Dr. Matthew Cooperberg:

Good morning. I am Matt Cooperberg from the University of California in San Francisco. It's a pleasure to welcome everyone to another installment of the UroToday Prostate Cancer Journal Club for Patients, where we are presenting groundbreaking and practice changing major papers from the literature as presented by the lead authors of these papers. This is a joint initiative with our patient services corps at UCSF and the leadership of that core who are joining us here on the call today. Our format, we will have a presentation from lead authors followed by commentary and then Q&A, some of which we have some prepared questions and then we'll take questions from the floor as well. So everybody attending as we go, please use the Q&A function in Zoom if you have any questions for the presenters. So today we are going to be distinct, the PATCH Trial using transdermal estrogen as an alternative to standard forms of androgen deprivation therapy.

This has been, I think, a long time coming and many have been tracking this story for many years as it's been unfolding. It's a real honor and pleasure to be joined by the lead authors of the paper which came out in the New England Journal earlier this year, Transdermal Estrogen Patches in Locally Advanced Prostate Cancer. So joined by Professor Ruth Langley from University of College London and Professor Noel Clark at the Christie Hospital in University of Manchester. We will then have a commentary from Dr. Paul Schellhammer who has long been a luminary in the prostate cancer world, is currently director at Urology of Virginia and has a unique perspective from a patient vantage point as well. And we're also joined by Dr. Rohit Bose, who is one of the medical oncologists with us here at UCSF. So without further ado, I'm going to pass it over to Professors Clark and Langley to present the study.

Professor Ruth Langley:

Good morning. First, I'd like to thank the organizers for inviting us to give this presentation, which we're doing on behalf of the trial management groups. So the transdermal estradiol PATCH program is aimed at improving lives of men with prostate cancer by personalizing androgen deprivation therapy. And this is a really important issue. As outcomes improve with prostate cancer, we need to think about minimizing side effects and protecting long-term health. Androgen deprivation therapy is very commonly used. Approximately one in two men with prostate cancer will receive androgen deprivation therapy at some point during the course of their treatment. And the aim of androgen deprivation therapy is to reduce testosterone. It's most commonly achieved by giving GnRH injections and that lowers testosterone effectively.

But what is less well appreciated is that when you lower testosterone, you also lower estradiol. So you get a dual set of side effects. You can see that by lowering estradiol, you have effects on bone health, cardiovascular risk factors, hot flashes, and this decreases quality of life scores. An alternative is to use estradiol. That will lower testosterone, but you can see from this slide that by maintaining estradiol, all the side effects in the second box are mitigated. And this is not a new idea. It was first tried out using a tablet of estrogen. The most common one was stilboestrol. But the issue is that when you take a tablet, it goes into your stomach and then into the liver. And this is called first pass hepatic metabolism.

When drugs hit the liver, there's often an interaction. And in this case, this increased blood clotting factors and this led to an increase in cardiovascular side effects. It was Professor Paul Abel from Imperial College London who's sadly not with us anymore that thought that if we can give estrogen through a patch or a gel, the estrogen will go straight into the bloodstream. And by going straight into the bloodstream it will avoid the liver and therefore you'll get the beneficial effects on prostate cancer, but you'll avoid the cardiovascular side effects. So this was the start of the PATCH program, which has been a randomized phase two, three adaptive trial. The key thing about all the data that we're going to show you is that the patients were randomized between either receiving estradiol patches or LHRH agonists or GnRH agonists.

We use LHRH in Europe. We've got two phase three trials, one for patients with locally advanced disease and one for patients with metastatic disease. And it's the results of the trial for patients with locally advanced disease, which we're going to show you today. Importantly, we've been following patients for nearly 20 years. So all the patients that took part in the early part of the study are also in the later trials so that we can really see what happens when people were given the estradiol. And we were delighted in 2017 when the STAMPEDE team, seeing the results that were coming out of this program, agreed to join the PATCH program and work with us.

So I'm just going to show you two bits of data before I hand over to Noel who's going to describe the M0 trial. The first one is around cardiovascular safety, and this has been really important because this was the key thing that we had to show before we could bring this approach into more general practice. And you can see from this slide that this was looking at major cardiovascular events and there was no difference between the two groups of patients, and that was published in the Lancet in 2021. We were also able to show in this publication that key cardiovascular risk factors such as a high blood glucose, high cholesterol and blood pressure were all worse on the LHRH agonist as compared to the patches. And these were quite significant results as you can see.

We've also been publishing data on bone health, and you can see from this study, which was published in 2016, it was measuring bone mineral density, which is really the strength of the bones. And you can see that the patients that were receiving the estradiol patches, which is the lines in blue, their bones were effectively getting stronger while there was a decrease in bone mineral density for the patients who were receiving the LHRH agonists. And this is our latest data. It's not yet formally published, but we've been able to use electronic health records and follow the patients for long periods of time. We've got over 700 patients in this particular study, and we can see that there's a substantial reduction in bone fractures for the patients that received the patches as compared to the GnRH based approaches. So with that as background, I'm now going to hand over to Noel, who's going to go through our recent publication.

Professor Noel Clark:

Thank you, Ruth. And what I'm going to show you now, we were lucky enough to be able to publish the data on the M0 component of the trial in the New England Journal of Medicine [inaudible 00:09:33]. And as Ruth has said, this was in high risk locally advanced prostate cancer patients undergoing radiotherapy to the primary site, what we call the stampede type high risk. So these are patients who've got a very high risk of progression of disease without treatment. And they were randomized to the patches against GnRH analogs for the standard of care, usually for 24 months in Europe in addition to radiotherapy. The patches were started with four patches twice-weekly. And when the testosterone level got down to what we define as castrate levels, we would reduce the patches number to three twice-weekly.

And these were extremely well tolerated by the men. And our endpoint was metastasis-free survival, which has been shown to be a direct correlative overall survival. And randomization confirmed. We were looking at non-inferiority. In other words, was the patch-based treatment the equivalent to the GnRH equivalent? And this was a very well-powered study with large numbers of patients followed for long periods. You can see the number in the trial, about 1360 patients randomized from 75 UK sites, and the baseline characteristics were pretty well-balanced between the groups, LHRH and tE2, for that total of 1360. The median age of the patients was a little older than had been seen hitherto with the PATCH study. For example, with the abiraterone component PATCH, the median age was about 68, and in the PATCH study it was 72 and a median PSA of 24 with quite a wide range. About 85% of the patients had T3 disease clinically, and 65% were N0.

When we look at the primary outcome, metastasis-free survival, the median for LHRH was metastasis- free survival is pretty much equivalent. As you can see the overlapping lines on the Kaplan-Meier curve with a three-year MFS rate of just short of 89% for the GnRHs and 87% for tE2. So equivalent in terms of a key prostate cancer outcome metric. And when we looked at the secondary outcome, this is overall survival. This is not prostate cancer specific, it's overall. You can see again that there is really equivalence in the two different treatments. We had a number of secondary outcomes, and the first I'm going to show you is the castration rate. And this is shown in this table at baseline at one month, three months, six months, and 12 months. And what we can see at baseline, the tE2 brings the testosterone down rather more quickly than the GnRH analog, as we probably would expect.

But at one month, 83% of the patients had castration. This was sustained at three months when we had 93% and out at 12 months, showing that this is a very efficacious way of suppressing the testosterone and is easily equivalent to the standard of care in most countries with GnRH analog therapy. And you can see how that castration rate stained in this Kaplan-Meier here. We're looking in the first year, but then in the patients, and we've got quite large number of patients out here from randomization, you can see that there is equivalence in castration rates. So this is really quite reassuring when it comes to asking the question, is a patch equivalent to what is used in the majority of cases? And the answer is yes. Coming to the question of side effects, and two of the major side effects we're looking at are with GnRH analogs and patches are gynecomastia and hot flushes.

What we found was the gynecomastia rate was higher with the patches. It was about 85% in the tE2 and 42% in the LHRH analogs. But when we factored that for the rate or the degree of gynecomastia, what we found was that in this central area around grade two events, this was running at about 35%. There weren't any to speak of grade three events. When we looked at hot flushes, these were reduced quite significantly by about a half. And that again fell into that area really where men are having real trouble. About a third of the men here, there was a reduction right down in the patch proportion to 8%. So a substantial reduction in the rate of hot flushes, and this is a symptom which bothers men quite considerably as we all know, both as patients and doctors. The question to raise is what does gynecomastia mean for me, the patient?

And in most circumstances, this is a yes or no question. In other words, if gynecomastia exists, then yes, it's put down as a complication. But the question really is to what extent does the individual patients suffer from gynecomastia? And this is a very interesting paper just published recently, and our discussant, Dr. Schellhammer, was involved in this study. And this looked at gynecomastia in men undergoing estrogen treatment in the transsexual community. And the fascinating thing about this was that when we look here at the histogram in the bottom right and you look at the bra cup sizes, then the great majority of men, whilst they may get gynecomastia, don't get it to a high degree. It's really quite modest. And this is a factor which is important for the subjective understanding of patients. If they're told they're going to develop breasts, well, most men would say, "I don't really want that." But if it is made clear to an individual that the degree of gynecomastia, whilst it happens, it is really quite modest.

So in conclusion, what we can say from our publication in the New England Journal of Medicine is the tE2 patches should be considered as a new standard of care for ADT in locally advanced prostate cancer where we know that this group of men get significant symptoms from the use of a GnRH analog. There are equivalent prostate cancer outcomes to GnRH analogs, and the benefits are significant in relation to bone health, cardiovascular risk factors, fewer hot flushes, and quality of life. Although there are higher rates of gynecomastia, this is relatively modest in the majority of men. And equally, when considering the choice of the mode of administration, most men will think that using a patch is a superior way of receiving treatment than having a monthly or three monthly injection. Thank you very much.

Dr. Matthew Cooperberg:

Thank you so much for that presentation. Very exciting results. We are going to move now to Dr. Schellhammer for commentary.

Dr. Paul Schellhammer:

Yes, yes. Thank you for the opportunity to speak. And you've heard from Dr. Langley and Dr. Clark the best scientific evidence which is necessary to guide the best clinical care, namely a large multicenter randomized trial subjected to statistical rigor showing that transdermal estradiol ADT is an alternative to what we'll say standard. Now, I'm going to add a personal touch to the science because it's what does touch the individual patient's lives. And I will say at the outset, were I not a physician, a urologist, and focused on prostate cancer with the contacts that were available, my story would've been very unlikely. So in the year 2000, I was diagnosed with prostate cancer, had a prostatectomy, had early PSA failure, had salvage radiation and six months of Lupron androgen deprivation therapy. Three years later, PSA rose once again, and I went on continuous LHRH therapy. 2008, castrate T, but a rising PSA.

What to do? Options very limited at that time. I consulted with Dr. Charles Myers and he tuned me into this information that was coming from the UK with regard to transdermal estradiol. And as you've heard, there were large studies from the veterans trial using oral DES. They were successful in managing and controlling cancer, but the cardiovascular side effects overwhelmed the benefit, so it was put aside. Transdermal, through the skin delivery, as Dr. Langley pointed out, obviated these significant cardiovascular thromboembolic effects, so it was safe. I started the patch, and while certainly one could debate how it affected my disease course with regard to cancer control over the past 18 years, I can say there is no debate how it affected my quality of life. My hot flashes resolved, my sleep improved, energy rebounded, fatigue disappeared. I felt alive, I felt well, and my wife very much agreed.

So fast-forward five years, 2013, bone scan shows metastatic disease. I was very much interested in a new trial that was combining abiraterone and enzalutamide for men with metastatic castration-resistant disease. But the requirement was to stop my estrogen ADT and begin, once again, LHRH analog ADT. I did. I did not feel well and received that happily, but I was intent on entering the trial, and I did. But after six months, unfortunately, it closed because of the endpoints did not reach appropriate significance. And I was disappointed as any clinical trialist would be, patient or physician conducting same, but I was looking forward to resuming my transdermal estradiol and putting my LHRH in the back mirror, and I was rewarded. I felt well again. And sometimes memories fade, so I am happy that at the time I recorded this back to wellness feeling in a brief commentary I had written on transdermal estradiol therapy.

So since then, I've been fortunate to experience and benefit from other therapies, metastases-directed therapy, provenge immunotherapy, and most recently a course of Pluvicto. Getting to some of the issues that Dr. Langley and Clark mentioned when I speak with physicians, there are two circumstances that pop up, the gynecomastia question and bone health. And you've heard the gynecomastia issue discussed. All ADT therapies produce some form of gynecomastia, maybe more with transdermal estradiol, but there's the opportunity for pre-therapy prophylactic radiation to minimize hopefully the changes, and if severe enough, a expeditious same-day surgical procedure can warrant some very satisfactory outcome. Now, I know surgery is something everybody wants to avoid, but I look at this as a cosmetic external issue balanced against a long-term metabolic health issue. And you've heard the report from Dr. Langley about cardiovascular health, metabolic syndrome, lipid profiles, blood pressure elevated, insulin insensitivity. So in the discussion, that shared decision model discussion, it's really important to deal with subjective fears versus the objective reality of future health.

Then a word about bone, because physicians will say, "Well, we have bone protective agents." Well, the data shows, yes, they are useful, but still, especially with doublet therapy, bone deterioration occurs, osteoporosis and osteoporotic fracture. I am 86 years of age. My DEXA scan last year had a T-score of plus 1.5. That indicates that I have 1.5 standard deviation bone mineral density above that of the reference standard, which is a 40-year-old man. About three months ago, I took a rather twisting jarring fall. I broke a bone in my foot, one of the small metatarsals, but I was able to get up and walk away with both hips intact. Now, someone listening to this discussion I think would say, "Geez, what is the cost of this agent with all its benefits?" And I think they'd be surprised and pleased to learn that it can be delivered at a cost of three, four, five times less than the standard.

So I'll sum up by saying that androgen deprivation therapy with transdermal estradiol is a very valid alternative to the current regimens. It preserves quality of life, bone health, cardiovascular health, metabolic health. It is cost-effective, and it does fulfill the pledge of first do no harm, or at least minimize the harm that our therapies deliver in our efforts to delay disease progression and cure. So I thank you for the opportunity to recount my story for you this morning.

Dr. Matthew Cooperberg:

Thank you so much for the perspective, for sharing your story-