Melanie Cole, MS (Host): Welcome to Better Edge, a Northwestern Medicine podcast for physicians. I'm Melanie Cole. And today, we're highlighting perioperative apalutamide in high-risk localized prostate cancer, the new phase 3 data that supports new standard of care for patients with high-risk localized prostate cancer.

Joining me is Dr. Ashley Ross. He's a Professor of Urology and Clinical Director for the Polsky Urological Oncology Center at Northwestern Medicine. Dr. Ross, thank you so much for joining us today. This is very exciting. So, this is the largest therapeutic trial ever conducted for localized prostate cancer. Start by describing a little bit about the significance and the implications of this study and its design.

Dr. Ashley Ross: Yes. Thank you very much for having me. And as you mentioned, it is a very large trial, like 18 countries, over 100 sites, and over 2,000 patients with either localized high-risk prostate cancer or locally advanced disease, meaning they had some lymph node positivity. And the trial is very impactful, but it's also very nuanced. And I appreciate the opportunity to be on the podcast because I think already after it was presented in ASCO and published in the New England Journal, I can see some misunderstanding from providers.

And so, if you would give me the liberty, it's nice to think about, well, what was or is still the standard of care for the management of these men with high risk or locally advanced disease and sort of set a backdrop? And so, essentially, when a man has high-risk localized prostate cancer, they are faced with a couple different options.

And in other cancer settings, usually, what they would do is do everything together potentially, maybe treat the systemic component together with the local component, maybe use a couple different modalities to treat the local component. But in prostate cancer, we've been sort of lucky to have one of the best sensitive markers of minimal residual disease that's putting people into remission after treatment for a long time, which is the PSA, a blood test that in its most sort of purpose-built fashion could recognize the staying of prostate cancer after treatment, and that was its first FDA approval.

And so, we used to do things in series, do one thing and then do the next thing. And so, the choice that a man would have is to either with high-risk prostate cancer, do surgery, radical prostatectomy, or do radiation therapy. For radiation-based therapy, that's a biological therapy. For surgery, it's mechanical. For surgery, you remove what's there. And, if you removed it all, it's gone. For radiation, you radiate the place you want to treat, and you need the cancer cells to die with the radiation. And for a long time, for high-risk disease, it has been known that adding androgen deprivation therapy, which is a way of blocking testosterone production, could improve outcomes for high-risk prostate cancer.

And moreover, for radiation, it's been known for locally advanced disease, like lymph node-positive disease or very high-risk prostate cancer, that by adding androgen deprivation therapy, stopping production, and then another androgen receptor pathway inhibitor, whether that be more stopping of production from the adrenals and other sources like abiraterone, which is a CYP17-20 lyase inhibitor, or adding on a drug like enzalutamide for at least N1 patients, so locally advanced lymph positive patients, could even further improve the quality of the radiation.

But the question was what does that do in surgery? And for surgery, what we know is if you start there and you don't treat any of the systemic components, that half the people after surgery would have a biochemical recurrence or persistence, and then they would need more therapy. And so, this trial looked at this idea of what could be that systemic therapy, and previous trials had tried to add on androgen deprivation therapy alone to surgery and had not shown improvements in overall outcomes, metastasis-free survival, overall survival. And so, doing that was adding harm without benefit.

And the question is, how about if you added on a more potent drug like apalutamide, which is a androgen receptor inhibitor with trimodal action, meaning it blocks the receptor, it blocks translocation to the nucleus and transcription of androgen-regulated genes. If you add that on to androgen deprivation therapy, could that improve metastasis-free survival, and the disease response in the context of high-risk or locally advanced prostate cancer? And just to say one more thing, the apalutamide had already shown that it could improve overall survival when added to androgen deprivation therapy in the metastatic hormone-sensitive setting. And that was a trial called TITAN.

So in PROTEUS, the idea was to do six months of apalutamide plus ADT, then do surgery, and then do six months after of apalutamide plus ADT and compare it to a comparator arm that actually is not the standard of care. The comparator arm was going to be androgen deprivation therapy plus surgery, where you do six months of just androgen deprivation alone, surgery, and then six months after.

And so, one thing to note, and we'll kind of get back to this, is that the trial is nuanced in its design, which is not doing standard of care versus a new standard, but rather something that's not standard of care, but maybe a better comparator versus a new standard. And I should also note that there is a sub-study of PROTEUS, which has not yet been reported of about four hundred men that went through the standard of care, which is surgery upfront, no hormonal therapy.

So in that backdrop, what did we learn from PROTEUS? What we learned was, first, apalutamide is a very active drug. If you gave apalutamide plus ADT and then went to surgery, the complete response rate, meaning that the disease sort of melting away in the prostate down to completely away or less than 5 millimeters of disease was tenfold more likely than if you gave hormonal therapy alone, androgen deprivation alone. And that's great. It's a very active drug, but it doesn't get you all the way there. Only about 10% of the guys on the study, the patients on the study, had that complete response or minimally residual disease. You still obviously need local therapy.

The second thing it showed in this co-primary endpoint is a 20% improvement in metastasis-free survival compared to giving androgen deprivation therapy alone. In other words, the absolute reduction in metastasis as you got towards five years of the average part in the study was about 5% if you did the combined androgen deprivation plus ADT versus ADT alone.

And then, the third thing it kind of reaffirmed was that apalutamide is very well-tolerated. There were adverse events that happened. But compared to androgen deprivation therapy alone, those adverse events were mostly increased rash that occurs with apalutamide.

So, what do we get from this? What we get is a new standard of care option. So before, men with this type of disease would either get surgery upfront or get radiation combined with some kind of hormonal modulation. But now, I think we're going to see an emerged option that they could also think about androgen deprivation therapy plus apalutamide, followed by surgery, and then further therapy with radiation if needed.

And that's emerged as a new standard, and certainly better than androgen deprivation , alone in that context, which again was not the standard of care. So, a little bit of nuance. And now, I'll have your help to, like, sort of dissect that more for the audience.

Melanie Cole, MS: No, that was fascinating, Dr. Ross. And what an interesting study. Such an exciting time. So, you're a member of the steering committee. So, tell us a little bit about those considerations. Expand a little more about the timing of the therapy before and after surgery, and the inclusion of PSMA PET as the endpoint for this.

Dr. Ashley Ross: One thing to note in terms of the timing, like, why give six months of therapy prior to surgery? I would say that, really Dr. Mary-Ellen Taplin, the lead investigator in the study, Dr. Keibel, who works closely with her, had done a series of phase 2 studies that have sort of optimized where they thought "the sweet spot" might be for having good response preoperatively. So, the six-month period comes a lot from those previous phase 2 studies.

And then, the idea of adding PET PSMA was to say that most of us now are doing our initial staging and many times the follow-up for people after treatment with PET PSMA. PET PSMA is a functional imaging where you're giving a tracer that identifies prostate-specific membrane antigen, usually labeled with either F-18 or gallium-68. And it's more sensitive than conventional imaging with a Tech-99 bone scan and CT scan. And by adding that in, they could ask can we take an early look at metastasis-free survival? And it did actually show a larger improvement if you use PET PSMA imaging versus conventional imaging in the study, which is somewhat expected. It's sort of saying it's more sensitive scan, you're going to see this disease earlier, and we see that the difference in outcomes between apalutamide ADT versus ADT alone is going to be greater there.

And I'll also say, as you mentioned the design, it's hard to compare one of the best evidence-based standard of care for surgical approach to prostate cancer that's high risk is that you would do surgery followed by looking at what the PSA does, followed at first sign of recurrence, adding in radiation, usually with hormonal modulation. And that is the best evidence standard of care going into the PROTEUS study. Because the design was doing this across 2,000-plus patients, 100-plus sites, 18 countries, not all the countries have the same management system where they can have access to radiation oncology like we do here. And I think that's one of the reasons that the investigators decided we have to compare the more active arm, which turns out to be the more active arm, apalutamide plus ADT to ADT alone.

Interestingly, PET PSMA, which seems like a very advanced modality, is widely available throughout the world, which it's interesting to see that the practice patterns may be different, but PET PSMA as an imaging modality for staging has been widely adopted across the world, which is nice.

Melanie Cole, MS: It certainly has. We've talked about that before, you and I. And so, Dr. Ross, the study showed improvements in both pathologic response and metastasis-free survival. So, give us those implications for clinical practice. Take us from bed to bench side here and direct for other providers how they can use this and integrate this into their practices.

Dr. Ashley Ross: Yeah. What do we do now with this data? One thing I would say is whenever you have a person who you think is a surgical candidate and they have high risk for locally advanced disease, and you are considering using hormonal therapy for that patient, that hormonal therapy should be a combined hormonal therapy with, if for example, androgen deprivation therapy and apalutamide as supported by PROTEUS.

So, you shouldn't think of just adding ADT alone. So now, the question then becomes, should you have hormonal therapy for the patient at all? As I mentioned, for half the men with high-risk localized prostate cancer and maybe up to like 10% of the men with locally advanced disease, again, one disease. They can be cured just by surgery or put into like remission just by surgery. And those men giving them hormonal therapy upfront and then after might be exposing them to harm with unknown benefit. And PROTEUS hasn't yet answered the question of is working in series better than working in parallel, because both arms had parallel processing with systemic and local therapy.

So, the question is, who do you want to give that hormonal therapy for? And even though it's an expansive trial, you get a sense of the patients on the trial and providers even recruiting to the trial voting with their feet on who they recruit. Ninety-five of the population on PROTEUS was high-grade disease, Gleason grade group 4 or 5, sums of 8 to 10. Thirty percent were locally advanced disease, people where if you did a finger exam, you said definitively this disease is out of the prostate, I can feel it with my finger, it's invading structures around the prostate, so clinical T3 or T4. And 12% were lymph node-positive

So for these patients that are like marginally resectable or all their disease can't really be resected because they have lymph node positivity and you're thinking about hormonal therapy, that would be who you're giving apalutamide and ADT to as opposed to ADT alone. You could say like another way to frame it is if you're pretty sure the person has a systemic component of their disease, that's when you need to give them the combination therapy, because it's going to do better than ADT alone, just like it does in the metastatic setting or in the castrate-resistant setting.

The hard part is how do you decide who's going to have that systemic "spread?" The advantage of metastasis-free survival was there, 20% advantage by hazard ratio. But the absolute risk reduction is about 5%. And it makes it difficult. And because only 12% were lymph node positive, if you go into the subset analyses and look at some of the forest plots to say, "Well, is there one subset that really stood out, that really derived the most benefit?" Not just benefit, but the most benefit, the answer is kind of no. You can sort of look at it in different ways and see a little bit of a shift where the N1 patients may be deriving more benefit or, in the same token, perhaps the younger, more fit patients are deriving more benefit. But it's hard on subset analysis to tease it out because the improvement in mets-free survival, although substantial and even shown more if you look at it in a deeper way by PET positivity only, it's not a dramatic change in absolute risk reduction.

But long story short there—and, again, I want to just drive home that this is nuanced If you're thinking about systemic therapy in your patient where you're going to manage them locally with surgery plus or minus radiation, it should be with ADT plus apalutamide, and maybe other drugs will come to the forefront too that are androgen receptor pathway inhibitors, but ADT plus apalutamide, it shouldn't be with ADT alone. And that's the takeaway. It's not that everybody needs this that has high risk for locally advanced disease. It just provides a new standard of care option in the surgical setting.

The radiation setting, as I mentioned, for locally advanced disease or very high-risk disease, you already had the option to ADT plus abiraterone, which is a CYP1720 lyase inhibitor from STAMPEDE. If they're locally advanced like N1, you could interpret the ENZARAD data to, say, add enzalutamide maybe. And the ATLAS clinical trial, a large trial that Janssen, which ran this trial, also is running in the radiation space, might bring forward apalutamide as an option there too. But it's more that it's adding to our repertoire. It's not dictating management, and I think that's been a confusing point to some providers when they think about high-risk disease where you're going to incorporate surgery into the management.

Melanie Cole, MS: So, is this shifting the standard of care then or just adding to it?

Dr. Ashley Ross: It's adding to it. It's providing a new standard of care option. I'm going to eagerly await the substudy of PROTEUS, which is the 400 men that did not have any hormonal therapy. They just went straight to surgery. It's a substudy within PROTEUS. And to see how did they compare to the apalutamide plus ADT before surgery. And that will tell me if it's done correctly, and time will tell, meaning like were they hawkish on those people and treating them in a serious and a deliberate way, or did they just get surgery and then sort of nothing else? But if that population was managed by what I think is best evidence standard of care, and they compare it to the active arm of PROTEUS that we're just talking about APA plus ADT prior to surgery, and treating hard early with combination therapy is superior for mets-free survival in that substudy, then I think our standard of care will change for patients getting surgery. It'll change to say you really should do ADT plus APA followed by surgery plus other therapy if you need it. Right now, it is just opening an option, and I think for providers out there, they should be discussing that option with their patients when they think about management of their high-risk or locally advanced prostate cancer, starting apalutamide and ADT prior to surgical management, and they should talk about the risks and benefits of that.

Remember, if you say, "What are the risks? It was well-tolerated compared to ADT." Absolutely. There's not much increased risk in my eyes of adding apalutamide to ADT versus ADT alone, particularly in this population, which was selected on the provider's thought that they could tolerate a year of therapy. So, slightly healthier men, mostly ECOG performance status zero, cardiovascular healthy. But 20% of the population in both arms or almost that amount never regained their testosterone. So, if I see a young man with high-grade disease that's locally advanced but maybe not lymph node positive, and I know that there's a 50% chance I might be able to put him into no evidence of disease just by doing surgery. Do I want to add on this doublet therapy and give him a real chance of having to have castrate levels of testosterone for the rest of his life or not? That's a real question, and you have to weigh the risks and benefits. But before, we said definitely not. ADT alone is not going to help. Now we know apalutamide plus ADT really as a more active treatment may have some benefit, and it should be discussed as an option.

Melanie Cole, MS: Wow, Dr. Ross. This is so fascinating. So based on the findings and how you've told us a little bit about patient selection for other providers as they're looking at their patients, what excites you right now? What analyses are ongoing? What are the expected outcomes and impacts for future care for this patient population? What are you looking to five years down the line?

Dr. Ashley Ross: I think there's two things that I would like to see in the next five years. One, very excited about there was the committee led by Dr. Taplin and  Keibel. I'm so glad that they opened the sub-study of the people who didn't get anything but surgery within the PROTEUS trial. So, it's following all the same trial procedures. I'm going to eagerly anticipate the results of that. That will really inform me quite a bit of what happens.

Secondarily, I think we have to be looking at biomarkers in this space, particularly, the genetic and genomic biomarkers. There was data from another trial using apalutamide alone in the radiation setting post-operatively. They call it the BALANCE trial that Dan Spratt, a radiation oncologist, presented at a recent meeting. And that data showed that more luminal cancers, strictly luminal B cancers, which are maybe more hormonally driven, that they seem to have the most benefit from the apalutamide.

And whether that's going to translate into this setting or not is one question. There's also mutations at the DNA level, like, SPOP mutations that may make people more sensitive to hormonal therapies. Can we use genetics and genomics to parse out who's going to be a better candidate for this therapy?

And so, those are the two things that will kind of lead to better patient selection that I'm eagerly anticipating results of the PROTEUS sub-study and, more results of analysis from genomics and genetic biomarkers linked into the precision medicine application for these men.

Melanie Cole, MS: Thank you so much, Dr. Ross, for joining us today. Really great information. And I hope that you'll join us again and fill us in more as the study continues and you find out more. So, thank you so much again. And to refer your patient or for more information, please visit our website at breakthroughsforphysicians.nm.org/urology to get connected with one of our providers. That concludes this episode of Better Edge, a Northwestern Medicine podcast for physicians. I'm Melanie Cole.