Zachary Klaassen: Hi, my name is Zach Klaassen, urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined on UroToday by Doctor Rob Reiter, who is a urologist at UCLA in Los Angeles, California. Rob, thanks so much for joining us on UroToday.

Robert Reiter: My pleasure.

Zachary Klaassen: So we're going to discuss an important topic, looking at neoadjuvant and adjuvant therapies for high risk localized prostate cancer. Before we get into this topic, just tell us why there's a need for additional therapy than maybe some of our traditional localized treatments for prostate cancer. And maybe discuss some of the work and the need for meaningful clinical endpoints for these trials.

Robert Reiter: Yeah. You know-- You know I think we all know that the management, at least the surgical management of high risk prostate cancer, is not optimal. That as many as 70% of patients may recur, many may develop metastases and die.

And really this current standard of care is still probably radiation plus two years or something like that of hormonal therapy. So I think there's clearly a need to see whether neoadjuvant or adjuvant treatments can really aid in bettering the outcomes of surgical management of high risk prostate cancer.

Zachary Klaassen: Yeah, absolutely. These patients are certainly at risk, especially from a surgical standpoint. Maybe just take us through some of the phase II neoadjuvant trials out there. For instance, the TAPS the Neo-Abi, et cetera those trials. What's the take home from those trials to date?

Robert Reiter: So as we all that this was-- it's not a new idea. People tried standard ADT together with surgery for many years. And ultimately, it really wasn't successful. It was really no difference in recurrence rates even though surgical margins were surgical. Positive margin rates were lower and things looked good. But that historically was just three months, even six months and eight months of ADT alone.

So given the fact that doublet and triplet therapy, with ARPIs and abiraterone has really improved the management of basically every single stage of prostate cancer later on, including hormone sensitive metastatic disease. I think it was reasonable to hypothesize that more deep AR blockade could actually improve the outcomes in a neoadjuvant adjuvant setting.

So there have been quite a few studies that have been performed, ranging from three months to up to six months, and even up to a year of ADT. Plus, one of the various ARPIs and in some cases triple therapy. And all seem to be demonstrating a higher pathologic complete response in near complete response rate compared to a standard ADT alone.

So I think that-- that served as an impetus to really study this concept further. And also-- Of course, importantly to ask whether or not pathologic response can be used as a surrogate for a meaningful clinical endpoint, such as metastasis free survival, which is a surrogate for overall survival. So that's something that's also been lacking for management of prostate cancer as you know.

Zachary Klaassen: Yeah, well said. I think these trials set the stage for a couple of really important phase III trials. That have the potential to change management particularly for the neo/adjuvant therapy for high risk patients.

Maybe just walk us through the PROTEUS trial design, the GUNS trial design. I know there's been a little bit of early data out of GUNS maybe just highlight that. Because that's really where the practice changing potential is.

Robert Reiter: Yeah. So I think it's important first to kind of step back a little bit and think about what are the purposes of neoadjuvant therapy. So on the one hand, it's to actually test the clinical hypothesis that we may improve pathologic response and metastasis free survival, et cetera, et cetera.

But the other is also to test in specific circumstances whether a drug may be-- that may be active against a certain genomic predisposition, whether that drug actually hits its target, whether it's active, and whether it can be tested, then in a more formal clinical trial setting as to whether or not it improves any of these clinical endpoints.

So in the case of PROTEUS, it's really based on all these studies of ADT plus an ARPI that look promising because instead of maybe a 4% complete pathologic near complete pathologic response rate, they're seeing up to 20% combinations of pathologic responses.

And early data do show that if you have a near complete or complete pathologic response, that your risk of recurrence and metastasis is significantly lower than those who do not. So that basically led to phase III registration trial testing of this hypothesis.

So the PROTEUS trial is basically it's apalutamide plus ADT versus ADT alone, given six months before and six months after surgery, and surgery at the six month point. Looking at both the pathologic complete response rate but also metastasis free survival as the primary endpoint.

And so we're still awaiting data from that. It's a very large trial, and it started now probably seven-- six or seven years ago even. It accrued completely a number of years ago. And so hopefully we'll get some data.

They did add a third arm, which is surgery alone. It's another comparator because as you can imagine, comparing ADT versus ADT plus ARPI in surgery doesn't really answer the question as to the role of surgery in all this. It basically is doublet versus singlet. So I think they added a third arm too, which I think will be very important to see.

Zachary Klaassen: And what about the GUNS trial. I of a little more of a nuanced trial. There's some sequencing in terms of-- I think this has got some potential as well, do you?

Robert Reiter: Yeah the GUNS trial is a great idea. This was started by Martin Gleave up at University of British Columbia. Neil Fleshner is helping him, it's up in a number of centers. But it's really an umbrella trial trying to essentially select treatments or choose treatments based on the genomic characteristics of an individual patient.

So as you can imagine, there are mutations that we hypothesized based on good preclinical data, will sensitize patients' tumors to AR antagonism, such as SPOP mutations and FOXA1 mutations. There are other mutations such as P53, PTEN, RB that may be associated with tissue plasticity. Tumor plasticity and might be targetable by some other drugs such as chemotherapy.

They're also testing the very rare case of a mismatch repair gene alteration like Lynch syndrome, which might predispose somebody to respond to immunotherapy et cetera, et cetera. So essentially patients are entered into the trial, they're sequenced, they're classified into one of a number of different categories the ones that I mentioned, and then-- and then they are-- then they're randomized to one of two arms within each of those subsets.

So it's a really cool trial. The largest population, as you can imagine, are those that are thought to be AR sensitive. And in that case, they tested a doublet versus a triplet. So it's an ARPI plus ADT alone, those two versus the addition of abiraterone. And they are seeing a higher rate of complete-- near complete pathologic responses in the group that got triplet therapy, which is very interesting.

And they're combining all of this with tons of sequencing and genomic data to really kind of try to tease out what's-- what's working. And they're using a Simon two stage design. So if the first stage looks promising, they're adding another a group of 24 patients beyond that.

So it's very early days for that trial to a long time to get off. It's really a monumental Herculean effort. But I think that this is the direction that we need to go is truly personal precision of treatment.

Zachary Klaassen: No doubt. A huge plug for-- you know we always talk about sequencing, metastatic patients and mCRPC patients. But again, the guidelines always say high risk localized, these are the patients. So I think this is as you mentioned, Herculean effort, but a really potentially important trial.

Robert Reiter: Absolutely.

Zachary Klaassen: So I would want us to switch gears just a little bit. We saw about two years ago LuTectomy, which was a really interesting trial out of Australia. When we've seen-- I mean radioligand therapy, we've seen it now with PSMAfore moving up pre-chemo in the mCRPC stage.

But taking it way to the front as a proof of concept trial in the neoadjuvant setting. Just tell us about that. What are your thoughts on it moving this far up? Is there any safety concerns? What are your initial thoughts on LuTectomy?

Robert Reiter: So certainly like many I'm very excited about radiology and therapy in general, I've been working in this field for many, many, many years and it's really exciting to see it take off. Conceptually, the idea is that you could treat microscopic, metastatic or even microscopic local extension together with the primary tumor itself. So that, I think, is the hypothesis underlying LuTectomy.

So that trial, was really interesting. They did one versus two cycles of PSMA lutetium therapy prior to surgery. They looked at PSA responses, the primary endpoint was just looking at radiologic effects. Basically PSMA PET before and after showing clear decreases in PSMA PET imaging SUVs after therapy.

So I think there's some promise there. They didn't see any complete responses. They saw a few-- you know one particularly a remarkable response in a patient who had very large lymph node. But I think they showed, at least in that instance of 20 patients it's safe. That there clearly some efficacy, there are PSA declines particularly in the group that got two cycles. As we use six cycles in patients with metastatic disease.

So it's early days. And of course it was also PSMA lutetium alone. So you can imagine perhaps doing it in combination with ADT, we're in the process of developing a trial. Exactly to do that, I think there's promise there.

At the same time, of course, there are concerns. I mean, the long term risks of PSMA lutetium therapy, bone marrow toxicity long term, renal toxicity long term. These may not-- these small molecules may not be ultimately the best agents. I think there's a lot to be learned and determined.

But given that we've moved every other treatment in prostate cancer from the end of disease to the beginning of disease, it makes good sense that something like this is really going to work better in patients who have microscopic residual disease or micro oligometastatic disease than in patients who have widely metastatic disease.

So I think moving it earlier is-- makes a ton of sense. And just figuring out where's the best place, is it safe, what dose is, et cetera, et cetera where we need to go.

Zachary Klaassen: And I think, too. We have two surgeons discussing, I think from what their initial experience was, wasn't any more of a difficult surgery. So I think that's important too so.

Robert Reiter: Absolutely.

Zachary Klaassen: My last question, Rob, it's the reason we have these discussions just to think about where the landscape is going. The Rad Oncs have done a great job of clinical trials. And they've got a good footprint with good data for high risk patients, radiotherapy plus let's say two years ADT plus or minus Abi.

Let's say PROTEUS and/or GUNS plays out to be practice changing phase III data. How are we going to discuss high risk localized prostate cancer management with our patients?

Robert Reiter: One of the reasons that patients oftentimes elect surgery with high-- when they have high risk disease is they may not need ADT. Even though we as surgeons that their recurrence rate is very high and that ultimately many of them will need ADT. So I think this will change the paradigm of how we use surgery.

I think again, until we someday have a randomized trial of radiation plus two years of ADT versus surgery plus ADT, we're never going to the answer. But we will be able to look at, I think, probably better endpoints, such as metastasis free survival in comparisons. Rather than looking at PSA recurrences, which as we know a the definition is different for radiation and surgery, they're almost meaningless.

So I think if these trials pan out where we actually have clinically validated endpoints that are meaningful, then maybe we'll have-- will be able to have better discussions with patients about the optimal way to manage their cancer.

As far as GUNS is concerned, I think that's going to lead to registration type trials for genomically selected patients. And I think clearly ultimately that's where we're going to be going.

Zachary Klaassen: Yeah great answer. Rob, it's always good chatting with you. This is a great summary of your interdisciplinary GU cancer forum 2025 talk you gave about a month ago. Any final thoughts, any take home messages for our listeners.

Robert Reiter: You know I think as urologists-- I mean I think the key thing is for us to be engaged in these kinds of trials to really be open minded about the role of surgery versus radiation and to keep pushing the field forward. That's where we need to go.

Zachary Klaassen: Yeah, absolutely. Well said. Rob, thanks so much for taking time out of your busy day to join us in the--

Robert Reiter: Thank you Zach. Enjoyed it. Take care.