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Neal Shore: Hi everybody. I'm Neal Shore, Medical Director of Carolina Urologic Research Center in Myrtle Beach, South Carolina. What a great pleasure to be joining you today with my dear friend and colleague, Jason Hafron. Jason is the Director of Research and a prominent uro-oncologist at Michigan Institute of Urology in Detroit, Michigan. He also was a key collaborator with multiple other sites on our Apa-RP study. We're really excited to go over some of the key aspects of that study with you today. Welcome, Jason.

Jason Hafron: Thanks, Neal. Thanks so much for being here today. Apa-RP is probably one of the most exciting trials I've been involved with in my career. Let's just talk to the audience a little bit about the Apa-RP study and why was it done, Neal.

Neal Shore: Yeah, thanks. This was a large Phase 2, a little over 100 patients, single arm study where we essentially said, "Let's go and try to understand is there an adjuvant strategy for our high-risk, newly diagnosed patients with high-risk localized prostate cancer who will undergo prostatectomy." So essentially, we wanted to say, "How can we decrease biochemical recurrence?" We know that from data sets, and we looked at the Martini-Klinik in Germany where they do over 2,500 patients a year, extremely expert robotic prostatectomists, but in the high-risk population, essentially defined as those with grade groups 4 and 5 or grade group 3 with very high PSAs, typically greater than 20, could we have an adjuvant strategy.

In our case, we looked at 12 months post-RP of ADT and apalutamide. One of the reasons why we did this was because in looking at data from the Martini-Klinik over 4,000 patients, there was essentially about a 25, 26% failure rate or biochemical recurrence. So could 12 months of adjuvant therapy, ADT and apalutamide ... Apalutamide obviously approved on the basis of the SPARTAN trial as well as the TITAN trial, already approved in nmCRPC and mHSPC ... Could we have a benefit for our patients with high-risk localized disease undergoing prostatectomy?

It was really a proof of concept study for a larger Phase 3 trial called the PROTEUS trial, which is now fully accrued, and in that Phase 3 study also high-risk localized prostate cancer patients, but a neoadjuvant adjuvant or a perioperative design. So those patients receiving six months of Apa-ADT, six months of ADT and a placebo, so two different cohorts having the RP, and then adjuvantly six months of ADT-Apa, six months of ADT and a placebo.

We've never really been able to crack the code to help these high-risk localized prostate cancer patients do better than just having their interventional treatment. Another thing that was great, and thanks to colleagues like Jason and other sites, we did this in all community US sites during COVID. So we're really super proud of that, and Jason, you beautifully presented this at a plenary session at AUA 2024 this year.

Jason Hafron: Yeah, no Neal, that's a great summary of the study and a good segue into the PROTEUS, but clearly an unmet need in urology today. When you look at high risk or very high-risk localized prostate cancer, it does represent about 15% of the cases we see today. When you look at some of the historical literature beyond the Martini data is that within five years 45 to 65% of these patients will recur. So clearly surgery alone is good, but we need to do better and that essentially, as you described, the impetus for the Apa-RP as well as the PROTEUS trial.

Neal Shore: Yeah. Thanks, Jason. I know you put a lot of patients on this. One of the things that was really great, we're going to talk about rash in a minute and the rash management strategy, which was a really great educational initiative. I'm going to ask you a question on that. But what was really nice was A, we did this in US community urology sites. We accrued the study in essentially a year during COVID, and we had almost a 20% African-American enrollment. I know you put a lot of folks on. Our site did as well. We're really proud of that.

But let me just segue for a second. I wanted to ask you about how we took a very proactive approach to the known side effect of rash management. Most folks outside of dermatologists, certainly urologists, we're not that comfortable or historically we haven't been comfortable with rash management. We see a percentage of patients who get apalutamide will have rash. So can you tell us more about and our audience, how did we think about this rash management approach?

Jason Hafron: Yeah, I totally agree. Rash can be intimidating for urologists, but we took a different approach in the Apa-RP study. We know skin rash is a known adverse reaction with androgen receptor inhibitors. The approach to rash has been mostly reactive. In this study, in Apa-RP, we took a very proactive approach to rash and included empowering our patients to identify early rash and to take measures to prevent rash. Patients on the trial were educated on best skincare practices. These were simple things that as a urologist we never think of, but were actually very effective like the use of lotion, antiseptic soap substitutes, sunscreen with SPF of 30, as well as just telling patients, avoid the sun, significant sun, avoid hot baths, saunas, things like that and even giving patients information on avoiding alcohol-based or fragrant skincare products.

We empowered the patients, we educated the patients before starting therapy, and then we provided the urologists or the investigators with a simple algorithm that they used for if rash did develop, they could use to manage their patients. What we saw in Apa-RP, which was very exciting, is with the use of the rash guide the incidence, the severity, the duration of rash was significantly improved when you compare it to the previously published SPARTAN and TITAN trials. What's even cooler is that we had no discontinuation in Apa-RP when we followed the rash guide.

Neal Shore: Yeah, I think that's really great points. Really important for our colleagues to understand. Look, you know apalutamide is a incredibly powerful antigen receptor pathway inhibitor. It's in that whole class of choices that we have and having a better handle on understanding the rash. Fortunately when you see it, it's low grade in the majority of patients who clearly have it. In a small percentage, it could be more significant. I think having a proactive strategy, as you point out, is really great. In that kind of concept, how should we be counseling other healthcare providers when prescribing apalutamide regarding this concern regarding this small but yet real concern of rash?

Jason Hafron: Yeah, I think it starts when you write that initial script for an ARPI is having that discussion with the patient. Rash may be a possibility. Here are measures that you can take to reduce that incidence, and also here are signs and symptoms of a rash and if you do develop it, just call me or call the healthcare team and notify that you may have a rash.

I think, like you alluded to, rash can be intimidating for urologists. What we've done in our clinic is within this publication, we just post the rash algorithm in our clinics. So if a patient calls and has a rash, me or my nurse practitioner or anyone on our care team could immediately address it. The algorithm's pretty straightforward, pretty simple. We know based on Apa-RP that we will reduce the incidence, duration of rash, and hopefully maintain no discontinuations in clinical practice.

Neal Shore: Yeah, I think it's a really great point. What I like about this is that it really expands our ability as uro-oncologists to say, "Look, we can monitor all sorts of things." We have grown over the course of our careers to be able to say, "We can check potassium, we can check LFTs, we can use steroids, we can address GI toxicities. We can address rash."

Jason Hafron: Yeah.

Neal Shore: That makes us more well-rounded oncologists. We live in a day where we have person-power shortages, lots and lots of patients so I think the more we can get uro-oncologists to complement the work of medical oncologists and radiation oncologists, it's just better for everybody.

Jason Hafron: Yeah, I think those are great points. As urologists, we are physicians and capable of managing many of the adverse events or side effects associated with these medications. Like you mentioned earlier, Apa-RP was a great study, so many great stories that came out of this study. One of the other things that came out of Apa-RP was we did a substudy, and we looked at the combination of relugolix and apalutamide. Neal, you want to talk to the audience about the results of this study and what we found in the substudy we did with Apa-RP?

Neal Shore: Yeah. Thank you, Jason. You've been instrumental in helping develop relugolix, the first and only oral androgen deprivation therapy. I'll never forget it. I was out and about, and I got a call from Tracy McGowan, who's one of the most important physician investigators, and she was part of the Janssen team. She said to me, she goes, "Neal, we should maybe do a substudy about combining apalutamide and relugolix because we need that data." Because relugolix had just been approved a couple years ago, and a lot of folks find the advantage of using an oral as opposed to a parenteral, and it's an antagonist versus an agonist. I was like, "Hey, this is great. We're already accruing so well, let's allow for the use of oral relugolix instead of the parenteral LHRH agonists." So because of the concomitant approval, there hadn't been any really nice PK-PD data.

So we put in this substudy thanks to Tracy's innovative thinking, where we used the approved dosing of relugolix and the approved dosing of apalutamide. And really what we were able to show despite there was earlier concerns because of their metabolic considerations and the drug-drug interaction, what we found in using those approved doses, the 240 mg Apa, the 120 mg daily relugolix after the loading dose on day one, was that we demonstrated effective low testosterone levels without the need to modify either dose, and I think this is really important. This really helps a lot of us who want to combine two orals and want to make sure we're doing it in a safe way. So it really gave us nice confidence that we could do this. We've presented this at meetings, and we've published on this as well. So it just was another really nice little pearl that we were able to take away from the Apa-RP trial.

Jason Hafron: Yeah, I think this an important trial for us because clinically we're constantly using double orals in our patients with advanced disease. This really answered that question is that we don't have to do any dose adjustment. We don't see any change in testosterone suppression. We're talking about the study, but the reality is with the Inflation Reduction Act and the cost of these drugs is that we found is putting patients on two orals actually can be cost beneficial to the patients. It can decrease their co-pays and allow these patients ... We know these drugs are expensive, but can potentially lower their co-pay. So this information has been critical for us for day-to-day operations and managing the volume of patients that we're seeing.

Neal Shore: Yeah, excellent points. Yeah, you've got to bring in not only the clinical utility but the economic value proposition. Excellent. Jason, thanks a lot, man. I was so happy that we were able to get this thing done for all the reasons we talked about. We've got our publication in Journal of Urology just this past month, so thank you for all your great work on this.

Jason Hafron: Thank you, Neal. I appreciate the opportunity.