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Tom Keane: Good afternoon, everybody. This is Tom Keane, coming to you from UroToday, and also from The Medical University of South Carolina. I have one of my favorite people to interview and talk with today, professor Daniel P.Petrylak, who's currently the Director of Genitourinary Oncology, professor of medicine and neurology, co-leader of the Cancer Signaling Networks and co-director of the signal transduction program at Yale University Cancer Center in New Haven, Connecticut. Dan has been active in prostate cancer for more years than either he or I would like to tell you, but he is one of the leading lights within us. And he has been at the forefront for a long time. And his work is recognized both nationally and internationally for his dealings with prostate cancer, for his research. And he is a recognized international leader in the urology field. He earned his MD at Case Western Reserve University School of Medicine in Cleveland.

And he then went on to complete his internal medicine residency at the Albert Einstein College of Medicine and the Jacob E. Medical Center in the Bronx. His fellowship was at Memorial Sloan-Kettering and he is one of another, in a very long line of experts who have been generated by that institution. Dan not alone is he an extremely wonderful doctor, but he's also a very good friend. He gives a great talk and he makes what is frequently a complicated issue appear simple, at least for five minutes. And then when you forget what he said, it goes back to being complicated.
But without any more to do, it's my great pleasure to welcome him again, to UroToday. And he's going to talk today about the ARCHES study, which was a randomized phase three study of androgen deprivation therapy with enzalutamide, our placebo and men with metastatic hormone-sensitive prostate cancer. And there will be time for us to chat afterward. Dan, over to you and welcome.

Dan Petrylak: Thank you, Tom. It's an honor and a pleasure to be here. It's always great to talk about data with good friends and we've been good friends for quite some time, and it's a friendship I will always cherish. So the ARCHES study is a trial along the lines of other studies that are trying to move next-generation hormonal therapy upfront in the treatment of castrate-resistant disease. The thought is not really a new one. I mean, this was used in other tumor types where we've used other endocrine agents in breast cancer and have shown a greater survival benefit. And this is along the same concept. So the question with the ARCHES trial is, is the addition of enzalutamide to standard androgen deprivation therapy. Does that addition improve radiographic progression-free survival or overall survival compared to a placebo combined with androgen deprivation therapy? So marches [crosstalk 00:03:01] yes.

Tom Keane: To clarify. This is hormone-sensitive prostate?

Dan Petrylak: Yeah. Right. Hormone-sensitive prostate cancer. So again, it's the concept of moving things up earlier. And so these are patients with hormone-sensitive disease who had confirmed metastasis by bone scan or CT scan. They had an ECOG performance status of zero one, and they could have started androgen deprivation therapy within three months of trial entry, or they could have had docetaxel. And then this had to be within six months of trial entry. So again, the concept of docetaxel comes into play because this was one of the first drugs that was shown to have a survival benefit in early-stage disease. Patients were stratified according to volume of disease, high versus low. And then prior docetaxel therapy versus no prior to docetaxel therapy. And then the number of cycles that were administered to patients. One-to-one randomization of 1,150 patients. Trial first accrued or started to accrue on March 21st of 2016.

And then the final rPFS analysis was performed in October of 2018. So patients came off because of radiographic progression, unacceptable toxicity, or the investigator's discretion, or a new agent for prostate cancer. So rPFS defines the time from the randomization to the first objective evidence of radiographic progression, which was assessed by central radiographic review or death. And this was defined by the resist criteria or the appearance of new lesions on bone scan. Of course they had to be confirmed with that, 13 weeks afterward. So trial well-balanced in terms of overall patients. It was an international study that took patients from Europe, North America and Asia. 47% of patients had bone-only disease, 9% had soft tissue-only disease. And then about 30 to 40% of patients had bone and soft tissue metastasis. The median duration, if they've had androgen deprivation therapy was 1.6 months prior to starting treatment.

And the median PSA was 5.4 and that ranged as high as 19,000 in the placebo arm and 4,800 in the control arm. So you see a wide mix of PSA's. Overall 18% of patients had docetaxel prior to entering on study. So this is the primary end point radiographic progression-free survival. As we see, the median is not reached in the experiment alarm of enzalutamide plus androgen deprivation therapy. The hazard ratio is quite impressive. It's 0.39. And in the placebo plus androgen deprivation therapy, the median rPFS is about 19 months. And that's what you would expect from this group of patients. So that's not an unexpected find. The significant finding is that there is improvement in radiographic progression-free survival in favor of enzalutamide.

So the other thing that's important to know is this trial used rPFS as its primary end point, but it did not ... OS was a secondary endpoint. And that data is still maturing at this point. So we now have abiraterone docetaxel, enzalutamide, and apalutamide. all drugs that are FDA approved in this particular space for hormone-sensitive prostate cancer. So this is a fact that we need to discuss with all of our patients. One of the trends I've been seeing in the community and in patients being referred in. And actually we just saw gentlemen like this yesterday, who had started androgen deprivation therapy about 18 months ago. And he was progressing as one would expect from this trial. And he never received the next-generation agent antigen. He had low volume disease. He had only two spots on bone scan, but he never received next-generation agent in addition to his hormone therapy, because he was thought to have low volume disease.

Well, one of the presentations that was made at ASCO this year looked at the number of bone metastases for patients on the ARCHES study in relationship to their overall radiographic progression-free survival. And there doesn't seem to be any correlation. So if you have as few as one documented bone metastasis, you still have a significant improvement in survival over those patients who are treated with androgen deprivation therapy alone. So this is a very, very exciting finding. I think that it is certainly something that all of our patients should be considered for. Again, the urologist or the oncologist, whoever's taking care of the patient,, the radiation oncologist really does have to have an informed discussion with the patient about what the risks are and what the benefits are of each individual treatment.

Tom Keane: So that being said, we have a lot of players in this area. You have abiraterone, we have enzalutamide, we have chemotherapy, and there are still people out there who are just continuing to use ADT alone. Do you think that using ADT alone now is substandard of care?

Dan Petrylak: I do think it's substandard of care. Yes.

Tom Keane: Okay. And would you say that volume of disease really doesn't have any role to decide one way or the other? If it's metastatic, it's metastatic? Or would you say there are some qualifiers?

Dan Petrylak: Well, there are some qualifiers. This is a little bit different than what we see with the trial that Chris Sweeney ran, Charted. Where patients were randomized between docetaxel for six cycles and androgen deprivation therapy versus androgen deprivation therapy alone. The benefits seem to be the greatest in those patients who have high volume disease and that's defined as more than four lesions on bone scan or hepatic mets. So I think that that's one distinction in determining whether somebody should receive chemo or somebody should receive next-generation agent. Is it, what's your volume of disease? Here, it doesn't really seem to hold, but with that trial, it did.

Tom Keane: Yeah. So, I mean, the standard of care then for people is combined treatments. So with this data, then what would be your go-to agents? Would you go with the chemo? Would you go with ... and I know there were some patients in this trial who had had previous chemo.

Dan Petrylak: Right. And that's an interesting question. Are you getting more bang for your buck with giving chemotherapy? So there was a very interesting presentation at this year's ASCO meeting, looking at the peace one trial. So the peace one trial took the standard of care, which is docetaxel. And this was a forearmed study. Standard of care, plus abiraterone. Standard of care plus radiation therapy. Or standard of care plus radiation therapy plus abiraterone. And when you look at the median event free survival, most patients who received standard of care plus abbey, the hazard ratio is 0.5. So that would imply that if you add abby to docetaxel, that there is a significant difference than if you just treat the patient with docetaxel. The real question is, and this trial does not answer that, is abby upfront versus docetaxel, then Abby. Do you get more bang for your buck that way? We really don't know. We don't have any data to tell us that at this particular point.
I think that the data to conclude anything about survival in those patients, who've received docetaxel and then went on to receive enzalutamide is going to be very, very difficult because it's only 18% of the overall patient population. So none of these trials, whether it's Titan or ARCHES will conclusively answer the question about sequential treatment. But I think that it's something that we do need to think about. Now, the question is, how do we select one treatment versus the other? And this is a difficult discussion with the patients because A, some patients may not want to remain on pills. They sometimes wouldn't take their six cycles of chemotherapy and be done with it.
This is assuming that your hazard ratio, their hazard ratio is the same, which they are. Very, very similar for all of these particular agents, chemotherapy or next-generation hormonal therapy. So really the crux is chemo versus not chemo. And then which agent do you choose afterwards? So we know that these next-generation agents do have cardiovascular toxicity. In fact, there was a very interesting presentation that came out of Fox Chase about two years ago, showing that the rates of cardiac toxicity with abiraterone were higher than expected in patients who had preexisting cardiovascular disease. Remember these trials are selected out for those patients who may not have cardiovascular disease, or at least significant cardiovascular disease. So we've got to think about this in terms of what the patient's comorbidities are. What are we trying to accomplish with our patients? Do they have a lifespan that's going to be shorter from their comorbidities than with the duration of these treatments are?
So you've got to balance this out against what the patient's overall medical condition is. But chemotherapy, you get neuropathy neutropenia. The neuropathy can stay with patients for a period of time, but it's pretty much over and done with. Some patients don't want to have to monitor themselves with high blood pressure, hypertension for hyperglycemia, for edema, if they're on abiraterone, which is something you do have to do as well as liver function abnormalities. And those can be, in some patients significant. But again, I think it's selecting an anti-androgen such as enzalutamide or apalutamide or zytega or abiraterone and docetaxel. You have to think about what are the overlapping side effects and how's the patient going to do?

Tom Keane: So another question that springs to mind is the use of radiographic progression-free survival is the endpoint. Certainly it gets us an answer much quicker. Do you think that the FDA, it must have accepted when this, when this trial was approved ... do you think that's going to be standard now, or do you think that they're still going to want overall survival?

Dan Petrylak: I think eventually you do want overall survival to help you. So, there is a trial that showed that the primary endpoint was survival, and that's the ESMO study that was run by Chris Sweeney, predominantly in Australia. And that showed a survival benefit in favor of enzalutamide compared to a placebo. So, there still are survival end points that are being used here. Same thing with docetaxel, both in stampede, as well as in charted. And same thing with Karim Fizazi's trial with abiraterone. The radiographic progression-free survival comes from a castrate-resistant disease where hormonal agents were used and rPFS did correlate with no OSPF difference. And the assumption would be that it would be the same here. Now, this may not be true for every agent for every class of agents, but I think it is an acceptable endpoint, particularly when we're starting to develop multiple sequential treatments. It's going to be harder and harder to find a survival benefit, or it's going to take longer to see it because our patients are doing better.

Tom Keane: Good point. So you were one of the original docetaxel investigators, actually et cetera, et cetera. What's your opinion? And I'm asking this really, because it's always been fascinating to me that if the patient does non- [inaudible 00:15:13], then you can deliver a considerably higher dose of docetaxel, without seeing the side effects. Do you think that you will see some, but you can get more docetaxel in because once the patient has castrated, the liver blocks substantial amounts of the docetaxel? Is it possible that we've been underdosing patients with docetaxel? What would your position be? It's always struck me as, well if he needs chemo, give him the chemo and then do castration.

Dan Petrylak: Well, it seems that there's a certain threshold amount of docetaxel that you do need to see the survival benefit. We actually looked in the castrate-resistant state at the number of doses of docetaxel in the randomized trial compared lenalidomide to docetaxel plus lenalidomide. And we found that there was a correlation at eight cycles ... that or greater ... that's where you tended to see the best survival benefit.
So it makes sense that the more drug you get in, the better. I mean, there's certainly going to be a threshold that you're not going to really see much more of an incremental benefit. But we do know that in the trial that was performed in Europe, stampede, that there was a high rate of neutropenia, neutropenic fevers. And the thought was is that by giving these drugs immediately at the same time, immediately, while you're depriving patients of androgens, that that may interfere with the overall metabolism of docetaxel. And, so I generally wait a month, maybe two, and trials were permitting docetaxel to be administered within three months of androgen deprivation therapy. Just so things normalize out in terms of the testosterone levels in the pharmacokinetics.

Tom Keane: Right? But that makes sense to me, but it is also one of the things that I've been intrigued by, was the fact that there's GETUG-15 study, which was a study done in France. Basically, they gave the docetaxel two to three weeks after administering the ADT. And there was a number of mortalities ... excuse me, which they felt could be due to the fact that a lot of the patients weren't actually castrated at that time because they were using an agonist and three weeks into it. They had a very high testosterone. And that was one of the reasons that they saw some deaths they felt. But again, that's what led me to think maybe we be trying to get as much docetaxel in upfront and then castrate.

Dan Petrylak: Well, this is actually ... you're raising a fascinating question, that not only covers this particular issue with docetaxel, but also covers the potential role of immune therapy. So there was a fascinating abstract that was presented by Emmanuel Antonarakis' group, using his bipolar androgen therapy, combining that with nivolumab. So this is the theory that by giving testosterone back, that high doses of testosterone may actually have an inhibitory effect on prostate cancer cells or cause cell death.
And we do know that it causes DNA damage. It causes DEA proptosis at these higher levels. So the question he asked was, if we add an immunotherapeutic agent to this bat therapy, do you see a better response rate in castrate-resistant disease? And the answer is yes. It's actually a 40% response rate. And it backed by itself was probably about 30%. Now it's a small study and it may be related to patient selection, but there's always been this theory that the immune environment and the microenvironment is going to be different in a hormone-sensitive versus a hormone-resistant specimen.
And, we do things because we had built upon the evidence and we have to also understand the basic science, as well as the clinical science to really think about how we sequence these drugs, because perhaps a drug like, or a checkpoint inhibitor is best used right at the beginning of castration for a patient, rather than when they're castration-resistant. We know that pembrolizumab, for example, only works 3% of the time, three to 5% of the time.
And predominantly in those patients who've got microsatellite instability. We're actually doing a randomized trial. Right now, we completed accrual on this of docetaxel plus or minus pembrolizumab, with the thought that we're causing damage with the docetaxel, which would be recognized by the immune system. And then the pembrolizumab would stimulate the immune system and exploit that particular damage. So, the sequencing of these drugs is fascinating. The biology as to how they interact is fascinating. And then of course, the important thing is applying this to the patients and giving them more time with a good quality of life.

Tom Keane: And that is the whole point about these things. And you're exactly correct. Dan, it's been, as usual, a pleasure interviewing you, and you just continue to produce excellent trials after excellent trial. And congratulations on this one. I'm really grateful that you gave us the time today to come talk to uro today. Take care.

Dan Petrylak: Thanks Tom.