Dr. Matthew Cooperberg:

Let's turn to our Q&A. So as I mentioned, we're joined by our patient services core leadership, Bruce Zweig, Stan Rosenfield, Jim White, Leszek Izdebski, and Nathan Roundy. So they're going to lead us off in questions, and we are seeing some questions coming in through the Q&A in Zoom. Please keep those coming. We will pepper back and forth, but maybe we'll start with Bruce to lead us off here.

Bruce Zweig:

Okay. Thank you, Matt. This is for Dr. Rohit Bose, who's joining us from the UCSF Medical Oncology faculty. And Dr. Bose, at this point in time, the FDA has not approved transdermal estradiol for use, and so any use of it has to be off-label. Have you been able to incorporate it into your practice at UCSF?

Dr. Rohit Bose:

Bruce, and the panel, thanks for the invitation. Very, very selectively, I would say. I think there are three issues that come up. I think the first issue is we use mono ADT increasingly less and less in each clinical states. And the data of combining these estrogen patches with an ARPI, that's emerging and maybe shorter term, and that will come down the road, I believe. The second issue is it's still an off-label practice, and so there is an issue of cost in people's minds. And the third issue I think is, as has been brought up by many people today, is the gynecomastia. And I think there is the data on the gynecomastia, which has been beautifully described, but there's also the patient sort of value judgment on a patient-by-patient basis. So there's a shared decision-making. Some patients, it doesn't really bother them, particularly when they hear about the mitigating strategies.

To other patients, that's a major barrier. And even the idea of receiving estrogen is, on top of gonadal testosterone suppression can be an issue, and it can also be an issue for the couple, if they're present at the visit. So we talk about this data, of course, I think it's important for that to happen, but the use and adoption of this has been quite selective in my practice, and I believe my colleagues, really, I think, skewing towards the patients that really have already been on ADT, the GnRH-based ADT, and have been unable to tolerate it often for cognitive side effects.

Dr. Matthew Cooperberg:

Let's talk maybe a little more about labeling and approval processes and all of that. One of the interesting things with this story is that estrogen is generic and has been around for literally decades in transdermal form. So there's no big proprietary interest driving this. There's no exclusive patents here, and there's no pharma company that has the... It is literally hundreds of thousands to millions of dollars to get something through FDA. So with that funding not likely to be forthcoming, what does the path look like here? I mean, to be clear, many of the places that we currently use ADT, LHRH treatment, for example, combined with radiation therapy, that is no less off-label, so to speak. It's not formally in the label, but it's endorsed by all the guidelines and it's used and we don't have any trouble getting insurance coverage for it.

So do you see a path, and actually this is a question both for you, Rohit, and for our UK guests, what does the path look like for future regulatory endorsement, both in terms of payers? This would be nice and equivalent in the UK and in the US, absent FDA, is this going to hit the NCCN Guidelines eventually? Is there a path forward or do you think this is going to remain a niche option? Maybe Rohit first and then we'll pass it to Professors Clarke and Langley.

Dr. Rohit Bose:

Personally, I think as the combination of estrogen patch plus ARPI data emerges with longer term follow- up, I think if you have this emerging body of data that there's other ways to suppress testosterone, and if it seems to be non-inferior, then I think it's going to be hard to ignore that. And patients are going to ask about that. And I think the scenario that was brought up by Dr. Schellhammer, "I was on this, it was okay, and then now my physician is actually asking me to switch because there's no data. Now I'm in a more advanced disease stage," patients are not really going to tolerate that. So I think as the body of data grows, then I think that's the path to widespread adoption, and I think regulatory agencies are going to have to take that into account. It seems odd to switch modes of ADT in the middle of a patient's life cycle.

Dr. Matthew Cooperberg:

What about in the UK? What are you seeing in terms of adoption and traction?

Professor Ruth Langley:

Well, I can give you some of the background to what we're doing at the moment. The first thing I just wanted to say, as was alluded to, is we do have the data for the combination of patches and RPIs. We've presented it in abstract form at a conference, and we're just about to submit a manuscript on that. So that data is out there, and the patches can be given safely from what we've seen with those drugs, with no loss of efficacy. So that's one thing which I think will help with adoption. We and others have made a submission to the NCCN Guidelines, and we've also made submissions to European guidelines, and we think that that's really going to help with more widespread adoption.

The other issue about the license is actually more difficult because you have to be a license holder to make an extension for the license. And we've got various discussions ongoing, but we will need a pharma partner to do this. But I think that the benefits are clear, and I think that the patient voice is so important in helping us along this pathway. I don't know, Noel, whether you wanted to add anything more to that.

Professor Noel Clarke:

Well, I'll add a little bit more in relation to the data on toxicity, Ruth, because I think this is really important. What we know is that if we use ADT in a man undergoing radiotherapy, an ADT for two years, the five-year fracture rate, clinical fractures, is about 16%, and it's about two to 3% in the normal population not receiving androgen deprivation therapy. We've just done analyses in the STAMPEDE trial, and for those of you who don't know this, it's a very large scale prostate cancer trial in high-risk M9 and M1s. We've looked at scans in about six and a half thousand patients for fractures. And what we find is that it's not the ARPI that is causing the issue, it's the ADT, the GnRH analog.

We've also looked at cardiac risk, and similarly, the ARPI is not the super added risk, it's the ADT. So those complications are inherent in modern day practice using doublet therapy, and that is abrogated with the use of a patch. And I think that that's a real advantage. And Dr. Schellhammer's statement really is really telling, I think, which is the metabolic consequences of using ADT with a GnRH analog are really quite consequential, and the patch overcomes some of that, and I think that's a very important message to take home.

Dr. Matthew Cooperberg:

Is this getting used in UK now as part of clinical practice, or is it still mostly in the ongoing trials' framework? Is it gaining traction in practice?

Professor Noel Clarke:

I think that... Sorry, Ruth. Go ahead.

Professor Ruth Langley:

It's beginning. You go now, Noel.

Professor Noel Clarke:

Well, I was going to say, recently I presented the data at the APCCC conference in Lugano, Matt, and you know that that's a congregation of the world's experts and virtually no one was using it. But then the paper has come out in the New England Journal, and it is really developing an interest amongst the clinical community. And we have started to use it in our clinic, but we have the problem of the off-label question which you've raised, and we have to address that and get it into mainstream, I think.

Dr. Matthew Cooperberg:

A few questions in the Q&A about prophylactic breast radiation for patients embarking on this approach. This is recommended, optional, something that we use only if there is onset of early symptoms? Any thoughts?

Dr. Paul Schellhammer:

Yeah, I'll take that because I recommended on the patients for whom I prescribed transdermal estradiol, I had prophylactic one dose radiation therapy to minimize the enlargement but, and the two points, an additional that were mentioned, the couple issue, and I can speak personally and relating stories from others, that the significant other is much, much life improved from having a partner who is not consumed with hot flashes, awakening, and some degree of depression. Also, with cognitive function, executive function for younger men who need to continue a occupation, not only for their own professional advancement, but for their economic well-being, they can be significantly dampened with ADT. And I can personally say I functioned as a reasonably good urologic surgeon using transdermal estradiol. These are two things that are not necessarily explained to patients in a way upfront that I think are embraced with well tolerated, that two words that are overused in the discussion of LHRH ADT.

Dr. Matthew Cooperberg:

Who would like to go next amongst our advocates?

Leszek Izdebski:

I can go. So my question is kind of two-part question. Most of the conversation about managing side effects using estradiol patch to manage side effects was focused on protection of bone density loss and hot flashes. Is there also benefit related to cognitive functions or so-called brain fog as very often patients talk about? And the second part, have you seen any evidence, because obviously there are different paths used to limit testosterone of greater or lower time of castration resistance development in cancer?

Professor Ruth Langley:

Well, I can start with the cognitive function. I mean, I think as we've heard today, there is a real issue that patients experience. We didn't formally do those kind of tests within the studies that we've completed so far, but we would really like to do that in studies to come. And there's sort of anecdotal evidence, but I don't have anything more than that at the present time. I don't know, Noel, if you'd like to take the second part.

Professor Noel Clarke:

Yeah, I think there's plenty of evidence in women, that reintroduction of estrogens does overcome that brain fog problem, but we need to prove it in men. So in relation to the castrate resistance question, if one looks at the older studies which we referred to, and classically this is the Bayer study looking at oral estrogens, when looking at the prostate cancer specific survival in that study published in 1976, a culmination of several studies, the prostate cancer specific survival was longer, but the cardiac death rate was higher. And now we are about to analyze the M1 data for the patch study, and that might give us a feel for whether patients are off, or should I say, are responding to an anti-androgenic approach using a patch by comparison with a GnRH analog. We'll have to report back on that. We just don't know. What we can see at the moment in the M9 population is equivalence in overall survival and metastasis-free survival, which is an encouraging sign, I think, but the overall follow-up is probably too short to be definitive about it.

Dr. Matthew Cooperberg:

We have one important question here. The fact that these are transdermal patches, are there any issues in terms of chronic administration through the skin? Is there any adaptation in the skin? Does the skin become less absorbent over time? Is there irritation? As treatment goes on for years, are there any dermatologic concerns?

Professor Ruth Langley:

I can take that one. And there are some patients who find that the patches do irritate their skin and chose to come off them for that reason, but it really wasn't many. And if you think about how well the patches are used in women and how many women use them, I think that generally, I don't want to use the phrase well tolerated in terms of... But we didn't see people coming off over time. If they did have any skin irritation, it was a fairly early event and then they just swapped back to the injections.

Dr. Matthew Cooperberg:

Another one here, and there may not be great data on this, but patients with a BRCA mutation, is there increased risk of male breast cancer if they use estrogen treatment?

Professor Noel Clarke:

So the BRCA mutation rate, as you know, Matt, in this group of patients, runs at about between two and 5%, and we didn't formally test for that. These are studies which we're looking at now going forward. But one thing that we are looking to do is, and we've got the scans and we've got all the biochemistry and so on, is to pull together all the tissue from as many of the patients as possible. So we could conceptually look at that, but we don't have that data at the moment, I'm afraid.

Nathan Roundy:

Yes, thanks. So in the paper it says that only 8% of the participants received prophylactic radiation, and it says that there was no difference between the irradiated group and the non-radiated group. So do you interpret that to mean that in this study there was no benefit in getting radiation prophylactically?

Professor Noel Clarke:

I think that's the message, Nathan, that we didn't see benefit in prophylactic radiation, but it was only 8% of the population. Having said that, it was a large scale trial, so 80% of a large number is actually quite a large number. So that is slightly discouraging, I think, in looking at that as a prophylactic treatment to prevent the problem.

Dr. Paul Schellhammer:

Noel, was it always given prior to the initiation of the patch? Because I think that's an important point. If you begin and then receive the radiation, the effect may not be as critically manifest.

Professor Noel Clarke:

Yeah, I think that's a very germane point, Paul. I think that the timing of the radiation is quite variable in our study. I think that's fair to say, Ruth, isn't it?

Professor Ruth Langley:

Yes, I think so.

Dr. Matthew Cooperberg:

There's a number of questions here about cost, and maybe I would ask Paul to comment on this. Being that this is still off-label, my sense is the out-of-pocket would typically be around 150 to $200 a month. Does that sound about right?

Dr. Paul Schellhammer:

Yeah.

Dr. Matthew Cooperberg:

Have folks had success with these GoodRx type services?

Dr. Paul Schellhammer:

Yeah.

Dr. Matthew Cooperberg:

Mark Cuban and [inaudible 00:17:49].

Dr. Paul Schellhammer:

Yeah, Mark Cuban, it's about $120 a month with shipping. I, prior to my current status, was receiving it through my Anthem Blue Cross Blue Shield Part D for many years with a letter referencing the publications and stating the physician's support of it. So I think insurance companies recognizing the cost savings will often cover it. This is for veterans. When I lost my Part D because of the decisions made by Anthem, being a Vietnam veteran, I now receive my patches through the VA. So for those who might be in that ballpark, that's an avenue. Matt, you probably know more about that being at the VA right now.

Dr. Matthew Cooperberg:

Well, then the VA, of course, led the original oral estrogen trials back in the 1970s.

Dr. Paul Schellhammer:

Yes. Yes.

Dr. Matthew Cooperberg:

So it's, yeah. And that is an option. There's a question whether any trials have been done in Black men. Not to my knowledge. The panelists can comment, but I would say that for the most part, as trials that are out there in other contexts have been subseted, once we know grade, stage, PSA, former treatment history, et cetera, there are not typically substantial differences across outcomes according to race in the case of prostate cancer once we get into advanced disease. I don't know if anyone else has other comments on that, but I'm not aware that there are specific trials ongoing here for Black patients.

Bruce Zweig:

I could do one more question.

Dr. Matthew Cooperberg:

Please.

Bruce Zweig:

If anyone would comment, some people say that you can use the tE2 patches in addition to ADT, like Orgovyx or something like that, to alleviate some of the symptoms. And is that something that you recommend or do you have a response on that?

Professor Noel Clarke:

Well, it's an interesting question, Bruce, and it's not something which has been explored to my knowledge in any great detail. So if you look at the hormone synthesis pathway, as Ruth mentioned in her first and second slides, the estrogen does the heavy lifting in this regard. And whilst we're looking at a testosterone suppressing dose, the question remains as to whether the use of estrogen in combination with an ADT or any other type of anti-androgenic might ameliorate some of the problems, hot flushes and so on. And I think theoretically it may well do. Conceptually and scientifically, that would have to be proven in a larger scale study. It wouldn't need a huge study to do it though, I don't think.

Professor Ruth Langley:

There is one relatively small study that's looked at using an estradiol gel. I believe that they saw a reduction in hot flushes, but their primary outcome measure for that study was overall quality of life where they didn't see significant differences. Otherwise, the literature is very, very modest on this, I think.

Leszek Izdebski:

So this question came from our discussion before the session, trying to think about different strategies to manage different side effects, because each of those treatments have very different side effects. Is there a valid strategy in managing combination of two treatments or switching between two treatments as well is another strategy, ADT versus estradiol?

Dr. Paul Schellhammer:

I'll say that the primary focus of both transdermal estradiol and LHRH analog is reducing testosterone to castrate range, which by NCCN is less than 50. From my personal preferences, and I think accepted more now, less than 20. So I mean, that's been the sine qua non of androgen deprivation therapy since, I'll say, ADT was introduced into the playing field of therapy. So whether it's accomplished by one or the other from the standpoint of testosterone lowering, I think there's an equivalence. And I'll throw in a little curveball and I'd like to hear what Matt has to say.

We use now monotherapy, and we know that men on monotherapy develop breasts because their testosterone goes up because the blockage and the feedback response, and when your testosterone goes up, more estrogen is made, and so that's reflected in gynecomastia. So we have kind of a natural experiment of combining estrogen with an ARI with no apparent, in at least the EMBARK trial, adverse events. So I mean, I feel that the idea of doublet therapy being somewhat hazy is an overdone objection viewing the biology that we know about estrogen and its purpose and role in our natural everyday manly life.

Dr. Matthew Cooperberg:

[inaudible 00:23:58]. Question for me, I think it's a space we're going to have to continue to track because as you say, singlet therapy, ADT monotherapy has really fallen out of endorsement in most domains where ADT is indicated in the prostate cancer journey at this point. It's still used quite frequently across the country. In urology practice, maybe a little more than oncology practice, but we definitely see it. As doublet and even triplet therapy becomes more standard, I think we're going to need to continue to monitor to see if there are differences. But conceptually, the idea that the testosterone is effectively driven down to a castrate level and then you're layering in RPs, chemotherapies, HRR directed therapies, whatever the case may be, the mode of getting testosterone down presumably should not matter too much within each of those contexts. That's the assumption, but it is something we'll need to continue to test, I think.

We are near the top of our hour. Maybe I will ask for concluding comments from each of our panelists, including your thoughts on where this field should head and what the open research questions are as well, what we need to do next. Maybe we'll start with Paul.

Dr. Paul Schellhammer:

Well, yes, I think the primary discussion that is had with the patient is the deal breaker because if it's introduced as a female hormone that's going to grow breasts, my gosh, all American, all European male is going to head for the hills. So it's, I think, incumbent on physicians to take a deep breath and look at the pros and cons in a very deliberate and honest fashion in transferring that shared decision, discussion with their patient.

Dr. Matthew Cooperberg:

Rohit, what about you?

Dr. Rohit Bose:

I think the more... We're still driven towards gonadal testosterone suppression, and then now basically it would appear that we have a third reasonable way to do it beyond GnRH agonist and antagonist. And so I think understanding how that's going to be used in combinations, how that's going to be used in more advanced disease in the castration resistance, as we were talking about earlier, I think it's only useful to have these, and we've talked about approval and adoption. I think it's useful to have different options with different side effect profiles, and then we can allow patients to help us choose the best options for them given the data. So I think in that frame of mind, it's a good thing to have. We always need more options than what we have. We don't have the adequate treatments in our arsenal.

Dr. Matthew Cooperberg:

Ruth to Noel, final word?

Professor Ruth Langley:

When I think of... Well-

Professor Noel Clarke:

Yeah, go on Ruth. I'm sorry.

Professor Ruth Langley:

All I would ask is this is about shared decision-making, and one size of ADT doesn't fit all, and I think that we've got more data to come to really help with this discussion. I think Noel, would you like to add as well?

Professor Noel Clarke:

Yeah, I just think that this is an under-researched area and has been an under-researched area for many years, and that is what is the underlying etiology behind the side effects that men suffer when they're being treated with ADT? We know that some men aren't affected at all, and others are very badly affected, and we have failed to realize the metabolic consequences and act appropriately. I think what we now have is the opportunity to study this in some detail, questions like what's the influence of basic body composition on development of gynecomastia? What is the underlying endocrine functionality which brings about hot flashes in some men and not in others? And I think this will make a big difference to patients because the ADT question, well, we can suppress ADT, we can suppress testosterone in a variety of ways. We're making patients live a lot longer. Can we make them live a lot better? And I think that's a good goal to aim at.

Dr. Matthew Cooperberg:

Wonderful. Well, that is a wonderful place to end. Thank you so much. Congratulations again on the study and the paper. Thank you to our panelists. Thank you to the patient advocates, and thank you all for joining us. We hope to see you soon. We are targeting our next installment, hopefully in the next month or two, and are tentatively timing on the PROTEUS trial. So lots more exciting material to cover. Thanks all for your attention, and see you at the next installment.

Professor Noel Clarke:

Thank you very much.