Alicia Morgans: Hi, I'm so excited to be here with Dr. Neal Shore to talk about the enact trial, which is really investigating the use of enzalutamide in patients who are starting on active surveillance. Thank you so much for being here, Neal.

Neal Shore: Thanks for having me.

Alicia Morgans: Great. So, Neal, can you tell us a little bit about the purpose for this trial? Why did you put it together, and what was the study design?

Neal Shore: Yeah, thanks very much. So, at the time that we were thinking about the trial, it was very clear then, and even today, that we're still underutilizing active surveillance as effectively as we can. If you look back to the turn of the 21st century, it was low-single-digit percentages of patients who were receiving active surveillance. And one of the things that drive me crazy was doing prostatectomies on patients and seeing that they had a minimal amount of final pathologic disease. And my worry that, gosh, please be continent and please have good sexual function. Really pioneering work by many have led to the recognition that patients with grade group one and grade group two disease, with some exceptions, maybe not ideal for very high-volume grade group one patients who are younger and longer actuarial survivals, and maybe for some patients who have a higher percentage of pattern four in their three plus four grade group too may not be ideally suited, although I'm a big proponent of surveillance.

So, what appealed to me about this particular study was to take an improved oncologic agent, enzalutamide, and see if we could find something in a one-to-one randomization, approximately 115 patients in each arm. Clearly not blinded. Patients knew if they were getting enzalutamide, as opposed to them just staying on active surveillance. And to try to see if a drug such as enzalutamide, that next-generation AR pathway inhibitor, would have an impact on not only a biopsy and a positive impact on avoidance of upstaging of histopathology, perhaps also showing a lessening in the positive biopsies at year one and year two. Patients were only on the drug for one year, and then everyone was biopsied, at least who maintained in this trial, and then the drug was stopped, and then patients went on to have a second biopsy.

We looked at both PSA progression and histopathologic progression. So, sort of a composite endpoint for patients getting off a trial for either laboratory findings, their PSAs, and/or what they felt to be progression and thus a therapeutic progression endpoint. So, what is interesting is that we did achieve a hazard ratio of 0.54, or a 46 percent reduction in the risk of prostate cancer progression with that composite endpoint in the treatment arm versus the active surveillance arm, and a likelihood of a negative biopsy of 3.5 times higher in the treatment arm versus the surveillance arm. Now, there were AEs. We had fatigue, gynecomastia, which of course, you really don't see in the surveillance arm. And so I think that this was nonetheless an important study to do to demonstrate the impact on keeping patients with greater fidelity to active surveillance in the treatment arm versus the surveillance arm.

Now, what's happened since the publication of the study, which, by the way, was IRB-approved in 66 trial sites, and yes, it was industry-supported. It could have been industry-supported by anyone else who had an ARPI drug at the time, and I don't really think, having worked with all of the companies that have ARPIs, that they would assess this as anything but a desire to advance the field in terms of our scientific knowledge. So having said that, the design of the study was never planned as a registrational trial. And then it's interesting to see some of the Twitter responses and dialogue regarding ethics and economics and overall tolerability. And I appreciate where folks are coming from there, but as I said, this was never designed for that purpose.

We see in the United States and elsewhere that we don't practice the AS with the rigor that we need to be doing. Some have argued, well, just do more education. And whether it's through the media, through symposia, through additional papers. But we're 20 years into the active surveillance conversation, and we're nowhere near where we should be. So, perhaps at the very least, a paper like this creates a sort of a thought provocation to our colleagues to say, well, how am I approaching active surveillance, and is there or will there be other opportunities to enhance fidelity to it rather than having full-gland radiation or surgical removal of my prostate?

Now, of course, there's lots of focal therapy trials that need to be done that haven't been done. There's a lot of focal therapy that's being done that there's really a posity of evidence-based prospective studies. So on behalf of all of the authors of this paper, in Canada and the U.S., I stand by the principle of which we conducted the study and why we did it.

Alicia Morgans: So, I really do commend you and the authors on the study. I think the question is a really interesting one, and certainly we don't know the toxicity profile or the outcomes until we do the study. And finding what the toxicity profile looks like really helps inform how we might move forward in practice. There may be some patients who would rather take a treatment like enzalutamide or one of the AR pathway inhibitors and deal with the complications like gynecomastia or fatigue rather than deal with the complications of radiation or surgery. Really, I think what this paper gives us is more information, and it really does round out the thought process and the decision process, because there are some patients who, though we as physicians recommend active surveillance, feel a lot of anxiety and feel uncomfortable. What I also think is important to recognize is that this concept is not crazy ,actually, in terms of oncology care.

So, we were talking prior to this recording about how, in breast cancer, for patients who have a greater than 1.7 percent five-year risk of breast cancer, or patients with a history of lobular carcinoma in site two LCIS, or even atypia, these high-risk lesions in the breast, these patients are treated for five years if they're premenopausal with Tamoxifen or for five years with an aromatase inhibitor or Raloxifene if they're postmenopausal. So, it's just very interesting to me. Certainly, they've got data that suggests that this is going to improve their outcomes, and that's great, and it is supported by the American Cancer Society, but it's data like this that make it actually clear that these kinds of approaches can be helpful for some patients. And I think it's important for us to keep that in mind as we review the data and appreciate the patients who participated in this trial and helped provide some of that data for us to consider.

Neal Shore: That's a great parallel tumor strain to think about. And yeah, it is really interesting. Thanks for bringing that up. Look, I love nothing more than to avoid overtreatment of patients, whether it's through surgeries or radiation or systemic therapy, and certainly an oral therapy such as enzalutamide is a systemic therapy. So finding the right schedule and finding the right method of delivery is clearly what we're all striving for ideally to keep patients, not just kicking the can down the road, but their diagnosis of cancer, which is daunting for many clinicians and for many patients. You've now got this stamp on your passport that you have cancer. And so, to your point, there are many patients and many physicians who become extremely challenged to just do surveillance. I'm a huge believer in doing surveillance, but if we can come up with methodologies that are not overly toxic that are both clinically and economically feasible, I think that's the long-term goal. And so how we deliver it, what type of regimen, how frequently, those are things that require additional clinical study.

Alicia Morgans: Agreed. And there may be some populations at highest risk where these types of approaches may be of higher interest, as well. So there are some populations that we do have concerns about, and you mentioned some of the ones that may be at higher risk and may not be the best for surveillance, or perhaps they are if we use some sort of chemo-preventive strategy for those patients. So if you have to consider this study, which, of course, was not a registrational trial, was not meant to expand indication, what would your recommendation be to listeners, to readers who I encourage, of course, to read the primary paper and think through the outcomes for themselves?

Neal Shore: Yeah, thanks. First of all, we did enrich the population. It was almost 50 percent grade group two and 50 percent grade group one. We studiously excluded anyone with very low-risk disease by NCCN criteria. So, just want to make that clear. But having said that, if this paper is helpful in broadening the conversation to understand the importance of active surveillance, I think that's great. And also recognizing that we're still not going to convince all clinicians nor all patients to just do active surveillance. We still have controversy as to how often we do our mandated biopsies and our serial follow-up biopsies, let alone how the appropriateness of clinic visits and regular PSA monitoring, which adds to additional challenges, both psychologically for some patients, their families, but also economically.

So, I would say that, from my colleagues reading this, regardless of specialty, regardless of your educational background, but if you're taking care of prostate cancer patients, that AS is extremely important and how we can develop better regimens to maintain safe and effective AS is the key. And I would applaud my co-authors and the supporters of the study because we did this prospectively with typical clinical research rigor. I'd like to see more of that happen in a focal therapy design trials, as well.

Alicia Morgans: I think that would be great. I think more information for all of us is always a good thing. As you said, one size does not fit all, and having an understanding of how different patients may approach the same problem or different problems is really, really what we need in our clinical practices. So, thank you so much for your time and for your expertise today.

Neal Shore: Pleasure. Thank you.