Prof Declan Murphy on interpreting the PROTEUS trial in localized prostate cancer

[00:00:02][music] [bell] >> Once you see a trial like this being presented in the ASCO plenary, which is the absolute top tier of oncology presentations once a year, plus a simultaneous publication in the New England Journal of Medicine, you've got to say, "Okay, you know, this is a a significant study, and therefore we've got to look at it very carefully." So, I think that's already recognition of how important a trial this is that it it got into that forum and into that journal all in the one day.

[00:00:45]Uh but yes, so why does it matter? Why does it matter to urologists and anyone working in localized prostate cancer?

[00:00:52]Well, it's been long-awaited, you know, the the PROTEUS trial. I suppose we're sick of hearing for the last 3-4 years, "Well, you know, when the PROTEUS trial reads out." So, here we are. So, the reason we've been anticipating it is it's very large, you know, 2,100 patient multicenter international double-blinded randomized trial of surgery in high-risk prostate cancer.

[00:01:15]So, that is enormous. That's by far and away the biggest trial of that description we've ever seen.

[00:01:22]Uh plus, you know, it was testing an interesting hypothesis whether perioperative hormonal therapy, so 6 months before surgery and 6 months after surgery, might improve, you know, some key outcomes for patients.

[00:01:38]And that's an unmet need. These high-risk localized prostate cancer patients tend to have higher rates of relapse requiring further treatment. So, for for all those reasons, you know, huge trial in a big forum, unmet need, well-powered important questions, that's why PROTEUS got everybody's attention.

[00:02:06]So, certainly one of the challenges in interpreting a trial like this is the reality that the control arm in the trial which was ADT androgen deprivation therapy for 6 months before 6 months after surgery is not the standard of care. And you know, traditionally in in in randomized trials we are testing a new thing against a standard of care.

[00:02:29]But you know, as I highlighted in my discussion that ASCO ADT is not standard of care which begs the question, you know, why was it chosen? And you know, have we concerns that this control arm may be below at the standard of care.

[00:02:44]It's always a concern when you don't have a standard of care control arm.

[00:02:48]And Dr. Taplin, the lead author, did explain in the Q&A at ASCO a little bit about why this was chosen. She explained that for reasons to maintain the double blindness in the trial, they wanted to include it and they recognized that without it if patients were randomized to the non-intervention arm, there would be a lot of default in that arm. And she highlighted that we saw that in the VISION trial before they adjusted their protocol. The people are being attracted in because there's a novel thing and if they clearly know they've been randomized to the not novel thing, there is a problem in retaining and following up those patients and getting proms and so on. So, we understand that and also it was following discussions with regulators and sponsors and so. And it's not rare, by the way, to have that in a neo-adjuvant trial. So, we we can understand why the investigators chose ADT. But also in discussions with Dr. Taplin I know that when Proteus started out, it was an investigator-initiated study with just surgery in the control arm.

[00:03:50]So, so was following all those considerations in a trial probably costing hundreds of millions of dollars and that they you know also were dealing with regulators that that's why it was chosen. The second thing as I flagged is well, you know, do we have concerns about that in the interpretation and in my discussion I outlined the reasons why no. I mean I I have no concerns about that and I believe that it will and is can be compared to standard of care because what we know from you know neo-adjuvant trials of ADT going back the decades is that it doesn't make things worse. In fact, we do see pathological responses. We see better surgical margin rates, less lymph node positivity rates and so on. But what we haven't seen is improvements in key oncology endpoints like MFS and OS, you know, and in this trial, the Proteus trial, the co-primary endpoint was MFS metastasis-free survival.

[00:04:46]So I don't have any concerns that you know this is going to be a detrimental thing that it's not somehow making the intervention arm look good because the control arm is dragging things down. And finally, you know, as we heard in discussion, we are aware that there is this so-called Proteus sub-study that is also completed which has radical prostatectomy on its own with no ADT as the control arm. That's a 400-person study randomized three to one for radical prostatectomy versus the the Proteus intervention arm.

[00:05:19]So that data will help us understand, you know, what it would be look what it would look like without ADT and as I said that's fully accrued and so I suppose we'll see that data in the next year or so as well.

[00:05:33]>> [bell]