A five-part VJ Session featuring GU oncology experts Neal Shore, Bertrand Tombal, Robert Jones & Rana McKay who discuss their highlights in prostate cancer from the 2021 ASCO Genitourinary Cancers Symposium.

Welcome to The GU Cancer Sessions with the Video Journal of Oncology (VJOncology).

Neal Shore (Carolina Urologic Research Center, SC), Bertrand Tombal (Cliniques Universitaires Saint-Luc, Belgium), Rana McKay (UC San Diego Health, CA) & Robert Jones (University of Glasgow & Beatson West of Scotland Cancer Centre, UK) offer their perspectives on the most exciting clinical data and major milestones in prostate cancer presented at the 2021 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium.  

The expert panel explore the data from the practice-changing Phase III SPARTAN, PROSPER & ARAMIS studies in nmCRPC and debate the potential of theranostics, PARP inhibitors and GnRH receptor antagonist. They also consider next-generation imaging and PSMA-PET, the ACIS trial data and integrating genomic profiling in to practice.

Updated results from ACIS in mCRPC

“This study was looking at the combination of abiraterone plus apalutamide versus abiraterone alone in the CRPC space. The trial’s primary endpoint was radiographic progression-free survival and the combination did demonstrate an improvement of rPFS, however, we did not see a signal for improved overall survival with the combination. The utility of combination therapy in the CRPC space, I think, is really limited. There is certainly increased toxicity with the combination. So I think, combined with data from the Alliance study suggests we should not be using the combination together in the CRPC setting.”

     – Rana McKay

Phase III trials in nmCRPC & the role of PSMA-PET

“I think modern imaging may play a role in the low kinetic nonmetastatic CRPC, but for the other ones, to me, the real question is, if you are on ADT and your PSA starts to double every six weeks, why do you need imaging? ”

     – Bertrand Tombal

PARPi and associated challenges

“I think olaparib is a game-changer. The main reason it’s a game changer, though, actually is because it brings genomics in for patients with prostate cancer. And that opens up a Pandora’s box of opportunity, PARP inhibitors being the first one of those opportunities.”

     – Robert Jones

“I think there needs to be teaching around how do we do somatic tumor profiling and then what’s the right method. Tissue? Do you get a biopsy? Do you do cell-free DNA? If you’ve got a bone met-only patient, how the heck do you get the bone to process? So I think there’s a huge educational piece that needs to be had.”

   – Rana McKay

Theranostics and targeted radiopharmaceuticals

“The TheraP study, which was a multicentral Australian trial comparing PSMA lutetium with cabazitaxel is a really important trial, because, although it’s only a Phase II trial, it’s quite large, it was 100 patients in each arm, it’s got an active comparator. And I think that will really add to the understanding of this drug and our understanding of its potential position in the therapeutic pathway.”

     – Robert Jones

“Outside of academic nuclear medicine, the community nuclear medicine physicians have really exclusively dwelled in the diagnostic realm. And I think this is a great opportunity to also enhance the multidisciplinary aspects here, to really step it up. That’ll have to happen.”

     – Neal Shore

GnRH receptor antagonist & other highlights

“Actually, my personal dream would be that one day we got rid of androgen deprivation therapy. Because when you think, again, this is anti-precision medicine by definition. You suppress testosterone everywhere to get it working only in the prostate, at least at the low volume.”

     – Bertrand Tombal

Full Transcript
Neal Shore:
Welcome, everybody. What a great pleasure for me to have this opportunity to talk with my colleagues internationally, Bertrand Tombal, Rob Jones, Rana McKay. They'll introduce themselves. This is an international, small faculty. I'm Neal Shore. I'm here in the US and what we're going to talk about is what were some of the highlights at ASCO GU 2021 this year. We all had to attend virtually and there was some great data. There was some really interesting science, some of it controversial, some not, some things that are going to be potentially practice-changing. Maybe there's going to need to be some more trials and more evidence but we'll have a round table discussion and we'll ask the faculty what were the key trials and key presentations that they found compelling. I'll certainly want to hear any of their own work that was presented.

Neal Shore:
So, with that, I'm Neal Shore. I'll just be moderating and letting this distinguished panel do most of the speaking. I'm a urologist in the US and run the Carolina Urologic Research Center. Let me hand it over to you, Bertrand, then Rob, then Rana.

Bertrand Tombal:
Okay. Hi. I'm Bertrand Tombal. I'm a urologist in Brussels, Belgium, and I'm pleased to be with you today.

Robert Jones:
I'm Rob Jones. I'm a genitourinary medical oncologist in Glasgow, in the UK.

Rana McKay:
And I'm Rana McKay. I'm a genitourinary medical oncologist in California at UCSD.

Neal Shore:
So, Rana, let me ask you. Gosh, I think for so many of us our last meeting that we all went to live was literally a year ago at ASCO GU in California. I'm sure you were really busy then and I know you were busy at this meeting. Maybe just to kick things off, what one or two presentations really caught your eye this year at ASCO GU? Especially if you were involved with them.

Rana McKay:
Wonderful. Thank you. It was actually just such a robust meeting where there was just a lot of new data getting presented and, I think, across the board, including bladder and kidney, there was a total of four Phase IIIs that read out, which is just pretty remarkable to have that much progress happening in the field. I think probably the highest-level data that got presented, I guess, the newest data, was probably from the ACIS trial that was presented by Dana Rathkopf.

Rana McKay:
Basically, this study was looking at the combination of abiraterone plus apalutamide versus abiraterone alone in the CRPC space mirrored very much a similar trial that was actually conducted through the Alliance, led by Dr. Michael Morris, looking at abiraterone and enzalutamide in this context. The trial's primary endpoint was radiographic progression-free survival and the combination did demonstrate an improvement of rPFS, however, we did not see a signal for improved overall survival with the combination.

Rana McKay:
The utility of combination therapy in the CRPC space, I think, is really limited. There is certainly increased toxicity with the combination. So I thought that the data from the Alliance study and probably we should not be using the combination together in the CRPC setting, I think, in summary.

Neal Shore:
Yeah, I appreciate that. Interesting. I was part of that. Maybe all of you were, too. The interim analysis, the first analysis, was about a 6-month rPFS, the final analysis is 7.2, and I would say for me, disappointingly, that the OS wasn't statistically significant. Trying to combine this sort of concept of androgen access annihilation, impacting the AR as well as ligand stimulation. Rob, Bertrand, what were your thoughts on the ACIS data?

Robert Jones:
I'd agree that that's clearly not practice-changing, at least not in the UK where I work. To my mind, actually, almost the more surprising thing was that you were getting a signal on PFS because it does suggest there is biological, at least additive, some degree of additive activity. And I suppose it poses two questions because clearly these drugs are available. They're not licensed in combination but they're available to prescribe.

Robert Jones:
So I guess it would be really interesting to hear from you two on the other side of the Atlantic as to whether you think that actually there will be anybody choosing to use these in combination despite the data. And I guess the other question it really poses is what does this mean for using rPFS as a surrogate endpoint in future trials in mCRPC? Because I think we've all rather held that that's been quite an important step forwards.

Bertrand Tombal:
Actually, when I saw the result of the trial I went back to the result of the PLATEAU trial where actually the idea was the same. It was kind of switching versus adding. And then I start to look at most of the modern trial where abi or enza was used as the comparator, and it's funny that you almost have two to three months on PFS, which I really believe is more like an epiphenomenon. You don't really care about that. I think that overall these were great ideas we had when the drug came on the market, when people... You remember people like Chris Rogotitis was dissecting the specific mode of action.

Bertrand Tombal:
But in the end they are twin sister and brother. I think there's been a lot of discussion about second PFS and all of that. So to me we still don't have the real one, which has been kind of starting with the combo versus a sequence. And, in the end, I think that, with more options coming on, this will naturally disappear. It's true that in the country like I live, in Europe, more and more there are questions from reimbursement authorities about should we really allow to get a second line of AR-targeted therapy when we see the price, because the price is very high. The value is very low, if you combine or if you give it. So I think that it will disappear with all the modern... When we're going to get more agents, that kind of discussion will naturally disappear.

Neal Shore:
That's a really important point. We talk about this in so many international meetings. I think the APCCC has really made a point of addressing more prominently issues of accessibility or global disparities. Let's transition to the whole notion around the three Phase III nmCRPC trials, talking about use of new drugs that all received approval within the last two years, and then in 2020 at ESMO and ASCO and now at ASCO GU we also had presentations on final analyses and crossover of the SPARTAN, PROSPER and ARAMIS trials.

Neal Shore:
And, as you mentioned that, Bertrand, I was thinking to myself, and Rob, you as well, too, this notion of rPFS, is it no longer going to be an acceptable metric for approval? A big part of the MFS interim analysis, the first analysis in those three trials, PROSPER, SPARTAN, and ARAMIS, I think many of our colleagues were saying, "You know, expensive new drug, maybe there's toxicity. Why would I want to use this?" But then we saw the OS data. That resonated very strongly, I thought, in 2020 and again Kim Chi had a presentation looking at TITAN, different study, mCSPC.

Neal Shore:
But I presented a crossover analysis looking at four different statistical metrics of the crossover for ARAMIS, demonstrating that it had a really minimal dilutive effect and that the overall survival benefit, despite a crossover in the placebo group of about 30%, was real. So, maybe, Rana, I'll start with you. nmCRPC, where do you stand on this? Is this a game changer? And maybe also comment on the role of next-generation imaging.

Rana McKay:
Yeah. No, these three studies are landmark studies that are definitely practice-changing. There is no doubt about that. I think the field of nmCRPC is dwindling as we now have PSMA PET that's been FDA approved and is likely, over the next year, going to become further commercialized and further available for our patients. So I think we're going to be detecting disease a lot earlier, detecting oligometastatic disease. There was actually a wonderful presentation by Declan Murphy regarding the good, the bad, and the ugly of PSMA. It is here to stay. It's just figuring out how to actually integrate it into clinical practice in a manner that actually is aligned with clinical evidence, because I think people are just doing a lot of things without evidence.

Rana McKay:
But I do think the three studies are practice-changing and I completely agree with you, Neal, that I think without the overall... seeing the overall survival benefit across the three studies is really what made these studies practice-changing. You're not just delaying the time to mets. You're actually making people live longer and that matters.

Rana McKay:
I think when people are on these trials, they're on therapy for three to four years. These therapies work for a long time. So it's not inconsequential to put somebody on a therapy for that prolonged a period of time if you're not actually going to make that individual live longer. I do think that the updated TITAN data was good to see and confirm that, yes, the overall survival data was positive. So I do think these are practice-changing.

Bertrand Tombal:
There is, at least in Europe, there is a misconception when people say the drugs were approved on MFS. Actually, in Europe, for the three drugs and the three companies, EMA say, "We would like to speak about MFS-plus," meaning what is the meaning of MFS? Now, remember, at the meeting at EMA where they say, "We know the drug. We know enza. We know apa. Nothing new. Huge benefit on PFS." Could you justify that actually what you call MFS is really a benefit for the patient beyond just simply a bone scan turning out?

Bertrand Tombal:
The three works on that concept of MFS-plus which actually is recognized by ESMO in their rating of the drug activity. It's not only delaying progression, it's living a long period of time without having any deterioration in quality of life, with drugs that are accessible. So I think that there was a part of the physicians that were already convinced by that MFS but really the home run was that you had three trials that came with a benefit in overall survival.

Bertrand Tombal:
And also something very important is that we're not speaking about nonmetastatic CRPC, we're speaking about high-risk nonmetastatic CRPC, people with a rapid PSA-doubling time. And those, like in my country, who use PET, we have PET PSMA since seven year, whole-body MRI since 2005. We know that a vast majority of these patients actually are already metastatic. So we are speaking about low-volume metastatic disease with rapidly-progressing PSA. And it makes sense that if you start an active agent, you're going to keep the patient for a longer period in a good state and they're going to live longer.

Bertrand Tombal:
I think modern imaging may play a role in the low kinetic nonmetastatic CRPC, but for the other ones, to me the real question is, if you are on ADT and your PSA starts to double every six weeks, why do you need an imaging? We know you should stop something. Maybe the imaging will add something else but I think that we know these are poor-prognostic patients and it's not a surprise that they live longer and better if we start the drug rapidly. At least that's my view.

Robert Jones:
Bertrand, do you not think that actually we're maybe focusing on the wrong thing here because we know in M1 disease, de novo M1 disease, you know that you really accentuate the impact of ADT by giving one of these newer hormonal drugs. We've got LATITUDE, STAMPEDE, ARCHES, ENZAMET, TITAN, showing this. So actually we should be spotting these guys, these guys who've become the high-risk M0CRPC.

Bertrand Tombal:
Exactly, yeah.

Robert Jones:
Spot them before we castrate them. We could then be treating them properly even more actively at the get-go. So actually that's maybe where the modern imaging might really come in to help us actually target these patients so that they're actually getting more potent androgen-depriving therapy from the start.

Neal Shore:
Well, it's interesting that some of the conversations that I've been part of, I know you all have, as well, when you look at next-generation imaging and particularly the PSMA PET juggernaut, which is really, I think, going to just explode globally. We have countries that have had it for years and years and it's finally going to get accessibility in the US by this summer and I think in many other countries. Certainly many countries in Europe and in Australia have been way ahead of us for years for various reasons.

Neal Shore:
But when I looked at that paper that I think Boris Hadaschik is the senior author, when they looked at the SPARTAN, PROSPER, ARAMIS population, 200 patients in about five or six countries, Scandinavia, Canada, and Europe, and basically that same PSA-doubling time, less than 10 months in an mCRPC group, where 55% had disease outside of the pelvis, as opposed to the conventional imaging.

Neal Shore:
What do you think about that, Bertrand? And that was a group that had the same criteria for the SPARTAN, PROSPER, ARAMIS trial. Some of our colleagues, I think, are thinking maybe there will be a different systemic therapy approach or maybe there will be a role for SBRT. Or maybe a combination. How do you-

Bertrand Tombal:
SBRT, to me, that's actually our reading. It has a different efficacy in men which are not castration-resistant and in men who have castration-resistance. We know that, radiation oncologists know that. I don't think data, and I think that, alone... and that's my worry. My worry is that you have people who showed up, they have an aggressive cancer, they're progressing rapidly, but they get a PET PSMA and it's got two lesions. And then they receive stereotactic radiation therapy instead of starting one of these anti-androgen.

Bertrand Tombal:
Personally, I believe this is wrong. I believe that there's a great role to make many hypotheses, such as combining with stereotactic ablative radiotherapy and then pausing the AR-targeted therapy, looking at shorter course, intermittent use, but not simply replacing. Because you're replacing something that may work versus level-one evidence from three trials. So I think that, to me, it is a game change and there is no reason. It is wrong to assume that those, you see something on the PET PSMA, have a worse prognosis than those who have a normal PET PSMA. Nobody knows that.

Bertrand Tombal:
We have tested the diagnostic accuracy of PET PSMA but not its prognostic value. We cannot say that because a PET PSMA is negative, despite the fact that they have a very short PSA-doubling time, they have a better prognosis than those who have one, two, three. We can't say that. So it will generate more clinical trials, but today it is wrong to say, "I do a PET PSMA and if it's negative or if there is one or two metastatic deposits, I can do something else."

Neal Shore:
Well, let's stay in the theme of game-changing milestones in prostate malignancies. Let's talk about PARP inhibitors. Let's talk about the fact that, at least by EMA and FDA, there was approval for consolidated use of BRCA-1 and 2 for patients who are mCRPC who progressed on a novel hormonal agent. There was a nice presentation by Yohann De Bono and the entire PROFOUND team, of a gene-by-gene analysis, looking at that cohort B. Rob, let me ask you and then maybe, Rana, I'd love to have your follow-up with Rob's comments. Where are PARP inhibitors, and for prostate cancer, in terms of the UK for approval and what are your thoughts about their role? Do you agree that it's a game changer to have a PARP inhibitor for mCRPC?

Robert Jones:
I'll tell you where we're at. The marketing authorization is there since the end of 2020. The access in the UK NHS is not there yet, it hasn't had payer acceptance. It hasn't been rejected but it hasn't been through the process yet. I think this drug is a game changer. The main reason it's a game changer, though, actually is because it brings genomics in for patients with prostate cancer. And that opens up a Pandora's box of opportunity, PARP inhibitors being the first one of those opportunities. But we've already seen others coming temptingly close.

Robert Jones:
But of course that is also the real challenge because even if the NHS in the UK agrees to pay for olaparib tomorrow, we don't really have the full infrastructure to deliver the genomics to make it happen. We've got a full infrastructure. The pharmacy, I can get it off the pharmacy shelf. But until I know which patients to give it to, that's not terribly helpful. One of the really encouraging things from this meeting was of course we saw both from PROFOUND but also from other studies, we saw some really nice data about circulating tumor DNA and its ability to reveal somatic mutations in DNA repair genes. So actually this brings the whole thing a bit closer, hopefully.

Neal Shore:
So, Rana, what's the teaching now? I think what Rob said is just spot on. I love the fact that this landmark trial, to date the only Phase III trial prospectively done, globally conducted, clearly demonstrates the benefit of olaparib, a PARP inhibitor which we know has been efficacious in breast and ovarian and pancreatic cancer. Now it brings it to prostate cancer, where that's where we all live, in the prostate cancer world. But, Rana, what is the teaching that Rob wants to see, and Bertrand and I want to see, and what are you doing for your residents and fellows? Because that, to me, is right now a real limiting factor. So many of our colleagues are like, they just are confused by how to test, when to test, germline somatic. Maybe, could you comment on that?

Rana McKay:
Absolutely. I completely agree that this trial was landmark because it's bringing precision medicine to prostate cancer and I think it's exciting to see that PET assertive data, as well, because I think this is just part of that whole entire theme. But I do agree with you, I think this is going to be a huge shift in practice because now that there are guidelines for germline testing for men with prostate cancer, and not just people who are metastatic, people with localized high risk. The NCCN in the US has come down with recommendations for testing those individuals. And even some intermediate-risk patients who may have a family history or have intraductal carcinoma.

Rana McKay:
The majority of those patients are, in practice, being followed by urologists. They're being seen by urologists or even radiation oncologists. So, one, there's huge teaching that needs to be had regarding how do we roll this out systematically? There's a great shortage of genetic counselors and some centers are just not resourced with genetic counselors. So this really puts the onus on the actual clinician. You can't just do your pre and post-test counseling with genetics anymore.

Rana McKay:
So I think some of that has to be done within the context of the practice, how to appropriately screen? And that's just the germline piece. Then I think the other piece with regards to somatic tumor testing, I think any man with advanced prostate cancer, metastatic advanced disease, not just CRPC but advanced prostate cancer, should undergo somatic tumor profiling. And what we learned from PROFOUND was actually, while there is enrichment in the primary, in that I think 86% or something like that of patients that were enrolled in PROFOUND had genomic profiling done off their primary prostate specimen, you do miss some individuals. Just because the prostate is negative doesn't mean that somebody couldn't have developed an acquired mutation and some people, they may have had their prostatectomy 10 years out. There may not be viable DNA there.

Rana McKay:
So I think there needs to be teaching around how do we do somatic tumor profiling and then what's the right method. Tissue? Do you get a biopsy? Do you do cell-free DNA? If you've got a bone met-only patient, how the heck do you get the bone to process? So I think there's a huge educational piece that needs to be had and, quite honestly, I actually think that our industry partners need to help in facilitating that educational component, in addition to the community and academia and guidelines associations, because I think that there's no way to get olaparib to a patient unless somebody orders the right test in the right individual. The two need to be completely linked. You can't have one without the other.

Bertrand Tombal:
What you say is funny because I met with a company, AZ, to be precise, and I said, "You guys remember when you came with EGFR inhibitor in lung cancer, you realized when the drug was already on the market that basically there was no market because you hadn't teach pulmonologists to do a proper biopsy and to look for EGFR mutation." And it was so slow that they wouldn't wait and they would give chemotherapy when they came with first-line EGFR. Great study but no result. And I said, "You haven't learned your lesson because we are now 10 years down the line." Everybody knows about olaparib but you ask a general urologist, "How do you get a patient on olaparib?" He knows how to do the prescription but he has no idea what to ask, what tissue, when to do it.

Bertrand Tombal:
There is a huge confusion between germline testing and genetic counseling. We told them every country has to get organized so that we... I think that organizations such as EAU, ESMO, are trying to come to practical recommendations. Because there is also cost issue. If you send the prostate and you've got a whole genome sequencing on the prostate and it is negative, you're going to have to repeat the test on a new biopsy. So we really need to sort this out or it's going to be a huge mess because people will simply be incapable of ordering the good test to the good person.

Neal Shore:
Yeah, I agree. I think what's very encouraging to me is the flood gates have opened in all these companies and the competitive nature now of this biomarker segment of genomic profiling is really good for all of us. It will clearly lower the cost. You look at germline testing a decade ago, it was in the order of thousands of US dollars, and now it's down to just a couple of hundred US dollars. I think, similarly, we'll see that same competitive market pressure on somatic tissue testing, as well as somatic liquid testing.

Neal Shore:
But one of the things that you all said that really, I think, is important, here we have medical oncologists and urologists speaking together. We certainly would typically always benefit from a radiation oncologist. But we need to start thinking about incorporating our interventional radiologists and our pathologists. They've really become quite key into this multidisciplinary team in figuring out how we're going to perform, get great tissue integrity, making sure that we're not wasting tissue samples, and moving forward.

Neal Shore:
Because, as you were saying earlier, Bertrand, getting back to combining an ARPI with shorter durations, intermittent use, it's all about precision and tailored medicine, and I think that's really what the future holds. So, with that comment, let me go to a third area. I have two more game changers to bring up to you. There are probably others and I want to hear, if I missed them, please let me know. The next one is the theranostics and targeted radiopharmaceuticals. Rob, where do you think, what's going to happen, and let me start with you regarding maybe potentially the first big Phase III that may read out, well, should read out this year, the VISION trial.

Robert Jones:
This is about PSMA lutetium as a therapy but obviously that's linked to gallium PSA PET as a diagnostic and moreover, actually, as a predictive marker. And you're right, we don't yet have the results of the VISION trial. We hope we'll get them sometime in 2021. Of course that's a randomized Phase III trial, essentially in patients who've run out of options because the control arm was essentially best supportive care. You weren't allowed to have active agents such as crossover, enzalutamide or apalutamide.

Robert Jones:
And the primary endpoint, or co-primary endpoints, of rPFS but also overall survival. Again, as we said before, the overall survival I think is really important to me in that trial. We don't have the results of that yet. What we did get out of this meeting though was the results of a randomized Phase II trial. This was the TheraP study, which was a multicentral Australian trial comparing PSMA lutetium with cabazitaxel.

Robert Jones:
I think this is a really important trial, obviously dependent on the positivity of VISION, because, although it's only a Phase II trial, it's quite large, it was 100 patients in each arm, it's got an active comparator. And I think that will really add to the understanding of this drug and our understanding of its potential position in the therapeutic pathway.

Robert Jones:
The trial's primary endpoint was PSA response rate and you saw about a doubling of PSA response rate, that is more than 50% reduction compared with cabazitaxel. But it also showed quite encouraging hazard ratio for rPFS. I think it was 0.63. So really, I think, this is for the first time we're now seeing this drug showing that it's got not just activity, we already knew that, but activity that really might have an important place in the therapy of prostate cancer.

Robert Jones:
My one caution on it is that actually the way the patients were selected, it was a little bit more stringent than just doing the PSMA PET scans. Because the patients also had an FDG PET scan and you were excluded from the trial if you had discordant disease, which means if you had disease which was FDG avid but was not PSMA avid. So even if other disease was PSMA avid, if you had FDG-only disease present, you would be excluded from the trial. So this is quite a stringently selected population in this trial.

Neal Shore:
Yeah, great point. Great work by Michael Hofman in that... It'll hopefully be remarkably supportive to the VISION trial readout. Rana, what are your thoughts on this burgeoning field of theranostics and targeting radiopharmaceutical antibody conjugates? The lutetium is a beta. There's a lot of work going on in alpha molecules.

Rana McKay:
Yeah. No, I think it's incredibly exciting. I think it's going to definitely change the field, I think hopefully with the VISION trial reports out positive. I think there's been a lot of tremendous enthusiasm behind PSMA-targeted theranostics as the say-all, end-all, be-all. But I think we probably need to temper some of that. I think there are probably going to be another therapy that hopefully will be effective for patients but I think it's essentially what's coming to the field. I think the other piece, just as we talked about with the genomics, is going to be how do you actually make this a reality, to be available at centers across the world?

Rana McKay:
I think radiopharmaceuticals can be challenging. You're working with a nuclear medicine department or a radiation oncology department. I think look at the rollout that happened with radium. So I think that, if the VISION trial is positive, I think there's going to be a huge lag with actually making this a reality for patients. And I think it's going to shift the landscape because I think if PSMA, if the trial is positive, I think we're probably going to be seeing a phasing out of radium in clinical practice.

Bertrand Tombal:
There are some interesting hurdles, though. One is the fact that you have to carefully select your patients. If you send somebody to, for instance, Dusseldorf, where they have the... They always do a PET PSMA, PET FDG, and if the patient has any FDG-positive, PSMA-negative, they won't treat him. And that's the key to success. There are very interesting papers in European Nuclear Medicine recently that show that actually your response rate to PSMA lutetium. If you have FDG-positive, PSMA-negative and if you look at the Hofman trial, it's always been very careful on this and actually there is always one third, 30% of the patients, that get excluded, or they have low PSMA expression or FDG-positive.

Bertrand Tombal:
So my worry, once again, is that I worry that the message may be diluted in that amongst people in that they believe that because you have a positive PET PSMA you will respond to PSMA lutetium or other drug. This is not true. You need to have a PSMA-exclusive patient. That's something we're going, as academics, we're going to have to be guardian of this. We have to secure that.

Robert Jones:
But we're going to have to work with the nuclear medicine specialists, as well.

Bertrand Tombal:
Yes.

Robert Jones:
I really worry that we don't have the capacity in the UK to deliver basically the diagnostic part, actually living the therapy part, I think we can do that. It'll have its challenges, but I worry that getting the diagnostics right will be a challenge. I'd be interested in your views, Neal and Rana, in the US, in terms of nuclear medicine capacity.

Rana McKay:
I think about the PSMA and the FDG validity. I think it's going to be, one, difficult to actually be able to get two nuclear medicine scans performed for any given patient. And, quite honestly, just because somebody has positive FDG disease, when we look at genomic drivers, we don't necessarily exclude people that have alternate drivers of diseases. Look at the story with PARP inhibitors. If you had some other driver alteration, you weren't necessarily excluded from receiving a PARP inhibitor.

Rana McKay:
I think it just speaks to the, not to say how homogeneous... I do agree that I think people that are purely PSMA-positive are probably better apt to respond but if you're not, are we going to actually exclude a therapy? Some of these men, they're getting their drugs earlier. They've gotten their AR antagonists. They've gotten their docetaxel or chemo, and they still feel very well. They have a good performance status and you're kind of running out of options. I may be a little more lenient around the exclusion of FDG positivity in somebody that may have PSMA and FDG avid disease. I'd like to see that data teased out a little bit more.

Neal Shore:
Yeah. I think there's going to be some practical challenges to doing that. I know that in a lot of trial designs that I'm seeing currently, I think by just getting a comparator CT scan/bone scan in conjunction may solve that problem. It remains to be seen. But, Rob, to your point, I bring the nuclear medicine specialty in the US. Outside of academic nuclear medicine, the community nuclear medicine physicians have really exclusively dwelled in the diagnostic realm. And I think this is a great opportunity to also enhance the multidisciplinary aspects here, to really step it up. That'll have to happen.

Neal Shore:
Let me transition this issue of... Let's assume a radiopharmaceutical antibody conjugates get approved and maybe also asking you to think about this in terms of the PARPs now, specifically olaparib and, in some countries, rucaparib. What about a combination of the PARPs with a AR pathway drug? A lot of those Phase III trials happening there. And then also arguably the ARPIs with radiopharmaceutical conjugates? It kind of makes pretty good sense in terms of tolerability but what do you think about that, Bertrand?

Bertrand Tombal:
I think one of the problems is that you need to be sure you don't mess with the PSMA expression. And that, as you know, with AR pathway inhibitor, we don't have yet extremely good studies showing what is the kinetic of PSMA expression during the early phase of treatment with the ARPIs. I think that we have a tendency, we haven't learned from the past, again, and we throw Phase III based on, "Oh, there is two great drugs. Let's combine them. Boom." We remember, we've done that with docetaxel and, to my knowledge, it hasn't succeeded one time. So we-

Neal Shore:
We have the ERISONS trial readout later this year. Who knows?

Bertrand Tombal:
Yeah, yeah, maybe that will be the first one. But we have to be careful with PSMA expression and maybe do... We wrote an editorial with Yohann De Bono on this. Yohann wrote a beautiful paper on the relationship between PSMA and DNA repair so, yes, it makes sense but PSMA is a tricky drug because it's really linked to the PSMA expression and we don't know, really, what is the kinetic when you combine with a PARPi. So, once again, we're going to have to see what it does.

Bertrand Tombal:
My worry is that, exactly like radium, people will start to combine without any evidence. We managed to have pretty bad surprises when we did that. I think the Ra223 trial should remain a good example that you take two good drugs, you end up with major catastrophe.

Robert Jones:
But I think, though, we do need some intelligent combinations.

Bertrand Tombal:
Exactly.

Robert Jones:
I think actually with theranostics, therapeutic major nucleides, there is a real opportunity there because there's a lot of potential to synergize with radiation. Which has not been particularly well exploited with conventional radiotherapy, in my view, in the past. So if we can really bring in intelligent preclinical design and then intelligent trial design to that, we might be able to make a real difference here. And I think the PARP inhibitors are a potential because there's a strong rationale for combining them with radiation.

Robert Jones:
Actually, we did see the results of the LUPIN trial, which was a Phase I/II trial combining lutetium with another radiosensitizer. In my view they were encouraging early data, too early to really call it out. But it's nice to see that kind of intelligent approach to combinations going on.

Rana McKay:
Yeah. I think, to piggyback on that, we actually had a trial in progress of the combination of olaparib and radium that just completed Phase I and will be transitioning into Phase II. I do think that the toxicity is something that we're going to have to pay close attention to, with the myelosuppression that we see with radiopharmaceuticals, the myelosuppression of radium and olaparib. And now these patients are ever so more heavily pre-treated that I think the bone marrow toxicity can become a real problem.

Neal Shore:
Well, thanks. That's great, a great conversation. Let's go to another area that I don't want to be overly hubristic about it but I think it was a game changer. And maybe I'll be quiet. I'll just introduce it. Bertrand was part of this paper in this trial, too. It was the HERO trial. That was the relugolix versus LHRH agonist therapy for patients with advanced prostate cancer, metastatic, biochemical relapse, locally advanced disease.

Neal Shore:
There was a nice presentation, Dan George was the first author, looking at the safety and the efficacy of the two different arms, the oral relugolix, the GnRH antagonist, versus LHRH agonist, looking at the combination of docetaxel, looking at it with enzalutamide and radiation therapy patients. But let me ask you, Rob and Rana, because Bertrand is an author on the paper alongside me, and take the gloves off. Tell us what you really think. Is an oral GnRh antagonist, one pill daily, if you've read that trial, is this a game changer?

Robert Jones:
Rana, do you want to go first on that?

Rana McKay:
Sure. I think it just is another available treatment option for patients. I think it's good to have it. Some patients don't like injection therapy. I think the cardiovascular data that were presented is provocative. I think, though, the risk is, though there seems to be a tremendous decline in the relative risk when you look at the absolute numbers of actually people who have had cardiovascular events, I think it's pretty low in both patients who had a prior CV versus not. So I think it's great that we have this option.

Rana McKay:
What my worry is, is that we're going to start to extrapolate that data into patients getting definitive curative therapy with radiation and hormones. How do we know that a more rapid rise in testosterone post-therapy completion isn't going to somehow affect efficacy outcomes in that context. It was mainly tested in the hormone-sensitive setting so what's the role in CRPC? Is there any role in CRPC? And then now you're combining it with other drugs. I think when you look at the drug compendium, there's potential for drug/drug interactions with enza. There's potential for drug/drug interactions with abi, with QTC prolongation.

Rana McKay:
So I think we just don't really know and I think it's going to just open up a can of worms of people just saying, "Oh, it's just like Lupron. We're just going to use it whenever, wherever we would otherwise use that agent." I think there's a little bit of caution that needs to be had around that.

Neal Shore:
Let's have Bertrand counter Rana and then you, Rob. How is that? Bertrand, what do you think about Rana's commentary?

Bertrand Tombal:
No, I agree on some things. My view on antagonist is that, for a majority of patients, they probably just like Lupron. Then the problem is that we need to find... I think there is no benefit in castration-resistant. We've done trials with the degarelix and showed there is no benefit. But there are a subset of patients which actually may, I would say, in which the acute rise in testosterone and also, more importantly, in the late NSFH, may be detrimental.

Bertrand Tombal:
There is a lot of work done, especially in Hamilton, Canada, on patients with unstable atherosclerotic plaque. We haven't yet fully identified these patients. These are the one we actually call a patient with previous cardiovascular disease. But, saying that, we have excluded from the trial anybody having a mild cardio infarction within six months, so we have not taken the worst of the worst. So I think that in these patients, and the same to me for radiotherapy, is in patient with urinary symptoms.

Bertrand Tombal:
We're trying to look at that. So I think that for the vast majority of patients yet it's probably just another ADT, probably. There are benefits, I believe, for few patients to receive short course of hormone therapy, like six months and then stop. But we still have a lot of work to do to really identify those subgroup of patients that may benefit from an antagonist.

Bertrand Tombal:
And to me, the highest level of evidence today, although it's not yet fully Phase I, level one, are those who suffer myocardial infarction or a stroke within six months to one year because there we have a Phase II done in April, a beautiful small Phase II by David Margel. We have concording argument for that subgroup of patients. But the guy which is 72 years old who has no comorbidity, who start with a metastatic cancer with ADT plus enza, no, there is no benefit probably.

Neal Shore:
Unless he has multiple cardiovascular risks.

Bertrand Tombal:
Exactly. This is the one you would give it.

Neal Shore:
I think there are some days where it seems like all of my patients have numerous cardiovascular risks, but that may just be the doom of practicing in the southeast part of the United States where obesity and hypertension and dyslipidemia and glucose dysregulation and prior arrhythmia is really highly prevalent. But that's my own personal background but, Rob, what do you think?

Robert Jones:
Yeah, I think potentially living in Glasgow is of itself a cardiovascular risk factor. But I'm kind of with Rana and Bertrand on this, really. I think it's a player in the game but it is not a game changer. I would say that if we'd started off with a once-daily castrating tablet, we probably wouldn't be striving to make a monthly or three-monthly depo version of it. Clearly, once daily is a fundamentally important concept. But I would share the concerns that Rana raises that all of our evidence base, really, is based on using depo, LHRH agonists, by and large.

Robert Jones:
And whilst the potential for losing those gains by switching to an oral, and you're looking at combinations with radiation, combinations of other drugs, is relatively small. Actually, well, how much do we gain by doing that? So we need to be just cautious before we throw away the convention too quickly. But, yes, clearly there's groups of patients with whom this will suit because they want oral therapy, maybe the ability to stop it quickly, and of course the growing interest in the cardiovascular risk patients.

Bertrand Tombal:
But to me the big competitor in the segment we're speaking about, men who need short course hormone, is the development you start seeing by using antiandrogen monotherapy. And I think it's the same in the UK. We've been using a lot of bicalutamide 150, and there still are a lot of patients treated with that one, a specific segment of low-volume disease. And I think that to me the number one challenge will be what we're going to do with antiandrogen, enza, the whole apa monotherapy, in a few years.

Bertrand Tombal:
Actually, my personal dream would be that one day we got rid of androgen deprivation therapy. Because when you think, again, this is the anti-precision medicine by definition. You suppress testosterone everywhere to get it working only in the prostate, at least at the low volume.

Neal Shore:
It's interesting. I agree with you, Bertrand. And just to make an inappropriate political analogy, it would be like the cancel culture. We'd have to get Huggins and Hodges out of all the papers.

Bertrand Tombal:
Yeah, yeah.

Neal Shore:
It would be terrible. They're the pioneers of T suppression. So, with that, let me just thank you all and let me go around one time. Did we miss any really major things that we want our colleagues to be thinking about? I'm sure we did. I'm sure I did so that would be my fault. Rana, any last things for our colleagues who are listening to be thinking about from ASCO GU and prostate cancer?

Rana McKay:
No, I think you really covered the clinical significant topics of new therapies. I think Yohann De Bono presented some updated data from a potential trial and some more elegant biomarker work. I think we're still not 100% there. I think we also want to see an OS signal from that study. But it was interesting to also see the PI3K data get embedded, the AKT data get embedded. I think that just speaks to where the field is going. But, yeah, it was a super exciting meeting with a lot of interesting topics addressed.

Neal Shore:
Rob?

Robert Jones:
I'd just like to put in a word from my radiation oncology colleagues here because I thought there was some interesting results concerning radiation. We haven't got time to go into the detail but particularly there was some interesting work about using molecular prognosticators to maybe select patients with good prognosis who may not require androgen depravation therapy in addition to the radiation therapy in the intermediate and high-risk groups.

Robert Jones:
And also potential to define a group of patients, to use molecular diagnostics to maybe intelligently select patients for that adjuvant radiation after prostatectomy. Because of the way the whole field's changing quite quickly, the trials themselves don't immediately present those changes in practice in my view, but I thought that was a real potential because I think that's a real issue, how to better choose patients for these treatments.

Neal Shore:
Yeah, I love that you brought that up. Actually, Jonathon Tward was the first author. I was one of the many coauthors on the study we did looking at a CCR score, combining the CCP and the CAPRA and giving you an opportunity to think about a percentage of patients with either intermediate or high-risk disease who might not necessarily need ADT with radiation treatment. So I agree with you.

Robert Jones:
It wasn't a predictive marker but it's the intelligent use of a prognostic marker to let men whose additional benefit, and quite morbid ADT was so small, but they may not choose to receive it.

Neal Shore:
Yeah, yeah. Thanks.

Bertrand Tombal:
Clearly we all agree on the fact that removing ADT is an important target.

Neal Shore:
That's right. That's right. Well, anything else that we missed, Bertrand?

Bertrand Tombal:
No, no. I think it was a great meeting. A lot of confirmatory result and a lot of work to be done in educating people on when and how.

Neal Shore:
Yeah. Well, I think with that final word, thanks Rana, Rob, Bertrand, thanks very much. I look forward to seeing you at the virtual ASCO and maybe the in-person EAU, still to be in-person, and hopefully in-person AUA and ESMO, and have a great 2021.

Rana McKay:
Thank you, Neal.

Bertrand Tombal:
Bye-bye.

Rana McKay:
Bye-bye.

Disclosures

Neal Shore

Dr Shore reports consultancy for Abbvie, Amgen, Astellas, Astra Zeneca, Bayer, BMS, Boston Scientific, Clovis Oncology, Dendreon, Exact Imaging, FerGene, Foundation Medicine, GConcology, Invitae, Janssen, MDxhealth, Merck, Myovant, Myriad, Nymox, Pfizer, Propella, Sanofi Genzyme, Sesen Bio, and Tolmar; speaker’s bureau for Astellas, AstraZeneca, Bayer, Clovis Oncology, Janssen, Pfizer, and Guardant Health.

Bertrand Tombal

Dr Tombal reports advisor and/or an investigator for Astellas, Janssen, Ferring, Myovant and Sanofi.

Rana McKay

Dr McKay reports research funding from Bayer, Pfizer, Tempus; serves on Advisory Board for AstraZeneca, Bayer, Bristol Myers Squibb, Calithera, Exelixis, Janssen, Merck, Novartis, Pfizer, Sanofi, Tempus; is a consultant for Dendreon, Vividion; serves on the molecular tumor board at Caris

Robert Jones

Dr Jones reports research funding from AstraZeneca, Astellas, Exelixis, Novartis, Pfizer and Roche; serves as an advisory board member for AstraZeneca, Astellas, Bayer, BMS, Dendreon, Janssen, GSK, Ipsen, Merck Serono, MSD, Novartis, Pfizer, Roche, Sanofi Genzyme, EUSA; is a consultant for Curevac, Dendreon, Exelixis, Steba, EUSA; received honoraria from AstraZeneca, Astellas, BMS, Janssen, GSK, Ipsen, MSD, Sanofi Genzyme.

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