Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU medical oncologist and Associate Professor of Medicine at Northwestern University in Chicago. I'm so excited to talk today with a good friend and colleague, Dr. Chris Sweeney, who is a Professor of Medicine at the Harvard Medical School, as well as being a GU medical oncologist at the Dana-Farber Cancer Institute. Thank you so much for being here with me today, Dr. Sweeney.

Christopher Sweeney: Right? Pleasure to be with you, Dr. Morgans.

Alicia Morgans: Wonderful. So I wanted to talk with you a little bit about some classifications, subgroups, of men in metastatic hormone-sensitive prostate cancer. There's a lot of data out there. We're really excited to have so much information on treatment intensification strategies, whether it's with systemic treatments, whether it's with radiation and we think that these are all strategies that we can apply and we've been doing so in some cases quite broadly. However, I have learned from you today and have learned from some of your recent work in European Urology that maybe we should think a little bit more about what's most likely to help, in which patients, and really try to use some of the clinical characteristics that we have to identify subsets and really try to personalize the treatments that we give in a way that's maybe a little bit more personalized than as discussed. So let's see what your thoughts are on this. Can you tell us a little bit more about it?

Christopher Sweeney: Oh, I think that's a great idea, Alicia, because one thing we're also having a conversation about is, are enough patients actually getting the right treatment? There are a lot of abstracts out there saying, very few patients, maybe up to a third, are getting the intensification. So let's actually do a deep dive into that data. And what we should do with any article is a journal club-like, pros and cons limitations. It's good that we're actually asking the question, are the patients getting the right therapies? What we're missing in a lot of those questions is, what's underlying a lot of this? So what we're measuring in those and what they're measuring in those data is systemic therapy alone. Who's getting systemic therapy? And there's a lot of wailing and gnashing of teeth, but people aren't getting the right therapy. And I do agree with that concern, but actually, let's look into a little bit of the data as to why that could be part of the issue.

It's quite recognized that in the United States, most men who get a prostatectomy or cystectomy have it performed by a urologist who does one to two of those a year, that's most prostatectomies and cystectomies in the country. That's probably the same with men who are getting treated for metastatic hormone-sensitive prostate cancer. So not high volume centers who are aware of the data. We need to get the message out. And so that's one side of the equation. The other thing is, I don't think we're measuring all the right metrics in the data that's saying, oh, only a third of patients getting therapy. First of all, are the patients actually fit for chemotherapy? What's the percentage of that? The other question is, are they right for chemotherapy? I don't think patients with metachronous low volume disease are right for chemotherapy because we've shown toxicity with no survival benefit whatsoever at one extreme, but they are the people I think where there's a clear benefit, that's easy to explain to people, patients, and doctors.

High volume chemo fit patients. Docetaxel is an option. So it's actually a small pie who will probably fit and appropriate for chemotherapy. Now what about the other option for a patient with not chemo fit or chemo at high volume, Abiraterone and Enzalutamide, Apalutamide. Easy to sell. And the only people who are not fit for that, people with seizures, frailty, liver disorders, CHF. There is a small portion of patients who may not be eligible granted, but it's a small portion now let's actually think about, and are we capturing what is the right treatment for patients with De Novo Low Volume disease. A few billion metastasis, PSA 1520. And it's the first diagnosis. We actually know that radiation to the prostate is a very good therapy with well tolerated and prolongation of survival. None of those abstracts I've seen are actually measuring who's getting that intensification

And I say, I propose that is actually the baseline data and any therapy on top of that. And if we're going to do intensified systemic therapy at work as well, I think the hormonal therapy Enzalutamide, Abiraterone or Apalutamide are very reasonable to add onto that. I don't have data to support that, but I do think that's the right intensification approach, but those abstracts are not measuring them. So in the next traunch of these abstracts, I want to know, what's the fitness for chemotherapy and who with de novo low volume, got radiation as an option. Now what about this entity of metachronous low volume Dr. Morgans?

Alicia Morgans: Agree. So this is actually an entity that you have explored in your recent paper and you pointed out so rightly, and I had not really thought about this, that this entity had not been adequately explored in some of the publications. Now, certainly, the LATITUDE data is not going to cover this patient population. That's a high risk metastatic hormone sensitive population getting treated with Abiraterone and STAMPEDE [crosstalk 00:05:23]...

Christopher Sweeney: And all of them are De Novo metastatic. All of LATITUDE is De Novo metastatic.

Alicia Morgans: Exactly as are the majority of STAMPEDE treated patients, which is the other piece. So even if we think about extrapolating STAMPEDE data to ensure that we understand results or outcomes for patients with low volume metastatic disease, the majority of men, I think over 90% were actually De Novo metastatic. And so does not cover this metachronous entity, which of course is patients who have had their prostate primary treated in the past and now have a recurrence. That's how you're defining this metachronous metastatic population, but these patients could have been included and were included in ENZAMET. And that's what you try to focus on in your paper. Can you talk a little bit about that?

Christopher Sweeney: Absolutely. So there are two things. It's all about how we capture the data and the data in the case report forms between the different trials. And ENZAMET and TITAN, both have these patients for... and to Apalutamide and Enzalutamide. We actually had them in CHARTED as well. In CHARTED we actually referred to them as prior local therapy and we captured it with prostatectomy radiation with curative intent in the database for that. We saw, and the [inaudible 00:06:44] 15 team, saw no benefit for docetaxel with that group as well. So we actually have that data for [inaudible 00:06:50] 15 and charter no benefit for docetaxel, prior local therapy. And the other thing that we actually drill down on is when we looked at it in the ENZAMET data, we actually captured prior local therapy, but it got lumped in with radiation to the prostate and patients with De Novo metastatic and also a patient may have had a TERP and that got called prior local therapy.

We actually have that in the PSAP and we followed the statistical analysis plan. And that's what we presented in the forest plot in the New England Journal paper at the interim analysis. When we realized that was included, we actually said, okay, let's now go back and look at the patients who were diagnosed. Their first diagnosis was M zero. So we have that first diagnosis date. So the case report form was M zero at diagnosis, and then metastatic later, and that group is also captured in TITAN and two thirds, maybe 70% of those patients are actually low volume, metachronous low volume because they're the patient. They have a rising PSA. And then they have imaging and after the originally took diagnosis. We also know in ENZAMET, about 80% of it had prostatectomy or radiation. So some of them may have been men who had relatively low volume, low risk disease, and they will put on watchful wait and then found to have metastatic disease.

That was only about 20% of the patients in the metachronous low volume. So it's a unique entity and it's how it's captured in the case report form. What we also know from charter detailed and the Dana-Farber registry is the median survival of these who have this metachronous, low volume also known as relapsing oligometastatic or... The median survival of testosterone suppression alone is eight years. We also know a number of these patients were enrolled in the ORIOLE study where they were treated with just radiation alone. So when a patient like this presents to a physician, they may be actually offered radiation alone to delay systemic therapy, to delay the testosterone suppression and all the side effects and the stigma of having their testosterone suppressed. So now we come to... And that's why I wanted to look at that data very, very closely. And in ENZAMET, we actually see that there is a profound survival benefit at the interim analysis in the original database.

And that's what's in the European urology. There's an increase in the survival from three year survival from 83% to 92% in that subgroup. We've never seen that with any therapy ever be it docetaxel, can't see it with our Abiraterone. We see M zero including high and low volume benefit from that therapy Apalutamide, but they haven't broken down. So this is the first time... And if we looked at the hazard ratio, the hazard ratio was 0.4 and the confidence interval was below one. So it is a clear group that has a strong survival benefit, just like the high volume patients who did not get docetaxel, have a survival benefit with it.

So now when we come back to the question about who's getting intensification, is it possible that a lot of the patients out there who are in those databases, are they just getting SBRT alone and not getting offered enzalutamide or Apalutamide because they're getting SBRT because people think there isn't a benefit. So I think this data from the European urology actually fills a knowledge gap that the patients should be informed about the intensification with a double hormone approach increases their three-year life expectancy. And that actually I think maybe why there's not as much intensification as we think there should be is because a lot of these patients are treated as oligo metastatic with radiation alone or a short course of testosterone suppression alone.

Alicia Morgans: So to put this in context of some other data that I think also demonstrates the utilization of SBRT, let's think about the non-metastatic CRPC patients. And these patients of course have a biochemical recurrence data, at least by conventional imaging now developing maybe PSMA positive disease on a pet. And sometimes rather than adding an AR antagonist, which we know is associated enzalutamide, Apalutamide and Darolutamide with a survival advantage. In addition to a prolongation of metastasis-free survival and improving quality of life. Some people are using SBRT there rather than intensifying because they think that SBRT is better. Similarly, in this recurrent state, in the hormone sensitive setting, we have seen an increase in SBRT to local lesions rather than saying this patient population in fact has a very low volume, but still a low volume metastatic hormone-sensitive patient. You and your European urology study have looked at this subgroup.

And now demonstrate a clear survival advantage, not only to the addition of ADT, but also to the addition of this intensified strategy with adding enzalutamide. And similarly, I think you mentioned that this was shown in TITAN as well. If you look at that subgroup analysis. So I think as as a field, we need to recognize that SBRT is an interesting and exciting modality for us to try to target these lesions. But the survival data at this point in time at least is really to intensify our systemic therapies. And patients should be aware of that even as we are grabbing for our SBRT approaches and using those potentially in addition or instead, but we should be informing patients of this. Am I understanding you properly, Dr. Sweeney?

Christopher Sweeney: That's a hundred percent correct, Alicia Morgans. So, absolutely. What I do know is how long should we treat these patients if we do put them on the hormones is another very big, important question. The proponents of the SPRTC, where we think we can delay it and capture them and salvage systemic therapy later, that's possibly true. But I do know that there's this survival benefit that I think patients should know about with starting with the hormones. What do I actually do in practice? For years, I've actually treated them for two years with hormonal therapy, radiated everything I can see and then stopped. And I've had a number of patients who are now 5, 6, 8 years off therapy with recovered testosterone and their PSA hasn't ever been recovered. So yes, I delayed the systemic therapy... Sorry, I didn't delay their therapy, the testosterone suppression, but it's possible that I've delayed future therapies with an intensification upfront and save them from chemotherapy radium.

Lutetium PSMA, long-term lifelong hormones with that approach. I don't know. But I think that's something we should look about. Can we actually cure these patients with an intense course of hormones plus SBRT? And this is a wrap for clinical trial. Stop the therapy after two years and save the patients from lifelong testosterone suppression. If they have prolonged PSA remission, radiographic remission with testosterone recovery. That's where I think we should go is throw it all at them up front and see if we can prevent them ever needing any more therapy is the next clinical trial question.

Alicia Morgans: Absolutely. And how long do we need the systemic therapy? Because I had a patient just yesterday, is nearly an identical, if not an identical approach. Two years is my timeline. And a patient said yesterday, "Well, how do you know I need it for two years and not one?" And I said, "Well, we need to figure that out. That's a great question." So I think as we do this, there, there will always be more questions we can ask. And I appreciate that you ask them. And that you have shared with us not only your vision of now and how we can capture better outcomes for our patients based on data and really understanding our clinical subgroups very, very well, but also where we can go in the future because it is important to us, of course. But it's most important to patients as we try to make sure that they are not only cared for, in terms of the disease control, but that we limit the adverse events that we can cause with our treatments. So thank you so much for your time for your expertise. Do you have a closing thought?

Christopher Sweeney: No, I think let's do this. Let's a intensified therapy, but let's get the data out there to the right people who actually treat the patients and make it very clear who benefits from what. And we'll see numbers go up. I suspect.

Alicia Morgans: Thank you so much.