ASCO 2022: Latest developments in mHSPC and mCRPC

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Published: 6 Jun 2022
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Prof Heather Payne, Prof Kim Chi, Prof Laura-Maria Krabbe and Prof Kurt Miller

Prof Heather Payne (University College Hospital, London, UK), Prof Kim Chi (Vancouver Prostate Centre, Vancouver, Canada), Prof Laura-Maria Krabbe (University of Muenster Medical Center, Muenster, Germany) and Prof Kurt Miller (Charité - Universitätsmedizin Berlin, Berlin, Germany) discuss the latest developments in mHSPC and mCRPC. Prof Payne initially introduces doublet and triplet therapy in mHSPC.

Prof Krabbe discusses the updates from ENZMET study and compares the results to other triplet therapy studies. Prof Miller discusses the results from the VISION trial and explains the updates on TheraP.

Prof Krabbe and Prof Chi also comment on radioligand therapy options.

Prof Chi gives an overview of the MAGNITUDE study and discusses the gene-by-gene analysis in the MAGNITUDE study of niraparib with abiraterone acetate and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations.

He also talks about the results of HRQOL and pain outcomes in MAGNITUDE. The panel concludes by giving their final comments on the topic.
 

This programme is supported by an unrestricted educational grant from Janssen.

HP: Hello and thank you so much for joining us for this ecancer expert round table discussion on

some of the latest data from ASCO looking at metastatic hormone sensitive prostate cancer

and metastatic castration resistant prostate cancer. My name is Heather Payne, I’m a clinical

oncologist from London and this data is pretty hot off the press. To guide us through our

discussions today we have an expert panel who I’m going to ask to introduce themselves to

you.

 

KC: Hi, I’m Dr Kim Chi, I’m a medical oncologist from Vancouver, Canada.

 

LK: Hi, I’m Laura Krabbe, I’m a urologist from Muenster, Germany.

 

KM: Hi, I’m Kurt Miller, I’m a urologist from Berlin Germany.

 

HP: Thank you very much. Now, once again we’ve had some really good data coming out of ASCO

and to start with we’re going to think about metastatic hormone sensitive prostate cancer. Now

this has been an area of huge development over the last few years. For decades we treated

men with ADT and added in other drugs at recurrence when they developed resistance. Then

we had doublet treatment – docetaxel, the androgen receptor targeted agents, which showed

huge long-term benefits including overall survival. Now, despite that, real world evidence would

tell us that not every man is even getting doublet treatment when they present with metastatic

hormone sensitive prostate cancer or relapse to that stage. While we were getting our heads

around doublet treatment, we’ve had two studies presented looking at triplet therapy with the

addition of docetaxel and an ARTA to ADT. Now, when these two studies, PEACE-1 and

ARASENS, were developed ADT and docetaxel were standard of care. So in these trials we

haven’t had an ADT and ARTA arm. The community is fairly divided as to who should be

having triple therapy. Now, Laura, we’ve seen today some results from the ENZAMET study

and we’ve all been waiting for the next bit of data. Could you tell us what that showed?

 

LK: I’d love to, thank you. So the ENZAMET trial is a little bit of a special trial in this space because,

a) it’s an investigator-initiated cooperative trial so it’s not primarily a registration, company-

sponsored trial. And then the second thing is that it did as a control arm have active control. It

was not ADT alone, it was ADT plus a non-steroidal anti-androgen. So that’s a very different

control arm than what we had in other trials, for example. The question of this trial was is

ENZAMET in addition to ADT beneficial, as compared to ADT plus the non-steroidal anti-

androgen of the first generation, if you want to. We have seen data from it with a benefit,

despite the control arm being more active than ADT alone. Now we’ve received data from a

longer follow-up. The follow-up is 68 months which obviously is very mature and the first thing

that we see is that the OS benefit of the addition of enzalutamide is sustained through all this

time. So after five years there’s an OS benefit of 10%, 67% versus 57% for the control arm, so

that is still a very positive trial with a positive signal.

 

Then there was another speciality to ENZAMET, if you will, because patients were allowed to

receive up to two cycles of docetaxel previously to entering the trial and then from 4-6 cycles on

the trial. So physicians could basically plan to also add docetaxel. That was obviously a little bit

different than in the other trials and about 45% of patients in the ENZAMET trial had planned

docetaxel, two-thirds, round about high volume disease, a third about low volume disease. That

obviously makes this trial a little bit special and maybe also a little bit complicated.

 

Still, we have this whole trial beneficial result which is sustained, as I mentioned, and we also

see that when we look at the subgroups that especially patients with low volume disease did

benefit from the addition of enzalutamide in comparison to the control arm. That, for one, is a

very important take-away because I know many physicians ask themselves do low volume

patients actually need treatment intensification. We have added data here that it’s not the whole

group only that’s benefitting but in the subgroups the low volume patients do benefit. So we

have another bit of data saying, yes, they do need intensification.

 

HP: Do you think this has… I’ll ask everybody this, do you think this has helped us? Should we be

using doublet or triplet therapy? What about the docetaxel, did that add anything?

 

LK: Well, it added another bit of information. First we have to think a little bit about the differences

between the ENZAMET trial and the two trials you’ve mentioned, PEACE-1 and ARASENS. If

we go from the most recent trial, ARASENS, and look backward then obviously they are a little

bit different in this set-up. So in ARASENS standard of care was ADT plus docetaxel for the

whole trial. So every patient received ADT plus docetaxel and the question of this trial was

does the addition of darolutamide add something for this patient population. Then in PEACE-1

over time the standard of care changed as was adapted by the data coming out of CHAARTED

and STAMPEDE, so there was a point in time where ADT plus docetaxel as a standard of care

was permitted and it was physician’s choice but then it was made mandatory. Still large

numbers of patients received ADT plus docetaxel so the question of this trial basically became

does the addition of abiraterone add something to ADT plus docetaxel. In both of these trials

the answer was yes and there was big statistical power for that.

 

In ENZAMET it’s a little bit different because it was at physician’s discretion if they wanted to

add docetaxel. So that’s obviously a little bit of an individual choice that was made for the

patients and even though it was stratified for docetaxel use, it’s different than it was protocol

mandated. Also, the question in this trial is a little bit different because it’s a side question. The

primary question of ENZAMET was does the addition of enzalutamide to ADT, is that beneficial

in comparison to that control arm. The side question that we can get some bits of information

from is does the addition of docetaxel add something to ADT plus enzalutamide. So that’s really

nice because you said that that was missing in the other trials. We see that there is a group that

is in favour of this triplet therapy and those are patients with de novo high volume disease

which we see in those other studies too. So it’s fairly in line and helpful to select patients

between doublet and potential triplet therapy.

 

KC: I’m going to disagree with you here because I think all three trials, what they’re showing are

that the addition of an AR pathway inhibitor, whatever you want to call it, to a standard of care,

whether it be ADT or ADT docetaxel, improves overall survival. So this is just re-emphasising

again that no patient should have ADT alone, they need to have an AR pathway inhibitor added

on to it, whether or not they receive docetaxel or not. I think the answer of the triplet, or the

question of the triplet, is unanswered. That’s because none of the trials looked at the addition of

docetaxel to an ADT AR pathway doublet.

 

Now, with ENZAMET we have that opportunity to do an exploratory analysis because the

docetaxel wasn’t being randomised, it was already being selected. Interestingly, if you look at

the five year survival between ADT enzalutamide versus ADT enzalutamide docetaxel, the five

year survival is actually better for the ADT enzalutamide. But the problem is, as you mentioned,

if it’s a selected patient population – people did not randomly get docetaxel, it was up to the

investigators. But there’s not a big benefit there, a big difference between those arms. If you

look, they put all the survival curves against each other, there wasn’t a lot separating them. The

only thing that separated were the patients that got ADT alone.

 

So the question of the triplet, in my mind, is still unanswered. Further to that, we know that prior

to these triplets the use of ADT docetaxel was very low. In North America it was around 10%, I

think in the UK it was around 20-25%, maybe higher.

 

HP: It was 36% when it was our only choice, it’s now less than 10% since COVID.

 

KC: Yes, so I think people have kind of voted with their feet. We actually don’t use a lot of ADT

docetaxel and I’d be cautious about pushing a triplet regimen at this time. That’s my opinion.

 

HP: I agree. I think what all of these studies have shown us, as you say, is that we need to be using

an androgen receptor targeted agent with our ADT. I guess for those men who you would

choose to give docetaxel, the important thing is that they get an ARTA as well. So I think this

debate will go on and on, won’t it really – doublet, triplet. But one thing we do know is ADT

alone shouldn’t be given except in very exceptional circumstances.

 

Moving on to metastatic CRPC, something that we’ve all taken up, I think with quite a lot of

enthusiasm, is radioligand treatment. Theranostics has become something that we’ve all been

talking about quite a lot and for many of us this is a new treatment with lutetium, although we’ve

used radium for prostate cancer in the past. I say for many of us but probably in Germany and

in Australia lutetium was… you were ahead of the game, weren’t you really, with that particular

treatment. At the meeting we’ve had further data from the two lutetium studies and I’m going to

ask Kurt to tell us a little bit about that. Perhaps we could start with VISION and, obviously,

VISION the comparator arm was standard of care. What have we learnt about the standard of

care arm in VISION from this meeting?

 

KM: It was standard of care with the exception of chemotherapy which is important because…

 

HP: Yes, or radium.

 

KM: Or radium, right, but in reality as was the comparison arm in therapy you could think about

giving these patients cabazitaxel which was not allowed in the VISION study. So it was a weak

comparator which must be taken into account when you look at the results still having an

overall survival advantage against another ARTA, so to speak, where the patient has gotten

abiraterone before and then enzalutamide or whatever. So this makes it a little bit easier for

lutetium to win than if you are… It’s always difficult to make cross-study comparisons; if we look

at the comparison in TheraP between cabazitaxel and lutetium, little bit other design, but then

there’s no difference in overall survival whereas in VISION there was still a benefit in overall

survival when you look at the lutetium arm. So that must be taken into account. Nonetheless,

it’s now a part of the standard of care. I think it’s not approved yet neither in the United States

nor in Europe, but it will be standard of care in the armamentarium of mCRPC treatment.

 

HP: TheraP, as you say, there was no difference in overall survival but the quality of life and toxicity,

surely, is the main outcome from this?

 

KM: Absolutely. It’s an easy decision making because it’s much less toxicity and it’s better quality of

life. So if you have two compounds and you have a similar overall survival, although it was not

a non-inferiority study, but it turns out it’s basically pretty much the same. So, for me, and that’s

very subjective, it’s an easy decision making in favour of lutetium.

 

KC: I have to say, I was a little disappointed in the results because the TheraP trial was somewhat

biased in favour of lutetium-PSMA-617. They had a higher bar to cross in terms of the PSMA

positivity; they had a higher response rate; longer time to progression yet overall survival did

not emerge.

 

KM: Yes.

 

KC: So I was a little disappointed.

 

LK: When I saw the abstract I would agree, I think the presentation did help, though, because

Michael Hofman alluded nicely to what the following therapies were. I thought that was kind of

nice because we saw that a relevant proportion of patients in the cabazitaxel arm received

lutetium-PSMA afterwards and we saw that a relevant proportion of the lutetium-PSMA arm did

receive cabazitaxel afterwards. Obviously in Germany we have faced the question should we

use it and if so when, at which position should we use it for a little bit of a longer time than

maybe in other parts of the world. So I thought it was okay to see that probably the sequencing,

do I do the one first or the other, this pressing question that everybody was asking, is not that

important. So after this explanation of the following therapies I was a little bit appeased, let’s

say, by the initially felt disappointment that I can relate to a lot.

 

KC: I guess what it also does, it points to that we really need to understand the biomarker better

and do we actually raise it up the bar to ensure that the patients that are going to get lutetium-

PSMA are going to be the ones that benefit the most?

 

HP: And also we had the other data presented looking at the original PSMA PET scans and SUV of

10 seemed to be the take-home number of above that. What do you think of that, Kurt? How do

we choose patients? Should we be doing FDG-PETs as well?

 

KM: Yes, that’s what Kim just mentioned, can we better select these patients that undergo lutetium.

They tried to differentiate with SUVmax and SUVmin. SUVmin is probably something new to

measure but it turned out that those having SUVmin over 10 doing better than the other ones

although they emphasised that even if you have an SUVmin of 6 or 7 they still would benefit.

There it’s going to be tricky because, as we discussed, if you have a negative predictive factor

it’s almost never black and white saying if the factor is less than this none of the patients do

benefit, you can’t say that. That makes it a little bit difficult to really make the decision and say

all those patients under 10 now get cabazitaxel instead of lutetium. That would probably not be

my choice either.

 

HP: People who have discordant positive FDG-PET scans you don’t want to miss the opportunity to

give them cabazitaxel or rule out small cell cancer. So lots to think about for radioligand

treatment. The other big topic is PARP inhibitors and the beginnings of precision medicine with

the PROfound study and then we’ve seen some new data coming out from MAGNITUDE as

well with combined treatment. Could you tell us a bit about that?

 

KC: Yes, so MAGNITUDE we first reported on the results just in February GU ASCO. That looked at

patients with metastatic castration resistant prostate cancer and they were randomised to

receive either abiraterone or abiraterone plus the PARP inhibitor niraparib. What we saw in that

study in that the patients who had BRCA1 or BRCA2 alterations had a big radiographic

progression free survival benefit, a hazard ratio of 0.53. We also saw that patients in general

that had a defect in a homologous recombination repair associated gene also had a benefit, a

hazard ratio of 0.73. But what we didn’t see is a benefit for patients that didn’t have an identified

alteration in a homologous recombination repair associated gene.

 

So that’s what we presented in February and at this ASCO we’re seeing a couple of other

abstracts, one of them looking at a gene by gene analysis. That’s because homologous

recombination repair, there’s a lot of genes associated with homologous recombination repair

and some of them probably have more influence over that pathway and some have less. So we

have to understand what these individual genes and how well they predict benefit. So we for

sure know that BRCA1, BRCA2 big benefit but when we break up the other homologous

recombination repair genes these occur at very low frequencies. We saw that in the PROfound

study as well, that there was a difference in response rate and so on.

 

What we’re seeing in the MAGNITUDE study is indeed the same thing, that we’re seeing some

genes are associated with benefits across the board with the combination but we’re seeing

some genes with less benefit, as an example CDK12. We saw this in PROfound, there wasn’t a

lot of response rate right there, same with ATM, and we’re seeing this also in the MAGNITUDE

study, CTK12, ATM. But the other alterations that were identified we’re still seeing some of

those benefits.

 

HP: I believe there’s also some quality of life data coming out from MAGNITUDE?

 

KC: Yes, quality of life and in particular toxicity. What we know about PARP inhibitors is that they

can cause nausea and they also cause a lot of anaemia and the anaemia can lead to fatigue.

So these are some of the main side effects that we’re seeing in terms of people and what

they’re feeling – nausea and fatigue. So this analysis was looking at their overall quality of life,

which didn’t really seem to be different between the two, but also side effect bother. This is

important because when we’re adding on additional treatments that have side effects then we

need to understand how that impacts patients. Reassuringly, although there were more side

effect bother with fatigue and nausea in the patients receiving niraparib, in terms of those that

were having severe bother there was very little difference between the two arms. So, yes,

people are having more side effects but it doesn’t appear to be that much of a bother to them.

 

HP: That’s really good, it’s one of the questions that people have been asking so it’s wonderful to

have that data. Now, sadly I think we could go on for a lot longer but time is over for this

session. Thank you so much for joining us, I’m sure that the discussions will carry on within

your groups and hospitals at home as we gain further and further information on the optimal

way to treat our men with prostate cancer. So I’d like to say a huge thank you to the panel for a

very interactive discussion and please take care. See you soon.