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Alicia Morgans: Hi. I'm delighted to have here with me today, Dr. Cora Sternberg, who is a GU Medical Oncologist as well as the Clinical Director of the Israel Englander Institute for Precision Medicine at Weill Cornell. So, lovely to have you here.

Cora Sternberg: Thank you. It's nice to be back here.

Alicia Morgans: Of course. So we always have great conversations and I really wanted to pick your brain today on some of the updates that we heard about at GU ASCO this year. Some big studies really presented that I think are somewhat transformative, at least in the landscape and what's open and available to us as we think about treatment options. The first is really in the non-metastatic CRPC (nmCRPC) setting, the ARAMIS Trial that was presented by Karim Fizazi and I'd love to hear your thoughts on this. This was darolutamide in the non-metastatic CRPC setting.

Cora Sternberg: Exactly. So, the ARAMIS Trial is a trial very similar to the Prosper Trial, which was with enzalutamide and the SPARTAN Trial with apalutamide. And those two trials were both presented at GU ASCO last year, so a year ago. So all of this data is very new. In the past, patients with M0 CRPC, for instance, a patient who has been on hormonal therapy and developed some castration resistant prostate cancer but has no metastatic disease. All of these studies were done with traditional bone scans and CT scans. All three of the studies. We had really nothing to offer them and nothing in the guidelines to offer them until about a year ago.

And, then a year ago, the PROSPER Trial and the SPARTAN Trial, were both presented at GU ASCO and they've made it into the guidelines because both of them showed a significant improvement in the 70% range of a decrease in metastasis free survival. When either enzalutamide or apalutamide were added onto ADT as compared to ADT alone. And they also showed improvements in quality of life.

These two drugs are very similar. Were invented by the same person, Dr. Charles Sawyer, and they have very similar toxicities in terms of some fatigue, falls, some fractures, especially in elderly patients. They are very similar drugs. It's hard to say that one is better than the other and nobody compared the two trials. Yesterday, we heard another trial. These are all very large trials. These trials have some 1500 patients in them, all of the trials. Again, these are for patients who have been on LHRH analog and by technetium bone scan and by CT scan have no metastatic visible disease. They opt for patients who have a PSA doubling time of fewer than 10 months. So these are patients at higher risk. And, these patients, again, were randomized 2:1 to either receiving daralutamide plus ADT or ADT alone.

Darolutamide is a little bit different than apalutamide and enzalutamide. We all have less experience with darolutamide. It's a newer drug, the newer kid on the block, and it has a different chemical structure. One of the main advantages is supposedly that it doesn't cross the blood brain barrier. So by not crossing the blood brain barrier, theoretically we probably will be seeing, and have seen at least in what was presented yesterday, fewer side effects that are related to cognitive impairment, fatigue, falling, seizures, things like that that have been a potential problem with some of the patients with apalutamide and enzalutamide. In addition, there's probably, from what I understand, less cross resistance with other drugs as we've seen with apalutamide and enzalutamide and the results with this trial, again a large randomized trial, patients randomized 2:1 to darolutamide and ADT versus ADT, what they showed was a 60% improvement in metastasis free survival.

Again, very similar to what was seen with SPARTAN and with the PROSPER Trial with the apalutamide and enzalutamide and we saw a decrease in bone pain as well. Good quality of life, similar to what we saw in the other trials, but perhaps a better toxicity profile. Now, many of us don't have experience with this drug. We don't know in the long run, and in a few years from now, which one are these drugs, if we have a choice of all three, will we use? I think it'll depend on our experience. It'll depend on cost. It'll depend on reimbursement. So there's a number of things that have to be sorted out in the future. But I think that we have a third good option for these patients with what we call M0 CRPC.

Of course, the future is changing because what we do know is that by treating patients earlier and earlier, we seem to be doing better. And these studies were all done with technetium bone scans and CT scans and perhaps a future with using more sophisticated PET scans, we'll be seeing more small metastatic disease. And that may be explaining why these patients are doing well by treating them earlier and earlier, as we've seen in the hormone sensitive metastatic setting.

Alicia Morgans: Absolutely. I thought it was really interesting too that the prolongation in metastasis free survival looked very similar to the SPARTAN and PROSPER Trials. That was at 22 months. And then really the side effect profiles did seem to be a little bit different with darolutamide side effects in terms of cognitive change and falls and fractures to actually looking pretty much the same as the placebo arm.

So that was really interesting. And then as you mentioned, the drug-drug interactions. But like you said, ultimately it'll be a test of time to understand where this really fits. One thing that was presented that someone asked Karim about and he ended up kind of coming back to it, it looked like the overall survival data, which was not yet mature, just like the other studies there, there was the trend ...

Cora Sternberg: There was a trend towards an improvement in overall survival. And we don't have those data yet on PROSPER or on SPARTAN.

Alicia Morgans: Yeah. So that'll be interesting too for all of these studies to really understand what happens. Is earlier treatment really shifting the direction of the disease, shifting the trajectory of the disease..

Cora Sternberg: I think it is. Yesterday they presented an update on the SPARTAN data with another year of follow-up looking at the second of progression free survival. So after patients have progressed, they wanted to look in to see if they gave them another drug.

And in that particular trial in patients who had apalutamide, they were all offered to be given abiraterone, for instance, and many of the people crossed over. And what they found there was that the curves held up, that there was still the difference in progression free survival even on the second progression free survival. So that's a different kind of a new end point. But we still haven't reached the overall survival end point either with the SPARTAN Trial or the PROSPER Trial and we do have a trend in the darolutamide trial.

Alicia Morgans: Yes. That'll be very, very interesting and more data to come. You know. The other disease space that I really wanted to touch on, just to shift gears a little bit, is the metastatic hormone sensitive setting where we already have multiple options, abiraterone or chemo/hormonal therapy, and certainly we will always also have ADT alone should people choose to use that. But there was new data presented. Andy Armstrong presented some data there in the ARCHES Trial. Uh, so I'd love to hear your take on that.

Cora Sternberg: Well, I mean there's been a lot of interesting data and the field has really changed beginning with the trials using chemotherapy with the CHAARTED Trial in America and with the STAMPEDE Trial in Europe and there was French GETUG trial and a meta-analysis all showing that giving chemotherapy at six cycles of docetaxel upfront with ADT, significantly prolonged survival. In the CHAARTED trial it's very clear that patients with high-risk, high volume disease are the ones who benefit the most. And then afterwards we had a very interesting data with abiraterone from the LATITUDE Trial and also from the STAMPEDE Trial.

They're the high-risk patients. The LATITUDE definition of high risk was a little bit different than the high volume. Those patients had 2 or 3 of a Gleason 8 or visceral disease or at least three bone mets. There was also shown an improvement in overall survival with abiraterone. And this was also shown with the STAMPEDE Trial done in England. So we have two different kinds of agents that are being used early on in the hormone sensitive metastatic space. In the past we gave patients ADT and then when they progress we gave them chemotherapy or then we gave them abiraterone or enzalutamide. But what we've shown now is that giving either abiraterone or docetaxel upfront really does improve survival. And when the people from STAMPEDE looked at patients who had been randomized, simultaneously at the same time, to either abiraterone or docetaxel neither one was better.

So, they couldn't really say that giving six cycles of docetaxel or giving indefinite abiraterone was better. So it becomes a matter of choice, reimbursement and a lot of other things. What we heard yesterday was the ARCHES Trial that was presented by Andy Armstrong. This was a trial looking at enzalutamide given up early upfront to patients with metastatic hormone-sensitive disease. Now what's happened in many of these trials is since we have the data on chemotherapy, the chemotherapy has sort of gotten a little bit mixed up and none of the trials really are looking at chemotherapy and hormonal therapy or very few are, at the same time. But in the trial that Andy presented yesterday, he'd mentioned that 18% of the patients had received up to six cycles of docetaxel chemotherapy before being randomized onto enzalutamide and ADT versus ADT.

And there he showed really impressive results. Their primary end point was progression free survival and they had amended that, not to get rid of overall survival, but they had amended it to make the statistical parameters even tighter, to make it 0.67. But the hazard ratio was 0.39 in a difference in radiologic progression free survival. So I think that that was really quite impressive. We don't have overall survival data yet, but in absolutely all parameters that they looked at, the patients who got enzalutamide with hormonal therapy did better than the patients who got hormonal therapy. So I think these results are very, very, very interesting. And there's another trial, it's a primarily Australian trial led by Chris Sweeney, but also being carried out at the Dana Farber Hospital in Boston where he's working now.

It is called ENZAMET, which is a similar trial looking at enzalutamide, and there too I think people were allowed to get up to two cycles of chemotherapy before being put on the trial. So I think combining those two trials in the future, we'll have a better idea of what enzalutamide upfront does and whether it's similar to what abiraterone does. Of course, we don't have head to head trials of abiraterone versus enzalutamide. So we don't have abiraterone versus chemotherapy, but what we're seeing is that treating patients earlier is leading to improvements for sure in radiologic progression free survival, and probably ultimately in overall survival.

Alicia Morgans: Absolutely. So a rapidly changing landscape.

Cora Sternberg: Absolutely.

Alicia Morgans: I really appreciate your time and walking us through these advantages.

Cora Sternberg: Thank you.

Alicia Morgans: Thank you so much.

Cora Sternberg: Thank you. It's been a pleasure.