NS: Hi everybody, what a great pleasure to be joined today; we’re here at ASCO 2022 in Chicago.

I’m Neal Shore, I’m a urologist in South Carolina in the US, and what a great pleasure to have

myself as a urologist, Phil Cornford who’s a urologist in Liverpool and two esteemed

colleagues, medical oncologists, Eleni Efstathiou and Cora Sternberg, Houston and New York

respectively. ASCO 2022, a great amount of attendance, a lot of great presentations. We’ll

focus on a few topics and let me first start with you, Phil, if it’s okay. A lot has been going on in

the mCSPC landscape for quite some years now. There have been some things that were

presented here, again trying to discern the differences between benefit of triplet versus couplet

therapy. Maybe you could begin with your thoughts about how we’re looking at mCSPC and

historical monotherapy, ADT and couplets and now triplets.

 

PC: I think it’s really clear that monotherapy is finished for really anybody who is capable of having

anything else. The addition of a novel antiandrogen to standard androgen deprivation should be

for everybody and you should have to explain why you’re not going to do that, rather than why

that is an appropriate thing. It’s slightly more complicated when you get to triple therapy

because although it’s clear that adding a novel antiandrogen to docetaxel gives a benefit, and

we saw that again this morning with the ENZAMET data that was presented, it isn’t quite so

clear that giving docetaxel in addition to a novel antiandrogen plus ADT gives a proven benefit.

That’s the question, a little bit, is which patients would we give docetaxel to. If you’re going to

give docetaxel you’ve got to give a novel antiandrogen with it but the question is who should

have docetaxel.

 

NS: I think that’s great. I love your first comment about monotherapy is really not a standard of care

anymore where it was for almost 70-plus years. Yet we still see a lot of monotherapy ADT

being administered throughout all parts of the world, including the US. This is tragic, we have

seven, if not more, phase III trials, level 1 evidence for couplet/triplet therapy. But let’s talk a

little bit… maybe, Eleni, you want to address this issue about the differences in, for example,

top line ARASENS, PEACE-1 versus what we heard regarding the updated analysis from

ENZAMET?

 

EE: I actually love that you say you have to explain why you won’t give it, I love that. It’s unethical to

not give it.

 

PC: It is unethical not to give it.

 

EE: Unless it’s not available, but back to what you’re asking.

 

CS: But the fact is that 60% of people in the world are not getting it.

 

EE: Or not, they are giving bicalutamide.

 

NS: And that’s a tragedy.

 

CS: Bicalutamide or ADT alone.

 

EE: Back to being disciplined here, we’ve got, as you said, about 16 trials in all across the spectrum

of prostate cancer showing benefit, and overall survival benefit, in all of them with the addition

of an enhanced androgen signalling inhibitor. I don’t think there is any other domain where

we’ve seen 17 phase III registrational trials, all positive, for all four available agents right now.

So when it comes to… earlier, actually, today let’s say we sidebar when we’re talking about this

data, when you’re looking at a trial like ARASENS, which is an industry sponsored registrational

trial, it has a different level of granularity. It gives you all the details that you want to see about

the specific question, which is ADT plus docetaxel plus darolutamide versus ADT plus

docetaxel. Period. Positive trial. When it comes to ENZAMET, as is with PEACE-1, more

convoluted trials with not very clearly those questions, addressing multiple endpoints, as we’ve

seen also with STAMPEDE. So very, very important trials but we can’t base completely our

decisions on them.

 

So what we saw today was a wonderful update that reaffirms the impact of adding

enzalutamide to ADT across the board. But then when you do the sub-analysis looking at

docetaxel added on, you see a nuance that this is not a universal effect. Can you hang your

decisions on that? Probably not but it is hypothesis generating.

 

With that in mind, what I really enjoyed, and Ian Davis really pointed that out, is that if you look

at the high volume disease, specifically at those men who received ADT plus docetaxel plus

enzalutamide, you see for the first time a bump in that curse of losing 20% of your patients

within the first two years. If you go back and you look at CHAARTED, look at all the trials that

used agents, you lose about 20% of your patients in the high volume cohorts early on, the very

aggressive disease. There was a bump, there was a dent this time. It was about 10% of those

lived longer. Is that enough? No, we need to understand aggressive disease, but there is

something there that made me today say for high volume de novo metastatic disease, what he

called synchronous, I would go for the triplet after today’s data. Any of the triplets that we’ve

seen.

 

NS: Yes, so that’s really in keeping with PEACE-1 conclusions and keeping with the same

conclusions of ARASENS. So, Cora, what do you think? If you have somebody who presents,

and I guess it’s all different stratification for what is high volume. So, for you, is there an ideal

kind of patient who comes in with high volume mCSPC disease who is chemo-fit, who you

would do triplet with, or are you not sold?

 

CS: You must realise that in PEACE-1 everyone had synchronous metastatic disease, all of the

patients, and in ARASENS some 88% of the patients in both arms had synchronous metastatic

disease, meaning these are not patients who had a radical prostatectomy and slowly, slowly,

slowly had a little bit of oligometastatic disease. So we’re talking about sicker patients to start

with in both of those trials and in both of those trials patients received triplet therapy and they

all received docetaxel. The main side effects were in the first six weeks from the docetaxel and

that was definitely seen with the ARASENS trial, that there were not a lot of side effects

afterwards in the long run. I think that was also presented at the AUA recently by Crawford. So

with patients who are fit and who are young and who have metastatic disease, that present with

metastatic disease, I am offering triplet therapy. What we don’t know, based on these studies,

is the fact that this was all compared with docetaxel in both arms. We don’t have a study

comparing with novel hormonal therapy. So we really don’t know, compared with novel

hormonal therapy, if they might have done just as well; we’re just assuming that they would. We

have enough trouble getting patients to even get off just ADT alone. If you look at studies from

England, from the US, most people in the community especially are only giving ADT alone. So

it’s hard enough to explain to them why they need doublet therapy and it’s harder to explain

why they need triplet therapy.

 

NS: I agree and in the spirit of not optimising approved therapies with novel mechanisms of action

in a life-threatening illness which is de novo or synchronous mCSPC or recurrent or

metachronous CSPC, we have a lot of verbiage which confuses…

 

EE: It’s all Greek to me.

 

NS: But the thing is that we would all agree with, and tell me if you feel otherwise, is this is a

terminal illness so making sure that patients receive as many novel mechanisms of action

approved therapies as they can, so 12 life-prolonging therapies by the FDA in the US, seven

novel mechanisms of action, and yet we have publications of contemporaneous findings that

the average patient in North America – US, Canada, Mexico – receives 1.7 therapies. So on a

certain level I’m like if I’ve got somebody who has got high volume disease, is good

performance status, is chemo eligible, I lean towards triplet therapy. Now, I may not do it

concomitantly but I’m adding the ART-targeted agent, androgen receptor antagonist, novel

hormonal agent, again verbiage, verbiage, verbiage, but I’m starting it pretty quickly, I’m not

waiting for them to become resistant. Do you all do it differently or is that…?

 

CS: No, I think that that is the way that we need to go at this moment. There was a meta-analysis

that will be presented in a poster later on at this meeting in which they explained that they really

weren’t compared to just the doublet with the novel hormonal therapy. But I agree with you, if

we have a patient who is fit, young enough and has high volume disease or high risk disease, I

would try to give them triplet therapy. I think that’s the best that we can give them.

 

EE: I do one more thing: I actually treat with a triplet, these high volume patients, who also have

constitutional symptoms related to the cancer if they are able otherwise, don’t have other

comorbidities. We’ve studied that with even geriatric oncology and we’ve seen that they need to

be treated aggressively. And I’ve seen some wonderful turnarounds in those men, the ones that

we’ve just described, the really high volume, a lot of symptoms.

 

NS: Yes, this is great. Let’s just switch to some other… there are so many great topics going on

right now in prostate cancer here at ASCO 2022. Let’s talk about the whole concept now which

has really revolutionised, another novel mechanism of action and that’s PARP inhibition. PARP

inhibition really important to understand who is biomarker positive, as we say, as opposed to

biomarker negative from the initial approvals of drugs such as olaparib and rucaparib by FDA

and EMA. But we have had some recent interesting studies and, Eleni, maybe if you would

begin. We saw at ASCO GU 2022, and now some additional data coming forward in this

meeting on safety and tolerability profiles, the combination of adding abiraterone with niraparib,

a PARP inhibitor not yet approved in prostate cancer. That was the MAGNITUDE study and

then the PROpel trial, mCRPC first line, just like with MAGNITUDE but PROpel was olaparib

and abiraterone. Different trial designs, a little bit more complicated on the MAGNITUDE than

the PROpel, comparable to what you were saying earlier about PEACE-1. But, Eleni, help us

understand your thoughts on the bottom line of those two studies and also your concept – are

all PARP inhibitors the same, are there differences?

 

EE: We went all through the trauma and surprise of GU ASCO, which was a phenomenal meeting,

of seeing two great industry trials being both positive but having completely different design.

AstraZeneca dared go agnostic in mCRPC, for those who haven’t watched it, targeting all men

with mCRPC who are progressing with abiraterone plus olaparib without looking for a PARP

signal. I want to make a comment on that because we saw some great data here at ASCO

that’s very promising. On the other hand, MAGNITUDE went the conventional, conservative,

appropriate by many, precision-driven way – let’s look for DDR events, DNA damage response

events, and target those patients after looking for a short period of time at the DDR non-

mutated cohorts and did not see an initial signal. Both trials were positive, MAGNITUDE for

those DNA damage response mutated cases, PROpel for all comers. We saw the data, we’re

still having some trouble processing the all comers wild-type.

 

But, going back to your point, there was a lot of discussion, even during the podium

presentations, on whether we should consider all agents the same, all PARP inhibitors, this is

one way to troubleshoot it. Another way to troubleshoot it is to actually understand fully that

these are different studies and there is a possibility that the truth is somewhere in the middle.

There could be in the wild-type cohort a subset that has a BRCAness type signature that is not

yet identified.

 

There was a beautiful abstract that’s a poster that actually has a PET methodology to identify

PARP activity and that brings a lot of promise because it will give us the opportunity to actually

look beyond, if we develop such an approach, beyond just what we find with looking for

BRCA1/2 and the like.

 

One more comment – MAGNITUDE had a very nice analysis, full disclosure – I’m part of the

trial, where they looked at the gene by gene response. It was very nice to see, of course,

BRCA2 reaffirmed but other genes showing responsiveness – CHEK2 included, PALB2;

nothing coming out of CDK12 though this time. So you see the differences – we don’t have

enough numbers to know whether we should treat CDK12, yes or no. ATM, again it bombed,

we didn’t get anything out of ATM.

 

NS: So, Phil, let me ask you, as a urologist, some of your thoughts just on the importance of doing

genomic profiling, clearly in mCRPC patients, based upon the guidelines, maybe even some of

your thoughts on mCSPC. Then if you’re going to have an all comers population and combine

an androgen blocker like abiraterone with olaparib or abiraterone with niraparib, what do you

counsel now in your teachings about testing in your approach to this. Then even some of your

thoughts on the toxicity management.

 

PC: I think we’ve got an interesting question with abiraterone because there is, of course, some

preclinical data that suggests that it might affect homologous gene function anyway. So maybe

what you’re seeing is a synergistic effect between the abiraterone and PARP inhibitors. At the

moment we don’t really understand what’s going on there. Study 8, which was the phase II

study which led onto PROpel was positive in the same way with olaparib that PROpel has

seen, again, only with radiographic progression free survival. But you’ve got two studies that

show very similar things. It’s a bit unlikely that it’s aberrant because that’s why you run a phase

III study – because you ran a phase II study and you got a positive result and you think is it

really true, we’ll do it again with bigger numbers. And they did and it still showed a positive

response. So I don’t think it can just be swept under the carpet because we weren’t expecting

it. Because we do that, don’t we? Because we go to a meeting and we say…

 

EE: “No, we don’t like that.”

 

PC: “We didn’t like that; that isn’t quite the way we were expecting.” So I think that is true. From a

urologist’s point of view, it has made the discussion about testing much more complicated

because before this, and based upon what we thought we knew about PARP inhibitors, I was

all for testing people as soon as they developed metastatic disease. Because I felt that testing

them early would allow you to make a decision and it might not influence treatment immediately

but it would influence treatment when they became castrate resistant and at that point you’d

need to know and it would save delay. So I was really keen on this. But if we did end up in a

situation where suddenly PARP inhibitors it might help you make a decision between

treatments. So you might say, “Do you know what? Olaparib plus, or a PARP inhibitor, might be

appropriate because you’ve got a gene mutation and you’ll get a bigger response with that

treatment than you would do if you’re wild-type.” So it’s a bit more borderline about whether that

will be. You still might and if you’d run out of other options you might be very keen to try that,

despite. But, at the moment, I’m still really keen on testing everybody when they become

metastatic because I think information is power and if you know what’s going on then you can

advise people appropriately.

 

NS: Yes, and of course you have the importance of cascade family testing if you get that

information.

 

CS: Absolutely.

 

NS: But you’re right, the concept of lowering resistance to the AR pathway drug as abiraterone,

that’s always at our forefront. We’re trying to take a drug that’s well tolerated and decrease the

likelihood of developing resistance. Can adding a PARP inhibitor do that? Well, these trials

have demonstrated that there; that efficacy has been shown. Then likewise can we enhance

the ability of a PARP inhibitor in a wild-type or a biomarker negative population to develop what

some would describe as additional PARPness, BRCAness? Any more thoughts?

 

PC: I think we’re going to see other combinations too because I think that PARP inhibitors, we might

talk in a minute about lutetium and radioligands, but the idea that you might put PARP inhibitors

with radioligand therapy because one is interfering with gene repair and the other one is

causing DNA damage, so maybe those two would be an appropriate thing to put together.

 

EE: And then you’ll have to pick the safer one, of course.

 

PC: And then you’d have to pick the safer one and all of that. But there are some really interesting

combinations to come.

 

CS: I agree with you that I still think that we should be testing everyone. We should know for

prognosis, for cascade testing of the family afterwards. We’re just learning more and more as

we go along. I think it’s very important to be testing everyone.

 

NS: What about, Cora, one drug works and a second drug is added simultaneously, what are your

thoughts just on adverse event management, safety profile, toxicity, for our colleagues

listening, when you add a PARP inhibitor to abiraterone?

 

CS: There are a few abstracts at this meeting showing that it’s actually pretty safe and there’s not a

lot of toxicity by adding a PARP inhibitor to abiraterone. Not anything more than you would

expect, it’s really not very difficult. All of the abstracts have concluded that you can add a PARP

inhibitor. There’s another interesting abstract, though, I think it’s by Andy Armstrong, about

patients who are hormone sensitive. He looked at genomic testing in all of those patients and

he found out that the positivity of BRCAness and PARP and all of these others is much lower

than we first thought and what we found in patients who are castration resistant. So I think we

need to figure out a little bit more what that means too.

 

PC: That was from ARCHES, wasn’t it?

 

EE: Yes, exactly, from ARCHES.

 

NS: I think it’s very interesting, a lot of it has to do with the populations that you’re looking at. But a

great discussion. Let’s switch topics to a third topic – what about this whole burgeoning field of

PSMA antibody radioligand therapy? It’s such an interesting field and we’ve had the first FDA

approved agent in lutetium-617 based upon the VISION trial that was presented at last year’s

ASCO. We’ve seen some sub-populations that have been looked at now. The thing that I’m

particularly keen on maybe discussing is the notion around the imaging and PSMA PET

scanning. So the heterogeneity of that, the response to that. Eleni, do you want to start off with

that?

 

EE: Again disclaimer, I’m a big fan of Mike Hofman and all the work that they’ve done in Australia.

Kudos, they’ve been phenomenal in really championing this. And this, of course Europe as

well; you’re not part of Europe anymore, it’s okay. So in any case I think that today we saw

some data coming from Michael Hofman that might make our life easier if we are to pursue it.

He showed some final data from TheraP, and I will focus on what you said. There were three

take-home messages but the one that pertains to the concordance and discordance of imaging,

for me, is important because when I can I practise it at home. So he showed that out of this trial

where they included about 300 patients they actually had eligibility failure of 25% because there

was discordance between FDG-PET scan and PSMA. In fact, a discordance to favour FDG

being positive in spots of metastases where PSMA was negative. He also showed data on

these patients who were, and that’s a nice point, followed outside the trial, yes. Michael

attributed that to real world practice because these patients did not perform well. I would say

that they probably represent the really aggressive variant that we need to test further. But since

we’re talking about TheraP, he also made a good point by showing us the final overall survival

data where, to everyone watching us, cabazitaxel, which is probably not as sexy as lutetium,

did not do any worse in overall survival. Of course, there were subsequent treatments for both

suggesting that we still don’t know what’s the right place to put it, unlike what we know with

androgen signalling inhibition you should start early.

 

NS: Was there also a cut-point on the SUV of 10?

 

EE: That was very nice as well. They showed us that probably omission matters, so a higher SUV,

better outcomes. Now, I’m not sure that there was a cut-off; for VISION there was none.

 

PC: No, but there was for TheraP.

 

EE: But I think there was in TheraP.

 

PC: Yes, TheraP used a cut-off of 10. But it was also true that if you used 20 as a cut-off you had a

better response than if you were just over 10. So that was also true. And in many ways it

makes sense because you’re going to absorb these molecules into your cancer cell and you

are hoping that the beta particle causes DNA damage. But it’s not just going to damage this

cell, it’s going to damage the cells around it, only for a millimetre or so but it’s going to damage

the cells that are around it. Because that’s true you are looking for multiple hits for any one cell.

If you’ve got washout so that the lutetium leaves the cancer cell, it’s not there long enough in

order to do the damage and cause the cell death, whereas if it’s being accumulated and stays

there then all the radiotherapy is delivered where you want it in the cancer. For a urologist, I like

it simple, I like that idea that if it’s taken up in the disease then that’s when you’re going to see

the response and that makes sense, doesn’t it?

 

CS: The problem is that PSMA is a biomarker and we have not developed properly yet how to do

trials, how to understand what we’re doing. Karim Fizazi gave a very nice talk, talking about the

SUVs in four different ways of looking at it on the PSMA and whether or not we should be

looking at the mean PSMA in all of the lesions or the ones in the largest lesions or… There

were so many different ways and I think that we all have to come together as a community and

start to speak the same language because the way the VISION trial was done was done

completely different than the way the TheraP trial was done. The way we’ve been working at

Weill Cornell with actinium and with lutetium, we’ve been doing it completely differently as well

and not necessarily even doing the other scans. Michael Hofman always said that he wouldn’t

give hormone therapy to an ER negative breast cancer patient, why would you not do it this

way? I think it makes sense but, on the other hand, Scott Tagawa would say that these patients

are far gone, they will benefit anyway. And we’ve seen great benefit. So we need to start

speaking the same language because it has been done in so many different ways. The way

that the FDA has approved it is for patients who are positive, who have had a positive scan. We

hear that the scans are exactly the same, the two kinds of scans, I’m not sure if they’re the

same and I’m not sure that if we start trials that we shouldn’t make sure that people do the

same kind of gallium scan either. We should be more rigid about how we talk about things.

 

NS: Yes, a great final point, the importance of serial follow-up. Regardless of the imaging,

conventional or next generation, we need serial follow-up and comparisons. So an excellent

final point. Thank you Eleni and Phil and Cora, thank you so much. Fantastic to be on a panel

with medical oncology experts and a urologist because we all have to work best together and

serve patient needs. It’s a great time for our advanced prostate cancer patients, we have the

proverbial embarrassment of riches. So many new things and great trials that are ongoing and

more data to reveal. So, with that, thanks very much to the folks from ecancer for sponsoring

this programme. It’s a pleasure to review with my colleagues here from ASCO 2022. Thanks

very much.