians were 0.03 in both arms. Really PSA does not really seem to discriminate with regards to pathologic outcomes because we see great heterogeneity in regards to their path response.

So the big kind of like, what we actually found from the pathologic data was the paths, CR or minimal residual disease rate with abiraterone was 20%. With the abiraterone and apalutamide was 22%. There was actually no difference between the two arms, though with this approach we do observe that about a fifth of patients actually had dramatic responses. But again did not seem to be a difference between the two arms.

When we look at toxicity there's no new signal of toxicity. We don't see any grade 4/5 toxicity. Grade 3 toxicity was low, peri-op and postop toxicity was actually low with this approach. We do demonstrate the intense neoadjuvant hormone therapy appears to benefit a subset of patients, there was actually no difference between the two arms.

Alicia Morgans: But I think it's important too, is that this neoadjuvant approach didn't prevent patients from getting their surgery, did not really seem to affect it. Now, the combination doesn't necessarily seem to be active in any way, but none of these patients were really prevented from having their surgery, which I think is important. I mean, that was the goal of all of this was to get this high-risk patient population to surgery, hopefully for definitive treatment and cure, right?

Rana McKay: That's correct. That's correct. I think our data actually really support the current design of the Phase III randomized double-blind study that's currently ongoing, the PROTEUS trial. That's looking at answering this very question. So it's good to sort of have our data to support this large trial.

In that study patients will be randomized to apalutamide and leuprolide, versus leuprolide alone for six months pre-surgery, six months post-surgery. This is going to be a landmark trial that's going to, not to say, put this question to rest, but really try to definitively answer the question of, what's the role of neoadjuvant hormonal therapy, or neoadjuvant adjuvant hormonal therapy for people with high-risk disease?

I think another critical, important aspect of this trial is it's actually going to also seek to validate the early pathologic endpoint for prostate cancer. So this trial actually has a co-primary endpoint of pathologic response and metastasis-free survival. I think a huge landmark for the field would be if we can actually try to identify an early endpoint of efficacy for people with prostate cancer. So we don't have to wait 10 and 20 years for our trials to read out for OS.

Alicia Morgans: I completely agree. I think that the PROTEUS trial is so intelligently designed, and I love the neoadjuvant/adjuvant approach with that co-primary endpoint. Because I think that in the field, as you have mentioned we really need these interim endpoints to help us understand benefit before we get the five to 10, to 15-year followup that's really required for overall survival type endpoints.

So I'm very excited as PROTEUS is launching and will be accruing over the next few years. I hope that many patients really learn about this trial and engage in it because I do think that it's going to be a great opportunity for patients with this high-risk disease. So as you think about this trial, which I think again, your study has been a really important way for us to continue to think about neoadjuvant therapy. I know that you and the team at Dana-Farber, has been working on this for a long time. What is your overarching message, and what should we take home from this work?

Rana McKay: I think while there's a subset of patients that appear to benefit from neoadjuvant therapy, I think there's a lot of really interesting questions that we're very much excited about moving the field forward. So one is the integration of imaging and tissue biomarkers that guide therapy selection. So in this trial, all patients had a baseline multi-parametric prostate MR. A subset of patients actually had a pre-prostatectomy, repeat MRIs. So we have paired MRIs on 71 patients in the context of this trial. We're excited to be hopefully presenting that data in the near future.

There's also going to be embedded rich tissue biomarkers to help guide therapy selection. So can we deescalate therapy for some patients and intensify therapy for other patients? So, interesting questions are defining who the exceptional responders are. From our initial preliminary work, it seems that patients who have SPOP alterations and lack ERG, PTEN, and p53 alterations seem to have the most exceptional responses.

So, with the integration of our imaging, with the integration of our tissue biomarkers, and also now better treatments, very provocative question is, can we get away with not doing a radical prostatectomy in some patients? I know that's like, it's heresy to even say that, but I think these are sort of some of the interesting questions that we're seeking to answer.

Then for those non-responders, is there an opportunity for escalation of therapy? Are there some patients that are better served with a chemotherapy approach, just like was done in the PUNCH trial, as opposed to a hormonal therapy approach. Or is there an opportunity to modulate the adjuvant therapy component based on what happens at radical prostatectomy? So, there's so much more, I think the field has to grow and learn from these studies, and we're excited about helping to shape the field in that space.

Alicia Morgans: That's wonderful. I certainly share your enthusiasm and so appreciate it. But as you said so much work to be done, and I really look forward to hearing more from your group over time about how we can not only improve outcomes, but really help to do that by understanding the heterogeneity of disease, whether it's a localized disease, or whether it's in more advanced disease. Escalating and de-escalating is really the way that we want to practice in the future. I sincerely appreciate your efforts in helping us get there. Thank you so much.

Rana McKay: Thanks so much for having me, Alicia. It was really a pleasure.