Introduction

DR BRYCE: Welcome to our session tonight, “Consensus and Controversy, Clinical Investigators Providing Perspective on Current and Future Management of Prostate Cancer.”

Here’s our faculty tonight. Introducing everyone. Dr Aggarwal, Professor of Medicine here at UCSF. Next to him, Emmanuel Antonarakis, the Clark Endowed Professor of Medicine from University of Minnesota. Then next to him, Oliver Sartor, the Chief of Genitourinary Cancers and Director of Radiopharmaceuticals at Mayo Clinic. And then Dr Elisabeth Heath, the Associate Cancer Center Director of Translational Sciences at Karmanos Cancer Institute. And, of course, myself, Alan Bryce from City of Hope.

I’ll run through everyone’s disclosures here. And then by video, we’ll have Dr Andy Armstrong and Dr Rana McKay as well.

This activity is supported by commercial support from the following companies. Remember that Research To Practice CME planning committee members, staff and reviewers have no relevant conflicts of interest.

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All right. So for the agenda today, we have 5 modules, as you see there.

The consulting faculty, Drs Armstrong and McKay, are presented here.

Optimizing the Management of Nonmetastatic Prostate Cancer — Dr Aggarwal

DR BRYCE: We’ll go ahead and start with module 1, optimizing the management of nonmetastatic prostate cancer, with Dr Aggarwal.

DR LOVE: Good evening, everyone. I’m Neil Love from Research To Practice. Over the last few weeks, I worked with Dr Andy Armstrong and Dr Rana McKay to make this CME event as relevant as possible. And as part of that initiative, I met with these faculty consultants and recorded a series of questions to pose to the faculty on this stage tonight beginning with this first module and Dr Armstrong, who commented on some of the key issues he’s faced when deciding on a systemic therapy approach to patients with localized prostate cancer.

DR ARMSTRONG: We all know that the STAMPEDE data showed improved cure rates with abiraterone for 2 years with ADT in a very high-risk setting localized prostate cancer, hormone sensitive setting, but many patients may not tolerate abiraterone or not desire to take long-term prednisone or suffer from an abiraterone side effect such as hepatotoxicity or cardiac toxicity.

What would be your recommendation for the extrapolation to other AR inhibitors such as darolutamide, enzalutamide or apalutamide?

I think one of the more exciting areas, Neil, in the field is the movement of these AR inhibitors to earlier disease spaces. Now we’re seeing even improved cure rates in localized high-risk prostate cancer. A number of Phase III studies are ongoing, like enza/rad and DASL-HiCAP and ATLAS that are testing these newer AR inhibitors.

What’s your thoughts about these trials and using these AR inhibitors in clinical practice before we know the results of all of these Phase III trial data sets?

DR BRYCE: All right. So a question for the faculty. Would you extrapolate from the STAMPEDE data and substitute another AR pathway inhibitor, ie, apalutamide, darolutamide, enzalutamide, for abiraterone for a patient with high-risk localized prostate cancer? I guess we’ll start with Dr Heath. How do you feel about that?

DR HEATH: That’s a great question and one I think that we face often in our practice. I always have a hard time extrapolating in this particular group. Even though I recognize they’re very high-risk patients, these drugs are not without their side effects. So I think after a thoughtful discussion, it’s something we could consider. But most of my patients know there’s really no established data that’s going to support that. They like the idea of the combination piece. But I try to stick with the data if possible, and that’s really sticking with the abiraterone as indicated by STAMPEDE.

DR BRYCE: Yeah. Fair enough. Dr Sartor, thoughts on that?

DR SARTOR: I’m going to go with the published data which is abiraterone. But if somebody is abiraterone intolerant, then I would not have trouble switching. So my first choice is abiraterone, but my second choice if there are intolerable side effects is something else. And even though we don’t have the data, we have an awful lot of darolutamide, enzalutamide and apalutamide data that all says they’re going to be very active. So I don’t have that much trouble.

DR BRYCE: Fair enough. Dr Antonarakis, what about your thoughts about ongoing trials evaluating the AR pathway inhibitors for high-risk localized disease?

DR ANTONARAKIS: I think they’re needed and they’re going to provide answers. And I would say that one issue that we didn’t discuss here is reimbursement. And I’ve had a hard time getting anything other than abiraterone in the nonmetastatic high-risk localized. So while darolutamide would be attractive in that setting, it’s very hard to get.

DR BRYCE: Yeah. So you’ve kind of answered the second question. You’re really not using the other drugs in this setting. All right. We’ll move on to the next video here and then talk about the management of biochemically recurrent prostate cancer and the EMBARK data.

DR LOVE: A key issue in this first module is management of M0 disease. And Dr McKay has a challenging case in this setting.

DR MCKAY: He’s a lovely gentleman. He’s 90 years old, but he’s very high functioning. Still driving, manages all of his finances. Had surgery for his prostate followed by radiation after a period of time when he relapsed and then has developed a biochemical recurrence and does have a rapid PSA doubling time. PSA is 11 to 13 oscillating from there, and his doubling time is right around 6 months. And just thinking about what we’re going to do for this gentleman. And honestly, he had a PSMA PET scan. His PSMA PET scan was negative.

DR ARMSTRONG: The most exciting data of the year was the recent FDA approval based on the EMBARK data showing that intermittent potent ADT can provide a significant delay in metastasis-free survival and may be associated with improved survival.

I’m curious as to your approach for this intermittent process and patient selection in general. How do you fit the PSMA PET scan and metastasis-directed therapy into this algorithm? And how would you approach intermittent therapy? Would you just give them a single break? Would you be communicating about multiple breaks over the many years of therapy?

Another one to the panel is that the FDA for the first time approved a form of hormonal therapy that did not have ADT in it, just enzalutamide monotherapy. What’s your approach to following patients carefully with enza monotherapy? What’s your opinion about prophylactic breast radiation? The FDA did not restrict the label based on a PSA doubling time. Are you going to offer this to patients with slightly longer doubling times than was eligible for the EMBARK data?

DR BRYCE: All right. So a whole list of questions there. Rahul, Dr Aggarwal, let’s go ahead and start with you for Dr McKay’s scenario there. What do you recommend for that 90-year-old man with biochemical recurrence?

DR AGGARWAL: Yeah, that’s a great question. This is a challenge because the functional age is much lower than 90 and we always want to look at functional age, not actual age. But you also have to take into account life expectancy and long-term outcomes here with metastasis-free survival, potentially an overall survival benefit with enzalutamide, but that’s many years down the road. So I think it really does come down to that risk/benefit discussion. Even in a really fit 90-year-old, I would worry about fall risk and toxicity with a combination with enzalutamide. So this is really a challenge. I’d probably lean towards single agent ADT. Or if we do the combo, really think about stopping therapy maybe a little bit earlier than they did in EMBARK and doing multiple cycles of intermittent therapy as opposed to just the one that was in EMBARK.

DR BRYCE: Do you think a 90-year-old would ever get intermittent therapy? Once you suppress the testosterone, is it coming back?

DR AGGARWAL: That’s a great question. It’s highly variable. Definitely, older age is associated with lower rates of testosterone recovery in intermittent therapy patients, but it is variable from patient to patient. And even if you’re not getting complete recovery up to 200, 250, if you get some amount of recovery, there is some associated quality-of-life benefit with that. So I think, again, that’s very individualized.

DR BRYCE: Okay. And then I guess we’ll take the next question and keep it with you, Dr Aggarwal. What about enzalutamide after definitive local therapy? Where are you incorporating that? Are you thinking about enza monotherapy? And then intermittent versus continuous, right?

DR AGGARWAL: Yeah. The EMBARK data, I agree with Dr McKay and Dr Armstrong, these are exciting data. The primary endpoint of the study, as I’ll show in my slides, is really the combination versus leuprolide monotherapy, and that’s really what the study was powered on. I haven’t used a lot of peripheral blockade where we use things like high-dose bicalutamide or enzalutamide alone. I think the risk of gynecomastia, breast tenderness is pretty substantial. And I haven’t really personally seen a huge quality-of-life benefit associated with that. So if I was going to use intensification of therapy in this setting, I would opt for leuprolide plus enzalutamide.

DR BRYCE: Fair enough. All right. And I guess the panel, is this group ordering a lot of prophylactic breast radiation for patients on enza monotherapy? Maybe a show of hands. Anybody who orders it? Not too often. It’s out there, but we’re just not doing it a lot it seems like.

DR HEATH: Yeah.

DR BRYCE: Dr Sartor?

DR SARTOR: Tamoxifen or aromatase inhibitors can also work.

DR BRYCE: Yeah. Absolutely. All right. So for this series, there was also survey questions sent out to the panelists in advance. And these are the answers they provided. So the question here was, how would you approach the management of high-risk localized prostate cancer in a patient with negative CT imaging, but a PSMA PET suggesting metastatic disease? And I’ll say my answer here was I would add radiation to the metastatic sites. I would say that my rule of thumb is I stage the patient or I clinically classify the patient according to what I think I would see on conventional imaging, that is CT and bone scan. So if someone has no disease on CT imaging but disease on PSMA PET, I still treat them as nonmetastatic. Having said that, the opportunity to come in with radiation for oligometastatic disease, to me, is an attractive option. But in contrast, and I’ll ask maybe Dr Antonarakis to follow-up because he recommends adding ADT or an AR signaling inhibitor and an AR signaling inhibitor. I always have this bias. If I’m doing radiation for oligometastatic disease, I’m really doing it to be systemic therapy sparing. That’s my hope. So I tend not to give them at the same time. Emmanuel?

DR ANTONARAKIS: Well first of all, I think we all agree that the staging is done by the conventional imaging. So the important point is if conventional imaging was negative in this gentleman, then he has on PSMA PET 4 bone lesions, one of which is outside the axial skeleton, I would not classify that as a high-risk de novo, right? So here, I’m meshing 2 different datasets. I’m looking at the STAMPEDE M0 high-risk localized. And based on that, I’m justifying that 24 months of ADT plus the abiraterone. But I also want to look at STAMPEDE Arm H which is primary RT to the prostate gland which improved survival if you have 3 or fewer mets on conventional imaging. And then the piece with the least data is the metastasis-directed stereotactic as well which I would like to do if the gentleman wishes to be aggressive as possible.

DR BRYCE: Absolutely. All right. And then we’ll talk about Dr Heath then. What was the age of the last patient in your practice with locally advanced prostate cancer and their PSA level? And I’ll stick with you for the follow-up, if you don’t mind.

DR HEATH: Yeah, I think I put 62 with a PSA of 23 there.

DR BRYCE: Right. And then for that scenario, what were the tumor characteristics and what treatment did they receive?

DR HEATH: Yeah. So it was a Gleason 8 (4+4) and clinically, a T3b. So that put the person, unfortunately, in a very high-risk category. So we went with the RT with leuprolide and abiraterone.

DR BRYCE: And then, Dr Sartor, let’s have you walk us through this next question. So a patient who receives systemic therapy for biochemical recurrence after local therapy. What was their PSA and their doubling time?

DR SARTOR: Yeah, and I was looking at a 75-year-old with about a 9-month doubling time, had a PSA of 0.3.

DR BRYCE: Okay. And then how did you treat that patient?

DR SARTOR: One of the problems especially with the EMBARK is we did not take advantage of the PSMA PET scanning which is so, so sensitive for disease. And we’ve really, at least at the Mayo, believed that the ability to discern metastatic disease is strong. We don’t have a lot of false positives. On the other hand, I know that there’s likely to be some disease that is not seen on the PET. How do we handle this? And I think it’s controversial, but what we’ve been doing is using the PSMA PET-directed SBRT. And then the question is, how much of the hormonal therapy do we want to give or spare? And I think there’s a little room here for some patient-centric decision making. And this was a little bit of a weird case, but I actually ended up choosing abiraterone monotherapy for this patient. That’s an outlier. He wanted to get the benefit of the abiraterone, but he didn’t want to get the prolonged suppression that you get with a leuprolide-type agent. So we’ll see. I’m not saying it’s right. I’m not saying it’s wrong. That’s just what we did.

DR BRYCE: Fair, okay. And I’m going to have to move past the rest of these questions just in the interest of time. And we’ll give the mic to Dr Aggarwal.

DR AGGARWAL: Sure. Thanks, Alan. I’m going to run through some slides talking about optimizing the management of nonmetastatic prostate cancer and really summarizing some of the data that we’ve begun to discuss here.

And we’ll really cover 4 topics. How do we risk stratify and stage patients? That’s an evolving topic with the integration of molecular testing and imaging. How do we manage high-risk nonmetastatic biochemically recurrent prostate cancer, biochemical recurrence? And then in the nonmetastatic CRPC.

So really talking about risk stratification, we have our well-defined clinical risk criteria. The NCCN criteria puts this into 4 different risk groups there. You can see based on the T stage, PSA, and Gleason Grade group. It’s worth noting that maybe all these factors are not created equal. And this was an interesting retrospective database analysis that came out last year that really looked at the Gleason group 4 to 5 as being perhaps even more high-risk than those that are solely defined as high-risk based on T stage and PSA. Those patients seem to have worse long-term survival outcomes. This requires prospective validation.

When we add in molecular testing, there are a number of gene expression assays that are now on the market and are validated prognostically to add independent information on top of our clinical risk scoring criteria. So this is the GPS scoring which looks at the gene expression levels of 17 genes having to do with stromal response, androgen signaling and so forth. You can see that across the different clinical risk groups, there’s added information provided in terms of risk of recurrence and metastasis with a higher GPS score with an improvement in the AUC curves as you see on the right.

So this is just a snapshot of the most recent version of NCCN. You can see all the different tools that are there for risk stratification. I think there’s a couple things to highlight here. It clearly extends beyond clinical factors. It now integrates even AI-based evaluation of the pathology, gene expression testing, potentially germline testing. You can see the level of evidence and the endpoints it’s trained on vary based on the test. And importantly, the column of predictive. Not one of the markers is yet validated in terms of deciding what type of treatment should they get. So we really look forward to a lot of the ongoing trials that are integrating these assays and really randomizing patients based on the outcome to one treatment versus another to really move the field forward.

There’s no question that PSMA PET imaging in high-risk newly diagnosed patients improves the accuracy of staging. This was the ProPSMA study published by Michael Hofman and colleagues from Peter Mac where they randomized patients to either conventional imaging or PSMA PET with subsequent crossover and use a composite reference standard to really define the sensitivity and specificity of the PET imaging agent. You can see that both the overall accuracy as represented by the area under the curve as well as particularly the sensitivity of detecting not only pelvic nodal mets, but distant metastases was clearly improved with the use of PSMA PET imaging. And increasingly, we have data that PSMA PET impacts management decisions with radiation oncology as well as potentially provides prognostic information that’s used in part of that initial staging.

This is just a nice meta-analysis looking at all the data with ADT coupled with radiation and really highlights the point that ADT added to radiation improves long-term outcomes for unfavorable intermediate and high-risk patients that are newly diagnosed that are getting primary radiation. And the strength of this analysis is really just the sheer size and number of patients included as well as the long-term follow-up. You see with the question of ADT versus no ADT, there’s a long-term benefit with metastasis-free and overall survival as well as the question of should we give short versus long-term ADT, we see a similar benefit with long-term ADT in the higher-risk patients. Nevertheless, there’s still a lot of variability and I think still a lot of room for improvement in risk stratification. A lot of the trials ongoing are really looking at questions of deintensification of hormone therapy for select subsets that maybe have more favorable molecular features.

So this is just a further question of looking at, well can we further intensify patients? So we know that ADT plus radiation improves outcomes. What about adding abiraterone? And this came up in the case examples here. This was the STAMPEDE study which I think a lot of us are familiar with. This is looking at the nonmetastatic cohort which was a heterogeneous mix of patients with node-positive and node-negative. The lack of metastases was defined based on conventional imaging. And high-risk features here, it’s really worth noting that these were different than the NCCN criteria. These were really high-risk patients that had Stage T3 to T4, PSA over 40 or Gleason 8 or higher. And they had to have 2 or more of those features to really be characterized as high-risk, so this is really high-risk. Though they included relapsed patients as part of the study eligibility, there was actually very few of those patients. So really think about STAMPEDE as a newly diagnosed patient cohort.

So this is the primary endpoint of the analysis of adding abiraterone with or without the further addition of enzalutamide with respect to metastasis-free survival in the high-risk nonmetastatic, so both node-positive and node-negative patients. You can see the Kaplan-Meier plot on the left, the primary endpoint of the study. Unequivocally, there’s an improvement in metastasis-free survival with the addition of abiraterone. If you look at the plot on the top right, there’s really no further improvement with the addition of enzalutamide. The hazard ratios are nearly identical. This just corresponds to some of the data we’ve seen in other clinical settings where triplet therapy doesn’t seem to add much compared to doublet when you talk about dual AR blockade. Overall survival also appeared to be benefited although I think we need longer-term follow-up and further number of events to really get a mature assessment of overall survival. But clearly, benefit in this really high-risk localized group of patients.

So now moving and talking about biochemically recurrent castration sensitive prostate cancer. We know that there are very well-established prognostic criteria including the doubling time, the Gleason grade, the time interval from their definitive local therapy to relapse. And then I think increasingly emerging factors, molecular features, PET imaging which plays a role. This is a seminal paper looking at the natural history of patients with biochemical relapse showing a nice separation in long-term survival curves with respect to PSA doubling time.

And this was a seminal study presented by Juanita Crook and colleagues, it’s hard to believe it’s been more than 10 years, randomizing patients to intermittent versus continuous therapy for nonmetastatic CSPC. It really set the groundwork for how we think about intermittent hormone therapy and the framework for our contemporary studies showing that you can give successive cycles of intermittent therapy. And actually in the study, patients randomized to the intermittent arm were off therapy for about two-thirds of the time and on therapy for one-third. Primary endpoint was noninferiority with respect to overall survival which was met as shown in the Kaplan-Meier curve on the right.

So taking us to our 2 Phase III studies which I’ll talk about first is the EMBARK study. This was a study of high-risk biochemically relapsed patients with a doubling time less than 9 months, no metastases on conventional imaging who were randomized to 1 of 3 arms, enzalutamide plus leuprolide, placebo plus leuprolide, those are both double-blind treatment arms, and an open label enzalutamide monotherapy. After 9 months, if the PSA was less than 0.2, patients could stop and then resume treatment at the time the PSA reached a threshold of 2.0 or 5.0 based on prior surgery or radiation. Importantly, treatment was then continued until metastasis. So this is really like 1 cycle of intermittent therapy. Primary endpoint was MFS in the combo arm versus leuprolide monotherapy.

And to cut to the chase, these are the primary results of the study. So in the top left, you see a clear improvement in metastasis-free survival defined by conventional imaging with the combination versus monotherapy. And the secondary endpoints are shown on the top right in the forest plot. There’s a trend towards overall survival benefit. It didn’t meet the prespecified threshold, but further follow-up is ongoing. Interestingly, with the enzalutamide monotherapy versus leuprolide monotherapy, there also was an MFS benefit. This was one of the key secondary endpoints of the study with further follow-up ongoing with respect to the secondary endpoints.

The safety profile is shown here. Just in the interest of time, I want to point out a couple of things. Clearly, there was an increased risk of — increased grade of fatigue. With the combination therapy, you see a higher risk of falls. And overall, about one-fifth of the patients, 20% discontinued treatment due to an adverse event. So clearly, there’s a trade-off between benefit and safety.

There’s one other Phase III study in this setting. That was a study with triplet therapy versus doublet therapy versus leuprolide monotherapy. Some differences here, this was a PSA progression-free survival primary endpoint really treating patients for a single block of treatment of 12 months and then stopping. Following that, really treatment was per investigator discretion.

In this study, we really compared the doublet to single-agent ADT and the triplet compared to single-agent ADT. Both arms did better with respect to PSA progression-free survival. Follow-up ongoing to really assess MFS. When you look at those 2 curves, really not much benefit with the triplet versus the doublet although the study wasn’t really powered to look at that comparison.

Safety here is really no surprise. There’s a higher rate of hypertension and so forth with the addition of abiraterone without a clear benefit with respect to the doublet.

So just thinking about, what are the current and future directions? What are the other secondary hormonal therapies that we might evaluate in this setting? I think we’re all really excited about metastasis-directed therapy based on metabolic imaging. Can we get away from ADT and really think about some new trial designs that are really ADT-free? And I think there’s a lot of interest and enthusiasm there.

And just to highlight a couple of studies. This is the ARASTEP study, a Phase III study with darolutamide also in a high-risk biochemically recurrent population. A couple of the interesting things here is that they allow a 24-month treatment period and then a PSA — excuse me, an rPFS based on PSMA PET imaging as the primary endpoint. So I think this will be a really nice integration of metabolic imaging as part of this study.

And this is what I alluded to a second ago. This is really an ADT treatment approach. So you take patients with biochemically relapsed disease who have oligomets on PSMA PET, randomize to receive radioligand therapy targeting PSMA plus SBRT based on an interim PET scan versus SBRT alone, so no ADT in either treatment arm. What is the role of targeted radioligand therapy in this setting? I think a lot of interest in seeing these trial results.

So just at the end, we’ll talk about nonmetastatic CRPC. I think we all recognize this is a shrinking patient population with the use of metabolic imaging —

DR BRYCE: You better cut it off.

DR AGGARWAL: Cut it off? Okay.

DR BRYCE: All right. So we’re going to actually — we need to move on to module 2, so just to keep us on track. And we’re all friends here, we all know how this runs. So no problem, Rahul.

Evidence-Based Selection of Treatment for Metastatic Hormone-Sensitive Prostate Cancer — Dr Antonarakis

DR BRYCE: All right, we’ll go on to module 2. We’ll start with a video, as usual.

DR LOVE: The management of men with hormone sensitive metastatic prostate cancer has been dramatically affected by a series of major Phase III randomized trials and the focus of this second module as commented on by Dr McKay.

DR MCKAY: A lot of revolutionary changes in how we manage mHSPC now in the modern era. I think the standard of care now is ADT plus an ARSI, quite honestly. I think you can make caveats for who are the people that need to get triple therapy. We have no data comparing ADT/ARSI/doci versus ADT/ARSI. I think there’s really no role for ADT/doci alone without an ARSI. But in who would you escalate with an ARSI?

And I think the number of patients that I think are getting ADT monotherapy is still pretty high in just routine practice in this setting. There’s 4 ARSIs that are out there that are used, 3 of which have indications to be used without chemotherapy, and then darolutamide is approved with chemotherapy, though is being tested without chemotherapy in the ARASEC and the ARANOTE study.

DR LOVE: What about patients with negative conventional imaging who have mets on PSMA?

DR MCKAY: PSMA PET has been so disruptive. It causes a lot of disruption, and there’s a lot of clinical trials that are looking at trying to better answer how do we integrate SBRT. Not only do we have a new hammer and we’ve got a new tool, we’ve got all these new tools, so we’ve got new nails and new hammers, so we’re like all want to do is just use them all over the place.

DR BRYCE: All right, very good. So a question for the faculty. Dr Heath, we’ll start back with you. Is ADT intensification with an AR pathway inhibitor now the standard of care in this setting? And when combining with ADT for a patient with mHSPC, do you have a preference for a specific agent?

DR HEATH: So no real preference. I think the messaging for everybody is the answer is yes. We need to intensify when appropriate. I think there’s overall survival benefit that’s a potential loss. You don’t want to leave survival benefit on the table if it’s at all possible. I think that messaging is getting out there but, again, until the real-world data catches up and actually shows that that kind of data is being implemented, I think we’re still having programs like this to make sure that word is out. But from a patient standpoint, I think they like the idea that you’re doing more, that there are other things that they themselves can do. I think the messaging, as Rana was saying, with the addition of just docetaxel being not adequate, I think that messaging is out there as well.

DR BRYCE: Yeah, absolutely. And so I’ll remind the audience, please send in your questions through the iPads. We didn’t get to it in the last segment, but we’ll certainly try in each segment. Dr Sartor, the next question. In what situations do you utilize the triplet therapy with ARASENS, the ADT/doci/daro?

DR SARTOR: We’ve kind of divided the world into the de novo patients or the synchronous versus metachronous, metachronous recurring later. I’ll simply say for the de novo high-volume patient, and right now I’m going to use high-volume in sort of a charted type manner, that those are the patients I feel that we’re going to consider the triplet therapy. It’s not for everybody. If you’re low-volume, the answer is no in my book. And if you’re recurrent or metastatic, even high-volume, I think it’s a little more of a discussion. De novo, high-volume, conventional imaging, yes that’s where the default is.

DR BRYCE: Yeah, fair enough. And the third question, I think Dr Antonarakis already answered earlier, right? PSMA PET, but negative conventional imaging. We tend to treat these as nonmetastatic. So in the interest of time, we’ll go on to our next video here.

DR LOVE: A critical issue in the management of hormone sensitive metastatic disease is choice of endocrine partner with ADT. And an important issue in making this decision is the side effects and tolerability profiles of the various options.

DR ARMSTRONG: I’d love to hear the panel’s thoughts about the real-world experience of the toxicities and how you manage these toxicities, for example, cognitive effects with enzalutamide or rash with apalutamide, and mineralocorticoid excess and cardiovascular/hepatotoxicity and steroid toxicity with abiraterone. Do you feel like these are actually major problems for your patients, and what percent of patients don’t tolerate because of these? And do you make choices between these treatments based on age and comorbidities?

A common scenario that I encounter is liver injury from abiraterone and I would be interested to know how the panel manages this, whether you’ve been able to maintain patients on abiraterone who suffer from hepatotoxicity with lower doses and treatment holds. Likewise for enzalutamide, a common scenario is fatigue and cognitive effects. What’s been your approach with dose reductions or giving lower doses longer-term and getting patients through some of those toxicities who are otherwise doing quite well?

DR BRYCE: Emmanuel, what do you think? What about your experience with managing the toxicities of the AR pathway inhibitors?

DR ANTONARAKIS: My initial choice is usually between ADT/abiraterone or ADT/enzalutamide. And I haven’t found that many advantages of apalutamide over enzalutamide. I don’t think there are, in my practice, advantages in terms of neurocognitive or ataxia. I think those are the same. The rash is pretty problematic for my patients when it occurs which we don’t see with enza. So for me, the decision is if they have brittle diabetes, if they have heart failure, Class III/Class IV hypervolemia, edema, I avoid abiraterone in that setting. I would prefer enza. And if a patient has seizure disorder, extreme fatigue already, ataxia, sarcopenia, I would avoid enzalutamide. So in a nutshell, that’s my decision.

DR BRYCE: Yeah. Dr Aggarwal, what do you think? How do patient age and comorbidities affect your choice?

DR AGGARWAL: Yeah, I think similarly to Emmanuel. I usually will choose abiraterone in terms of intensification in the hormone sensitive setting. I’d say it’s probably 5% or less patients where I feel like abiraterone is just contraindicated because of poorly controlled diabetes or significant fluid overload. And then I’m thinking about enzalutamide although there, you have to watch in terms of falls and frailty risk.

DR BRYCE: Yeah, absolutely. All right. So we’ll go through some of these scenarios. So what are the usual criteria, your usual criteria for using ADT with docetaxel and darolutamide for patients with mHSPC? And I’ll just start here. I tend to classify the patients according to timing of disease, so metachronous versus de novo. And then high versus low-volume. And I think of them more or less as being in 3 categories. The metachronous low-volume, for these patients, my default is doublet therapy. No real role for docetaxel. For the metachronous high-volume or the de novo low-volume, these are the intermediate-risk, still most of the time looking at doublet therapy without docetaxel except in higher-risk scenarios often driven by genomics. But then my default for de novo high-volume disease is triplet therapy. In that scenario, and I base this on meta-analyses that we published. Dr Riaz has led a lot of that work. He’s here in the audience today. The question is not, should I give triplet therapy? What I have to justify is, why wouldn’t I give the docetaxel? The default in that scenario would be triplet therapy, in my opinion. And then we’ve got a number of other answers here, but we’ll keep moving on through the rest of these.

Outside of a clinical trial, have you recommended ADT and darolutamide without docetaxel? I guess, Dr Heath, you’re the one outlier. You stick to the data. You won’t do it. How do you see this?

DR HEATH: Well yes, I do stick to the data because I tend to have very complex patients. And when things go sideways, you have to be able to quote why you did something. So if I go off-road, it’s hard to do that. So I really do try my best to stick to the data. I think also just from a reimbursement standpoint, we struggle when you’re kind of going off-road, at least where I practice in Detroit. It’s a little bit more challenging to justify what you’re doing, so they read the notes.

DR BRYCE: Yeah, yeah. Fair, absolutely. All right, next question. I’ll ask you, Oliver. Globally, which comorbidities are likely to steer you away from choosing ADT and abi?

DR SARTOR: Yeah, what I put was liver dysfunction because that’s the one that’s really hard to overcome. Hypertension may not be optimally managed. It could be problematic. But oftentimes, with a little bit of management, you can do that. Hypokalemia, I can fix that. That’s not a big deal. Now if they’ve got significant edema at baseline, I didn’t put that down, but I have to consider that and congestive heart failure are a little more problematic. But the one I cannot fix is the liver dysfunction. I’ve got a guy with cirrhosis right now, and he’s not a good abi candidate and I won’t even try.

By the way, a comment about the diabetes. I might disagree with you a little bit, Alan, on the diabetes. The dose of prednisone is so low at 5 mg, I think the problems with the glucose control are really due to the ADT more than the abi.

DR BRYCE: That’s fair.

DR SARTOR: And that’s just a personal opinion.

DR BRYCE: That’s fair. Yeah, absolutely. Okay. All right. What about comorbidities that steer you away from apalutamide, Dr Antonarakis?

DR ANTONARAKIS: Well the rash is about 15 to 20%. It’s hard to manage. Initially, we had hoped that ataxia would not be an issue with this one, at least that was the party line at first. And the very first patient that I had on the Phase I/II study of ARN-509, which ended up becoming apalutamide, was a 45-year-old American football player. And after 1 week, he fell over. And this was a fit guy with huge muscle mass. And the ataxia is real. It’s not always due to the sarcopenia. There’s a central component to it. And it’s pretty scary when you see it in a young person.

DR BRYCE: Yeah, fair. All right. Dr Aggarwal, what about enzalutamide, same question?

DR AGGARWAL: Yeah, I think it’s similar. I think we’ve touched upon that. The fall risk I think is real. I think it is central. I think the cognitive dysfunction you can see. So one thing we haven’t talked about, the high functioning patients who really have a high cognitive load based on their occupation, those tend to be the patients that notice it the most and where we’re probably thinking about something else to start with first line.

DR BRYCE: Yeah. All right. This is pretty straightforward. No one thinks there’s much in the way of specific comorbidities to steer away from daro. All right. Then we’ll get into Dr Antonarakis’s talk.

DR ANTONARAKIS: All right. Thanks very much. So why is metastatic prostate cancer important? In the US, we don’t think about it much. We think it’s the minority of people that present with de novo disease, but this is not the case in other parts of the world. As you can see in some European countries, it can be as high as 30%, present with metastatic disease. In some Asian countries, it can be as high as 60%. So although the global prevalence of de novo M1 disease is declining in some parts of the world, it’s still an issue, so a global problem.

This slide is courtesy of Neeraj Agarwal and it shows all the beautiful faces of the people that did the key trials going back now 11 years. So the last decade has really given us new information on this paradigm. And I’ll go through some of these trials one by one.

So I kind of thought I would start with the conclusions so those who are falling asleep can forget everything else after this. So ADT is the mainstay of treatment but it’s no longer sufficient, so that’s very important. Secondly, as we’ve said many times today, doublet therapy is the current standard. And it’s doublet containing the ADT and the ARPI. I put that in red. A doublet with docetaxel as its base is no longer recommended. And we’ll talk about why that’s the case. And by the way, it’s been removed from the NCCN guidelines as well. So I can’t think of a single scenario in my practice where we’ll give ADT and docetaxel and omit the anti-androgen. Triplet therapy we’ll talk more about. High-volume and de novo patients. Let’s not forget about radiotherapy to the primary. This might, at least in 1 trial, improve overall survival in low-volume disease, 3 or fewer metastases.

So let’s start with the historical data. This is historical because the ADT and docetaxel by itself is no longer standard of care. But this study opened up the whole field, and also came up with an arbitrary yet very important definition of high-volume versus low-volume disease which we all use to prognosticate.

Now let’s show one slide on the STAMPEDE Arm H. So this was a study that was looking at the use of the best systemic therapy plus radiotherapy to the primary prostate gland. In a post hoc analysis, this was an overall study design, but in the post hoc analysis of low burden defined as 3 or fewer metastases, a little bit different from the CHAARTED criteria, versus high burden, the addition of prostatic radiotherapy improved overall survival in patients with 3 or fewer metastases. So this was the first time I started to think about treatment of the primary in the context of metastatic disease.

This is just a reference slide for those that want to come back to it later, but the bullet points are on the righthand side. The doublet therapy containing an ARSI plus ADT reduced risk of death by 30 to 40%. And then if you look at the bottom right, the triplet therapy compared to ADT plus docetaxel reduced death by an additional 25 to 32%. So this is a compound improvement.

So these are the studies that led to the conclusion that ADT plus abiraterone is better than ADT alone. Study designs are similar for both LATITUDE and STAMPEDE and they both had remarkably similar hazard ratios for improving overall survival between 0.6 and 0.66. And I’ve included the most recent updates on this slide and in the references.

And there are some other partners here, enzalutamide, again enzalutamide in the ARCHES study, an apalutamide. And, again, these are the most recent updates showing a consistent improvement in overall survival with, again, very similar hazard ratios in the 0.6 to 0.7 range with the other anti-androgen agents. So a very consistent message.

Now the triplet therapy. This was the ARASENS study, metastatic, hormone sensitive. These were de novo or metachronous. Had to be candidates for ADT and docetaxel. They were stratified by extent of disease and alkaline phosphatase. Randomized to ADT plus docetaxel versus ADT, docetaxel and darolutamide. So as was mentioned by Dr McKay, the control arm here was not hormone therapy doublet. The control arm here was ADT plus docetaxel. That’s what they were trying to beat.

And the addition of darolutamide in this setting improved survival by 32%.

We then have the 2 important subsets. Some people thought, does this apply to high-volume and low-volume? And it does. And if you look at the low-volume, the hazard ratio is going in the same direction although the curves don’t separate as much. And if you look at it by risk groups instead of volume groups, high-risk being classified as Gleason 8 and above or visceral disease or more than 3 bone metastases, again there were benefits in the high and low risk so that was encouraging.

PEACE-1 is a complicated study. It has a so-called 2x2 factorial design. A European study. These were all de novo metastatic hormone sensitive patients, so all synchronous metastatic disease. The 4 arms, standard of care, standard of care plus abiraterone, standard of care plus radiotherapy, and then abiraterone plus radiotherapy, so answering 2 questions. Does abiraterone improve survival when added to ADT? And the second question, does primary radiotherapy to the prostate also improve outcomes? Halfway through this study, the standard of care changed when docetaxel at that point in time became included in the standard of care and actually mandated. So the SOC, which was initially ADT alone, changed as you can see there in 2017. So of the 1,100 patients, 710 of them in the control arm, standard of care, actually had to get ADT plus docetaxel. And that made it possible to look at the question of triplet versus doublet in the subset of patients who were enrolled after the change was made to the protocol.

So this is showing the patients that were on the ADT plus docetaxel standard of care with and without the addition of now abiraterone. And, again, there is an improvement in not just rPFS on the left, but OS on the righthand side. So this is now a second triplet combination which is ADT/docetaxel plus abiraterone.

High and low-volume metastatic burden went in the same direction favoring a benefit of triplet.

And this is consistent across additional studies. So the ARASENS shows, again, a benefit of triplet. And on the righthand side, a study we didn’t talk about, ENZAMET. There was the addition of a subset analysis because patients were allowed, permitted to have received docetaxel. And those that did receive ADT plus docetaxel as their standard of care who also then were randomized to enzalutamide or not, had a benefit. So 3 consistent studies although the enzalutamide-based triplet doesn’t have the level 1 evidence at this time.

So as we can see, we are extending survival. Again, this is for reference showing that with ADT alone, you extend survival by adding docetaxel, even more so by adding an ARSI. And then the triplet is now giving us a median of about 5 years. This is unprecedented times.

The last question that PEACE-1 wanted to answer was the role of the primary radiotherapy. And this was interesting and a bit counterintuitive. So the addition of primary radiotherapy improved rPFS and, surprisingly to me, time to castration resistance. So radiating the primary source of the tumor delays time to castration resistance.

However, the overall survival in this study, unlike STAMPEDE, even in the low-volume patients, no survival advantage. The interesting thing about this study is less GU events, meaning urinary obstructions, hydronephrosis, other urinary complications. So the urinary tract complications were reduced here even though overall survival may not have been improved.

There are a number of studies here in this space exploring other agents, PD-1 inhibitors, AKT pathway inhibitors, PARP inhibitors, and lutetium. And these studies are likely to change the standard of care again.

And as we’re moving into an individualized precision oncology approach, there might be patients who may benefit from certain classes of these agents based on molecular and clinical characteristics. And we may have the opportunity also for de-escalation of care in these patients. And perhaps not everyone will need doublet or triplet based on biomarker assessments.

So in conclusion, my opinion with rare exceptions, there’s almost no role for ADT alone anymore. Doublet with the backbone being ADT plus ARPI I think is the default for the vast majority of patients. As we mentioned before but it bears repeating, ADT plus docetaxel as a doublet is no longer sufficient in my opinion in any setting. And in those patients who are chemo fit, they should be getting triplet. As was mentioned by Oliver, the clearest benefit for the triplet is the de novo patients and the high-volume patients, so that’s the slam dunk. Prostate radiotherapy in one study improved survival, in another at least reduced GU events. And biomarker treatments may guide us in the future.

DR BRYCE: All right. Very good.

New Considerations with PARP Inhibitors for Metastatic Castration-Resistant Prostate Cancer (mCRPC) — Dr Bryce

DR BRYCE: All right. We’re going to move on to module 3.

Talking about new considerations for PARP inhibitors for mCRPC. And I’ll be presenting on that.

We’ll start with a video here again.

DR LOVE: PARP inhibition is now an approved and widely utilized strategy in both cancers of the ovary and breast. And in these diseases as well as now in prostate cancer, PARP inhibition is moving up into earlier stages of disease.

DR ARMSTRONG: A major breakthrough in 2023 was the FDA approvals of the PROpel regimen and the TALAPRO-2 regimen, so we have olaparib and abi, talazoparib and enza. The niraparib/abi combination got FDA approved.

How are you deciding between these if you have an appropriate patient? Are there patients that have non-BRCA alterations that you consider appropriate for this combination? And then the final question is are there patients without homologous repair deficiencies that you’d consider for an AR/PARP combination like they have approved in Europe?

Would you extrapolate the PROpel and TALAPRO data to be extremely positive in the hormone-sensitive setting waiting for the results of AMPLITUDE and TALAPRO-3 and evoPAR, for example, a new Phase III study? What would be your approach, for example, to a BRCA-mutated patient in the hormone-sensitive setting?

DR MCKAY: There’s been a lot of controversy over how mission critical each of the HRR genes are and actually being an effector of homologous recombination and whether that said gene is actually directly impacting the ability of the cell to be deficient in homologous recombination. And so there’s controversy around ATM, which seems to be more of a sensor of DNA damage as opposed to an effector of DNA damage. There’s other genes as well, PALB2.

So in your clinical practice, how do you reconcile the differences in PARP sensitivity across the different HRR gene sets or genes? For example, with a CHEK2 mutation.

DR BRYCE: All right. So we’ll get into the questions for the faculty here. So the first question, I’ll speak to what Dr Armstrong was asking. For a patient with BRCA mutated mCRPC, how do you choose among the 3 approved PARP inhibitor-based combinations? I’ll say the first point is in my practice, I don’t have that many patients that are hitting mCRPC without having seen one of the androgen receptor pathway inhibitors. That’s probably the biggest issue in terms of, am I going to use combination therapy? My feeling is if someone has already had an ARPI in the first-line setting, then I’m treating them with a PARP inhibitor monotherapy rather than combination. I’m not convinced that there’s value in adding the ARPI for a second step.

Having said that, should I come across a patient who comes into my practice with only having had ADT in the first-line setting. I certainly think in terms of comorbidities, slight differences, we’ve touched on it with regards to the ARPIs and enza versus abi, whatnot. But I would really say we’re a long ways from being able to confidently or definitively say a difference between any one of the PARP inhibitors being better than the other in terms of efficacy. There’s a lot of management I think in choosing the appropriate doses of them all. There’s lessons that we learn in terms of the toxicities of each. So I think that you’ll see evolution in this space quite a bit in the future as we get better with the newer drugs.

Perhaps I’ll ask Dr Heath here the second question. In which situations would you offer one of these combinations to a patient with mCRPC and some mutation other than BRCA?

DR HEATH: Yeah, I think there’s hope when you do these testings that you’re going to hit something. And I still would offer if it’s appropriate, for example, olaparib for HRR mutations with other family members in there. When we get to ATM, there’s a lot of handwringing, mostly by me but still a lot of handwringing. But a lot of them would be like well it’s there, can we not try it, doc? Because then, it’s just the setting up of the what’s next. And the what’s next might be this may not work as well as we would like it to. And then have a strategy to move ahead quickly afterwards. But one of the challenges, I think you mentioned, is just getting the right patient at that right time and coming in with all sorts of different treatments, especially what’s happening around the community. When we get those referrals as a tertiary center, I think it really is a challenge.

DR BRYCE: And where do you stand on the HR wild type issue?

DR HEATH: I’m not there.

DR BRYCE: Okay, yeah. All right. I agree. All right, let’s move on to the next video here.

DR LOVE: As in breast and ovarian cancer, a central principle in the use of PARP inhibitors is prevention and management of side effects, particularly cytopenias and GI toxicity as commented on by Dr McKay.

DR MCKAY: I think one of the biggest things that people encounter with PARP inhibitors is the fatigue and the anemia. So what’s your strategy? Do you tend to be quick to dose-reduce to maintain duration of therapy? We know that dosage matters with PARP inhibitors. We know that the effect is very dose dependent. Or do you try to maintain dose intensity?

There’s a lot of questions that arise with early prolonged use of a PARP inhibitor about risk of MDS/AML down the road if you’re using it earlier on. In the mHSPC setting, for example, where somebody’s hormone sensitive for a long period of time and they can stay on therapy for years on end. What does that look like versus in the CRPC setting where usually people are staying on therapy less than a year?

DR BRYCE: All right. Oliver, how do you typically manage fatigue and anemia associated with PARP inhibitors?

DR SARTOR: Fatigue is really tough, and I’m going to separate it from anemia because they’re similar but they’re not the same. So one of the things that I might think is using things like methylphenidate which can actually alleviate fatigue to some degree. And by the way, anemia is potentially treatable. It might be a little more transfusion oriented than using an EPO agonist, but I’ll simply say that it’s a risk/benefit story as well. Some of the patients have really had great responses such as BRCA2 patients, and you’re really going to work to keep them on. And other people may not be responding as well. And then, I’m thinking about the risk/benefit and how I can best handle that individual patient. Sometimes, it’s a discussion. But the bottom line is individual decision making, risk/benefit ratios, managing fatigue and anemia with what you can as well as dose reductions, all part of the story.

DR BRYCE: Yeah. Fair enough. All right. Emmanuel, what about your threshold for dose reduction?

DR ANTONARAKIS: With BRCA2s, I try not to if I don’t have to. Nausea, anorexia, weight loss because of decreased appetite can be major issues. If the drugs are taken with food or with a snack, the nausea is less severe. Fatigue can be profound in some patients even without the anemia, so there’s a direct drug effect. But again, in these settings, in the first-line mCRPC setting, the marrow is in better shape than in the later lines. So I’ve used olaparib primarily in this setting as opposed to talazoparib, and I think the anemia might be a little bit less with that.

DR BRYCE: Rahul, increased risk of AML/MDS. How do you incorporate this into your decision making, your conversations with patients?

DR AGGARWAL: Yeah, I think it has to be part of the risk/benefit conversation with patients. The problem is that all the trials we have, we know that the follow-up is not sufficient. And this is really under-reported. Early MDS can be very subtle and difficult to diagnose. And we’re not doing bone marrow biopsies left and right in our patients. We’re just used to a certain degree of cytopenia. So I think it is part of the conversation. I do have concerns about a doublet in the first-line mCRPC or even in the hormone sensitive setting. We’re really thinking about years-worth of duration of exposure in a more elderly population than in breast and ovarian cancer. So I think it is part of the conversation as these drugs move earlier.

DR BRYCE: Fair enough. All right then. And Dr Antonarakis, we do have comments from the audience commenting on how you’re channeling Dr Love with the turtleneck. The comments are coming in. So well done, well done.

DR HEATH: That’s good.

DR BRYCE: All right. Let’s go into the faculty responses. What’s your usual approach to mutation testing, well we all agree, don’t we, for possible use of a PARP inhibitor in a patient with mCRPC? Everyone is doing germline and somatic NGS. I don’t think there’s much to comment on here, right? You can’t find what you don’t look for.

In addition to BRCA1/2 mutations, pathogenic variants, what other homologous recombination repair mutations would lead you to attempt a PARP inhibitor for mCRPC? What about LOH? Emmanuel, how do you approach this?

DR ANTONARAKIS: It’s the rare, rare exception but more and more of these NGS reports, if you look hard enough, you can find the genomic LOH. So this means throughout the genome, how much of the genome is under loss of heterozygosity? This is a surrogate for homologous recombination function as a snapshot. There’s a 16% threshold that has derived FDA approval for the ovarian cancer patients with rucaparib. So in prostate cancer, the gLOH score is usually 8 to 9% even with BRCA2 patients.

DR BRYCE: Yeah.

DR ANTONARAKIS: So sometimes, you might have a report and there’s no mutations, and that gLOH score is 30%. I have done that in the past where I’ve treated a patient like that, but it’s the rare exception.

DR BRYCE: Yeah. Fair enough. All right. What about, I’ll ask Dr Heath here, what was the age of the last patient in your practice with mCRPC who received a PARP inhibitor with ADT and a secondary hormonal agent? And what mutation were you treating? And which regimen?

DR HEATH: Yeah. A pretty healthy, pickleball-playing 74-year-old, happy guy. BRCA2, so I did the combo. He wanted to be as aggressive as possible. Very well-informed patient and knew the risks and is actually doing great.

DR BRYCE: Sounds like a pickleball player, right?

DR HEATH: That’s it.

DR BRYCE: Let’s be aggressive. Absolutely. All right. And let’s go on to the next case. Actually, we’ll give this over to Oliver here. A 65-year-old man, germline BRCA2 mutation, mHSPC to the bone, gets docetaxel/ADT and then progresses with PSMA-positive disease. Regulatory and reimbursement issues aside, what did you recommend here?

DR SARTOR: I’d use abi/olaparib. And that’s just based on good data. Whether or not it’s germline or somatic, it really doesn’t make that much difference. And I’ll just simply say I’m comfortable with the olaparib/abi combo and that’s what I trust.

DR BRYCE: Sure, fair enough. All right. Dr Aggarwal, let’s ask you this next one. Again in germline BRCA2, had been on enza plus ADT, now PSMA-positive progression. What would you recommend?

DR AGGARWAL: Yeah, this is really where we just don’t have data with the combination with a second-line ARSI. So abiraterone plus olaparib, we just don’t have that data in prior enza treated patients. And we know that olaparib as a single agent works well for germline BRCA, so that’s why I chose that option. And certainly, familiarity with that agent.

DR BRYCE: Fair enough. All right. Well we’re on time. We’ll get into the talk here.

So as we well know, this is familiar data, reviewing it quickly. We know that now the prevalence of germline pathogenic aberrations in patients with metastatic prostate cancer is going to be something on the order of 10 to 15%, right? And this is why it’s now an NCCN and AUA and ASCO recommendation that men with high-risk, very high-risk or metastatic prostate cancer should have germline testing.

We also think about the somatic side of things. And this is a dataset always worth going back to. This was from the Memorial group and looked at patients with locoregional disease versus hormone sensitive disease versus mCRPC. These are not the same patients, right? These are different cohorts of patients. But it’s looking at how the mutational profile evolves over time and the fact that certainly there is enrichment for the HRR genes as we move from localized disease to metastatic disease in metastatic CRPC. And at the end of it all, what we end up with is about 10% to 15% of patients with metastatic prostate cancer will have germline aberrations in HRR genes and about the same percentage will have somatic aberrations. And if you put it all together, something around 20 to 25% of patients are going to have DDR variants. I exclude ATM. I don’t think ATM belongs in that family. That’s my personal position, but it remains a somewhat controversial position.

When we talk about PARP monotherapy, everyone is familiar with PROfound and with TRITON2. Both very positive studies. Of course, PROfound had a somewhat earlier patient population, some pre, some post-docetaxel. Had BRCA1, BRCA2 and ATM patients. And you see an overall survival signal there, a strong hazard ratio of 0.69. TRITON2 was a single arm post-docetaxel study of rucaparib, so not comparative, somewhat later population. And you can see the difference based upon the genes of the patients, the genes for which the patients were enrolled in the study. No surprise, as always, BRCA shows the best outcome on all these studies when treated with a PARP inhibitor.

But then we got into the era of doing combination studies of PARP inhibitors with other agents in mCRPC. This is always what we do in clinical trials. And so this slide, we won’t walk through it, but it’s just meant to be a reference summary for you of various combination studies that have happened with PARP inhibitors in prostate cancer.

But, of course, the most attention, the most data we have so far is in those 3 combination studies looking at a PARP inhibitor with an androgen receptor pathway inhibitor. And these were done based on preclinical data suggesting crosstalk between PARP and the androgen receptor, really bidirectional crosstalk under which androgen receptor activity would lead to increased HRR activity, but androgen receptor inhibition then would lead to decreased HRR activity and potentially then setting up a scenario for synthetic lethality. At the same time, PARP activity increase AR transcription, PARP inhibition decreasing AR transcription. So really a bidirectional interaction and potential for synergy, at least based upon preclinical data.

So this led us to the 3 studies that we’ve been referring to. TALAPRO-2, as everyone knows, enzalutamide +/- talazoparib. I’m not going to go through all the details. They’re here for you to review if you’d like later.

But unequivocally positive, rPFS very positive. Nothing subtle about the curve. And overall survival also positive. Again, a very good hazard ratio even though the confidence interval still crosses 1.03 — or 1.0 at 1.03.

But the safety data, and we always want to focus on this. As we’ve talked about, the anemia can be very significant with talazoparib. And here is, as I was kind of alluding to, maybe some more thought going into how exactly we’re dosing these patients. I think there’s a significant advantage to oral agents and our ability to finetune the dosing, if you will. But at the end of the day in this study, median dose intensity was fairly good at 83.5%. But the MDS/AML issue is certainly there. And importantly on this study, there was a slight excess in pulmonary embolism on the combination therapy arm.

Here's the breakdown by genes. We won’t go over it in detail. But as always, BRCA1 and 2 really drive the response more than anything else. PALB2 as well. Interesting that CDK12, this is the only study amongst all the studies we’ve had where there’s potentially a positive signal in CDK12 patients. I don’t believe we’ve seen that in any other PARP inhibitor study. And I ask the other moderators — the faculty to correct me if I’m wrong. So that, to me, was one of the striking aspects of TALAPRO.

PROpel, so now talking about olaparib — abiraterone +/- olaparib. Again, slightly differing designs, but I’ll let you review it in detail if you want at a later time.

Positive for rPFS in the HRR mutant population. And a less significant signal certainly, but still a positive signal, in the non-HRR mutated population. And this is, of course, where so much of the conversation and controversy is for the combination studies. What do you with the non-HRR mutated patients?

The overall survival here, positive for the HRR mutated population. We feel quite good about that result. But here for the HRR nonmutant population, no significant difference with the hazard ratio extending from 0.7 to 1.14.

Safety data, again, we always are talking about the myelosuppression with PARP inhibitors. Without question, this is where most of the toxicity is. And you can see the rate of dose interruption or dose reduction being very significant here, right? You’re talking about half of patients. And even with the limited follow-up, a couple of cases of MDS/AML. So we’ve talked about this in the main session earlier today and alluded to it this evening. But, again, myelosuppression, cumulative myelosuppression, MDS/AML, significant management issues for these patients.

Now with MAGNITUDE, again, not reviewing these details at great length. But this was abiraterone +/- niraparib. In this case, given in combination pills. And I will have you note that the gene list for each of the studies can be slightly different, right? And that’s relevant because as the BRCA1 and 2 drive response, and really BRCA2, if you enrich the proportion of BRCA2 on any PARP inhibitor study, you’re going to see a stronger response. And that could lead to differences between studies when we do what we’re not supposed to do and do cross-study comparisons.

So here again, here we’re focusing just on the HR mutated cohort and the BRCA1/2 cohorts. But very strong results, unequivocally positive.

Again, significant degrees of dose interruption and discontinuation and reduction are required when we’re using PARP inhibitors. No real surprises here. Anemia, thrombocytopenia being the biggest toxicities.

Somewhat greater detail. Again, myelosuppression is really what we’re thinking about when we’re trying to manage the long-term of PARP inhibitors. And with PARP inhibitors, you have those patients who can be on, especially the BRCA2, can be on therapy for a couple of years, right? So, again, management of the marrow prospectively is critical.

So I provide this slide for you just as a reference. I won’t go over it. But really thinking about some of the differences and similarities between the studies in terms of outcomes.

Emphasizing here the transfusion rates are significant. And I emphasize this because of the variety in different practice environments where patients were treated with PARP inhibitors. It’s really important to closely manage the anemia and be prepared to transfuse patients. These aren’t like the androgen receptor pathway inhibitors. You can’t just see patients every 3 months, right? They’re going to need their consistent follow-up.

And then just closing then with the ongoing studies in the hormone sensitive setting. Certainly, questions about the increased risk of MDS/AML when you give these drugs earlier. When you give it in settings where you anticipate that the patient should have 2 to 3 years of progression-free survival just based upon the partner drug, never mind the PARP inhibitor, so that prolonged exposure is something we’re really going to have to pay attention to.

So multiple studies including this one, AZD5305 which is a PARP1 inhibitor. So this is an active space. You’re going to see plenty of data coming out in the coming years.

So in summary, without question, PARP inhibitors continue to prove effective in patients with metastatic prostate cancer harboring HRR mutations. Combinations are certainly manageable and effective while the toxicities vary across the different combinations and require careful management. Data in earlier lines of therapy are expected in the near future.

Role of Novel Radiopharmaceuticals in Therapy for mCRPC — Dr Sartor

DR BRYCE: So we’ll go to module 4, the role of novel radiopharmaceuticals in mCRPC.

DR LOVE: In recent years, the development and approval of radioligand therapies has radically changed the management of prostate cancer, particularly the use of lutetium-177 in patients with PSMA-positive disease. Dr Armstrong comments on a number of clinical questions that arise in this setting.

DR ARMSTRONG: Do you use PSMA PET characteristics to identify patients who may do better with this agent than cabazitaxel like in the TheraP study? And what’s your approach to identifying patients who may not be appropriate for PSMA lutetium even though they may meet the VISION criteria?

The second question is how do you image patients after you’ve started PSMA radioligand therapy? Do you follow them with PSMA PETs or conventional imaging? How do you track the PSA and communicate the changing prognosis to your patients based on PSA declines?

DR MCKAY: I had a gentleman who had mCRPC. His PSA was greater than 5,000. He was actually the second patient that we treated here with lutetium, and his PSA went to less than 1 on therapy. And he did phenomenal. We were kind of like rushing to try to get him on therapy. It was really kind of having that okay, we really don’t have anything else. He had a spectacular response, he did well. He went through all 6 courses. I think towards the end, he struggled a little bit with anemia. We had to delay, transfuse him. And he was able to be off therapy for almost a year. Now his PSA is starting to tick back up a little bit. It’s in the double digits. But at the present time, there is no data for retreatment. We saw data at ESMO this year getting presented from the ENZAp trial. And in the ENZAp trial, where they did the combination of enzalutamide/lutetium versus just lutetium, it looked like actually combination therapy did better.

DR BRYCE: All right. So, Dr Aggarwal, we have to get through our questions I guess in one minute here, so maybe you’ll take these for us. Go ahead and walk through. I won’t read them. Go ahead.

DR AGGARWAL: Yeah. So our radiologists will use both the therapy and VISION criteria, so they’ll comment on whether the uptake is good. And that does help us in sort of trying to choose between chemotherapy versus lutetium treatment.

Follow-up imaging, we actually do SPECT CT scans the day after each lutetium dose at our institution which is sort of like a surrogate PSMA PET. And we do get a diagnostic CT with contrast every 2 cycles because you will pick up sometimes some PSMA-negative soft tissue disease, particularly in the liver. And on a very select basis, we have retreated some patients who, as Rana described, have had a great response and limited other treatment options with the second course.

DR BRYCE: Yeah. Very good, thank you. You’ve got the best possible imaging at UCSF, right? You guys can lead the way in this space.

DR AGGARWAL: Yeah, it’s been, the SPECT CT, actually I was a skeptic at first, but I actually have found it to be really helpful in terms of monitoring response and progression in the bone.

DR BRYCE: Yeah. All right, we’ll move on to our next video here.

DR LOVE: Lutetium-177 is a well-tolerated therapy, but the consulting faculty identified a number of issues that require attention during treatment.

DR ARMSTRONG: A challenging scenario that I often encounter, not completely frequently but sometimes, is many of these patients have ureteral obstruction or bladder outlet obstruction. They have catheters. They have nephrostomy tubes. They have stents. They may have impaired glomerular filtration rates and impaired kidney function, and that can be concerning because of the radiation exposure to loved ones who are changing the bags or handling the urine. And so what’s your approach to managing that patient who has external drains or impaired kidney function?

DR MCKAY: What’s the best way to manage xerostomia, 1) prevent it, and 2) ensure that patients — because that could really be a — when it comes on and it’s severe, it can be really detrimental to patients’ quality-of-life. And so what are the best strategies to manage?

DR LOVE: What do you do for xerostomia?

DR MCKAY: Well, one I think it’s guiding patients to constantly be hydrating and flushing. And I think a lot of times it’s saliva generating, like little candies, things like that they can just constantly be stimulating their salivary glands to be producing saliva.

I think the other thing too is dry eyes because their lacrimal glands express PSMA as well, and some people will get dry eyes. So artificial tears, Biotene. Plus/minus on the Biotene. Some people hate the way it makes their mouth feel. But yeah.

DR BRYCE: Dr Heath, how do you approach radiation protection precautions with external urine collection devices?

DR HEATH: That’s a true challenge, I think, that we’re all facing. I have to say our radiation oncology colleagues are really good at educating the patients. Whether they’re actually adhering to said guidelines is a little trickier. So I think that adds to the decision making. We know that they’re just not going to be able to do a great job managing that, and perhaps chemotherapy is the right answer. So I think here, patient selection and understanding that the toxicity isn’t just here’s the drug and here’s what’s happening. It’s a little slightly different for lutetium.

And I just want to jump in from what Rana was saying about the strategies. The dry mouth, dry eyes thing I think is a very real side effect. Everyone tends to play it down because, oh we’ve got the best drug. So I think having that discussion up front, I do the same things that Rana does too. So I’m glad to hear her say that that’s what she does.

DR BRYCE: Dr Sartor, we heard from Dr Small about your decades-long career in radiopharmaceuticals, right? Any pointers here for managing the xerostomia and dry eyes?

DR SARTOR: I think it’s been said well already. And unfortunately, I don’t have much to add. I will say on the prophylactic front, I don’t know what to do. I think the ice packs are not working and I think it’s about moisture and about saliva production. You do your best. You counsel the patient unequivocally. But on the other hand, these are tough issues. And by the way, if we go to actinium, they make it tougher.

DR BRYCE: Yeah, fair. All right. We’ll move on to our third video here.

DR LOVE: Prior to the approval of lutetium-177, the alpha particle, radium-223 was available to treat prostate cancer. And Dr Armstrong is curious how the faculty sequences this agent in patients with bone disease along with lutetium.

DR ARMSTRONG: Here’s a question for the panel about radium. What’s your approach to still delivering radium-223 to your patients? Where does it fit into taxane, cabazitaxel, and PSMA lutetium therapies?

DR LOVE: Which do you use first, lutetium or radium?

DR ARMSTRONG: My default is lutetium. But during the period where we had a shortage, I would use a lot of radium. I don’t think they’re necessarily mutually exclusive because I can give both.

DR LOVE: Any sense of efficacy comparatively?

DR ARMSTRONG: They both improve survival pretty similarly. But in terms of response, the lutetium is great, you get 50% responses, and progression-free survivals of 9 to 12 months. But with radium, the disease keeps marching on so you progress more slowly. There are patients that can’t get lutetium, those with impaired renal function, for example, and those who may not want to have their radiation safety precautions with their loved ones. They can still get radium.

I’d like to ask Oliver here. What are you most excited about for radioligand therapies targeting other molecules besides PSMA? What are we looking forward to in the future? We all worry about lineage plasticity and prostate cancer cells that lose PSMA. So what are you most hopeful for for those kinds of approaches?

DR MCKAY: The nice thing about radium is it’s an alpha particle. It’s a naked alpha particle that goes to the bone areas where there’s bone turnover. That’s where there’s predominant activity. Its side effect profile as an alpha particle is probably a little bit more favorable. It mitigates pain, treats pain. So whether you do it pre or post lutetium, I don’t think we necessarily know the right answer. I think there’s probably a predilection to want to use lutetium because of the fact that it’s treating disease across the entire body.

DR BRYCE: Well, Dr Sartor, they pitched this to you. So why don’t we let you take the questions here. In which clinical situations are you prioritizing radium, if any? And then this question about investigational radioligand therapies, what do you think is most promising there?

DR SARTOR: Yeah, so 3 components here. So the clinical situation with radium. Well first of all, we have PSMA PET imaging today and you really do have an advantage by using the PSMA PET because you exclude those patients with significant soft tissue disease. The pure bone patient, let’s think about things like SBRT. Yes, we can use lutetium. Yes, we can use radium. But maybe we can use combinations as well. But I’ll simply say that with the addition of PSMA PET, we can select our patients maybe a little bit better.

Question 2. We can use — oh, this is the PSMA PET positive, yeah. I sort of addressed that here and so I’ll move on to number 3.

Now investigative therapies beyond PSMA. Okay. So we don’t have a lot of data. What I’ll do to answer that is watch HK2. Let’s just watch HK2.

DR BRYCE: Okay. All right. So we’ll get into the faculty questions here. So we’re going to talk about the last patient in your practice with mCRPC who received lutetium. What prior treatments did they receive, Emmanuel?

DR ANTONARAKIS: Well at the beginning, these were the end-of-life patients because they were second, third, fourth line. So the example that I gave was a 78-year-old who was fit enough to go through abiraterone and docetaxel then darolutamide and had a PSMA avid scan with uptake above the liver and no metastasis in the liver, so he was an ideal candidate.

DR BRYCE: All right. Let’s leave this question with you as well, Emmanuel. A 65-year-old man receiving ADT and abi/pred for mHSPC now has PSMA-positive progression, no HRR mutations. Where would you go with this patient and how do you reason through it?

DR ANTONARAKIS: Yeah. At the present time, we don’t have a label for lutetium-177-PSMA-617 in the pre-taxane situation. That may change in the future, but not right now. And if this patient had received a triplet containing docetaxel, my answer here would have been likely cabazitaxel.

DR BRYCE: Yeah, okay. All right. Let’s go with Dr Aggarwal. Regulatory and reimbursement issues aside, what do you generally recommend first for a patient with PSMA-positive mCRPC? Is it chemo or lutetium?

DR AGGARWAL: Yeah, it’s similar to the last scenario. Right now, we know that it’s approved post-taxane and we don’t have head-to-head data showing that there’s a survival benefit with lutetium over chemotherapy, so I think those things drive me towards thinking about chemotherapy. There clearly are toxicity differences and a QOL advantage, at least based on the TheraP study with lutetium versus cabazitaxel. So I think you clearly can see sort of the 2 answers there.

DR BRYCE: Yeah. All right. And then not a lot to say here, everyone agrees we generally prefer lutetium over radium. And we’ll wrap up here. Just overall, most of the panel thinks that xerostomia is not very or only somewhat problematic, right? We talked about the strategies. I don’t think a lot of surprises here, right? It’s a lot of supplements, things that will stimulate saliva production. Dr Sartor?

DR SARTOR: All right. Thanks, Alan. And I’ve got a big challenge here because I’ve got 8 minutes and I have too many slides. But Neil made me do it, I promise.

When we look at theranostics, it’s a pretty simple concept. I don’t like the magic bullet part. I didn’t put that. This was a figure from a manuscript. But nevertheless, radionuclides can be targeted to receptors by taking a ligand, having a linker, putting the radionuclide on, and then you can potentially either image or treat, and that’s the concept.

So when we begin to look at the data, I think the VISION trial really set the stage. And this was in the post-therapy, post-docetaxel, even post-docetaxel/cabazitaxel setting, 2:1 randomization and was standard of care +/- lutetium, which standard of care did not include chemo unlike the TheraP trial which was randomized against chemo, by the way. rPFS and OS both present.

And this was really the critical figure out of the New England Journal. And what I’ll say is this led to the FDA approval, so this is really, really important. But I think most people know this. This not new news at all.

One of the things that was being asked by Andy Armstrong a bit earlier is, what about sort of within the VISION criteria who might do better than others? And you can look at the PSMA PET and then make some sort of prediction like the overall survival. That curve on the lower left is really looking at the hazard ratio between the 2 arms. Lower hazard ratio, of course, is better for lutetium. And you can see when you start having higher SUVs, that you do better when you give the lutetium. Now this is SUV^mean and it’s not so easy to calculate, but it turns out that SUV^max is a pretty good surrogate. So find those hotspots. If they’re really hot, you probably have a good lutetium patient.

Now we put together this nomogram and this was presented at ASCO by Ken Herrmann. And one of the most important parameters is that SUV uptake. But guess what? Some of these old, familiar parameters like hemoglobin, if you’re very anemic, if you’ve got a high alk phos, if you’ve got a high LDH, you’re on opioids, other parameters will fit into the survival calculation. This has now been submitted for publication, so we’ll see what happens.

Now PSMAfore is a pretaxane metastatic CRPC study. This was presented at ESMO. And what I’ll say is that it was a little bit different than the use of the VISION study because crossover was allowed. In the VISION study, there was a lot of problems with patients in the control group because everybody wanted to get the lutetium. Well here’s the rPFS analysis for PSMAfore, and it’s good. I think it’s good. You’re basically more than doubling the rPFS on median and hazard ratio of 0.43, positive, no doubt about that.

But in the intent to treat overall survival, there was no difference in the survival. And I think that’s because 84% of the patients actually crossed over. So if you had progressed on the ARPI arm by BICR, you had to progress by BICR and be asked to crossover, you could. And 84% of those patients crossed over, so I think it’s a big issue.

Now I don’t have a slide on the PNT2002. That’s the PSMA I&T lutetium, not PSMA-617 lutetium. There is a press report. And I thought I could say that the bottom line is we have a difference between 6.0 in the control arm which is an ARPI versus 9.5 in the PSMA I&T lutetium. That hazard ratio is 0.71, different than the hazard ratio below 0.5 in the PSMAfore study. We haven’t seen the data yet, so we’ll just have to wait.

ENZA-p takes a different approach. This is enzalutamide +/- lutetium. That, by the way, is Emmett. And I’ll say that the PSA response rates were spectacular. If you look in the PSA 50 when you use enza and lutetium together, 93% of the patients had a 90% decline — I’m sorry, a 50% decline. That is just spectacular. And 78% had a 90% decline. That is really good PSA. But the studies are compromised because you can’t quite get the rPFS and OS too soon, so we need to know more.

PSMAddition used the ADT/ARPI, ARPI of choice, +/- the lutetium. And this is a hormone sensitive, castrate sensitive patient population. It’s also going to crossover. We’re just going to have to see how it works out. But anyway, that’s underway.

And then this is one I actually kind of like. This is PSMA-DC. This is a little bit similar to the trial that was presented a little bit earlier by Dr Aggarwal. But now, we’re taking the PSMA PET positive oligometastatic disease, hormone sensitive, doing SBRT +/- lutetium. This is not a Phase II. This is a Phase III. Has an FDA approval endpoint with MFS. This could change practice. We’ve just got to get to the end and see.

Now targeting DNA damage, well that might be important. And if we look at data from Shahneen Sandhu last year at ASCO, she showed some pretty interesting results for the combination of the lutetium and the PARP inhibitor, in this case, olaparib. We need to see more, but it’s interesting.

And immunotherapy might have synergy. Lots of handwaving. We stand here right in front of Rahul. So thank you, Rahul, for providing this particular publication. And I’ll simply say I thought it was pretty interesting. Single-dose lutetium and pembro. Need more data. But guess what? Provocative. I liked it.

Alpha particles, we like those. Yes, radium. Actinium, lead. Also, astatine-211. Lead-212, you’ve got to watch that. That’s an up-and-comer.

Big alpha particles, big and bad. Little beta particles, bad but not necessarily big. So there’s a lot of differences and the alphas are probably going to be better.

We have radium leading the way, way back in 2013, a long time ago. We also have Phase III with radium. In this case, we have enzalutamide +/- radium in a Phase III trial. Watch for results maybe later this year.

The DORA trial is going to be using docetaxel +/- radium. Still in working order. Not yet completed.

And then the AlphaBet trial. AlphaBet is a combination of lutetium, in this case, PSMA I&M, with radium, okay? Might be interesting. So we’ll just have to look at the data.

And then the BAT-RAD. This is the one I kind of like. It’s bipolar androgen therapy and radium. I will just say wrap your head around that for a little bit. It’s a paradox. But guess what? It might be interesting.

Metastatic hormone sensitive prostate cancer, PSMA-actinium, PSMA-617-actinium, and no hormones. How about that? I’m jealous.

Metastatic prostate cancer, genetically heterogenous disease. Radiation can kill them all. Put that alpha particle in the right spot, you’re going to kill it.

And with that, I made it. I even had 10 seconds to spare.

DR BRYCE: Good job. All right. Thank you very much, Dr Sartor. I think we’ve got some time, actually, do we have time? We have time for a couple of questions here. So let me get to some audience questions.

All right. So let’s ask Dr Sartor, do you have a PSMA SUV cutoff for not pursuing lutetium in clinical practice?

DR SARTOR: The answer is no. I’m always thinking not only about the use of lutetium, but other agents. Sometimes, your hands get forced. You’ve had abi/enza. You’ve got docetaxel, cabazitaxel. You take a risk with that patient. If you have an alternative and say cabazitaxel has not been used, tolerated taxane well, good response to initial taxane, I’ll simply say that you do have choices. You don’t have to feel obligated. You can give cabazitaxel first and potentially follow-up with lutetium. We have activity there. And I don’t have an absolute cutoff. All the cutoffs work that we used in the VISION trial. And when you have alternatives, then you might choose them. When you don’t have alternatives, well that’s different. Then we have to go with that we’ve got.

DR BRYCE: Fair. Emmanuel, how about you? Would you offer lutetium to a patient with a PSMA-negative lesion?

DR ANTONARAKIS: No.

DR BRYCE: No? Nice and simple. Dr Antonarakis is very direct.

Promising Investigational Approaches for Patients with Prostate Cancer — Dr Heath

DR BRYCE: All right. We can get started on our next segment then.

DR LOVE: There are a plethora of new agents and treatment strategies being evaluated in the management of prostate cancer, and one important area is the use of checkpoint inhibitors, which generally has been disappointing outside of patients with mismatch-repair deficiency.

DR MCKAY: IO monotherapy in an unselected population in prostate cancer just has not worked at all. I think the atezo combo data, cabozantinib has a long history in prostate cancer dating back to the original COMET studies. Hopefully, they will be presented at a forthcoming meeting. We saw in a press release that the trial was actually positive for its primary endpoint of rPFS, and so I think it’s going to be really important to try to understand what does this data look like. But I’m excited because it’s a new mechanism of action.

Abemaciclib is being tested in the context of 2 large Phase III trials, CYCLONE 2 in the M1 CRPC setting in combination with abi, and CYCLONE 3 in the mHSPC setting in combination with abi. So I think everybody’s eager to see the results of those studies. Thinking about the different cell surface markers in prostate cancer, DLL3, and STEAP, others. There’s bispecifics. AR degraders and different hormonal agents that target upstream to abiraterone.

I would ask the faculty, what are you most excited about that’s being developed? And if you had to pick the next approval, which one would it be? What class of drug is it going to be that’s going to get approved in the mHSPC setting?

DR BRYCE: All right. Dr Heath?

DR HEATH: Right. Well I think there’s no great answer for that other than we haven’t cured anyone yet, so there is still lots of room for investigational strategies. I know we’re going to talk about some of the ones that Rana had mentioned. But I think for the audience, it’s just important to know why we’re there. Sometimes, we go into these meetings and it’s the, oh by the way, here’s a trial of X, Y, Z drug and we’re not understanding really why we’re pursuing that. So what I’m really hoping is just that the ability for these drug trials to complete in a timely way because the landscape keeps changing so quickly, I think that’s really the main challenge. As I will mention in this upcoming talk, there’s over 800 trials now accruing in prostate cancer, if you go on clinicaltrials.gov. So pick one, any one, and it might be right. And, of course, every strategy is we’re going to get at it. But understanding the heterogeneity of this cancer I think will really help us figure out what’s the next one if we can stay still long enough to know where to put that in the ground.

DR BRYCE: Okay. Dr Aggarwal, what are your thoughts? Recent data about the combination with cabozantinib and then kind of separately to the use of CDK4/6 inhibitors in prostate cancer.

DR AGGARWAL: Yeah. And I think the data with atezo/cabo was interesting. I think it’s, you know, it met the primary endpoint of rPFS. High-risk population, a lot of visceral mets, pretty inactive control arm with a second ARSI at a higher-risk than typical study. So I think you could certainly challenge the control arm. I liked Ken Chi’s discussion. I think he hit the nail on the head. I think we need longer follow-up to really understand the OS benefit if there is one. And we still don’t have a clear sense of the contribution of the individual components there. Is there a tail on the curve that suggest that atezo is doing something? I think we still need further follow-up.

With the abemaciclib and the CDK4/6 inhibitors, I think the jury is still out. There’s some preliminary data. I know there are multiple Phase III studies underway. And so I have a healthy degree of skepticism, but we’ll see where those trials land.

DR BRYCE: Yeah, fair. Okay. All right. Let’s go to our second video here.

DR LOVE: And finally, Dr Armstrong has both a practical clinical question and one relevant to ongoing research, namely the role of further endocrine treatment in a patient with disease progression on an AR inhibitor and ADT.

DR ARMSTRONG: What is your approach in practice to offer a second AR inhibitor even though the efficacy seems quite diminished compared to other available therapies? And do you think we should have control groups that have a second AR inhibitor in future trials?

For Dr Antonarakis is a question around AR-V7. What’s your practice about ordering that test, whether it’s the Hopkins or the Epic Sciences assay? In conjunction with standard germline and somatic testing, do you find that it adds any value to the standard commercial assays that we all order?

Maybe I’ll ask this to Alan. What’s your feeling on the CAPItello study and PTEN null patients for abi plus capivasertib? And what’s your feeling in general about some of these oral targeted agents like cabozantinib in this setting?

DR BRYCE: All right. We’ll start with Dr Antonarakis. You want to talk to us about AR pathway inhibitor sequencing in AR-V7?

DR ANTONARAKIS: So the Canadian study led by Kim Chi and his group showed that there is some activity with enzalutamide after abiraterone but not the inverse. And so if the first ADT that the patient receives, let’s say in conjunction with abiraterone, as a 4 year response with a very slightly rising PSA, you want to do something, there’s no symptoms, PSA is the only measure of disease progression, it will be quite reasonable in that setting to use enzalutamide as a next step. So I wouldn’t go as far as saying that it’s unethical to do a back to back ARSI. I don’t think it should be the control arm of clinical trials moving forward. There were reasons why that was done up until this point.

You know, my dream for AR-V7 was to determine a biomarker that can help us select between AR directed therapy and chemotherapy at that first line mCRPC setting and clinical trials like the CARD study have made AR-V7 a bit less relevant because irrespective of a biomarker in that setting, cabazitaxel was the clear winner in a patient who had received prior AR-directed therapy and in that particular study also docetaxel. So I think its utility has declined over time and I’m ordering it a lot less, if at all these days.

DR BRYCE: Fair. All right. And then Dr Armstrong pitched the question to me, talking about the other oral agents, capivasertib, cabozantinib. I’ll say I’m relatively underwhelmed by the data so far. Modest PFS benefits aren’t, I don’t think, enough to really change practice. Especially we look at the cabo data today, the difference of 1 prespecified follow-up period for imaging. A 2 month difference is really likely to be an artifact of trial design, right? Two months, 8 weeks, is just the interval between scans, assessments. If the study had been designed slightly differently that 2 months could look like 2 weeks for all we know. I wouldn’t get too excited yet. I really think we need to see more long-term follow-up with these agents before it can be convincing.

All right. We’ll move into the scenarios then. So we’ll start, Oliver, with you. What was the last patient you enrolled in a clinical trial who had mCRPC?

DR SARTOR: Yeah, so a patient who had already had lutetium started to fail. You know, the whole issue of being able to repeat the lutetium is just, say, problematic. And I actually referred the patient to a trial to enroll on Actinium-225 PSMA-617.

DR BRYCE: All right. We see a lot of different studies listed here. So, again, as Dr Heath was mentioning, there’s a lot of studies going on in prostate cancer, a lot of reason for optimism moving forward.

Dr Heath, what do you think with the emerging data from the CONTACT-02 study? In which situations, if any, would you consider cabo atezo?

DR HEATH: Yeah, well, you know, we had to fill this out before the presentations today.

DR BRYCE: That’s right. Now we’ve seen it. That’s why I said TBD, right?

DR HEATH: Right.

DR BRYCE: But now we’ve seen it so you can amend your answer if you want.

DR HEATH: Yeah. I mean, I think it really is TBD. You know, it’s an intriguing combination but it’s far from a slam dunk. So, I think we just need to wait to see what happens.

DR BRYCE: Yeah, yeah. Fair. Okay.

All right, let’s see, Emmanuel, do you believe 1 or more of the CDK4/6 inhibitors will someday be endorsed for use?

DR ANTONARAKIS: There’s a rationale there. We do need to remember, though, that there has been a small randomized Phase II, led by Maha Hussain, with palbociclib with ADT in that HSPC setting. That was a negative trial. It was small. So I would say healthy skepticism. But some patients, yes.

DR BRYCE: Yeah, fair. Okay. Dr Aggarwal, you think no?

DR AGGARWAL: Yeah, I mean, I think it’s sort of trying to have a crystal ball but I think that, given that negative trial — now that was palbo. Maybe there’s a little bit more single agent activity with abema and then you can get patients on longer. We did a study with docetaxel plus ribociclib and didn’t see a huge signal there. But, given the data in breast cancer I think there’s a lot of rationale to combine with a hormone receptor blocker and I think we’ll see where the data goes.

DR BRYCE: Yeah, all right. And Oliver, what types of tolerability issues do you anticipate with the CDK4/6 inhibitors?

DR SARTOR: You know, I’m a little worried. There’s a pretty significant GI side effects and low blood counts that have to be taken into account. And right now, we have the risk benefit ration, I’m not sure it’s going to be improved in prostate — this class of agents will be approved in prostate. But, let’s get the trials and let them read out. Then we’ll know. We don’t have to conjecture.

DR BRYCE: Yeah, fair. Okay.

All right, Dr Heath, what investigational approaches are you most excited about here?

DR HEATH: Well I think there’s a new area of agents known as bicyclics or bicycles, that’s really emerging in space, very intriguing in terms of concept of a new drug. I think the PROTACs are still in the game. I think as they get better and much more fine-tuned, and we know exactly which mutation is going after that would really actually be quite intriguing. And I think BET inhibitors are still in the game as well. I know that’s been around for a little bit but there are newer agents that are showing more promise, another generation again. So, we’re learning but I’m encouraged.

DR BRYCE: Yeah, yeah. I agree. All right. All right, Dr Heath.

DR HEATH: Okay. Well I’m taking us — I’m the closer. Here we go.

So I think part of the discussion today about CONTACT-02 is why? Why are we sticking these 2 agents together? And it really comes down to this idea that we all recognize prostate cancer has an immune suppressive tumor marker environment. So if we really dig deep as to the why, when we’re looking at Tregs and the M2 macrophages that seem to pop up in all the wrong places, and CD8 T cells, they just do worse. Patients do worse. And I think that the idea of promoting an immune-permissive tumor marker environment is a strategy, and that’s 1 that many of the other trials that have been in play have really tried to capitalize on. As Rana said, we’re, I think disappointed with immune checkpoints that seems to work in every other, and as GU oncologists, certainly has its role in bladder and in renal cancer. But in prostate cancer it’s a bit of a letdown. The idea of all of these receptor tyrosine kinase inhibitors kind of improving and showing its merit in preclinical studies, have really sort of continued to support cabozantinib, because cabozantinib, with a lot of the emerging data, now I think pretty well established, this is a drug that, against TAM, promotes this immune-permissive environment. So it kind of makes sense, perhaps, that 1 would put both of these together.

So how did we lead up to CONTACT-02? Well, COMET-1 was — many of us, I think, participated in this large Phase III of cabo versus prednisone and that was a big disappointment with having no overall survival benefit. But I think if you look at those with visceral metastasis there were some hints and of course a higher OS rate.

Moving on, there was COSMIC-021 which was a Phase Ib. And that was a study that had just multiple cohorts. So lots of us put renal and prostate patients and so on. And specifically though, in Cohort 6 it was really looking at the metastatic castrate resistant patients and these were folks who had a prior NHT. And when you start to see some of these numbers you say, well it’s small numbers but your overall response rate is 32%. And, what, we have 2 patients with a CR. You start to get a little excited that that’s more than I think what you were hoping to see and perhaps we were having to doublecheck that that wasn’t maybe the renal cohort doing that versus the prostate cohort.

So, as we’ve learned today, from Neeraj’s presentation, I think the Phase III data that was reported is quite provocative. You know, when you’re really looking at the patient population, it’s reasonably early. I mean, it’s 1 prior NHT. We’re all stuck in this hole where patients have been treated with this doublet and then, uh oh, what’s next? And I think a lot of the discussion today was this idea of, you know, we’re still a bit puzzled as to how to integrate it. But with all the drugs talked about today, there’s maybe 1 or 2 of these lines of therapy that many of the patients around the world get. So although we’re talking about 5 or 6 or 7, that is not the norm. So I think getting it right right away and identifying the patient is key.

So here, this is cabo plus atezo versus the second line NHT. And I think we’ve heard from all of the discussions and perhaps a little on Twitter as well, that maybe that’s not the right control arm. But it is what it is and I think it’s 1 where at least in the past it was reasonable. And here’s the results of the PFS. And as I think Kim Chi gave a very elegant discussion, and Alan as you said, it’s sort of 1 treatment cycle away. So do I like to see curves where I could see the separate curves? Of course. Do we need to know more? I think so. So this has really been, I think, a very robust discussion all day today about this. The interim OS is the interim OS so I won’t beat that up to much other than that’s what we need to follow, then just see where that lands. Would that change my standard of care today? For me, that’s a no. And I think that’s sort of the general consensus but digest the data as you can.

We just talked about CDK4/6. So these are, again, cyclin-dependent kinases. They’re enzymes that function in the transition of G1 to S. So in the cell cycle, they play a really critical role because these kinases are activated when they bind to the regulatory proteins and that’s what’s known as cyclin. So once they’re activated, they phosphorylate the retinoblastoma protein or Rb, and then that then releases a particular transcription factor and then off you go into progressing into the S phase. So it kind of makes sense if we target this that we would sort of stop the proliferation of cancer cells. So, yep. And in breast cancer it works great. Those are the 3 drugs that are already FDA approved, so really important.

The AR acts as a master regulator of this G1-S progression. AR can activate CDK4/6 and so they’re also direct transcriptional targets of c-Myc which is not our friend in mCRPC. And the bottom line is there’s enough scientific rationale to really investigate these agents in mCRPC patients.

So CYCLONE-1, this is the study design. Again, it’s the same group of after 1 NHA. But, this is a group that has had 2 taxanes, so a little bit more heavily pretreated. Here’s the treatment. Here’s the endpoints, and these are the results. So, again, small study. Median age here is 68. Your PS is 1. But 47% of these patients, although it’s only 44 patients, had visceral metastases, 28% with liver metastases. The primary endpoint really was not met. So it’s, I think, disappointing. You’re looking at a median rPFS of 2.7 months. And then the Grade 3, as we just had mentioned in our poll. These are real, with neutropenia and anemia and lots of GI issues. So abemaciclib was modest but okay.

So then you say, well, is there other, or are there other investigations in this, and there are. So just be aware that there is CYCLONE-2 and this is now done in mCRPC. You can see all of the complicated, sort of Part 1 lead-in. There’s a Part 2 as well as a Part 3 with all of the different arms. There’s also CYCLONE-3. So there’s 2 more to be aware of. This 1 is in metastatic hormone sensitive patients and it’s the abemaciclib plus abiraterone versus abiraterone plus placebo. And I think to get these kinds of studies done it has to be in this kind of setting where it’s a global study. But, what’s important for all of you to know is just, this is going to finish, you’re going to get an update, and now we’ll know why there’s a scientific rationale for that.

And these are all of the other trials that are all in play, to keep an eye on, that are in this pocket of drugs. And we just mention again, the third agent, capivasertib. This is the whole AKT, PI3K signaling pathway and I think there’s enough scientific rationale. The study to watch out for here is ProCAID. So capivasertib is an inhibitor for all these AK3 isoforms and it’s a Phase II trial. And here’s the results where 150 patients were enrolled and you can see the numbers here. Interestingly enough, if you’re looking at this — and I’ll just move this along. There was an updated overall survival benefit showing that, if you actually added capivasertib to docetaxel in this group you might have an improved survival. So, intriguing. I’m personally not sure what to do with that data myself. But there are other trials that are also in place that will, I think, help us make a decision on how to insert that information. And, as I mentioned before, there are 877 interventional accruing trials on clinicaltrials.gov. So please try to enroll your patients in trials whenever possible.

With that, we will thank you all for your attention this evening. Thank you.