Read the Full Video Transcript

Nicholas James: I'm just going to plug my new podcast as well. The Twitter feed for it is listed underneath my name here. So behind the scenes look at setting up clinical trials—it's, I have to say, rather challenging. These are my disclosures, probably mostly not that relevant to this.

So what do we know about triplet therapy? And a lot of this ground has been partly covered already.

So we know that some patients getting ADT and docetaxel benefit from adding ARPI, and I'll have a quick look at the data on this. We also know, just going one step back, that only some patients getting ADT benefit from adding docetaxel. And finally, we know that adding docetaxel to ADT has a bigger impact on quality of life than adding abiraterone. So there's a few things that are pretty nailed on. And what we really don't know, and again, this has already been said, is whether adding docetaxel to an ARPI improves any outcomes at all.

So just to quickly go over the data on the triplet therapy because you've seen this already. So there are a number of trials, so PEACE-1. And in this case, we're interested in the later patients who all got docetaxel, who were effectively randomized to ADT docetaxel with or without radiotherapy plus or minus abiraterone. And what we saw, as reported by Karim Fizazi in The Lancet in 2022, was that there is a benefit, but the benefit is restricted to the high volume metastatic burden patients with no real benefit in the low burden patients. So some patients benefiting, but definitely not everybody.

The second trial in terms of when they were reported, ARASENS. And in this case, the benefit was seen in all subgroups. And again, very similar hazard ratio actually around 0.7 from adding darolutamide on top of ADT docetaxel, in this case given to everybody in the trial, so this is a pretty robust result.

The third trial though, and I haven't really got time to go into all of the fine detail of this, is the ENZAMET trial. So this, like PEACE-1, started out as a trial of ADT versus ADT plus enzalutamide in metastatic patients. And as the standard of care changed around 2015, 2016, docetaxel was introduced. And so later patients had ADT docetaxel as the base therapy plus or minus enzalutamide. And I know Chris Wood in particular has different views on this to me. But I think it's fair to say it's a less clear cut result in favor of triplet therapy than, say, the ARASENS trial is.

So just to highlight one result from this. The upper panel is synchronous hormone sensitive prostate cancer. The lower panel is metachronous. And I think it's the synchronous/metachronous thing that drives the differences here, not the high/low volume on the basis of our STAMPEDE data. And as you can see, there's no real convincing benefit in the metachronous, but there is a benefit in the synchronous.

So how do we resolve this? I think it's reasonable to say there are no randomized trials in progress or planned. I don't think anybody is doing one that I don't know about. So I think in order to decide who should get triplet therapy, what we have to do is to look at the suitability of the individual components and look at the side effects of the individual components.

And in terms of meta analysis, the only way we can do this really is via network meta analysis. So we can do it for the triplet, doublet versus triplet. We can do it directly for ADT versus the doublet. So in terms of meta analyzes that are useful here, I think we can probably agree it's only worth giving the triplet therapy if you're going to benefit from the docetaxel. And so we can work out who's going to benefit from docetaxel. And again there's a lot of literature on this. I'm just going to highlight this paper from our meta analysis group led by Claire Vale, published last year.

And there were a number of things that came out from this, one of them quite surprising, to be honest. So the first is that, apologies for the size of this. If you've got high volume disease, you benefit from docetaxel. And this applies to both synchronous and metachronous. And in contrast, if you've got low volume metachronous, you're quite possibly being harmed by having docetaxel.

And the second thing which came out was that if you've got high volume bulky primary, you appear to benefit from docetaxel as well. How do I go back? Sorry. So I have to say I was quite surprised by this, and I'm not quite sure how to integrate it into practice, but it does appear to identify an important subgroup of patients who maybe should be thinking about giving docetaxel to. It's quite a strong effect, as you can see from the forest plot.

Moving on. We know that-- of course, everybody in the room knows that docetaxel and the AR targeted therapies have different side effects. And this data was a sort of serendipitous spin-off from STAMPEDE and Hannah Rush, whose data I'm going to show you, is in the audience. And I was very surprised when these data came out. So within STAMPEDE, the tail end of the docetaxel arm overlapped with the beginning of the abiraterone arm to the tune of just under 600 men randomized directly between the two.

So these are a particularly interesting data set because they have all the same salvage therapies and all the rest of it and managed by the same clinicians. So we get a direct head-to-head look at quality of life. And what we can see is, of course, you get a dip in quality of life in red with the confidence intervals shown for docetaxel compared to the control arm, which is the black line. We didn't put the confidence intervals on this slide. It got a bit messy. And you can see that abiraterone actually increases your quality of life.

But the thing that was surprising to me was how long your quality of life decrement with docetaxel persisted for. It persists well beyond the end of the docetaxel. And so this is, it's reasonable to assume that if you go from a doublet with an AR targeted therapy to a triplet by adding docetaxel, you're imposing a big quality of life penalty on these patients.

So in terms of clinical case selection, I think we can reliably identify who does not benefit from docetaxel. And these patients, I would argue, are very unlikely to benefit from triplet therapy. And we also know there must be a quality of life penalty from adding docetaxel to ADT to ADT ARPI to get the triplet therapy.

So moving on to is there any evidence that there it might be better? As I said, the only way we can look at this is by doing a network meta analysis. And quite a lot of these are rattling around in the literature. And this is, I think, one of the better ones. So what you've got is a relatively tenuous link in the middle between ADT and ADT docetaxel, and then rather more populated links on the left and right hand side between ADT and ADT plus a doublet and ADT docetaxel plus versus a triplet.

And what this allows you to do is to compare the extremes of this. In this case, at one at the bottom left, the triple therapy, and at the top right, the doublet therapy with an AR targeted therapy. And what you see, this is the Bayesian probabilities with the reference treatment being the ADT AR targeted therapy doublet, is that probably the triple therapy is better. But as you can see, this is the second one down, the confidence intervals substantially overlap with one for this, but it is probably the best treatment. You can see that probably ADT docetaxel is an inferior treatment to ADT AR targeted therapy. And ADT alone is definitely the worst treatment with a very low probability of it being the best treatment.

So finally, what about biomarker approaches? And again, you're going to see some data that you've already seen, which is data from STAMPEDE with the decipher score from the abiraterone arm. Now, what I can't show you, but you will see at ESMO is the data—assuming the program committee accepts it, but I think they will—is the data from the docetaxel arm.

What you will also not see now, but you will see at some point in the future, is the data from the MMAI arterial profiling. So these may or may not show that we can select patients on the basis of biomarkers for receiving abiraterone. And I think it'll be very interesting to see these data.

So to wrap up, this is kind of a personal view of what I think the standard of care is. I think we should be splitting prostate cancer routinely into four boxes, synchronous, metachronous, and low and high burden. And pick your number for the number of mets, and it obviously is a bit dependent on your imaging modality.

And I think for the task I've been set, which is triple therapy, we're looking at the bottom rows here, and I think it's reasonable to say that some patients with high burden disease should be getting docetaxel. I think probably most low burden should not be getting it. And just to flag, we're just starting STAMPEDE2. It's a painfully slow business, as outlined in my podcast, starting a trial nowadays. And we're going to evaluate PSMA lutetium and PARP maintenance in relevant biomarker positive patients.

So in summary, some patients are unlikely to benefit from triple therapy and should not get it. Some patients may benefit from triplet therapy in terms of survival, but actually, we don't know the size of that benefit, if indeed it is there at all. And finally, all patients will pay a quality of life penalty for the triplet versus the doublet. And this is clearly a key component of the discussion that you have with the patients. Thank you for your attention.