Michael, thanks for joining us to break down this exciting trial.
Michael Ong: Thanks so much for having me.
Zachary Klaassen: So we have a plethora of doublet and now triplet options in metastatic castrate sensitive or metastatic hormone-sensitive prostate cancer. What's the landscape look like and what's the genesis for the TRIPLE-SWITCH trial?
Michael Ong: The genesis is that really we observe, thankfully now because of advanced hormone therapies, a lot of patients are doing just fantastic on hormone therapy. ADT and AR pathway inhibitors together. I mean some of the data, like say from ARCHES where you're at like five year survival, 58%, that seems fantastic.
So how do we begin to then personalize our choice of therapy? Not everyone needs the kitchen sink approach.
Zachary Klaassen: Sure.
Michael Ong: And I think that we have wrestled with for several years now, what is the role of docetaxel chemotherapy? What is the role of triplet on top of ADT ARPI? Our challenge has been there's no randomized trial. And what we're really lacking is what is the proper patient selection criteria?
Our selection criteria largely has been dependent on high volume disease, but we know high volume disease is actually just a surrogate, like it's a prognostic marker. And it's not a marker of whether you're sensitive to docetaxel or not. So that's the genesis of this trial, is when we've looked at many, many, many randomized clinical trial analyses, what is the single most important predictor prognosis long-term? It's PSA response. PSA and through analyses of, say, TITAN and Latitude and Enzymet, et cetera. And also real world databases like Ironman, all of these data points say the same thing. A PSA of under 0.2 nanograms per mil, patients are doing excellent. You have very good three to five year survival. You may not need to do more. There's even deescalation studies out there.
Zachary Klaassen: Sure.
Michael Ong: Whereas patients that have a persistently high PSA, 0.2 or greater at six to 12 months, they may need more. Time to progression is about one year on average. Survival's about three years. So this is the origin of this trial.
Zachary Klaassen: It's a great background. I think the trial design for TRIPLE-SWITCH is really important. So take a minute just to walk our listeners through what the trial design looks like.
Michael Ong: So when I'm talking to a patient, metastatic hormone-sensitive prostate cancer, we talk about all the doublet options and then we talk about triplet intensification. For those, the vast majority of patients do not get triplet intensification. They are in doublet. And this has a lot of advantages for patients.
Zachary Klaassen: Sure.
Michael Ong: But first of all, I think when you start on this and you look six to 12 months later, a lot of patients, if you are thinking about triplet but their PSA ends up being undetectable at six months, they've been spared chemotherapy. We've been looking at some databases. That number is about 50% to 68% of patients actually they normalize their PSA within the first six to 12 months. So the whole idea, that this patient population, you could be sparing patients with that TRIPLET.
Now, if you look at the patient population of this study, this enrolls patients that have PSA, hormone-sensitive prostate cancer that's metastatic, PSA of 0.2 at six to 12 months after at least six to 12 months of ADT and at least four months of AR pathway inhibitor. It can be any of the AR pathway inhibitors, so abiraterone, enzalutamide, darolutamide, apalutamide. The PSA start... At the start of ADT need to be at least two or greater. They need to have metastatic disease. Can either be by PET PSMA or conventional imaging when they started on their hormone therapy. And then of course they're eligible and fit for docetaxel chemotherapy.
And the trial design is a one-to-one randomization where you either continue your standard of care ADT and AR pathway inhibitor or you add on six cycles of docetaxel chemotherapy on top of that standard of care as per the charted regimen. The primary endpoint of this study is overall survival.
Zachary Klaassen: Excellent.
Michael Ong: Sample size of 830 patients. We do not have radiographic progression-free survival as a secondary endpoint, which means we are not doing regular scans, but we are doing the regular PSA type endpoints, PSA response, depth of PSA less than 0.2 NADR, less than 0.002. We are doing some very interesting correlatives by Alex Wyatt at the Vancouver Prostate Center looking at circulating tumor DNA. And also we're collecting the primary tumor samples to look at all the potential predictors of docetaxel sensitivity.
Zachary Klaassen: This is great. I mean, I think if you look at the trial design, we're going to appropriately keep people on ARPI and ADT that are doing well, as you mentioned, going to potentially escalate with docetaxel and those that aren't doing so well.
So we look at potentially practice changing trials, this really is one of them. Where do you see this fitting in? How's the trial accrued going? I think it's been open for about a year now. What's the status of the trial?
Michael Ong: Yeah. So it's just such an exciting space because there are multiple entities and players interested in this for other drugs potentially.
Zachary Klaassen: Sure.
Michael Ong: This approach. What we're talking about is personalizing prostate cancer treatment based on how well you're doing with the hormone therapy and not necessarily introducing difficult drugs unless you have evidence of androgen insensitivity.
Zachary Klaassen: Sure.
Michael Ong: So I think there are going to be multiple potential trials down the line if we're successful with this approach. What's new for patients is that we're kind of trying to increase the bar for success. It's not good enough just to bring your PSA down from a thousand down to a hundred. It's actually that we want to make it undetectable. And if you're doing really well, you might be spared other treatments. So this idea of personalizing treatment less for some, more for others is very attractive. And using a biomarker that we all agree is a very important biomarker rather than some of these fancy biomarkers that we don't necessarily have access to. I think it's a very pragmatic way of selecting patients.
Now it still doesn't mean that you're sensitive to the drug and we need to develop more biomarkers, but I think that it's this trial and it's my hope that it's going to change the landscape in general regardless of the result of the study. We do these studies we don't know, is this trial going to be positive? It's not going to be positive. I mean, truly if adding docetaxel at this time point, six to 12 months, doesn't improve survival, we shouldn't be adding in docetaxel. I think that actually... A lot of people believe that it may not be necessary.
Zachary Klaassen: Sure.
Michael Ong: So I think this would help to answer that question. I think there's just so much enthusiasm about the concept worldwide. Honestly, the kind of feedback that we've gotten everywhere is that this is so exciting.
I should mention who is running the study then is the Canadian Cancer Trials Group as the sponsor, but this is a NCTN sponsored study. Our collaborators and my co-chair, Alexandra Sokolova from SWOG and she's at OHSU in Portland. They're accruing as much as we are accruing at the Canadian Cancer Trials Group. So the entire NCTN network is involved.
Zachary Klaassen: Excellent.
Michael Ong: I think there are multiple concepts around the world that are also interested in this exact concept, meaning personalized accrual at six to 12 months based on PSA. So it's an exciting time. And so we're on the rise of accrual.
Zachary Klaassen: That's awesome.
Michael Ong: And hopefully many more interviews that come about how we're doing and as we get this new concept going.
Zachary Klaassen: No question. And you've laid it out beautifully. This is one of my favorite trials. And I think these conversations are great because it gets the awareness out there. People want to get involved. So thank you for joining us, breaking down TRIPLE-SWITCH. It was great.
Michael Ong: Okay.