Fred Saad: Well, great. So it's a pleasure to be here. So like you said, we've been anticipating and waiting for this trial because we've done many trials in neoadjuvant prostate cancer, giving them prior to surgery and trying to improve outcomes and they've all basically failed. I mean, using ADT alone, using ADT even combined with docetaxel. And so we were a little bit apprehensive what these results were going to give, but this is a well-designed trial. Over 2,000 patients randomized one-to-one to getting ADT plus or minus Apalutamide for six months prior to surgery and then six months after surgery. And the beauty of this is that we always had an impression that the patients most likely to benefit in the old neoadjuvant studies were the really high-risk patients. So these are the only patients who were included, and I think that's really important. We don't want to overtreat, but these are patients destined to recur and actually destined to become metastatic and die from prostate cancer.
And this thought that you don't die of localized prostate cancer is not true. If patients live long enough, I have lots of patients who are localized at diagnosis who are dying with metastatic castration-resistant disease.
Zachary Klaassen: It's a really interesting space because radiation oncologists have done a really good job with their clinical trials. And now we have a very good design, as you mentioned, surgical trial, plenary session at ASCO, big deal. Dr. Mary Ellen Taplin presented the data.
So let's just talk a little bit more about the trial design. What are your thoughts on that six months before, six months after the control arm being ADT alone, which typically isn't how we've done things with surgery?
Fred Saad: Yeah, exactly. And this is why we're including myself a little apprehensive because the standard of care would've been nothing, but it would've been hard to do a trial and I was involved in the discussions early on and I'm part of the biomarker steering committee. So that bar was high to do better than basically 12 months of ADT just by adding an ARPI, Apalutamide in this case, that had the guts to do this trial. So when we're looking at these results, we have to keep in mind that this is not against nothing. It's against something that is quite effective with ADT, which is what is used in most radiation therapy patients.
Zachary Klaassen: Absolutely. Let's go through the key results. There's sort of two primary endpoints, pathologic complete response, longer endpoint down the road, metastasis-free survival. That's why it took so long to get to these data because they're looking for an MFS endpoint. Just walk our listeners to those two results.
Fred Saad: Yeah. And I was actually surprised that the data came out this early because to get to metastases takes a long time because we act on PSA, we act on recurrence. So to become metastatic is a really high bar in this day and age. And the trial hasn't been going on for decades. I mean, this is, started basically in 2019. So this is six, seven years. This is amazing and it really highlights that these are high-risk patients.
So basically, as you said, pathologic complete response, which is a really, really high bar, but also this minimal residual disease has become more and more of an endpoint that is used in many tumors, including prostate now. And so at that endpoint, it was significantly better by adding Apalutamide to ADT. So just imagine if there was no ADT control and there they had a tenfold increase likelihood of reaching pathologic complete response or minimal residual disease, which is really quite amazing.
And if you look at overall there, it's between 11% with ADT alone and 30% if you look at the minimal residual disease. So it really is very impressive what adding an ARPI can do to the disease control.
Zachary Klaassen: Absolutely. And even maybe more importantly, is this metastasis-free survival benefit. So just walk our listeners through that.
Fred Saad: Right. So here the hazard ratio by central review was 0.8, which was statistically significant, a 20% reduction in the risk of becoming metastatic. But if you look at investigator, which I think is really important, how the investigators viewed and the local, that went down to 0.74. So even higher likelihood of reducing the risk of metastases. We have to remember a lot of these metastases, if we look closely, are probably metastatic CRPC because you would've probably introduced hormone therapy when the PSA was rising, post local control. And it reduced significantly the risk of requiring salvage radiation therapy, which is also something we'd like to avoid, the risks and the morbidity of adding radiation therapy after surgery.
Zachary Klaassen: That's a good point. Actually, it was going to be my next question. These multimodal therapies often is what we need to get these patients to a good result. So if we think about reduction in adjuvant or salvage radiotherapy at the sort of trade off of 12 months of ADT plus Apalutamide, how do we operationalize this for our patients now?
Fred Saad: Well, I think we've, as a community of urologists, have not done as good a job as our radiational ... We have to hand it to them. They've done really good studies, randomized thousands of patients. We've been lagging behind. So we couldn't claim ownership of these very high-risk, locally advanced, and they include even patients with what would appear as local regional lymph node metastasis.
And so now I think we can say based on this data that this is a viable option and it's no longer true to say the only valid option is radiation with two or three years of hormone therapy for these kind of patients. So here we might be exposing to less because the majority of patients recovered their testosterone in a question of months. You give three years of ADT, many patients will never recover their testosterone.
Zachary Klaassen: I think it gives the surgeons options here. I think, you and I both are surgeons, and it's still that shared decision-making, right?
Fred Saad: Right.
Zachary Klaassen: So the 75 to 80-year-old, those patients, we have great data that the RTOG trials will benefit them. What if you have that 55-year-old patient? I think this becomes a discussion point. Would you agree?
Fred Saad: Absolutely. And I would go even further that even older patients, the older patients suffer a lot from ADT. So if we can get them, cure them and the patients I put on PROTEUS, and I can talk about the small number of patients that I included in this 2000 patient, we haven't had to restart ADT or give them salvage therapy. I'm really quite impressed because these patients, I would've never predicted I would've been able to cure. I think everybody's worried about using that four-letter word, but I think we are curing some of these patients that we would've believed would be incurable.
Zachary Klaassen: Yeah, absolutely. Always a great discussion, Fred. Anything we haven't touched on from PROTEUS you want to mention before we wrap up?
Fred Saad: Well, I think the next phase is going to be the biomarkers, right? I mean, we all want to know who we can predict needs this intensification, who's likely to do well with this combination of ADT, ARPI and surgery. And so I think biomarkers are going to play an important role because I think within those patients that benefited, there are some patients who clearly benefited more than others. And if we can figure that out, it'd be hugely important.
Zachary Klaassen: No doubt. We'll hear a lot more from PROTEUS, so we'll be excited to discuss that going forward as well. So Fred, thanks as always for joining us.
Fred Saad: Thanks a lot.