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Alicia Morgans: Hi, my name is Alicia Morgans and I am a GU Medical Oncologist and an Associate Professor of Medicine at Northwestern University in Chicago in the U.S. I'm so excited to have here with me today Dr. Lisa Horvath, who is the Director of Research at the Chris O'Brien Lifehouse as well as being a Professor of Medicine and a GU Medical Oncologist at the University of Sydney in Australia. Thank you so much for being here with me, Dr. Horvath.

Lisa Horvath: Thank you very much, Alicia. It's great to be virtually in the U.S.

Alicia Morgans: Wonderful. Well, we can't wait to have you here in person, hopefully by next year, but in the meantime, let's review a little bit about what you discussed at ASCO 2021. You were a phenomenal discussant on three abstracts, two in the metastatic hormone-sensitive setting, and one in the metastatic castration-resistant setting. Can you tell us a little bit about the abstracts that you reviewed, starting with those metastatic hormone-sensitive patients?

Lisa Horvath: Thank you. And it was fascinating reviewing these abstracts. They were quite a range, and I think there was quite a robust discussion, which is always good. The first abstract I reviewed was the PEACE-1 abstract, which was presented by Dr. Fizazi on behalf of the group. And that was really the first analysis from the two by two factorial design, which was looking at abiraterone and radiotherapy in the role in metastatic hormone-sensitive prostate cancer. And they were able to look at the abiraterone together due to a lack of interaction between the radiotherapy. This was particularly interesting because it was the first... It's one of the largest studies that has been able to look at the triplet therapy of ADT, abiraterone, and docetaxel. The overall cohorts show what we would expect from STAMPEDE and LATITUDE in de novo metastatic disease that there is a significant improvement in radiographic progression-free survival with adding abiraterone standard of care.

But in the subgroup analysis where they were looking at a large number of patients who had received a standard of care ADT and docetaxel, there was also a very significant improvement in rPFS with the use of abiraterone. And this improvement was in the order of two and a half years. It is a very large benefit and it is very interesting, but at the moment, there is no overall survival data to look into that. I think that the key aspect of this is, where does this put triplet therapy? So the ENZAMET study had a very similar design to the PEACE-1 study except using enzalutamide. And again, docetaxel was stratified for in the two arms, same sort of population, although ENZAMET was not all de novo metastatic disease, unlike PEACE-1. At the three-year analysis in ENZAMET, despite a very similar improvement in progression-free survival, there was not an improvement in overall survival.

There was a lot of discussion about how are we going to use this data, is the rPFS data sufficient to change practice? I think we need to wait for the overall survival data. It's very difficult to know at the moment the granularity, how many of these patients were low volume versus high volume, what was the difference in outcome in the high volume versus the low volume? What was the quality of life? There is a whole range of issues that I think we will get more information on in time. The other thing that is going to be very important is the ARASENS study, which is giving ADT with docetaxel plus or minus darolutamide, which will give us additional information as all of the patients upfront, not just a subset were receiving docetaxel.

Alicia Morgans: I completely agree. And I think it's so interesting to have you as a discussant because you were engaged in the ENZEMET trial. Of course, you disclose this as well. And there was, as you mentioned, a very similar separation of curves, but then the overall survival was just neck and neck in ENZAMET. So it was interesting to me in that discussion that you gave and, and certainly to think through, how do we decide to move forward? Because Dr. Fizazi was very passionate about this progression-free survival means a lot, and I think it is very meaningful, but at the same time, there are trade-offs in every decision that we make. And as you acknowledge, there are trade-offs potentially in terms of quality of life, taking four pills plus a prednisone every day, there are complications that we get from that besides the financial toxicity that some patients will face in terms of paying for these pills, that it was very, I think pressing to have you as an ENZAMET investigator commenting on that.

So I'd love to dig into that a little more. What are the things that you are looking for? Is there anything besides overall survival that would make that progression-free survival meaningful to you?

Lisa Horvath: I think from a statistical point of view, overall survival data is going to be very important, but I do think we've really got to look at more detailed analysis into risk stratification, and ICECaP and STOPCAP Group, I think, are doing an amazing job putting all of this data together because one study is not going to answer all the questions. We need to work collaboratively. The proposed risk stratification based on clinical criteria like de novo disease, visceral disease, high volume versus low volume, certainly is going to be the basis of the first part of it. But I'm a clinician-scientist, so I am passionate about what are the molecular subtypes. And we are already starting to get inklings of that. There is certainly emerging data that people who have p53 mutations and RB loss seem to do much more poorly. The p53 mutations in the recent Piet Ost study really demonstrated that there was a much higher prevalence if you had multiple metastases and de novo disease compared to oligo metastasis and metachronous disease.

So this is the tip of the iceberg where these studies are looking at transcriptomic signatures, immune signatures, lipidomic signatures, as well as the germline work to look at how we can molecularly pull apart these cohorts. We all know there are people that do really badly, no matter what we do. And we also know there are people who do really well, even if they are not on the trial drug. We all know that there are people who sit out at five and seven years on ADT alone. So I really think that we need to get more granularity about the populations from a clinical and molecular perspective. So we can start tailoring treatments to the individual patient.

Alicia Morgans: I could not agree more. And let's talk a little bit more about patients who seem to have really robust responses to initial hormonal therapy. Let's talk a little bit about the SWOG trial. What did you discuss? What were your thoughts on this particular trial?

Lisa Horvath: I think this particular trial had some really interesting elements. It was very sad for the investigators. They had done a massive amount of work to not reach the primary endpoint, I think is very hard, but they have clearly been able to do some really important things like with 10% of the population being African-American men on the study, and showing that this can be done in a mainstream environment. What is very interesting is how long both the control arm and the treatment group, that long median survival. It's a little difficult to tease apart because they used a different classification of extensive versus minimal disease rather than the standard high versus low volume to know precisely what the mix of good prognostic versus poor prognostic factors is. Certainly, they were not all de novo diseases, like PEACE-1. They had 25 percent who had had previous surgery. So we know there are some group prognostic factors in there.

But the second thing is, and this was mentioned by Dr. Agarwal, is that this is a cohort of patients who had access to a wide number of life-prolonging therapies in a modern environment. And that is really important, given that we've made a huge amount of progress in the metastatic hormone-sensitive disease, but we've also made a lot of progress in castration-resistant disease. And it's probably one of the first studies to show the continuum of those improvements across time.

Alicia Morgans: I would agree. I think it was so striking the way this control arm even was pushing 70 months. And we look at our contemporary trials that were more recently reported, but that was not able to capture that same maybe sequence of all of the therapeutic advances that we've made that are... survivals somewhere in the 35, 36, even 40 months, but nowhere approaching this. This was, I think, phenomenal news for patients, even if TAK-700  is not the blockbuster drug that we wish it would be. This gives me something to say to patients when I'm in the clinic and they say, "Well, doc, what can I expect? How long do people live with metastatic prostate cancer?" What do you think?

Lisa Horvath: I completely agree. And it's wonderful to be able to talk to people who are terrified and say, you need to think of this as a chronic disease, you are going to live for years, and this is the data because you live in a modern society where you can access this range of drugs. But I think it almost sequentially leads into the next abstract, which is really about bone protection agents and also the issues of survivorship, which you are very well acquainted with. If these men are going to live, for a long time and that is absolutely fantastic, how are we going to make sure that they live their best quality of life, that they are able to do all the things they want to do, and that they, we can minimize the side effects of the medications that we've got them on?

It's a bit twitty, but the reason that my institution is called Lifehouse is that it was named by our founder, who was a cancer surgeon, who in fact had a brain tumor. And his comment was, that cancer was a bit of a downer and that life was for living, and he wanted that in the name of the building.

Alicia Morgans: Well, I think that there is no better sentiment to have when you are living with cancer. The keyword should be living and not cancer. And so I agree with you, it is a wonderful transition into PEACE-3, which really looked at how do we maintain not only the quality of life, but certainly reduce fractures, which can of course increase mortality in these patients. What were your thoughts on PEACE-3? And this was a specific assessment, not of the complications by CTCAE or of other disease control outcomes. This was really focused solely on fractures.

Lisa Horvath: Yes. And it was very interesting, not only to see that the fracture rate in the treatment arm with enzalutamide and the radium 223 was reduced by mandating bone protection agents, but also that the control arm, the enzalutamide arm, the dramatic change in the fracture rate was quite startling for me because a lot of us are very scared by thinking community practice. If you've had a patient who's had osteonecrosis of the jaw, there's a lot of fear about giving patients high doses of denosumab and causing morbidity in those patients. But given that the rate in the CRPC dosing for bisphosphonates and denosumab is really 5 percent or less compared to a dramatic reduction from a fracture rate in the teens down to 2 percent, I think it's a false economy that we are trying to do this.

I also think, and this is data that we don't have, but I see from my clinical practice, 10 years ago, dentists weren't aware of all of these issues. Now all our patients get dental reviews. Their dentists ring me and ask me what they are on. You plan treatments. I would be fascinated to know what the real-world data is now with regards to osteonecrosis of the jaw because I certainly think in my own practice much better communication with the dental practice has improved that. However, these are also things that both ERA 223 and PEACE will tell us in the future, PEACE-3 will tell us in the future because they will be able to record those toxicities.

Alicia Morgans: Absolutely. And really just to emphasize that the combination of radium and enzalutamide was associated with a higher rate of these fragility fractures than enzalutamide alone. But to your point, enzalutamide alone had quite a significant rate of fractures. And I think that we as clinicians, exactly as you said, get so focused on disease control and avoiding harm in this area that we're willing to give and to sort of push aside that we do not realize, as you said, this fallacy of our trade-offs here. We don't realize that the risk of fracture is actually so much higher than that risk of ONJ.

And I agree with you, our patients now are always routinely getting their dental evaluation first. It's something we talk about. And also, I think patients come to us when they have, when they are aware because we have those conversations and they say if they have any pain or discomfort, and it is quite rare. I still, in the modern era in the last few years, have had, knock on false wood here, no patients with ONJ. It's something that I worry about, but it is something that I think we are doing pretty well with as a field. And we do need to move into using these agents routinely because the complications are much more severe than I think we acknowledge.

Lisa Horvath: I absolutely agree. And I think that the long survival in the SWOG study really comes to that point. Our patients are going to live for many years on androgen deprivation therapy. We need to go back and actually start the osteoporosis prevention at the beginning and then take it all the way through because otherwise, we are going to have people disabled because we did not think about their bone health while we were controlling their cancer.

Alicia Morgans: Absolutely. And not within this abstract, of course, but there is a Swiss study that is going to look at the frequency of dosing and the rate of prevention that I think will be helpful. If we can back off on our frequency and still have a good rate of fracture prevention, maybe that will be helpful. And I also think that we, as a field, need to understand, "How long do I do this? At what frequency in the early part of the disease? At what frequency in the latter part of the disease?" Because if we're having patients live for 70 months and that's on a control arm, then we really need to define this over time. So lots of work to do, which will keep you and I busy for years, Dr. Horvath. But thank you for going through all of this. What would your concluding message be to folks who are either clinicians in the field working to try to do their best for patients with prostate cancer or patients who are watching, trying to learn from you tonight?

Lisa Horvath: I think I would say that we live in very exciting times, that we are debating what drugs in what order to get the best benefit for our patients and the best quality of life. And I've been in prostate cancer for 20 years. And when I started, we got excited when docetaxel had the first survival benefit ever in metastatic castration-resistant disease. And that was only three months. And now we are talking about a two-and-a-half-year improvement in radiographic progression-free survival. So I am enormously excited about the possibility for our patients. We have an enormous amount of work to do in order to be able to give the clinicians more information, to be able to tailor treatments better. But we have a wealth of riches in our treatment options, and that's fantastic for our patients.

Alicia Morgans: It absolutely is. And we continue the momentum, I think because we have lots of trials that we expect to report out in the next few years to answer some of the questions that you raised within your discussion and here in our conversation. And also, of course, to raise new questions and possibilities and more work is being done. So as a community, I think there's lots to look forward to, lots of work to do, and a lot of enthusiasm and optimism.

And I sincerely appreciate you talking through all of this with us. Thank you for your time and for your expertise, Dr. Horvath.

Lisa Horvath: Thank you so much. It's been a pleasure to chat.