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Alicia Morgans: Hi, I am so excited to be here with Professor Oliver Sartor, who's joining me from the Mayo Clinic, and also joining me from a recent presentation that he gave at APCCC 2024, thinking through how we treat patients with low-volume metastatic disease and when we really want to use total therapy. And we'll talk about what some of those definitions mean as we go through some of the main highlights of his talk.

Thank you so much for being here with me today, Oliver.

Oliver Sartor: Thank you, Alicia. Glad to be here, but it was even better to be in Lugano.

Alicia Morgans: It was wonderful. One of the highlights of my meeting was your talk, and I really loved hearing you think through these different aspects of treatment. Let's talk through, first, what we mean by the definitions of this total therapy and low-volume disease. How did you define, for the context of your talk, what total therapy was and what is low volume? What does that mean to you in this setting?

Oliver Sartor: Yeah, great questions. Because unless you address these definitions, you never really get to any interesting points.

The standard definition has really been coming out of the CHAARTED trial from Chris Sweeney and the STAMPEDE trial, and they have used conventional imaging to define low volume, but I don't think that's the current state of the art. I think almost everybody today is using molecular imaging. Everybody's using PSMA PET, and we have to look at these low-volume patients through a new lens.

So we can look at it through the PSMA PET, and the classification that I like to use right now is oligometastatic or polymetastatic. And by the way, those definitions are changing as well. It used to be that oligometastatic might be somewhere between one to five, but I'm seeing the definition of oligometastatic change because we're attacking the disease a little more differently. And even when you have many mets, maybe even up to 10 mets, we can still approach it in an oligometastatic fashion.

Let's take a look at low volume and define it by the PSMA PET, and let's think about oligometastatic. When I think about this kind of low-volume oligometastatic, I think it's these individuals that we can treat with targeted therapy to all of the lesions that are apparent on the PSMA PET. So that's the low-volume way that I've attacked it.

Number two, total therapy. Well, total therapy includes all the modalities and approaches we have at our disposal, but we don't necessarily have to use everything on everybody. Thinking for a brief moment, we're going to have androgen deprivation in the traditional sense. That's lowering of testosterone with a typical LHRH agonist or antagonist. And then we're going to have our novel hormones, and that might be abiraterone, enzalutamide, darolutamide, and apalutamide. And then we might have chemotherapy like docetaxel. And then we might have radiation. Radiation could be applied either in an SBRT type of format to the metastatic disease or it could be applied to the prostate. And of course, we also have to consider pelvic lymph nodes as well.

So when we're thinking about total therapy, we're probably thinking about some combination of those. And I'll tell you in my practice today, it's not uncommon that I'll use SBRT to the metastatic disease seen on the PSMA PET, and will use pelvic radiation and prostate radiation to handle the prostate and pelvic nodes. And then we're going to be using ADT and one of the novel hormones, and we're going to be using it not forever, but probably for some limited duration of time. I don't use chemotherapy much in these oligometastatic patients, I just don't think we have the good data there.

Let me stop for a second. And so now we've defined low volume perhaps in a relatively novel way, and we've divided total therapy in a pretty particular way, at least how it applies in my practice.

Alicia Morgans: That's fascinating. And I would also say that you defined, or at least laid out, that you would do all of this therapy and treatment from a systemic perspective for a defined period of time, which is also something that comes into this where you're hitting it really hard with total therapy as you define it for that given patient, and then you're trying to back off.

Can you speak to that for just a moment, and how that comes into your paradigm and how imaging and treatment availability may affect that?

Oliver Sartor: Absolutely. First of all, imaging is totally key because we can't even begin to approach this in a truly defined way without molecular imaging. We have trials like the ORIOLE trial, which I'm sure you're familiar with; it uses conventional imaging and it overlaid the PSMA PET. And what we found from the ORIOLE trial, one of the key findings was that if you radiated all the metastatic lesions, you had a much better outcome than if you only radiated some. And in order to get to all the lesions, you had to be able to use micro-imaging like PSMA PET.

And by the way, we have beautiful studies from Europe with people like Piet Ost and others that have also done molecular imaging added to this SBRT approach, and demonstrated you could prolong the time for hormonal usage. Now that's a little bit different because we're not using all the available therapies, we're trying to delay the use of antigen deprivation. That is another topic, but I may want to touch on it at the end.

Going back, and I forgot to address the other part, and that's the duration of therapy. And let me mention, Alicia, that there's a whole lot that we don't know here. Traditionally for metastatic disease, it's been hormones forever. And then we've potentially introduced the idea that intermittent therapy could be appropriate. Maha Hussain's old SWOG trial was a good attempt at that, but it wasn't really a perfect attempt. And it turned out to be not non-inferior, which was not a very satisfying conclusion.

But rather than think about intermittent therapy all the way up front, with this kind of total therapy approach we're going to be giving it for X amount of time, stopping, and then seeing what happens. And whether or not that duration of hormonal treatment might be six months, one year, or two years, I don't know how to tell what the right answer is because we don't have any data. For those with particularly low-volume disease, I've actually been doing as little as six months, for those with a little higher volume disease, perhaps two years. But I'll be the first to admit, these are arbitrary distinctions, not one driven by the current data available to me through prospective trials.

Alicia Morgans: And that's pretty common with the APCCC where we're really talking about areas of great data and trying to understand how we can all come together in consensus around these when we don't have the Level I evidence to answer the question.

But I really want to highlight some of the key points that you're making. One, that in your mind we need to shift to an oligometastatic or low-volume metastatic hormone-sensitive definition that really does rely on this molecular imaging, PET imaging. And we are absolutely in transition with that, and I think that we are trying to define that and continuing to act as you described. And two, just to emphasize, that total therapy from your perspective is not really focused solely on systemic therapy alone but is a multimodal approach that includes radiation to the prostate, to the pelvis, and to those lymph nodes, as well as potentially to a couple of areas of oligometastatic disease.

So this type of treatment paradigm is one that is absolutely rolling out into clinics all around the world, and one that we're testing and is exciting because it may limit the ultimate duration of systemic therapy for our patients with prostate cancer.
As you think about that, and this is what you talked about and presented, how did people in the room respond? And was there consensus on this? Did 99% of people say, "This is the way we need to go." Are we still in the process of getting everybody to that point, Oliver? Where do we stand as a field in terms of consensus on these types of issues?

Oliver Sartor: Yeah, great question. APCCC is really a global setting. It includes people from low-resource countries, middle-income countries, as well as Europe, the United States, Australia, Canada, etc. So it's a very diverse audience. It's a little bit hard to talk about total consensus when the resources are so distinct between the individual investigators.

I will say that for those investigators who have access to all of the above, and now we're talking about the novel hormones, the SBRT, and the molecular imaging, all of which are combined in this total therapy concept, I think there's a lot of consensus that the path forward is going to be utilizing all the above. I think there's very little consensus about duration. I think there's very little consensus about exactly how the radiation ought to be employed. And I think it's just going to be evolutionary; I'm going to have to do trials going forward.

But I did speak with my friend Ken Pienta, who's at Johns Hopkins, a great investigator, and he thought that the era of being able to demonstrate a PSMA PET-positive lesion in an oligometastatic patient and not radiating, he thought that era has passed, in part because of the ORIOLE trial, which showed that if you don't radiate all the above, you don't get a maximum effect. So it'll be interesting to see which of these ideas will be testable and which won't.

Now we have an ace in the hole, and that ace in the hole is called STAMPEDE. And the UK is just amazing, along with Switzerland and a few other sites that are active in the STAMPEDE trial. And people like Nick James really do have the capacity to do trials that we may not be able to do in America. And I was having a sidebar with Nick, even on the stage. And I'll say that Nick is very dedicated to being able to look at these in a prospective randomized fashion, and I think we're going to get some answers, particularly about metastasis-directed therapy and more.

So I'm very enthusiastic about the concept. I'm actually enthusiastic about our ability to learn, and I think we're going to get some answers going forward. It may not be perfect, but it'll be like the clinical trials we always do, and that is going to inform our path forward, not only as clinical investigators but as doctors for our patients. And that's what patients want; they want us to be as good as we can be.

Alicia Morgans: That is absolutely what they want. And I think these are the kinds of conversations that can happen at APCCC that continue to move the bar forward. So thank you for going through where we need to go in terms of our understanding, where our trials need to go.

And one other area where we need to understand more thoroughly is how we hit a patient intensely with our therapies. And then, when we're through with therapy, we stop, we try to ensure that patients have testosterone recovery, recovery to their normal state of being as much as possible. And even potentially someday sparing castration altogether, this is the holy grail. Can you tell me as we just wrap up, where are we going in terms of this in ensuring that patients can stay as normal as they possibly can, even as they're trying to intensely treat their prostate cancer?

Oliver Sartor: Yeah, so two components here, Alicia. Number one, it is kind of an odd mix of intensification and de-intensification all wrapped into one. We want to hit it hard, we want to hit it thoroughly, and then we want to back off to give that quality of life that comes with a normal testosterone level and being off therapy. So it's a little bit oxymoronic perhaps to go hard and then go soft, but that's what we want to do because I think it offers the patient potentially a longer time off therapy, which is what we really want.

Now, the second issue to me is really fascinating. And by the way, PSMA-DC has started, it's now activated. It's activated in Asia, Australia, Canada, and Europe, but not yet in the US. PSMA-DC is the following. We're going to define oligometastatic by PSMA PET. We're going to decide that every lesion is going to be treated with SBRT. And these are patients who, by the way, have already had their primary treated, so these were recurrent patients, not de novo. And then for our systemic therapy, we're going to be using PSMA lutetium instead of androgen deprivation.

So the paradigm is PSMA PET positive, conventional imaging negative disease, SBRT plus or minus lutetium, with an MFS endpoint by conventional imaging. And guess what? That's FDA-approvable. If this turns out to be a positive trial, then I think we have a shot at the FDA of treating oligometastatic disease without androgen deprivation, and that to me is honestly a bit of a holy grail. So we'll see what happens. The trial is underway, Novartis is supporting it. I'm chairman of the steering committee, been very involved with its design and getting it underway. It'll take a while to find out, but I'm really looking forward to finding out.

Alicia Morgans: Wonderful. Thank you for walking through where we are today, where that area of gray data is, and what studies we should be working on.

And I also want to congratulate you on that study. I think that PSMA-DC is going to be something that is going to hopefully change the paradigm. And it is not just improving the quality of life that we're after, we're hoping to protect cardio metabolic status, we're hoping to prevent frailty. There are so many things that can improve. If we can, like you said, go more intensely and then back off when appropriate, not overdo it, the just right amount like Goldilocks, if we can find it, I think that is the way to go.

So thank you so much for your time, for your expertise, and for continuing to advance the field. Especially in this area where we're talking today in this de novo or synchronous oligometastatic or low-volume metastatic hormone-sensitive disease. Really wonderful talking with you.

Oliver Sartor: Right. Thank you, Alicia. Thanks for having me.