Introduction

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice, and welcome to Year in Review, as today we talk about some of the most recent data sets and presentations that have come out over the past year in prostate cancer.

We have a great faculty today, Dr Tanya Dorff from the City of Hope National Medical Center in Los Angeles and Dr Oliver Sartor from the Tulane Medical School in New Orleans.

As always, if you have any questions or cases you’d like to run by our faculty just type them into the chatroom; we’ll talk about as many of these as we have time.

As always, we have a very brief, 1-minute survey, a questionnaire, that we’d like you to take now and at the end of the conference. You’ll get a lot more out of the meeting if you do that.

We know a lot of people end up listening to these webinars. If you’re into audio programs and podcasts, check out or Oncology Today series, including a recent program on metastatic bladder cancer with Dr Tagawa. And speaking of bladder cancer, we’ll be back tomorrow night with our Year in Review program on renal cell and bladder cancer with Dr Milowsky and Prof Powles. So many things happened in this past year in GU cancer and the recent GU Symposium. It’s hard to even get through it in an hour.

Next week we’ll continue our ER-positive, Triple-negative breast cancer series with Dr Tolaney from Dana-Farber. And then we’ll be doing a program on next Wednesday, March 8^th, as a follow-up to 2 satellite programs we did at the GI Symposium on gastroesophageal, HCC and biliary cancers. And we’re going to take an interesting approach to it we haven’t done before to try to get more into depth about practical management of these patients.

March the 22^nd, Dr Strickler will be there. We’ll hear about his trastuzumab/tucatinib anti-HER2 strategy for colorectal cancer and much more about what’s going on with CRCC.

We’ll be going to the Society of Gynecologic Oncology meeting, as we always do every year. We’re doing 2 satellite meetings there, but they’ll also be put out online live — 1 will be on ovarian cancer and the other on endometrial cancer.

But today we’re here to talk about prostate cancer. And as we do in all our Year in Review series, I’ve met with both of the faculty separately in the last couple of weeks to record an in-depth presentation that they both have, highlighting a whole bunch of papers that I’ll show you in a second. So if you want the details, the best way to get everything out of this program is to watch both of those presentations. And then tonight what we’re going to do is sort of take it to the next level and chat a little bit about some of the clinical and research implications of some of the data sets that came out.

Here are the papers that Tanya reviewed, mainly on hormonal therapy. You can see there’s a ton of papers. We’re going to just talk about a bunch — a few of these. And then Oliver, who handled PARP inhibitors as well as radiopharmaceuticals, also reviewed a whole bunch of papers. And we’ll pick out a few of these to really get into the nitty-gritty.

Here’s where we’re heading. We’re going to start out talking about hormonal therapy of prostate cancer, particularly in the castrate-sensitive situation. Then we’ll talk about PARP inhibitors and then radiopharmaceuticals.

Before we get started — I was very surprised, Oliver, when we did chat, and first of all, I’ll mention you’re in South Africa right now attending a radiopharmaceutical conference there and it’s midnight — so it’s a little bit late for you there — but maybe you can share with the audience, after a long history in New Orleans, where you’re about to head?

DR SARTOR: Well, thanks, Neil. And maybe I surprised myself. I’ve accepted a position up at the Mayo Clinic. I’ll be moving up there in about 6 weeks. Mayo is a rather extraordinary place, particularly when it comes to the radiopharmaceuticals. They have an amazing Nuclear Medicine Department: 2 cyclotrons, radiochemist; the whole works. And to be blunt, I’m really excited to be able to join that team, as well as the team in Urology/Medical Oncology, and try to keep prostate cancer moving forward.

DR LOVE: So, yeah. I’m really looking forward to seeing what happens up there. I didn’t realize that Mayo is so strong in nuclear medicine. That should be really fascinating.

Tanya, any thoughts — we’re going to talk about radiopharmaceuticals, but this seems to be such a fascinating area of interest. Any thoughts about where you see — too, at the end, we’re going to let Oliver talk a little bit about some of the things he’s hearing at the conference he’s at right now, some of the new things. But any thoughts about where things are right now with radiopharmaceuticals, Tanya?

DR DORFF: Yeah, it’s a whole new frontier. And I think with lutetium PSMA being the second theranostics; we already have the lutetium-dotatate agent, there’s likely to be an increasing number of effective therapies in this domain. And so I think a lot of cancer centers are really trying to focus on building up their theranostic capacity so that we have enough treatment rooms for the impending demand as we get more of these agents.

Castration-Sensitive Prostate Cancer

DR LOVE: All right, well let’s jump into some of the papers from this past year and some of the issues that I hear oncologists and urologists asking about in terms of prostate cancer. And a lot of questions about hormone-sensitive disease, particularly metastatic disease. But there are a couple, sort of global issues I pulled out of the conversation with you, Tanya, and your presentation, that I just want to highlight in a more macro point of view.

So there are 2 questions I want to really kind of explore a little bit more in-depth with. The first is this issue of — it almost reminds me, we did a program a couple of weeks ago on ovarian suppression in breast cancer, and there you see that if you add stuff to ovarian suppression, whether it’s tamoxifen or an aromatase inhibitor, patients do better. And it kind of seems like this intensification strategy is also starting to play out in prostate cancer, Tanya. Because I want to talk a little bit about the issue of, let’s say, doublet or intensified hormonal therapy in earlier-stage disease, M0 disease, localized disease. These are all new data sets and really, a real sea-change in the view of that.

And the other issue I want to get into is metastatic hormone-sensitive disease. And the trend that I see happening, in terms of people turning towards triplets — and I just want to chat a little about sort of the research basis of that.

So here are several of the papers that related to the first point. And I’m just going to put the titles up. We know a lot of people will listen to this without the slides. So I was really surprised — I love this idea: androgen annihilation that’s interesting, for the PRESTO study. But the bottom line, Tanya, we’ve always used ADT as a first therapy, if we use it, for M0 disease, but it looks in this study, by adding onto that you’re going to get better outcomes. Can you just summarize your take on this PRESTO study? And then also, the FORMULA-509 study, similar idea of going earlier, now looking at patients who had prostatectomy, PSA relapse, and then salvage radiation. Can you kind of talk a little bit about these 2 studies and how you see that in terms of where things are heading in earlier-stage prostate cancer, Tanya?

DR DORFF: Sure. We’ve always known that prostate cancer can find other sources to feed itself, even when testicular production of testosterone is suppressed. So it actually makes a lot of sense that we’re missing part of the story when we only use castration therapy. And that’s where adding androgen receptor antagonists or CYP17 inhibitors that are able to block adrenal production of androgen precursors as well as intra-tumoral synthesis of testosterone, it makes so much sense to add it on top of testicular testosterone suppression.

So, as you mentioned, FORMULA-509 is the earlier that we’ll be talking about. So this was study for biochemical recurrence where men were receiving salvage radiation and they were randomized to either 6 months Lupron or 6 months of Lupron with apalutamide and abiraterone, so it was triplet. Most of the studies I would say don’t show a lot of added benefit from combining these 2 classes of drugs — each of them is so powerful in and of themselves. But, at any rate, the FORMULA-509 used the triplet and did see a significant increase in the 3-year progression-free survival.

Then PRESTO is sort of the next set, the next recurrence after salvage radiation, where men are typically facing intermittent hormone therapy. And the question was, if we double down or triple down, a year of Lupron, of a year of Lupron, and they did allow other castration agents like degarelix as well, a year of that with apalutamide or a year of castration with apalutamide and abiraterone, could we get to 0 cancer? I think it was a lofty goal. They were looking to really irradicate micrometastatic disease.

So the only data we’ve seen so far are for PSA relapse-free survival. And it was significantly prolonged on either of the double or triple therapy arms.

So generally, what we’re seeing is just a convergence of this theme across different prostate cancer disease states. We do better when we achieve a deeper remission, when we maximally suppress the androgen receptor from signaling, and that really means doublets are being used in a broader spectrum of prostate cancer.

DR LOVE: So, Oliver, I’m curious on your take on this. Any time you add things, you’ve got to imagine you are adding the possibility of toxicity. Also, we have to have a vision of the long-term impact of these drugs. Are they going to affect survival? So difficult to determine with a disease like prostate cancer.

So, while you can maybe make the argument that theoretically this would be a better therapy, the question is, is it worth the additional risk? The additional cost? What kind of endpoints do you think we need in order to embrace this type of strategy? Any general thoughts about this, Oliver? Are you sort of already on board with that? And Tanya reviewed another paper from STAMPEDE, looking at patients with locally advanced disease. We saw the same thing happening when you add, I think it was abiraterone.

Any comments, Oliver?

DR SARTOR: Yeah, Neil, great question. And the STAMPEDE data was Gerhardt Attard presented in Lancet, is really a beautiful study in which there is actually overall survival benefit. Now these are very, very high-risk prostate cancer. And truth is, a whole bunch of the patients were actually de novo patients with lymph node-positivity. No mets beyond the pelvis. But nevertheless, metastatic lymph nodes.

So this very high-risk subset I think is a great target and the STAMPEDE investigators showed — and by the way, they had a little bit of a funky design. They had an ADT/abiraterone and then they had an ADT/abiraterone/enzalutamide. The addition of enzalutamide really didn’t really seem to make much difference, so they kind of resorted to the ADT/abiraterone, but it showed a survival benefit.

Now, these smaller studies, PRESTO and FORMULA-509, no survival benefit. I think the 509 shows an MFS, but remember, it’s only in a subset of MFS — we didn’t really talk about that. But the idea about intensification I think is here and now. And I think the question is, how early can it go? And we might be able to take it too early. And let me explain that, because some of the high-risk studies that we’ve done, and I’ll mention things like NRG-0521, really shows that the control group, if you use 2 years of hormonal therapy with radiation, that a lot of high-risk patients do extremely well.

One more quick point. None of these studies that I’ve cited like the STAMPEDE or the RTOG-0521 incorporated PSMA PET imaging. I think the truth is, a lot of these individuals are going to have PSMA PET-positive oligometastatic disease. And as we begin to stage patients better, we’re going to have a whole new class, not only the oligomets, but now a new and better prognosis localized prostate cancer because we’ve weeded out those micromets that can show up on PSMA.

So it’s a very, very intriguing area.

DR LOVE: So Tanya, you referred to 1-year of therapy. And when you did your presentation you said the same thing. And I said, are you talking about intermittent therapy? Which I think is what you’re talking about. Can you talk a little bit about how you do intermittent therapy, particularly if you’re going to bring on, as in this PRESTO study, a hormonal agent, or the FORMULA study, apalutamide, are you going to do intermittent therapy with the anti-androgen, too?

DR DORFF: So I think intermittent therapy applies to a specific population of biochemical recurrence. FORMULA-509 was kind of a definitive salvage-defined course, with the intention that you would never need to do anything again, right. You’re aiming for cure. But in biochemical recurrence, we know that, thus far, we haven’t been able to get to cure with systemic therapies that we have.

I suspect that PRESTO will show that most patients relapse. I had a significant number of patients on the trial, most of them did seem to relapse, who recovered their testosterone, which is another topic. But intermittent therapy in the JPR-7 trial, published by Juanita Crook many years ago, showed equal survival. More men on the intermittent arm died of prostate cancer, more men on the continuous arm died of cardiovascular disease. So there may be trade-offs. But certainly now that we’re looking at intensification, if we get a deeper remission, intermittent therapy makes sense.

And as you alluded to earlier in your conversation with Oliver, there can be toxicity. And we want to make sure we’re not overdoing it. So we need to do some more studies, I would say, about how to optimally do intermittent therapy with combination strategies. But, for now, I think monotherapy is probably still acceptable in the biochemical recurrence setting, even with the presentation of PRESTO, until we see whether there’s an overall survival impact, which could be years. And we know this population lives a long time, so I didn’t expect us to have overall survival data at this earlier date of presentation. But this is a conversation that has to be had.

I do find it reassuring, when you look at all the non-metastatic CRPC studies, like SPARTAN and ARAMIS, when they add this androgen receptor antagonists on top of castration therapy, quality of life typically was maintained; in fact, there was a delay in the deterioration of quality of life, presumably due to the development of cancer-related symptoms.

So, they do have more side effects. Like with apalutamide, we look for the rash. We should be vigilant about bone density and cardiovascular risk. But generally speaking, they are well tolerated. And so far, in most of these studies, the advantages are quite significant.

DR LOVE: So Oliver, right now with locally-advanced prostate cancer in men who are going to get 2 years of radiation therapy — I mean are going to get radiation therapy and 2 years of ADT, are you going to add-in abiraterone?

DR SARTOR: I will in the ultra-high risk. When you look at patients with a PSA over 40, lymph node-positive disease or a combination of T3/T4 plus PSA over 40, these are types of patients that are really at super high risk. They’re not just the regular high risk by D’Amico, these are super high risk. And I will use it in that circumstance. I basically use the STAMPEDE data as a guide and that’s the Attard, et al, Lancet paper. So I believe in that study. I think it’s very, very significantly positive.

And in that particular case, by the way, the quality of life was not particularly detrimental. I mean ADT is a negative thing. I don’t mean to say it’s not. But on the other hand, the addition of the abiraterone did not make much more difference.

DR LOVE: So Tanya also reviewed in her talk the issue of hormone-sensitive, metastatic disease, and of course, the ARASENS study. And widely adapted. We’ve had several questions in the pretest, I’m already seeing the answers, that a lot of people are using that in the various scenarios of hormone-sensitive, metastatic disease. But I guess one of the things I wondered about, and Tanya, you and I talked about this, is the lack of data showing that adding docetaxel to ADT plus novel therapy has a benefit.

We have outlined there, the ENZAMET study, where you saw a little blip of docetaxel in the beginning that, maybe for patients who are symptomatic, et cetera.

But Tanya, people are using triplet therapy. And I guess my question is, where’s the data for docetaxel? To what extent are you using docetaxel in hormone — I mean it’s a basic question, but do you use the triplet therapy? And if so, in what situations, Tanya?

DR DORFF: So most of patients will get doublets. And we feel like there’s been inadequate uptake even of doublets and are skeptical that triplet therapy will, therefore, be adopted. But we did modify NCCN Guidelines to take out ADT/docetaxel as a doublet. It really should be ADT with an AR-targeted agent because of the studies like PEACE-1 and ARASENS that showed that even if you get up-front docetaxel, there’s still a significant survival advantage to using the AR-targeted agent, the abiraterone or the darolutamide, in the case of ARASENS.

So, doublet with docetaxel I think should not be utilized very often, if at all. But almost every metastatic, hormone-sensitive prostate cancer patient, except for the very elderly, frail, comorbid, can really benefit from a doublet rather than monotherapy.

So you’re right, none of the data, PEACE-1 doesn’t say what was the marginal added benefit of the docetaxel. ARASENS doesn’t say what was the benefit of the docetaxel. They asked the question of do you still need the AR-targeted agent if you use up-front docetaxel? And the answer was yes.

Does that mean we should never use triplets? I think that’s not right either. I think we all see patients who are just exceptionally high risk, whether it be very high volume, very symptomatic. Perhaps a lower PSA relative to the amount of disease burden, which makes us suspect, although not proven, that they may be less hormonally driven. And because ARASENS and PEACE-1 are out there, triplet therapy is an option. But I would say the majority of patients are probably appropriate for doublet, or my preferred option, is enroll on a clinical trial. Because there are other triplets that really need to be explored such as in genomically-selected subgroups, like using PARP inhibitors up-front as a triplet in BRCA-mutated patients. There’s the PI3-kinase inhibitor that may be synergistic. There’s the lutetium radiopharmaceutical.

So there’s all kinds of exciting drugs that we want to move into the front-line setting in a clinical trial and see if amplifies their benefit.

So I think if we feel comfortable enrolling on that, that means we think that not every patient needs a docetaxel triplet.

DR LOVE: So Oliver, curious about your perspective. These are some data from the STAMPEDE study, showing what, of course, we know, which is down there in the blue, it drops down quality-of-life-wise, is the docetaxel. And I guess my question is, you have a patient, for example, a patient who’s presenting with metastatic disease. They’ve never been sick. They never got a PSA. They’ve got metastatic disease. First of all, they have to deal with that. They’re dealing with ADT. They’re going to be dealing with an anti-androgen. Do they really need to also have that dip there because of the docetaxel?

I mean it’s a very practical question, Oliver. How often are you using triplets? I mean take Tanya’s point, and maybe there are people who haven’t heard the doublet regimen, but there are a lot of people using triplets and docetaxel. Do you, Oliver?

DR SARTOR: Rarely, Neil. And it’s interesting, I was listening to Tanya’s answer, and I didn’t know what she was going to say, and I’m almost in complete agreement. We use doublets. We use hormonal doublets. We never, at this point, use ADT/docetaxel doublet. The only patients that we’re kind of using triplet in are those maybe be very young, very bad. But that’s a very distinct minority.

I think the way Tanya worded it, and boy, I think we can be partners on this, clinical trials represent a terrific option. And there’s some really good clinical trials ongoing in this space, trying to bring precision medicine into this up-front setting, trying to bring the PSMA lutetium into this up-front setting. Clinical trial’s a great option. But doublet for me is typically 2 hormones, not docetaxel.

DR LOVE: And here are some examples of the trials both our faculty have just been talking about, all these really are great opportunities. You can imagine how many questions we have in the chatroom already about lutetium not being available. We’re going to get to that. We’re getting there. Of course, that’s a stunning development that occurred in the last 2 days.

But in any event, here are some of the trials that might be considered for these patients.

PARP Inhibitors in Castration-Resistant Disease

DR LOVE: We’re going to go on and talk about PARP inhibitors in prostate cancer which Oliver covered in his talk. One question incidentally, I have to give an answer to Dr Kumar. Tanya, what is the current role, if any, of Sip-T in prostate cancer?

DR DORFF: Sip-T was developed in the absence of drugs like abiraterone and enzalutamide. So, it was a de novo mCRPC. That population doesn’t exist as much in practice today. However, you still do have patients who are slowly progressing on their up-front doublet who may not be ready to jump straight into chemotherapy, who are asymptomatic or minimally symptomatic. And we know there’s an overall survival advantage, not only from the registrational trials, but from multiple subsequent data sets, including a registry.

So I think there is still a role. But it’s certainly smaller than what it was when it was the only other treatment we had besides docetaxel for CRPC.

DR LOVE: When was the last time you used Sip-T, Tanya?

DR DORFF: I have 3 patients on it right now.

DR LOVE: Really? Interesting.

Oliver, do you have patients on it?

DR SARTOR: None now. Probably the last patient was about 6 months ago. And by the way, I agree with Tanya. The developmental pathway for Sip-T was in the context of ADT, when CRPC meant failing ADT. Today, in my practice, CRPC, castrate-resistant prostate cancer, means having failed typically 2 or more hormones.

So it’s a totally different game today. And I’m not sure that 2010 data applies in 2023.

DR LOVE: And that paradigm shift that we’ve seen also, I think, affects this next question which is the issue of PARP inhibitors. We saw a couple of new papers at the GU Symposium, was it last week or the week before? But anyhow, big Phase III papers that came out, really interesting that Oliver reviewed in the talk. But I again want to approach it more from a global point of view of PARP inhibitors. And one of the questions — we’ll talk about what we know right now and what makes sense to think about doing or what you might like to want to do and how it’s going to play out, but also the question of ideally, where — I think we have a pretty good idea of the downside of PARP inhibitors. Keeping that in mind, where is the ideal time to maybe introduce them, and in which patients?

And also, I want to get a little bit more feedback from both of you about how PARP inhibitor toxicity plays out in a prostate cancer setting as opposed to the other settings, for example, breast and ovarian cancer where a lot of PARP inhibitors have been utilized.

So I guess one question is the issue of sort of the genomic profile of the typical patient with prostate cancer, or metastatic prostate cancer. And Oliver, one thing you commented on was this initial paper looking at genomic testing and actually the challenge of doing it, and the role of liquid biopsy in trying to assess these men.

So can you comment a little bit about what kind of assay to do? And globally, what do we know about the genomic profile of these men?

DR SARTOR: There’s a great question, so I’m going to kind of break it into components. So first of all, when I think about genetic testing, first of all, I wonder about germline because germline has huge impact on the patient. And, by the way, there’s FDA-approval for the BRCA1/BRCA2 germlines, and those are relatively small percentage of the patients but very important.

Then we get into tissue somatic testing. And if you look at this paper from Maha Hussain, you have it the top there in bold, what you see is over 4,000 men who were tested as part of the PROfound trial and that was with olaparib. And the report demonstrates unequivocally that a lot of these patients, even though they may have tissue, are not going to be able to get good tumor genomic testing because the tissue is either too old, the DNA too degraded, and you don’t get good assays.

From this paper, you can say that fresher assays, more tissue, are better and that old, little slivers of prostate that may have been 10 years ago, well, guess what, they’re not so good.

So if you want to do tissue genomic testing, it’s hard to rely on old paraffin blocks from 10 years ago. Bottom line.

Now, circulating tumor DNA. Very, very important. And so, by the way, have FDA-approval now for ATM, BRCA1/BRCA2 for olaparib, and for rucaparib, BRCA1 or BRCA2. And I get pretty much, circulating tumor DNA on all my castrate-resistant patients and I’m looking to try to understand their profile. And yes, I will use the PARP inhibitors when I find those BRCA mutations. For the other mutations, I’ll say it’s a lot dicier, but we can get into that a little bit more if you like.

DR LOVE: So, of course last year at the GU Symposium we saw 2 big trials, very, very interesting, the PROpel study using olaparib with abiraterone, which showed benefit not only in the BRCA HRR patients, but also in the non-BRCA. The same thing was seen with niraparib in ovarian cancer incidentally. But also, we saw data from the MAGNITUDE study, looking at niraparib, and there really just seeing a benefit in the BRCA patients.

So that’s where we were last year. And we’ve been kind of thinking about that, dissecting it.

And then we had these 2 new studies, the TALAPRO-2 study, again just presented with talazoparib, a PARP inhibitor used in breast cancer already, combined with enzalutamide as opposed to abiraterone. It looked a lot like the results, to me, from the PROpel study. And the benefit, it looked like there was benefit both BRCA and non-BRCA.

And then the TRITON-3 study, looking at rucaparib in patients with advanced disease compared to docetaxel.

So just want to kind of reflect back with both of you about how you see these data now and where you see things heading in the future. And before we get into that, I just want to ask you — I’ll start with you, Tanya — theoretically when you — again, think about the downside: PARP inhibitors can cause symptoms, GI symptoms, cytopenias. There’s an issue of AML/MDS out there. If you have a patient with a BRCA2 germline mutation, Tanya, theoretically where do you think the idea place would be to introduce a PARP inhibitor?

DR DORFF: That’s a really good question. Up until the TRITON-3 presentation, we didn’t have any data that could answer the question of whether there would be a relative advantage of choosing the PARP inhibitor first, versus the taxane/chemo, in a patient with a BRCA mutation. TRITON-3, because they did allow the physician’s choice to include docetaxel, unlike PROfound, which was largely post-docetaxel, here, we got to see that the PFS was certainly longer for the BRCA mutation patients who received the PARP inhibitor, as compared to the taxane/chemo, and way longer than with the second AR-targeted agent which we all know, abiraterone after enza or enza after abiraterone has limited utility.

So, many patients are a little bit hesitant about chemo. Here’s an oral agent. It does have toxicity but I find the toxicity to be pretty manageable. And I sort of have this dichotomous experience where some patients essentially no toxicity with the PARP inhibitor and then some have like a severe drop in their hemoglobin or have a lot of the GI toxicity. So I think it is manageable with dose-hold, dose reduction, although some patients really can’t tolerate and have to come off. But when you talk about the options, chemotherapy definitely a valid option, PARP inhibitor as well. And now with the TRITON-3 data, I think many patients will prefer to choose the PARP inhibitor first.

DR LOVE: So Oliver, one of the questions that goes across here, and again, I’m only bringing it up — I know it’s a different disease, ovarian cancer, because I know oncologists have heard this, so they’re going to be thinking it like I’m thinking I right now — is the issue of patients who don’t have any evidence of HR deficient, no BRCA, nothing. Their LOH scores they do in ovarian cancer. It looked like there was benefit, at least at this point, both with olaparib as well as talazoparib. Any thoughts about where that’s heading? In ovary, there’s a lot of skepticism about whether it really helps or not. A lot of debate about whether to use PARP inhibitors. What’s your take on that in prostate cancer, Oliver?

DR SARTOR: I’m a little more cautious perhaps, than others. I have looked at the BRCA1/BRCA2 data and, look, it’s blazingly positive. And, by the way, in the TRITON-3, they broke out an ATM subset and there really was not much in the way of benefit. But BRCA1/BRCA2 with PARP is a good mixture, whether or not you use olaparib or rucaparib. They’re both very reasonable options.

I think the new data with the TALAPRO-2 introduces the concept of enzalutamide plus talazoparib. So now we have multiple PARP inhibitors coming into play. And I’ll simply say, if you’ve got a BRCA1/BRCA2, then I think pretty early use of a combination makes a lot of sense with a PARP inhibitor, whichever one it is that you might be choosing.

Now, the non-BRCA. The non-BRCA is going to be divided, to me, into 2 different subsets. Number 1, you’re going to have the HRR-mutated non-BRCA, and then those with no mutations at all. And I am skeptical in both of settings. I know there’s some rPFS benefit. But the risk of these agents over long-term I think are still a little bit under consideration. We don’t have mature survival data; even the latest data from the PROpel study only had 47% of the patients who were informative for overall survival. Now, it came close when you look at the OS for the overall all-comers trial. But then if you begin to break it out, most of that benefit is being driven by the BRCA patient.

So I still want to see more data. I personally believe in precision medicine. And I want to keep my PARP inhibitors to be used in precision medicine, not for all-comers. That’s a personal opinion. And believe me, there are a lot of people who disagree.

DR LOVE: Yeah, that’s for sure. And a lot of confusion about what the best way to approach this is.

I’m going to sort of try to answer my own question and come back to you, Tanya, to say, I feel like, if I had a patient with hormone-sensitive, metastatic disease who had a BRCA2 mutation, I kind of wouldn’t want to be waiting for them to relapse to give them a PARP inhibitor. And I know we don’t have data — you’re doing a trial looking at that Tanya — but is that where you think this is going land, or do you think it could even land earlier?

DR DORFF: Well, as Oliver and you have mentioned, there are some toxicities that we really have to think about when we’re moving very early in the disease. So, there have not been many reports of MDS or leukemia. For example, from PROfound, we didn’t really see much of that. But if we’re talking moving even earlier, I think that’s something we would really have to look at over the long-term. But the up-front metastatic, castration-sensitive trials, I think, will be very interesting, especially, obviously, in the BRCA-mutated where we anticipate the greatest benefits. And then the question would arise, how much of the PARP inhibitor therapy do you need? Could you use it in an induction kind of strategy and not use it indefinitely? Which might impact the risk-benefit ratio.

DR LOVE: Yeah, that’s a really good point.

So, in terms of this question then of when to introduce a PARP inhibitor and what kind of benefits we’re going to see, Oliver, what kind of data would you want to see in order to be able to use this? Do you want to see a good overall survival benefit? Is PFS going to be adequate for you? And, also, what about the question of the synergy between the hormonal therapy, the novel agent, and the PARP inhibitor? What do we know about that? I don’t know if it affected the dosing. It looks like the dosing — I don’t know if you’ve used niraparib in men, Oliver. In ovarian cancer, they have this weights and plates thing that they decided whether to use the full dose, 300, or 200. I think that was actually used in the MAGNITUDE study, based on the weight of the patient and whether or not the platelet count is normal.

Any thoughts about the synergy that occurs, Oliver, between the hormonal therapy and the olaparib? And again, dosing issues with niraparib?

DR SARTOR: Number 1 is, I think the preclinical data does look pretty good about the possibility of synergy, even in the absence of the HR mutations. And that really was the underpinnings for the initial trials. And Noel Cart presented some Phase II data a while back that sort of laid the foundation for the Phase III and PROpel, and then also helping to underscore the potential impact of the TALAPRO-2 trial.

Now, the niraparib turns out to be a little bit different. It did not potentially benefit those individuals with a non-HR mutation. It turns out that there was actually a closure of the MAGNITUDE trial in the non-HR-mutated because there really did not appear to be any benefit.

In terms of the dosing, I believe that the initial dose ought to be pretty much the full dose, and then we modulate as necessary. What’s interesting, and Tanya, I think, said it well, it’s almost a dichotomy in the patient. Some of the patients do very, very well. And then other patients are the ones that have their problems, whether it be anemia and GI, being the top 2 in my own experience. And for those patients, you’ve got to dose-hold/dose adjust, really work with them to get the dosage you think is right.

One other thing, Neil, it’s not quite what you asked, but I did want to address this point. There are some non-BRCA mutations, and I’m going to point out particularly PALB2, that appear to be very PARP-sensitive. And there are a few others that are rare, like RAD54L.

So it turns out that, if you go gene by gene and you look at the literature carefully, BRCA1/BRCA2, PALB2, and then a few rare genes, I think all have very substantial benefit. But the all-comers, to me, I just want to see a little bit more than rPFS, because the toxicity and expense issues. But maybe I’m being a stick in the mud. Maybe I’m being too conservative. I think the field is gravitating in diverse ways, and good investigators that I respect are on-board with the PARP combo. I’m just waiting to see a little more data myself.

DR LOVE: You mentioned Johann de Bono, who’s been such a leader in this field. He told me in an interview, he likes to call PALB2 BRCA3.

DR SARTOR: I like that. But it’s a pal of BRCA2, the PALB2.

DR LOVE: That’s right. Same thing.

DR SARTOR: I thought it was a pal!

DR LOVE: Anyhow, so I don’t know how this is going to affect — now we have this great trial with rucaparib that just got reported, and yet, the company that makes it went bankrupt. I assume in some way they’re going to figure out a way to bring rucaparib back. But that should be fairly interesting to follow.

This is one of the slides Oliver showed, getting into this issue of synergy between the AR pathway and the issue of PARP inhibitors.

So we’ll see where that’s heading.

Radiopharmaceuticals

DR LOVE: But I wanted to get Oliver’s take on radiopharmaceuticals. He’s excited enough to make a huge career move about it. You’re down there in South Africa, trying to learn more about it.

Let’s start out with what’s going on today in terms of lutetium. So I was going to ask you to summarize where you think the lutetium should be used right now. And then we started to see press releases about the issue of access to lutetium. What’s the current situation right now? Are you able to actually start a patient on lutetium nowadays, Oliver?

DR SARTOR: No. About 48 hours ago, there was an announcement from Novartis, and it was carried on one of the newswires, said they’re actually not going to be stating new patients. I can go into some detail, but I’ll simply say that there is a plant in Italy that is trying to supply the entire world. And they’re quality issues in a plant in New Jersey that had prevented it from being able to be brought into commercial production. And there’s a plant in Indianapolis that is not even fully constructed yet.

As it turns out, this latest announcement is really, really tough. There’s so many patients who could benefit from the drug. I generally believe in the activity of the drug. And having these sorts of shortages, I hate to say it, Neil, it’s heartbreaking.

DR LOVE: Yeah, it is a terrible situation.

Here are some of the papers that Oliver went through, talking about radiopharmaceuticals. Not too much on lutetium at the last ASCO GU meeting. But Tanya, can you kind of summarize where you were in terms of using lutetium outside of a trial setting, at least theoretically, if you had access to it? Right now, based on the data, the FDA posture, et cetera, in what situations were you using it? And what are some of the issues that come up in using this agent?

DR DORFF: Right now, we’re really trying to stick to on-label use, especially since there’s been such difficulty getting adequate supply. So we’re really only treating patients who have progressed after taxane chemotherapy, which is consistent with the label. We also look at the PSMA PET scans and really try to make sure we’re selecting patients who met the VISION criteria for PSMA PET scan positivity — especially since there was that presentation of some UCLA data where during the compassionate access, they were treating patients with a broader set of PSMA PET criteria perhaps, and those who would not have met VISION criteria really didn’t benefit as much.

So, especially when we have limited supply, we’ve got to prioritize patients who are going to benefit. So we need to look at the PET scans. And we’re staying on-label for now, even though we know there’s that press release about using lutetium PSMA pre-chemotherapy from the PSA-4 trial. But we haven’t seen the data. It hasn’t gone to FDA. So, right now, pre-taxane use, strictly on trial.

DR LOVE: Oliver, what’s your thought about this? Assuming you had unlimited access to this and you could use it in any situation, where would you be using it right now, outside a trial setting?

DR SARTOR: Gosh, I am exactly like Tanya here. I am sticking to the VISION label right now, or I was until 2 days ago. And the data from PSMA-4 was announced positive on December 5th. I’ll simply say that that data has yet to be presented in any public forum. And I’m really going to look at the data once its available and then make up my mind. I’m not really ready to push into something that would off-label today. I want to get that data in from the pre-chemo set and take a good look at it and make risk-benefit assessments.

DR LOVE: Tanya, can you talk a little bit about your experience in terms of the practical issues in patients who go on lutetium, not only side effects, but sort of —what they have to deal with in terms of convenience, et cetera? What do you tell your patients to be prepared for? And what have you observed?

DR DORFF: Yeah, those are really important issues. One thing that we stated to deal with a little bit in the era of radium-223, is just the back and forth with our nuclear medicine colleague and making sure that patients don’t just get treated without clinical assessments. So coming back to us in between doses to check the counts, make sure they’re tolerating treatment in terms of what toxicities they’re experiencing – the dry mouth, are they losing weight because of the difficulty eating if it’s very severe — and making sure after 2 doses in my practice, that we get a scan to assess for my response. And we’re looking at their PSA kinetics as well.

So, it’s that sharing of patients, that multidisciplinary management, that is really important for us to remember that we still have to maintain primary management until there comes a time when the nuclear medicine physicians are ready to take on a full role of not just administration, which they do so well and evaluating the PET scans, but also keeping track of all the labs and the toxicities.

One thing that’s come up a lot with my patients is really the questions about their radioactivity and going back out into the world. So they’re really concerned about their spouses, their grandchildren, and they need to logistically distance themselves. Can they drive themselves so they’re not in the car with someone while they’re radioactive right after treatment administration.

So I think there’s a need for more education about those practical aspects.

DR LOVE: We’re going to the ONS, Oncology Nursing Society meeting in a couple of months. our whole theme is What I Tell My Patients. I’m curious, Tanya, what do you tell your patients about what to expect?

DR DORFF: I mean I do tell them about the major side effects, primarily the dry mouth. And we have some management strategies, really basic like using the Biotene mouthwash. But we also give them a little bit of information about you’ll be in the lead-lined room for a couple of hours until you excrete enough of the tracer. And so, we’re releasing you back out into the world where we think you’re safe but you still want to be cautious and maybe don’t be around very vulnerable groups of people for the first couple of days. But we really actually rely heavily on the nuclear medicine team to provide a lot of that education as well. And generally speaking, this is well tolerated. It’s once every 6 weeks, which makes it relatively easy for patients.

So there’s a lot of positives that we discuss. There’s a high rate of PSA decline. And so far, our experience has been very favorable.

DR LOVE: So Oliver, I’m curious again what you say to your patients. Also, what the pathophysiology is of the dry mouth?

DR SARTOR: So if you do a PSMA PET scan, Neil, you see the salivary’s light up. Now that’s one of the characteristics of these small molecule PSMA binders, is there appears to either PSMA or PSMA-like molecule, it’s on the intraluminal side of the salivary ducts and you can damage those glands. And if you look at the VISION data, about 41% of the people had some degree of dry mouth. Most of the people, it’s pretty mild, but a little bit of a nuisance. A few people, it can be more severe.

Simple sort of hydration, maybe even some hard candy or sugarless gum, we try to keep people away from too much sugar, by the way. Those sort of issues are important to stress if there are problems.

One of the other things, and I want to expand just a tad on what Tanya said, it’s not just managing the side effects of the disease, which she alluded to — excuse me, the side effects of the treatment, it’s also the disease itself.

So I just have a radiopharmaceutical guy and what did he do, he developed some really significant arm pain. And I said, well, gosh, let’s get a look at that. He got an x-ray; he had a pathologic fracture. The nuclear medicine docs are not really that accomplished or comfortable in dealing with the complications of an advanced prostate cancer patient. Many of these patients have anemia, fatigue, not just the dry mouth, but also complications of the disease itself that need to be managed, bone health agents, et cetera.

So I really like this team approach. I want to be able to see those patients. I know prostate cancer and I want to complement with the nuclear medicine docs do, but I don’t want them to substitute for somebody like me.

DR LOVE: So you mentioned bone health and as always, when we do programs in prostate cancer, people are asking about the use of bone-protective agents. Tanya, particularly in the hormone-sensitive setting, what’s your approach? And which agent do you use?

DR DORFF: Absolutely I think bone health is critical. So my approach in hormone-sensitive disease is to check a bone density test and if it’s showing osteopenia, then I’ll offer patients either alendronate oral weekly, or denosumab at the 60 mg every 6-month dosing, or zoledronic acid at the once-a-year dosing because the bone metastasis treatment doses have not been shown to be beneficial in the hormone-sensitive setting. And, because there are risks and they be on them a long time, again, I do start with a bone density. That’s not how the trials were done. You could treat everyone that you’re starting on long-term ADT, but to me, if someone’s starting out with very, very strong bone density, they’re not going to lose enough in a year or two and we can delay the start of the bone supportive agent. Although, certainly, once they become castration-resistant, we turn to the full dose bone metastases-treating bone support.

DR LOVE: Yeah, sounds similar to breast cancer in patients on AIs.

Oliver, what are some of the ongoing trials with lutetium that you’re excited about? And combinations that are being looked at?

DR SARTOR: So, first of all, there are the Phase III trials. We already heard about PSMA-4 very briefly. That’s the pre-chemo metastatic CRPC trial. Announced its positive in a press release, the data not yet presented. Another one, and Tanya made an allusion to this earlier, called PSMA-addition. And this is a double of hormones, it could be ADT/abiraterone, ADT/enzalutamide, ADT/apalutamide, and then plus or minus the PSMA lutetium. So, really, it’s the doublet of choice, with or without the lutetium, to really find out if lutetium makes a difference. So I’m excited about that.

There are also those, and this gets a little bit complicated, we’ve talked entirely about lutetium ¹⁷⁷PSMA-617. Well, guess what? There’s also lutetium ¹⁷⁷PSMA-I&T and there are 2 trials and one of these is called the SPLASH trial, the other called the ECLIPSE trial, that are similar to PSMA-4. And now you’re using PSMA-I&T, not PSMA-617. And I can simply say that at the ESMO meeting last year, some initial data on the PSMA-I&T run-in looked pretty positive to me. And then, it’s already completed accrual. So, I’ll simply say there’s going to be more to go.

Now combination therapies, gosh, I don’t have a lot of time to kind of wax poetic, but I’m going to simply say that there are trials looking at PD-1 inhibitors such as pembrolizumab in combination with lutetium. There are DNA-repair inhibitors such as olaparib being looked at. And I think that both of those, both the immune therapies as well as the DNA-repair inhibitors, are both very important.

I could go on a little bit more, but those are the main ones.

DR LOVE: Tanya, what about cytopenias with lutetium? To what extent do we see that?

DR DORFF: I think anemia is the most common. And we are trying to select patients who are coming in with relatively robust blood counts, so, ideally, a hemoglobin at least 9, since anemia is the common. There is some risk of high-grade thrombocytopenia. I think it’s about 8% Grade 3 or higher. So we will look at the platelets and ideally, have patients have adequate platelets, not only for dose 1, but again, this is why it’s so important, as we’ve been saying, that they come back to us in between doses to check. In case they do drop, we may want to delay the next dose of the lutetium. We don’t want them going into it with counts that are too low. And, of course, we’re using transfusion support, when necessary.

I personally am not using erythropoietin stimulating agents in this particular setting. I think there’s just a complete absence of data for using that as a strategy to manage the anemia. So again, I think a little bit patient selection, a lot patient monitoring.

DR LOVE: So Oliver, you talked about waxing poetic. And you do that a lot in the talk that you gave in detail. But I thought you could just wax a little bit here, too, just to give people a flavor of some of the excitement about what may or may not be happening in the near future. Also to let you know that Charles Lattuada is in the chatroom says to say hi to you. He treated several of your patients 25 years ago in Monroe, Louisiana, with 5-FU and mitoxantrone was the only drug approved in prostate cancer. So, anyhow, hi from Charles.

DR SARTOR: Hi, Charles.

DR LOVE: All right, theranostics. Love it! Why do you love it?

DR SARTOR: Well, Neil, when you can see the target that you’re trying to hit with your therapeutic and then potentially monitor the effect of that therapeutic, you really begin to see and understand the disease better.

So we talked about the VISION criteria when it comes to choosing patients with PSMA lutetium. That’s a PSMA PET scan. So you want to see the cell surface expression of PSMA in the patients you’re going to treat. And if we can predict, in part, based on those findings, how the patient’s going to do.

Tanya mentioned about the trial at UCLA where they did not follow the VISION criteria and guess what, the patients who were treated who did not have much PSMA uptake did very poorly.

So you can select your patients. It’s a predictive biomarker.

Then you can have the radionuclide, and yes, there are supply chain problems. We’re going to get through that at one point. But in addition, you can use follow-up scans, and this is something we’ve begun to do, to look at the effects of the treatments you’re using. And I realize that there can be imperfections because CAT scans can show progression even though PSMA PET scans can show improvement, because not every lesion is PSMA PET-positive. But you can have a response biomarker.

So predictive biomarkers, response biomarkers, and you understand where the drug goes after you give it. It’s a way to accelerate drug development. And a lot of these therapies that are coming along right now, particularly some of the actinium drugs, are very, very exciting.

DR LOVE: So we talked about the idea of combinations. Maybe you can talk a little bit about sort of the biology behind the thinking there.

DR SARTOR: Sure, very simple. If you look at lutetium and the other radiopharmaceuticals, the way they actually kill cells is to damage the DNA. If you inhibit the DNA repair within a cell, then those cell damaged — those cells that are damaged are more likely to have a lethal hit as opposed to a partially lethal hit.

And so, there’s data to show, lots of preclinical data, and a little tiny bit of suggestion in the clinical front — we’re going to be hearing more about this — that adding something like a PARP inhibitor to lutetium can equal 1 + 1 is equal to 2.5.

So, it looks like there could be some synergy. Extremely interested in the data as it evolves. Preclinically, beautiful data. But of course we need the clinical data, too.

DR LOVE: What about this issue? I don’t know if this is related to the so-called abscopal effect, but the idea of antigen release and then combining that with immunotherapy? What’s the thinking there? And is that being actually tested in trials?

DR SARTOR: Absolutely, Neil. There are 2 trials: one coming in the from the PeterMac in Australia; another one coming in from UCSF. We’ve had some preliminary data on both. And I’ll simply say we need to learn more about it. But when you do radiate cells, you often are going to be generating neoepitopes, and these dying cells can be particularly immunogenic. And that immunogenecity can then translate into responses if you’re using it with a PD-1 or PD-L1 inhibitor, potentially.

Now, I don’t want to go too strong on this but I’m going to say I’m watching the field very, very carefully, and I think there’s going to be some interesting data. We just have to keep our eyes open and see what the data really show.

DR LOVE: So I think you said that this conference in South Africa is about alpha — I think I went too far here — about alfa-emitters? What is that? And how’s it being studied?

DR SARTOR: So the conference I’m attending right now is in Cape Town. It’s called Targeted Alpha Therapy or the TAT conference. And the targeted alphas are typically focusing on 1 of 3 different isotopes: actinium/lead -212 — actinium 225, lead-212 and also astatine 211.

So these are moving forward relatively quickly. Lots and lots of small trials. Lots and lots of small companies. And I’ll simply say, I had an incredibly stimulating day today listening to the targeted alpha therapy people, talking about all sorts of interesting biology and interesting modeling, interesting ways of interacting with the immune system. And I’m just having a great time down here at the conference.

And then, when I finish the conference, I’m going to have a great time because I’m going to go on safari as well and take some great photographs. So it’ll be fun.

DR LOVE: Wow! I want to see that.

Let me ask you naively, is radium like an alpha emitter?

DR SARTOR: Yes, absolutely. Radium was the first alpha emitter. Obviously, 2013. That was the ALSYMPCA trial. I happened to be the North American PI on that. Chris Marker was the overall PI. So radium, absolutely is an alpha emitter. But it turns out that the targeting of radium is very difficult beyond that of the bone because you cannot chelate radium. And if you really want to have it targeted, the soft tissue, you’re got to be able to have a chelate in order to get it into the tumor with the ligand. And here you’re looking on this particular slide, this is PSMA-617, again the same one we use with lutetium, now conjugated to actinium-225 and you see a dramatic response.

Interesting responses have been seen with these agents. Getting the drug development up and going has been very exciting. Lots of little companies are moving forward, pretty quickly actually now.

DR LOVE: Any final comments from you, Tanya? I’m kind of curious how you see this whole radiopharmaceutical experience and where you think it might be heading?

DR DORFF: Well, I think one area of unmet need is the patients whose cancers are not strongly PSMA-expressing. So I do think it’s so important for, not only exploration of other particles, but also other antigen targets. And there are several already that we have in active clinical trials that look really promising. So I think that will be helpful, since not every patient with prostate cancer will have PSMA expression.

DR LOVE: So I’m still kind of thinking about that.

DR SARTOR: Good point, Tanya.

DR LOVE: Thinking about Dr Lattuada, who commented on 25 years ago all we had was mitoxantrone. Here we spent a whole hour; we can barely even skim through some of the new things going on. This is oncology the way it is today. It’s so exciting.

Anyhow, I want to thank both of you, Tanya thank you so much. Oliver, thank you. Get some sleep. I guess it’s time to go to bed there.

Audience, thank you for attending. Come on back tomorrow night. We’re going to continue our Year in Review program with a GU flavor, RCC and bladder cancer. Whole lot to talk about there as well.

Be safe. Stay well. And have a great night.

Thanks so much, Tanya. Thanks, Oliver.

DR DORFF: Thanks, everyone. Bye.

DR SARTOR: Thank you.