Introduction: Quality of Life

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice, and welcome to Year in Review, as today we talk about the management of prostate cancer. We have a great faculty: Dr Emmanuel Antonarakis from the University of Minnesota in Minneapolis, Minnesota, and Professor Karim Fizazi from the University of Paris-Saclay in Villejuif, France.

Today we’re here to talk about the big papers and presentations over the past year in prostate cancer. And as we do with all of these Year in Review programs, we will be talking about the use of nonapproved agents and regimens, so check out package inserts for more information.

So in all of our Year in Review series I meet with the 2 faculty individually prior to the webinar and record a presentation. I did that with both of our faculty tonight. Here are the titles of that. It’s in the chat room if you want to take a look at it now, but we’ll also be emailing that out when we send this program.

These presentations cover a lot of papers, a lot of really interesting papers. We’re not going to go through all of this tonight. I picked out some of the themes and particularly interesting papers and presentations for further discussion tonight.

We’re going to start out chatting a little bit about quality of life in prostate cancer and new agents in prostate cancer, then we’ll talk about PARP inhibitors, M0 disease, metastatic hormone-sensitive disease, radiopharmaceuticals and a couple really interesting new agents that are coming along.

But before we get start racing down there I just want to reflect back. We just got back from the Annual ONS meeting for nurses. We’ve gone there for 17 years. This year we did 11 programs. We usually do that there. This is the 50th anniversary of ONS. And we did a program, actually a week ago today, on prostate cancer. We had Drs Aggarwal and William Oh. We had 2 really great nurse practitioners we’ve worked with a lot over the years, Monica Averia and Katie Burns.

And when we go to ONS we talk more than anything about quality of life, management of symptoms, management of toxicity. And I would say, thinking back to last week, and really I would say in oncology in general, I don’t think there’s any cancer right now that there are more quality-of-life issues than prostate cancer. And we were talking, obviously, about advanced disease. Prostate cancer has a long history of quality-of-life issues with localized disease, but we just, to me, entered a whole new era, Emmanuel.

And I just want to take a step back before we get started and just kind of reflect back. It seems like yesterday when we were just beginning to even look at randomized trials in prostate cancer. For a long time people were wondering if that was ever happening. M0 disease, it used to be at Hopkins we would look at the Hopkins database, et cetera, and then boom, so many Phase III trials coming out, and so many of them with huge implications. We’re going to get into that today, particularly in hormonal therapy. Now we have the issue of intermittent therapy on the line, the issue of even, as Karim calls them “lutamides” as single-agent therapy. Any reflections back, Emmanuel, on what’s been going on in this disease? It’s just amazing to me.

DR ANTONARAKIS: I mean the patients are telling us that they want to live longer, but they also want to live better, and we are hearing a lot about that. We are now designing for the first time in prostate cancer history de-escalation trials, the opposite of escalation, so which patients can we eliminate or reduce the therapy as opposed to add something new. And almost every Phase III clinical trial has a mandatory quality of life. The quality-of-life tools are imperfect. They’re not measuring everything that the patients want us to measure, but it’s a good start, and I think we’re going to see a lot more of that in the future.

DR LOVE: Any thoughts, Karim? Another kind of issue that goes along with that is patient involvement in decision making. A lot of times we have a number of evidence-based options. We’re going to talk about a lot of that today. And particularly, again, in really a palliative situation, at least with metastatic disease, I don’t know that we’re curing prostate cancer, but I think patient and family involvement in these decisions is also critical. Anything you want to add to that, Karim?

PROF FIZAZI: Yeah. I would fully agree with what Emmanuel just said. And maybe if I can add very often, or often let’s say, we have given trials showing overall survival in prostate cancer. And the question, because of the long natural history of the disease, is whether we should use the same just earlier in the course of the disease.

And because we already know that survival is prolonged very often we want to have the patients in the control arms of these earlier Phase III trials to have potentially access as a crossover to the active drug. And of course this may confound the potential overall survival benefit, and this is why radiographic progression-free survival is used as a registrational endpoint, but it has to come with other benefit, and here is our quality of life. Because, again, rPFS is at the end of the day just an image which becomes white to black or black to white or whatever. It’s not directly measuring benefit to a patient. And this is why time to deterioration of quality of life, or time to deterioration in pain or in this particular disease, prostate cancer, time to skeletal-related events, are so important, together with rPFS.

So we’re kind of changing, I think, the way we’re conducting trials, and I think also the agencies are changing the way they are looking at new drugs and now we should say yes or no for this same drug to be approved.

DR LOVE: Yeah. Actually, I’ve been thinking a lot about that since we went through — we’re going to talk about the PSMA4 study with lutetium-177. Survival’s always been, as you were pointing out, a big endpoint for the FDA and all, but in that study there was a very high rate of crossover, so I was actually thinking last night in a way it becomes a study of lutetium now or lutetium like in 6 months or something, so you wouldn’t necessarily see a survival benefit because of that. But if you look at it that way it’s really easy to understand why you might not see a survival benefit. Emmanuel, any thoughts?

DR ANTONARAKIS: I would agree, but at the same time, if the quality of life was not improved, I think that trial in the US may not have been FDA approved.

PROF FIZAZI: Agreed.

PARP Inhibition (PARPi)

DR LOVE: Alright. Well, let’s talk a little bit about PARP inhibitors. And of course we talk about that all the time. This really started out with ovarian cancer in 2018, the SOLO-1 trial of olaparib, then breast cancer, prostate cancer, even pancreatic cancer.

And Karim, of course we’ve seen several trials looking at PARP in castrate-resistant disease. Not too many patients like that who haven’t had either abiraterone or one of the lutamides. This was the PROpel trial with abiraterone. And one of the things, first of all, that I thought was interesting, and this came out in ovarian cancer very early, is you see benefit with — whether it’s somatic or not.

Right now, Karim — and it’s pretty impressive hazard rates and the curves looking pretty good there. When you first look at these curves you think oh, this must be hormonal therapy. No. This is PARP. But in any event, Emmanual, any thoughts about right now from your point of view (A) does germline equal somatic in general, BRCA and otherwise, and what else beyond BRCA do you feel is sensitive enough to justify hoping to — whether it’s approved or not, using it? For example, PALB2 or other non-BRCA mutations, Karim?

PROF FIZAZI: Yeah. You know, what you’re sharing here on the screen, Neil, I think is the most important stuff about the PARP inhibitor story in prostate cancer. We have currently an ongoing debate as to whether we should use PARP inhibitor together with AR pathway inhibitors in patients without DNA repair defects. But what you’re showing here is really the key thing, and people tend to forget about it because they saw this data several times already, but this is really impressive.

In PROpel and in TALAPRO-2 patients with CRPC and BRCA alterations, and we’re speaking about really nasty disease, because those are 2 bad things, CRPC and BRCA. This is really typically associated with poor outcomes. These patients live super, super long when they receive a PARP inhibitor together with ARP. The hazard ratios are very impressive for overall survival, and anyone can see that on the curve, the shape of the curve. The PARP inhibitor curve is really fantastically high.

In TALAPRO-2, for example, we had probably 4 years of follow-up, and still the median is not reached, typically in a situation when you would expect patients to be dead in just a year and a half or 2 years, something around that. So that’s very important.

And yes, actually, it’s good news also to see that whether the BRCA alteration is a germline alteration or somatic alteration doesn’t necessarily make a big role regarding the prediction of benefit from the PARP inhibitor, which is great because before I saw the data I was thinking the opposite. I was thinking if it’s a germline it means that all the cells from the patient, meaning all the cells from the cancer, will be affected, so the drug should work better, as opposed to somatic, where it might be just clonal. But no, it’s not the case, and that’s good news. So I’m really happy to see those curves.

And coming back to your second question —

DR LOVE: Yeah. I mean, a hazard rate —

PROF FIZAZI: Sorry.

DR LOVE: Go ahead.

PROF FIZAZI: Yeah. Coming back to your second question about other genes. Number 1, BRCA and BRCA2, very likely BRCA1, and I’m saying very likely because the numbers are smaller in the trial, so we need to be cautious, but it really seemed to turn to the same direction as for BRCA2, meaning a big benefit. PALB2, same caveat about small numbers, but same direction, same trends. And probably also CDK12, even if this is probably with the largest lower magnitude.

There might be also some other genes, but here and there, it’s really more difficult to make sure this is true. We said for a long time that ATM patients do not benefit. It’s probably true for most of them, but there might be exceptions. We just need to figure out which are those patients because ATM, for example, is a long gene, and there are multiple alterations, so we need to dig into more details.

DR LOVE: So Emmanuel, anything you want to add to that? We also have LOH. I’m not sure to what extent that’s been looked at in prostate cancer. That curve over on the left there, germline BRCA PFS, hazard rate of 0.13. That’s like what you see in ovarian as well.

And Matt Smith, your colleague, a couple years ago had a very amusing graph he showed. Actually, he put it on top of the EMBARK study. I’ll show you that in a second. But he called it the “pelican graph”, and so I thought I’d put the little pelican over here because those beaks are as wide there as they were, I think, in EMBARK, Emmanuel. We always joke in oncology, even in other cancers, the whole object is to get those — get the pelican to open the mouth up more.

But any other thing you want to say about that? And what about LOH, Emmanuel?

DR ANTONARAKIS: For me the lesson here, also, that we didn’t talk about, is that a germline BRCA test is not enough because you are going to miss those patients that have the somatic BRCA alterations, which have enormous benefit, as you can see from that pelican mouth, and the overall survival on the right-hand side. So we cannot just stop at germline and say we did not find a BRCA in the germline because there may be one at the somatic level.

The loss of heterozygosity score, I think that is very experimental, Neil. It has not taken off in prostate cancer. We do not know what the threshold for elevated versus nonelevated is. We probably cannot apply the same threshold that was used in ovarian cancer. It’s probably going to be different for prostate cancer. So for the moment we’re not using other genomic scores or LOH to make decisions.

DR LOVE: And here’s the summary from the BRCAAway study. Also, just to mention — you mentioned the TALAPRO-2 study, really exciting findings there, as well, with talazoparib, and particularly an issue — or it seems like overall they had a survival benefit in the entire population, what that’s going to mean for the HR-proficient patients I don’t know. In ovary there was a lot of excitement. Niraparib still is approved in non-HR, but we were just at the SGO Meeting; people aren’t really using that too much.

So EMBARK caught my heart 2 years ago, but this trial caught my heart more recently, BRCAAway, a really cool study. I don’t know how many people are aware of it, but pretty interesting. So Emmanuel, I guess they — what was interesting about this is they looked at the combination of PARP and endocrine therapy, in this case olaparib and abiraterone. Anything you want to say about the study, and particularly its quite interesting results?

DR ANTONARAKIS: Yeah. So I love this study, Neil, even though it’s a small one. It teaches us a few instructive things. This is the only study that has 2 different control arms. What do I mean by that? I mean of course the interventional arm was the ARPi plus the PARP inhibitor, but the control arm in all the Phase III studies was just the ARPi agent alone. There was never a PARP inhibitor alone arm, and this trial did exactly that.

So in this Kaplan-Meier curve for progression-free survival the patients that got abiraterone alone are shown in blue, the patients that got olaparib alone are shown in red, and then the patients that got the combination of olaparib plus abiraterone are in purple. And you could show a pelican’s mouth wide open on this curve, too, because that purple line is so far apart from the red and the blue lines.

The other thing I love about this study, if you can go to the next slide, is that there was a —

DR LOVE: Yeah. I love this graphic. Yeah. This is awesome.

DR ANTONARAKIS: There was a crossover design. So patients that started with abiraterone, shown on the left in the blue bars. At the time of progression they could cross over to olaparib, and you can see the blue changes to red. In the middle, the patients that began with olaparib, also at progression, could cross over to abiraterone. Those are the red curves that change to blue. And then on the right you can see the patients that just got the combination up front, shown in purple.

And what I like about this visual is you can see that the added length of the red and blue lines on the left-hand side are still shorter than the length of those purple lines. And that indirectly suggests, to me, that the combination up front is better than sequencing A followed by B or B followed by A.

DR LOVE: So I remember the first time I saw a waterfall plot I think it was in renal cell cancer. I was like wow, that’s so cool, but this chart is really wild because it’s — you can see the 2 consecutive therapies.

Karim, any other thoughts about this really fascinating, but, as Emmanuel said, small trial?

PROF FIZAZI: Yeah. That’s the main weakness of a trial. We always need to be cautious when we’re comparing 20 patients versus 20 patients versus 20 patients, especially when the population is quite heterogeneous in terms of gene alterations.

But I agree with Emmanuel. The data are quite compelling. Even if it’s not a formal demonstration it just makes sense logically. It’s indirectly partially supported also by the Phase III we just discussed. So it appears that combining an ARP with a PARP inhibitor makes sense, especially in patients with specific gene alterations.

I’m still not necessarily convinced for all-comers without DDR alterations. I think something is happening, but whether the magnitude of the benefit is sufficient to justify use I’m still on the fence. We have to recognize also that this association comes together with some side effects, especially anemia, so we really want to treat patients who really deserve less toxicity because they are benefiting.

DR LOVE: So a question from the chat room, Emmanuel. This is from Douglas. He wants to know if you find out a patient’s germline positive do you need to do somatic testing. Obviously, if they’re positive on somatic testing you wouldn’t necessarily need to use germline unless — if the patient didn’t have a family or for some reason didn’t want to know that. But what about if they’re germline positive? Is there any reason to get NGS, Emmanuel?

DR ANTONARAKIS: My answer’s always going to be yes, and it’s going to be to discover all of the other things going on in that patient’s tumor. From a PARP inhibitor sensitivity perspective you already know the answer if you have a germline mutation, but you may not know the tumor mutational burden, you may not know the PD-L1 status, you may not know the microsatellite status in the tumor. And also, if you sequence the tumor you can discover or infer whether there’s a biallelic hit, in other words a second loss of the other allele. So I still would say if possible, if there’s a biopsy available or safe to do, I would get the somatic testing as well.

DR LOVE: So Emmanuel in his talk also got into the issue of ongoing trials in the hormone-sensitive metastatic setting. Nothing mature at this point. A lot of people are very optimistic that this is going to be positive, but right now we don’t have the data or an approval. So here is the study AMPLITUDE with niraparib. Also there’s a study with a new PARP, saruparib. I don’t know if we’re going to call is saru or something in the future. But Emmanuel, can you talk a little bit about why this PARP — it seems like it’s more selective? It’s the one that’s actually going to be — it’s going to be studied in the hormone-sensitive metastatic, similar design to what we just showed you with niraparib. Emmanuel, any thoughts about this agent?

DR ANTONARAKIS: There are 3 metastatic hormone-sensitive trials testing ADT plus ARPi plus or minus PARP inhibitor. You showed the TALAPRO-3 and the EvoPAR-01, shown here, and the AMPLITUDE. Now this one, EvoPAR-01, stands out because this is a PARP1-selective. What does that mean? The older or first-generation PARP inhibitors, they would target PARP1 and PARP2 enzymes and maybe a few others. There’s a total of 16 PARP enzymes altogether. And the thought is that inhibition of PARP2, which is a nonspecific factor, might be associated with cytopenias and toxicities, whereas PARP1 is the one that has the antitumor activity and perhaps less toxicity.

So the theory of using saruparib, I’m not sure what the nickname is going to be yet, Neil, is that we’re targeting only the tumor-relevant PARP enzyme, which is PARP1, and that we might be eliminating or minimizing off-target toxicity such as cytopenias.

DR LOVE: So Karim, another issue, if any of these trials or all of them are positive, is how long to treat. I mean, patients to start with with hormone-sensitive disease can be on a long time. If the trial’s positive I imagine they’re going to be even longer. In ovarian cancer they really look at duration because they’re concerned about AML and MDS. I’m not sure how much of a consideration it is going to be in a man with — an older man with metastatic prostate cancer. Any thoughts about whether it’s going to be indefinite, or maybe at some point people are just going to stop, Karim?

PROF FIZAZI: I actually share your concern, Neil. I think these trials all probably have a theoretical duration until evidence of progression. And I agree with you, in metastatic hormone-sensitive disease that can be very long. I saw patients never progressing after 10 or 20 years actually. So not necessarily the BRCA patients because this is typically more aggressive, but still.

And I’m a bit anxious about patients receiving 4 years, 5 years, 7 years of a PARP inhibitor because you’re right, theoretically at least there might be a risk of secondary leukemias and myelodysplasia.

So as always, data will tell. I think we should see the first data from at least some of those 3 trials that Emmanuel mentioned perhaps this year, and actually likely this year, I believe. So we’ll see what the data show, but I think this should be watched very closely, and I hope the independent data monitoring committees of these Phase III trials are indeed watching this very seriously. I think this is key. I agree with you, Neil.

M0 Disease

DR LOVE: Alright. Let’s talk a little bit about M0 disease. Of course we’ve talked a lot about it over the last couple years since we saw EMBARK. Also we have a study that was done, the PRESTO study, with apalutamide. Maybe not as much follow-up and as much data as the EMBARK study, which I think everybody at this point knows was a 3-armed comparison of ADT plus enzalutamide to enzalutamide alone without ADT to ADT, which had been the standard.

And Emmanuel, this has sparked a lot of questions about M0 disease, and I want to ask you about that in a second. But the other thing I want to point out, and this is really why I brought up quality of life in the beginning here, is that this was in the pre-PSMA scan era. So the thinking is that these high-risk biochemical patients, I don’t know what the exact likely prediction is, but a lot of them would have positive PSMA scans. And so basically hormone-sensitive metastatic disease, Emmanuel, and the thing there was they used intermittent intensified hormonal therapy. They also used intermittent ADT and intermittent enza, which I don’t think was done very much for metastatic disease, and yet we know there were a bunch of patients in there.

So it also brings up how you diagnose metastatic disease, Emmanuel, the difference between a patient who comes in de novo, who never had a PSA, who comes in with bone pain and a bunch of positive lesions on scan, to a patient who’s had local therapy, has been followed carefully, that gets picked up with PSMA, and maybe they get diagnosed with metastatic disease just with PSMA-only disease.

So I guess part of my question here, Emmanual, is (A) how are you thinking through a decision with biochemical recurrence, PSMA negative. But has this changed the way you look at hormone-sensitive metastatic disease to start with, Emmanuel, because to me it seems like it should.

DR ANTONARAKIS: There’s a lot packed in there, Neil, and I’d say that when the PRESTO and the EMBARK studies were done these were patients that had a BCR by the old definition, they’re PSA was above 1, they’re doubling time was less than 9 months, and then their median PSA on enrollment was between 4 and 5. I didn’t say 0.4 or 0.5, 4 and 5. So if we had done PSMA PET scans on these patients 80 to 90% would have been either oligometastatic or polymetastatic on a PET scan.

If you keep that fact in mind the new generation of trials that are being done in this population, they are allowing PSMA PET scans, and they are allowing people with oligometastatic disease detected on those scans, because if they didn’t the screening failure rate would be enormously high. It would be like a 90% screen failure rate.

I think it was appropriate in these studies to use an intermittent or a finite course of the systemic therapy. Many of us, including myself, are very, very reluctant to give a patient with biochemical recurrence lifelong hormone therapy of any type. And I love to give these patients 9 months of ADT followed by a break, as was done with the EMBARK study, or ADT plus enzalutamide, or, as was done in the PRESTO study, 12 months followed by a break. And many of the ongoing trials now are also building in a finite course of systemic therapy and then a stop.

DR LOVE: So Karim, again, we’ll get back to true M0 disease, I guess, but right now are there situations where you use intermittent therapy with metastatic disease? Are there situations where you’d use enzalutamide alone in metastatic disease, Karim? If you could.

PROF FIZAZI: Yeah, no. In metastatic disease I’ve been using intermittent ADT even before we started intensification treatment, but this was mostly in situations where the ADT was becoming dangerous to the patient; patients getting a lot of weight, becoming diabetic or suffering from cardiovascular disease, all these things.

It’s always a question of balance in medicine, between benefit and harming, so when I was feeling this was becoming dangerous I was stopping, so nothing new. So I still do that. Also, situations where patients are miserable, psychologically or sexually, and this is really a disaster for them. Again, we’re treating humans. We’re not treating diseases. So those are situations when I was deciding in favor of an intermittent treatment. So I still do that to be honest.

With enzalutamide alone I’m still on the fence because people think okay, this is nice, et cetera. First, it’s probably not as active as the combination of the 2 drugs, ADT and ARP. And second, it’s not nontoxic. Patients still report significant cognitive impairment or intellectual fatigue. They have also big breasts, gynecomastia, which is not that easy to treat. You may consider prevention of course. So again, it’s not just a magic pill without toxicity. It has toxicity. It’s more of a question of which toxicity also patients prefer suffering from.

So in practice I’m mostly using ADT plus ARP. It’s quite rare that I’m using ARP alone. Again, there are several exceptions but not so many.

DR LOVE: So any other thoughts on this, Emmanuel? Karim went through a paper looking at sexual activity in patients on the EMBARK study. I have a hard time understanding these quality-of-life studies with the numbers. I just like to ask people, so I’m going to ask you.

First of all, Emmanuel, do you present the option or the possibility of enzalutamide monotherapy even if you’re going to recommend intensive therapy? And any sense of about whether sexual activity or function is better in the enzalutamide arm?

DR ANTONARAKIS: I do have a bias against it, Neil, and I present that bias to my patients probably unconsciously or subconsciously. The gynecomastia is very real, and it can be severe, and most men do not like the idea of radiating their breasts as a prophylaxis. It seems quite benign, but it is radiation. We don’t know if that can cause a second cancer or other issues down the line.

And the other thing I have to say is there is an increase in cardiovascular risk. We don’t talk about this very much. If you look at the adverse event table, at the enzalutamide monotherapy arm in EMBARK, there was about a 9% risk of heart attack and other cardiovascular complications compared to 4% in the other 2 arms. And the reason, Neil, is that when you use an unopposed antiandrogen you have a negative feedback loop to the brain whereby GnRH secretion goes up, and then FSH and LH goes up. And this FSH surge, which we’ve talked about a lot in the context of LHRH antagonist versus agonist, this FSH surge occurs in a big way when you give enzalutamide monotherapy, and that is a significant risk for cardiac disease. So I’m not sure if I want to trade a little bit of better sexual function. Yes, it was marginally better in the enzalutamide monotherapy, but the tradeoff is gynecomastia and then a doubling of cardiac risk from about 4% to 9%.

DR LOVE: We should have put that question on the pre-/post-test. I didn’t know that about the FSH. That’s fascinating. It’s amazing how much I hear over the years, and yet something — that’s the first time I’ve heard that.

So Karim, this is one of the studies that you were — the new generation of “biochemical recurrence” trials that allows metastatic disease, I guess on PSMA, and you actually have people who have oligometastatic disease getting local radiation, and then you get the randomization. This is with apalutamide. Darolutamide seems like a very similar trial, the ARASTEP trial.

Anything else you want to say about that, Karim? Do you typically use radiation therapy? Do you use that a lot on oligometastatic disease?

PROF FIZAZI: We do. We still don’t know whether we should. Phase III trials are still ongoing, testing SBRT in oligometastatic disease. And actually we will need to be patient because these trials take time to enroll, of course, but most importantly they will probably take time to read out because these patients typically do well for a long, long time. So for probably the 5 coming years we will have to live with some uncertainty about whether we should irradiate all the patients with oligometastatic disease, yes or no, and perhaps also who should we irradiate.

But anyway, we have — you’re right, Neil. We have created a new setting of patients with biochemical failure with now detectable oligometastatic by PSMA PET. The issue is that we don’t know how best to treat these men. I just mentioned the SBRT, yes or no, but also I think Emmanuel mentioned that we would not treat these patients continuously with systemic treatment, and I would also agree.

The issue is that we don’t know. If we don’t treat them continuously how long should we do that. And indeed the 2 trials that you just showed decided 4 different durations of treatment, and this is partly empiric, of course. The first one uses 6 months, and this one, ARASTEP, used 2 years. And of course you may argue both ways, and yes, no problem about it. The good thing is that we will have eventually data with short-term versus let’s say middle-term duration of systemic treatment, and we will know whether truly an AR pathway inhibitor added on top of ADT in the context of irradiated metastases. We already know from EMBARK that this is the case without radiation, but in a patient who was irradiated in all of his oligometastatic deposits, does that remain the case? We don’t know, and this is why we’re conducting these Phase III trials.

Metastatic Hormone-Sensitive Prostate Cancer

DR LOVE: So let’s talk about metastatic — hormone-sensitive metastatic disease. Again, we talked about it relating to PARP inhibitors in the future. And Emmanuel, I guess this is one of the least surprising results we’ve seen. I think people, ever since we saw ARASENS, or ever since we heard about darolutamide, have been wanting to do it and have been doing it, I think. Any thoughts at this point kind of reflecting back, Emmanuel, in terms of relative tolerability of the 3 lutamides?

DR ANTONARAKIS: I think darolutamide is clearly the most tolerable for most patients, I would say. This study was the least surprising but also one of the most important. We knew that ADT plus docetaxel plus darolutamide, the triplet for the metastatic hormone-sensitive patients, irrespective of disease volume, let’s say, provides a survival benefit. What we couldn’t do in practice, and we still can’t, is we could not use a doublet that consisted of ADT plus darolutamide. We could go ADT/enza, ADT/apa, but not ADT/darolutamide before this study ARANOTE.

Now, the interesting thing, and I’ll close with this, this study was entirely enrolled outside the US, there was not a single American patient here, and it’s not clear what the FDA, which is a US organization, will say about a trial that was conducted entirely outside the US. Many of us expect that this will be FDA approved in the US, but this was an ex-US study.

DR LOVE: Another really interesting —

PROF FIZAZI: If I may jump in here. Sorry.

DR LOVE: Go ahead, Karim.

PROF FIZAZI: If I may jump in, if you don’t mind. Actually, there’s a precedent, which is LATITUDE. LATITUDE, Neil, you remember, was the first randomized trial of an AR pathway inhibitor in castration-sensitive disease, and it showed a benefit from abiraterone in overall survival. And similar to that one there was not a single patient from the US enrolled in the trial. Still, the FDA actually requested the company to provide a dossier, and the drug is and was — was and is approved in the US. So I agree with you, Emmanuel, I think there is a reasonable chance that the drug will be approved, and actually not only in the US, but also in many other Western countries because this trial was not conducted in countries where lutamide or abiraterone were the label for ethical reasons. Which is fine, I think, which is good, because otherwise you would not be in an ethical situation when you have access to these drugs to enroll a patient in the control arm.

DR LOVE: So a quick question from the chat room. Joseph, Emmanuel, wants to know what your preference is. If you can’t access darolutamide for a doublet, is it enza or apa? Or abiraterone?

DR ANTONARAKIS: Yeah. I like abiraterone in that setting. We have great evidence behind it. In the short term it’s extremely well tolerated except for the patients who have diabetes. And also, the prednisone does make people in the short term, first 1 year, feel better, with more energy. The ADT/enzalutamide causes very significant fatigue, especially for anyone older than the age of 75 or 80. Apalutamide, I don’t like the 15% risk of a rash. The rash is quite hard to manage if it occurs. So in the absence of darolutamide, if I can’t access that one, still for me ADT plus abiraterone plus or minus docetaxel is my standard.

DR LOVE: So Karim, again, assuming all options, and I just put up a slide you showed about why not to give abiraterone in older patients. Maybe I should have asked that to Emmanuel. I was assuming that patient’s older. Anything you want to say about what we’ve learned about abiraterone versus the lutamides, Karim? And again, if you are not able to use darolutamide what do you use?

PROF FIZAZI: Well, first I think I actually agree with what Emmanuel just said. I think this is an important piece of data that we just saw at ASCO GU. This comes from the STOPCAP meta-analysis, which is a meta-analysis based on individual data, so scientifically very robust data. And it’s always comparing 2 drugs versus 1 directly, if you will, so it’s not a network analysis, which has some flaws.

And here what it showed was that of course all these ARPs provide an overall survival benefit, as we already know from the Phase III trials, but if you dig into the details you then figure out that abiraterone has a different form in younger versus older patients. And indeed in younger patients you clearly see a benefit in both PFS and OS, but for older patients, older than 75, the OS benefit is gone, so you’re not helping these patients by survival. And what is important is that for lutamides, at least here in this analysis, apalutamide and enzalutamide, the benefit in overall survival is preserved even in older patients.

So this actually made me change the way I’m treating patients. Similar to Emmanuel, I’m quite a fan of abiraterone because of the history of this drug and its overall good tolerance, but in my patients who are older than 75 I actually stopped mostly using this agent. And when I can I use darolutamide for the same reasons Emmanuel mentioned, and if I cannot then I try to switch to apalutamide or enza, sometimes using lower doses because I think that the dose, at least for enzalutamide, the initial dose for Phase III development was just too high historically.

DR LOVE: So I’m going to move on in a second and get into radiopharmaceuticals, but just to mention, I love trials in progress. This is the LIBERTAS study, a Phase III of apalutamide in hormone-sensitive mets. But this is kind of cool because it’s apalutamide with either intermittent or continuous ADT. We’ve been talking about this whole issue of intermittent, and here are the ADTs intermittent. EMBARK, I think they both were intermittent.

I guess another thing that Karim went through, we won’t get into it now, just to mention in terms of intermittent, that with the oral agent relugolix you see a lot quicker return to testosterone level, so maybe that’s a consideration if you’re going to use an intermittent strategy.

Also, Emmanuel, we’ve seen more and more people looking at the issue of seeing response, a PSA response, and looking at that in terms of prognosis. We have in the past spent a lot of time talking about when to use docetaxel in hormone-sensitive metastatic disease. That still continues to be debated until the — I think it’s an intergroup study that’s going to really look at the right randomization.

But what about the idea, Emmanuel, of starting out with intensified hormonal therapy and then adding in chemo in patients who don’t have a good PSA drop? Any thoughts about that strategy?

DR ANTONARAKIS: Yeah. None of the studies that you showed us were testing that. It was actually the opposite, for patients that do have PSA less than 0.2, or less than 0.02, can we remove either the ADT or the ARPi. I think the alternative, the thing that you mentioned about incomplete or suboptimal response, many of us, including myself, we kind of use that in the clinic as a litmus test. If I have a patient who starts off with a doublet, ADT/ARPi, and their PSA drops by only 80% or 60%, that’s clearly suboptimal. And frankly, in those patients, even a stabilization of the PSA above 5 or above 2, to me that’s a sign of castration resistance. So it may be semantics whether you call it suboptimal effect or castration resistance, those patients are going to develop CRPC very, very quickly, and I will often offer them docetaxel, especially if I know that they have some molecular alteration like a p53 mutation or RB1 mutation that predestines those patients.

DR LOVE: So I also want to mention, I mentioned earlier, the issue of capivasertib, the AKT inhibitor. We’re actually doing a program, which hopefully you all can watch in a couple weeks, at the AUA Meeting on AKT inhibition. There’s a big Phase III trial right now. We’re not going to really talk about it because it hasn’t been presented, although there’s a press release that’s positive. Karim went through this in his talk, the interesting interaction between AKT and androgen receptor, prior data with another AKT inhibitor, ipatasertib, that looked like it was effective in patients with PTEN loss, which is pretty common in prostate cancer, but that didn’t move forward.

But this did, capivasertib. All general medical oncologists are very used to that. Of course, the interesting — and here’s the press release. The interesting thing is, of course, urologists have no experience whatsoever with capivasertib. It took a while for medical oncologists to get used to it, glucose issues, a lot of things, 4 days on, 3 days off. Of course Karim’s not going to be able to comment because he’s the only one here who knows what it actually shows. Hopefully, we’ll see the data soon.

But Karim, all I can say is if this study is positive — and here are the 3 AKT/PIK3 inhibitor trials in breast, and you’ll notice all 3 of them have really good hazard rates, 0.5 or under. We have no idea what we’re going to see in prostate cancer, but all I can say, and Emmanuel, I don’t know if you have any thoughts about it, if it turns out, if, hopefully, keep your fingers crossed, this is a practice-changing trial, urologists are either going to have to get up to speed very, very quickly or they maybe send the patient to oncologists. Any thoughts about how that’s going to play out, Emmanuel?

DR ANTONARAKIS: What I love about this is the biological rationale is strong. We have evidence in other diseases. We have evidence even from metastatic CRPC in the IPATential trial using ipatasertib, which actually met its progression-free survival endpoint, but it was so modest, and the GI toxicities and hyperglycemia toxicities were so high that the company decided not to file for FDA approval.

So here we will be looking for a better hazard ratio. I’m going to speculate, Neil. I’d like to see rPFS hazard ratio of 0.7 or better in prostate cancer, and I also would like to see Grade 3 toxicities being less than 15%.

DR LOVE: Well, only one of us knows the answer, and he’s not going to be talking about it right now. But I will tell you, Karim, on Monday I’m going to do a video with Hope Rugo, and we’re going to show that at AUA just to get people kind of ready if they need to be.

Radiopharmaceuticals

DR LOVE: Alright. A few words about radiopharmaceuticals. Kind of cool stuff going on here. And this one was a big surprise, Karim, Emmanuel presented it in his talk, the PEACE-3 study, enza plus or minus radium. Pretty interesting. Not only PFS benefit, survival benefit. Any thoughts, Karim? And is this a strategy that you would like to use in your practice?

PROF FIZAZI: Yeah. Actually, this trial comes from a long way, and I’m saying that because it was designed first a long time ago, 10 years ago, in 2015, but also because it survived the negativity of another Phase III trial, which is the ERA 223 trial also testing the same hypothesis with a different drug. And the hypothesis was that adding a radiopharm here, radium-223, on top of an AR pathway inhibitor, here in PEACE-3 enzalutamide, but in the first Phase III trial this was abiraterone, whether this combination would be better than the ARP alone.

And in the first trial, the ERA 223 trial, not only the trial was negative, but also it was a disaster because there was an excess in fractures in favor of the experimental arm. So this was really a shock when we first saw the data back in 2018 or 2019. Actually everybody said at that time that we should stop combining abiraterone with radium because this is obviously dangerous.

So at this time the PEACE-3 trial was already enrolling patients, and the chairs had probably 2 options, either stopping their trial to avoid repeating this disaster or amending their trial, and this is actually what they did. And the amendment consisted in making mandatory the use of denosumab or zoledronic acid, but in most patients it was denosumab, to try to prevent the onset of fracture as a … potentially with association.

And it worked. Not only the incidence of fracture was much more reasonable as compared to what we saw in ERA 223, but as you just showed us, Neil, the trial is positive by both PFS and overall survival.

So coming back to your question, will I use this combination in my practice, the answer is yes, in a situation when I’m facing a man with old-fashioned CRPC, so in other words a man who is now progressing while on ADT alone because in that trial these patients had received ADT alone. But this is, as we all know, not what we’re typically doing anymore, we are now intensifying patients with metastatic hormone-sensitive disease. So in other words, when they become CRPC patients they have already exhausted 1 AR pathway inhibitor, and we don’t really know whether this combination works in patients who have exhausted an AR pathway inhibitor. So this is the question we want to address now before really making this combination ready for prime time for most patients when I’m treating.

DR LOVE: So I recommend you to check out Emmanuel’s presentation where he goes through more about this fascinating trial. But Emmanuel, I’d also like your thoughts about this practice-changing trial. You’re talking about quality of life again. Docetaxel versus lutetium, that’s a pretty difference in quality of life here. What do you want to say about this, Emmanuel? And right now where are you using lutetium-PSMA-617, and where do you think you’re going to be using it in the next couple years?

DR ANTONARAKIS: So when this study was designed, PSMAfore, the lutetium was approved within the post-ARP, post-taxane scenario. Here, this was a pre-taxane population, and instead of comparing the lutetium-PSMA against a taxane these patients were — those in whom the physician thought that a taxane could be safely delayed or postponed, it wasn’t that they weren’t fit for it, it was that the physician thought it could be safely postponed or delayed, and they were randomized to the alternative ARPi that they had not received or the lutetium-PSMA-617. There was a crossover built in. So 84% of the people that got the ARPi initially were allowed to switch, meaning that the majority of patients eventually got the lutetium-PSMA.

The primary endpoint of rPFS was not affected by the crossover, and as you can see there on the top left, hazard ratio of 0.49, so a doubling of radiographic progression-free survival with lutetium compared to ARP switch. The overall survival, as you can see, was not better. It was also not worse. And the thing to keep in mind is this was in spite of an 84% crossover, so this may have diluted the potential ability to see a survival benefit.

On March 28, 2025, the FDA did expand the use of lutetium-PSMA-617 to the prechemotherapy patients, and the package inserts states that it’s appropriate for patients with mCRPC who have received 1 ARP and who are eligible to safely or postpone taxane chemotherapy. So the language is interesting. It doesn’t say for those that are not eligible for a taxane, it says for those in whom it can be safely postponed or delayed.

And of course the side-effect profile was very manageable. One thing that we must remember, dry mouth and dry eyes. The PSMA receptor is expressed on salivary glands and on lacrimal glands, so there will be some radiation damage to the salivaries and the lacrimal glands. There is going to be some diarrhea, and then there’s some mild cytopenias, mainly anemia, but it’s primarily Grade 1.

DR LOVE: So my mouth is still pretty dry from being in Denver because they have no humidity there, so I can really relate to that.

Karim, what about the Enza-Patient study looking at enzalutamide plus lutetium? Any comments on that?

PROF FIZAZI: Yeah. This is a very interesting, randomized Phase II trial as well. This has been conducted by the Australian group, and they’re very innovative, I have to say, for radiopharms. The beauty here is that not only we are comparing whether adding lutetium-PSMA to enzalutamide is interesting or not, this is not fantastically original, it’s important but not very original, but the design of the trial is interesting because in patients who are responding very well to lutetium-PSMA by SPECT and by PSMA PET, you stop early the lutetium-PSMA delivery. So in other words to avoid toxicity, because in these patients when the cancer does not express anymore the protein you might expect, the lutetium-PSMA to go to normal cells and to generate damages there. So to prevent that we are just stopping, and then we might come back with an intermittent way of giving lutetium-PSMA. And that, I think, is very innovative.

It makes all sense. And actually the trial showed that it appears to be working, with a quite nice synergy between the 2 drugs and quite modest toxicity. So that, I think, is clearly interesting.

DR LOVE: So check out Emmanuel’s talk to hear about the SPLASH study Oliver Sartor did with another radioligand, lutetium-PNT2002. I call this the splash that maybe wasn’t because it doesn’t look indirectly maybe as effective as 177, and Emmanuel talks about the comparative data, indirect comparisons that you’re ever supposed to do, but of course we have to do all the time. It doesn’t look like — you can check out his presentation for more data.

Other Novel Investigational Approaches for Metastatic Castration-Resistant Prostate Cancer

DR LOVE: But I’ve got to ask you real quickly about these 2 agents because prostate cancer’s starting to get kind of interesting in terms of targeted therapy. I was really surprised when I heard about this. So first, Emmanuel, this agent CYP11 — yeah, CYP11A1 inhibitor, kind of sounds a little similar to abiraterone, but not really, but what is it? And looking pretty good.

DR ANTONARAKIS: You know, the urologist Charles Huggins who got the Nobel Prize for discovering surgical castration also discovered that when patients became — had recurrent disease after surgical castration they could respond to a surgical adrenalectomy. He would actually remove 1 or both adrenal glands.

So opevesostat is actually a molecule that Karim introduced me to. It’s made from a small Scandinavian company called Orion. They were the same company that developed darolutamide, actually. And this is an oral agent that blocks the very, very first step in the adrenal steroid synthesis pathway, CYP11, and this prevents the formation of glucocorticoids, mineralocorticoids and sex steroids, including androgen. So it blocks everything.

So this drug appears to work best in patients that have tumors with androgen receptor ligand binding domain-activating mutations. It also must be given, however, glucocorticoid replacement, such as dexamethasone, and mineralocorticoid replacement, such as fludrocortisone. So it’s a 3 for 1. You’re taking the drug, opevesostat, you’re also taking fludro, and you’re taking dex.

The data looks interesting, and there are 2 randomized Phase III trials ongoing at the moment, 1 is in the prechemotherapy mCRPC setting and 1 is in the postchemotherapy. They are both comparing the opevesostat against the alternative ARPi agent.

DR LOVE: So androgen receptor mutations, haven’t heard too much about that. We talk about that all the time in breast cancer, ESR1, we look at it. Karim, anything you want to say about this fascinating agent? How’s it tolerated?

PROF FIZAZI: Well, actually, it’s quite well tolerated with the dose we’ve been able to identify in the Phase I trial, and it took us a long, long time because the initial dose we were testing, based on animal models and experience, was far too high, and hence some toxicities in the Phase I initially with these high doses. But we’ve lowered this, which is now what we’re doing, you see the efficacy, what you just showed us, but basically with no or minor toxicity. And hopefully the Phase III trials will confirm this, so I’m quite optimistic about it.

You’re right, Neil, regarding the mutations. We’ve known that they exist for more than 20 years probably now. We know a big part, I think, of their physiology and what other the biological consequences of those AR mutations. And indeed, different ligands are able to stimulate the mutated androgen receptors, such as progesterone, estrogens or glucocorticoids, for example, and hence why we decided to develop this agent, which actually prevents from the making of all steroid hormones. So it should make a lot of sense to develop such a drug in patients with AR mutations.

And the primary data we have confirmed that it appears to be the case, that we do see very promising efficacy in these men with mutations and much more modest efficacy in patients without detectable AR mutations. So stay tuned because the Phase III trials are rapidly enrolling patients, so hopefully we’ll see data in the coming months or years.

DR LOVE: So it seems like there’s a new agent every day in follicular lymphoma. You’ve got CAR-T, you’ve got bispecifics, but also we have an EZH2 inhibitor, tazemetostat that oncologists are using. It kind of has a reputation of being not necessarily spectacularly effective but very, very well tolerated. Check out Emmanuel’s talk, and you’ll hear about mevrometostat, an EZH2 inhibitor. It looks like it has some decent activity, but he talks about it more in the presentation. Pretty well tolerated. Who knows? Maybe we’ll be using EZH2 inhibition in prostate cancer.

So Emmanuel and Karim, as always, it was a great experience to be with you today. Audience, thank you for attending.

Be safe, stay well and have a great night. Thanks so much, Emmanuel. Thanks Karim.

DR ANTONARAKIS: Thank you.

PROF FIZAZI: Thank you very much, Neil.