Isaac Kim: Thank you. It's my privilege to be here, Dr. Agarwal.
Neeraj Agarwal: So we really enjoyed your presentation at the 2026 annual American Urology Association meeting in Washington, DC on the use of neoadjuvant apalutamide in patients with localized prostate cancer. Could you tell us more about the background first? Why did you decide to do this trial? And then we can talk about the primary endpoints and the results.
Isaac Kim: Sure. So we all know that throughout the training in the early or late 1990s that neoadjuvant androgen deprivation therapy has been used, unfortunately has shown no survival benefit at the time. But at some point in my early point in my career, I began to think that is that the only relevant endpoint for our patients. Really, if you talk about prostate cancer patients, as a surgeon, even though the operation has been done well, after one year, two years, if their sexual function does not return, many men will consider it a failed operations or failed intervention. So I got to think about this whole issue that in patients also who have high-risk disease, that as a surgeon for the best oncologic control, that we have to do a wider resection to ensure that the negative margins, the patient will just have a better oncologic control.
So then I began to think because patients started coming in and they started asking, "Can you spare my nerves?" And actually I had one patient who said, "I don't care what the margin is. I need you to spare all the nerves around my prostate. That's what I want you to do. I'll take the risk." And he fully knew. So I did the operation. Patient did fine. The margin was positive, but he did not recur. So patient did okay. But that's the story that I go back to thinking about this is that in patients, again, even when they have a high-risk of positive margins, a high-risk of having a really extensive disease locally, a lot of these men still consider to have a erectile function preservation to be of a paramount importance.
Then against the backdrop, then I had the drug and all these newer drugs are coming out. So I began to think that, can all these drugs can revisit the whole neuro adjuvant approach with this newer drug that's coming on the market? But at the time again, I was trying to figure out what is a practical sample size, what can I do?
So ultimately, I think I arrived on that because the quality of life is such a short endpoint that we can get at the answer quickly as to how efficacious these newer agents are. So again, with the blessing of the sponsor, Johnson & Johnson, they were able to get the apalutamide trial off the ground. And the whole idea is that much like the era of when we had a patient with the breast cancers that we used to do radical mastectomies, but preservation of breast architecture, very important for these patients.
So much like that, the whole idea is that can I downstage based on the previous history that we can decrease positive margins? So if I know that I can shrink the cancer back into the prostate, then we can do a much more conservative approach and spare all the nerves around that, therefore resulting in a much better potency or erectile function preservation for our patients. So that was the whole premise of the study.
Neeraj Agarwal: This is a very nice segue to the design of the trial. So neoadjuvant apalutamide, but who are these patients who were selected for this trial and what was the design of the trial?
Isaac Kim: Right. So it's a randomized one-to-one-to-one, three-group trial. The inclusion criteria, these are patients who are likely to have aggressive disease locally, who need a wider section. So these are patients with a high-risk disease, grade group eight, grade group four or higher. So these are Gleasons 8, 9, 10s, PSA over 20. Patients had to have at least two or more positive cores on biopsies.
And of course had the metastatic workup that was negative. For this patient, they were then randomized to monotherapy, apalutamide arm. Second was an apalutamide abiraterone plus the conventional androgen deprivation therapy. And third was straightforward surgical arm. Patient was randomized and then based on that approach, I was certainly trying to spare all the nerves around the process as much as we can. And again, the result speaks for itself now.
Neeraj Agarwal: So what was the primary endpoint?
Isaac Kim: Yeah, the primary endpoint was a sexual function preservation at 12 months. We had a predefined definition based upon the sexual health inventory for men based on the question number two and number four. So this is again, previous defined endpoint. And we're just trying to, again, assess how many of the patients basically met this endpoint. So those questionnaires are, are you able to have sexual intercourse at least 50% of the time?
Neeraj Agarwal: New adjuvant therapy with apalutamide alone or apalutamide plus abiraterone, both given with ADT?
Isaac Kim: Yes.
Neeraj Agarwal: And third was the observation, the standard control who straight away went for surgery. And then after 12 months you assessed the sexual function. So let's talk about the results. What were the results, something striking, anything was better in the apalutamide arm versus abiraterone plus apalutamide versus observation?
Isaac Kim: Right. So it was a little bit surprising for us the findings at the end. It was positive. But which arm was positive was actually surprising to us because as a surgeon during our training, I remember my attendings telling us at the time, I was trained at Baylor, that patients had a neoadjuvant androgen deprivation therapy that oftentimes that posterior plane, also the tissues around the neurovascular bundles are going to be scarred down. So it's going to be difficult, more difficult operation. So that's what I expected from this. So initially when this trial was designed, we wanted to have, I felt that the more conservative approach would be just to have a monotherapy apalutamide arm. But again, we talked about earlier today, the Johnson & Johnson was also taking this PROTEUS trial at the time. So I think they wanted to know from the quality side what this combination potentially would do.
So apa-ab ADT arm was actually added after again, discussion development trials. It turns out that that was actually the better move because the positive endpoint or positive group was exactly in the combination arm, which was surprising because as a surgeon when I was operating, certainly with the monotherapy arm, I felt that I was able to do a better nerve-sparing than the combination arm. I felt the combination arm that there was a little more scarring, that there's a little more bleeding that I was running into. But nevertheless, again, that's why we run these randomized trials because surgeon's bias or our physician's bias is often reflected. We think that's how the result's going to come out. But it turned out the combination arm was positive.
Neeraj Agarwal: That's absolutely correct. Randomized trials, take care of those biases or dogmas we have always believed in. And by the way, how many patients were there in each?
Isaac Kim: We screened 96 patients. At the end there were 74 or 76 patients that were actually went into the trial and underwent treatment as designed.
Neeraj Agarwal: Would you like to summarize these results for our audience today before we talk about the future implications of this trial?
Isaac Kim: Yeah. So again, this is using a currently available drug therapy based upon some of the most potent blockers of the androgen pathway, so apalutamide-based approach, that if you use this for three months prior to the operation for men with high-risk disease, there's I think a good probability that the surgeon will be able to spare all the tissues around the prostate thus resulting in a better quality of life for the patient.
Neeraj Agarwal: Thank you. And we all are awaiting the results of the PROTEUS trial, which we know is publicly available information now, that it will be presented in one of the upcoming meetings. And PROTEUS trial based on the clinical trial.gov data, this is a very operative trial where apalutamide was used before and after the surgery. Based on these data, we are looking forward to really exciting results from the trial. What do you say about that?
Isaac Kim: Yeah. So I'm certainly as an investigator in this disease space, I am certainly curious to see what the results would be. And anxiously awaiting the disclosure of the sharing of the results. But I do think at the end, I'm assuming that the trial's going to be positive just based upon how this study is being prioritized. But I think if you look at how the PROTEUS trial is designed, it's a six months of neoadjuvant treatment followed by 12 months of the adjuvant therapy. So it's a total of 18 months of therapy for these patients.
I think the quality of life is still going to be a profound issue for these patients because again, as you know, patients who are on it androgen deprivation for such a prolonged period of time, significant number of them are not going to recover their testosterone to normal levels. So I think once the trial comes out, and I'm assuming it'll be positive, then I think we're going to have to start thinking about what is the optimal regimen that's going to allow our patients to be able to have a better quality of life as well as oncologic control.
So I think there's going to have to some dose adjustments, some sort of approach in terms of the de-intensifying therapy. I do think again, that given our results, imbalance I think with PROTEUS, that if I can say, I think some sort of strategy for de-intensifying this treatment probably going to have to be developed to, again, to improve the care for our patients.
Neeraj Agarwal: It looks like it is very clear based on all the emerging data that systemic therapy will be a part of radical prostatectomy based approaches in patients with localized high-risk prostate cancer.
Isaac Kim: Absolutely agree. Yeah.
Neeraj Agarwal: Well, congratulations, Dr. Kim, for your presentation and we look forward to more data in the manuscript in the near future.
Isaac Kim: Thank you very much. It's been an absolute privilege.