Episode 119: In the Clinic - Discussing the INTENSIFY trial in metastatic prostate cancer with Professor Simon Crabb and Dr Sarah Chamberlain

Welcome to the Simply Oncology Podcast. 

Today we are focusing in on the prostate cancer trial called INTENSIFY. 

This is a trial where we will look at intensifying metastatic prostate cancer patients.

Those patients established on combination LHRHa and ARPi therapy could then be randomised at 6months to adding chemotherapy or not if they don't have an optimal PSA tumour marker improvement.

We have brought the wonderful Professor Simon Crabb, and Dr Sarah Chamberlain from the oncology team at Southampton. They are part of the leadership team for the trial. 

This trial is already running in some centres and we discuss why it is happening and how it would be delivered.

Transcript

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Simply Oncology Podcast Recording INTENSIFY-20260813_153702-Meeting Recording

 Welcome to the Simply Oncology Podcast. On our next episode, John, we are focusing in on a prostate cancer trial called INTENSIFY. Mike, I think we are seeing so many changes in this frontline setting in prostate cancer. I love it. We've been living it and seeing
 the new treatments coming along, but this trial is looking at using known treatments, but in a different way. And who have we brought? We have brought the wonderful Professor Simon Crabb, who's a consultant medical oncologist at Southampton. And alongside him, we have Dr. Sarah Chamberlain, who is
 a medical oncology trainee and currently undergoing a PhD, but heavily involved in the inception and delivery of this trial. Welcome both. And what trial is it? Simon, tell us.
Simon Crabb   1:30
 Well, yes, thank you.
ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST)   1:32
 This is like, if this was a like a chat show, this would be like you bringing your book out.
Simon Crabb   1:37
 Yeah, yeah, yeah, that's exactly how it feels. First of all, thank you very much for having us to talk about this. So yeah, Intensify is a study where we're going to look at patients who have started hormonal therapy doublets, so ADT, androgen deprivation therapy.
ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST)   1:41
 Oh.
Simon Crabb   1:58
 and an ARPI, an androgen receptor pathway inhibitor. And they're approximately six months into treatment and their PSA has not yet got below 0.2. And we're going to look at that group of patients because we know they have less good outcomes. And we're going to see whether or not intensification
 hence the name, of their treatment at that point is a useful thing. And we're going to do that in a very simple way. We're going to randomise them to whether or not they get dose attacks or chemotherapy for six cycles or not. And everyone carries on with their hormonal therapy and then we will follow them up. The study is quite simple in the sense that we're
 powered for overall survival. So you're going to see whether or not this makes people live longer. But in addition, everyone's going to have some genomics done. We're going to do something called the decipher score and something else called a PTEN inactivity score to look at whether or not those genomic classifiers are able to
 identify patients who benefit from the addition of the chemotherapy. And that's based on some respective data that was published last year from Gert Attard's group that suggests that it may be the case that those scores can predict who benefits from the chemotherapy.
ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST)   3:20
 Okay.
Simon Crabb   3:20
 So, that's the sort of nuts and bolts of the trial in very simple terms.
ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST)   3:25
 I'm just going to cut in there, Mike. An early interrupt. And that's really interesting. I think I love the P10 aspect of it because we've seen that story of P10 changes showing some chemosensitivity. Sarah, just talk us through, is this all comers? So is this...
 Are we in a charted or a latitude high volume, low volume stratification or a kind of, are there exclusions within that kind of group of patients on double ADT or double hormone therapy?
Simon Crabb   4:02
 So, I mean, it's to a degree there will be. So there are some patient groups that we aren't currently including. So for example, when we talk about the RP that they're going to be on, we at the moment are excluding patients that are having apalutamide. And that's based on an interaction
 pharmacologically with the docetaxel. However, I understand from speaking to Simon recently that we're currently putting through an amendment based on some recent data that suggests that actually we could be including those patients. So obviously we want the trial to be as inclusive as possible. So hopefully when that amendment goes through, we will be able to include those patients as well.
ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST)   4:32
 Thank you.
Simon Crabb   4:42
 In terms of how we're stratifying the group, it will be an all-comer group, but we will stratify by what androgen receptor pathway inhibitor the patients are on and also by those scores that Simon mentioned, so the decipher score and by the P10 inactivity score and also
 by another stratification factor will be for patients that have had prior prostate radiotherapy, obviously pulling out that separate group as well. But we've really tried to make this a trial that's very pragmatic, I'd say, and one that can be as inclusive as possible. Obviously, as you've mentioned at the beginning, it's using drugs that are in routine
ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST)   5:15
 Okay.
Simon Crabb   5:20
 for prostate cancer. So we've tried to make sure that it's not just including sort of the big tertiary centres that do a lot of the trials, but actually that perhaps smaller centres can be involved. And that means that more patients have access to cancer trials, which is important.
ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST)   5:37
 And ultimately, I think what I really like this trial is it's trying to be a bit more clever about selection of patients because we know that out of our options in that first line setting in metastatic hormone sensitive prostate cancer, you've got your doublet choice, which is ADT plus ALPR, but you also have that triplet choice, don't you, for
 with the inclusion of docetaxel up front. And although we try and decide based on things like volume and extrapolate from the trials that we know who could get, who's going to benefit most from it, in practise, you have a general feel from that, but you definitely have some low volume disease, low grade
Simon Crabb   5:56
 Okay.
ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST)   6:15
 you know, low risk or lower risk metastatic disease that you think on paper should do incredibly well and doesn't. And then you've got some people in the high volume who were technically high volume by criteria, but because of comorbidities, you choose to use doublet and do incredibly well on doublet anyway for many, many years. So it's really how many people are we
 over treating with that triplet therapy and how many treatment people are we potentially under treating by giving them double it. And what I love about the pragmatic aspect of this trial is giving a bit of biological feel to how are they actually going to do, have they hit that prognostic mark? And then can we then intensify based on that rather than just upfront scattergun approach?
 where we are probably over and under treating people.
Simon Crabb   7:01
 I mean, the only thing we don't have any prospective data. We don't have any randomised data to tell us whether or not we should be adding in the chemotherapy. So I've actually no objection, first of all, to people using a triplet. If they choose to do that, they've discussed it with their patient. I would say also they discussed with their patient.
 that we don't actually know whether you need the chemotherapy upfront. There is nothing wrong with doing this. It is an acceptable treatment. That said, certainly my experience is a lot of patients are not that keen to get on with chemotherapy when they're first diagnosed.
ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST)   7:35
 Mhm, mhm.
Simon Crabb   7:37
 quite commonly, we want to have just a doublet hormonal therapy. And I think that is also a very reasonable option. So my feeling is you should be offering a choice to patients. Clearly, there'll be some where you won't feel that chemotherapy in addition is appropriate, but for most patients, I think it's reasonable to offer a choice. We, when we set this trial up,
 One of the things we did in the feasibility work was to survey our prospective centres and say, okay, so you know, how much triplet therapy are you actually giving? It turns out it was somewhere between, and this was of suitable patients, so it's not all comers, this is people you think could tolerate it. It was somewhere between 5% and 30%.
ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST)   8:06
 Mm.
Simon Crabb   8:17
 between investigators for the trial. So the practical, I mean, in simple terms, a significant proportion of people in this country are getting a hormonal therapy doublet, rightly or wrongly, that's what they're getting. And actually, if you look internationally, including the states, that is a similar pattern.
ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST)   8:20
 Mm.
 Mm-hmm.
Simon Crabb   8:37
 So clinicians are not completely convinced, patients are definitely not completely convinced, and we need some prospective data. So hopefully this trial will at least provide some of that.
ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST)   8:37
 AND.
 And that would resonate a little bit with me. Whenever I have a patient, metastatic prostate cancer patient, I do actually come out and say, we will fall out if you do not want to have combination hormone therapy, because it has been the biggest advance that we have seen in the upfront setting since Huggins.
Simon Crabb   9:01
 You.
 And.
ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST)   9:06
 And a game changer. The docetaxel is an option. It's a discussion. There are pros and cons. And you know, there's fors and against. But if you can have ADT, in my opinion, you can combine that with an RP. You can certainly at least try that.
Simon Crabb   9:07
 Yeah.
ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST)   9:25
 I am shocked, however, at 5% of eligible patients, that, you know, at the lower end of that spectrum, whoever put 5% in, I would say, well, gosh, I would have more patients that want to try to hit the do everything button than 5%, but it does show how good a backbone the combination hormone therapy is that
Simon Crabb   9:31
 Yeah.
 Yeah.
ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST)   9:45
 people don't feel they need to go beyond. So I really like this trial because it's saying to people, let's take the concrete, the doublet, and then let's add in chemo if there's other factors at play. And I think from again, and it'll be interesting to see, because I know, Sarah, you did a lot of.
Simon Crabb   9:59
 Yeah.
ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST)   10:04
 patient involvement in the project, and we'll come on to that in a little bit. It'll be interesting to see because, again, thinking about when you want chemotherapy, and particularly when there is a lot of uncertainty about the potential benefit, then that makes you much less likely to want it. Whereas, you know, when there is, you know, when there is more potential concrete benefit, more
 objective evidence that, oh, this things are not going to plan. Maybe we need to try and hit it harder. That makes it much more attractive and you'll be possibly more inclined to deal with some of those toxicities because there's potentially more gay. You know, we, you know, that's why we always think, you know, in the castrate resistance setting, if you've not had chemotherapy up front and you're still fit, then people will consider it at that point because, well,
 you've been kind of pushed towards that decision for a reason being that you've progressed. Whereas when you're up front, it's so uncertain. Where does, so... Talk to us about.2. Sarah, I want to. There'll be people out there. We're going to have some bullet-like questions. With people out there, Simon, I want you getting ready with Decipher in the background here.
Simon Crabb   11:00
 Big.
 And.
ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST)   11:08
 But why.2? We've heard this quite a bit recently.
Simon Crabb   11:12
 Yeah, so I think when we were sort of setting up and thinking about designing the study, we looked a lot at published data in clinic, mostly in the clinical trial setting, but also in real world, where, you know, real world data have been published. And quite consistently when you looked across the board at patients, but they were on doublet treatments,
 you could see that this was the mark that when you got to a, it was a, you know, there was a range probably of between sort of five to eight months, but essentially around six month mark for patients that didn't get below 0.2 for their PSA, their outcomes were worse, their survival was worse.
 So I think that we obviously were using a combination of what was available data wise in clinical trial, but also looking at real world data that suggests that, you know, patients that don't get, you know, what I guess we would term a suboptimal reduction in their PSA. So we know that all patients when we start them on treatment, they will get a reduction in their PSA.
 but we obviously watch, you know, carefully as they're on treatment to see what the response is and where that plateau comes. And when it happens before they get below 0.2, their outcomes are poorer. So it's trying to kind of pick out an easily identifiable group of patients, I guess, through something that we're doing really routine.
 routinely in clinical practise to monitor them and say this is probably a higher risk group that potentially might benefit from an intensification of their treatment. There is also some simple practise, we're going to say pragmatic quite a lot in this discussion.
ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST)   12:43
 Every UK based trial, every UK based trial always uses the word pragmatic.
Simon Crabb   12:46
 Yes.
 But so one aspect in this in truth is, you know, clearly it's a continuum. You know, there's nothing magical about pointing. But if you pick.2, first of all, there is quite a lot of data out there. That's that helps when you're trying to design the trial. But also,
ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST)   12:55
 Yeah.
Simon Crabb   13:07
 If we'd done this trial at baseline, just included everyone, it would have been, you know, 4000 patients. We just never got it done. If you do it at this stage and you select people who have a poor outcome because of this cut point in PSA, suddenly you can do a trial in 500 patients. So you can actually do the study. I mean, so some of it is just simple pragmatism that this is
ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST)   13:15
 Mm.
Simon Crabb   13:27
 gets us down to a sample size we can actually take on. I think also clinicians get it. I think one of the things that have struck me about trying to sell this to sites, everyone seems to understand the idea that yes, these are the people that I know don't do quite well and I'd like to do something differently, but I don't really have the ability to do that.
ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST)   13:43
 Mm.
 Mhm, mhm.
Simon Crabb   13:46
 Currently, this is a trial that hopefully that will make sense to. I hope also, and it's going to be important that it makes sense to patients.
ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST)   13:56
 Yeah. Yeah. And you're absolutely right. There's been so much data coming out as that 0.2 cut off, you know, so I think I'm in, I'm in. The other, the other, the other really pragmatic thing that I really liked from your study design is about about when we choose that cut off and the timing around that cut off, because the cut off is very binary, 0.2 or not.
Simon Crabb   14:01
 Mm.
 Mm.
 Mm.
ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST)   14:18
 But there is a time frame that allows for a bit of flexibility to get people in. Can you tell us, Sarah, a bit about that?
Simon Crabb   14:24
 Yeah, I guess, again, well, I'm not going to say pragmatic now, am I? I'm not allowed to, but...
ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST)   14:29
 I'm going to Google, I'm going to get a thesaurus site, and then we'll find another word for pragmatic.
Simon Crabb   14:31
 Yeah, the thesaurus. We need the thesaurus.
 I think it was more thinking about, you know, again, that inclusivity of thinking about how sites might be set up to recruit these patients. So when you look at the data, again, it's not a cut off of if you're past six months, that it's, you know, there's no way that it's going to be of any benefit to you. But what we wanted to do was make sure that there would be time to identify these patients.
ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST)   14:54
 Mhm.
Simon Crabb   14:54
 And ideally, you know, because we're obviously watching the trend in their PSA, we hope that that could be done fairly early, so that if people, you know, are kind of mindful of the study, that they'll start identifying patients where it looks like their PSA isn't responding as we might hope. And then it gives you time to kind of do the screening processes, you know, talk through. I think it is quite a nuanced discussion with the patient, as you guys, you know, everyone has kind of alluded to that, because you're not saying
 Well, two things, I suppose. One thing is that you're not saying that someone's never going to get chemotherapy because obviously if they didn't get it in this setting, they'd still be eligible, potentially eligible later, providing that they were still fit at that time. But also that if they don't get randomised to the treatment arm, they're just going to continue on what they're having. And
ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST)   15:25
 Mhm.
Simon Crabb   15:39
 you know, that's obviously quite a perhaps quite a challenging discussion to have with a patient to help them to understand that. But obviously, you know, that is the standard of care. That's what we would normally do now, even in the setting of that PSA result, we would just be watching them carefully and deciding, you know, when might be the right time to continue treatment or change treatment. So I think those, you know, were kind of all important things that fed into we don't want to be too
ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST)   15:42
 Mhm.
Simon Crabb   16:03
 specific about when that time might be and that we, you know, the data doesn't suggest that it has to be that rigid, that we can, you know, provide a time frame and that as long as it's within a reasonable time frame, which we've done 5 to 8 months, so we've given a 5 to 8 months of the ADT and then have had at least 12 weeks of their
 and their RP. So we're trying to be, you know, provide a degree of flexibility that allows more inclusivity, but still is relevant in terms of what data we have to support the study.
ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST)   16:23
 Right.
 And how we discuss this with our patients, as always, is going to be so important because what we don't want to say is you're in a high risk group. We think you might need chemo. You've gone in the trial, you're not getting chemo because you've been randomised to it. And then they feel that they have had something taken away. And with trials, it's
Simon Crabb   16:38
 Yeah.
 Yeah.
 Yeah, 100%.
ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST)   16:52
 always about the language that we use when we speak to patients. When you talk to the patient groups, how did they feel about it?
Simon Crabb   17:00
 I think again, it was about careful selection of language. So I think if they, providing that I explained to them very clearly about what we would normally do in this setting and where the evidence lies for what our current practise, it's they understand and you know, there were people within that group, the focus groups that we had that had metastatic prostate cancer and they were on this these combination treatments. So they potentially could have been recruited into this.
ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST)   17:04
 Mm.
Simon Crabb   17:25
 trial. So I think they really, you know, they had a lived experience of potentially being, you know, in this group. And I think that they definitely understood it. I'm not sure that still people won't feel a degree of disappointment if they don't get randomised to chemotherapy, but equally, they're, you know, as we talked about, there's a balance because they're
 going to have the toxicities that are going to be associated with adding that extra treatment in. The message is going to be quite important here as well. These people are not progressing. No, they're responding.
ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST)   17:48
 Mhm.
 Yes, yes. And they just haven't hit on more PS. They're actually responding. That's the thing, isn't it? Yeah.
Simon Crabb   17:57
 Yeah. Yeah. You think about most of our drug trials, they come at the point that the cancer has progressed and you're having a conversation about, okay, what next? Or at the beginning of the pathway, you know, they've just been diagnosed and you're talking about, okay, this is the, this is your options for how we might treat this. This is a little bit unusual in the sense that you've got to have that conversation where you say, okay, well, your PSA is coming.
ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST)   18:03
 Yeah, yes.
Simon Crabb   18:17
 down, your scans looked okay, we're happy that your cancer is coming under control, but your PSA is not yet as low as we might optimally like. And that's an interesting conversation to have with a patient, I think, which we'll need to keep a careful eye on, I think, is how that's going at sites, how investigators are finding that.
 Yeah.
ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST)   18:39
 You mentioned imaging there, Simon. Do you, in the trial, is there a requirement to see ongoing response on imaging or is it more to do with the PSA and less to do with the imaging?
Simon Crabb   18:48
 So we went backwards and forwards a lot about this, about whether we were going to mandate imaging, whether we're going to mandate imaging during the, you know, once patients were in the trial and treat. In the end, we stripped it all out and said, no, we're going to trust the investigators to do sensible things in how they're managing these patients.
ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST)   18:54
 Mm.
 Mhm.
Simon Crabb   19:07
 And so the way that the protocol talks about this, patients are not allowed to have progressed, clearly, that they haven't got CRPC. But we're going to allow investigators to do that by their institutional standards. My assumption is
ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST)   19:17
 Yeah.
Simon Crabb   19:27
 My assumption is probably, generally, that will mean patients will have had some scans by six months. But we are going to trust the investigators to do this the way they would normally do it. Now, you can sell that and say, well, that's real world. That's, you know, we're not going to put in scans that aren't always going to happen.
ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST)   19:46
 Mhm.
Simon Crabb   19:46
 But we thought that it was a difficult decision. We thought about this quite a lot. One of the challenges with a trial like this, which we're very pleased to be funded by Prostate Cancer UK, if you put lots of scans in, you mandate and it makes the trial extremely expensive and difficult to do. And then also you've got to decide, well, exactly what imaging are you going to do?
ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST)   19:49
 Hmm.
 Yeah.
Simon Crabb   20:08
 Of course, trying to get people to agree on that is not necessarily easy. The truth is, these are people who the investigator believes has responding hormone-sensitive prostate cancer. I think we should trust the investigators to investigate properly as these patients come to the trial and make a decision about whether or not that's the
ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST)   20:11
 Mhm.
Simon Crabb   20:30
 Nice.
ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST)   20:30
 Mhm.
Simon Crabb   20:33
 Rather than you know forcing them fixing it, you can imagine this is a commercial study that they're having scans every.
ROWE, Michael (ROYAL CORNWALL HOSPITALS NHS TRUST)   20:38
 Oh, it'd be 8 weekly, 8 weekly. I would have prostate prostate working group counting of the number of bone mets and we'd be back and forth to radiology. Now, you took.
Simon Crabb   20:40
 
 Yeah.
 And I can't, the comparison I make would be with STAMPEDE, where we've shown that you can run, I'm going to say the word, pragmatic studies, and they work. I mean, and they can be delivered and you don't necessarily have to shove in scans every eight weeks, for example.

Thank you Simon and Sarah.

Join us next week for part 2 of our special podcast on the INTENSIFY trial in metastatic hormone sensitive prostate cancer.