Optimizing the Role of Hormonal Therapy and Novel Therapeutic Strategies for Patients with Prostate Cancer — Maha Hussain, MD, FACP, FASCO

DR HUSSAIN: Hello, everyone. My name is Maha Hussain. I am the Genevieve Teuton Professor of Medicine in the Division of Hematology/Oncology and the Deputy Director for the Robert H Lurie Comprehensive Cancer Center at Northwestern University. My conversation with you today will focus on the role of hormonal therapy and other novel therapeutic strategies for prostate cancer. I should point out that this is really reviewing emerging data that happened over the past year. Some of this is very promising, some of it is potentially practice changing.

So I wanted to start first with the different disease settings as there is data that I will be discussing in just about every disease entity aside from the newly diagnosed patient situation. As you know, patients who develop — who are treated with surgery or radiation and potentially develop a PSA relapse and have salvage radiation after surgery, they still can develop a PSA relapse, and this is what we call biochemically recurrent prostate cancer that is nonmetastatic.

And I have to say all of the data that we’re speaking about I want to underline that this is in an era where patients were not — did not go PSMA imaging, so we’re talking nonmetastatic by conventional imaging.

So there will be 2 data sets that I will discuss from PRESTO and EMBARK. In the setting of patients who have metastatic hormone-sensitive prostate cancer as you know there are several clinical trials that established the role of therapy intensification with AR inhibitors with or without chemotherapy in the setting of metastatic hormone-sensitive disease, and there is interesting emerging data that I will highlight there. And as you see here the different — lists of the different clinical trials that have been reported. And then definitely we will discuss also the space of metastatic castration-resistant prostate cancer, and I also will share some interesting data from the nonmetastatic castration-resistant prostate cancer.

So we’ll begin with the nonmetastatic prostate cancer with a PSA relapse. This is, again, a setting of patients who have still hormone-sensitive disease. The PRESTO trial was a Phase III randomized study of androgen annihilation for high-risk biochemically relapsed prostate cancer. This is a clinical trial that took men who had seen — who had been through radical prostatectomy, developed a PSA relapse, have no metastatic disease, have a short doubling time of 9 months or less, and they could have seen prior hormone treatment as long as the last dose was more than 9 months primarily to allow testicular recovery. And then they could have seen prior adjuvant or salvage radiation therapy unless they were not candidates for radiation treatment.

And the patients were randomized to 3 arms. Arm A was LHRH analog alone, so androgen deprivation. Arm B was intensified with apalutamide in addition to androgen deprivation. And Arm C basically had triplet treatment with, again, LHRH treatment plus apalutamide plus abiraterone and prednisone. And the patients were evaluated and followed for PSA progression, and then at the time of treatment — at the time of progression patients were treated per investigator discretion.

So this is basically the data that you see here, updated progression-free survival, which clearly demonstrates an improvement of progression-free survival favoring apalutamide added to androgen deprivation compared to androgen deprivation alone. And then the trial — I’m sorry, the arm that had apalutamide plus abiraterone also did better than androgen deprivation alone. The issue that comes up is whether there was a difference between the doublet treatment with apalutamide and androgen deprivation versus triplet with apalutamide plus abiraterone plus androgen deprivation.

And as you see here, while there is a slight trend in the median survival the hazard ratio basically crosses 1, indicating not a significant difference. And I think at this point the data would favor just a doublet treatment with abiraterone and — I’m sorry, apalutamide plus androgen deprivation treatment.

And essentially the conclusion is at the bottom, and as you can see here there was really no safety concern with regard to the combination treatment in this group of patients.

The other study is the EMBARK trial. And the EMBARK trial was a Phase III randomized study of enzalutamide or placebo added to androgen deprivation with leuprolide or enzalutamide monotherapy for high-risk biochemically recurrent prostate cancer. So the issue here is looking at gonadal suppression alone, so castration alone, versus castration plus enzalutamide versus enzalutamide alone.

Patients who actually had the leuprolide were randomized between placebo versus enzalutamide.

And as you see here, the trial was designed to treat patients for a finite period of time, so treatment was suspended at week 37 if the patients developed an undetectable PSA. Those who did not, they would continue on treatment. The primary endpoint was metastasis-free survival by independent central review looking at also the comparison between the different arms. And there were several secondary endpoints.

Now as you see here, the EMBARK data would strongly favor the combination of enzalutamide plus leuprolide over leuprolide alone, with significant improvement in metastasis-free survival. And I would want to highlight 2 things here, that the baseline imaging, as I mentioned earlier, is conventional imaging and not PSMA imaging. And so the question comes up is in the era of PSMA imaging how do we handle this set of data. The second part is that this treatment actually was very well tolerated overall, and definitely there was an objective improvement in metastasis-free survival based on the conventional imaging.

This is the other arm comparison between enzalutamide versus leuprolide alone.

And again, there is — the data would indicate, again, that there is an improvement with the enzalutamide over leuprolide, which in some way is a bit surprising to me. Having said that, maybe I shouldn’t be too surprised because, again, once blocking the androgen receptor it doesn’t matter if gonadal suppression has occurred or not. Having said that, I would say sustainability is an issue, and this is what I consult my patients about. Because if patients forget to take their pills or if there’s drug/drug interactions and things like that there could be fluctuations in the testosterone level. And my personal feeling would be I would favor the combination with both gonadal suppression and androgen deprivation — and the AR suppression.

DR LOVE: So if I could just ask a couple questions related to these last 2 trials. First of all, was PRESTO intermittent therapy?

DR HUSSAIN: Well, basically it’s not intermittent — intermittent in the sense that patients were treated and then stopped treatment. The same thing with this here. It’s not intermittent as in the way that we tested intermittent therapy before in the context of this patient population. Like again, these were intensify the treatment and then holding it.

DR LOVE: So I’m just kind of curious. With all the challenges of indirect comparison, I’m correct, I believe, that enzalutamide is approved in this situation and apa is not at this point.

DR HUSSAIN: Correct. Not yet. Correct.

DR LOVE: Could you tell me a little bit about why? In other words indirectly comparing the trials in terms of the maturity, et cetera, why enza was approved and apa is not.

DR HUSSAIN: I think basically the apa has just barely gotten — the data was reported. So as you know, it takes a while for the establishments to go to the FDA and all of that stuff. In reality I think they’re fairly comparable. Now, again, they were not compared head to head. The issue, I think, is going to be obviously FDA approval because you need insurance coverage, and if it’s not FDA approved it’s going to be hard to get coverage. The other part is going to be the cost factors.

The drugs, I think in my humble opinion, are fairly comparable in terms of their efficacy. I think a lot of us are more used to using enzalutamide just because it was on the market before apalutamide. But I think they’re fairly comparable, and my impression, again, clinically from drug/drug interaction and so on, they’re fairly comparable in that regard also.

DR LOVE: So in general in this situation, other situations, are there patient scenarios where you favor apa over enza and the reverse for example?

DR HUSSAIN: No. I think what we do, and this is the critical part I would say, from clinical decision making both of them have certain risks, cardiovascular issues, things of that sort. The other part would be the drug/drug interaction. And so definitely I work with our pharmacists to make sure that there is no specific issue that would preclude the use. As you know, a lot of the patients we deal with tend to be older patients with other comorbidities, and so that’s going to be the critical factor to focus on. The other thing would be, again, the cost, insurance coverage, and things like that.

But again, because apa is not yet FDA approved in this setting I generally have been using enzalutamide.

DR LOVE: Right. And the other question I have is assuming you have a patient in front of you who you want to treat, for example that you want to give enza and ADT to, for example the way the EMBARK study was done, if you have a patient like that who’s in your view high risk and meets the — you think you want to treat them, do you bring up the issue of enza monotherapy as an option?

DR HUSSAIN: Yes. Yes. But I also do discuss my, I guess, interpretation of the totality of the data and also our experience. I do think that there is, as I mentioned in my conversation earlier, or in my discussion earlier where I was mentioning the study, is that the difficulty is this: a lot of the patients are on multiple medications, understanding fully that the difference between gonadal suppression and an AR inhibitor, if a patient forgets to take their pills somehow, or feeling sick to their stomach and whatever, is missing taking the medication, the issue of the therapeutic effect may go down. So to me kind of the backbone of suppressing testosterone and then adding an AR inhibitor on top I think helps with optimizing the benefit.

DR LOVE: Yeah. I mean I don’t think anybody would argue that for somebody who wants the best possible efficacy outcome what the answer is. But I’m just curious. I don’t know how many times you’ve brought up enza. Have you had any patients who actually wanted to do it and actually did monotherapy? Or everybody goes for combinations?

DR HUSSAIN: No. And again, we counsel the patients, but one thing I would say, Neil, is the following: is remember, which is why I kept reiterating the story of the PSMA imaging, is now in this set of patients we’re doing PSMA imaging, and you can imagine in how many of them we’re identifying potential suspicious areas of metastatic disease. And so that is kind of shrinking this population from the perspective of “nonmetastatic” as in non-clinically metastatic disease. So I don’t see that many patients anymore with this disease setting.

And I do think one thing that I would like to add is that I would like to caution that even with the PSMA story the reality of it is this, is clinical judgment has to be taken into consideration because now that we’re having — and we published actually a paper on interpretation of the PSMA thing from a clinical perspective, is that there has to be clear indication that if you’re going to change treatment there is a convincing reason why you should be maximizing the treatment for the patient based on a PSMA scan in the context of negative conventional imaging.

DR LOVE: I mean the one scenario I hear a lot about is the people who are found to have oligometastatic disease on PSMA scanning, and that really makes a lot of sense. I mean that is an important finding.

DR HUSSAIN: Right. But how oligo is oligo? That’s the reality. And so I tend to always also verify it by conventional scans and then take the full picture together. So somebody who might have had cancer diagnosed 15 years ago and now has a PSA relapse now is different than someone who had a radical prostatectomy 3 years ago and now having all of these changes.

DR LOVE: Right.

DR HUSSAIN: So I mean it’s — one has to really personalize the care for sure.

So now we’re going to go to the other trial, which is the ARAMIS study. So the ARAMIS study was a randomized Phase III trial that was geared towards evaluating darolutamide in nonmetastatic castration-resistant prostate cancer. This was a trial that was reported demonstrating, again, a benefit for the use of darolutamide in this patient population. And this is the study design as you see here.

Basically the report that was reported just recently in European Urology had to do with the efficacy and safety of darolutamide in the setting of nonmetastatic castration-resistant disease by PSA doubling time. And this was a planned subgroup analysis of the Phase III trial. And as you see here basically there is benefit irrespective of the PSA doubling time situation, and there was no increase in adverse events based on, again, the disease setting with patients with doubling time less or more than 6 months.

Now, the other thing is relating to the nadir PSA effect in the context of nonmetastatic castration-resistant prostate cancer was, again, a manuscript that we reported on the PROSPER — from the PROSPER trial. And the specific question — this was again a post hoc analysis to evaluate the relationship between how deep did the PSA decline and clinical outcome in enzalutamide-treated men with nonmetastatic castration-resistant disease. And again, as you see here, basically there was significantly higher decline in the PSA in the patients who received the enzalutamide, with a significant percent of the patients achieving a PSA nadir that was undetectable and also leading overall to a better overall survival. The deeper the PSA went the better was the overall survival.

And I would say this is really not a surprise in that essentially effective treatment is leading to better cancer control, and that is reflected by the PSA depths of decline and essentially using this as a, I would call it a biomarker to really help with managing these patients. As you know, these are patients that had technically by conventional imaging no evidence of metastatic disease.

Now. We’re going to move now to the space of metastatic hormone-sensitive prostate cancer, and in this thing the first trial that I would like to go over some data with, which was reported by Dr Bossi and colleagues at ASCO last year, from the PEACE trial. And the PEACE trial is specifically an ongoing clinical trial that evaluates systemic treatment in de novo metastatic, I would call it hormone-sensitive, but per study castration-sensitive prostate cancer.

So the study design is outlined in here. Men with de novo metastatic disease, and de novo as in at time of diagnosis of their prostate cancer they had metastatic disease. And the definitions are highlighted in here. And again, these are based on conventional imaging, a bone scan and CT scan. And the patients were all receiving androgen deprivation treatment. The study allowed prior exposure to hormone treatment prior to entering into the study of 3 months or less. And the patients were stratified by essentially the disease volume, sites of metastases, and then whether they had LHRH therapy versus orchiectomy versus LHRH agonist or antagonist. And of course chemotherapy was allowed, and so patients were included if they had or did not have chemotherapy.

Now the patients were randomized 1:1 to standard of care, and again standard of care would have been androgen deprivation, with or without chemotherapy, standard of care with abiraterone, and then standard of care plus radiotherapy, and then standard of care plus abiraterone and radiotherapy. So essentially this is looking at maximizing treatment. And when I’m referring to the radiation treatment this is for the prostate because were, again, patients who had de novo metastatic disease.

And as you see here, for the radiographic progression-free survival clearly there was an advantage for what I would call triplet treatment specifically in patients who have received the standard of care treatment plus abiraterone plus radiation to the prostate compared to those who received standard of care treatment plus abiraterone or the others.

What was interesting is this. And as you look at here, the median in years is really favoring quite a bit the triplet treatment as it relates to progression-free survival. What was interesting, actually, the overall survival was really not that much different.

And I did actually reach out to Dr Bossi about his kind of thought about why that is the case, and there is certainly multiple potential factors playing in there. Having said that, I do think that the significant improvement in the radiographic progression-free survival and other secondary endpoints in terms of like complications from poorly controlled disease in those patients and so on, at this point favors, I think, the triplet treatment in the low volume. I would say there’s a difference here between this and the STAMPEDE trial, which clearly showed in the lower volume, or lesser disease patients, radiation therapy for sure did add an advantage to these patients.

Then we move into the issue of LHRH agonist versus antagonist. So as you know, historically gonadal suppression starting with first orchiectomy and moving into LHRH therapy, which is actually LHRH agonist treatment, has been the backbone of the management. Degarelix was actually approved, which is an LHRH antagonist. However, that’s a monthly injection. More recently relugolix, which is an oral LHRH releasing hormone antagonist, basically was also FDA approved based on the HERO trial.

So the HERO trial was designed to evaluate the oral LHRH antagonist versus leuprolide for patients with advanced prostate cancer, and the primary objective was actually sustained castration level in the US and in Europe and Japan was sustained castration noninferiority type design. And the US is outlined in here with — like lower amount of confidence interval had to be above a certain level.

Now the clinical trial was conducted and essentially enrolled patients who had prostate cancer who either had a biochemical relapse after curative local intent treatment or incurable locally advanced disease or newly diagnosed metastatic disease that’s hormone sensitive.

And one of the critical issues, of course, when you’re giving an oral agent is the issue of, especially in patients who have — who are on multiple other medications, including cardiovascular disease issues like hypertensive medications, antithrombotic medications, medications for lowering cholesterol and so on, and so one of the endpoints that was evaluated is looking at essentially is there an effect on drug/drug interaction such that castration is impacted. And as you see here basically there is very clear sustained castration rates from day 29 through 48 for the concomitant cardiovascular — different cardiovascular treatments.

And so one thing is this. This agent has been FDA approved for use. And again, one of the issues I think I would like to highlight, while it is important, there is not much drug/drug interaction. Again, many of these patients are taking quite a bit of medications for different reasons. I generally will counsel the patients, and to my surprise the majority of my patients opt for injection. And part of it is because they just want to minimize how many pills they’re taking.

Having said that, this is a great drug to use especially if you need to immediately lower the testosterone fast and things like that. And of course it’s an oral agent so you have to go through the whole process, but I do think it’s a very valuable drug.

DR LOVE: I’m kind of curious whether you find it more valuable or specifically valuable if you’re using intermittent treatment.

DR HUSSAIN: I generally don’t use intermittent treatment anymore, and so I don’t really necessarily use it. I do think it has an advantage should you want to use for a period of time. The difficulty, as you know, Neil, is going to be in the context, where the data is based on. And again, as I said, one of the issues I find with my patients, and I counsel them carefully, is they would rather minimize the number of pills they’re taking.

DR LOVE: That is interesting because —

DR HUSSAIN: Even though I explain to them they can recover faster once we stop. But even from the days of degarelix when you counsel the patients they tend to want to have the least potentially sort of like physical implication, right? So injections once every 3 months or 4 months people prefer that over an injection monthly, which is why we dropped off using degarelix. And then now we have this thing, and these patients are on blood pressure medications, different medications, cardiac medications, diabetes, whatever.

DR LOVE: Right.

DR HUSSAIN: And they would generally favor not taking a pill. But I do think it’s a very valuable drug if you can get it for patients, especially if you really acutely want to do gonadal suppression.

DR LOVE: But again, in terms of not doing intermittent therapy, I assume there are situations where you treat high-risk M0 disease if they have a negative PSMA. I know it’s uncommon, but in that situation you would not use intermittent therapy?

DR HUSSAIN: Well, it’s not intermittent. It’s kind of a la EMBARK. So technically kind of intermittent.

DR LOVE: So what’s the difference between what you call intermittent and EMBARK?

DR HUSSAIN: Okay.

DR LOVE: I know EMBARK had a date. Yeah, they had a date.

DR HUSSAIN: Yeah, yeah. I mean it is a date, but it is — in some patients you may never have to go back on treatment if you intensify treatment, but in some patients, yes, you may have to go. We just began using this combination, so it’s very hard to tell like what percent of these patients in our daily practice, I mean the clinical trial was very clear, but in our daily practice are going to need this kind of going back and forth on treatment.

The other thing I want to point out, too, if I’m going to go with treatment it’s going to be EMBARK style, which basically essentially used the combination with an injection. So the issue comes up is, again, I cannot say that we have data on the combination with an oral agent plus enza or plus apa. And that’s kind of going to be the other situation. Now you could probably extrapolate from it, but it’s one of those things where you’d have to be mindful, again, in that regard.

DR LOVE: So again, I’m sorry, but just to clarify.

DR HUSSAIN: Yeah.

DR LOVE: You have a patient outside a clinical trial who has M0 disease, their PSMA scan is negative —

DR HUSSAIN: Yes.

DR LOVE: — but they’re high risk, high doubling time, you want to treat them.

DR HUSSAIN: Yes. Yes.

DR LOVE: So I guess my question is you start your treatment, before it was ADT, now maybe it’ll be ADT plus, but my point is in that situation do you just keep the treatment going or at some point if the PSMA is not detectable do you hold the treatment.

DR HUSSAIN: Well, so basically, as I said, we barely started right now. I think the issue is going to be do you intend — do you want to treat with intent of cure versus not, and this is where the judgment comes in. At this point we are starting these treatments, and I am trying to follow essentially the EMBARK or the other trial that was just reported principles, assuming that patients are tolerating. Now a lot of the patients I tend to see have had really very aggressive disease before, like they might have had node-positive disease, things of that sort, where there is a real reason to think maybe about treating slightly longer. But at this point, again, we just started using the EMBARK data and applying it, and we’ll see how it goes in the clinic.

So the other trial that was recently also reported is the TITAN study. The TITAN study took men with metastatic prostate cancer that is hormone sensitive, and then prior docetaxel was allowed for this particular group of patients. And the patients were stratified by different criteria as you see outlined in here, and the patients were randomized 1:1 to essentially the addition of apalutamide versus placebo, and of course androgen deprivation was continued. And there were several secondary endpoints that were outlined in here. Radiographic progression-free survival and overall survival are the dual primary endpoints.

And basically what the TITAN data showed, which was, again, reported by Dr — published by Dr Chowdhury and colleagues in Annals of Oncology, was the fact that overall survival and progression-free survival was, again, better in the combination treatment. And looking by the nadir PSA of how well a patient responded, and looking at the differences between the arms, and what you’ll see here that apalutamide plus androgen deprivation showed a much more robust and rapid decline in PSA, and that was, again, associated with improved clinical outcomes, including long-term survival. Which by the way, again, this is not a surprise in that PSA is a response biomarker, and essentially it is a predictive biomarker for better outcomes, and there’s been multiple reports, including myself reporting on this there, both in the setting of hormone-sensitive and castration-resistant disease.

Now the TITAN treatment-emergent adverse events at 6 months, again overall nothing emerged as different than what you have seen. Clearly at 6 months of apalutamide treatment the treatment adverse events were assessed in the patients with or without deep PSA decline, and the overall safety profile was very similar to what was reported before.

Now, the other trial that I would like to also present, and I think it’s a very important point here, because the issue comes up there’s a lot of interest in the field of trying to maximize androgen deprivation. And one of the trials that were evaluating this issue is the STAMPEDE study where — the STAMPEDE is a very large study that’s a multigroup, multistage trial, generally to evaluate long-term outcomes in whether combining enzalutamide with abiraterone and androgen deprivation therapy improves overall survival.

And basically what was reported, this is the final result from the study, and as you see here essentially there was a superiority to the combination of AR inhibitor plus androgen deprivation compared to androgen deprivation alone. However, the combination of essentially maximizing the AR deprivation with the combination of abi and enzalutamide did not really add any advantage. And so the conclusion was that enzalutamide and abi should not be combined for patients with prostate cancer starting long-term androgen deprivation.

I do think that we have really a clearly recurring set of data that says adding more oral treatment does not add advantage, and so at this point I think the choice would be if someone is going to go with a doublet the doublet has got to be androgen deprivation plus an oral AR inhibitor. And that’s going to be, again, driven by safety and drug/drug interaction and other potential physician and patient preferences.

Then the ARCHES trial. So the ARCHES trial was, again, a trial evaluating patients with metastatic hormone-sensitive prostate cancer receiving placebo plus androgen deprivation or enzalutamide plus androgen deprivation. And the trial itself has been reported as a first analysis. Basically this particular report was looking at the disease extent and outcomes with regard to benefit from the combination of androgen deprivation and enzalutamide. And the investigators looked at the disease extent, and oligomets being 1 to 5 metastases, and anything beyond that, 6 lesions or beyond, is polymetastatic disease.

And I want to caution, by the way, the whole concept of oligomets definition can be very confusion sometimes. The other thing to remember, just because a person doesn’t have 5 lesions or 4 lesions doesn’t mean that they are technically oligomets. So if somebody had liver metastases, these are not the kind of patients you would really want to consider them under the oligomets category because their disease tends to be more aggressive.

So again, to go back to this particular trial, irrespective of the disease extent, whether it’s oligometastatic or polymetastatic, the combination of enzalutamide plus androgen deprivation resulted in significant benefit, including delaying radiographic progression-free survival and other criteria of clinical benefit.

Okay. Now, the ENZAMET study. So the ENZAMET study was, again, a randomized Phase III clinical trial that was evaluating the role of enzalutamide in the context of gonadal — and gonadal suppression or as the investigators were calling it in their report “testosterone suppression.”

The stratification of the trial was by volume of disease and then planned early chemotherapy versus not and other criteria. The Arm 1 randomization was, again, gonadal suppression or gonadal suppression plus enzalutamide.

The endpoints were castration resistance — evaluated every 12 weeks for the patients and then the — looking at castration-resistant therapy need at the discretion at time of progression. And then follow-up time to progression and overall survival were the endpoints.

And as you see here basically the combination with enzalutamide resulted in much better overall survival, and this was reported. And then when broken down by the presence of disease — when we call synchronous and metachronous I just want to maybe take a minute to define this. Synchronous as in the patients having de novo metastatic disease at diagnosis. Metachronous is those who underwent local therapy and then developed metastatic disease.

And what you see here is that clearly in the patients who have synchronous metastatic disease there is overall survival advantage. And as I mentioned, the overall population had benefit, but broken down by the timing of metastases there is benefit in both groups. You can imagine that the reporting on the synchronous happens earlier because these are generally a much higher-risk patient population. In the context of the metachronous group, again, there was an advantage, and the median has not been reached in the combination treatment with enzalutamide, leading the investigators to conclude that the addition of enzalutamide to standard of care treatment resulted in sustained improvement in overall survival for patients with metastatic hormone-sensitive prostate cancer.

And again, this goes back to reiterate that combination therapy with androgen deprivation plus AR inhibitor is now the standard of care. The issue is going to be deciding which drug to use.

All right. Now, one of the other things that we reported on the ARASENS trial as it relates to, and I will talk about, is the volume of disease impact on response to outcomes.

So the ARASENS trial, as a reminder, is a randomized Phase III clinical trial of darolutamide versus placebo for men with metastatic hormone-sensitive prostate cancer. All patients of course received androgen deprivation, and they also received docetaxel. And so the patients really had therapy intensification with the addition of an AR inhibitor versus placebo to see actually if darolutamide added advantage on top of ADT plus chemotherapy.

Now we reported the results of this study demonstrating an overall survival advantage for the triplet treatment which led to the FDA approval. One of the questions that we wanted to ask, and we wanted to address, because at the time of study design the issue of the volume of disease was not technically something that has been available from the — and/or accepted. The CHAARTED data was emerging at that time.

And so we wanted to go back and look at whether triplet therapy has advantage over doublet therapy based on the extent of disease. So the issue I always wonder about is do you have to give more? Is more always better? And we know that more is not always better.

So let’s look at this in the context of this trial. And so just as a reminder the high-volume disease by CHAARTED criteria is those who had visceral mets or 4 or more bony lesions with at least 1 beyond the vertebral column and the pelvis, as in axial skeleton. And then the LATITUDE criteria are outlined in here, which is high-risk patients. They had to have 2 or more risk factors of Gleason score 8 or above, 3 or more bony lesions, or visceral metastases.

And what you’ll see here, based on the disease volume, essentially there was clearly unquestionable and statistically significant advantage favoring the triplet treatment of adding darolutamide to ADT and docetaxel. When it comes to the low-volume patients, this is a very favorable group of patients, I want to highlight that actually there is a strong trend. However, the data is not mature. And as you can see here the median has not been reached for either arm, but you can see here a beginning of separation of the curves going forward. So I think the benefit is clearly there.

In the context of the group by risk criteria based on the PEACE data, basically there is benefit both in the high-risk patient population and the low-risk patient population, as you can see here, and this risk was really, I would say, clinically and statistically significant in this regard.

And so I would say at this point for patients’ decision in terms of giving triplet versus doublet I do think that in the context of the overall picture patients who are potentially where you think it’s safe to give chemotherapy to definitely the triplet treatment is favored based on the totality of the data. I don’t think we have any answers right now as to the value of adding docetaxel because there are no clinical trials evaluating the triplet treatment versus androgen deprivation and an AR inhibitor. And that I think is an area that is worthy of future investigation.

Okay. Now we need to move into the different emerging pathways and looking at novel potential opportunities for patients with work going on.

So abemaciclib is an agent that is being evaluated right now in prostate cancer, which is an oral inhibitor of CDK4/6. And essentially the CDK4/6 pathway interplays with the androgen receptor and basically has potential implications with regard to progression of the disease and responsiveness to the hormone treatment. CDK4/6 inhibitors have been approved actually in metastatic prostate — I’m sorry, breast cancer. Like the situation in the ER positive and signaling pathways in breast cancer there is evidence that indicates AR signaling pathway activates the CDK4/6-cyclin D1 axis, which leads to sustained cancer cell proliferation and survival.

Now. In preclinical models both hormone-sensitive and castration-resistant disease the abemaciclib demonstrated activity in the in vitro setting in combination with the AR blocker agents, and then the hypothesis was that the dual inhibition could result in better outcomes.

So CYCLONE 1 was a study reported by Dr Agarwal and colleagues which evaluated the agent in men with metastatic castration-resistant prostate cancer. And these patients, I should point out, have been fairly heavily pretreated, so essentially this is more like almost third-line setting of disease.

The study basically included the use of abemaciclib as a single agent basically as indicated in here, and the bottom line was that overall the results were modest at best. And I would say that’s not terribly surprising, again, because this was a fairly heavily pretreated group of patients.

But there was evidence of objective response rate and stability of the disease in the setting of patients who were heavily treated — pretreated. Overall there was no significant, or I would say high-grade, adverse events that were of consideration, though definitely there were treatment discontinuations relating to the drug itself, adverse events.

So the CYCLONE 3, which Dr Smith and colleagues presented at the — or actually submitted to the ASCO GU symposium, is a Phase III randomized, double-blind, placebo-controlled study again evaluating abemaciclib in combination with abiraterone for high-risk metastatic hormone-sensitive prostate cancer. And these are patients. The trial is ongoing at this point.

However, what was interesting is this: The CYCLONE 2 study, which is the combination of the abemaciclib with abiraterone, actually were reported that it did not meet the primary endpoint of improved radiographic PFS in men with castration-resistant prostate cancer. This is going to be interesting because of potential implications obviously. The question I think one would raise is the fact that the drug did not deliver in the castration-resistant disease. Does that mean it will not deliver in the hormone-sensitive or not? I would say it’s raising a flag, and it’ll be interesting to see what the Phase III trial looks like.

I would want to point out that I myself have published on a different CDK4/6 inhibitor, palbociclib, where we did biomarker preselected hormone-sensitive patients with RB-intact tumors and reported that. And unfortunately, again, in the hormone-sensitive space it did not seem to have much. Obviously not all drugs are equal, so it will be interesting to see what the data is.

Okay. The other agent is a pan-AKT inhibitor. So the AKT pathway is a pathway that has been associated with resistance to androgen receptor signaling and targeted treatment. And this is a pathway that has been of interest for really a long time I would say. Unfortunately there have not been to date any kind of treatment that has had any significant effect.

Basically in an open-label Phase IB study in 27 patients receiving abiraterone plus the capivasertib, which is a potent selective pan-AKT inhibitor, the combination seemed to be well tolerated, and there was no major toxicities. And certainly that led to interest in developing a clinical trial evaluating this specifically.

So this was a Phase I trial of this combination of the AKT inhibitor capivasertib with abi in patients with metastatic castration-resistant disease that Dr Shore, Neal Shore reported. And essentially the patients were preselected for having PTEN deficiencies in there and randomized to both combination versus abiraterone plus placebo.

And at this point the earlier reporting of the study indicated some early signal of response based on a PSA decline there. Overall it had acceptable toxicity overall and tolerability, and their conclusion was that the data would support moving forward and further evaluation in there.

So I do think it would be interesting to see what the set of data is going to be like with more larger-scale trials in this setting.

So I think we have reached a really tremendous progress in the field in this disease — in prostate cancer in an era where we have now multiple different disease states identified based on imaging and other criteria with significant activity and a high level of impact in terms of the overall survival.

As I tell colleagues when it comes to the field, when I entered the field the median survival of patients with metastatic castration-resistant prostate cancer was about 9 months, and the median survival of patients with, again, metastatic hormone-sensitive prostate cancer was about 2 and a half to 3 years. And now we’ve really more than quadrupled, I would say, in the setting of castration-resistant disease. And there are certainly data from clinical trials that would suggest significant improvement, again, in the past 30 years, in the improvement in median survival for men with metastatic hormone-sensitive disease close to 6 years and above.

And I will say in my practice actually I have now men with metastatic prostate cancer by conventional imaging in remission 7, 8, 9-plus years there. So I do think we’re moving into a very promising era of converting metastatic disease into more of a chronic disease with the hope that we can come up with much better treatments as we move forward.

DR LOVE: One thing I was just thinking about that’ll be interesting. I noticed when you were talking about capivasertib the schedule. It looked like they’re giving it every day because it’s interesting, in breast cancer it’s now approved, but they give it 4 days a week to decrease the —

DR HUSSAIN: Interesting. Yeah, tolerance.

DR LOVE: Because similar drugs, you get diabetes.

DR HUSSAIN: Yes.

DR LOVE: I don’t know if you’ve ever heard of alpelisib.

DR HUSSAIN: Yes.

DR LOVE: It’s a similar drug. So anyhow, it’ll be interesting to see how these men do taking it every day.

DR HUSSAIN: Yes.

DR LOVE: The other thing I was going to ask you about is there’s so much — I hear now so much in breast cancer about like resistance mechanisms to hormonal therapy. Where is prostate cancer in terms of resistance mechanisms to endocrine treatment?

DR HUSSAIN: Well, I think what is clear is this, is the androgen receptor is a very sneaky pathway, and it can stay dormant for a decade and then act up. And so I do think that better understanding of mechanism of resistance is going to be critical from a drug development perspective to overcome the androgen signaling kind of pathway.

The clear thing, I would say, where we have demonstrated clear impact is really in a multitargeted strategy. So the androgen receptor continues to be important, but it’s not the only pathway, and the tumor kind of exits the dependency on the androgen receptor, and it becomes kind of essentially potentially resistant.

So I do think going in with — understanding first the pathways and then working with multitargeted strategy is going to be the critical part. And this is where we have come. If you think about it, in the context of castration-resistant disease the combination of AR inhibitor and PARP is the first combination treatment, if you think about it that way.

Obviously everybody’s on hormone treatment, and when you add chemo that’s technically a multitargeted strategy. But in terms of like if you forget about the gonadal suppression part and think about systemic therapy the PARP plus has become like — is an area of critical importance. And I do think the triplet treatment in the hormone-sensitive space is really also adding significant advantage in there.

I mean if you think about it, what I would say is testes cancer, right? Even testes cancer we don’t cure with 1 drug even though it’s so chemoresponsive.

DR LOVE: Right.

DR HUSSAIN: So essentially a triplet treatment is what we do. So I would hope that, again, with better understanding of mechanisms of resistance and actually earlier detection of the systemic disease, with whether it’s imaging or other biomarkers, will help us, I think, give better outcomes for patients because there’s less bulky disease to treat.

DR LOVE: So one final question. In your diagram that you were showing the prostate cancer disease states, I guess in terms of newly diagnosed prostate cancer there wasn’t a big story that came out this past year, but there has been evolution of trial data in that setting. And I wonder where you stand today in terms of applying those data. I know there are data from the STAMPEDE platform for high-risk nonmetastatic prostate cancer, but I guess that wasn’t really updated this past year. Any other data in that setting? And how are you dealing with these scenarios yourself? I don’t know if you see those or urologists do. But any comment about that setting?

DR HUSSAIN: Yeah. The newly diagnosed patients generally are within the space of the urologist and radiation oncologist. I tend to see them coming into consult sometimes about should I take surgery, should I take radiation, do I need anything else. And I would say I’m just a little bit more biased based on my practice because I tend to see more of aggressive disease patients where I would recommend definitely proceeding with treatment for sure. And I would also see some of these patients post-surgery, where they’ve had node-positive disease.

The patient could have been the — the gentleman could have been 55 years old with Gleason 8 and pathologic node-positive disease, and PSA’s still detectable, and they were observed. And to me that’s not right because ultimately the issue isn’t about how I feel today but it’s how I feel when I say if I was a patient what is going to happen to me in 5 years and 10 years. And so I generally would counsel the patients on the potential of multispecialty type approach for the treatment, including potential radiation treatment, hormone treatment, and so on.

DR LOVE: In terms of I guess intensified hormonal therapy, in the past for a more typical locally advanced situation people got 2 years or less of LHRH agonist. For most of these patients are you intensifying therapy? And are you using abiraterone?

DR HUSSAIN: So yes. If the patients have, again, very aggressive disease, node positive, then definitely yes, and this is per STAMPEDE data using the — and I would add the abiraterone. There are times where patients have let’s say relapse, and there is really high-risk disease, then definitely I would err on the side of more than 6-months salvage. Again, they’re going to get radiation but on top of it getting hormone treatment and err on the side of at least for 2 years.

And what I tell my patients basically is this: There’s obviously not going to be data for every single individual or case setting, so there’s going to be a combination of tolerance, rationale, potential data that can support this. I call it judgment and experience with this thing, and ultimately it’s a shared decision. And I will tell you that in my experience practically all my patients would err on the side of going ahead for potentially salvage-type therapies with the hope of cure as opposed to waiting.

Now there’s been — one of the things I would say, and what I would advise my colleagues, is the shared decision ought to be driven, obviously, by data as much as possible, but there’s no data 100%. So the data and the clinical judgment plays a role.

Other Available and Emerging Therapeutic Approaches in Prostate Cancer — Andrew J Armstrong, MD, ScM

DR ARMSTRONG: I’m Andy Armstrong. I’m a medical oncologist with a special interest in prostate cancer. I run a laboratory here at Duke. I’m the director of research for our center for prostate and urologic cancers. And I’m going to give an update today and just diving right into some updates that we presented on PARPs and AR combinations.

And so the first study I’ll highlight is the PROpel study. Last year this led to the US FDA approval of abiraterone plus olaparib in combination in the front-line mCRPC setting for BRCA-mutated patients with castration-resistant prostate cancer. That was based on this double-blind Phase III study of abi/olaparib versus abi/placebo, so an abiraterone active control group. These patients could not have been treated with a prior AR inhibitor but could have had docetaxel in an earlier hormone-sensitive setting.

Now I just wanted to highlight some of the key aspects of the data. The primary endpoint for PROpel was met, delayed radiographic progression-free survival, by somewhere between 8 and 11 months, depending on the independent blinded review or the radiographic review by the investigator. This is what actually led to the European broad approval of this combination irrespective of homologous repair alterations.

You can see that all subgroups of patients, whether they were HRM or not mutated, benefitted from this combination in terms of delaying progression or death. The overall survival is still pretty immature, but this is the final analysis. The hazard ratio was close, 0.81. The p-value was close but did not reach statistical significance. The median improvement was 7.4 months, but the p-value was not beneath the prespecified alpha.

If you look at the patients who had the greatest survival benefit clearly it was those with homologous repair mutations. The hazard ratio there for survival was 0.66, and for patients with BRCA mutations the hazard ratio, again for survival, was 0.29, a huge survival benefit in this patient population. This is the curve that led to the FDA approval and many other global regulatory agencies have followed on this, although Europe has largely settled on the way that the PROpel design was conducted on the intent-to-treat broader population.

When you’re using PARP inhibitors it’s important to realize that these come with some class effects of anemia, fatigue, some GI upset. DVT and PE was also notably increased. In PROpel we observed about a 16% risk of Grade 3 or higher anemia which requires transfusion.

At the ASCO GU symposium we did present some new data that’s not yet published, which is looking at the non-HRR — non-BRCA HRR mutated patients, so there’s a great interest in well what about genes other than BRCA2. And this is looking at rPFS at the top and overall survival at the bottom, at the other more common HRR genes, like CDK12 and ATM.

And you can see here that in terms of delaying progression-free survival the patients with ATM mutations had a near 50% improvement in the risk of progression, and CDK12 was very similar, with overall survival estimates being on the same kind of trend as the non-BRCA patients, not statistically significant, very small subgroups only comprising about 5 or 6% of the patient population. This was never powered to answer these single-gene type questions.

I would point out that PSA outcomes were also better for CDK12 patients.

This data to me suggests that there is quite a lot of heterogeneity in the outcomes according to these individual genes, BRCA2 being the main driver of the benefit. The hazard ratio for PFS was 0.2, OS was close to 0.2. And there’s a lesser degree of benefit with PARP combos in the ATM and CDK12 group, but still a significant delay in progression or death in this subgroup, suggesting that these patients may derive some benefit.

DR LOVE: You didn’t really mention BRCA1. I mean I know it’s less common than BRCA2, but what about BRCA1?

DR ARMSTRONG: Yeah. BRCA1 is actually not thought to be a major contributor to prostate cancer. Germline BRCA1 carriers don’t actually have a higher risk of prostate cancer, so that’s an important little factoid, unlike breast cancer. BRCA1 germline carriers are very rare in medical practice in advanced prostate cancer, so in PROpel and PROfound we only see like a handful of such patients.

DR LOVE: What about somatic mutations?

DR ARMSTRONG: Yeah, also very uncommon. BRCA1 just doesn’t seem to be a common mutation that’s identified. I mean you do — they are included in this, so BRCA is lumped in together, but it’s largely driven by the BRCA2.

Many BRCA1 mutations are found that are monoallelic, not necessarily biallelic, unlike BRCA2, suggesting that BRCA2 is the real driver of the synthetic lethal relationship with PARP.

DR LOVE: So like if you see a patient with BRCA1 you’ll look into it more, or do you treat them the same?

DR ARMSTRONG: Yeah. Certainly if I encountered a patient where the BRCA1 mutation was found on tumor testing I would do germline testing to see if they might be a carrier. You can get a sense of their biallelic nature from many of the commercial vendors. But a BRCA1 would be within the scope of the label, so the BRCA-mutated prostate cancer label for PROpel would encompass BRCA1 and 2, and certainly in Europe the label is very broad. It doesn’t restrict to BRCA.

Same for single-agent olaparib. If you’re giving olaparib the BRCA1 or 2 is in that label. We just have just a little bit of data, and it seems like the responses are lower and less durable for BRCA1 carriers than BRCA2 carriers simply because many of these can be passenger mutations rather than driver mutations.

DR LOVE: Just out of curiosity, if you could utilize a PARP inhibitor in this situation in a patient who did not have anything, BRCA, LOH, anything, would you — do you think at this point it’s a good risk/benefit outside of the trial?

DR ARMSTRONG: Yeah. I think when we look at the subgroups of patients outside of the genetics who benefit from the PARP/AR combos it’s younger patients, those with good functional status, those with the worst prognosis from their cancer, like visceral metastases. So the younger patients have fewer comorbidities, fewer drug interactions. They’re going to tolerate the PARP inhibitor better; less anemia. And using these drugs earlier it’s going to be better tolerated. So I think that would be kind of the ideal patient, would be somebody who’s young and fit, good functional status but with a horrible prognosis with abiraterone or enzalutamide alone.

All right. We’re going to move on to the next study. It’s called MAGNITUDE. MAGNITUDE is a slightly different design, where instead of PROpel that lumped everybody together MAGNITUDE studied niraparib and abiraterone, a different PARP inhibitor, in 2 cohorts, so really 2 parallel trials, 1 that was HRR positive, biomarker positive in the top, and 1 that was biomarker negative. Both had the same randomization to an active control, abiraterone or the PARP/AR combo. Primary endpoint was progression-free survival.

In the HRR-nonmutated cohort this study closed due to futility. Hazard ratio was basically 1 with more adverse events, and the DSMB closed the study, this part of the study, early. People have argued that maybe they closed it too early, not enough events, but really there was no clear signal that it should be continued.

However, if you look at the HRR-mutated cohort there was a benefit, predominantly in the BRCA1/2-mutated cohort. This is what led to the FDA approval of the niraparib/abiraterone combination, about a 6-month improvement in the delay and progression-free survival with this combination over abi alone. Hazard ratio 0.53.

To put that hazard ratio into context the data I just showed you from PROpel the hazard ratio was 0.2 for that same BRCA-mutated cohort. So a little bit of a lower magnitude of an effect size. So that’s how I labeled this slide, not as much magnitude of benefit.

If you look at the overall survival data, again in PROpel the hazard ratio was 0.2, huge difference in survival here. Even in the HRR-mutated patients there was really no significant overall survival advantage with niraparib. So it does suggest that different PARP inhibitors may have both different efficacy and different toxicities.

Here I show in the table that niraparib had a 60% Grade 3 or higher anemia rate. That compares to about 16% with olaparib. A little bit more thrombocytopenia suggesting that maybe this toxicity may limit the ability to give an effective dose that can then delay progression and improve survival in this patient population. So there is an FDA approval, but the magnitude of benefit with the niraparib combination seems to be lesser.

Moving to the TALAPRO-2 study now this is looking at an enzalutamide combination with a PARP inhibitor called talazoparib. So you can see in the TALAPRO schema we have really 2 studies, an HRR-positive study and then an all-comer study like the PROpel study. Everybody’s randomized to an active control, enzalutamide, in the first line mCRPC setting, or enza plus talazoparib.

In the all-comer setting, much like PROpel, there is a significant delay in progression-free survival, hazard ratio of 0.63. when we look at the subgroups of patients there are benefits in delaying progression based on all subgroups, whether they’re — a patient’s HRR deficient or not, although the patients that are HRR deficient have a greater relative improvement in progression-free survival.

The overall survival data’s quite immature at this latest reading. Only 31% mature. There’s not a clear trend towards improving survival at this point, so please stay tuned. When patients were looked at according to the HRR deficiency status, this was the Cohort 2 part of the study, there was a significant delay in rPFS in that HRR cohort. This is the figure that led to the FDA approval of the talazoparib/enza combination in HRR-deficient mCRPC patients largely because this was a prespecified cohort with sufficient power within the HRR deficiency patient population, so a 55% delay in the hazard of progression or death.

In the more recent data, the gene-by-gene analysis, and again it was published in Nature Medicine, did suggest some benefits in the CDK12 and ATM patient population, mostly on PFS but not much data on overall survival at this early time point.

When you look, again, at PARP inhibitors you see a class effect of anemia with some PARP inhibitors contributing more anemia. Again, Grade 3 or higher anemias observed with talazoparib here about 46%. A lot of patients did ender this study with pre-existing anemia, so you do have to follow patients very carefully in the first cycle or 2 with type and screens and preparations for transfusion. Some nausea, some thrombocytopenia as well.

So that is our AR/PARP combination discussion.

As we move on to deciding what do you do for patients who’ve already progressed on an AR inhibitor, for example, and you’re trying to decide should you give another AR inhibitor or should you give docetaxel or a PARP inhibitor. That’s why I brought up the TRITON3 study. This is a nice Phase III study that was published in the New England Journal last year, so it’s important to be aware that this kind of study can inform on whether you give docetaxel or a PARP inhibitor to BRCA patients.

So let’s look at the data for rucaparib. In TRITON3 the physician’s choice control group included either a second ARSI or docetaxel, so really the first study to allow a physician’s choice as a control. And here you can see rucaparib, another PARP inhibitor, was superior to that physician’s choice in delaying rPFS in that BRCA-altered control, so 6.4 versus 11.2 months. It beat docetaxel in a separate subgroup analysis in this study.

Overall survival is not quite mature. There was a numeric improvement by about 4 months suggesting that a PARP inhibitor may improve survival but was not statistically significant.

What about ATM mutations? This is the second-most common HRR defect that we see in prostate cancer, so it’s an important subset. I show you on the left the BRCA subset, the ITT population beneath it, and then over on the right if you just pull out the patients with ATM alterations there’s not really a clear significant benefit to physician’s choice or rucaparib. I would say it’s a tie, and so that suggests that there’s not a clear synthetic lethal relationship between ATM mutations and PARP sensitivity. It's not wrong to give a PARP inhibitor in this setting. It’s about the same as docetaxel or a second AR inhibitor. It’s just not superior.

DR LOVE: The other thing I was thinking about is I’m just kind of curious. I know there are trials that are obviously ongoing earlier bringing PARP inhibitors earlier, and I might have asked you this in the past, but I’m just curious where you think theoretically the sort of sweet spot is.

DR ARMSTRONG: Yeah. For these AR/PARP combos the movement of the AR inhibitors has clearly moved into the hormone-sensitive space where there is a sweet spot. There’s improvement in survival above and beyond giving it in the CPRC setting, so enza, darolutamide, apalutamide, and abiraterone are all widely utilized, particularly in the US, in the earliest hormone-sensitive setting.

So that’s where the PARP inhibitors are moving right now, where there may be less resistance alterations, less cross resistance, and because of that AR/PARP synergy you may get even a greater synergy in that hormone-sensitive setting. So TALAPRO-3, AMPLITUDE, and the EVOPAR studies were huge Phase III studies that should read out over the next few years to give a sense of the early use of PARP inhibitors instead of waiting for resistance like we’ve seen with so many successful agents.

DR LOVE: How about earlier? You’ve got adjuvant in breast cancer.

DR ARMSTRONG: Yeah. That’s a great question, Neil. We do use ADT and AR inhibitors with radiation. PARPs are extremely potent radiosensitizers. I think we have to be very cautious. It’s a little different because of the anatomy of the prostate and the risks of bladder and rectal toxicity. So I haven’t seen too many studies moving PARPs with radiation. Certainly in an adjuvant setting it’s possible, but the prevalence of BRCA alterations makes that a formidable challenge to enroll enough patients in that kind of patient population. Certainly an all-comer population would be easier, using it after radiation or post prostatectomy is certainly reasonable. And there have been even some studies using PARPs without hormones, just finding BRCA patients, giving them a PARP inhibitor in a way to avoid medical castration. So those are just emerging studies.

DR LOVE: Also, did you mention PALB2?

DR ARMSTRONG: Yeah. PALB2 was included in many of these panels for HRR alterations. It’s very hard to pick out that tiny subgroup of less than 10 patients for most of these studies, but there seems to be a numerical advantage to giving the PARP/AR combinations in PALB2 patients, just wide confidence intervals. We probably need larger registries, big data sets, real-world data to get at that.

I think that’s important for people to realize. In the general community it’s probably not well appreciated.

DR LOVE: I mean I don’t know. Do you think most people know it? Anyhow, we’re going to find out. I’m literally going to let you know right in the middle of the webinar what they say because I’m like I can’t believe it.

DR ARMSTRONG: Sounds great.

DR LOVE: All right. Whenever you’re ready keep going.

DR ARMSTRONG: All right. One of the other great success stories of the last 2 years has been what we call phenotypic precision medicine using molecular imaging, PSMA imaging, both to diagnose and find relapsed disease, but also to pair that with radioligand therapy, so PSMA lutetium being the very first FDA approved radioligand therapy against PSMA. The question here in the past year was well is that better than cabazitaxel.

So the TheraP study was a comparative randomized trial of PSMA lutetium-177 in PSMA PET-positive patients versus cabazitaxel, the historic standard of care in a post-taxane, post-AR therapy patient population. I show this data to really emphasize that PSMA lutetium overall was superior in reducing PSA, 66% versus 37%, in having better PSA90 responses and delaying PSA progression.

The radiographic progression-free survival numerically favored PSMA lutetium, but particularly as the brightness of the PSMA PET increased. So as the PSMA SUV, or standardized uptake value, exceeded 10 you see, as I show in the arrow, a relative greater improvement and a trend favoring PSMA lutetium over cabazitaxel as the target is more brightly expressed on the tumor, which makes sense because that’s how PSMA lutetium targets tumors, by binding, being internalized, and causing DNA double-strand breaks. While this is not a predictive biomarker it does suggest some patient selection strategies that may inform that kind of decision making between the doctor and the patient about this medical choice which may result in better responses and more durable responses.

The updates of TheraP were presented just this year. It does show a survival time of about 19 months, no difference between cabazitaxel or PSMA lutetium, but this was confounded by quite a lot of crossover in both treatment arms.

When Michael Hofman and his colleagues tried to identify predictive biomarkers that said you should give PSMA lutetium they were not able to really identify any characteristics based on the PSMA PET or even the FDG PET. They were able to identify poor prognostic characteristics, meaning the brighter the PSMA PET scan the worse the patients would do, the brighter the FDG PET scan the worse the patients would do, and cabazitaxel and PSMA lutetium were able to rescue those patients. But not a significant what we call biomarker treatment interaction. So as long as your patient is PSMA PET positive using either the VISION criteria or this Australian criteria they would be appropriate to have that discussion for radioligand therapy with PSMA lutetium.

We have some data that we presented last ASCO and we submitted for publication that does suggest, again, this higher whole-body uptake of PSMA is associated with a better survival. So again, using that 10 cutoff, which is kind of like the range of the parotid glands express, you see a substantial improvement in overall survival with PSMA-targeting radioligand therapy.

A very cheap and easy way to identify a response to PSMA lutetium is the $50 PSA test. So once you start PSMA lutetium most providers will continue to track the PSA along with imaging, and the deeper the PSA decline, within the first 3 months particularly, you can reassure patients that they may have a better survival. You can see in the light blue those patients that have a 90% decline have the best survival, and then the dark blue those patients that have no drop in their PSA after 2 cycles. And that is translated to overall survival, as well as progression-free survival.

It's not just PSAs that we’re trying to improve, it’s how patients live, low long they live, and their quality of life. This data from Karim Fizazi in Lancet Oncology really was a nice quality-of-life paper from the VISION study really showing that the PSMA lutetium is not only improving survival, delaying progression, but delaying the deterioration in patient symptoms, whether that’s a symptomatic skeletal event, pain related to bone metastases, or interference in quality of life.

Like we talked about with PARP inhibitors PSMA lutetium is moving earlier and earlier into clinical trials. So the PSMAfore study was presented by Oliver Sartor at ESMO this past year. PSMAfore was attempting to move PSMA lutetium into a chemo-naïve setting, where I get frequent questions from patients who have not yet had a taxane, is when can they get PSMA lutetium. Do they really have to get a taxane in order to get to the other side and have that as a viable therapeutic option?

So PSMAfore enrolled patients who had already failed abiraterone or enzalutamide. They had mCRPC PSMA PET positivity, and they were randomized to a control group of a change in ARPI, so abi to enza/enza to abi, which we know in most patients doesn’t work very well, or PSMA lutetium. And they were given the same 6 x 6 standard of care dosing that we’ve used in the VISION study.

This trial, most patients screened in. 92% met the VISION criteria, suggesting maybe we don’t even need a PSMA PET scan to really identify these patients.

The primary endpoint was rPFS. This was significantly met. rPFS was 12 months with PSMA lutetium and about 5.6 months with a change in ARPI. Hazard ratio was 0.41, very statistically significant. Again, this was the primary endpoint of the study agreed upon with the FDA. And part of the study design allowed for crossover, so as soon as a patient in the control group meets an rPFS event, even before they’ve had a taxane, they can then get crossover to PSMA lutetium. So it’s really a trial where it’s early versus slightly delayed PSMA lutetium, and that helps to explain these survival curves where there’s really complete overlap of survival curves. You might not even expect with 84% of patients crossing over that there is — would be a difference because basically both arms in the end are getting the same therapy.

Using the prespecified crossover adjusted analyses there is some suggestion that earlier use may improve survival, but really the hazard ratios cross 1. There’s not a significant trend here. It would be certainly challenging on the FDA to look at this data. Because of the crossover it’s quite confounded. It’s, in my opinion, just very hard to interpret, and I think they should largely focus on the radiographic progression-free survival that’s clearly showing efficacy.

All right. So there’s definitely going to be questions in the coming year about PSMA lutetium, about other therapies, which I’ll cover the SPLASH study in a minute. But another really important context is what can we combine with PSMA lutetium to make it more effective, so kind of merging the first part of our talk to the second part of our talk, what about PARP inhibitors? As I mentioned, PARP inhibitors are extremely radiosensitizing, and PSMA lutetium is a form of liquid radiation/smart bomb therapy.

So Shahneen Sandhu at Peter Mac has presented a nice Phase I study of olaparib with PSMA lutetium, and she identified the recommended Phase II dose to take forward, which is 300 twice a day for days -4 to +18 of each 6-weekly cycle, and this is based on some overlapping toxicity and the inability to give the PARP inhibitor continuously because of marrow suppression. But she did observe a 66% PSA decline rate of 50% or more, and objective response rate of nearly 80%. Just very exciting data also showing clearance of PSMA-positive CTC. So this is enticing data, small number of patients, but certainly this suggests a therapeutic approach forward into larger randomized studies.

Another combination that works really well combining with PSMA lutetium is abi or enza, an ARPI. So the androgen receptor regulates PSMA itself. When you block the androgen receptor PSMA on the tumor tissue goes up. That may synergize because that’s how you target PSMA with a radioligand.

And so the ENZA-p study was an Australian study presented at ESMO just about 6 months ago now by Louisa Emmett. The ENZA-p study took front-line mCRPC patients, some of whom had had prior abi in an earlier setting, randomized them to enza or enza plus dose-adapted PSMA lutetium, and I’ll explain that in just a second. These patients had poor-risk disease. They had several risk factors for a poor outcome with enza alone, such as high LDH, visceral metastases, prior abi, and you can see that these risk factors were prevalent in the ENZA-p study.

The way they dosed patients was 2-4 doses were given, then they would do another PSMA PET scan. If they had a great response with disappearing lesions they would take a break, and if they had persistent disease they would continue to dose, so this is what we call risk-adapted treatment.

The ENZA-p study showed a significant delay in PSA and radiographic progression. Hazard ratio 0.4 to 0.67, and you can see the curves here. Again, this is against enza, a very effective historic control, highly statistically significant. Not powered for survival but better PSA outcomes. This is really a very important signal finding Phase II study. Similar adverse event profiles to what we already know.

Another common question is what about radium. Is radium dead? Are we still using it? Where does it fit into PSMA lutetium? Radium’s an alpha particle. PSMA lutetium is a beta particle. Radium targets the bone. PSMA lutetium targets soft tissue and bone. So they do have overlapping but unique characteristics that might identify patients.

What about giving PSMA lutetium after radium? The RALU registry or Phase II study was an important aspect and data set that we can use to really tell us whether PSMA lutetium is safe and effective after radium. So they looked at radium interrupted by docetaxel and then lutetium or docetaxel/radium going right into lutetium.

The bottom line from this study is that there is more bone marrow toxicity with sequential radioligand therapy. As you can see in the table below, and I put the VISION comparison data right next to it, the incidence of really significant Grade 3/4 anemia is about 35%. That compares to about 13% with VISION. More thrombocytopenia, 13%.

So this can be delivered. Most patients actually tolerate it pretty well and can have similar benefits, as I’ll show you here. They saw patients with PSA declines post radium with PSMA lutetium, 46% had a 50% or greater decline, similar trends with alkaline phosphatase, delays in progression, and a survival time of about 12.6 months regardless of the treatment sequence.

The conclusion from this is that it is safe, but there is more marrow toxicity. You have to follow patients more carefully for both thrombocytopenia and anemia because of the cumulative effect of all these radioligands.

Yes, Neil.

DR LOVE: Do you have data the other way?

DR ARMSTRONG: Yeah. Not from this study. I think that will have to emerge for radium after PSMA lutetium through a separate registry. I have personal experience giving radium. A common pattern of progression after PSMA lutetium is bone and bone marrow progression. That is a site that PSMA lutetium does not adequately eradicate, and so for those patients that have bone predominant symptomatic disease I do offer radium after PSMA lutetium.

My personal experience is that it is effective. It can delay progression. It probably does improve survival, but you do run into this cumulative marrow toxicity with the sequential use regardless of the way you give it, either before or after. It’s just the total cumulative exposure of the patient can result in just a lot of marrow toxicity by the end.

DR LOVE: How would you compare the ability to reduce tumor-related symptoms like bone pain? Lutetium ... I mean do you see any symptomatic —

DR ARMSTRONG: Yes.

DR LOVE: Do you believe that radium improves symptoms?

DR ARMSTRONG: Yeah. We’ve published on our Duke experience in radium, MSK as well. SIMCAP didn’t really track bone pain response in that Phase III study, but other institutional reviews have shown pain response with radium usually by the first or second cycle. PSMA lutetium, as well, has excellent PSA responses. It’s got a little more response data for objective and PSA and pain response than radium does. So all things being considered equal I tend to favor PSMA lutetium first and then radium or another taxane secondary to that.

DR LOVE: So speaking of things I should have thought about several years ago, have there been any antibody-drug conjugates to PSMA?

DR ARMSTRONG: Yes, and that’s certainly a hot topic. And there’s been PSMA ADCs developed by many companies, some of which kind of had poor linkers resulting in off-target toxicities, myelosuppression, and a lot of those drugs are discontinued, and that’s why you haven’t heard about them. But there are some important steps in that direction. We haven’t seen publications, peer-reviewed publications related to these yet, but abstracts and a number of companies moving into this space.

PSMA remains an important target even after failure of PSMA lutetium. Most patients that I see when they progress, especially after an initial response, remain PSMA positive. And so that’s kind of creating this interest in the field of further targeting PSMA with alpha particles or ADCs or bispecific T-cell engagers or CAR T cells.

DR LOVE: But I mean in terms of ADCs I feel like we’re talking about this every day in other solid tumors. It’s such a great marker. It seems like it ought to be at least as far along as I mean bladder. Bladder’s got 2 approved ADCs already. Obviously you know that. It’s just kind of weird in a way.

DR ARMSTRONG: Yes.

DR LOVE: I never thought about it. It’s just, is there any reason it wouldn’t work?

DR ARMSTRONG: Well, I think we’ve not had the optimal ADCs. The ideas have been there, but we’ve just really needed the strong chemistry to create things like enfortumab in prostate cancer. So I think it’s coming. We’re right now in the Phase I/II of many of these compounds.

DR LOVE: I mean they’re targeting TROP and HER2 and everything you can imagine, and it kind of works. But anyhow, I never thought of that.

DR ARMSTRONG: Yes.

DR LOVE: But it seems like it’d be great. But anyhow, please continue.

DR ARMSTRONG: All right. We’re going to finish with actually — finish the PSMA section on just a press release. This was originally going to be an oral presentation at the GU symposium, so I did put it in there, but it was pulled with the need for more mature data coming.

But the SPLASH study is another PSMA type lutetium therapy, a different binder to PSMA, so biochemically distinct to the Novartis compound. So this is POINT pharma’s PSMA lutetium PNT2002 compound. And this, much like the PSMAfore study, took a chemo-naïve mCRPC PSMA PET-positive population that had failed 1 ARSI and either gave them a second ASRI or the PSMA PNT2002. Here they gave dosing times 4 but every 8 weeks, so a little less dose intense and less dosing overall.

And I show the press release because I think it’s important for the field to realize what’s out there, what’s coming. The progression-free survival was met, so it technically was a positive study. But if you remember from the PSMAfore study there was a near doubling of progression-free survival from 6 to 12 months. Here in the SPLASH study it was maybe a 3-month improvement, 3 and a half-month improvement, from 6 to 9.5 months. Overall survival is immature, and you can see that hazard ratio from the press release was greater than 1, and that’s probably related to a lot of the crossover events and the early availability of the same drug to almost all of these patients.

The safety certainly is reasonable. Not a lot of Grade 3 or serious treatment-emergent adverse events. This is all I can really say about it. This is all that’s publicly available about the SPLASH study. I think we’ll all have to stay tuned to see if this data changes as the data matures.

All right. We’re going to take a big shift into some posters from the GU symposium. I have a particular interest in neuroendocrine prostate cancer. That’s a subset of prostate cancer that has a major unmet need. Most of these drugs that we’ve been talking about don’t work in neuroendocrine or small cell prostate cancer. About 20% of all men who die of lethal prostate cancer will have transformed or primary small cell neuroendocrine prostate cancer.

And so lurbinectedin is a small cell lung cancer drug. It’s FDA approved based on a single Phase II study of 105 patients showing a response rate of about 35%. It’s derived from a marine organism that inhibits transcription and leads to DNA double-strand break.

So we put together a large multicenter chart review basically for off-label use of lurbinectedin in small cell neuroendocrine prostate cancer, and lo and behold in 18 men we show pretty much identical results to the small cell lung cancer results, so partial remissions in 31%, progression-free survival of 3-4 months. Not great results. It’s just many of these patients are desperately ill. They’re searching for something that can cause a response. All of these patients had failed 1 or 2 or even 3 lines of platinum chemotherapy, the historic standard of care. So this offers some kind of off-label indication that this may be an agent with some modest activity. Certainly we can consider looking at combinations going forward.

Misha Beltran presented in an oral abstract the HPN328 drug, which is targeting small cell neuroendocrine prostate cancer in a very unique way. It binds to a cell surface receptor called DLL3. This is a bispecific T-cell engager; brings T cells right to the cell surface of these neuroendocrine cells. In preclinical models you can see fantastic cytotoxic activity and improving survival in these neuroendocrine models.

So she presented a basket study looking at patients with all neuroendocrine tumors but specific focus — specifically focused on GU neuroendocrine carcinoma showing a confirmed response rate of about 25%, overall response rate of 60%. This was pretty exciting data. It’s very early. This is really a step dosing model, inpatient hospitalization, a complex bispecific T-cell infuser, and it’s very early.

It’s not a large number of patients, certainly not a controlled study. We don’t have a lot of data on the durability of these responses. Many of these patients, though, have had durable responses going on beyond 6 to 12 months. So I bring this up because I’m particularly excited about it.

We finish with a poster that Dana Rathkopf at Memorial Sloan Kettering and myself had. This is a new class of compounds that targets the androgen receptor. So BMS-986365 is called an AR degrader. So this binds much like testosterone to the ligand binding domain of AR and then targets it through cereblon to the proteasome, so it puts AR in the cellular wastebasket. So much like we have in breast cancer with ER degraders one of the mechanisms of resistance to our AR inhibitors is a buildup of AR through amplification and overexpression. So the strategy here is to try to degrade AR and overcomes some of that resistance.

So this was the first report, first-in-human Phase I study with dose expansion looking at different doses. So we enrolled a very heavily pretreated patient population. Almost everyone had had both abi and enza. Many had had visceral metastases. They were very heavily pretreated with 7 or 8 lines of therapy. Despite that we show a response rate of about 46% using the PSA30 cutoff. And as you can see, at the higher dose levels we get PSA50 responses in about 45%. And about a third of patients are remaining on study beyond 6 months.

So this was a so far successful study, a very well-tolerated compound with not a lot of side effects, just a little bit of QTc prolongation, fatigue, hot flashes, and mild bradycardia. We do show activity even in patients with AR amplification and AR ligand binding domain mutations, which are classically fairly resistant to the AR inhibitors, and we show some vignettes and case reports of a patient here with a BRCA mutation, with PARP resistance, AR amplification, and a very nice RECIST partial response, and an ongoing 97% PSA decline going out for many, many months, still ongoing.

And so we conclude that this AR degrader is effective, and it’s safe. The dose is still being determined for the next randomized Phase II study, and the formulation is part of the equation of how to move this forward. But I thought I would just highlight this as it seems to be an active compound worthy of mentioning.

We’re going to finish with — the last oral abstract in mCRPC is called the CONTACT-02 study. Neeraj Agarwal presented this data as a Phase III study of patients with mCRPC who had progressed on an AR inhibitor who had some poor-risk features such as visceral metastases but also had some favorable risk features such as bulky lymph node metastases. And they were randomized to either a second NHT, again enza after abi or abi after enza, or the cabo/atezo regimen. The basis for this is that cabo has some nice off-target effects on myeloid-derived suppressor cells that may overcome the immune evasion of prostate cancer.

cMET itself may regulate prostate cancer metastasis. Atezo’s a PD-L1 inhibitor that may rev up T-cell activity to reduce exhaustion. And the cabo/atezo regimen can be thought of as perhaps an immune regimen that could overcome immune evasion in prostate cancer.

The primary endpoint here was a dual endpoint of PFS and OS.

As you can see in the patient population enrolled about a quarter of the patients had liver metastases, many patients had had docetaxel in the hormone-sensitive setting, a mixture of patients who had a good prognosis with lymph node-only metastases or visceral metastases in about 40% of patients.

The primary endpoint in CONTACT-02 was met. The primary endpoint of delaying progression-free survival was improved by about 2 months, so 4.2 to 6.3 months, hazard ratio of 0.65. I look at this as statistically significant but clinically a pretty modest benefit. A 2-month delay in progression survival over a pretty ineffective control group while statistically significant is not as robust as I would like it to be. If you remember, data from the SPLASH or the PSMAfore study showed PSMA lutetium in a similar type of patient population had a progression-free survival of 9 to 12 months, and docetaxel in this type of patient population would have a progression-free survival probably around 7 to 9 months. So again, a statistically impactful result but the clinical utility of this is to be determined.

The progression-free survival was improved in all subsets, but I would bring attention to the patients with liver metastases. These patients do particularly poorly with a second AR inhibitor, suggesting that cabo/atezo could be effective in that patient population. If you look at the PFS in that liver subgroup there is a more statistically significant hazard ratio. But again, I think this is driven by the second AR inhibitor being basically a placebo in this patient population.

I personally don’t treat patients with liver metastases with a second AR inhibitor. I would give them docetaxel, maybe even a platinum, because these patients have a very poor prognosis. There was a significant delay in progression-free survival regardless of prior docetaxel and in patients with bone metastases.

Now the interim overall survival analysis was presented as well. This was not statistically significant. p-value is 0.13, hazard ratio 0.79 that crossed 1, so not a significant delay in the risk of death in the liver metastases subgroup. Again, not a significant result but a stronger trend in the right direction, but again, probably related to the poor outcome of the patients who got a second NHT rather than cabo/atezo being specifically more active.

Cabo/atezo does have more toxicity. You can see here any treatment-related AEs, 33 versus 8% with a second NHT, more diarrhea, more fatigue, more liver injury, more hypertension. No Grade 5s but many more treatment-emergent adverse events.

DR LOVE: Yeah. Just a couple of follow-up questions. First of all, what do we know about the efficacy of cabo in prostate cancer, and do you think all of what you’re seeing here could be from the cabo?

DR ARMSTRONG: Yeah. I should have mentioned that. The COMET studies, Neil, have been published previously. Exelixis developed cabo as a monotherapy, for example in COMET-1 against prednisone in a post-chemo setting, and it did delay progression-free survival by a few months, statistically significant. Never improved overall survival, never was FDA approved.

This data, to me, looks a lot like cabo.

DR LOVE: Right.

DR ARMSTRONG: Slight delays in progression-free survival, no improvement in survival, more toxicity. I can’t really tell looking at this data that atezo’s doing anything. And as you know, atezo has not been successful either alone or in combination, for example with enza. Pembrolizumab has not been successful alone or in combination with any drug, whether that’s docetaxel, enza, abi, PARP. Same with nivolumab.

It’s really not been a great couple years for the PD-1/PD-L1 inhibitors in castrate-resistant prostate cancer. I think that’s largely because there’s other mechanisms of immune evasion in this disease, much like breast cancer, where particularly in the hormone receptor-positive subset these drugs have very little efficacy.

DR LOVE: So another thing I noticed, the thing with the androgen degrader is really super cool, obviously. And again, in breast cancer they’re also way out there, all these new drugs.

DR ARMSTRONG: Much farther ahead.

DR LOVE: Yeah, but you’re coming up. One thing you said that kind of struck me, one of the drugs, I guess it was this drug, I think you mentioned bradycardia, which actually I saw the other day was seen with one of the oral SERDs in breast cancer. And I was thinking at that point why would these drugs cause bradycardia. Any thoughts about that?

DR ARMSTRONG: Yeah. There are cardiac channels, the human hERG cardiac channel, which regulates heart rate. There can be some off-target binding of some of these drugs, so you do have to be careful as you’re screening the next wave of compounds that you don’t cause that as a side effect.

DR LOVE: Interesting. The final thing I was going to say is I love the DLL bispecific because as far as I know I think it’s going to — first of all, it looks like it works in small cell, and it looks like it’s working here, too, and it’s part of these CD3 bispecifics that the oncologists are starting to use all the time now with myeloma and lymphoma. So thankfully by the time it gets to you guys they should know what they’re doing.

DR ARMSTRONG: Yeah. I hope so.

DR LOVE: I don’t know what they’ve seen in prostate, maybe it’s different, but in lymphoma and myeloma they get admitted to the hospital, they get observed, people don’t know what to do. Do they all need to be admitted? It’s like a wild thing. And hopefully, again, it’ll get settled out in the next year or 2, I guess.

DR ARMSTRONG: I think the challenge in solid tumors with these BiTEs is the inpatient admission, the cytokine release syndrome, the need for at least 2 days of careful observation —

DR LOVE: Right. Right.

DR ARMSTRONG: — steroids, tocilizumab to reverse CRS.

DR LOVE: Right. Right.

DR ARMSTRONG: But also the short-lived responses. We are seeing responses, as Misha showed you, but many patients have acquired resistance within about 6 months to these kind of single BiTEs. So I’m hopeful that companies will start taking 2 BiTEs or 3 because of the tumor heterogeneity of many targets and the adaptive resistance that you see, plasticity of these tumors, we have to think kind of out of the box to target such a heterogeneous tumor that’s so adaptable.

DR LOVE: Yeah. There’s a bunch of these bispecifics where it hits 2 parts of the receptor, like I think it’s called zanidatamab in HER2.

DR ARMSTRONG: Right.

DR LOVE: So they have those too. But you’re right, I guess I’m assuming, because like I said, in lymphoma and myeloma they’re like really great drugs. But you’re right, maybe it’s not going to be the same thing with solid tumors. I don’t know.

DR ARMSTRONG: I mean look at CAR T cells. They work beautifully against CD19 or 20. They can wipe out an entire disease that’s basically monoclonal.

DR LOVE: Yeah. Right.

DR ARMSTRONG: But the thing of prostate cancer is many different clones, and so that’s why CAR Ts haven’t really worked so well.