Year in Review: Clinical Investigators Provide Perspectives on the Most Relevant New Publications, Data Sets and Advances in Prostate Cancer (Webinar Video Proceedings)
Year in Review: Clinical Investigators Provide Perspectives on the Most Relevant New Publications,
Data Sets and Advances in Prostate Cancer Emmanuel S Antonarakis, MD Andrew J Armstrong, MD, ScM Proceedings from a webinar featuring key clinical presentations and papers in prostate cancer. Featuring perspectives from Drs Emmanuel S Antonarakis and Andrew J Armstrong.
Introduction DR LOVE: I’m Neil Love from Research To Practice and welcome to Year in Review as today we focus on new data sets from this past year affecting clinical algorithms in the management of prostate cancer. We have an awesome faculty today, Dr Emmanuel Antonarakis from the Johns Hopkins Sidney Kimmel Cancer Center, and Dr Andy Armstrong from Duke University — Duke Cancer Institute Center for Prostate and Urologic Cancers. If you’re into audio podcasts, check out our new series Oncology Today, where we do interviews with clinical investigators and a recent one we did in GU cancer with Dr Kamat from MD Anderson. Lots going on in bladder cancer nowadays. But today we’re here to talk about prostate cancer, particularly what’s happened over this past year. And the way we put this together today, first of all, I met with both of the faculty separately. We recorded an extensive presentation and interview going through all this in detail. Today is really just a tasting menu to get you interested in this and some of the questions that have been addressed in the key papers this year. We picked out 11 topics that we’re going to try to get through briefly in this hour, starting out with some related to local therapy and then metastatic disease. These are the questions we’ll be discussing today with the faculty. And just to talk a little bit, this is from Andy’s presentation, where he summarized some of what he thought were the key developments this year, particularly we’re going to talk about survival data that's been seen now both in the M0 and the metastatic hormone-sensitive situation. More data on cabazitaxel as third-line therapy and of course precision medicine and the use of PARP inhibition. And so, Emmanuel, GU oncology now between what’s going on in bladder cancer, renal cell and prostate, to me one of the hottest areas in oncology. I hear oncology fellows say they want to go into GU oncology. Lots going on, particularly in this last couple of years, Emmanuel. any thoughts about reflecting back on what’s been going on with clinical research in prostate cancer, Emmanuel? DR ANTONARAKIS: Well, the genetically targeted therapies have been lagging behind. We’ve had the AR as a target for many years and then we kind of ignored everything else. And as the genomics matured and our understanding DNA repair become better and our understanding the PSMA target, we are now, I think, scratching the surface of precision oncology in this disease. DR LOVE: Absolutely. When should postprostatectomy radiation therapy generally be recommended? DR LOVE: And now we’re going to get into some of these questions. We’re going to rip right through them, starting out with this one we weren’t even aware of until Andy sent us the slides. So, Andy, the question is post-prostatectomy radiation therapy. Amazingly, we saw 3 trials mature all at the same time. Andy, what’s the bottom line? DR ARMSTRONG: Bottom line here, Neil, is that for men who have had a PSA recurrence after radiation, your survival and your risk of further metastatic disease and relapse is good if you get salvage radiation, particularly with early salvage. And, in the past, we used to offer many more men adjuvant radiation. And now we know that many of those men received overtreatment, that they could be spared the side effects, particularly on erectile dysfunction, bladder and bowel injury, from the salvage radiation after surgery. And these 3 studies and the meta-analysis that accompanied them in Lancet Oncology, just hot off the press showed that salvage radiation, particularly early salvage, results in equivalent outcomes. Which, as a population level, is a major impact in 2020 that many fewer men really need adjuvant radiation now and can be spared those side effects. DR LOVE: And with all the new agents and treatments, you also see advances in de-escalating therapy. DR ARMSTRONG: That’s right. DR LOVE: HER2-positive breast cancer, same concept. It's great to think about these men not having to come in for treatment, particularly nowadays. When should the oral GnRH receptor antagonist relugolix be recommended if it were available? DR LOVE: Emmanuel, another really surprising new data set that came out at the ASCO meeting, and then published in the New England Journal, was the so-called HERO study, addressing use of GNRH antagonist as opposed to an agonist in terms of leuprolide. And this was presented by Neal Shore at, again at the ASCO meeting. And Emmanuel, these patients were just given it for a year. Just not a therapeutic study, really a pharmacologic study. And it looked like the effects, the endocrine effects of the antagonist started more quickly and it seemed like were at least not inferior — actually superior — to what was seen with leuprolide. And amazingly, or interestingly, and I think this was seen also with the other antagonist degarelix, not only — actually, this is the testosterone levels. You can see that they dropped quicker and they come back quicker once you stop it. But the real cool thing I think to me, Emmanuel, with this — again was seen with the subQ degarelix was the reduced cardiovascular events, particularly in men with a prior history of cardiovascular disease. That just kind of smacked us in the face, Emmanuel. Of course, we’ve always been talking about oral versus parenteral therapy since COVID in particular. What are your thoughts about this paper, Emmanuel? DR ANTONARAKIS: Well, I think you summarized the highlights. So we’ve had degarelix for many years and it's not really been used that much. And all of a sudden now we have relugolix, which is an oral GRNH antagonist. And again, it has a theoretical advantage that it castrates patients more rapidly and, also, that potentially there are less cardiovascular effects. And, as we were discussing before and just to share with the audience, one of the theories as to why a GNRH antagonist, like relugolix or degarelix, may have less cardiovascular effects than the agonists like leuprolide, is the effect on the FSH, follicle stimulating hormone, which increases more when you use an agonist than when you use antagonist. And FSH is expressed on many other tissues, including the endothelial surface. And so, the cardiovascular and the vascular effects could be worsened in people receiving leuprolide versus either degarelix or relugolix. The other take-home quickly, for me, is that you get a quick on and a quick off effect. So, if you have a patient with, let’s say a biochemical recurrence where you wish to treat this patient for 6 months or 9 months, and then you wish to stop and you want to see that testosterone recovering quickly within a month rather than within 3 to 4 months, then the relugolix or degarelix, for that matter as well, will result in more rapid restoration of a normal testosterone. DR LOVE: Andy, if this agent becomes available, if it were available today, would you just utilize it instead of an LHRH agonist or would you selectively utilize it? Would you utilize it at all? DR ARMSTRONG: Great question, Neil. Let me just first throw out some caution, that in metastatic patients, the current standard of care is not in ADT alone anymore, but ADT plus one of the newer AR inhibitors. And relugolix has not been studied in combination with those agents. There may be drug interactions with enzalutamide or apalutamide, for example. Ongoing studies are trying to address that question. Many men don’t want to take additional pills for the rest of their life. So the real value for a drug, an oral drug like relugolix, is that rapid on/rapid off setting, perhaps with radiation in the salvage or primary setting, where maybe just 4 to 6 months or up to 2 years of therapy, followed by cessation and rapid testosterone recovery so men can get back to a normal life and quality of life. DR LOVE: So I have to, even though we have a lot to cover, I see a great case here, Emmanuel, that I’d like to you respond. This is Dr Kumar from FCS, a general medical oncologist near Tampa, I believe. The patient presented with hydronephrosis, Stage IV prostate cancer, started on ADT and antiandrogen. He has difficult urinating. Not improving. And although good pain improvement and PSA response. Any role for TURBT or radiation to the prostate, Emmanuel, in this situation? DR ANTONARAKIS: The first thing I would say is, it's important to be patient. Sometimes it takes 3 to 4 months of ADT or combined ADT, to see that prostate shrinking and relieving the obstruction on the urethra. We have done TURBTs that can be effective in relieving the obstruction. But usually what we do is, we consider the radiation to the primary prostate gland, especially in oligometastatic disease where there seems to be potentially a survival advantage. So I would encourage this patient and this physician to perhaps wait a bit longer before considering the TURBT because you may be able remove the catheter without it. When should ADT for PSA-only relapse (M0) after local therapy be recommended? DR LOVE: Great point. Let’s move on now and talk about M0 disease. So much has gone on in the last few years in that situation. And before we get into where we’re seeing all the new data, Andy, is more longer-term question, which is the issue of initially starting ADT in a patient who’s had local therapy and now has PSA relapse. And, also, the issue, in this situation, about when you start ADT in this classic situation? Of course, Hopkins, where Emmanuel is, has done a lot of the work over time. This is a poll question we want to ask you, audience. We know that PSA doubling time is a critical factor in determining whether or not you're going to start ADT in M0 prostate cancer — for the first time now I’m saying. So, what doubling time is the one that's going to get you to think very seriously about — of course, you’re going to look at other factors, but very seriously about starting therapy? And, Andy, it looks like the audience is split between 6 and 10 months, so in that range. Any thoughts about maybe commenting on how you make this decision? Where you factor in doubling time? And which doubling time gets you to take action, Andy? DR ARMSTRONG: The two most important factors, Neil, in this setting is the absolute level of PSA and the PSA kinetics, as the audience rightly points out. The first question, in these patients who have relapse after radical prostatectomy, is whether they’re a candidate for successful salvage radiation. Some of these me can be cured, even though they have a rising PSA. You’ve done scans. Maybe the new PSMA PET scan. If you see no metastatic disease, they have a high cure rate with salvage therapy. and the decision to use ADT with the salvage therapy is based, not on the PSA doubling time, but the absolute level of PSA. There’s been some nice data from Dan Spratt and the RTOG group related to the level of PSA by which there’s a survival benefit with ADT in this setting. So, usually, if the PSA is quite high, above 0.6 to 1, I’m considering a period of time, 6 to 24 months of ADT with the salvage radiation. If they’ve already had salvage radiation or they’ve had radiation, now they have a rising PSA, nonmetastatic disease, I’m having an informed discussion with the patient about their comorbidities, their goals, their preferences. We often do a lot of observation for a while. There may be patients who have a benefit for metastasis-directed therapy with some of the new PET scans that can identify oligometastatic sites of disease. The use of ADT can be offered in an intermittent strategy as well to minimize the side effects and maximize quality of life. So I don’t use the PSA doubling time per se as the sole factor. It's really with the composite of the patient’s comorbidities, their preferences, the level of PSA and other factors. DR LOVE: And Emmanuel, Swati from the chat room says, is PSA PET scan a standard of care now? I think that person is saying “now” because we saw the approval of that strategy. Is it a standard now, Emmanuel? DR ANTONARAKIS: Well, it's interesting. I was in clinic all day today and I didn’t see that until I reviewed the slides that you sent me 5 minutes before the meeting, and I was delighted to see that 1 of the PMSA PET scans was FDA-approved today. I think it will very quickly become the standard in the biochemical recurrence space. And I would certainly like to use it myself. One thing that I just want to point out, and I’ll do this very briefly, is the doubling time of 10 months versus less than or more than 10 months, that really applies primarily to the non-metastatic M0 CRPC situation. And I don’t want the audience to get confused. Here, we’re talking about noncastrate, also called hormone-sensitive biochemical recurrence, where the less than 10 versus greater than 10 is not really used, at least for me, to select therapy. But in the M0 CRPC we can use that more definitively. DR LOVE: Yeah, that's a great point. I see almost half the audience said 10 months and maybe they were thinking about castrate-resistant disease where, of course, the 3 trials we’re about to talk about used a 10-month doubling time. And that was another big development the 3 trials that looked at this strategy reporting, not only survival benefit, but a really interesting survival, maybe more than we were expecting. When should an antiandrogen agent be added to ADT for castration-resistant M0 prostate cancer? DR LOVE: And that's our next topic, the issue of adding an antiandrogen to patients who continue to have M0 disease on ADT, but are having disease progression. And we want your thoughts on that. But first, we’re going to start out with the audience and ask whether you have a preference about which antiandrogen agent, if you’re going to add one to ADT in this situation, you think you might want to use? And we’ll see whether you don’t have any preference or you prefer 1 of the 3 agents that's available. And, while we’re looking at the audience, it looks like again — well, it's interesting. Most of the audience does have a preference, more than 80% has a preference. And interestingly, in order it's enzalutamide first, with almost half the audience, and a lot less people saying darolutamide, but still 24%, and then 13% apalutamide. So pretty interesting. And of course, we saw — here are the approvals. We saw the approval of the most recent one was darolutamide, based on the ARAMIS trial. But what we saw most recently were the survival updates of this. And Andy, I was really personally — I think a lot of people were surprised at the magnitude of survival benefit. Because I think these patients you could imagine would be getting these same therapies or some similar therapy on relapse, so it's really early versus delayed, and still to see survival benefit. Any comments, Andy? DR ARMSTRONG: I guess the good news here is that all of these choices are winners. And that if you’re studying for your boards, they’ll never ask you this question, because there are equal winners here. The patients are living longer. And in the end, the patient is the winner here, because living longer is the critical aspect of this data. And this is adding probably 1 to 2 extra years of life. It's delaying metastasis, which is a clinically important event, by about 3 to 4 years, which is meaningful. The FDA did approve these agents based on this surrogate. And in the placebo group, just observation. These patients generally have a very rapid time to bone metastasis, which can be symptomatic. And so, delaying the onset of that can prevent symptoms without a major detriment to quality of life. So, again, the treatment selection, picking one of these agents is largely going to be based on cost, comfort level, availability. There are some comorbidity issues and side effects that do differ. Darolutamide tends to have a more favorable side effect profile in terms of hypertension, fatigue, lack of a rash. Enzalutamide, probably a lot more familiar to the audience because it's approved for so many different indications with improved survival, so very easy to use; also doesn’t have a rash. Apalutamide, very favorable side-effect profile with less fatigue, but does have this rash issue. So there’s all winners here. They’re all good choices. DR LOVE: So I do hear many investigators stating preferences. And I’m going to ask, Emmanuel, in a second. In general, Andy, do you have a general preference or kind of, as you say, you look for comorbidities, et cetera? DR ARMSTRONG: I think for the older man, particularly over 75, who’s a little more frail, may have cardiac disease, may have less muscle mass, I like darolutamide because of the lack of impact on skeletal muscle, on fall risk, on fracture and hypertension, cardiovascular risk. For a younger patient, I think enza and abi and enza or apalutamide are equivalent options. So is darolutamide. So again, you can’t wrong with any of those choices for the younger patient. DR LOVE: That's interesting. Because I so hear people bringing up the falls and CNS issues. And we can take a look at that now. And Emmanuel, maybe you can comment on the data that we have, obviously indirect comparison, fraught with lots of issues. But maybe you can comment on what’s been seen in the trials, and particularly this issue of the “CNS” issues such as dizziness and falling. And what your preference is, if any? DR ANTONARAKIS: When darolutamide was first being developed, one of the selling points was that it had a much lower penetration of the blood brain barrier. And the clinical data seemed to support that hypothesis. And the cognitive decline, the memory impairment is better. People are able to continue high functional activities and calculations, computations, taxes. In particular, people that are engineers, accountants, people that have to concentrate on higher brain function activities, really notice that more when they have enzalutamide or apalutamide; it affects their cognitive function a lot more. The other thing is the risk of falls. There’s some controversy on that, whether it's due to the muscle wasting and weakness that results for the androgen deprivation, or if it is from the, some sort of central nervous system effect that it affects balance and induces ataxia. I have to admit, I think it's both, Neil. And I’ll just share one anecdote, and anecdotes are only that, but I had a young gentleman who was in his mid-40s, otherwise very fit. Actually, used to be an amateur college football player. And this was before darolutamide was approved. He received apalutamide, and literally, within a month, this young 45-year-old guy started to fall over and was bumping into things, was having trouble estimating the doorframe, was walking into door frames. And he actually fell over and had a significant fracture of his femur, even at the age of — and this was not a pathological fracture, it was just a traumatic fracture. And we had to stop the medication. And then, just around that time, darolutamide was approved and we put him on darolutamide and the ataxia did not occur at all. And so, this is a N of 1 where they same patient become hist own control. And I have to admit, as a psychological thing for me, after that one patient, I kind of switched to darolutamide and I’ve stuck with it since. DR LOVE: And I hear people saying the same things both of you do. Before we move again, again, Andy, some quick questions or things from the chat room. I’ll just run through them and then you can pick the ones you want to comment on. So Alan says that they’ve been recruiting for postprostatectomy M0 biochemical recurrence, castrate sensitive. And the PSA doubling time has to be less than 10 months. Interesting. Also Phil Brooks, a general medical oncologist, brings up an interesting point. They have all this great survival data for adding an antiandrogen in M0 disease, but we kind of really don’t have that data for initiating ADT, Andy. Any thoughts on those two comments? DR ARMSTRONG: I think we're about to cover the metastatic hormone-sensitive setting, where it's very clear that the early use of potent AR inhibition improves survival versus waiting until castration resistance occurs. The data in the nonmetastatic CRPC also shows that early use of potent AR inhibition for those men with really rapid PSA kinetics, less than 10 months, have better survival. So that wasn’t anticipated necessarily. We all saw the MFS data, but it wasn’t until the OS data came out that we become more believers in the early AR inhibition approach. But the androgen annihilation study that's being mentioned that the Alliance Foundation is running, is an important study to address. It's throwing the entire kitchen sink at the tumor at that point. Certainly, you're going to see the same kind of resistance mechanisms emerge from tumors that survive that such as neuroendocrine differentiation and lack of AR dependence. When do you use prostate-directed local therapy for mHSPC? DR LOVE: So, we’re going to talk now about metastatic hormone-sensitive disease. And Emmanuel, we want you to make a brief comment about the idea of local therapy in these patients with metastatic disease. This is an unexpected, for me, outcome that came out. I’m not sure everybody’s quite as aware that it came out a couple of years ago. But I wanted to just bring it up. And before we get into the issue of the systemic therapy of hormone-sensitive disease, what about local therapy as an adjunct to that, Emmanuel? Do you do that in your practice? DR ANTONARAKIS: I don't think we’ve included the slide, but there was the so-called STAMPEDE study from the UK, had more than 8 arms. And 1 of the arms in the STAMPEDE study was the best systemic therapy, which evolved over time, with or without the primary radiotherapy to the prostate gland. They did not include surgery as one of the local options. It was just radiation therapy. And that was published in the Lancet. And the bottom line was that in the overall population, there was not a clear survival advantage. But in a preplanned analysis looking at the low volume or oligometastatic hormone-sensitive patients, defined as fewer than 4 metastases, there did appear to be a survival advantage when you radiate the primary prostate gland, but not so in the high volume patients. Based on that data, I think many people, including myself, will refer patients that have 3 or fewer metastases to radiation oncologist within a month or 2 of starting the systemic therapy, which is usually ADT plus something else. In my practice, it's almost always ADT plus abiraterone. And I think there is a role and there might be a survival benefit. When do you add an antiandrogen agent, abiraterone or docetaxel, to ADT for mHSPC? (Selection of agent) DR LOVE: So we want to move into the issue, again lots of new data on, is use of management of hormone-sensitive disease systemically. And Andy, one question that came into the chat room that I think is interesting, is whether or not the metastasis detected by PSA imaging, do you approach them clinically the same as patients who have metastasis by traditional imaging? Do you want to comment on that? DR ARMSTRONG: Yes, I was actually going to say that. When I give talks in other parts of the world where PSMA imaging has been available for more than year, this is their most common question because they’re’ not doing standard imaging, they’re only doing PSMA imaging such as even the Middle East or Germany or Australia. And so, those colleagues are seeing much more metastatic disease than the US colleagues are seeing. But I would point out that the data from STAMPEDE is based on conventional imaging. So, our evidence basis for the improved survival was based on standard bone scan, CT-MRI, not functional imaging, with Axumin or PSMA PET. It remains to be seen how to integrate disease volume metrics into decision to pursue local therapy. But I would say make your decision on local therapy based on your best available evidence which is conventional imaging. But it does suggest that perhaps in patients that have poly-metastatic disease, widespread metastatic disease by PET imaging, maybe they could be spared radiation, but we don’t know the answer to that. For now, I would offer them radiation because we have Level I data supporting better survival. DR LOVE: So we want to put out case here again for the audience. So we’re going to say you have 75-year-old man who’s presenting de novo with prostate cancer. Multiple symptomatic bone mets and 2 lung mets. So in a second we’ll see what the audience has to say about this situation. So far, it looks like they’re kind of split between ADT plus docetaxel or ADT plus enzalutamide and abiraterone. It looks like about a third, a third, a third. Emmanuel, how do you think through the choice, before we get into some of the new data that's come out in terms of survival, the choice of treatments in this situation? DR ANTONARAKIS: So there are many choices, and that's another win for the patients. The chemotherapy option is quick and over rapidly. So if someone wants to add just 4, 4.5 months of augmented systemic therapy and then stop, that's easier for them. But on the other hand, the toxicities of chemotherapy are a little bit greater, especially in these hormone-sensitive patients. And then with respect to the 3 AR targeting therapies, it comes down to comorbidities, maybe drug/drug interactions, the absence or presence of diabetes. The absence or presence of other medical conditions. And, of course, in this country, the cost and reimbursement, where 1 agent may or may not be reimbursed compared to the others. DR LOVE: So Andy, in your talk you go through the data of supporting the use of these various strategies. Maybe you can comment a little bit on some of the more recent data from both your ARCHES trial as well as the trial for apalutamide. DR ARMSTRONG: So again, the good news, like Emmanuel mentioned, is that both apa, enza and abi all extend life. And the hazard ratios for improved overall survival are nearly identical to each other at about 0.67. So phenomenal success. This also translates into delays in progression on imaging, delays in PSA progression, delays in symptomatic skeletal events and other endpoints. There are major drug interactions. I would point out in the case that was brought up, lung metastases are not actually as bad as a prognosis as you would think. Not all visceral metastases are created equal. We know that liver metastases have the worst prognosis. Lung metastases are similar to bone metastases in their outcome. And so, those patients tend to do well with AR directed therapies. It's really when you have liver visceral metastases that I really would choose docetaxel as a first-line treatment with ADT. And I would even worry that that may not be enough. I may consider for patients who have a suboptimal response and wish to be aggressive considering an AR therapy even after completion of docetaxel, such as what was done in the ARCHES or TITAN or ENZAMET studies, suggesting that those may delay clinical progression even further. So, really the decision between these is based on cost/comorbidities, as has been mentioned. DR LOVE: So, Emmanuel, you were mentioning abiraterone and we saw at the recent ESMO meeting, some follow-up data from the STAMPEDE trial. Any comments on what was seen there? I guess one of the things compared to chemotherapy, it looks like there was a benefit in both the high- and low-risk patients. Any thoughts. Emmanuel? DR ANTONARAKIS: Yes, this is the point that the STAMPEDE investigators have always made and will continue to make, that the volume of metastases should have no bearing on the decision about abiraterone in the hormone-sensitive setting. Whereas with chemotherapy, at least with the American study, there does seem to be a benefit that is restricted to the high volume in the CHAARTED trial. So the bottom line from these data, and there were kind of updates of previously presented data, is that the benefit of early abiraterone use seems to be present independent of the risk and independent of the volume. DR LOVE: So Andy, here’s a quick case from the chat room. A patient had radiation — this is gain from Kumar — radiation therapy of the prostate 15 years ago. Survived gastric cancer, head and neck cancer. Status-post chemo/radiation therapy. Colon cancer. Now has prostate recurrence with neuroendocrine differentiation. Status-post TURP. Any thoughts about how you approach patients with neuroendocrine differentiation, Andy? DR ARMSTRONG: Yes, that's a difficult case. I mean I would certainly order germline testing on that individual unless there’s some obvious exposure that may have caused those multiple cancer types like tobacco. But even so, I would do germline testing. But neuroendocrine disease exists in two main forms, there’s de novo pure small cell disease, which can present right from the beginning, and it should be treated similar to NCCN small cell algorithms, platinum-based chemotherapy. ADT really doesn’t work in those settings. For patients that have more of a hybrid tumor or transformed disease that emerges out of typical adenocarcinoma of the prostate, that's called transformed NEPC. That can also have small cell features and be treated similarly. These patients have aggressive genotypes and aggressive outcomes. And so, if the patient is fit, we would also consider them for trials, platinum/chemotherapy. We often combine AR inhibitors, ADT and AR inhibitor in those settings if you’re also dealing with a component of PSA producing adenocarcinoma, where you may be battling 2 cancers in 1 patient. So this is an area of rich clinical investigation right now, DR LOVE: So I see a great PARP question in the chat room. I’m going to hold off on that and we’ll go — until we get there. How do you generally approach the selection of endocrine treatment versus chemotherapy after first-line endocrine therapy for mCRPC? DR LOVE: But we want to talk also, Emmanuel, about the management of patients who have disease progression after first-line setting endocrine therapy. Of course, we saw the CARD trial in the past. We saw an update of that. But I want to see from the audience, here’s a case we put together audience. A 75-year-old man, BRCA wild type, metastatic disease to the bone. Gets ADT and docetaxel. Has disease progression a year later. Gets treated with enzalutamide for 9 months, then has symptomatic progression in the bone along with new lung lesions. What’s your most likely therapy in this situation? Emmanuel, can you talk a little bit about how you would think it through. It looks like overwhelmingly in the audience cabazitaxel, I think the CARD trial has been out there and people are very aware of it. Emmanuel, any thoughts about this case and the CARD trial? DR ANTONARAKIS: I think the CARD trial sort of rescued the use of cabazitaxel in this disease. It was really not used that much beforehand. And a lot of us would say that alternating between an AR therapy and a chemotherapy was the way to go, but we didn’t have the Level I evidence to back that up. And, in the CARD study, as was mentioned, these patients were all metastatic CRPC. They had all received docetaxel and at least 1 AR targeting therapy. And then they were randomized to receive a second AR targeting therapy or cabazitaxel. Again, these patients had all received docetaxel in the past. And both the primary endpoint of our rPFS, as you can see on this slide, and the secondary endpoint, which is a key secondary endpoint of OS, which impressed me as well, was positive. So I would say that this is Level I or as close to as a Level I as you can get, to say that if a patient has received at least 1 and up to 2 AR therapies and 1 prior taxane therapy, that the next step should be or could be cabazitaxel. The one thing that I will say that this study did not cover was the use of Radium-223. And in my practice, if I have patient that as bone mets, especially if they're symptomatic, and they are in this population, I think the use of radium would be a very reasonable alternative to the use of cabazitaxel, again, for symptomatic bone dominant CRPC. How do you generally approach the use of radium-223 for mCRPC? DR LOVE: That's a good point and actually leads into our next topic, Andy, which is the use of radium. And it's been kind of interesting tracking this story over the last few years and seeing where it seems like it's settling down. And we saw some, actually at the ASCO meeting looking at patients who get radium and then get subsequent taxane therapy. Can you describe a clinical situation or a typical clinical situation, Andy, where you think about radium, and any thoughts about this REASSURE presentation? DR ARMSTRONG: Sure. So Neil, an important question from the audience I saw pop up was whether it's to continue ADT in the face of all these secondary therapies, like docetaxel, cabazitaxel and radium? And the answer is yes. All these studies require that ADT be continued. The ideal patient for radium would be a gentleman who has good bone marrow reserve, but symptomatic bone metastases and lacks significant soft tissue metastases, such as lung, liver or bulky adenopathy, similar to ALSYMPCA trial There has been some negative data around radium with the early use of radium and abiraterone for early CRPC where there was a higher fracture rate. That was largely observed in a setting where bone protective agents were underutilized and that taught us all that when you’re using radium you should be using bone health agents and when you do so, the fracture rates are very low. They're not zero, because patients do progress on radium. Radium is a palliative care therapy. it is not a curative therapy. It results in patients progressing more slowly and living longer, but patients are still progressing at the end of radium generally, and you have to be ready for the next therapy at 6 doses over 6 months. So ideally, it's multiple bone metastases. The typical patient will have migratory bone pain, not just a single focal site of pain that can palliated with focal radiotherapy. DR LOVE: And I will say, too, again, in the two talks that Andy and Emmanuel did, you’re going to see a lot of slides that we’re not showing here tonight. Here’s an example of these conclusions slides, really helpful. Here’s Emmanuel’s conclusion about the REASSURE study. Just very practical points about what the clinical implications are in terms of treatment, here that radium can be given before or after docetaxel. If docetaxel is given afterwards you still see mild suppression minimally. And the reminder to us denosumab. Anything you want to add to that, Emmanuel? DR ANTONARAKIS: I think you covered it, Neil. And then there’s a lot of combination studies looking at radium plus, which are looking promising. How do you generally approach the use of PARP inhibitors for mCRPC? DR LOVE: So, let’s jump into the PARP question. Of course, this is one of the biggest developments in oncology, let alone in management of prostate cancer. And we’re going to start out and ask you, audience, if you’ve got a patient who’s got prostate cancer and a germline BRCA mutation and metastatic disease, in general, when are you going to be thinking about using it, making sure you have a patient evaluated at that point? Would you use it part of first-line therapy? After first-line hormonal therapy? How would you think this one through? And actually, it looks like — we’ll what our faculty thinks, but the most common answer in the audience given by about half of them is after first-line hormone and chemotherapy. So we’ll see whether or not our faculty agrees with that. Of course, again, this is reviewed in Emmanuel’s talk. We have 2 PARP inhibitors now approved treat, olaparib as well as rucaparib. General medical oncologists are well used to using those. Of course, we have talazoparib also in breast cancer. Emmanuel, can you talk a little bit — before we even get into the trials, just to take a step back and just comment a little bit about the biology and genomics of prostate cancer. How often you see germline mutations? Somatic alterations? And what fraction of patients with metastatic disease really are candidates for PARP inhibitors, Emmanuel? DR ANTONARAKIS: So, what we're interested in are these genes called homologous recombination repair genes. And these are a type of DNA repair genes. And these are found in about 10 to 12% in the germline of prostate cancer patients and they’re found at a prevalence of about 20 to 25% in the tumor, somatic mutations. Now, we have to remember that mutations in the tumor can either be somatic only, or they can be germline, which are found also in the tumor. So, a quarter of patients will have one of these DNA repair mutations in the cancer itself and about 12% will be born with one. Now, the most prevalent is BRCA2. Interestingly, Neil, and the audience obviously listens to many topics, in breast cancer the prevalence of BRCA1 and BRCA2 are roughly equal. Same with ovarian cancer. In prostate cancer, very, very different. The ratio BRCA2 is about 10-fold higher than BRCA1. So, BRCA1 is about 1 to 2% and BRCA2 is about 10 to 12%. So much, much greater skewed towards the BRCA2 in this disease. ATM is another common one. And then there are 2 other genes, 1 is called CHEK2 and 1 is called CDK12, which may not sensitivity genes for PARP inhibitors but they are prevalent. The way that we think PARP inhibitors work is through this mechanism called synthetic lethality, whereby the cancer cell loses its ability to fix both single-strand DNA breaks and double-strand DNA breaks. The single-strand DNA break is fixed primarily by an enzyme called PARP1 or PARP, and the double-strand DNA breaks are fixed by a protein such as BRCA2. And so, when you have a mutation in BRCA2 that cell is crippled in its ability to fix double-strand breaks so it compensates by requiring and using the single-strand pathway, in other words, PARP1, to maintain its genomic integrity. And so, by pharmacologically inhibiting PARP1 with the drug, in this case olaparib or rucaparib, you’re knocking out both single-strand and double-strand repair. DR LOVE: So why don’t we throw in a case that just popped into the chat room. This is from Alan, Andy. A 70-year-old man with prostate adenocarcinoma. Germline BRCA2. And Emmanuel, I forgot. I was going to ask you, any hypotheses about why you see so much BRCA2 in prostate cancer? Biologically why that happens? DR ANTONARAKIS: This is an open question. One of the things that we’ve noticed is that if you’re born with a germline BRCA2 mutation you’re tumor is very likely to have a second hit, 80 to 85% of those people have a second hit in the tumor. Whereas, with BRCA1 germline mutations, about 50% of these men develop sporadic prostate cancers that have nothing to do with a germline BRCA1 hit and there’s no second hit in the cancer. So the short answer is it doesn’t seem to predispose to getting prostate cancer in the first place as much as BRCA2. DR LOVE: Wow, that is really interesting. Let’s go back to this case, Andy. So a 70-year-old man. BRCA2, as we just heard, initially Gleason 4 +4 = 8. Status-post ADT, radiation 2017. Developed castrate-resistant and oligometastatic disease to the sternum and spine. Status-post sipuleucel-T, 11 months of abiraterone and prednisone. Currently on olaparib for 4 months. However, the PSA has gone from 18 to 35 to 45. Imaging stable. Tolerating olaparib well. “Should I continue olaparib?” DR ARMSTRONG: That's a good question. I wasn’t sure where that was going. But I would point out that olaparib is not a cure for BRCA2 positive, metastatic CRPC and that only about 40% of patients have these extraordinary response that we’re hoping for where the synthetic lethality is demonstrated clinically. Objective response in PSA declines are happening in about 50% of patients. So that leaves 50% experiencing outcomes like this patient whose PSA is going up and you expect inevitable progression. We are trying to understand the resistance landscape of PARP inhibition, such as reversion mutations, such as coexisting mutations like p53 that may prevent the cell from dying in the face of a PARP inhibitor. We’re looking at PARP combinations, PARP plus immunotherapies, PARP plus PSMA directed therapies. This would be a patient who I would consider referring for a clinical trial of a novel agent. But I would probably get imaging sooner, than later, and when the patient develops radiographic progression or certainly symptomatic progression, would consider a change. I have had patients who have had a delayed PSA response. I don’t know if Emmanuel has such patients. It's not been published in the literature very much. We know that this happens with docetaxel where you can see a delayed PSA response. But with olaparib, I think we don’t have a great sense of the characterization of how quickly the PSA declines. There can be some disconnects between clinical and PSA benefits. So wouldn’t just stop for PSA alone. But I would be worried about that patient. DR LOVE: Emmanuel, any thoughts about this case? And anything you want to add in terms of mechanisms of resistance? DR ANTONARAKIS: The short answer is, I’m not very optimistic about this patient. I don’t think he will respond. And the delayed responses that I have seen, they may not occur in the first or second month, but they typically do by the third. And this patient is clearly progressing, in my opinion. The mechanism of resistance, the first one is he may not have a second hit. He may have a monoallelic mutation with the second allele being wild type, so the wild-type BRCA2 compensates for the mutated one and then the PARP inhibitor doesn’t work. Or he may be one that has concurrent p53 and PTEN mutation. And those patients often do show resistance, because they have other mechanisms driving their growth. DR LOVE: This thing you were just mentioning about the second hit, so you’re saying that you could have a patient who has a germline mutation but they actually have a sporadic cancer. How do you know that? How do you determine that? DR ARMSTRONG: Through tumor sequencing. DR ANTONARAKIS: So Neil, this is a challenge of all the clinical NGS platforms, because most do not report the second hit. And this is something that I have petitioned to them for a long time to start reporting. But these companies have the ability to look at the second allele, but they almost never report it. One thing that you can do which is a little bit of a trick or cheating, is you can look at the mutation allele frequency, and that tells you what proportion of the tumor cells have that mutation, and you can use that as surrogate to figure out the second allele. But, in the future, I think they will report that. DR LOVE: So Andy, of course we have all the slides for these talks in our presentations. But I wonder if you can comment on what was seen in the PROFOUND trial. Of course originally we saw this improvement in PFS, but then now we’re seeing survival benefit. And interestingly also, they looked at crossover adjusted overall survival because most of these patients I think did cross over. Any thoughts about what this means, Andy? DR ARMSTRONG: Yes. So just to point out, Neil, the PROFOUND study enrolled men who had 1 of these germline or somatic homologous repair defects. They had to have progressed on an abi or an enza. They did not have to have had docetaxel. About half the patients did and half did not. The majority of the benefits in the PROFOUND study are driven by the BRCA2 carriers, somatic or germline. There are subgroups that seem to have benefits that have been mentioned by the audience, but there are clearly subgroups that are having not great responses to these PARP inhibitors, such as the ATM patients or CDK12 or CHEK2 patients, just as an example. But with, particularly the BRCA2 patients, you're seeing improved survival. You're seeing improved survival overall. But that's largely driven by the majority of the patients having better outcomes with BRCA2 mutations. DR LOVE: So more in the chat room, Emmanuel. I’m just going to read a few of them real quick. You can pick what you want to respond to. Germline BRCA, metastatic disease. Is there a place for platinums? Number one. Second, Rachna says, I have a patient with mCRPC who has a somatic BRCA2 mutation, responding very well to olaparib. And finally, Anthony says, can you comment on AR expression and NGS panel — kind of a different issue — for mCRPC patients. Does that affect whether you choose, for example, AR inhibition versus chemo? It's like being on Rounds, Emmanuel. They’re throwing things at you. DR ANTONARAKIS: It's like speed dating maybe. I used to do that. Let me address the BRCA2 question. The current evidence suggests that the somatic and the germline mutations can respond equally well, especially if there’s a biallelic somatic mutation. One of the things that we see very commonly is called the homozygous deletion. Homozygous deletion is always somatic and it means that both copies of the gene are entirely deleted. Those patients tend to respond very well to PARP inhibitors. The other issue, going into the second topic, is some of these other genes — there’s something on the chat about CHEK2. Those patients typically don’t respond as well. ATM, they typically don’t respond as well. And one of the things that is important to mention, and Andy touched upon this, is they showed docetaxel. With olaparib, unlike rucaparib, you do not have to have failed docetaxel to use it. But for me, if I have a BRCA2 patient, I would like to use olaparib prior to a taxane. However, with ATM, or CHEK2 or CDK12, I may still choose to use olaparib eventually, but I like to reserve that until after my patient has received 1 and sometimes 2 taxanes so I can justify using a drug that I don’t expect as much of a response from. DR ARMSTRONG: Agreed. DR LOVE: So you basically look at the genomic profile and try to figure out are they really likely to respond, less likely to respond, and that affects where you use it. Makes a lot of sense. Andy, we also had rucaparib being approved. Can you comment on what they looked at in terms of rucaparib and what they saw? DR ARMSTRONG: It was very exciting that the FDA chose to approve this based on an objective response rate. This the first time this surrogate has been used. And I think largely because it was a robust response. It was in a very well defined patient population who had an unmet medical need. The patients had mCRPC and failed abi, enza and docetaxel. They had a BRCA1 or 2 somatic or germline alteration and they had a greater than 40% objective radiographic response by RECIST, greater than 50% conformed PSA decline. You can see the waterfall plots where most of these patients are benefiting. The progression-free survival in this study was also very good. Similar to what was seen in the PROFOUND study in the post-chemotherapy setting. When you do cross-trial comparisons, the progression-free survival rate seems to be even greater in the pre-chemotherapy setting. And I think that's why Emmanuel and I tend to, for the BRCA2 patients, favor olaparib because it seems to have a superior progression-free survival to docetaxel in similar types of patients. While for ATM patients, the progression-free survival is shorter; it's probably in the 4- to 6-month range. So maybe not as good as docetaxel. Not quite a fair comparison. We don’t have any randomized data against docetaxel, but we're doing our best with cross-trial comparisons. DR LOVE: So Emmanuel, Sherry wants to know what the risk is of developing prostate cancer in a man who’s known to have a BRCA2 germline mutation? She says mother had ovarian BRCA2, so the man was tested. What do we know about lifetime risk of prostate cancer, Emmanuel? And the timing, what age it occurs? DR ANTONARAKIS: The lifetime risk of prostate cancer overall is about 14% in men in this country. And with a BRCA2 mutation, it rises to about 25 30%. So that still means that 70% of patients that have a germline BRCA2 will never get prostate cancer or any other cancer. That's very, very different from the risk of breast and ovarian cancer in BRCA1 and 2 females, depending on the gene which is 70 to 80% lifetime risk. So the penetrance, in other words the risk of getting cancer with a germline mutation in BRCA2 is much less than in females with breast and ovarian cancer risk. And with BRCA1, it's even less of a risk factor, as we discussed before. DR ARMSTRONG: I would point out that there is an NCI sponsored screening study using multiparametric MRI in those carriers that is designed to pick up cancer early and leave the prostate alone if there is no cancer. So, MRI may be superior to just PSA screening for these patients. But that's ongoing. DR LOVE: Interesting. Emmanuel, can you comment on some of the issues related to tolerability of PARP inhibitors in prostate cancer? Of course, we know, particularly from ovarian cancer, that cytopenias can be a problem. Anemia, thrombocytopenia with some of the agents, as well as GI disturbance. Do you see a similar profile in prostate cancer? These men have a lot of bone mets, maybe less marrow reserve? Do you see more cytopenias, for example? DR ANTONARAKIS: Yes, we do see cytopenias. About 10% of patients, they require even a blood transfusion for anemia. So it's not insignificant. We also see anorexia and weight loss. These drugs suppress appetite. It's not necessarily a nausea, but they’re appetite suppressants. And there is also a theoretical, but important risk, maybe 1% or so, of inducing or accelerating myelodysplasia and even acute myeloid leukemia up in case reports. So that's important to keep in mind. One thing that I want to mention about olaparib in terms of safety is, we are seeing a very small incidence of drug-induced pneumonitis. That can sometimes present as a dry cough. And it's very similar to an ACE inhibitor cough. When you stop the drug, within a few days the cough disappears. And then when you start the drug, even at a lower dose, it can come back. And it seems to be an idiosyncratic rather than dose-related. And that does not occur, at least it has not been reported with rucaparib. And the second thing is in the olaparib PROFOUND trial, there was a 7% risk of DVT or PE, so thromboembolic event, versus only 2% in the placebo — in the control group. So there might be something about olaparib specifically increasing the venous thromboembolic risk. What is known about PSMA-targeted treatment and imaging in prostate cancer? DR LOVE: So I wanted to close out with a couple of visions for the future where we saw some new data and new things happening, beginning with PSMA targeted treatment as well as imaging. We just looked at this when we talked about this press release But in any event, we saw this approval. But Andy, we also saw at the ASCO meeting really fascinating, this whole issue of the lutetium PSMA has been fascinating to I think everybody for a long time now. It looks like it's getting a lot closer to the clinic. Any comment, Andy, on what was presented there? And how this works pretty much? DR ARMSTRONG: Sure. It's important to understand that PSMA is a cell surface receptor. It's involved in folate and purine metabolism, so it has some normal biologic functions. But here it's being used as a target, like Velcro, for an antibody. And the antibody is being used as a warhead to deliver radioactive beta emitter called Lutetium-177. So the PSMA scan that was approved is not a therapeutic. It’s really just imaging. Much more sensitive imaging than what we’ve had to date. So very exciting. But this TheraP study was randomizing patients who had PSMA-positive disease by PSMA PET. They did not have discordant disease with an FDG PET. So some cancers, like neuroendocrine disease, lack PSMA and they can take up sugar. And those patients were excluded. And then those patients with progressive mCRPC were randomized to cabazitaxel, like the CARD study, or PSMA Lutetium-177 every 6 weeks. And the primary endpoint being PSA response rate was actually superior for PSMA Lutetium, 66 to 37%, with a slight improvement in the PSA progression-free survival as well. And more importantly, I think quality-of-life toxicity was lower with PSMA targeting therapies than taxane/chemotherapy. So this will set the stage for the Phase III VISION study. That's PSMA Lutetium targeting therapy against best standard of care. That's being done. That's completed. And we should have results in 2021. So something for next year’s symposium. DR LOVE: But, I mean, would you like to be using it right now? DR ARMSTRONG: No. We’ve been treating patients on study. And the only way to get it right now would be to fly to Germany or India and that's not really a great idea during a pandemic. So we would love to have it right now. If it is approved it's going to be in high demand. And our nuclear medicine colleagues are going to be in high demand as will their facilities. DR LOVE: And, if it is approved, assuming you could access it in any situation you’ want, Andy, when would you utilize it? DR ARMSTRONG: So there’s already studies in the hormone-sensitive metastatic setting, combining it with our best potent AR therapies. It may even work without the need for hormonal therapy, honestly. But that hasn’t actually been tested yet. It may work well with immunotherapy or DNA damaging sensitizers like PARP inhibitors. Those are all under study. I think patients will love to get this therapy instead of chemotherapy. So, even though the VISION study was a post-docetaxel trial, depending on the results, I would suspect that there will be high demand for this instead of docetaxel, for example, or cabazitaxel. DR LOVE: So Emmanuel, I’m going to let you have the last comment. One more from the chat room, Rachna has asked a couple of times, so I’m curious what you think. She has a patient who has significant edema in third spacing on a PARP inhibitor. Is that coincidental or can you see that with a PARP inhibitor, Emmanuel? And then the second question is about COVID and male gender in this incredible paper that you were part of, discussing the TMPRSS alteration. But let’s start out with Rachna’s question about edema in third spacing with PARP, Emmanuel? DR ANTONARAKIS: I have not seen significant edema with PARP and I wonder whether this patient has progressive disease with retroperitoneal lymphadenopathy that's causing the edema. So I have not seen that. What is known about TMPRSS2 and COVID-19? DR LOVE: So Emmanuel, we had a poll question but we’re not going to show it that asked do you see higher incidence and higher complications in men or women? What’s the answer? And can you talk briefly about this paper? DR ANTONARAKIS: Yes, the answer is it's unclear. I’m not convinced there’s a link. The theory is that there are 2 receptors on the surface of the alveolar lung cells that are used for the virus to attach and then enter into the respiratory epithelium. One of the two is TMPRSS2 and one of the two is ACE2. And TMPRSS2 is a gene that we know in the prostate gland, is regulated by androgens. Its expression is increased with androgens and decreased with androgen deprivation. And this came to attention more than 10 years ago when we discovered — when the field discovered a fusion called the TMPRSS2-ERG fusion, where ERG is an oncogene that is usually not under the control of the androgen. And when that TMPRSS is fused to ERG, TMPRSS itself is under androgen control and then the ERG becomes oncogenic under the influence of testosterone. So what the hypothesis was is that male respiratory epithelia might express more TMPRSS2 than female pulmonary epithelia. And if this is the case, it may cause more viral entry into the lung, so not necessarily that males would be more likely to catch it, but that males might have more significant pulmonary complications. And then the corollary to that would be that if you could decrease TMPRSS2 expression in the lung by using an antiandrogen or androgen deprivation therapy, that you could then potentially attenuate to some degree the entry of the virus into the lung. There have been 4 studies that are each case series that have been published. The first one and the fourth one seem to show a protective effect of androgen deprivation therapy in men who happen to be taking ADT just by chance for their metastatic prostate cancer. The first was from Italy and the second was from the New York City area. But the second and third studies that were done in European countries did not show a protective effect of androgen. So I don’t think we have the answer. And I’m not sure that the link is as direct as we had hypothesized in that editorial. DR LOVE: So to be continued. Again, check out the 2 presentations that Andy and Emmanuel did. Thanks so much to you Andy and Emmanuel. Thank you for attending audience. Be safe. Stay well. DR ARMSTRONG: Thank you, Neil. DR ANTONARAKIS: Thank you very much. DR LOVE: Thank you. DR ARMSTRONG: Good night. |