Introduction

DR LOVE: Good morning, everyone. I’m Neil Love from Research To Practice, and welcome to Breakfast with the Investigators, as this morning we talk about what’s up with the management of prostate cancer. We have a great faculty today, and they’ll be presenting cases from their practice as we go through this session. We’re going to make rounds with them.

You have iPads in front of you that have all the slides we’re going to try to show. We may not show all of them, but they’re on the iPad and also on our website if you want to download them. If you have any questions or cases you’d like to run by the faculty, just type them into the chat room, and you can also do the evaluation on the iPad.

For our many attendees online, first of all hi to you all. The last couple days we’ve had a lot of people tuning in here online. I wonder if maybe even some people here in Chicago. In any event, the same functions are available to people online in the chat room; the slides, you can ask questions, as well, and also take the CME.

We’re going to record all of our programs we’re doing this week here at ASCO, and we’ll post it within the next week or so for your colleagues who weren’t able to make it today.

This is the third of 9 symposia we’re doing this weekend here at the Hilton, covering a variety of topics with a variety of formats, but our one mission is really to target the general medical oncologist in community-based practice trying to keep up with lots and lots of things going on in medical oncology. We have 40 investigators that are going to be working with us this weekend. We’re really thrilled to be able to have that opportunity.

Tonight and tomorrow night we have 2 very unique programs I’d really love you to check out. For the last 2 years during the pandemic we’ve been doing 1-on-1 sessions with general medical oncologists, having them present cases. We’ve actually presented more than 2 thousand real cases in webinars in the last 2 years, and tonight and tomorrow night you’re going to see some real cases from practice by these general medical oncologists.

Optimal application of hormonal therapy in prostate cancer management

DR LOVE: So we’re going to — as I said, this morning we’re really going to make rounds. We’re going to actually talk about some patients in the practice of our faculty. We’ll start out with a quick update on the many things going on with hormonal therapy of prostate cancer, then we’ll talk about metastatic castrate-resistant disease and particularly the exciting introduction of lutetium into practice. And we’ll finish out, again, with one of the hottest topics of all of medical oncology, PARP inhibitors in general and now specifically in prostate cancer.

So this — we’re going to show some of the questions we asked you this morning on the iPad, as well as online based on the cases we’re going to present. In a second you’ll hear about this 76-year-old man who’s status post IMRT and 2 years of ADT but then has PSA progression and now the doubling time is 4 months, the PSMA PET scan is negative, and so the question is, and Alicia I’m going to ask you how you think you would be thinking through this situation. The audience is thinking ADT and enzalutamide, and almost all of the audience is thinking of an antiandrogen, but as you can see there’s a little bit of difference in which one they utilize. Any thoughts, Alicia?

DR MORGANS: Sure. So I think you have options here, which is what is being reflected. If you have negative conventional imaging, you have a negative PSMA PET, you have a rising PSA, this is really a setting where we think about if the patient’s on ADT this is really a nonmetastatic CRPC type of a setting. So we have 3 drugs available. We can choose those drugs based on the side effect profiles, based on what’s available, based on what’s comfortable for you as a clinician. So I think apalutamide/enzalutamide/darolutamide are all options in this setting, and what I would choose really depends on the patient in front of me, and even considering drug-drug interactions can be useful.

DR LOVE: So for example what would be a patient where you would utilize enzalutamide?

DR MORGANS: So I think that’s also a great question. So any patient in this setting, as long as they don’t have a seizure history, and as long as the drug-drug interactions don’t prevent that patient from getting that drug.

DR LOVE: So we’ll kind of pursue this a little bit more as we go through in terms of how people see the various side effect profiles, but Andy, I’m kind of curious, if a patient in this scenario came to you who had seen a prior doc, and the doc said how about — I think maybe you ought to take abiraterone, less expensive, et cetera, would you say that’s what I would do? Would you say that’s not a good idea? Or it’s okay but not my treatment?

DR ARMSTRONG: Yeah. I think it’s important to ask this question because we see it sometimes, and abiraterone has what we call Phase II or Level 2 evidence to support this in the nonmetastatic CRPC. We’re all comfortable with abi in the hormone sensitive and the CR — mPRPC setting. It does work in this setting, but it doesn’t have Level 1 evidence. You won’t find it in our NCCN Guidelines for that reason as a Level 1 category of choice. And that’s because it hasn’t been shown to improve survival like the other 2 agents.

But if there was an issue with cost and affordability or availability abi is available, and it’s generic now, and you can have a food effect, where some patients cannot afford even abi. So in many parts of the world abi is still not affordable. So if you had an issue with resources, taking abi, for example, 1 pill with a low-fat diet is 75% cost savings.

DR LOVE: In terms of optimal therapy, people who would have the option of taking any of these approaches, how do you decide which strategy, which antiandrogen, and what’s your take on the differential side effect profile?

DR ARMSTRONG: I’m very much aligned with Alicia here in looking at the patient’s comorbidities. Age is a major factor, but biologic age is probably more important than actual age. So there’s physiologic age. If you have a frail patient who’s having falls I probably would steer away from enzalutamide because of the higher fall and fracture risk, and darolutamide’s a pretty good choice for that patient. A patient who has many drug interactions with anticoagulants or statins or heart medicines also would have problems with apalutamide or enzalutamide. So darolutamide is a great choice for elderly patients who are more frail, infirm, take a lot of other medications, polypharmacy issues.

DR LOVE: So Alan, take a look at this question we asked the audience. Kind of some interesting answers here. We said regulatory issues aside, which of course is not exactly real, but we said in this same situation, you have this patient who’s got rapidly increasing PSMA — PSA, and they get treated with an antiandrogen, we talked about each one, but now they have disease progression and they’re still M0. PSMA is negative. Now the audience is saying if they could they’d give maybe chemo. They may give lutetium or both. Pretty let’s say interesting answers. What do you think, Alan?

DR BRYCE: Yeah. We’re up here smiling because the scenario is very contrived. I’ll say a couple of things. So number 1, even on the last question there’s retrospective data from UCSF, UCLA, the other PSMA groups that really established it, looking at the nonmetastatic CRPC population. And they said retrospectively for patients who would have qualified for any of the 3 registration trials how many of them would have been PSMA positive, and it was 98%. So the patient with nmCRPC who’s PSMA negative, PET negative, really almost doesn’t exist. Everyone has disease.

So now we have someone who’s progressing after having been on combined androgen blockade with a next-generation AR inhibitor, and they’re still PSMA PET negative, okay. So number 1, I would never do lutetium in a patient who’s PSMA PET negative, right? So right off the bat I don’t think it’s an option, and for 2 reasons. I mean 1) without question PSMA PET positivity’s the biomarker for the efficacy of lutetium-177, and we’ll say it for a couple of reasons. I mean 1) of course lutetium is a targeted therapy. It’s a drug antibody conjugate in a sense, so you have to have the target for the drug to work. But even beyond that the data out of the Australian/New Zealand group shows that SUV is predictive of response. SUV of 0 is, I would say, no response. I wouldn’t do that.

DR LOVE: Great. So — and we could spend — almost spent an hour, I feel like, talking about PSMA scanning in the faculty room, so we’ll try not to spend too much time on it. But obviously with what you just said, when you look back at the trials that we’re basing our therapy on, and now we have a tool that changes the whole staging, you get into a little bit of the art of oncology. So we’re going to try to tease that out, how you integrate PSMA scanning at this point.

But Andy, let’s get into some real cases here. You have this 67-year-old man. What happened with him?

DR ARMSTRONG: Yeah. So I brought up this case, Neil, because he’s an African American male, and if you look at all of our Phase III trials in nonmetastatic CRPC African American men are underrepresented pretty woefully, actually, less than 5%. It should be about 20% based on the prevalence in this population. And so I wanted to bring up what an experience might look like for a patient who had a toxicity.

So this gentleman has nmCRPC. He has node-positive disease, which meets the criteria for nonmetastatic disease. So even though the patient has metastatic disease after IMRT, ADT, and has pathologic pelvic nodes, that’s N1, so it’s metastatic to the nodes, but it’s not outside the pelvis so it’s not technically M1. So he’s nonmetastatic disease. His PSA doubling time is fast. And we chose apalutamide for him.

And I want to show you what he experienced. So a couple months into therapy he developed a hyperpigmented rash. It was not particularly itchy. It could be covered by his sock, so nobody saw it. It spared his palms and soles. It caused a little bit of itch. We tried a little topical hydrocortisone. We held the drug. But his PSA — he was very happy his PSA was 0 now. He felt great. His nodes had resolved.

And so I wanted to talk about the — of how you manage the rash with apalutamide. Because it’s not an uncommon phenomenon. In African American patients you can see more of a hyperpigmentation finding. And so skin rash with apalutamide tends to be mild to moderate. About a quarter of the patients will get it. Some patients it resolves with just drug hold, and you can resume at either a dose reduction or the same dose, and it frequently doesn’t recur. So patients can do well with it.

For this patient we dose reduced. The rash resolved, but he remained with this hyperpigmentation under his socks. But it didn’t really bother him that much. And his PSA has remained 0 to this day, which has been now 3-plus years.

There’s a lot of treatments for skin rash, topical hydrocortisone, sometimes systemic steroids were required in the SPARTAN trial, but most patients can get away with topicals.

DR LOVE: Yeah. We did a lung cancer symposium, and Heather Wakelee from Stanford said she never used to ever talk to dermatologists, now they have 6 that do nothing but deal with their patients.

DR ARMSTRONG: Right. Exactly.

DR LOVE: So many agents cause dermatologic issues.

Well, this is another case that Alan’s going to present in a second. We want to kind of take the temperature of the audience in terms of hormone-sensitive metastatic disease. We said what’s your usual approach to that. You see a variety of answers here, interesting. ADT/abiraterone, ADT/docetaxel, ADT/docetaxel/darolutamide. The ARASENS regimen seems to be pretty popular in this room. ADT/docetaxel and other hormonal therapy, Alicia, also very common. we’ll let Alan talk about his case, and then Alicia you can react to it. Alan, what happened with this 71-year-old man?

DR BRYCE: Yeah. So this is a gentleman, initial diagnosis of Gleason 4 + 3 disease, and within a couple of short months he undergoes surgery, he has a PSA nadir that’s undetectable, but within less than a year you already see a rising PSA. So at that point he starts on ADT. He gets salvage radiation therapy. Next slide.

DR LOVE: Sorry.

DR BRYCE: And unfortunately, fairly quickly, again the PSA starts to go up despite castrate levels of testosterone. So we see it continue to climb over 3 months, and at this point, several years ago, choline PET/CT showing uptake in an iliac node, 1.7 cm. So at that point we start him on apa, which he doesn’t tolerate very well at all, so within a couple of months we stop that and switch him to darolutamide, and he gets a good response that’s durable for a couple of years there.

DR LOVE: So actually we got a question about the case before. As I walked up here I saw this question popped in about your case saying what about stereotactic radiation to that node.

DR BRYCE: Yeah. It’s an option, right? When you have limited-volume disease you can radiate a spot. The data around that is really about time off treatment, right? You do the local therapy; you buy the patient some control before they have to move on to other therapy.

In this patient one of the things you saw was fairly rapid progression. Things were really moving, right, so I really didn’t think that just radiating 1 spot was going to buy him a meaningful disease-free interval, which is why we said let’s give the systemic therapy.

DR LOVE: Yeah. I think maybe the thought was to do both. Alicia, can you talk a little bit about your current approach to hormone-sensitive metastatic disease, and in particular how the ARASENS data that was just presented at the GU ASCO Meeting, what you think about those data and how you’re thinking about this decision nowadays?

DR MORGANS: Sure. I think first that the ARASENS data was incredibly compelling at GU ASCO, especially because it came on the heels of the PEACE1 data, which was also looking at a triplet-therapy approach. In both settings patients with metastatic hormone-sensitive prostate cancer were treated with ADT and docetaxel as a standard backbone. And then in the ARASENS trial patients had darolutamide in addition to that, versus placebo.

Really importantly, in the ARASENS trial, of course, all patients are really getting an active control arm. ADT and docetaxel, that’s a standard of care for metastatic hormone-sensitive disease, and it was the standard when the trial was designed. So this is, I think, really important. We’ve got a very active control, and now we have active control plus darolutamide.

And the patients in this trial were metastatic hormone sensitive and fit for chemo. They weren’t selected because they had de novo metastatic disease, and they weren’t selected because they had high-volume disease, though a majority of patients had de novo metastatic disease, and we think probably more patients had high-volume disease. But volume hasn’t yet been reported for ARASENS.

So what we found in this trial is that, as you can see here, there was a really nice reduction in mortality, with a hazard ratio of 0.68 associated with ADT/docetaxel and darolutamide as compared to ADT/docetaxel. And the drugs were given concurrently, ADT/docetaxel/darolutamide, so the docetaxel and the darolutamide were given together. And the tolerability profile seemed actually quite good. And darolutamide, of course, was continued until progression.

So from my perspective, in a drug combination that’s well tolerated and really this maintenance approach with darolutamide, it’s a no-brainer to really add that drug for chemo-fit patients with metastatic hormone-sensitive disease. And with a hazard ratio like that, and a reduction of mortality, it’s something that patients find both tolerable and is highly effective.

DR LOVE: So Alan, obviously the audience is thinking more about both chemo, as well as hormones in the hormone-sensitive situation. We saw the PEACE1 data combining abiraterone with androgen deprivation and docetaxel. And then we saw this really interesting, I guess another part of the STAMPEDE platform, in high-risk nonmetastatic disease, where they add it, and not a huge surprise. You kind of wonder why it wasn’t done already. We added abiraterone. The patients did a lot better.

Where does this land you, in general? This patient actually had pretty limited disease, right?

DR BRYCE: Yup.

DR LOVE: This is not high-volume disease. You had that 1 node. But he was young. So the audience is saying chemo plus hormones. Do you agree?

DR BRYCE: Yeah. So the — we’re talking about 3 different populations, and this is where prostate cancer, I think, has gotten really difficult for a lot of practitioners because most community practitioners aren’t seeing the early patients. These patients are in the urologist’s clinic. The 3 of us on stage see the early-disease patients because of the centers we were at — we are at.

The STAMPEDE is a high-risk, localized-disease patient. The slide we’re looking at now. PEACE and ARASENS are the metastatic hormone-sensitive, right, so much more advanced form of disease. And then of course my case was looking more at the nonmetastatic CRPC patient.

So distinguishing those populations is kind of the first and key step, but the story is over the last 7 years, since 2015 with CHAARTED, we’ve proven that treatment intensification works in prostate cancer, right? I mean we have an unbroken series of positive studies going back several years. This is not new in cancer in general. It’s just new in prostate cancer; that the field has finally gotten around to doing the intensification studies. And the messeae is bring the best agents up front. Getting them in earlier improves survival in almost every setting.

Selection and sequencing of therapy for metastatic castration-resistant prostate cancer (mCRPC); Novel investigational strategies

DR LOVE: All right. Well let’s move on now and talk about castrate-resistant prostate cancer and the challenges of a new indication. Some really amazing — these last couple years talking to general — we’ve had so much opportunity to talk to oncologists in practice trying to keep up with things going on, not to mention all the complications of COVID in terms of taking care of patients. But let’s talk about this as well.

So Andy, this is a 71-year-old man. It’s based on a case we’re about to hear from Alicia. History of coronary artery disease who’s had abiraterone and ADT for hormone-sensitive prostate cancer, now has disease progression, gets docetaxel, now has disease progression again, is now going to be standard — should be standard now, genetic testing is negative. We asked the audience what they would be thinking about doing, and the audience is saying cabazitaxel, interestingly. Number 2, if PSMA is positive, lutetium. Andy, any thoughts?

DR ARMSTRONG: Yeah. This is a great question, Neil. It will never be on your boards because there’s 2 right answers. And you’ll see that, I think on Monday in the — or Sunday in the oral abstract session, the TheraP study will be updated, where cabazitaxel and PSMA lutetium will be head-to-head compared in an Australian trial, where the survival difference is no difference. So that would give you 2 right answers.

Now there are differences in tolerability and PSA outcomes where PSMA lutetium tends, in most patients, to be very well tolerated. A guy with coronary artery disease, you might ask him about his neuropathy and his functional status, how he tolerated docetaxel. There’s 2 different doses of cabazitaxel. I think cabazitaxel is a right answer for some patients, particularly if there’s only mild uptake. If the SUV on your PET scan is modest cabazitaxel may have more activity in the PSMA-negative lesions, particularly if there’s liver metastases.

I think PSMA lutetium’s a great choice when it becomes more widely available, if you can get to a center that’s offering it. There has been shortages over the past 2 months that have limited this globally. But we’re looking forward to giving more and more PSMA lutetium to patients who are most likely to benefit, those with very bright SUVs. And there will be some data at this meeting that will kind of go at those nuances of which patients for the right treatment.

DR LOVE: So Alan, we have someone who sent in a question, “Why hasn’t cabazitaxel replaced docetaxel first line? Are we using optimal dose schedule of cabazitaxel?” We asked the audience how they approach the use of growth factors with cabazitaxel. Most of the audience says they use it prophylactically. Do you agree with that, Alan? And any thoughts about this question of are we optimizing cabazitaxel?

DR BRYCE: So remember, first line has been tested, right? There was head-to-head versus docetaxel, and cabazitaxel wasn’t superior in that setting, so that’s why it hasn’t replaced doce. We’ve looked at the question. It was an important question to clarify. So docetaxel’s firmly established first line for taxane-based chemotherapy, cabazitaxel is second.

I agree with doing prophylactic growth factor. I also start patients at 20 mg/m2. There’s really no compelling reason to start patients at 25 anymore; 20 is noninferior. So you can reduce toxicity by giving cabazitaxel at the lower dose.

And it’s also important to recognize cabazitaxel is generally less toxic than docetaxel head-to-head. That’s the other thing we saw in the clinical trial data. Less neuropathy, less toxicity overall. So it is an easier drug.

DR LOVE: Andy, quick question from the audience. “Have you seen nightmares in patients on enzalutamide?”

DR ARMSTRONG: Yeah. Enzalutamide has CNS penetration, so does apalutamide, and you see some effects on cognition, memory, in about 3% to 5% of patients. And nightmares I’ve seen reported in some patients. I’ve also seen restless legs. I’ve seen other neurologic manifestations, sometimes neuropathy. And so it has some neurotoxicity, I think, because of that blood-brain barrier. And it’s a GABA antagonist, so that’s one of it’s off-target effects when it enters the brain.

DR LOVE: So Alicia, what happened with your 71-year-old man?

DR MORGANS: Sure. So the case is, as we heard, a 71-year-old gentleman. He has some cardiovascular comorbidity. He had progression of disease after his prostatectomy, with his PSA rising and some metastatic disease. ADT and abi was started. Within 11 months he had progression again, and of course it was radiograph and PSA progression. You can see here he has liver lesions and progression of his bone metastases. And he was started on docetaxel at that time, especially because of the liver lesions I think that there was an interest in some cytotoxic therapy, and of course a change in mechanism of action because sequencing AR-targeted agents really doesn’t give us much mileage on that second agent.

So he tolerated that well, but then of course, as we heard, had progression again. And for this patient, as you also heard, he received cabazitaxel, and he really met the criteria for the CARD trial, which was a Phase IV trial looking at a second AR-targeted agent in patients with progression of disease on an AR-targeted agent and docetaxel in their past versus cabazitaxel. And really it focused on patients who had had a progression with an AR-targeted agent of 12 months or less, and that was this patient.

So he did really well on cabazitaxel. I also dose reduced it to 20. I just think of that as a standard dose, in my practice at least, at this point, and I always use growth factor. And lutetium wasn’t available. That would also be an option. But we have to remember that patients need access not only to the lutetium; they also need access to a PSMA PET scan. As the label’s written it has to be a gallium PSMA PET scan, so this is another thing that we have to think about.

And I do worry about patients having access to therapy. This is a couple barriers to get there, but I think as a field we’re making some strides in having availability of PSMA PET for these metastatic CRPC patients. And then, of course, as was mentioned, we also need availability of the drug. So that will hopefully be resolved in the near future as well.

DR LOVE: Andy, any comments on what we know about the availability in the United States and the rest of the world of PSMA scanning? And how — we have patients now who are getting PSMA scanning, and they’re having metastatic disease not seen on conventional scanning, how to deal with that situation, Andy.

DR ARMSTRONG: Yeah. There’s multiple PSMA PETs now approved. And one of the things in the recent NCCN Guidelines update I’d like to point out is that we brought in the approval, or the recommendation, for PSMA lutetium to any patient that has an FDA-approved PSMA PET scan, including the PyL PYLARIFY® imaging. So we generally think of them as interchangeable. They differ slightly. If you’re a nuclear medicine doctor you will notice some differences in the liver uptake, for example, but the — if a patient’s positive by one of these scans they’re likely going to be positive by multiple scans.

But availability’s pretty widespread globally now. In the United States it’s increasing. I seem to have a hard time finding a patient that hasn’t had that scan in my clinic now. The availability of PSMA lutetium is now just becoming available.

So I wanted to comment on this case because multifocal liver metastases, one of the worst prognostic factors in this disease, and a liver biopsy is recommended for many patients to rule out small cell differentiation. This would be considered like an MD Anderson aggressive variant patient. So there is a randomized trial of cabazi plus or minus carboplatin for very fit patients who — in this category if they had RB loss or p53 loss or liver metastases; some of these aggressive features. They had a survival benefit with the addition of a platinum.

DR LOVE: What about time to response, Alan, of lutetium versus chemotherapy? A lot of liver mets there. And also response in the liver, lutetium versus chemo.

DR BRYCE: Yeah. So with lutetium there’s subtleties in terms of the SUV uptake in terms of the liver metastases. We’ll see some more of this data, as Andy mentioned, later here in ASCO from the TheraP group because that’s the only randomized study, right, of lutetium versus cabazitaxel. And in the abstract we already see that the overall survival in those 2 arms is equivalent, right?

Now, the subset analyses, I think, will be relevant, and we really have to think about that. The more common scenario in somebody with that much volume of disease is you’re going to see mixed lesions, some that are very SUV positive, some that are SUV negative. And of course it only takes 1 lesion to kill the patient, right, the aggressive one, right? So I think there’s going to be subtlety that we’re going to have to work through, and I don’t think all the answers are there, to your specific question of can we say confidently what’s going to happen with that volume of disease in the liver. But it does tend to push us, frankly, towards — towards thinking about chemotherapy because I think we mostly expect that neuroendocrine or small cell variant is PSMA negative.

And the Memorial group has really shown if you do concordant — synchronous FDG PET scan and PSMA PET scan you’ll see different readouts between those 2 scans, and when FDG dominates you’re really headed towards chemo.

DR LOVE: So Alicia, here’s — this is Andy’s case. This is super juicy. I love it. Can you imagine? You have 4 different doctors. One doctor’s going to give you abiraterone. The other’s going to give you chemo. The other’s going to give you radium. The other’s going to give you lutetium. How about you, Alicia, in general? This is a 68-year-old man who has metastatic disease. He’s had docetaxel/enzalutamide, and the question is what’s next. What do you think about these answers?

DR MORGANS: Yeah. So importantly I think there are 3 potential answers here that are the right answer: cabazitaxel, radium, and lutetium. I would not use abiraterone in a patient who’s had progression of disease on enzalutamide. Abiraterone and olaparib I think we’ll get into, but I’m not necessarily sure that’s the right answer, at least at this point. But we’ve got survival data on the other 3. We don’t have perfect comparative data to say which is best.

This, from my perspective, is a perfect opportunity for a shared decision with patients about what you can get, what are your options, what is the toxicity like, and what’s the expected benefit. And for these options the expected benefit is probably relatively similar. We do have the luxury in this patient of having bone-only disease, from what I can tell, which gives us the opportunity for radium because that’s not always going to be on the list, depending on where the metastatic sites are. But I think this is an absolutely perfect opportunity to talk about what are your choices now and what can we use now that we may not be able to use later, and how is sequencing going to come into play for the future.

DR LOVE: And if you wanted to get a fifth opinion you could get a little PROpel, even though the HRR was negative. So Alan, a simple question I’ve been thinking about for a while. I’m not really sure what the answer is. “Does radium relieve bone pain?”

DR BRYCE: Yes.

DR LOVE: The audience says yes.

DR BRYCE: Yeah, no. It does. It does. I mean obviously there’s the resistant patients, but effective therapy, extends survival, improves symptoms, improves quality of life, yes.

DR LOVE: So Andy, I’m curious how you would answer this question. “If a patient’s about to begin PSMA lutetium what’s the likelihood they’re going to have a PSA decline? They’re going to have some evidence of objective response?” How would you answer that question, Andy?

DR ARMSTRONG: Yeah. I think patients are not necessarily hanging their hat, like investigators are, on what necessarily the magnitude of the decline is. We’re focused on either 30% or 50%. I think as long as you’re seeing a decline you’re going to have better outcomes. The larger the decline the better the prognosis of that patient long term. And the vast majority of patients that are PSMA PET positive, like in the VISION or TheraP studies, are going to have a good response. It’s probably around 50% to 70% will have a striking confirmed decline that tends to be fairly durable.

DR LOVE: So Alicia, your colleagues are most focused on renal cell cancer using TKIs and IOs all the time, they’re trying to decide which of the 4 that have been proven to work. What do you think is the future for that strategy in prostate cancer, antiangiogenic VEGF-TKI plus PD-1?

DR MORGANS: I think this is a question that remains to be answered. So the really interesting data is with atezolizumab and cabazitaxel, and I think the preliminary data suggests that there’s some disease control activity there, which is fascinating because cabazitaxel had a negative trial years ago in the mPRPC setting, and atezolizumab, of course, isn’t something that we expect as a single agent to be highly effective in prostate cancer generally. So the combination suggests that there may be some micro —tumor microenvironment activity perhaps induced by the cabazitaxel that allows the atezolizumab to be active. I think there’s an ongoing trial, so we’ll have more data. But maybe there will be an opportunity for this. I always hope there’s more for our patients to choose from.

DR LOVE: Yeah. I remember when cabozantinib was being tested in prostate cancer, and it kind of went away, and everybody else started using it in the other tumors, and it kind of never came back. But anyhow, we’ll see whether this strategy —

Andy, how about this 68-year-old man? What happened with him?

DR ARMSTRONG: So this is a gentleman who is actually on the VISION study. He’s another African American patient who is a very high-functioning lawyer, and he was doing very well until he started to develop disease progression after docetaxel/ADT. He had good disease control with multifocal bone metastases while on enzalutamide, but then suddenly the switch happened, and his PSA started to rise rapidly. His functional status started to deteriorate. He wasn’t able to get to work as often. So he is post AR therapy, post docetaxel. PSA doubling time was fast. I think you can probably click on the image, and it scrolls you through his 3D.

DR LOVE: Oh, not. It didn’t. Sorry.

DR ARMSTRONG: Go back, and I think you can click on his PSMA PET image.

DR LOVE: No.

DR ARMSTRONG: Maybe not. All right. Anyway, he has diffusely very bright — SUV is very high. SUV mean, which we’ll be presenting on Sunday, was above 10. So he has a phenomenally bright PSMA PET scan, and so he was fortunate enough to be randomized to the PSMA lutetium. He completed 6 cycles. I would say within 2 doses he was back at work and feeling great, back to a normal functional status. So he went from nearly being hospitalized and feeling miserable to feeling normal again, which is a great outcome for him. His PSA, I think you can see on the next slide, mirrored his clinical response, so going from 809 down to 13 with just the monotherapy. So there’s just ADT, denosumab, and PSMA lutetium.

DR LOVE: And I see he subsequently got some additional treatment. How did he tolerate the lutetium? What did you see there? And what have you seen in general in terms of side effects, tolerability? I’ve heard about dry mouth. How much — what do you see?

DR ARMSTRONG: Yeah. Dry mouth for him was transient, and we tend to see that with each cycle a little bit. You can resolve that with chewing gum and just staying hydrated. He was good about flushing out his kidneys every cycle. His bone marrow function would transiently drop but never to the point of neutropenic fever or infection.

But like all good things this came to an end. You only get 6 cycles. We don’t actually know if that’s the optimal dose. We’d like to see more studies testing retreatment. He’s actually looking forward to still maybe being able to get retreatment now that we have the commercial availability.

He progressed and was able to respond to cabazitaxel just as well, actually. So subsequently he’s responded to that after a PSMA lutetium. You do worry about bone marrow toxicity with the sequential cytotoxics, but he tolerated this pretty well.

DR LOVE: Alicia, any comments? And we’re going to go through some of the studies. I really want to hear more of you all talk about how you’re actually — what your experiences are clinically. But can you talk a little bit about what you’ve seen with lutetium, both in terms of response, but also you were mentioning to me in terms of cytopenias, which I haven’t heard too much about?

DR MORGANS: Sure. So lutetium does seem to have some nice responses. I actually think in some patients it can be at least life prolonging to an important extent. I had a patient, actually, enrolled in the VISION trial who screened to be eligible for the trial with normal LFTs. But on the day he came in for day 1, cycle 1 had LFTs that had actually risen into the hundreds, around 400 or 500, and his T-bili went up to about 4 1/2, which is obviously extremely concerning. He had a liver full of metastatic disease.

And I was able to get permission from the sponsor to proceed with treatment, and we really didn’t have another choice. This gentleman had no other treatment options. His control arm, best standard of care, would have been steroids, which he was receiving.

So he was treated, and he actually had resolution of his elevated bilirubin within 4 or 5 days. It was unreal. So not to put too much emphasis in a single patient, I think that’s really important, but in this patient it allowed him to have actually many months of time with his family, which was important. He had extremely bad metastatic CRPC and progressed, actually, by the end of cycle 5. So we were unable to have a durable, really long response there, but because cycles happen every 6 weeks this was a sizeable amount of time for him and for his family. So that was important.

These kinds of really miraculous almost things can happen with all of our therapies in the right patient, and so I think it’s important for us, again, not to think of an N of 1 as driving everything we do in practice.

And there are downsides to all of our treatments too. And as we heard, cytopenias are an issue. I’ve had patients treated with lutetium who have had pretty significant cytopenias that have been a bit long lasting, and so we always hope that they’re going to resolve. I still hope for some patients that they are going to resolve so we can continue treatments, but cytopenias are real effects because we are delivering radioactivity to the bone marrow, and patients have metastatic disease to bone. So something we need to be aware of, and in heavily pretreated patients or in patients who have a history of MDS or other bone marrow disorders, this is something that we have to be cognizant of and speak with our patients about, watch and monitor very closely.

DR LOVE: So Alan, we’ve been showing the slides from the VISION study. Any comments about your experience with the drug, particularly in terms of tolerability? We have a question from the audience. “Can you use radium and PSMA lutetium in the same patient sequentially?”

DR BRYCE: Yeah. So I think the sequential question gets to what both my colleagues here have already brought up, is the idea of cumulative myelosuppression, right? These are older gentleman. A lot of them have had pelvic radiation. They’ve had chemotherapy. So eventually myelosuppression will become a rate-limiting whether toxicity or development. And that’s probably what defines whether you can go sequentially from one radioligand to another.

But I do not think of this as being so much a case of resistance to one or the other. I think you can go sequential. It’s really just a toxicity question for the most part, a tolerance question. So yes. I would feel comfortable if you had a patient who had previous radium at some point then moving on to lutetium, I think that’s okay.

DR LOVE: So Andy, I think this is the study you were mentioning that we’re going to see some more data, and again from the abstract even though these were initially very impressive and still are impressive, apparently we’re going to see data showing a lack of survival benefit. Does that surprise you, incidentally? And would you feel differently about your approach if you had seen a survival benefit?

DR ARMSTRONG: Yeah. I think in this nice Lancet paper the TheraP study showed that PSA outcomes were better with PSMA lutetium. PSA and PSMA are often aligned with each other, so it’s not surprising that when you’re hitting an AR-driven factor like PSMA you’re going to hit another AR-driven factor like PSA, and that those outcomes will be better if you carefully select the patients that have very bright or intense PSMA-positive PET scans.

Those patients who are PSMA negative were excluded from this study, and they should probably get cabazitaxel.

In the abstract that will be presented there is basically no survival benefit. That’s why on your boards there will be equivalent answers. These would be both right choices. There may be differential benefit based on some nuances of the SUV. So a brighter patient maybe would be better for cabazitaxel, and a patient with a weaker PSMA PET scan might be better for cabazitaxel.

DR LOVE: I took the boards a couple years ago just to see what they were doing. They’re like about a year and a half behind. There’s no way.

DR ARMSTRONG: Maybe 5 years from now.

DR LOVE: Maybe — yeah, 5 years from now it’ll be on the boards. Alicia, here’s what we were talking about before, this TKI/IO that’s so successful in other diseases. HCC, we’re going to talk about tonight, again IO/bev in that situation. In any event, we’ll see. As you mentioned, there’s a Phase III trial that’ll give us an answer to that interesting question.

Current and potential role of PARP inhibitors in the management of prostate cancer

DR LOVE: So let’s move forward with a really interesting development in terms of PARP. And we got some interesting surprises a couple months ago at the GU ASCO Meeting, too. Spectacular presentations that we’re going to talk about. So Alan, we’ll start out with this question. A 69-year-old man with a germline ATM mutation, just to be different, Alicia has this case, receives ADT/docetaxel for mets to the liver, and now has progression. And the question is what’s next. We have people saying olaparib alone. We see the PROpel olaparib/abiraterone. We see the MAGNITUDE niraparib/abiraterone. Any thoughts, Alan?

DR BRYCE: Yeah. Lots of different answers here. You can certainly understand where they’re coming from. In terms of which drugs have evidence in this space, I mean it’s really going to be abi/enza/cabazi, right? Olaparib was approved based upon having at least 1 of the next-generation androgen pathway inhibitors. Rucaparib, of course, for the time being is only approved after an androgen pathway inhibitor and docetaxel and not for ATM. And then the abiraterone/olaparib or abi/niraparib, we have the PFS data from GU ASCO, but we don’t have any OS data or approvals yet, so I really wouldn’t consider them options at this point.

So I think you’re really looking at the top 3 choices are your choices that have evidence to support their use at this time.

DR LOVE: So we now said the same situation except you have a BRCA2 somatic mutation. Alan, does that change anything?

DR BRYCE: Yeah. Even still, technically speaking, olaparib’s not approved for this scenario because the patient hasn’t had an androgen pathway —

DR LOVE: But we’re saying regulatory issues aside.

DR BRYCE: Yeah. Well, so now you get into the issue of what about ATM mutations, right? So this is a more subtle point, and I’ve made this argument at ASCO but also in publication, but the hazard ratio for ATM-mutant disease with olaparib is 1.04, right? There is no evidence of benefit from any study in a statistically significant way for the use of a PARP inhibitor with ATM-mutant disease.

DR LOVE: So let’s get more into the mainstream here with the BRCA2 because now we say regulatory issues —

DR BRYCE: That’s right.

DR LOVE: — aside, so now we have the PROpel and MAGNITUDE options. Are you ready to go with that for BRCA2?

DR BRYCE: Sorry about that. Yeah, no. You’re right.

DR LOVE: Well it’s 2 cases. We have 2 cases. ATM. But okay, now somatic BRCA.

DR BRYCE: BRCA2, PARP inhibitor, I love it. Absolutely.

DR LOVE: Okay, but which one?

DR BRYCE: Regulatory aside —

DR LOVE: What specific treatment?

DR BRYCE: I’m still not jumping in with the abi/PARP combinations yet. I mean it’s okay. It would work. There’s no reason it won’t. Do we have to do the combination up front, payor issues aside? I think in the PARP — in the BRCA-positive population it’s going to work nicely. But I’m not sure you need to combine all that expense and toxicity for the patient. So I’d be comfortable with a PARP monotherapy at this point.

DR LOVE: Do you think if you explained the PROpel and MAGNITUDE studies to an educated patient, the type of patient who wants the best possible therapy, they’d be okay with taking abiraterone?

DR BRYCE: You can. I mean I think abi’s still a perfectly good option in this patient.

DR LOVE: I think it’s time for a second opinion to Alicia.

DR MORGANS: Thank you for that. So I think the point that you’re making, Alan, is completely valid. We only have PFS data for the combination of abi/olaparib and abi/niraparib. It’s compelling data, and it looks in a BRCA2 population like both of these combinations may be beneficial or are beneficial in terms of PFS prolongation. What we don’t know is if you need to take that toxicity, which includes financial toxicity because you have 2 copays at this point, and lots of pills each day, or if we could sequence these agents and get similar efficacy. We just don’t know that yet, and we will find out when we have the survival data, or we’ll have at least a better idea.

I do think for a patient who is young and healthy and who understands the data that we’re talking through you could have a shared decision-making process about this combination. So I’ll take the bait and say I think it’s a reasonable conversation to have, Neil.

DR LOVE: Interesting. I’m actually kind of surprised because we had a symposium that Alan ran at GU ASCO. He was a real pro when we talked about mutant disease. Of course, Andy, you really get — and we saw somebody actually voted for abi/olaparib on an HR-negative patient. So what’s your take on these data in terms of how it’s affecting your practice or how it would, putting aside reimbursement?

DR ARMSTRONG: Yeah. I think if it were approved and available it’s exactly the BRCA2 patients that I would offer a PROpel regimen to. And I would just point out, yesterday the PROpel regimen was published in The New England Journal of Medicine Evidence, so you guys can go read the trial.

DR LOVE: How many people know there’s another New England Journal out there called New England Journal Evidence? Right? Another New England — because they have so many papers. It actually looks different. I like the layout. It’s kind of cool.

DR ARMSTRONG: Yeah. It’s an online journal. It’ll never come to your offices in print.

DR LOVE: Oh, really? It’s only online. Wow.

DR ARMSTRONG: Yup.

DR LOVE: That’s awesome. But anyhow, so bottom line, what about — we’re going to look at the data in a second. It’s in the —

DR ARMSTRONG: The hazard ratio for the HRD-positive patients in PROpel is around 0.46, and that’s above and beyond abi. So that’s with an active comparator. And the progression-free survival with abi is about 16 months, so when you’re doubling that that’s a major difference.

DR LOVE: Well let me ask you, why olaparib and PROpel as opposed to MAGNITUDE and niraparib? Or is that a coinflip?

DR ARMSTRONG: It’s always challenging to make cross-trial comparisons when the patient populations slightly differ. MAGNITUDE allowed a prior AR therapy, allowed a period of abi lead in, so that may have created some differences. And niraparib and olaparib are different drugs with different tolerabilities and toxicities that led to differences in dose intensity.

But if you look in the HRD patient positive populations across these trials you see a superior hazard ratio for olaparib.

DR LOVE: If you compare it indirectly. And of course, Alan, the really provocative issue, because to me I didn’t see that much difference in the HR mutant in niraparib verus olaparib, and it’s hard, as Andy said, hard to compare indirectly. But the — I don’t know if I’d say shocking, but super interesting thing was the hazard rate with PROpel with HR negative. And of course with the MAGNITUDE they got pushed out because they didn’t really see anything.

DR BRYCE: Right.

DR LOVE: We’ll see. An excellent hazard rate if there wasn’t any BRCA. Any thoughts about that?

DR BRYCE: Yeah. That’s really the compelling piece, or the interesting piece that we have to dig into about PROpel, the HR-negative patients. The hazard ratio was markedly different, much higher with BRCA positive. It was 0.7-something, 0.7 what, 2?

DR ARMSTRONG: 0.76.

DR BRYCE: 0.76. 0.76 in the HR negative population. Whether that translates to overall survival we’ll see. I mean that’s a little bit soft on PFS to get to OS. So I think it’s not a sure thing. I really want to wait and see. And I want to dig into that population more, right, really understand them.

DR LOVE: Tomorrow morning, same time, same place, we’ll be talking about — tomorrow morning, right, our ovarian program. There you see activity in niraparib in the HR proficient and not necessarily — well, maybe even with olaparib, we’ll see, not as much data. But it’s approved in ovary for niraparib HR proficient. So really interesting data that’s going to affect practice.

Alicia, you have this patient. You brought up a really interesting subtle point that I’m not sure I understand, but maybe the audience will. Tell them about CHIP and ATM.

DR MORGANS: I will. And I’m sure that they will understand it.

DR LOVE: They will. I won’t.

DR MORGANS: It’s exciting, and it’s something that we think about with circulating tumor DNA assays to identify HR mutations. So this patient is a 69-year-old gentleman who has some hypertension and localized prostate cancer diagnosed many years ago and underwent a prostatectomy but did develop progressive fatigue and signs of recurrent prostate cancer a few years after that. PSA was elevated, and he had metastatic disease on his imaging, as we can see in this picture here, with some liver metastases there.

He was diagnosed with metastatic hormone-sensitive disease. He did have some retroperitoneal adenopathy as well. He was treated with docetaxel and tolerated that well, then had progression again. This was bone-only progression and stable disease in the liver.

So now he has, as I said, stable disease in the liver, retroperitoneal disease and bone disease. What do you consider in terms of his workup? This is metastatic castration-resistant disease. And this is really to get to the point if we have not already performed germline and somatic — germline and somatic genetic testing this is where we want to do it. Importantly, we do both germline and somatic testing because 50% of the HRR mutations, including BRCA1 and 2, are going to be germline, and 50% are going to be somatic. We also need to make sure we do somatic to find things like MSI-high status, which might give us the opportunity to use pembrolizumab.

So this patient had both germline and somatic testing. Just a note, he was eligible for germline testing at the time of developing metastatic disease, so all patients with metastatic prostate cancer should undergo germline testing. And what was identified here is that he did have an ATM mutation. ATM is a little bit tricky when we’re using circulating tumor DNA. And this is the CHIP issue that we talked about, this clonal hematopoiesis, which is something that can interfere with the ctDNA assays and give us false-positive ATM mutations for the ctDNA assay.

So we have to be cognizant of this if we’re not going to be using tissue-based studies to do somatic testing. We can use the primary prostatectomy for somatic testing, so do think about that if we can’t get a new biopsy, which would be, of course, ideal. That is important because truncal — the HR mutations are truncal and in many cases be present in the primary prostatectomy specimen if you have access to that tissue.

But I don’t know. I’d love to hear Andy’s thoughts on CHIP and ATM.

DR ARMSTRONG: Yeah. Our institution has actually started a CHIP clinic, and this is the new thing. So because CHIP is now associated with cardiovascular risk, emphysema, myeloid neoplasms, sorting out what that patient’s future may be, it’s kind of like MGUS in myeloma. CHIP is now a predisposing factor for leukemia and MDS, as well as heart disease, and it’s a major cardiovascular risk factor.

So sending off a myeloid CHIP panel could basically figure out whether the cell-free DNA that you’re finding for ATM is not coming from the tumor but coming from the myeloid cells. And then if you identify that you could avoid the PARP inhibitor, which would not be expected to work, if it’s not in the tumor. So that could be helpful.

If it’s in the germline, I think you’re pretty confident that it’s maybe important, but not all germline ATMs have biallelic loss, and as Alan mentioned, the hazard ratio’s not particularly striking for olaparib. I think ATM is not necessarily the same as BRCA1 and 2 in terms of synthetic lethal relationships with PARP inhibition, and we’re looking at ATR inhibitors and other combination trials for these patients. These patients are not deriving the benefits of PROpel or MAGNITUDE. It's really the BRCA-type patients.

DR LOVE: So let’s talk a little bit about utilizing these drugs. Actually, it’s interesting, Michael Savona was here yesterday. He has a CHIP clinic at Vanderbilt, and we were talking about that in our MDS/AML program yesterday.

This patient got put on olaparib. What happened — and abiraterone in the PROpel regimen. What happened?

DR MORGANS: Sure. So this patient was on olaparib and abiraterone per the PROpel data because obviously ATM is not expected to have a huge response to single-agent PARP. But because there was activity in the population that was DNA repair defect negative, or HRR negative, that gives us an opening for saying that even though he has one of these mutations, if it’s one we wouldn’t expect to necessarily respond, perhaps at least if we’re having responses in all comers, even in wild-type patients, he could have a response too. And so that’s why this combination was considered for him.

He tolerated it well. Did have some GI effects early on that resolved, had some blood pressure issues also. Because what we saw in PROpel is that the side effect profiles of abiraterone and olaparib were as expected for these drugs as single agents. There were no new synergistic toxicity profiles, but there were additive toxicities, and hypertension is something that we do see with abiraterone. So he had some blood pressure control issues. We fiddled with those and got blood pressure under control.

One thing that I would mention is that cytopenias are things that we do need to watch out for with PARP inhibitors. Anyone treating other solid tumors knows that because you’re using these drugs in other settings.

And importantly for our patients with prostate cancer, and for all patients I think, there can be multiple things that could cause an anemia for example. So we want to make sure that we’re identifying nutrition deficiencies and supplementing with folic acid or B12 if it's something as easy as that, or iron supplementation. So these are easy things that we can fix in oncology and not necessarily related to drug; may also then help patients maintain better hemoglobin levels and tolerate their drugs better.

So we did do a workup. This patient had an iron deficiency, and we were able to supplement there. That’s what was really contributing to the worse than expected anemia that we saw with this patient.

DR LOVE: That’s really interesting. We’re talking about PARP not only here tonight for pancreatic cancer, tomorrow morning for ovary, and then Monday night in breast cancer. So PARP is coming into oncology in general.

This is an interesting issue, Alan, we first heard about in ovary, which is dosing of niraparib, a weights and plates approach they developed in ovarian cancer for women. But I was curious the way it’s getting applied in men. So I asked the audience — we asked the audience, you have a man who’s 180 pounds, has a normal platelet count, what dose they would start. Interesting, a lot of people aren’t sure. That was my guess, a lot of people would use 200. But what do you do, Alan?

DR BRYCE: Yeah. So it’s a fair response, right, as we get used to niraparib because we haven’t been using it a lot in prostate cancer yet. And to your point, it’s come up a couple of times, we do need to study the breast and ovarian data, but we are finding that not all principles translate directly, right? So I think there’s a lot of space for further investigation within prostate cancer, learning from our women’s malignancy colleagues.

Generally the 200 is where we’re landing with the niraparib. I don’t think there’s a need to get more aggressive in starting, nor is there a need in this patient to start lower, so I think that’s where I would start. But we’ll learn more. I mean I’d think about, as we talked about, that history of myelosuppression. It’s a thing that really concerns me with combination therapy. Because with PARP inhibitors you have various scenarios, let’s say where the median PFS with monotherapy would be say 9 months or something, and then you add abi, which the median PFS should be maybe a year and a half, for example, you might be giving an extra 9 months of a myelosuppressive therapy. And I think you do prostate cancer long enough and you find out that hematopoiesis becomes a rate-limiting step late in the disease, so I really want to be thoughtful about chronic exposure to myelosuppressive therapy.

DR LOVE: So Andy, I was curious about this also. I’m not sure if we know for sure of this. Obviously, it’d be indirect. But I’m just kind of curious what people think. You might think with a lot of bone disease, maybe more marrow compromise, that you might see more cytopenias with PARP inhibitors in prostate cancer. But I’ve kind of been hearing that they seem about the same. The audience either doesn’t know or thinks that it is about the same. Andy, what do you think? Do you see — do you think you see more cytopenias?

DR ARMSTRONG: It’s really challenging to answer this because each PARP inhibitor will give you different answers.

DR LOVE: Right.

DR ARMSTRONG: If you look at cytopenias, like thrombocytopenia, in PROpel and MAGNITUDE, you get different answers. So they’re not all the same. And a woman with ovarian cancer who’s had multiple platinums may have a different cytopenia profile than an older man who’s had pelvic radiation versus those who have not. So I think it’s very individualized. I don’t think there’s necessarily a PKPD difference between women and men, but we don’t know. There can be effects on pharmacokinetics in the castrate state. We see that with docetaxel. So I think it’s — when we look across trials we see pretty similar overall toxicities in terms of the need for transfusions, a little higher with niraparib than olaparib. But — and that could limit the dose intensity and efficacy of that agent.

DR LOVE: So again, we put the slides in the slide deck. We’re not going to talk about all of them. We wanted to hear more of the experience of the investigators. But notice here in PROpel, down there at the bottom, non-HRRm, as Alan was saying, hazard rate’s positive, 0.76, statistically significant. Response rate greater.

We saw pretty similar data in tolerability, we just talked about, the data in there in terms of thrombosis. MAGNITUDE study, again, they broke it out in terms of mutation positive or negative, didn’t really see much benefit or any benefit in mutation negative. But to me, pretty similar results, maybe indirectly, I don’t know. We were commenting on that before, at least in this patient population, increasing response rate and tolerability issues as has been seen in ovary. A little bit more thrombocytopenia.

Maybe we’ll close out with Alan’s case, if we can go back to that, a patient who actually was treated who had a BRCA2 mutation. Alan, you had your patient, a 57-year-old — a 67-year-old man. Can you tell us what happened?

DR BRYCE: Yeah. So this is a gentleman. He started out with Gleason 7 disease, eventually went to Gleason 4 + 3, had a radical prostatectomy but unfortunately was node positive at the time. Nevertheless, he got a couple of years in before he had PSA recurrence while on ADT, was nonmetastatic at that point, had salvage radiation therapy. And we did early germline testing; no pathogenic variants there. And actually just to back up a sec, the somatic testing off of the —

DR LOVE: Sorry.

DR BRYCE: The somatic testing off the prostatectomy tissue was not showing any HRD or DDR mutations at the time. So he continued to progress. We took him through a fairly routine series of treatments. He got sip-T. He got abi. Eventually he moves on to docetaxel, and now we’re 8 years out. He had only stable disease on the doce, so we decided to get cell-free DNA because really he had bone predominant disease at this point. So my bias is always I want tissue for NGS if possible, but if there’s nothing to biopsy we’ll get the cell-free DNA.

And now in this gentleman we see a BRCA2 mutation, which we didn’t see in the primary prostate tissue. So we put him on a PARP inhibitor, and you can see here he starts the rucaparib at a PSA of 163, initial rise in the beginning, as we see with so many treatments, so we don’t react to that. But you see a nice response, right? And he had a durable response over several months, radiographic response with these lymph nodes regressing.

So one of the things I’m highlighting in this case is the importance of retesting. Even though BRCA mutations are generally early events there’s still limitations of testing. There’s limitations of testing old tissue. If you do NGS on a prostatectomy sample from 10 years ago the yield is fairly low. You’ve got a good chance of missing relevant mutations. I say I always retest, really for the most part, at every progression event, and you can see the disease evolution. And don’t assume that BRCA negative in the beginning is going to be BRCA negative later.

DR LOVE: So I want to thank the faculty. Thank you all for attending. Thanks everybody online. Come on back online tonight. It should be really interesting. We’re going to talk about GI cancers in clinical practice. Have a great day. Thank you.

DR MORGANS: Thank you.