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Tom Keane: Good morning, everybody. This is Tom Keane coming to you from UroToday and from the Medical University of South Carolina. Today, we have a real treat, professor, Heather Payne, and it is wonderful to have you here, Heather. Please take it away.

Heather Payne: Thank you so much. It is a great pleasure to be sharing this with you today talking about the trials and tribulations of the management of metastatic hormone-sensitive prostate cancer. And I think if we'd had this discussion 20 years ago, this would have been a very short talk. These are my disclosures. And the reason that it would have been a very short talk was that 20 years ago, we treated men who presented with metastatic disease with ADT, androgen deprivation therapy, alone. And as a young registrar, this was something that I felt very confident in treating, and we saw great results. By reducing testosterone, men felt better, and their symptoms improved. However, after two to three years, cancer became resistant and came back. And in those days we were left with very few options for what was then called hormone-resistant prostate cancer.

Now, why is it important to treat this stage of disease? Well, certainly the number of men presenting with metastatic disease is going to vary from one place to another. In the UK, it is somewhere currently between about 13% and 18% of men present with metastasis at the time of diagnosis and 40% of prostate cancer-related deaths are in patients with primary metastatic disease.

Is ADT enough? Well, I think my battle cry and the purpose of this talk is that we now have compelling data to determine that indeed, ADT is not enough for these men presenting with metastatic disease who are fit and willing to receive additional treatment.

So this is a much-used slide, and the hypothesis as to why these chaps relapse after initial ADT, is that right at the very beginning of treatment, there are already resistant cells. We treat the hormone-sensitive clones, they get better, they regress, the PSA goes down. But these resistant, hormone-resistant clones continue to grow and they reemerge and then become the driving force with the progression of cancer.

And the initial studies showed that adding docetaxel to ADT improved survival, and these were tremendous results. We're going back 10 years now, but the addition of six cycles of docetaxel showed this significant improvement in overall survival, both in the CHAARTED study and in the STAMPEDE trial and the STAMPEDE study gallops along with initially six different arms added to ADT and this was the docetaxel arm showing a significant improvement in overall survival for patients presenting with metastatic disease.

Now, the CHAARTED study, and later the LATITUDE study, which we will come onto, gave us for the first time different categories of metastatic disease with high volume in CHAARTED and high-risk in LATITUDE. And this divided patients up, certainly with high volume, they needed to have at least one of four or more bone mets with one or more beyond the vertebral bodies and pelvis and/or visceral disease.

And one of the interesting things in the CHAARTED trial was that although it showed significant survival benefits for men with high volume disease, the low volume or low burden group did not seem to have any benefit. This may be something we will discuss later, but CHAARTED wasn't really powered to look at these two subgroups. STAMPEDE did a retrospective analysis on what is, without doubt, a prospective study and they reallocated all the patients who had docetaxel to high or low volume and this data showed that all men with metastatic disease, irrespective of volume, had a survival benefit when docetaxel was added to ADT. Now, docetaxel can have significant side effects for some men. And certainly, in the UK, only 36% of men were having additional treatment with docetaxel despite these phenomenal really durable increases in survival because they weren't fit and willing.

So what about the androgen receptor-targeted agents? What would happen if we added those to ADT? We know that abiraterone, and enzalutamide give very good results in castrate-resistant prostate cancer.  What if we added those at the beginning because we know that resistance to ADT may develop due to androgen synthesis by the adrenal gland or the prostate cancer cells themselves, abiraterone, and enzalutamide giving triple block to all of these three pathways. And so we saw in the STAMPEDE trial again, which went on to have an abiraterone arm, and the LATITUDE study that adding in abiraterone and prednisolone, five milligrams daily to ADT, again, significantly improved long term overall survival.

And I think it's very interesting that these two different studies have similar hazard ratios, .61, .62, showing this survival benefit perhaps for those men who may not have been suitable for docetaxel. And this STAMPEDE data presented long-term with a six-year median follow-up of ADT and abiraterone versus ADT alone. And the results of this long-term follow-up showed an almost three-year improvement in overall survival by adding abiraterone and prednisolone early.

If we compare this, there was a part in the STAMPEDE study...there was a period of time when men could have been randomized to ADT alone, ADT and docetaxel or ADT and abiraterone. So looking at this period of time, we can see here that the group who were treated with abi and pred actually had a more durable response, and you can see those Kaplan-Meier curves in the top continue to separate where the curves are coming together with docetaxel.

There was also, I think this was one of my favorite Kaplan-Meier curves of 2020, but this is a lovely study looking at the global quality of life. And certainly, if we are adding extra drugs into ADT for these men, we have to be able to maintain their quality of life because they are going to be taking this therapy for many years. And this study looked at the quality of life in men from the STAMPEDE study, they were randomized to abiraterone or docetaxel during this contemporaneous period. And we can see, we expect the quality of life goes down a bit with docetaxel while they are having treatment. But what I didn't anticipate was that it would take a year for the quality of life to return and that it never quite caught up with the abiraterone arm. So the abiraterone group showed a maintained and better quality of life when added to ADT compared to docetaxel added to ADT in this study.

We have a saying in England that, if you wait for a bus for a long time and then three come along, and we now have the next two buses, the ARCHES study hot off the press reported at ESMO this year. This trial was ADT and enzalutamide versus ADT and placebo. And again, the addition of enzalutamide to ADT shows this 34% improvement in overall survival, and obviously abiraterone, and enzalutamide have different side effect profiles, allowing us the choice of the best androgen receptor-targeted agent for our individual patient.

The third bus was the TITAN study. This looked at a newer androgen receptor-targeted agent, apalutamide with perhaps less blood-brain penetration. And the TITAN study, again randomized apalutamide and ADT to placebo and ADT, and also showed a 35% reduction in the risk of death. And this quality of life study in TITAN with apalutamide showed that health-related quality of life was preserved with apalutamide in ADT and actually wasn't different from placebo and ADT. So we've just hit two boxes, significant improvements in the overall survival, the length that our men have to live, but by adding these drugs, we're not reducing their quality of life.

And then also from STAMPEDE and indeed many other trials, such as the [inaudible 00:11:33] study, we discovered that treating the primary tumor, treating the prostate with radiotherapy for low volume disease, not high volume, but for the low volume disease, this also increased overall survival and life expectancy.

So what are our current options for metastatic hormone-sensitive prostate cancer? Well, the ESMO and the EAU guidelines say this is strong evidence, and I certainly do believe that it is and that we should offer ADT combined with docetaxel, enzalutamide, abiraterone, and prednisolone, or apalutamide for all men who are fit and willing to have these additional treatments. And, that we should also offer prostate radiotherapy just to the gland alone at the present time to men who have low volume or low burden disease at first presentation.

So does this happen? Are we actually offering our patients these really important and life-prolonging treatments? Well, there are a number of reports from all over the world. This was a real-world evidence study from the US looking at treatment patterns in the first presentation of metastatic hormone-sensitive prostate cancer. And in this study, 62% of men had ADT alone, only 8% had the additional docetaxel, and 6% had the addition of abiraterone, although these drugs were available.

So why doesn't every man have additional treatment? Well, I think it's going to vary depending on where you live and practice, but I think for many of us it's been the availability and the funding of these drugs and perhaps education of these huge differences that this combined treatment and early treatment can give. Certainly in the UK, we only had docetaxel until the COVID pandemic when we were allowed to give enzalutamide and I'm going to talk about this in a little while with a case.

Now, just when you think you have it sorted, along came this study PEACE-1, and this study recently presenting both at ASCO and then recently at ESMO, and it was a two-by-two factorial design in men looking at whether the addition of abiraterone and/or local radiotherapy improved outcomes, especially survival in men with de novo metastatic hormone-sensitive prostate cancer. And we saw that there was a significant improvement in radiographic progression-free survival at ASCO. I think this is a very interesting study and one I'm sure that Tom will want to talk about a little bit later, but the great thing about this trial was that the investigators changed their standard of care arm. It was initially ADT alone, but with results of docetaxel from CHAARTED and STAMPEDE, the standard of care became ADT and docetaxel, and abiraterone and/or radiotherapy was added to this new standard of care.

And in PEACE-1, there was a 25% reduction in the risk of death with the addition of abiraterone to docetaxel, and ADT versus docetaxel and ADT alone, even when 84% of men in the control group received at least one life-prolonging therapy. Now, I think one might perhaps argue that the standard of care changed again, it became ADT and abiraterone rather than ADT and docetaxel for many of us who were able to prescribe these drugs and I'm sure this study is going to continue to cause a lot of discussion as to whether or not we consider triple therapy is better than double combined treatment.

Now, I would like to introduce you now to Brian. Brian is one of my patients. He's a 67-year-old man. He is married with three children and he's a retired architect. Brian has always enjoyed extremely good health, he's fit and active with a performance status of zero. When he was questioned, he had a little bit of lower urinary tract symptoms, but nothing of any significance. Now, Brian has been well trained, he has an annual PSA every year. And for the last seven years, this has been extremely stable and measured less than two.

But in May of this year, he went along for his usual annual health screen and his PSA had increased to 9.3. It was rechecked and it was 12.1. He was then referred to my local urology colleagues. He did some other blood tests and sadly found that his alkaline phosphatase was also elevated at 176. So Brian had an MRI scan, he had bulky locally advanceable prostate cancer invading both seminal vesicles, and he had a PSMA PET scan which confirmed the activity in the prostate and seminal vesicles that showed some spread to the pelvic lymph nodes in the right internal iliac region and also to the common iliac nodes. But in addition, he had three bone metastases in the right inferior pubic ramus, L1 and L3. We did a couple of targeted biopsies and these showed high-grade Gleason, 4+5 [inaudible 00:18:20] carcinoma.

How did we treat Brian? Well, as I was saying earlier, prior to the pandemic, we only had the option of adding in docetaxel and only 36% of men in England and Wales actually received docetaxel, the rest having ADT alone, despite the evidence. During the pandemic, NHS England and NICE produced rapid guidelines recommending a switch from intravenous treatment to oral alternatives, where this would be beneficial to reduce time in hospital and optimize clinician resources as many of us were deployed to work on the COVID force. They also added that the concomitant use of steroids should be reduced if possible, again due to the risks of immunosuppression.

So we were for the first time allowed to prescribe an androgen receptor-targeted agent for hormone-sensitive prostate cancer and the recommendation was that we treated with enzalutamide. If somebody was unable to have enzalutamide, for example, if they'd had seizures in the past, we could give abiraterone. So when I met with Brian, he had three options. He had ADT alone, ADT and docetaxel, ADT, and, in my circumstances, enzalutamide, triple therapy, or local radiotherapy to the prostate. And I think that when we are treating with hormones, especially with double hormones, we need to very carefully monitor the toxicity, especially bone density. We need to give additional treatment to prevent osteoporosis, osteopenia and to carefully monitor the metabolic and psychological complications of systemic treatment so that our chaps can really live their lives to the full without these toxicities.

So Brian was treated with enzalutamide, ADT, and radiotherapy to his prostate. He had lifestyle counseling and an exercise program, which he actually quite enjoyed, and made friends with some of my other patients and they formed a little gang. We monitored his lipids, glucose, and blood pressure and I'm delighted to say that when I met with Brian just a few weeks ago, his PSA was less than 0.03, and his alkaline phosphatase was 68. He remains fit and well and despite having metastatic prostate cancer, Brian is enjoying his life. Thank you so much for your attention.

Tom Keane: That was excellent, that was really good. I mean, there is so much in that talk. It looks like ADT alone, that was a fascinating slide where you showed me that the vast majority of people are still getting ADT alone. And I think it's probably, I would not be surprised if it's the same case, maybe not quite as many, but I think the States are also, there are a lot of people who are giving ADT alone still. And I would agree with exactly what you said, I think it needs to be hit hard and hit fast and hit with whatever we have.

And I think the way you identified the chemo arms, yes, they are effective. They work very well. But I do like the androgen blocking agents, the ART receptor blockers. I think that's the way initially to go, just looking at the toxicity that you showed. And I think the combination of the three, I mean this year's ESMO, just listening to it and looking at it, was such a dramatic change that we haven't seen before. And of course, now there's a lot of these agents are basically not new which means that they will become freely available now and they will be a lot cheaper as things are moving down. I mean, that was one of the comments that was made at ESMO that none of these agents that we are talking about are necessarily brand new, so they should be becoming much more available to people at less cost, which I think is something that's wonderful to hear.

But I think overall, I mean, I love that radiation now has another home, if you like, that you can actually treat it and it makes total sense to radiate the prostate. I mean, I'm a big believer in the crosstalk that goes from metastatic to original sites there and back and I do think doing something with the primary is extremely important.

Heather Payne: And I guess we await some of the surgical studies as well, don't we?

Tom Keane: Well, I was about to say that, don't forget that we can still cut it out. But no, that was super. That was just a very good summary of where we've been and where we are now. There's been a lot of strides taken. It was interesting, I mean, we have enzalutamide, apalutamide, darolutamide, where are we going to end up with these? What's your opinion on that?

Heather Payne: I think it's difficult. Personally, I would treat with an androgen receptor-targeted agent rather than chemotherapy for the majority of my patients. Perhaps those men with really rapidly progressing disease or liver metastasis, or those men obviously who do not have a very high PSA, and I think they need to be biopsied because perhaps they should be having platinum-based chemotherapy if they've got small cell prostate cancer, but for the vast majority, I would give abiraterone, enzalutamide or apalutamide. At the moment in the UK, we have the availability to give enzalutamide or apalutamide, they've both been registered by NICE.

And I think it's probably, I'd be happy to give any of them, to be honest, the results are all very similar. It's good to have a choice. I think it would be good to have a choice with abiraterone as well for those men who have neurological problems and who perhaps you wouldn't want to give one of the antiandrogens to, and similarly for those people who have very significant cardiac problems or heart failure, you might want to give those enza or apa. So I think it depends on what you have available. The important thing is to give something because they are all improving life and that long-term STAMPEDE six years median survival when we were bushy-tailed and fresh, you tell people they would live for two years, and now we're talking about an increase in three years and all the metastatic CRPC drugs. So I think it's been an exciting time.

Tom Keane: It really is. But I also feel that chemo needs to be sorted out as to when to use it. And there has been a lot of talk about, well, we start off with the androgen receptor targeting agents and we do know that if you use one and then you use another, like the abi and enza, that came back and forth, if you gave one after the other when one failed, and this is in metastatic disease, it didn't seem to work. My own feeling is that I think the tumor changes, and I think that once you've failed one, then the next move may be with the chemo, because I do think you get a neuroendocrine type tumor that can develop as a result of the treatment and then you would switch back, give the chemo and then it may switch back again to being androgen sensitive. There's been some talk about that I'm seeing, but I don't think we know exactly yet. This is a huge step forward, but I think there is more to the story that still exists.

Heather Payne: I guess it's also important to say that it comes down to patient choice and there are those men who say, "If I'm going to have chemo at some point, I'd like to have it in the beginning and get it over with." And that's the right decision for them, but it's all about communication, isn't it? And I agree with you that prostate cancer evolves and changes, and we need to learn more about that. The new biomarkers coming through, I think, are going to change the whole scene again, aren't they? And obviously, we are waiting with triple therapy for ENZAMET and ARASENS [inaudible 00:27:45], and darolutamide, and docetaxel to see what that shows because the initial ENZAMET study with triple therapy didn't show any advantages for three treatments, and those men had worse side effects. So I think the whole PEACE-1 really shook us all up and made us rethink, but it would be good to get some more data.

Tom Keane: And it will be interesting as we move into the castration-resistant groups to see exactly where we are at that stage. I think that will be a different story also. Well, Heather, it's been wonderful, it always is. It's so good to see you. I can't wait to get back over to London at some stage and that will be lovely.

Heather Payne: You'll be very welcome.

Tom Keane: So take care of yourself and thank you for this.

Heather Payne: Oh, thank you.

Tom Keane: This was wonderful.