Introduction: Genitourinary Cancers Symposium 2022

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice, and welcome to Meet The Professor, as today we talk about the management of metastatic castration-resistant prostate cancer with Dr Andy Armstrong from the Duke Cancer Institute Center for Prostate and Urologic Cancers in Durham, North Carolina. We have a great faculty for this series. This is actually the last in our series of programs on this topic. And later on we’ll show you the results of a survey we did of the faculty of their usual treatment practices.

As always, if you have any questions or cases you’d like to run by us, just type them into the chat room, and we’ll talk about as many of these as we have time today.

If you’re into audio programs, check out our Oncology Today podcast series, including a recent program on castration-resistant metastatic disease with Dr Yu. And this program tonight, as well as all of our webinars will go into the audio series as well.

We do webinars all the time. Tomorrow we have a really interesting one on CLL with Dr Wierda from MD Anderson. On Monday we’ll be talking to Dr Aggarwal about immunotherapy in lung cancer. On Tuesday we do our Year in Review program, and this time we’ll be meeting with Drs Plimack and Powles, Dr Armstrong’s colleagues in GU cancer, to talk about what happened last year in GU and bladder cancer. On Wednesday, March the 9th, we’ll be talking about AML with Dr Olin, and then on Thursday, March the 10th, we’ll be launching our myelofibrosis series with Dr Verstovsek. We’ll be coming back and talking with Dr Hillmen about CLL on March the 17^th.

But today we’re here to talk about prostate cancer, and really great timing, the GU symposium, cancer symposium was just a couple weeks ago. We did a couple big satellite programs there, and we’re actually going to talk a little bit about what happened there as well.

As always, we have some general medical oncologists in community-based practice who are going to be presenting cases today. I sit down with these docs, and they’re going to give — they gave me cases of not only prostate cancer, renal, bladder, lung, CLL, myeloma, and ask pertinent questions for all of these. What an exciting time to be a general medical oncologist, and so challenging.

Here’s where we’re heading today with Dr Armstrong. First we’re just going to briefly chat about some of the big papers that came out at the GU symposium, and then we’ll get into the cases. We have 6 cases to go through today, and then we’ll finish up with some papers and a journal club from Dr Armstrong. And Module 8 is just a bunch of slides for you, as always, as an appendix.

So we want to get started now, and Andy, before we kind of go through the slides, just to take a deep breath, and I would say this is one of the most exciting GU symposiums in a while, particularly in prostate cancer. Bottom line had 3 really interesting Phase III studies, and of course the 2 that got a lot of attention were PROpel and MAGNITUDE. Can you kind of just, before we start looking at the data, kind of talk about your take about kind of what these 3 trials you think are going to mean to clinical practice, Andy?

DR ARMSTRONG: It’s always a pleasure to be with you. And I agree, the Thursday of the GU symposium really had several practice changing or at least I would say potentially practice-changing clinical trial data sets. And I was privileged to be part of the PROpel study. Fred Saad did an excellent job presenting this very positive study on behalf of our team, and this is a front-line mPRPC trial that demonstrated that the addition of a PARP inhibitor, olaparib, to abiraterone in the mPRPC setting was associated with a significant delay in radiographic progression-free survival.

You can see right here on the slides nearly a 9-month improvement. That’s a major difference. And by independent review was actually 10 to 11 months, hazard ratio 0.61. In the BRCA and homologous repair deficient patient population the hazard ratio gets even better, doesn’t cross 1, hazard ratio of 0.5. Now the overall survival data is not yet mature. We expect that at some point in the near future. And so whether it’s practice changing based on this huge magnitude of rPFS in all comers is the question. And certainly in the homologous repair deficient population that is a major potentially practice-changing difference.

DR LOVE: And of course the —

DR ARMSTRONG: But even in the HRD-negative patients this is unexpected and a positive signal. Sorry. Go ahead.

DR LOVE: No. That’s exactly what I was going to ask you. Because we polled investigators about what they thought the PROpel study was going to show, and nobody was very excited about the non-HRR patients, and then not only was this trial positive, as you say, and you can see here statistically significant, but the thing that really made it problematic is this, the other study, which was with niraparib.

DR ARMSTRONG: Absolutely. Right after — right after PROpel we got niraparib, which in the unselected group very much similar type of patient population, abi plus/minus PARP inhibitor. The unselected group was closed due to futility. And I think we’ve all come to appreciate that olaparib as a single agent is not active unless you have a homologous repair deficiency. So we all learned that. But I think you can see from these studies that the magnitude of the efficacy differences across these trials are very different from each other. And the safety profile is different.

So these are different drugs, and I don’t think you can extrapolate one PARP inhibitor to another; different trial designs, different answers, different biomarker stratification. You see the hazard ratio of 0.73 in the homologous repair deficient patient population as compared to PROpel, which was 0.5, so they are different. MAGNITUDE was positive for the BRCA subpopulation, but overall was a negative study. So it’s not something that I would routinely recommend. If I’m going to use a PARP inhibitor I’d probably stick with olaparib based on the positive results that we had, and I would particularly focus that on the homologous repair deficient patient population. But both studies didn’t have the survival data yet.

DR LOVE: So our audience knows because we’ve done a ton of CME programs in ovarian cancer and PARP inhibitors, that there actually niraparib you saw a benefit in patients without BRCA, HR proficient. It wasn’t really looked at with olaparib in the SOLO study, but it was a hazard rate of 0.5, similar to what you were just saying. And it’s a big debate in ovarian cancer whether to use it in those patients. I’m sure it’ll be a debate here. But they saw a statistically significant benefit in those patients.

DR ARMSTRONG: Yeah, and here I think the biology is related to AR — AR-regulating DNA repair, and so there’s this relationship between blocking AR and PARP together giving you a synergy. And it is strange that one was so positive and the other was not, and I think there’s going to be a lot of debate, particularly when the publications come out very soon.

DR LOVE: Right. And Dr Bryce put together this summary slide, and you’ll see in a second what happened at the actual meeting. We did a couple hours after the data was presented.

But I also — before we jump into that and the cases, I want to also get your take on the other big study. But before we get off of this, I’m just kind of curious, putting aside reimbursement issues, assuming you can do what you want, let’s see what happens with the FDA, what would you do outside a trial setting in this situation? Are you going to treat people with BRCA? Are you going to treat people who are HR proficient?

DR ARMSTRONG: It’s a great question, Neil. In general I’m communicating this data to patients and making decisions with them. Informed decision-making’s critical over the risks and benefits. So the risks are more toxicity, particularly anemia, fatigue, GI toxicity. We didn’t see more myelodysplasia or leukemia. No toxic deaths. So there is — and there wasn’t a negative impact on quality of life, which is good news for patients. But there is more toxicity, and there’s more cost.

But outside of cost, I think particularly in the homologous repair-deficient patient population there’s a huge benefit for delaying progression. Many of these patients when they progress become very symptomatic, and many patients don’t make it to that next line of therapy. And so I think hitting the cancer hard up front may be better than waiting until using single-agent olaparib later. And so that’s what I would do for those patients.

In the unselected patient population I think it’s not unreasonable, particularly if you’re projected to have a poor response to abi single agent. There’s definitely prognostic models that you can use to indicate which patients are going to have these extraordinary responses to abi or enza and those who may blow through it in a shorter timeframe, like a year. So I think you can use those data sets to inform your patient and your decision.

DR LOVE: It’s always challenging in oncology when you have situations, particularly early on, where you see PFS, and you don’t see survival. A lot of that ties into what the toxicity’s going to be, what the cost is, and you just went through that.

DR ARMSTRONG: Absolutely.

DR LOVE: So the other thing, again, before we start kind of rocking and rolling with cases is this. This is the third Phase III study, darolutamide in hormone-sensitive disease but with docetaxel. So can you explain what this trial looked at and what you think it means?

DR ARMSTRONG: Sure. So ARASENS builds on prior data where we learned many years ago that docetaxel in the CHAARTED and STAMPEDE trials improved overall survival in the hormone sensitive setting much more so than in the later castrate-resistant setting. So early use of chemotherapy plus hormones extended life. And so ARASENS was designed when that was all the data we had, and obviously since then we’ve had enzalutamide, apalutamide, and abiraterone all hit homeruns and show the same benefits of greater improvements in survival early versus later.

So ARASENS was really a triple therapy, darolutamide plus docetaxel, and it was very positive. Significant improvement in survival with delays in symptomatic progression and second progression. Mostly a de novo patient population. Nearly 90% of these men had newly diagnosed metastatic disease. Dr Smith did not clarify how many were high volume. I suspect most were, but we don’t have that data.

But we would like to know how darolutamide works without docetaxel because a lot of men don’t need the docetaxel, particularly if they have low-volume disease or relapsed disease, and we just don’t have data from this trial to speak to that. But it’s a very well-tolerated agent, Neil. These patients hardly notice the treatment other than additional hot flashes and maybe fatigue, but they don’t have a lot of the other toxicities that we see with abiraterone in terms of prednisone use and liver abnormalities. They don’t have as much fall risk or osteoporosis or fractures, cognitive problems that you can see with enza and apa, and they don’t get a drug rash like apalutamide. So it’s got some valuable properties for patients.

DR LOVE: And these were the actual toxicity data that Dr Smith showed from this study that reinforced what you were just saying, particularly in terms of fatigue and having to stop therapy, et cetera. I was just curious, though, what you thought. There was a paper presented at last year’s ASCO, a patient preference study, and I’ve been hearing from all the investigators — we’re all hearing from you how darolutamide’s so better tolerated, but this was a study that asked the patients, and it wasn’t as dramatic as I was expecting based on what I was hearing from you all. What did you think about this study? And do you still — I guess you believe that it still is a better-tolerated agent.

DR ARMSTRONG: Well, what I would say is that all of the AR inhibitors, whether that’s apa, enza or abi are in general very well tolerated with very high levels of quality of life. But you do see a minority of patients that suffer from issues of fatigue or cognitive dysfunction. You see patients with abi who have liver problems or cardiac problems, and you see patients with enza that may have frailty issues, fall risk. And the ODENZA showed that a modest number of patients preferred darolutamide, but that was not statistically different, mostly due to fatigue.

DR LOVE: So I kind of want to go through a few of the things related, and then we’re going to go through the cases. But one more thing I want to go through is a little bit more about PROpel and MAGNITUDE, and I also want to get the audience reaction to kind of what you’ve been saying so far.

So here’s where we started. We did this survey — this survey here before the GU symposium. We said in general, at that point, when were you bringing in a PARP inhibitor, and we said a patient with a germline mutation. Most people were saying after 1 line of hormonal therapy for metastatic disease. You said maybe both hormonal therapy and chemotherapy. But of course nobody was saying first line at that point.

DR ARMSTRONG: Yeah, if you ask me that question now I might say first line, and certainly it’s moving up earlier with every month that passes.

DR LOVE: Right. Yeah, no. I was just saying the way it was a few weeks ago. But in any event, this is where PARP was a few weeks ago, I think, which is after novel hormonal therapy for most people. You bring up sip-T, which of course is another important issue.

I want to ask the audience, audience, at this point I want to know if you go to clinic tomorrow and you see a patient who’s 65 years old who’s getting ADT for M0 disease after prostatectomy and now is found to have asymptomatic bone mets, and the genetic testing is negative, there’s nothing HR proficient, whatever you want to say. I want to know in general what would be your approach to this patient with castrate-resistant prostate cancer who doesn’t have any abnormalities. Would you go with hormones? Would you go with docetaxel? Would you go with PROpel? So I’ll be real curious to say. And I guess your answer to that at this point I guess is going to be maybe hold off for a while in a patient like this. We’ll see what some of the NCCN, et cetera, says.

Interestingly, when we asked at the GU symposium, we did a survey of 20 investigators, and we asked this question to the 20 investigators. And for 19 of them I think it reflected what they knew at that point, but for 1 of them, down there at the bottom who had some knowledge of the trial, that person voted differently. And this was the symposium we did on the 17th. Again, a couple hours after the data was presented. We showed this, and Dr Bryce who was moderating called on the person, who happened to be the principle investigator of the study who had just presented it, Dr Saad, to explain why he gave the answer he did.

DR BRYCE: Dr Saad, you jumped right in with abiraterone/olaparib. The world has changed tonight.

DR SAAD: Well, I had knowledge of some data that was just presented this afternoon.

So this is a 65-year-old man. And we actually did a subanalysis, and these younger men really have significant improvements in at least radiographic progression-free survival in unselected patients that did not have biomarker-positive testing for HRR.

We need to do better than what we’re doing first line. That’s the bottom line. And what we found was an 11-month improvement in radiographic progression-free survival.

Whether it’s going to be approved, I just wanted to be provocative and say that I would at least consider this in a young patient who’s first-line mCRPC.

DR AGARWAL: There are 2 trials, 1 trial was negative in — biomarker negative patients; 1 trial was positive. I think we need a deal-breaker trial down the line to settle this.

I have a lot of regard for Dr Saad. I look up to him. But I need time to go over the data of abiraterone plus olaparib.

DR LOVE: So actually almost a quarter of the audience says they’re ready to do it. They agree with Dr Saad, but the majority are buying into what you said. I guess we should actually ask them what they would do if a patient like this had a BRCA germline mutation.

Case: A man in his late 50s with metastatic hormone-sensitive prostate cancer, a history of breast cancer and a germline BRCA1 mutation — Julia Saylors, MD

DR LOVE: But let’s bring in a case. This is not exactly a PROpel situation. You’ll explain why. I mean it’s hormone sensitive as opposed to castrate resistant, but it’s just such an interesting case I was really curious what you thought about it. This is Dr Julia Saylors.

DR ARMSTRONG: Sure, sure. Yeah.

DR LOVE: She has a 58-year-old man, prior history of prostate cancer, removed with prostatectomy, high risk, a couple years later had PSA relapse, actually went on a clinical trial, the RTOG 0534 study for PSA relapse, got radiation plus 6 months of hormones, and then was found to have a breast cancer and was found to be germline BRCA positive, got chemo, surgery, is now on tamoxifen for breast cancer. And guess what? The PSA’s going up. Here’s Dr Saylors.

DR SAYLORS: He underwent a prostatectomy. He was found to have a T3bN0, Gleason 4 + 5, lymphovascular invasion.

Around 2017 he started to have an increase in his PSA.

Received radiation as well as 6 months of hormonal therapy.

In 2019 when he actually palpated a mass in his left breast. Subsequent workup with biopsy revealed an ER/PR-positive invasive ductal carcinoma. He underwent bilateral mastectomy.

And he has been on tamoxifen.

Genetic testing revealing the BRCA1 mutation, and so it was in that context when we noticed that his PSA began to rise.

I had recommended ADT with additional androgen blockade.

At what point will we be thinking about a PARP inhibitor as part of his treatment plan? He’s just now getting started with ADT.

He’s definitely a gentleman that is open to all the different options.

DR LOVE: So there are people who can cay well, where’s the research looking at a PARP in this situation. There are others who are going to say I kind of let this patient go out of my office who’s got a BRCA germline mutation. What are your thoughts about this scenario? Any recommendations?

DR ARMSTRONG: Yeah, Neil. So great question. BRCA2 is probably the most common mutation that you’ll find when you screen men for germline alterations, but BRCA1 is probably about 1% of men with metastatic prostate cancer. And these guys do have, often, a positive family history of breast or ovarian syndrome in the women and male breast cancer as well. So it’s not that rare, but it is a rare situation. And this is not a PROpel patient, as you point out. He has metastatic hormone-sensitive not castrate-resistant disease.

So we actually don’t have any data of a PARP inhibitor in this early of a setting. We do worry that using a PARP inhibitor too early might cause mutagenesis and create a more aggressive cancer later. It could also cause AML, myelodysplasia. I would save that PARP inhibitor for more when we have evidence that it’s going to work.

Certainly, if he was a first-line mPRPC patient I would strongly consider abi plus olaparib and ADT, but in the absence of that, I think if he has metastatic hormone-sensitive disease I would consider ADT plus a potent AR inhibitor to extend his remission.

DR LOVE: We’ve got a crack team there in the chat room. There are a bunch of people who always show up and ask these incredible questions. I love this one from Nicholas. He’s a regular. “Would this man not have been a candidate for adjuvant olaparib for his breast cancer anyhow?” What a great question because you know we just saw adjuvant PARP in breast cancer. Now this man was not probably high risk enough with his breast cancer. I think he was node negative, et cetera. But what a great question. You see 2 intersecting PARP now in 4 different diseases, including pancreas. So a great question.

DR ARMSTRONG: That’s great. You can learn so much from the breast cancer experts. And I also worry about tamoxifen perhaps stimulating his prostate cancer. It has some estrogen receptor agonism properties. So I might even consider switching his tamoxifen.

DR LOVE: That’s an interesting thought as well. Okay, let’s go onto another case. This is from Dr Ibrahim, a 70-year-old man. It’s kind of hard to find people who’ve been on lutetium, but we need to talk about it. I’m hoping, thinking it’s going to be — Andy, is it coming soon? People have been asking me about it.

DR ARMSTRONG: Coming soon. We’re prepared. In my patients it’s the number 1 question I have in clinic, this week even.

DR LOVE: Absolutely.

DR ARMSTRONG: So it’s — lots of people waiting, quite desperately in some cases, for this treatment to be available. And I think in 6 months we’re going to be dealing with what do you to after lutetium in a large group of men. Certainly, we’re learning that from our VISION study and what happens after the VISION approach.

DR LOVE: And this is a good example because this was a patient who was on the VISION study previously, responded, got 6 courses of treatment, went off the study, had disease progression, went on another trial of — actually the trial they went on I think was — included a checkpoint inhibitor, interesting enough. And we’re going to talk later on about some of the new research. This patient was very, I guess, into trials. In any event — and was now progressing.

Case: A man in his early 70s with multiple prior therapies for metastatic prostate cancer, including lutetium on the VISION trial — Sulfi Ibrahim, MD

DR LOVE: Anyhow, here’s Dr Ibrahim talking about this patient who had previously been treated, and here’s his question.

DR IBRAHIM: I actually saw a patient yesterday who was actually treated on the VISION study with lutetium 177. He got the 6 doses I believe on the study with an excellent response. At that time, on study, I think it was 6 doses that were allowed. He had PSA progression. He went on to a subsequent study with pembrolizumab and another investigational agent and now has rising PSA on that. When I saw him yesterday, he asked me, so my PSA never stopped responding to lutetium when I got it on the study. I tolerated it well. If the drug is going to be approved now, can I get it again? So in a patient who responds to lutetium 177, can you rechallenge the patient until a response is lost?

DR LOVE: So when you think about it, wow, things are really happening in prostate cancer all of a sudden. I mean some major, major things going on. So let’s talk about lutetium. Well, maybe you can start out with this case. What about retreatment? Is that something you’ve ever done? You had a bunch of patients on your study. Have you retreated any?

DR ARMSTRONG: Right. Yeah. Neil, it’s a great question. And I’m facing that decision in my own VISION patients who have had extraordinary responses to the experimental group, which is PSMA lutetium-177. And when they’re resistant to it, meaning they’ve had a great, extraordinary response and then progressed, we often do think about retreatment. It’s unclear how to manage these patients, whether you need another PSMA PET to document that they still have the target. Certainly, if their bone marrow reserve and their tolerability of the treatment is good, I think certainly they would be eligible for the commercial availability of PSMA lutetium since they will not have had it commercially. And I would offer it and follow them carefully.

But we do know that there are many ways for patients to fail lutetium. They can develop neuroendocrine transformation with loss of PSMA. They can develop loss of AR dependence, and that PSMA heterogeneity can explain a lot of the downregulation of the target. And so getting a repeat PSMA PET/CT is not unreasonable to make a judgment.

There was a nice GU symposium abstract from the TheraP study that actually looked at the SUV uptake of PSMA. The higher the SUV uptake, particularly above 10, the greater the benefit from PSMA lutetium relative to an alternative such as cabazitaxel. So I think you can use the parameters to judge the benefits of this therapy. And I think you’ll see a lot of new data on retreatment.

Certainly, the Germans have been doing retreatment in Europe as part of a compassionate use protocol for many years, and they have documented responses to many lines of re-treatment.

DR LOVE: So we asked the faculty where they think lutetium fits in, where they’d like it to fit in. They say third line, which I assume means after a novel antiandrogen and after docetaxel. What about before docetaxel in an older, frail patient?

DR ARMSTRONG: I think it’s a great question, and as a member of the NCCN Guidelines I can’t say how it will be received, but you can imagine that many patients do not want docetaxel, or they have neuropathy or frailty that preclude that, but you wouldn’t want to not be able to offer them a life-prolonging therapy like PSMA lutetium. So I do think there’s some patients who can get this as a second-line therapy who are not candidates for a taxane, but certainly after a taxane.

And once it’s approved we are going to see a likely bottleneck of patients who really demand this treatment and want it. There is going to be element of triaging patients who really need it urgently and those who have life-prolonging therapies available to them, where they can wait a few months.

DR LOVE: That’s interesting. And we see here, again, in this other survey, again people are talking about third line. We asked people kind of if they had the choice kind of what would come first, lutetium or cabazi. People generally say lutetium. Radium, same thing. What are your thoughts about that, Andy?

DR ARMSTRONG: Yeah. The TheraP study showed that the PSA responses were greater with PSMA lutetium versus cabazi. The times to PSA progression favored cabazi — favored PSMA lutetium over cabazi. And like I mentioned, the PSMA PET parameters can actually help predict those who benefit even more from the PSMA lutetium.

I do worry about certain patients who have this loss of PSMA expression or lesions that have low PSMA avidity. I would tend to favor cabazitaxel for those guys because the target’s not there. So, and particularly those with liver metastases are going to be more likely to have PSMA-low disease.

DR LOVE: That’s interesting. What about speed of response and response rate? I mean would you prefer to give let’s say docetaxel first? Does it have — indirectly in your clinical experience do you think it has a better response rate? Quicker response?

DR ARMSTRONG: Yeah. I don’t think so. I think docetaxel and cabazitaxel usually take 3 to 6 weeks to have a response, and that’s about the time you see PSMA lutetium is usually by that first scan. And so, again, I think it’s the pattern of spread and the PSMA avidity that’s probably going to determine that. Patients with liver metastases may have a slower or lack of response. Those who have very bright PSMA-avid lesions, SUV above 10, are likely to have a very homogeneous extraordinary response, where 90% of the guys are going to have a PSA that drops 50% or more.

DR LOVE: So another really interesting case from the chat room, one of our regulars, Dr Gupta. “75-year-old man with a great performance status, Gleason 9 prostate, gets mets in the bone within a year, on abi for metastatic disease, progression in the bones, subacute compression fracture at T12, soft tissue mass in the prostate bed, somatic PALB2 mutation.” What do you think?

DR ARMSTRONG: So PALB2 is —

DR LOVE: Chemo or PARP?

DR ARMSTRONG: Yeah. PALB2 is in the same BRCA family. Some have called it BRCA3, for example. It’s a binder of the homologous repair pathway and the same — very similar biology as BRCA2. And the PROfound study did include those patients. Although there was only 3 patients with PALB2, but it did show that some patients do have responses. I personally have had responses with PALB2. I like olaparib for this patient, but docetaxel is fine choice as well. We don’t have head-to-head studies of taxanes versus olaparib, but we think in the BRCA pathway olaparib probably is a little superior to a taxane. For non-BRCA homologous repair I think a taxane’s superior to olaparib. So I think that’s probably where I stand in terms of BRCA1/2, PALB2 I would favor olaparib first. And all the others I would favor, like ATM, I’d favor a taxane first.

DR LOVE: So you were referring to this study, the TheraP study, comparing lutetium to cabazi, and you can just visually see the difference in the waterfall plots. But I want to ask you also about tolerability issues, and particularly dry mouth. It’s hard to get a granular feel like how often that happens. I had a case presented to us that had really bad dry mouth. I don’t know how often that happens. So going beyond the numbers, what do you see with lutetium that’s clinically relevant?

DR ARMSTRONG: Yeah. With a beta emitter the dry mouth tends to be mild, tends to resolve with just drinking fluids or chewing gum; tends not to be as significant as like with the alpha emitters that are being studied right now against PSMA, where it tends to be more high-grade dry mouth. The same with dry eyes. You do see some GI upset. There’s a little PSMA uptake in the small bowel, thrombocytopenia, but not neutropenic fever, not neuropathy, not as much fatigue. I think in general quality of life is a bit superior with the PSMA lutetium therapies. And these patients can respond for a very long time. These side effects do continue to recur, so I think you have to counsel patients that with each dose that they may recur.

DR LOVE: I was just curious, I’ve never thought to ask anyone, but you see dry mouth with radium?

DR ARMSTRONG: No. Radium is really bone targeted, so it’s not PSMA targeted. The salivary glands have PSMA, so that’s why radium — radioactivity —

DR LOVE: Oh. Because you said alpha. Oh, that’s interesting. Okay.

DR ARMSTRONG: But when PSMA is bringing an alpha particle, which is lots more potent, it’s going to really fry your salivary glands.

DR LOVE: Sure. Right, right, right.

Case: A man in his late 80s with metastatic prostate cancer who received leuprolide/enzalutamide/denosumab and sipuleucel-T — Yanjun Ma, MD

DR LOVE: Okay, let’s go onto another case. This is an 88-year-old man with metastatic disease, multiple prior therapies. Here’s Dr Ma.

DR MA: He lives by himself. He’s an elderly male.

This is kind of a pretty common case. The patient who has upfront Lupron enzalutamide and had sip-T and now is progressed. But he is bone only metastases. So in this case, what would be the panelists’ suggestion about next line of treatment? Would they stay with the alternative antiandrogen treatment like abiraterone or what are the thoughts about Radium 223? Or, I know this patient’s elderly, but he’s kind of still independent living, performance status somewhat between 0 to 1, what about chemo? One is tolerability. But even if we take his age out of the picture, what is their preference about these options?

DR LOVE: So again, circling around this same scenario and how you think through that. 88-year-old man. She was not very excited about giving chemo, and I guess really the question’s going to be lutetium also in a patient like this. I would think this might be a perfect situation. What do you think?

DR ARMSTRONG: It’s a great question. And this is actually a very common scenario. The average age of these guys is in the late 70s, so it’s not uncommon to have men in their late 80s. He’s had very much proven therapies with sip-T and enza. With a bone-only predominant spread radium offers very good quality of life, so it could be an offering to kick the chem can down the road. If he does choose docetaxel, in older men I like the q2wk regimen, which offers a lower dose but a good dose intensity a little more often, which is more tolerable. And that’s been published by the Norwegian Finland group up in Scandinavia a couple years ago in Lancet Oncology as being equivalent to the standard every 3 weeks 75 mg/m² that we’re all comfortable with. So I like a 45 to 50 mg/m² every-2-week dose for older men. They tend to tolerate it better.

I would also consider at this point molecular profiling. We wouldn’t want to discriminate based on age. We’d take a good family history and see if he might be a candidate for a PARP inhibitor. Certainly when PSMA lutetium gets approved I’d do a PSMA scan, and he might be very happy to avoid docetaxel and get PSMA lutetium.

DR LOVE: So that’s a really great point.

Case: A man in his mid-50s with metastatic adenocarcinoma of the prostate with neuroendocrine differentiation (genomic LOH high, germline PALB2 VUS) — Spencer Henick Bachow, MD

DR LOVE: Let’s go onto the next case. This is a patient of Dr Bachow, a 55-year-old man with metastatic prostate cancer, but the interesting thing about him is first of all he’s had 2 different biopsies that show neuroendocrine differentiation. But also he has a germline PALB2, we were talking about PALB2, but variation of unknown significance, but has a genomic LOH score of 24, which is high. So general oncologists have been looking at this with ovarian cancer for the last 2, 3 years. They want to know how does all this stuff apply to prostate. Here’s Dr Bachow.

DR BACHOW: He had an FDG PET CT scan that showed hypermetabolic lymphadenopathy in the pelvis, some lytic lesions in a variety of different bones as well. Biopsy of the prostate showed adenocarcinoma of the prostate, Gleason 5 + 5 = 10 in 10 out of 12 cores with neuroendocrine differentiation felt to be grade group 5.

Because he was also having a lot of pain and we felt he was having a lot of progression of disease and 2 biopsies said that he had a significant neuroendocrine component, we started him on platinum and etoposide.

Genetic testing showed a PALB2 VUS.

Next-gen sequencing from his primary tumor tissue showed what was called genomic loss of heterozygosity at 24% which they read out as high.

The question is, is there a role for PARP inhibitor therapy in patients with metastatic prostate cancer who harbor a genomic loss of heterozygosity on somatic tissue panel, kind of like if a patient with ovarian cancer is HRD positive?

And how about PALB2?

DR LOVE: And how about a checkpoint inhibitor as a possibility as well. If you think about small cell of the lung, extensive-stage disease, standard of care, they’re going to get either durvalumab or atezolizumab. I’ve heard oncologists tell me they’ve done that with neuroendocrine cancers. Have you, Andy?

DR ARMSTRONG: I certainly have. And Dr Bachow has a very challenging case in front of him. This patient has not a pure small cell, it sounds like. It sounds like there’s an adeno mixed hybrid component, and these patients have what’s called aggressive-variant prostate cancer with lytic FDG-positive lesions, probably low PSA it sounds like. And so either a carboplatin/etoposide or a taxane/carboplatin regimen with ADT. Usually I’m offering ADT to treat the adenocarcinoma component.

We don’t have data at all on PARP inhibitors in just a pure genomic LOH population in the absence of a bona fide pathogenic homologous repair deficiency. The data that we showed from PROpel suggests that there are men that benefit from olaparib who are HRD negative, and maybe we can learn from that study a genomic LOH score could be useful. But we just don’t have that yet. I suspect that the greater the LOH score the greater the benefit from a PARP, but it's really kind of an unknown.

Certainly, the data around pembro is more in patients that have mismatch repair deficiencies rather than homologous repair deficiencies. And so a PALB2 VUS is not considered pathogenic. About 90% of those end up being normal variants. Some patients who have a rare ancestry, many African American men, men of different ancestries, are not well represented in the genomic data sets. And so we see more VUSs in minority populations, for example, and some of these actually are pathogenic. They just haven’t been characterized yet.

If he does receive a PARP inhibitor I don’t know if he would respond. It’s really an unknown question. But getting a platinum is in many senses very similar. You can see extraordinary responses to platinum therapy in these types of patients, so I would offer that.

As a second line I might consider cabazi/carbo. There’s a great randomized MD Anderson trial published in Lancet Oncology about 2 years ago that showed in these types of patients a survival benefit from that doublet.

DR LOVE: So yeah, I have to say, and I don’t know whether my colleagues out there also are starting to feel a little confused about how the genomic assays were done with PROpel and MAGNITUDE. Because you kind of talk about it, you use this generic term, I forget, whatever, proficient, et cetera, but you’re saying you didn’t really look at any kind of score. Because like in ovary they have scores —

DR ARMSTRONG: Right.

DR LOVE: — like this LOH. So you just — when you say they have, I don’t know, deficient, it means they have a specific mutation.

DR ARMSTRONG: Correct. Yeah.

DR LOVE: Is it BRCA? Is it just BRCA? Or what else?

DR ARMSTRONG: Yes. Exactly. So homologous repair deficiency in the PROpel study means you have a mutation in 1 of the homologous repair enzymes, like BRCA1/2, ATM, kind of like the PROfound data set. There isn’t an LOH score, although you could compute that and look at that as a separate score. When we say that in PROpel patients were negative, that means they had ctDNA and a Foundation test on their tumor tissue, and both were negative for any of those alterations, and so they would be truly wild type for both somatic and germline.

DR LOVE: Really interesting that they still saw a benefit with olaparib.

Case: A man in his mid-70s with metastatic castration-resistant prostate cancer and Lynch syndrome (BRCA-VUS, MSH6 and BRAF V601E mutations) — Kapisthalam (KS) Kumar, MD

DR LOVE: Okay, here’s another real-world case. Once you get into the real world you never know what kind of variations you’re going to get. This is a really wild case. So a patient with metastatic disease, 74 years old. An NGS is done, and they end up saying that he’s got actually Lynch syndrome, and as you’ll hear it actually gets diagnosed in a family member. And even more amazing, he turned down getting immunotherapy. He did not want immunotherapy, which I’ve never heard that one before. But then also this unusual BRAF mutation. Here’s Dr Kumar.

DR KUMAR: I did a myRisk panel from Myriad, BRCA mutation, which was negative. There was a variant of unknown significance. It was positive for mutation of MSH, so incidentally when looking for BRCA we found he has a Lynch syndrome, positive MSH, so we notified his family. One of his sons was also positive, and so he’s undergoing colonoscopy. So that one good thing came out of this.

We did a liquid biopsy also. That showed a BRAF V601E mutation. What does that mean? Does this respond to BRAF inhibitors?

Should I give him chemotherapy as the option for this patient, PSMA lutetium will be a great option for this patient, especially at this age, with not a great candidate for chemotherapy.

DR LOVE: So what about radium?

DR KUMAR: Well the radium now is an option, but I’m not sure whether that would be approved for that because there are some positive lymph nodes on the PET scan, although they are small.

DR LOVE: So a lot of things to talk about. But first I’m curious, have you seen MSI-high prostate cancer? Have you treated anybody with prostate cancer with MSI high with immunotherapy? And what kind of immunotherapy do you use?

DR ARMSTRONG: I absolutely have, and they are some of my most memorable cases here at Duke in my clinic, where I’ve seen probably a dozen such patients. It’s about 3% to 5% of all men will have MSI-high CRPC.

DR LOVE: Wow. That’s high.

DR ARMSTRONG: And they can have — yeah, 3% to 5%.

DR LOVE: That’s a lot.

DR ARMSTRONG: And the response rate to single-agent pembro is about 50%. And we’re not talking about modest responses here, Neil. These are extraordinary responses. So I have a group of patients, maybe 5 or 6, that have had complete response, meaning PSA that went from 60 to 100 down to 0, resolution of their disease on imaging, and after a year of therapy have been able to stop their treatment, including their ADT. So we’re talking about durable remissions of CRPC now allowing them to stop therapy.

So I would strongly encourage this guy to consider a checkpoint inhibitor. I think a lot of these other mutations are more likely to be passengers. When you have MSI-high disease and mismatch repair deficiency you see mutations in all sorts of genes because it’s just a mismatch repair-deficient tumor, so you see a high TMB. That’s what allows the immune system to recognize it and see it as foreign and for these patients to do really well. So I would continue to encourage pembrolizumab for this patient unless there’s some strong contraindication. I don’t think using a BRAF inhibitor’s going to do anything.

DR LOVE: So a quick question for the audience. Audience, have you had a patient with any solid tumor and MSI high, colon, whatever, that had a great response like Andy’s describing with his patients to a checkpoint inhibitor? Have you had a patient like that in your practice? I’m curious because I’m going to bet the vast majority of people have, not in prostate cancer, but I think certainly in other cancers. But let’s just see. It might be kind of interesting.

While we’re waiting for that, I’m just kind of curious, breast cancer was a long time coming to get checkpoint inhibitors, but it finally got there, even in the adjuvant setting now with triple-negative disease. But prostate, not quite yet except for MSI high. But I guess my question is it coming. And one strategy that we see a lot of is a TKI plus IO. Of course, the poster child for that is renal cell, where you have so many of these great combinations. Where are we today with checkpoint inhibitors in MS-stable prostate cancer, particularly the idea of TKI, for example, on this slide here atezo and cabo. Pretty good response rate, although maybe that’s the cabo. I don’t know. What are your thoughts?

DR ARMSTRONG: Yeah. Before I get to talk about the cabo I would like — for single-agent PD-1 we have looked at this in several large data sets. One identified CDK12 as an immunogenic subset of prostate cancer with a response rate to pembrolizumab and nivolumab of about 25%. We published that as a multi-institutional case series in JCO Precision Oncology last year.

A second subset molecularly that we published from our Duke experience was a mutation in this gene called LRP1B, which is a low-density lipoprotein receptor. And patients who had this had a 75% response. So there is probably a molecularly-defined group of patients, besides MSI, that can respond. But most patients are MSS, as you mentioned, and this COSMIC study is trying to build on that.

A lot of the companies, like Merck and BMS, are studying cocktails, combinations of enza or olaparib or docetaxel with a PD-1. We haven’t seen any studies be positive yet, although we’re very hopeful. But these are unselected patients, and just like in this study, the cabo/atezo cocktail, which has demonstrated activity in multiple solid tumors, is designed to overcome some of the myeloid checkpoints that are impairing immune response to PD-L1 inhibition.

You do see some higher PSA responses than you might expect with either drug alone. We don’t know how durable they are. The ESMO update from this past fall showed kind of a dwindling response rate compared with what was published. You see here that now we’re down to maybe a 23% response rate.

So the cocktail is a bit more toxic. Cabo has some significant toxicities in terms of hand-foot and hypertension, cardiovascular risk, and diarrhea.

So I think we will have to wait for that CONTACT-02 trial to read out. Now the CONTACT-02 is designed before we had PSMA lutetium. It’s designed before we have the CARD trial, where this is not really the standard of care anymore to give a second AR inhibitor.

The earlier case from Dr Bachow and Kumar and others have asked can abi work after enza and vice versa, and the answer is generally no. These drugs do not work as a second-line AR switch. You’ve got response rates down in the 10% to 20% range lasting 3 to 5 months, that’s it, and should not be considered the standard of care, particularly for a clinical trial. Cabazitaxel/docetaxel should be considered the standard of care by which cabo/atezo should be compared against. So I think the trial has some issues that it’s going to have to work out.

DR LOVE: Let me just ask you, you mentioned something I haven’t heard before, and maybe you can elaborate a little bit. It’s always, to me, been a mystery why you see synergy between IOs and antiangiogenics, whether it’s bev or a TKI. I always thought it had to do with the vasculature or something, but you were saying something about a checkpoint. Is that on this thing here?

DR ARMSTRONG: That’s right. So yeah. So on here you see the macrophage phenotype that’s immune suppressive. There’s these cells called myeloid suppressor cells, and there’re tyrosine kinases within these immunosuppressive cells that can be blocked. TYRO3, AXL, and MER have activity in immune cells. So it’s got nothing to do with their antiangiogenic property but really an off-target effect of engaging what’s called a myeloid checkpoint.

So myeloid cells are really important in regulating immune invasion in prostate cancer, and that could be how cabo is working.

Case: A man in his late 80s with mCRPC and a CHEK2 mutation — Dr Ibrahim

DR LOVE: So I want to go for one final case. This is an 89-year-old man, again of Dr Ibrahim, a patient with metastatic disease and a CHEK2 mutation. Here’s Dr Ibrahim.

DR IBRAHIM: 89-year-old elderly gentleman with metastatic castrate resistant prostate cancer. Has had the standard lines of therapy including leuprolide, bicalutamide historically, enzalutamide, abiraterone and prednisone. Was then treated with dose reduced cabazitaxel.

A liquid biopsy reveals a CHEK2 mutation.

When we discussed this patient’s case at the molecular tumor board, they mentioned the CHEK2 mutation, but they also mentioned the allele frequency was low.

My question here is, how do you distinguish in a case like this, if the CHEK2 mutation is a true actionable mutation?

And then my second question here will be, is there any data regarding the use of PARP inhibitors in patients with prostate cancer who have the CHEK2 mutation?

DR LOVE: And I would enlarge it, Andy, you have such a great basic science background, just in general about allele frequency. I hear this question comes up in AML and all these other diseases. Like is there a way to look at it? If it’s low it’s not relevant? I mean how do you look at that?

DR ARMSTRONG: Yeah. This is a great question, and it’s also spurred by the presence of something called clonal hematopoiesis, where you can have normal cells, immune cells, that undergo mutation. And sometimes these DNA repair defects are actually not present in the tumor at all. They’re present in your normal cells. That’s called CHIP, and CHIP is actually a risk factor for myeloid and lymphoid malignancies, as well as heart disease. So we’re learning a whole lot about CHIP.

When we’ve looked at this in older men with prostate cancer we find CHIP in about a quarter of these patients. And CHIP mutations are commonly in genes like p53 but can also occur in DNA repair enzymes like TET2, ATM, and even BRCA1. CHEK2 I’ve not yet encountered, but it’s possible. The CHEK2 is a passenger for a CHIP lesion. And there are myeloid panels you can send off to look for CHIP. So instead of sending his plasma looking for tumor DNA you can send his white cells and see if the mutation’s present in his normal cells to rule out that.

So in the absence of that, if you’re going to assume this is pathogenic and just at a low level, the allele frequency, Neil, kind of gets that is this homozygous/heterozygous and the depth and the coverage of your probe and how many fragments of mutant DNA are there in the plasma. And it’s sometimes very challenging to figure that out if the disease burden is very low. You can have a low allele frequency just because there’s not much tumor DNA there. Certainly a germline alteration, you might expect a much higher allele frequency. But CHIP can be present even at high allele frequencies, so it doesn’t really rule that out.

CHEK2 is present in the PROfound study. I think they had just a few patients. They had I think 12 patients with CHEK2 mutations in PROfound. There was a slight benefit from olaparib in those patients. I personally have had 1 patient who’s responded and 1 who hasn’t. It’s a little bit like a coin toss. CHEK2 is a little bit of a different regulator. It’s not quite as bona fide as a BRCA1 or 2 DNA repair deficiency, but it’s not wrong to try olaparib in a patient like this as an attempt to improve his survival.

DR LOVE: So I think Raje in the chat room is asking a question that a lot of people might be asking, like how do you order a CHIP assay, or how do you find out about CHIP. Is it like a research tool, or is there a commercial assay?

DR ARMSTRONG: Yeah. So we — at our university we have what’s called a myeloid NGS panel. If you’re a leukemia or MDS doctor you order these all the time, and so in a way you’re ordering an MDS NGS panel. So you’re basically sending the white cells for sequencing, and if you find the same mutation in the white cells that suggest this is CHIP.

DR LOVE: So Demetrius in the — oh, incidentally, for the poll, 57% of the audience has had a patient who had a dramatic response to an MSI-high tumor.

DR ARMSTRONG: That’s fantastic.

DR LOVE: I’m sure most of those —

DR ARMSTRONG: That is why we recommend testing. Yeah.

DR LOVE: Yup. And once you see that, you test everybody.

DR ARMSTRONG: Everybody.

DR LOVE: So interesting question from Demetrius. I don’t know if you’ve ever seen this. Have you ever seen a patient, I would imagine maybe, who’s MSI high and has some kind of BRCA abnormality or HRD abnormality?

DR ARMSTRONG: Yes. That is well known to happen.

DR LOVE: And if so, what you do — what do you do first? Are you doing both or what?

DR ARMSTRONG: So here I think in general the BRCA mutation is probably the passenger. It’s the MSI that’s driving mutations just like that BRAF mutation. In a true MSI patient you’re going to get a list of many genes that are mutated. There’s just mutations throughout the entire genome. And these patients probably don’t benefit from the PARP inhibitor, but they do benefit from the pembrolizumab. Great question.

Journal Club with Andrew J Armstrong, MD, ScM

DR LOVE: So I want to go through a few of the — a few of your papers. I don’t know if this is more of historic interest or it actually is relevant at this point, but I’d love to follow it over the years in terms of this assay.

DR ARMSTRONG: Sure.

DR LOVE: Maybe you can kind of bring us up to date with where we are with AR-V7.

DR ARMSTRONG: Right. So in 2019 or so we led and published the PROPHECY study, which looked at the Hopkins and the Epic Sciences AR-V7 test in a multicenter prospective study. And it did demonstrate the prognostic significance of AR-V7 testing in circulating tumor cells in men who are undergoing AR therapy.

Whether you should order it is an entirely different question. I consider an AR-V7 test to be useful if I’m on the fence between an AR inhibitor, as a second-line therapy after an AR inhibitor, or a taxane. Certainly, as PSMA lutetium or radium become options this can help you sort out what the next-best thing from the menu might be. I don’t order AR-V7 testing in isolation. It is a specialized test, and I’m ordering it in combination with other molecular profiling tests, either on a tumor biopsy or a liquid biopsy. So it’s really to help kind of sift through the big menu that we have now. And so it can be helpful.

The commercially-available test right now is the Epic Sciences nuclear AR-V7 test, which was validated in our PROPHECY study for improving — associated with very short survival, short progression-free survival and basically a 0% response rate to enza after abi or abi after enza. So really a strong negative predictive value.

DR LOVE: Of course as you say now hopefully we’ll have lutetium there as a consideration. But still getting back to this issue of chemo or cabazitaxel versus a second hormonal therapy, I mean first of all it kind of looks like second hormonal therapies in general don’t work very well at all.

DR ARMSTRONG: That’s right.

DR LOVE: In general, so I would assume you’re still applying the CARD data, but just maybe you’re going to move lutetium up. Is that the way you kind of broadly see it?

DR ARMSTRONG: Yeah. I’m really not recommending a second AR inhibitor except in patients who really are not candidates for a taxane. Sometimes we will try out of the box approaches like bipolar androgen therapy. That’s an approach pioneered at Hopkins that did have a response rate of about a third and can restore sensitivity to an AR inhibitor. So occasionally I’m doing that. It’s certainly off label, giving testosterone in a bipolar manner.

But yeah, CARD indicates that cabazitaxel is a Level 1 evidence third-line treatment. PSMA lutetium would also be in that choice. And again, biomarkers that might help you between those 2 would be the PSMA PET scan itself, the pattern of spread, such as to liver or lymph nodes, the symptoms of a patient, and what their experience was like with their prior chemo.

DR LOVE: So we actually — we’re talking about this wild concept of testosterone, but we were talking the other day in a breast cancer webinar, there’s this drug fluoxymesterone, it was like an impeded androgen that caused responses in breast cancer. Has anything like that been tested in prostate cancer?

DR ARMSTRONG: Yeah. So high-dose testosterone in the setting of a castrate level basically cycles the testosterone up and down, and that’s called bipolar androgen therapy, or BAT. And the TRANSFORMER study, published by Sam Denmeade and colleagues, did show a response rate. They’re still working on the mechanism, whether it’s differentiating cells, whether it’s causing a DNA double-strand break through AR-mediated recombination, which is very intriguing. Or maybe it’s even having an immune response. They show STING pathway activation with this. It’s really unknown, and people are now combining BAT with lots of other approaches to try to optimize that.

DR LOVE: So little known historic fact that tamoxifen, when it became available, was in a Phase III trial compared to high-dose estrogen.

DR ARMSTRONG: That’s right.

DR LOVE: DES.

DR ARMSTRONG: Yes.

DR LOVE: And you know what? It was only the toxicity that was better. The efficacy was the same.

DR ARMSTRONG: Interesting.

DR LOVE: It got approved because it was less toxic, so not the first time the concept has come up.

Talking about new things, I don’t know if I told you, we have this contest for best trial name, and I’ve decided I’m going to enter the COURAGE study. Right now the GLOW study from CLL is my favorite, but the COURAGE study sounds pretty good. And also I want you to go through some of the biology here; always interested in a little translational work. So what’s this new agent?

DR ARMSTRONG: Sure. So let me mention the target. The target here is called CBP/p300. This is an AR coregulator. It’s an epigenetic regulator of AR activity, and it may also regulate the Myc oncogene, so it’s kind of got multiple functions. And so we have this small molecule inhibitor made by Forma. It’s called FT-7051. It’s a blocker of CBP/p300. We know this target actually goes up as men progress on drugs like enza and abi, and that it’s very much responsible for AR-positive castration resistance.

And so this COURAGE study is a first-in-human Phase I dose-escalation traditional study of this new small molecule inhibitor. So I presented the trial in progress at ASCO this past year, and at AACR we had some preliminary results with a responder already. So we’re happy to present that data. It’s an ongoing study. It’s open at our center and many centers around the country.

DR LOVE: When you think about it, just to see 1 good responder for an agent like this —

DR ARMSTRONG: That’s great, yeah.

DR LOVE: — I think would be really, really exciting. Really cool.

DR ARMSTRONG: Absolutely.

DR LOVE: All right. So we were talking before about neuroendocrine disease. This paper you were involved with from the GU symposium looked at avelumab. I’m getting the feeling that it’s not very effective by itself, but maybe with chemo. Is that where it’s being looked at right now?

DR ARMSTRONG: Right. This was a small study, but it was the first time anybody had given a PD-L1 or PD-1 inhibitor in a trial to men with this neuroendocrine prostate cancer. We know that small cell lung cancer patients respond really well to PD-1, but we have no idea about neuroendocrine prostate cancer. We had about a 7% response rate, which is not very good. This patient who did respond had an extraordinary response. Of course, he was MSI high, so explainable through that, but he had small cell.

We are moving on from this to look at more doublet cocktails. We have the CHAMP trial, great acronym, which is cabazi/carbo/ipi/nivo, a 4-drug combination, that is open at our center. And several other centers are coming onboard with that soon.

DR LOVE: CHAMP. I like that one too. Okay, I’m going to finish out. Even though you have all these great translational papers I’ve got to ask you about this study looking at diet with Dr Freedland who’s had an interest in this for a long time. What did you guys find out?

DR ARMSTRONG: Yeah. So we studied the Atkins diet, which is a low carb, very intensive diet approach —

DR LOVE: Wow. Cool.

DR ARMSTRONG: — in these men who are undergoing ADT. Many of these men do suffer from obesity and weight issues, and we did find that the low-carb diet helped them lose weight, reversed metabolic syndrome, reduced their waist circumference, and in some men their doubling time slowed down, suggesting that a dietary intervention may reduce the rate of progression, just like in the preclinical studies. So this was a low-toxicity intervention that may help patients be healthier.

DR LOVE: So is that what you recommend to your patients? What kind of lifestyle alterations or diet, exercise do you recommend, particularly men about to start ADT?

DR ARMSTRONG: Certainly exercise for all men. Exercise has cardiovascular protection. It reduces hot flashes, builds bone density, builds muscle mass, cardiovascular fitness. That’s for everybody. And certainly 3 to 5 days a week, 45 minutes of aerobic mixed conditioning is kind of a minimum, but you can certainly do more than that.

A low-carb diet is reasonable. There’s lots of heart-healthy diets out there, whether you follow more of an Asian diet or a South Beach Diet or a Mediterranean diet. Generally it’s the carbs that are creating a lot of the weight gain and the insulin resistance, so reducing those can really help moderate some of the side effects of ADT.

DR LOVE: So Andy, thank you so much for working with us today. Audience, thank you for attending. Come on back tomorrow. We’ll see what Dr. Wierda thinks about combining BTK and venetoclax in the same regimen up front or whether he wants to split them out. Be safe, stay well, and have a great night. Thanks, Andy.

DR ARMSTRONG: Thank you, Neil.