Optimizing the Use of Hormonal Therapy in Prostate Cancer Management — Tanya B Dorff, MD

DR DORFF: Hello. I’m Tanya Dorff, the Section Chief for Genitourinary Cancer Program at City of Hope. And a big theme that emerged in the world of prostate cancer this past year was intensification of systemic therapy in earlier stages of disease.

So we’ll start with the PRESTO study, which was in the setting of biochemical recurrence after prostatectomy and salvage radiation, when men were facing rising PSA yet again, the question arose with some of our newer more intensive and more effective hormonal therapies could doubling down or even tripling down lead to eradication of micrometastatic disease. So the study was a randomization between 1 year of LHRH therapy alone or with apalutamide or with a combination of apalutamide and abiraterone.

The primary endpoint was PSA progression-free survival, but they will be looking at some firmer oncologic endpoints such as metastasis-free survival. Patients did have to have a PSA level of 0.5 in order to enter, and a doubling time of less than or equal to 9 months. If they had findings on PSMA PET that were not visible on conventional imaging they were still categorized as biochemically recurrent and eligible for the study, and I think that’s just an important side note for the world of prostate cancer. We’re all grappling with these new PSMA PET scans, but most of our studies are still using conventional imaging to categorize, and therefore our treatment paradigms are really based around that.

So the patients definitely did better when they had double or triple therapy. The 2 apalutamide-containing arms were combined for the primary analysis, and you can see there was a prolongation of PSA progression-free survival.

In terms of adverse events, you can see that there were more treatment discontinuations on the double and triple arms, as well as a higher rate of Grade 3 and 4 adverse events. And looking down at the bottom, these include a little bit greater rate of fatigue, there’s also, of course, the potential for rash with apalutamide, and hypertension is something we have to watch a little bit more carefully as we intensify our hormonal therapies.

So this is not yet really maybe on label. It’s not clear whether it will become something the FDA will review, but it fits with the whole spectrum of what we have been seeing in other stages of prostate cancer.

So FORMULA-509 is a great example of that. So here is taking 1 step earlier, biochemical recurrence not yet treated with salvage radiation, and here the same question was essentially asked. We’ve heard from the SPORT trial, as well as GETUG, in the setting of salvage radiation that adding ADT increases metastasis-free survival. But here the question was could we intensify and achieve even a higher rate of cure.

So in this study patients receiving salvage radiation, again with a PSA level that had reached — stratified for PSA of greater than 0.5 or less than 0.5, so they did allow treatment to start a bit earlier, as is common with salvage radiation; 6 months of just castration therapy with bicalutamide, one of the older nonsteroidal antiandrogens, or a triple therapy with LHRH plus abiraterone plus apalutamide. So this was just reported at GU ASCO by Paul Lin, and you can see that there was a significant improvement in the 3-year metastasis-free survival, from 66% to 84%, leading to really a pretty favorable number needed to treat of 5.

DR LOVE: The main question I wanted to ask you about both of these trials, and again, we can talk about it more with Oliver, but in a way I’m not exactly sure of the impact of the control arm versus doing nothing. So in other words, do we know, for example, that ADT adds to salvage radiation after prostatectomy? And do we even know whether or not treating people with a doubling time less than 9 months, et cetera, et cetera, is better than not treating at all? Is that — I mean I know it’s a basic — yeah.

DR DORFF: Two separate questions. So with regards to PRESTO, is early hormone therapy impacting survival in the setting of biochemical recurrence? There are not really strong data. The single trial that we all refer back to over and over again is the TROG trial, which did suggest that there was a survival advantage if you started ADT before your PSA reached 5 and for patients with a doubling time less than 15 months compared to waiting for metastasis to develop. But it has become more accepted that metastasis-free survival is significant. So patients may be willing to accept hormonal treatment simply to avoid seeing the cancer growing in their bones, for instance. And it would delay the time to having a symptom from their cancer.

But separately for FORMULA-509, in the setting of salvage radiation, there were 3 trials that showed increased cure rate when you added — when you added ADT to salvage radiation. So that has been answered. It’s separate from biochemical recurrence beyond salvage radiation. But that was the SPORT trial, the GETUG, and then there was one other, radiation alone versus radiation plus ADT. All 3 favored adding the ADT.

DR LOVE: Great. Okay. That’s very informative. And of course, yeah, the — I mean the biochemical relapse question has been out there forever, and I guess it’ll probably never really be answered, but — as you say.

Let me ask you another question. From your point of view, I mean putting aside approvals, would you like to be able to use these strategies right now?

DR DORFF: There are patients for whom I feel like getting a deeper remission is helpful. I’m still kind of grappling with weighing that against the toxicity, and I really want to see the testosterone recovery data because my experience on the PRESTO trial, I had 25 or so of the patients on that trial, is they did have more toxicity, and it felt like it took longer for testosterone to recover. So I think all that information has to go into the discussion. But I do have patients right now for whom I do want to use intensification, and we can usually get it approved. But I do have other patients for whom I’m still using monotherapy.

DR LOVE: And just to clarify, when you treat people in the — I guess the PRESTO scenario, biochemical recurrence, in that situation it’s indefinite treatment?

DR DORFF: It was 1 year. It’s intermittent.

DR LOVE: Just 1 year. But I mean normally when you treat — you have a patient who has PSA relapse, let’s say doubling time less than 6 months, do you just do short term or indefinite treatment?

DR DORFF: Short term.

DR LOVE: And then stop.

DR DORFF: Yeah. Yeah. I find that those breaks — I mean first of all JPR7 said that intermittent versus continuous in the biochemical recurrent setting you had equal survival. You had more deaths from cardiovascular disease at 10 years on the continuous arm, you had more deaths from prostate cancer on the intermittent arm, but the same number of men were alive at 10 years. So that forms the basis for continued use of intermittent therapy, but honestly from a quality of life standpoint JPR7 clearly favored intermittent, and that’s what we see as well.

You actually do get reversal of some of the toxicities during those gaps when testosterone recovers, and those, I think, provide very meaningful benefits to these patients. And the switch, once you switch to long-term continuous, that’s a big deal for patients.

DR LOVE: Yeah, no. I was actually just — when I said is it temporary or not what I meant was — what I meant was intermittent therapy that you don’t stop it. So is that the way you approach it, that you treat them, the PSA comes down, then you stop therapy, let the PSA come back, and restart? Or you just treat for a year and stop treating? I’m sorry to ask such a basic question, but I just don’t know the answer.

DR DORFF: Oh, no. Intermittent implies that we know PSA is going to come up when testosterone recovers, and we will do another cycle. So the intention is that they’ll be on and off treatment just with gaps.

DR LOVE: Right, yeah. It’s just terminology. That’s what I meant, that they would — this would continue indefinitely, the intermittent therapy.

DR DORFF: Until they switch to continuous, yeah.

DR LOVE: Great. Okay. Please continue.

DR DORFF: So of course when we’re looking at benefits we also have to look at toxicities. And again, apalutamide, one of the most notable toxicities is the rash, as well as a high rate of hypertension.

So we will be talking a little bit about rash management a little bit later, but that’s part of the conversation we have to have with patients. We can improve metastasis-free survival, we can delay the cancer coming back, but here’s what you’re going to go through for the 6 months or the year that you’re on this treatment.

So continuing with that theme of earlier intensification a couple of the STAMPEDE arms, which we think of STAMPEDE as a metastatic hormone-sensitive prostate cancer trial, the same way we maybe categorized CHAARTED and LATITUDE and ENZAMET. But in fact there were a fair number of nonmetastatic prostate cancer patients who were eligible and included in STAMPEDE. So 2 of these arms became relevant in answering a question of whether intensification was beneficial in earlier stages of disease, nonmetastatic. So that was the abiraterone arm and also an arm with abiraterone plus enzalutamide.

So Gerhardt Attard published in Lancet last year a meta-analysis where he pooled the data from these 2 arms for the nonmetastatic population. And what was shown was that the combination therapy, whether it was the doublet or the triplet, resulted in significantly longer time to metastasis, as well as overall survival. And the treatment period in these cases was 2 years.

So this forms the basis for allowing us to recommend adding abiraterone on top of castration therapy in a high-risk localized setting, or a high-risk biochemically-recurrent setting even though the trial wasn’t specifically designed.

But the meta-analysis, you can see the survival cures for metastasis-free survival are quite compelling, and there’s a big difference when we add the stronger therapies early on.

One other theme that emerged was the use of PSA response as a biomarker that is prognostic for overall survival. So we saw things like the ICECAP and STOPCAP groups looking at some of these big trials and showing that a PSA nadir below a certain level, less than 0.2 at 7 months, very prognostic for survival.

So an analysis was performed from the nonmetastatic CRPC trial called SPARTAN, which was with apalutamide. So these are men on castration therapy for biochemical recurrence who become castration resistant, but their scans are still negative. They were randomized to apalutamide or placebo, and you can just see these deep, deep PSA responses on the waterfall plot with the apalutamide. And in fact, 90% of patients achieved a greater than 50% drop in PSA by 6 months. So this is not yet a biomarker that’s been validated as a surrogate for metastasis-free survival or overall survival, which were the endpoints in SPARTAN, but I wouldn’t be surprised if we start to see this PSA response biomarker being more widely applied.

They did show in this particular trial that the deep PSA response, less than 0.2, was associated with overall survival and not just time for PSA to recur. But again, I would say this is not yet quite as validated as this same biomarker in the metastatic setting.

DR LOVE: Let me ask you. How come the waterfall plot on the placebo arm doesn’t come down? Because they’re getting ADT, right?

DR DORFF: But they’re already developing castration resistance on the ADT.

DR LOVE: Oh, right. Right. Castration. Okay. I was thinking it was —

DR DORFF: So it’s actually surprising any of these guys dropped. I don’t know what happened to those guys.

DR LOVE: Yeah. Yeah. Actually, that’s a good point. Yeah. Maybe they — interesting. Okay, great.

DR DORFF: So as I mentioned earlier, with apalutamide one of the major side effects that can be seen is rash. And this has many different manifestations. So there was a very helpful publication last year just kind of describing it ranges from dry skin, xerosis, to maculopapular rash. There can be oral — a finding of lichen planus, a little bit less common. It can be sometimes acneiform or looking like psoriasis, but primary it’s going to be more of a maculopapular, erythematous eruption. And there is a number of wonderful photographs in the publication, and one of them is presented here.

Now how do we manage this rash? Well first of all, it’s important to note the median time to onset is 80 days, so if you don’t see it in the first month it doesn’t mean your patient is in the free and clear. You have to warn them that it a rash comes on in the second or third month that it’s likely still related to apalutamide, and they should still call in so you can give them guidance.

I often stop the drug and then apply topical corticosteroids. Antihistamines can be helpful if it’s very itchy. So you can see distribution of what types of treatments were used. There are some patients where we just stopped drug and don’t administer any specific treatment, and the rash can go away. Certainly in those cases it’s easy to see where you’d want to rechallenge sometimes at a lower dose. When patients do require oral corticosteroids then that might be a scenario where you’d be less inclined to rechallenge.

DR LOVE: Quick question. I’m assuming that people have looked at whether there’s a relationship between rash and efficacy.

DR DORFF: Yeah. I don’t know that that was in this publication, actually. I don’t think I’ve seen those data, but I’ll have to go back to this publication.

DR LOVE: About what fraction of patients actually get clinically meaningful rash that requires intervention?

DR DORFF: About half.

DR LOVE: Yeah. Probably it’s not correlative, but I’m just kind of curious.

DR DORFF: Yeah. It would be interesting to understand like what the basis of it is.

So one question that many of us have is how are patients with prostate cancer and visceral metastases fare with some of these newer intensified strategies. Because when we think of visceral metastases we often think of maybe more of an aggressive variant, maybe something that’s less hormonally driven.

And so there was a very helpful analysis published in the European Journal of Cancer last year analyzing the LATITUDE trial, which was with abiraterone in metastatic hormone-sensitive prostate cancer, and pulling out the subset of visceral patients. So what you can see here is that there was a significant improvement in the median overall survival from something in the range of the 30s for placebo up into the 50s with abiraterone, and that held true whether you had a more traditional pattern of metastases or whether you had visceral metastases.

So I think this is very helpful when we’re looking at doublets and triplets and whether we want to add docetaxel, to have this kind of nugget that kind of tells us that even though this patient has a little bit unusual presentation they could still benefit from a traditional AR-targeted agent like abiraterone.

And that is also important when we’re trying to talk to our patients about which way we’re going to intensify therapy, with an AR-targeted agent or chemotherapy, since we know both can prolong survival. So we want to be able to show them what their quality of life is going to be like.

The chemotherapy that we use in the up-front setting, of course, is 6 cycles, so that is 4 1/2 months. And so in this quality-of-life analysis from 2 of the arms of STAMPEDE, the arm with docetaxel and the arm with abiraterone, you do see a sharp drop off in quality of life during the initial treatment with docetaxel but then recovers to baseline within a year, whereas the abiraterone-treated patients tended not to have a steep drop off in their quality of life. So I think this is not maybe surprising to many of us. We know that during docetaxel chemotherapy there are periods where patients feel ill, but it is nice to see that the quality of life rebounds as patients recover from that time period. And overall that quality of life with intensified therapy using abiraterone is maintained.

There have been many, many analyses from the STAMPEDE and LATITUDE trials. These are very important studies for the world of prostate cancer. One big question; because LATITUDE was designed only in a high-risk metastatic hormone-sensitive prostate cancer population, whereas STAMPEDE allowed much more of an all-comer population, including nonmetastatic, as we saw earlier with the meta-analysis, so people have been waiting to hear from the STAMPEDE group about subsets and who benefits. So they did perform an analysis looking at the LATITUDE criteria that defined high risk and looking at whether survival was favorable with abiraterone in a non-high-risk subset, a population that would not have been included in LATITUDE.

So here you can see the high-risk subset in Graph A, and the low risk, or not meeting the LATITUDE high-risk criteria, in B. So essentially we’re seeing a similar effect favoring intensification with up-front abiraterone regardless of risk status. So this just helps us better extend these kind of big clinical trial findings into our day-to-day practice.

The ARCHES study using enzalutamide in metastatic hormone-sensitive prostate cancer is one of the other seminal papers that has created this shift in how we treat prostate cancer. And again, there’s just been a lot of interest in subsets. So there was a publication by Andy Armstrong and colleagues looking at things like high volume and low volume, and you can see this forest plot essentially shows that up-front intensification, in this case with enzalutamide, is really beneficial across the board.

One other question that had arisen in this whole conversation about triplets versus doublets is they did have some docetaxel use in ARCHES, and so they did pull out that subset, as well. You can see towards the bottom the benefit of the up-front enzalutamide was maintained regardless of whether the patient had received the docetaxel, so paving the way for triplet therapy using this combination.

We also saw an update last year from ENZAMET, which was also a study of enzalutamide in metastatic hormone-sensitive prostate cancer. And what really stood out to me, this study had a significant use of docetaxel, quite a bit higher than what we saw in ARCHES, and so they were able to look at, again, whether enzalutamide was still beneficial even if you had received docetaxel. And the group that really stood out was those patients who had de novo metastasis, or what we call synchronous metastasis, and high volume. So that includes 4 or more bone metastases with 1 outside the axial skeleton or visceral involvement.

So in the circle part of the Kaplan-Meier curves what you see is very early on triplet therapy, enzalutamide and docetaxel added to LHRH therapy, really separates out these synchronous high-volume patients and preserves their early survival. So this is a group for whom I really push a conversation about triplet therapy to include not only an AR-targeted agent but also docetaxel.

DR LOVE: So I was asking Oliver about this, and I was going to ask you the same question, which is in hormone-sensitive metastatic disease do we have any evidence that adding chemotherapy yields any benefit beyond ADT plus secondary hormonal therapy. Is there evidence? Is that what this shows?

DR DORFF: So there’s no Level 1 evidence. There was no study designed to ask that question, but these subsets do allow us to see because this is — the gray line is triplet, the black line is doublet, and you can see this early separation, which would suggest that for these patients the early docetaxel was quite beneficial. It kind of saved them from early mortality within that first 2-year period.

DR LOVE: Right. Okay, great. Yeah, no. I see it there. Interesting.

Could I just ask you, so then it sounds like there are situations where you are using triplet therapy, because Oliver said he basically almost never uses it. I said, “What about young patients with a lot of disease?” He said, “Not usually.” But your answer is more like usually you do that?

DR DORFF: Not usually. So many patients present with much less aggressive disease than what’s represented here.

DR LOVE: Right.

DR DORFF: But for those patients who present high-volume de novo, younger, low PSA for volume of disease, I definitely have some patients on triplet therapy right now. The majority are doublet, I will say, but I think it’s important to call out people like this, where significantly more of them are alive at 2 years who got triplet. I think that’s really important.

DR LOVE: All right. Please continue.

DR DORFF: So many of our patients are concerned when we discuss with them a reduction in the dose of their treatment because of side effects. We’re always trying to balance longevity with quality of life, and we’re sometimes reducing some of these powerful AR-targeted agents due to fatigue or other side effects that we’re seeing.

So this was an interesting analysis looking at the relationship between dose exposure and response in the context of apalutamide for metastatic hormone-sensitive prostate cancer. So similar to some of the other drugs in the class, it takes at least 4 weeks to achieve a steady state.

So they did these complex calculations for AUC after patients had reached a steady state, and then they analyzed core tiles to see whether those patients who maintained a higher dose level or had a higher pharmacokinetic level had better outcomes. And I think what stands out to me is at least for progression-free survival that lowest core tile of drug exposure doesn’t do as well. It eventually ends up with a little bit of a difference in the overall survival curves, but I would say generally this is pretty reassuring. Core tiles 2, 3, and 4, we don’t see a lot of difference in the curves, which should mean that we’re able to dose reduce for toxicity. Of course we don’t have the pharmacokinetic data to guide us, but this is suggestive that benefit can maintained.

And a flipside of how I talk to patients about dose reduction is in the Phase Is, where they dose escalated drugs like enzalutamide, they saw efficacy at lower doses. They explored a wide range of doses, and they didn’t pick the maximum tolerated dose, they picked a dose at which they were seeing a nice balance between responses and toxicity, but that didn’t mean they weren’t seeing responses with some of the lower doses.

So now I’ll move on to triplet therapy. The ARASENS trial was really one of the only trials that specifically intended to have everyone receive docetaxel and then randomize patients to darolutamide, the AR-targeted agent, versus placebo. It does not answer the question of what did the docetaxel add, unfortunately we don’t have any studies that do that, but it did answer the question that even if everyone is getting docetaxel, and we’re not just doing a post hoc subset analysis, but even in that context receiving darolutamide did result in significantly better survival.

A lot of these trials are unfortunately plagued by a lack of racial diversity, and that is a limitation in terms of treating the real patients we see in our clinics. But age I think is an important question a lot of clinicians face. Should I intensify even in my older patients? So we can see in ARASENS that at least 16% of patients were over 75, although not a lot of octogenarian representation, probably because of the chemotherapy in this trial. But there are studies of chemotherapy in older populations. I think docetaxel for the most part really can be tolerated even in older patients.

The toxicity in ARASENS that I wanted to highlight was febrile neutropenia, which I think we can clearly say is related to docetaxel. And it was 7.8% on each arm, so adding the darolutamide did not exacerbate chemotherapy toxicity, and it’s up to clinicians to think about whether that risk is an acceptable range for offering triplet versus pursuing a doublet with an AR-targeted agent.

At GU ASCO this year Maha Hussain presented a subset analysis for high volume and low volume, as well as high risk and low risk. So these are using the CHAARTED criteria. Again, 4 or more bone mets with 1 outside the axial skeleton, or visceral involvement is what qualifies you for high volume. And you can see that there’s definitely a stronger signal for benefit in the high-volume subset, although there is a trend, even for the low volume, in favor of triplet.

When it comes to the LATITUDE high-risk definition versus low risk, I think there’s a little bit more consistency across the results. So bottom line is we don’t have great biomarkers that tell us which patients need intensification and which patients can get away with maybe less treatment.

There is a lot of work ongoing analyzing some of these big, pivotal Phase III trials. Like CHAARTED has published looking at basal versus luminal, as well as using Decipher genomic classifier risk scores, to try to tease out so eventually we hope that we won’t be treating every metastatic hormone-sensitive prostate cancer patient the same or using things like synchronous metachronous high-volume/low volume. But I think the sum total of these subset analyses that we’ve just looked at in the context of triplet therapy do give us a little bit of clinical guidance.

PEACE1 is the other trial that people talk about as triplet. This is a very complex study. It was initially more of a 2 x 2 factorial asking the question of whether radiation to the prostate primary was still beneficial when we intensified systemic therapy because the prior STAMPEDE arm that showed radiation to the prostate primary was beneficial was in the context of castration alone and not what we would consider optimal systemic therapy in the modern practice. However, as this trial was being done CHAARTED reported out, STAMPEDE, docetaxel, and so it would not be ethical not to allow patients to receive docetaxel.

So this trial was not designed to answer the question of triplet therapy with docetaxel, but it does give us some evidence about this.

So they were able to show statistically that there was no interaction between abiraterone and radiation to the prostate primary, which allowed them to lump those patients for an analysis of docetaxel — I’m sorry, of the docetaxel-treated patients and ask the question of benefit of abiraterone versus no abiraterone. Again, not answering the question of the docetaxel contribution, unfortunately. But what we saw was across the board for overall survival there was a benefit when you added the abiraterone, and that held true whether or not you got docetaxel and whether you were high volume or low volume.

So the new paradigm in metastatic hormone-sensitive prostate cancer is intensified therapy. Most patients who present to our clinics can tolerate doublet, and we have a choice of agents so that we can look at their comorbidities and look at their concomitant medications and make a choice that’s going to fit well for them.

We have to think about triplets for certain groups, but I am open to triplet therapy as part of a clinical trial. We have some really great active new agents like lutetium-177-PSMA that’s moving into clinical trials in the hormone-sensitive setting. There are also a lot of molecular agents that we’ll look at very briefly in a moment.

But we also have to think about treating the prostate primary because there are data that suggests radiation to the prostate, if it’s previously untreated in a low-volume metastatic patient, is going to be beneficial. If they are higher volume or don’t quite fit into that we do have an ongoing trial through the cooperative groups, SWOG S1808, that’s trying to answer the question of cytoreductive prostatectomy in the face of intensified systemic therapy or radiation to the primary. So it’s a randomized trial comparing that kind of local treatment versus no local treatment to answer the question of whether that is beneficial. And then there’s a whole gray area when it comes to metastasis-directed therapy in low-volume patients.

So there’s a lot to talk about with our newly diagnosed patients, but clinical trials remain a very good option, and this is a select list of some of the trials that are going on in the metastatic hormone-sensitive space. You can see some of the most exciting agents are represented, including PARP inhibitors, including lutetium-PSMA.

There are some other targeted agents, such as the PI3-kinase inhibitor, capivasertib, that’s being looked at in PTEN-deficient setting, and abemaciclib, which is a CDK4/6 inhibitor, which in breast cancer really partners very well. It’s very synergistic with hormone therapy. And there’s a lot of data showing synergy in the setting of prostate cancer, as well. So this is in a genomically unselected population looking at whether the synergy of abemaciclib with abiraterone will improve long-term cancer control and survival.

And then there’s immunotherapy, in the purple group. At least one of the studies, KEYNOTE-991, has not shown an advantage, although we haven’t see the full data. It’s just a closure of the study. It doesn’t mean none of the studies will be positive, especially when you throw in a drug like cabozantinib, as they’re doing in the CABIOS study, but this is to say that although we have triplets, and although we have doublets, there is still room to improve. We still want more patients to achieve a deep and durable remission.

In the future, of course, we may have multiple different triplets, and it is hoped that we will have some kind of biomarkers to guide us so that we can start to treat prostate cancer patients a little bit more with personalized medicine. For this patient a doublet might be perfectly adequate, for this patient a triplet with a PARP inhibitor or with lutetium, or for this one chemotherapy. And so there’s a lot of effort going into developing those types of useful prognostic and predictive tools, so continue to keep your eye on the literature for more data coming out from these big Phase III trials.

But overall intensification in earlier-stage disease, as we saw with biochemical recurrence and in metastatic hormone sensitive, is a unifying theme of what’s been happening in prostate cancer.

Evidence-Based Utilization of Other Therapeutic Approaches — A Oliver Sartor, MD

DR SARTOR: Neil, really a pleasure today to be able to present some selected highlights in advanced prostate cancer. I’m Oliver Sartor from Tulane.

And I’m going to start off by talking today about some of the recent data with PARP inhibitors. And PARP inhibitor has been around for a good while. And they’ve become a really interesting topic through combinations, new PARP inhibitors being tested in clinical trials. And there’s definitely an update that I think people need to hear about.

This is just a reminder. This is not updated from 2023. But there was a very important trial called the PROfound trial and it showed not only an improvement in rPFS but an overall survival benefit in prostate cancer. And this was done specifically in men who had homologous repair — homologous recombination deficiency repair mutations in genes like BRC1, BRCA2, ATM, et cetera.

So that particular trial has now been having a few updates. And here’s one of the updates, and here we’re looking at pain and health-related quality-of-life with olaparib versus physician’s choice, and this is typically an abi/enza switch. And remember, everybody has got homologous recombination repair gene alterations. And here what you see is that there is some preservation of the quality of life and pain, I could show you a bunch of the slides, but the bottom line is, these are patient-reported outcomes. And these patient-reported outcomes show a benefit of the addition of olaparib for those with HRR mutations.

Now, it turns out that one of the things that’s really interesting if you’re trying to look and find the HRR mutations is that there’s trouble when you go to the tissue. So, this is a small part of a large study.

So this study, published by Maha Hussain, demonstrates that when you’re trying to get next-generation sequencing done and you’re pulling from a variety of samples, some archival and some recently obtained, yes, you can submit a sample, but the truth is you don’t always get a result. And there are a variety of reasons why you may not get a result when you submit the tissue to try to get your sequencing done. Maybe you don’t have enough of the pathology there, not enough prostate cancer. Or maybe they try to extract the DNA and they just don’t get it. Or maybe when they try to do the extraction and do the sequencing, they just don’t get what they need to get. In this study, only about 57% of the men who were tested actually were able to get informative sequence DNA.

So samples submitted does not mean results obtained. And that’s very important.

Now, this is just a little more detail on this. And I’m going to summarize a lot of data in a short period of time. If you have a fresh sample, that’s better than an older sample. Guess what, that’s not so surprising. And if you use a prostate primary, that’s probably not as good as a biopsy of a recent metastasis. And if you have more tumor content, well, guess what, you do better than if you have less tumor content. These are sort of intuitively obvious things but it’s nice to really see the data.

So the bottom line is, if you’re trying to get tissue, you’re probably going to do better with a fresh sample from a metastatic site as opposed to an old sample from an archived prostate. And, by the way, the age of that archived prostate may be 8 years or more and you’re not going to get good sequence data out of that a significant portion of the time.

Now, one of the things that has risen, and this is an important topic, is if you have trouble about getting tissue and getting genomics from the tissue that you have, what about the obvious? What about circulating tumor DNA? And here, you have nice data showing the circulating tumor DNA, in fact, works. And we’re looking for a BRCA1/BRCA2 and ATM, and that’s the way the PROfound study was organized – this is their so-called Cohort A. And then you can look if you’re just relying on circulating tumor DNA, that you can get the answers you need. And, of course, almost everybody you can draw a blood sample from, but, by the way, still, not everybody has circulating tumor DNA. But if you get the results, it’s informative. And that’s an important message: circulating tumor DNA works.

Now this study, TRITON 3. Rucaparib, another PARP inhibitor. Just published in New England Journal. Presented by Alan Bryce at ASCO GU 2023 in San Francisco. Published in New England Journal the same day. So TRITON 3 did screening and what they were looking for is the BRCA1/BRCA2 and ATM. And then there was the randomization, it was the PARP inhibitor rucaparib, 600 BID, versus physician choice. And this is important. It could either be docetaxel, it could be abiraterone, or it could be enzalutamide. Whatever the physician wanted to use among those 3 choices they would get. So 2:1 randomization and they’re looking at rPFS.

Now, when we begin to look at these data, and this is from the New England Journal article, you look at the BRCA subset and it is unequivocally positive. Here you see the median progression-free survival and it’s really rPFS, radiographic progression-free survival. You see the rucaparib, it’s 11.2 months. Median control is 6.4. That’s an important finding. But go down to the ATM subgroup. The ATM subgroup did not benefit. There was no difference between the rucaparib and the control group when it came to the ATM subgroup.

So I think that’s an important message. And that did not come out completely clearly in the PROfound study.

Now it turns out that there were 2 control groups here. One would be the novel hormones and the other would be docetaxel. So here you get a chance to break it out and look at rucaparib versus docetaxel, physician’s choice. And guess what? Got a hazard ratio of 0.53. That’s a winner for the rucaparib. Then you look at the second-generation hormones, and that would include either abi or enza, and again you have a very good hazard ratio, in this case 0.38. 

So I think this is important. This is head-to-head, if you will, for rucaparib versus docetaxel. And you turn out in the BRCA patients the rucaparib, the PARP inhibitor, is better. I think that’s important. And physicians need to know about that.

Now niraparib is another PARP inhibitor and here we’re going to be looking at the GALAHAD study. Now this is an open-label, Phase II. This is not a randomized study. This is taking people who have a variety of homologous recombination repair defects and looking at BRCA versus non-BRCA. And guess what? Those individuals with a BRCA mutation do better than those who have a non-BRCA mutation. And that’s not a surprise to me because one of the things that we’ve learned gone through the olaparib and more, is that the BRCA is almost uniquely sensitive. And when you go to some of the others, like ATM, CHEK2, et cetera, that you don’t find a lot of activity with the BRCA inhibitors, in my opinion.

Now there’s some subsets about that. And I’ll simply say that things like PALB2 is important.

DR LOVE: I guess I almost want to apologize when I make analogies to other cancers, but I can’t help thinking about ovarian cancer, where, of course, there’s all kinds of trials, mainly with the 3 PARP inhibitors. But the question is — there a lot of times you’re stuck with indirect comparisons.

And so first question is when you look at these new data with rucaparib, compare it to what we’ve seen in the same setting with other PARP, I guess mainly olaparib and niraparib, indirectly, how do they compare? And if you had a choice, any thoughts about which one might be better?

DR SARTOR: I think the niraparib may not be as an active. And I’ll be talking about niraparib as we go forward a little bit. I think olaparib and rucaparib look pretty similar in my mind. It’s hard to sort of choose which one might be better. I think the olaparib has the benefit of probably more data, other diseases, et cetera. But I think the rucaparib data is also quality data.

DR LOVE: So again, not to make the analogy too far, but I don’t know if you know all the kind of craziness that’s been going on with ovary with this scenario, later-line monotherapy. Because now the patients are all getting it earlier, but they still have this sort of legacy trials out there and they’ve all been cut off by the FDA because of, not only lack of survival benefit, but adverse survival. I don’t know, have you been following that story?

DR SARTOR: Not really, Neil. I’ve heard a little bit of rumblings about it. But what I’ll say is that the chronic administration of these agents is not always so easy for the patient and not so easy for the bone marrow. And that’s one of the cautions I think that I have in my own mind about some of the studies that we’re going to look at here in a moment, about PARP inhibitors being given for a long period of time.

DR LOVE: I mean I don’t know how it’s been evolved in the prostate space, but again, in terms of what we saw there with ovary, it wasn’t clear exactly what the reason was, maybe there were some MDS/AML element for it. But I think the big thing was, there are a lot of patients without HR deficit who got treated, who aren’t going to have any benefit. And they’re all mixed in. So with ovary, if you separate them out, it looks a little different. Anyway, it’s a huge mess in ovary. But I don’t know that that’s going to happen with prostate. But just it is interesting. I’m sure oncologist are going to look at this and think about what’s going on with ovary.

DR SARTOR: Well, I think it’s a really good point. And we’re going to be looking here in a moment at some of these combo trials and when we do, I think there’s some questions that are apparent. Right now, we have an rPFS endpoint, but there’s a lot of other endpoints we don’t have the full benefit of seeing yet.

DR LOVE: Okay, please continue.

DR SARTOR: So here we’re now going to talk about combination of PARP inhibitors in AR pathway inhibition. And there’s a variety of preclinical rationales about why you might put these 2 types of agents together. ADT could upregulate PARP-mediated repair and then you can have a PARP inhibitor that can help to inhibit that repair. And I won’t sort of wax poetic forever and forever, but the bottom line is, there is preclinical rationale for putting together AR inhibition and a PARP inhibitor and that has led to clinical trials.

And I’m not going to spend a lot of time going into all the background clinical trials that may have led to this point, but the bottom line is that now we have some pretty large trials. And this data is being looked at and scrutinized now by the FDA.

What I’ll say is, this is first-line metastatic CRPC in the PROpel study. And, by the way, I don’t see a lot of these patients anymore because so many of the patients I’m seeing have been treated with a novel hormone either for metastatic disease up-front or for non-metastatic CRPC prior to them getting to the metastatic CRPC. So, this patient population is nowhere near what it used to be.

And bottom line is, we’re going to be looking at olaparib plus abiraterone versus placebo plus abiraterone. Pretty good-sized trial, about 400 patients in each arm. And this is an all-comers trial. So the HRR mutations were looked at after randomization, in other words everybody got randomized and then they kind of sorted it all out later. They had a variety of endpoints. The primary endpoint was rPFS, radiographic progression-free survival, or death, by investigator assessment.

Now this has been presented in a variety of settings. So, we’re going to look at sort of mature data that is becoming more mature with the overall survival. And then we’re going to be looking at rPFS, which isn’t going to change.

First of all, it’s a little bit interesting. There was a bit of a distinction by the investigator assessment of the rPFS versus the central review. And I’m not going to say it’s a dramatic difference but there’s a little bit difference if you start looking at medians with the blinded independent central review, we’re going to call that BICR, as opposed to the investigator assessment. And if you look down at the bottom, you end up with a median of 8.2 months with the investigator, and a median of 11.2 months for the BICR, in terms of the median improvement.

So the trial met its primary endpoint.

Then they started to look at the breakdown on the rPFS. And you see things that are kind of trending towards positive; I’m going to mention this. And then you look down, there’s one subset, and that’s the BRCA-mutated subset. Here the hazard ratio is 0.23. Knocks it out of the park. You got a BRCA mutation, it’s like a big win.

Now what happens if you don’t have a BRCA mutation? Well, it turns out that the hazard ratio is 0.76. Remember, this is rPFS, not OS. And so, you have a movement that is on the positive side. But the BRCA is absolutely definitive and the non-BRCA is not so definitive. And this, by the way, is also true for the non-homologous recombination repair mutated.

Now this is the newer data. This was just what was presented at ASCO GU. And what you see is that there is a trend toward improvement in the OS. Now, it turns out that it did not sort of meet the prespecified endpoint, but it is close. You’re looking at 0.81. But this has taken all-comers. And if you begin to slice and dice this a little bit, what you see is the HR-mutated population, which is about 28%, and there, you see a hazard ratio of 0.6 range and the other, it’s in the high 0.8 range. So there’s a difference. If you’re mutated, it looks like you may have a survival benefit. And this is almost all driven by the BRCA gene. And you look at the non-HRR-mutated, and I would not call that a survival benefit.

So just for a brief moment, and we’ve been talking about precision medicine for a long time. This is unprecise medicine, in my mind. You’re looking at those are not mutated and giving them a drug that is known and proven for a mutated subset. But I think what we’re seeing here is, if you’re mutated, particularly within BRCA, you’re going to benefit. If you’re not mutated, at least for survival, I think it is maybe a small trend in the right direction, but it doesn’t meet the kind of significance that we would really hope to see.

Now, this is another study called MAGNITUDE. And MAGNITUDE sort of took this HR-mutated group, and you can see the genes: ATM, BRCA1/BRCA2. BRIP1, CDK12, CHEK2, FANCA, HDAC2, PALB2. And it divides them into biomarker-positive with a randomization, a biomarker-negative and a randomization. Okay. And here we’re not using olaparib; we’re using niraparib with abiraterone and this is the PARP inhibitor that is being looked at. So this is an interesting study.

And the first thing is, in MAGNITUDE, there’s no benefit of niraparib in those without the HR mutation. And this is a compositive point of radiographic and PSA. This was presented last year, but I think it’s an important lesson and part of this discussion.

So what you see here in the non-HR-mutated, there is no effect. And this aspect of the trial was just continued in the MAGNITUDE study. But now if you come to the rPFS and you’re looking at the BRCA1/BRCA1-mtuated, and here you can see that there is a clear improvement, a good hazard ratio, 0.53, 0.5, whether assessed by central review of the investigator. So the bottom line is that the niraparib plus the abiraterone makes a difference for those that are BRCA-mutated. I think we’re starting to get a theme here and the BRCA-mutated clearly benefit.

Now, new study. Just presented at ASCO GU. This is the TALAPRO-2. And now we’re not talking about the abiraterone, we’re going to talk about enzalutamide. And we’re not going to talk about niraparib or olaparib, we’re going to talk about talazoparib. And the first thing to note, I just want to mention there’s drug interaction in which you have to use a different dose of talazoparib than you might use in the non-enzalutamide pretreated patient. So you have to pay attention to the doses. And the talazoparib here was 0.5 mg.

Now the primary endpoint, in this case they’re using BICR, the blinded independent central review, here’s the rPFS. And you have a very good rPFS of 0.63, okay. That looks good as the primary endpoint. And, by the way, we’re talking about people with a mixture, some of these are going to have the BRCA, some of these are going to be unmutated, et cetera. So in that mixture you went.

Now the HRR-deficient population is on the left side, and this is going to be predominantly driven by BRCA, hazard ratio 0.46. In the non-deficient, it’s 0.79. And again, this is rPFS. So you’re getting the trend. And it’s got a p-valuethere that’s positive. But we’re not looking at the OS yet. What we’re looking at with OS is these data and so far, hazard ratio of 0.89.

Now, I’ve been part of these discussions, Neil, and I think that there’s an interesting sort of dichotomy. OS is our ultimate endpoint. But rPFS is a primary endpoint. I think we need to look at the totality of evidence. I think we need to look at patient-reported outcomes. We need to look at toxicity. We need to look at the rest of the story. It’s not just about dots on a scan. You need to try to understand who’s benefiting and who’s isn’t. And I’ll simply says there’s a lot of debate on these topics. I don’t have the time to go into all the different parts of the debate, but I think that we’re treating patients, not scans, and that’s very important in my mind. So we need to look at the totality of the evidence and ask whether or not are patients benefiting or not? And in particular, since me — I’m just going to speak for Oliver Sartor for a second — I’m doing genetic testing on every single patient, either tissue or ctDNA or both, is it worth it to treat the patients without a mutation with a PARP inhibitor? That’s the question.

And by the way, the PROpel trial is in front of the FDA right now.

So, kind of summary on the PARP inhibitors just for a brief second. Look, these are not FDA-approved in combination right now. We don’t have the overall survival.

There’s no question in my mind that the BRCA-mutated subsets are substantially positive. And what about this rPFS? The FDA is going to decide. The FDA is looking at some of these data right now. So that’s, I think, important.

DR LOVE: So just a couple of quick follow-up questions. First of all, is the issue of platinum ever going to come back to prostate cancer, particularly in the BRCA patients? This is, again, in ovary they have the whole thing with platinum and then maintenance. I assume these BRCA patients with prostate cancer are sensitive to platinum. Is platinum ever going to come back?

DR SARTOR: That’s a great question, Neil. And you know as well as I do, that platinum has no patent protection, so there’s no sponsor out there who’s trying to take advantage of it. I know that these patients can respond beautifully to platinum because I’ve used it in my practice. And, by the way, sometimes the expensive oral drugs are just not obtainable because of co-pays and other problems that we encounter. So I do use platinum in my practice in some of these patients.

Will it be tested prospectively in trials? I doubt it, simply because the sponsors don’t have an interest in doing so.

DR LOVE: So the other question I want to ask you is, if you have a patient in front of you who’s presenting without a prior history, with metastatic prostate cancer, so hormone-sensitive prostate cancer. Classic situation, who’s got a BRCA germline — say a BRCA2 germline mutation. Putting aside reimbursement, as you look at that patient, when you would like to be able to use a PARP inhibitor?

DR SARTOR: I think I’d like to be able to use it up-front, Neil, because I know those patients are going to be sensitive. And when we can add the PARP inhibitor to a sensitive patient, I think that’s when you get the best benefit. If I’ve got a BRCA2 patient in front of me, I want to use that PARP inhibitor early.

DR LOVE: Yeah, I mean that’s what I figured you probably were going to say. Not that you can do that at this point. It’s just, it seems a shame that you’ve got to wait until, if you have to — if we get to a point where it gets approved, castrate-resistant, it kind of seems a little strange to have to wait for that point, but I guess we’ll have to do it, huh?

DR SARTOR: Well, there’s studies in progress right now. So that question is being addressed in trials. But right now with the reimbursement and the fact that it is an expensive drug, trying to be able to prescribe that drug outside of the current indication, I’ll simply say it’s not easy because of the insurance pushback.

DR LOVE: Yeah. No, absolutely. It’s a kind of interesting situation right now. I would imagine those trials, hopefully they’ll get reported fairly soon, but I don’t know.

DR SARTOR: Well, you’ve got to identify the patients, that’s part of the key the idea of treating all-comers up-front long-term PARP. I didn’t really talk about the toxicity here. It’s a brief talk; I just don’t enough time to cover everything. But anyway, these were all important issues.

DR LOVE: I mean they’re using adjuvant olaparib now in breast cancer. Adjuvant!

DR SARTOR: I’m aware.

DR LOVE: And, of course, mainly much more emphasis on BRCA. All right, let’s get into the really great stuff.

DR SARTOR: Okay. Well, we’re going to move over to the theranostics. You see it. You treat. And I love it! That’s my little slide.

What do you take? A lot of people are trying to sort of understand this. You need, at this point, a cell surface receptor. Okay? You’ve got a receptor up there. And then you have something that will bind to that receptor, that’s a ligand. And you need a linker and you need a radionuclide. And you typically put the radionuclide on with a chelate.

So the idea is targeted radiation. The term I actually prefer is not theranostics but that’s sort of what is out there — the term that I prefer is molecularly targeted radiation.

Now, we have the Lutetium study, the Lutetium-¹⁷⁷-PSMA-617, FDA-approved. Positive study. That’s behind us, okay. So now we need to begin to think about looking forward.

This is the VISION trial that led to the FDA approval, overall survival and rPFS, endpoints both being positive.

One thing that was a little bit interesting, and I’m still trying to fully understand this, is we know that as a whole, that when you have a high SUV, and that’s Standardized Uptake Value, on your PET scan, that you’re going to have more ligand binding and more isotopic delivery. And you can see here for those that are high SUV if there was a stand-out, that these patients’ overall survival was really benefited. But if you fell into the lower 3 quartiles, there was not a lot of difference. And I think this is just an important slide. We’re going to be looking at more and more data about who benefits, who doesn’t, but this was just one little slice that I thought was interesting.

Another thing I thought was interesting, this was presented at ESMO last year, Andy Armstrong, and if you look at the PSA decline at 12 weeks, you kind of know what’s going to happen in terms of survival. And this breakout is either no decline, 0 to 50, 50 to 90 or greater than 90%, let’s just look at the extremes. The greater than 90% is that upward part of the curve, these individuals have a strong overall survival; in fact, this does make up the median. On the other hand, if your PSA is going up, then guess what, you’re not going to do so well and your median survival here is going to be 8 to 9 months’ type thing.

So there’s a big difference between those people whose PSA declined at 12 weeks and those people whose PSA does not decline.

So that’s a lesson from that one.

Now, what I think is also very interesting is on December 5^th, the pre-chemotherapy trial was announced positive.

The bottom line is, PSMAfore trial with the Lutetium¹⁷⁷-PSMA-617 met the primary endpoint for patients who’ve not been previously treated with chemotherapy. And I think we’re going to need to look forward to a future meeting and find out more about that. But it’s important.

There’s another trial out there called TheraP trial. This trial had come out of the Australian Group, ANZUP, that’s the Australian, New Zealand Group, and, by the way, it’s a good trial. These were patients who did not have prior cabazitaxel — by the way, the VISION, 41% of the patients had cabazitaxel — and they selected their patients a little bit differently. They looked at PSMA PET and FDG-PET both, and then they randomized from Lutetium to cabazitaxel.

Now, patient selection is different in Australia. They’re still using 2 PETs. They’re looking for discordancy. And if you look at these patients, say on the left-hand side, you see the PSMA is essentially negative on the PET scan and the FDG is positive, or you look at the brackets second from the left, and you see some PSMA-positivity, but clearly the FDG is picking up dots that the other ones did not. Those patients were not eligible. So they excluded 28% of the patients because of the scans that we’re not using in the United States.

So they had 200 eligible patients. And the bottom line is their primary endpoint was revolving around PSA. Their PSAs were better in terms of decline for those getting Lutetium as opposed to cabazitaxel. But there’s more to the story. When they followed the patients up for survival after 3 years, first of all, these are pretty good survivals. But if you look at the median for cabazitaxel, it’s probably running, why don’t we say 19 months. And if we look into the hazard ratio, there’s no difference.

So one of the things I think we need to take out of this is there could possibly be a class effect. I didn’t show you the rPFS data, but again, the rPFS data looked better with the isotope, but the overall survival was equal with cabazitaxel and the isotope. So there’s a discordance between what you would predict from the rPFS and the PSA declines and the overall survival.

There could be a class effect here that’s important. And I’ve always thought cabazitaxel punched above its weight. I was a co-investigator, a co-PI a long time ago on the TROPIC trial and cabazitaxel did better than expected. Cabazitaxel is a real drug.

Now, side effect profile was very good when it came to the PSMA Lutetium. But nevertheless, that’s sort of the point that survival benefit did not vary. So cabazitaxel is fine for these patients. This is different than VISION. And VISION, 41% of the patients had already been treated with cabazitaxel. And in the VISION trial, the patients were not receiving the chemotherapy because of the standard of care, plus or minus, design.

Synergistic opportunities with radiopharmaceuticals. I’m just going to throw this out. There’s some interesting data that’s emerging from preclinical models on DNA damage repair pathways. Maybe you inhibit it with PARP and then you give the Lutetium, or ATR inhibition you give the Lutetium, or ATM or DNA-PK. And there’s a lot of interesting work going on now and I think we’ll be hearing more about this later. I’m looking forward to seeing the data.

There’s some rationale for antigen release from radiated tumors, maybe synergy with immunotherapy. Maybe not. We’ve got to learn more. That’s all reasonable.

And then sequencing radiopharmaceuticals. There’s a little bit of data, retrospective data coming out of the RALU study. These are patients who got Radium first and then the PSMA Lutetium¹⁷⁷ second. And nothing is randomized here. This is just basically a look back. It’s a patient experience. But what happened is that when you start looking at the overall survival for the patients who received Lutetium, it’s pretty close to what you were seeing in VISION. And these are patients, by the way, who are not typical Radium patients, 33 months from their first dose of radium.

So this is not like the ALSYMPCA trial where you’re talking about the 13-, 14-month stuff. These are 33 months. So these are special patients. But the bottom line is that Radium given before the PSMA Lutetium did not seem to impair efficacy.

Here are the PSA responses. On the left-hand side, all patients, 42%. In the VISION study was 46%. So again, it looks like you might be able to preserve things.

Briefly moving on to targeted alphas. Really super alive right now. Lots and lots and lots of activity.

You see these types of slides you get people really motivated. Here you’re looking at PSAs of almost 3000 and they go down to undetectable. By the way, if you look carefully, the patient on the left-hand side in the pre-Lutetium state, has salivary glands. And you look at the late-stage and you don’t really see salivary uptake and that’s because you probably ablated the salivary glands along the way. So this is great stuff, but we’ve got to work it out in prospective trials going forward.

Chemotherapy — not a lot new, but I’m going to touch briefly on what we call the CABSTY trial presented by Stephane Oudard at ESMO. And he took the cabazitaxel 25 mg/m², not 20 but 25, and compared it to the cabazitaxel 16 mg/m² given every 2 weeks instead of the conventional dose every 3. And what did he find? He found, first of all, if you look at the bottom part, overall survival is about the same. But then you begin to look at the side effects and the Grade 3s and the neutropenic complications where you’re giving q2-week cabazitaxel, you really knock down the neutropenia. It’s only 5.1% instead of 62.9%. And these are patients, I think it’s just a gentler way of giving the cabazitaxel. By the way, there are other studies that looked at it with docetaxel q2-weeks that also looked good.

Docetaxel plus pembro. My friend, Dan Petrylak, presented this at ASCO GU. Nothing. Dead. You don’t need to give pembro in unselected patients in combination with docetaxel. Does not make a difference.

So those are my highlights. I hope you’re able to enjoy the brief overview. Neil, thank you for giving me the opportunity to cover some of these interesting concepts and some of these controversial concepts. So I look forward to how our readers are going to react, and to your questions.