Integrating PARP inhibitors into the treatment algorithm for patients with prostate cancer (PC)

DR ANTONARAKIS: I think first we must remember and point out to the audience that PARP inhibitors are not FDA approved for any scenario in prostate cancer right now. Their use is still investigational. We all expect that within the next 3 to 6 months at least 1 PARP inhibitor may become FDA approved for castration-resistant metastatic prostate cancer in the second or third line and beyond. In other words, for patients who have received chemical castration plus 1 or more of the novel antiandrogens plus or minus 1 taxane chemotherapy. That is the population where we expect the FDA approval to come.

At least in my practice, when I see a patient with metastatic prostate cancer, if they have no genomics performed, the first thing I do on the initial consultation is I send a germline test, and I use any tumor that I can to do a somatic test. And that’s not necessarily because I’m going to act on it right away.

To answer your question more specifically, in the first-line systemic therapy setting I typically would not use a PARP inhibitor, or I may not even use the information about a BRCA2 test in that scenario. But I like to know that information to plan for the future, as we know almost all of these patients, if not all, will develop castration-resistant prostate cancer in 2 to 3 years after starting their first systemic hormonal therapy. And at that moment in time I may decide to use an investigational PARP inhibitor on a clinical trial. Outside of a clinical trial, the off-label use of PARP inhibitors, I have done that infrequently, but sometimes I have. And typically it would be in the third- or fourth-line CRPC setting.

DR LOVE: Oliver, so from that point of view, when you look at PARP inhibitors in the situation that Emmanuel described with castrate-resistant disease after primary endocrine therapy and a taxane? Is that the way you would have liked to use it right now?

DR SARTOR: Thanks for the question, Neil, and yes, I would like to have the PARP inhibitors available now. We’ve been using them to some extent off clinical trial through compassionate use. And, actually, the olaparib has been available to some patients for compassionate use. I think that the post-AR synthesis inhibitor or novel AR inhibitor agent, kind of postabiraterone/enzalutamide setting, is one where we’re considering it now and where we have used it now. I think when the FDA approvals will come in, it will be in that second-line CRPC setting initially. And the taxane will be plus or minus. If we look, for instance, at the large olaparib Phase III trial, it did not require a taxane. And if we look at the rucaparib, it did not necessarily require a taxane.

The PDUFA dates are coming up pretty soon. The first PDUFA date that I’m aware of will be in May. And so we could actually get a designation even in May of this year. I’m interested in using the agents. I have used the agents. They’re unequivocally active in a subset of the HRR mutations, but not all. I think one of the things we need to sort out a little bit better is exactly where the activity is going to be seen. BRCA2 yes, and for ATM, not so much CHEK. The ability to look at a variety of the other HRRs, CDK12, for instance, not so active. We need to be able to dissect these mutations individually and not consider them as a class, in my opinion.

DR LOVE: Neeraj, I’m curious about your thoughts about this.

DR AGARWAL: I think these drugs are going to be very exciting to use in my clinic. Oral pills, easy to monitor, easy for the patients, less visits to the hospital. If olaparib and rucaparib are available in my clinic, I’m going to use them for my patients who are harboring those DNA repair defects, especially with BRCA2 and BRCA1.

Role of PARP enzymes in DNA damage repair and mechanism of action of PARP inhibitors

DR LOVE: The other question that we want to start with now, relating back to Emmanuel’s talk, relates to the biology of prostate cancer. I’m curious how, if you’re walking down the hall with your fellows, how would you intuitively explain it to them?

DR ANTONARAKIS: Neil, there’s 2 issues here. One is to explain how DNA repair works, and the second is to subcategorize prostate cancers into different molecular phenotypes that have clinical utility behind them. In other words, 4 or 5 different types of molecular prostate cancers that each have a drug or a class of drugs that can be used against them.

The way that I briefly explain DNA repair to my colleagues or my fellows is that the cell has the ability to fix DNA damage 1 strand at a time, or it can fix both strands of the double helix at the same time. The main way that it fixes DNA 1 strand at a time, which is a single-strand repair, is the mismatch repair pathway, which involves all the Lynch syndrome genes, which are also called mismatch repair genes. And the second is base excision repair, which involves the PARP enzymes, primarily PARP1 and 2.

Double-strand DNA repair occurs primarily through homologous recombination, and BRCA2 is probably the main protein there. And then there are 2 other ways that double-strand breaks can be repaired, but those are basically high-error, not high-fidelity mechanisms. In other words, they’re more error prone, and those are called nonhomologous end joining and translation synthesis.

To keep it simple, the way that I like to describe synthetic lethality is, you have to have both an inhibition of single-strand repair and double-strand repair to induce cell death. In the case of a BRCA2 mutation, that wipes out the double-strand repair pathway, and then the single-strand repair is inhibited by the PARP inhibitor drug. You have a genetic inactivation of double-strand repair, a pharmacological inhibition of single-strand repair and, as I like to call it, 1 plus 1 equals death, and that’s what synthetic lethality is.

Genetic testing for patients with PC

DR LOVE: Neeraj, I’m kind of curious right now how you approach and how you think a general medical oncologist in community-based practice, for practical purposes, should approach genomic testing in a patient with prostate cancer. Let’s assume there’s no family history. Of course you have a number of options. You have multiplex tissue assays like NGS. You have liquid assays, and of course you have germline testing. Can you talk a little bit, Neeraj, about how you think a general medical oncologist ought to approach prostate cancer patients, even those with localized disease, at least if they’re exposed to them?

DR AGARWAL: So first of all, availability of comprehensive genomic profiling through commercial vendors such as Foundation Medicine, Tempus, Caris, has really democratized the comprehensive genomic profiling of these tumors. And pretty much anyone can test them now. Anybody can order. Even from the remotest areas of the country, people have access to this testing. That’s the most important tool available to our colleagues in the community.

When I see patients with metastatic prostate cancer, our practice says every single patient with metastatic disease, regardless of family history, undergoes — at least we suggest that they undergo — comprehensive genomic profiling of the tumor. The reason being family history is unreliable. How many minutes do we have to go through the family history beyond first or second generation? Again, relying on family history really depends upon so many other factors: patient’s memory, recollection, how much they’re connected with their family, are they adopted or not, and really there are a lot of other factors.

We have decided that every single metastatic prostate cancer patient will undergo somatic tumor genomic profiling. And, as Emmanuel said, we want to be prepared for the eventuality of them developing castrate-resistant disease down the line. And we shouldn’t be hurrying up to get those test results when they are developing castrate-resistant disease.
Be ready with those tests results.

DR LOVE: Oliver, for practical purposes, I mean, I kind of see this has been going back and forth. It started with ovarian cancer — a number of cancers now where PARP is on the table. And I guess one of the questions is, if you just do germline panel testing, are you going to miss some things that you maybe might want to know? And if you just do tissue testing, are you going to miss some things you would want to know germline?

DR SARTOR: Yes, great question, Neil. And the answer is, with germline you definitely do miss important issues that can arise within the tumor. If we look at the BRCA mutation, for instance, we know that about half of them will be present in the germline, but the other half are going to be somatic only. And for things like mismatch repair associated with an important finding, and that is PD-1 inhibition has activity. We know that if you do simply the germline that you’re going to be missing the majority of patients.

So really we need to look at this as a package. Germline yes, because of the family implications. But somatic yes, because it gives additional information. Now, if you look at somatic only, you’re going to be deriving important information, but there’re a lot of limitations with somatic testing. First of all, we haven’t mentioned the degree to which the quality control is often problematic. For prostate cancer patients, the tissue that’s available may be old tissue from prostate biopsy. If we look at the olaparib Phase III, they actually screened around 4,200 patients, but only about 69% or thereabout actually were able to go on and get the testing done because of quality control failures.

Now, we use some circulating tumor DNA, but there’re a lot of deficiencies associated with circulating tumor DNA, and those are evolving assays, in my opinion. What we do is germline everybody within NCCN guidelines, and then we somatically test, particularly when there’s appropriate tissue available. And we try to get tissue as a priority, but it’s not always available, and so ctDNA is also part of our spectrum of assays we order in the clinic.

Correlation between Gleason score and incidence of DNA repair gene mutations in patients with localized PC

DR LOVE: Emmanuel, I want to start moving into some cases, but before we get into that, I’ve got to ask you to follow up. I was thinking about the talk that you gave. I was asking Neeraj about this. I understand that maybe it’s not practical for docs in practice. But I thought the stuff you were presenting on what’s known about localized disease was really interesting. The correlation between Gleason, et cetera. Can you kind of capsulize that a little bit, Emmanuel?

DR ANTONARAKIS: Sure. Most of the publications have focused on metastatic disease, but the very first publication, which was the so-called PCGA effort, this looked at primary localized prostate cancers, many of which never metastasized, or information about subsequent metastases was not present. What we saw from that initial publication was that approximately 9%, let’s say up to 10% of those localized nonmetastatic prostate cancers had at least 1 homologous repair deficiency mutation.

A subsequent publication that was led by one of our junior faculty at Johns Hopkins took all of the publicly available PCGA localized prostate cancer data, and there’s very little clinical annotation in the PCGA, but one of the things that is reliable is Gleason grade. And so we looked at all of the available data about 12 months ago and tried to correlate the presence or absence of an HR mutation with Gleason grade. And what we found was this: In Gleason grade 1, which is 3 + 3 = 6, the rates were very low, about 5% overall. The rates of HR mutations increased in Gleason grade 2, which is 3 + 4 = 7, and then increased further in Gleason grade 3, which is 4 + 3 = 7.

Interestingly, and to our surprise, once you get to a Gleason score of 4 + 3 = 7, when you go above that, for example, to Gleason grade 8, 9 and 10, you do not seem to get a further enrichment of HR pathway gene mutations. You kind of peak around 10%, 11% overall, and specifically for BRCA1 and 2 you get about 4% to 5%. And anything that is Gleason grade group 3 or above, which again is a 4 + 3 = 7 or higher.

DR LOVE: So Oliver, you may have seen the slide, I think Emmanuel was alluding to it, that he concluded his talk with, where he broke down prostate cancer into genomic biologic subsets, I think about breast cancer, San Antonio Breast Cancer Meeting, we did 3 separate meetings: triple-negative breast cancer, HER2-positive breast cancer, ER-positive breast cancer — different diseases.

Do you think prostate cancer’s heading in that direction, Oliver? And how do you think it through right now?

DR SARTOR: Yes, I do Neil. But when you look at the prostate cancer itself, certain things are actionable. The mismatch repair is absolutely actionable.

And pembrolizumab, very specifically pembrolizumab, is FDA approved for MSI high or mismatch repair, regardless of the assay that is utilized in the recurrent setting. This has huge implications. It’s not a large subset of patients, but it’s a very, very important subset of patients.

In addition, the homologous recombination repair, which would include the BRCA2, is particularly important for the PARP inhibitors. And we need to talk about at some point there may be platinum sensitivity as well. And that’s something that we should discuss as clinicians, because not always the PARP inhibitors are available.

Dissecting beyond that, I think we have some insight into things like PALB2, but less insight into others. Now, CDK12, and Emmanuel has helped to lead a project on this, has also been associated with responses with PD-1 or PD-L1 inhibition. CDK12 is potentially actionable. We need more data there, unequivocally. The BRCA mutation’s actionable. Mismatch repair, actionable. And then a lot of the others we need to learn more about. That’s my classification.

Role of platinum-based chemotherapy for patients with PC and DNA repair gene mutations

DR LOVE: Neeraj, one of the things that Oliver just referred to was the issue of platinums. And, of course, for example, in ovarian cancer that becomes a really critical issue. They use it as maintenance after platinum. In breast cancer, not quite as clear what the story is. Of course, platinums are already being used in pancreatic cancers. What do we know right now about platinums in prostate cancer, Neeraj, particularly as it relates to genomic subclasses?

DR AGARWAL: Obviously we do not have levels of evidence from big randomized clinical trials comparing platinum versus standard of care in patients who have metastatic castrate-resistant prostate cancer with DNA repair defects, so homologous recombination defects. Having said that, what we all know, based on anecdotal experiences and large case series, is that platinum may be effective in these patients. PARP inhibitors are not available easily in the clinic. I’m presenting a case where we were able to get off-label olaparib for 1 of my patients who had BRCA2 deficiency.

But the bottom line is, it’s extremely difficult to get PARP inhibitors off label for all our patients. When patients are progressing on standard novel hormonal therapies and they have homologous recombination defects in the tumor, I think this is a very viable option, in my view. Of course if they are healthy enough to tolerate platinum-based therapy.

DR LOVE: Emmanuel, what about platinums? I have this vague memory of this drug, I think it was satraplatin? But what do we actually know clinically about responsiveness to platinums? Do we have much data in prostate cancer based on, again, genomic status?

DR ANTONARAKIS: You’re going to date me now, but in 2009 there was a JCO publication with Cora Sternberg and Oliver Sartor using an oral platinum agent called satraplatin. There was some activity there in about 10% to 15% of patients. There was a slight PFS benefit versus placebo and no overall survival benefit, if I remember correctly. And the takeaway from that study, for me, was — and in those days we had no idea about genomics, of course — is that there is a clear subset of patients that do benefit quite profoundly from these agents. But at the time we had no idea who they were. And, unfortunately, tissues and blood samples were not back in such a way that we could go back and ask that question now.

I think that the question of platinums in prostate cancer is complicated, Neil. It’s complicated, because there might be a differential response between BRCA1/2 and platinum agents and ATM with platinum agents. This is my own personal experience, not published. I also recently heard a lecture from Judy Garber in the breast cancer world that they had hypothesized that the BRCA1/2-deficient breast cancers would be more platinum sensitive compared to taxanes. And my understanding is, a number of studies that have been unpublished and published have shown this is not the case in breast cancer. There really isn’t a clear benefit over a taxane using a platinum agent in a BRCA2-deficient breast cancer.

That was disappointing to me, because we all thought that breast would lead by example and we could follow. Of course, they’re separate diseases, so it still could be the case in prostate cancer that these patients benefit.

And the third complicating factor is, in prostate cancer, at least, I don’t ever use a platinum by itself. It’s usually in combination with another agent, such as a taxane. What I’ve typically done in the past is, if I think a patient has clinical features that would suggest more platinum sensitivity, for example a more neuroendocrine or anaplastic or small cell type carcinoma, then I would use docetaxel as the backbone, and I would add a platinum, typically carboplatin. But I don’t typically use either carbo or cis on its own in a metastatic prostate cancer patient.

DR LOVE: That’s really interesting.

Sequencing PARP inhibitors and chemotherapy for patients with PC and DNA repair gene mutations

DR LOVE: Neeraj, before you comment, I’m just kind of curious, your talk — you went through some of the combination strategies, and one of the things that you don’t see too much outside of ovary, but you see this is the way it was done in ovary, is platinum-based therapy, for example carbo/paclitaxel that they often use, and then PARP maintenance. And it’s interesting, a lot of the general medical oncologists use that strategy in breast cancer, although there’s no data, just like prostate. All the trials have been monotherapy. But I’m just kind of curious, Neeraj, what you think about that model of chemo, for example, a platinum agent followed by PARP maintenance.

DR AGARWAL: I do not see much rationale backed by data to use the strategy of treating my mCRPC patients with a carboplatin-based regimen or taxane-based regimen followed by PARP inhibition. If I’m going to use PARP inhibitors as monotherapy in HRD-positive patients, I’m going to use them likely before chemotherapy.

DR SARTOR: I’m going to rephrase the question a little bit and ask about biomarkers for platinum sensitivity. And Emmanuel alluded to that in the satraplatin trial, and he’s correct. It was a very slight advantage in PFS, not in OS, but some activity in a subset of patients.

It turns out that William Oh and I had ended up using the platinum-based regimens, typically in combination with a taxane. At that time it was just paclitaxel. And we combined data sets and published, I think it was about 11 years ago, on platinum sensitivity in prostate cancer in the second-line chemotherapy setting. And what we found was, somewhere around 15% to 20% of patients would respond. And at that time we did not have cabazitaxel and really had nothing beyond the first-line docetaxel. And the ability to use a novel AR antagonist, et cetera, was simply not available.

In an interesting publication we had stored — and this was from the time period that I was at Dana-Farber — a number of samples from those platinum-treated patients and went back and did an analysis. And it turned out that BRCA2 germline was a biomarker for the platinum sensitivity, at least as measured by PSA. We didn’t have, in this retrospective-type design — all the parameters were not properly measured. But I can tell you that the BRCA2 did come out. And it turns out, the BRCA2 germline is associated with biallelic changes and additional somatic loss that raised a significant percentage of patients.

The other DNA repair defects did not show. This, and based on studies from Bruce Montgomery in Seattle, makes me think that, particularly in the BRCA2 setting, that there’s a viable option for platinum. And we’ve used it. Now, interestingly, in the case I’m going to present, Neil, we administered platinum in combination with a taxane to an agent and ended up having to stop the platinum and moved on to the maintenance strategy that you just alluded to. And in that particular setting, the patient had a very nice response.

I think we need more data. I’m not really pro that approach, because how could I be? The absence of data speaks loudly. But on the other hand, I think it’s a reasonable hypothesis to test based on anecdotal evidence.

Case (Dr Antonarakis): A man in his mid-40s with castration-resistant PC (CRPC), a BRCA2 mutation and lung metastases attains an excellent response to olaparib on a clinical trial

DR LOVE: Emmanuel, let’s talk about your case, your 45-year-old man. Can you briefly overview what happened with him?

DR ANTONARAKIS: These are all real cases, Neil. An African American gentleman diagnosed with prostate cancer at a very young age of 45. At the time of diagnosis he had a Gleason 8 disease. PSA was 6.9, and he had extracapsular extension, meaning T3a. Because of his young age, I did probe on the family history. I usually don’t go beyond 2 generations because of time, but in this case his mother, it turns out, had developed actually lethal breast cancer at the age of 39.

The gentleman, of course, had localized disease. He was young. He was fit for prostatectomy, so he had that and unfortunately developed a biochemical recurrence, had early salvage radiotherapy. And as often happens in these young men, he ended up having a further biochemical recurrence following salvage radiation. He was then treated intermittently and then continuously with ADT for nonmetastatic disease, which was effective for only approximately 20 months, which is on the short end of the spectrum. And then his PSA was rising with a castrate level of testosterone, and imaging studies for the first time showed new pulmonary metastases.

Interestingly, Neil, this gentleman had no other evidence of metastatic disease at the time, so nothing in the bones, nothing in the lymph nodes. This is what you’d call a pulmonary-only or pulmonary-tropic metastatic disease, and I’ll get back to that in a second.

DR ANTONARAKIS: This gentleman underwent germline testing, as you would expect, especially with that family history. He has a loss-of-function BRCA2 mutation. The report helps you by seeing his pathogenics.

And as you can see, ­results in a frameshift — isoleucine 605 tyrosine frameshift 9. That means that this is a protein truncating mutation, clearly pathogenic.

This patient, Neil, was treated on a clinical trial using a PARP inhibitor, in this case olaparib, as a first-line mCRPC therapy. He had not received abiraterone. He had not received enzalutamide. He had not received a taxane. This was truly his first-line mCRPC therapy.

DR ANTONARAKIS: PSA level was approximately 15 when he developed his pulmonary metastases. And he was enrolled on a clinical trial using olaparib as a monotherapy 300 mg twice a day.

And as you can see there, over the next 9 months his PSA virtually became undetectable. Not initially. It took about 6 months for that to drop.

But this patient, Neil, has an ongoing response. On the left you can see January 18, 2019, some pulmonary metastases there. I think I count there are at least 7 or 8 on these images. And approximately 9 months later, the radiologists basically said that they could not identify any remaining pulmonary mets. Again, this is a guy that presented with lung-only metastases, germline BRCA2-positive, took olaparib at the 300-mg BID dose and developed a complete serological response and a complete radiographic response without the concurrent use of abi or enza.

I wanted to use this case to highlight a publication from our group suggesting that patients that have unusual metastatic patterns could harbor a greater rate of DNA repair mutations. We looked through our clinical database at Hopkins, and we identified 25 prostate cancer patients who presented either at the time of metastatic hormone-sensitive disease or at the time of metastatic castration-resistant disease with pulmonary-only mets. In other words, lung mets only that were biopsy proven without any other lymph node or bone metastasis. And then we looked at the genomics of these patients. It was only 25 gentleman.

Fifty percent of patients who present with pulmonary-only metastatic prostate cancer, 50%, half are going to have either an HR mutation like this gentleman or a mismatch repair mutation like some of my other patients. And this might be true of other unusual metastatic patterns. For example, we are now currently looking into patients that present with brain metastases, either isolated or following castration therapy. When you see unusual patterns of metastatic disease, it should make you think of potential unique or unusual genomic patterns.

Tolerability and side effects of PARP inhibitors

DR LOVE: Emmanuel, can you talk a little bit, I guess this man’s been on therapy now for a while. What happened in terms of his tolerance of therapy? Any side effects? Any cytopenias? How’s he done in terms of that?

DR ANTONARAKIS: He’s been on drug for at least a year and a half at this point. Fatigue was his main problem. This occurred within the first 2 months. This was a young man in his mid-40s, was very active politically, with his family life, was very active with sports, basketball primarily, and he did notice, at least on exertion when playing sports or when spending time with his family or when doing long days he would get more tired. If he was on a clinical trial, we would probably grade that as a Grade 1 fatigue.

And the other thing that he noticed immediately was an appetite suppression. This was a man that used to have a veracious appetite. And he started not to be in the mood for eating his favorite foods. Actually did lose some weight. It was not necessarily unintentional. It was because he was eating less. Interestingly, he did not describe the sensation as nausea or queasiness. He just described it truly as anorexia. He just wasn’t in the mood to eat his favorite foods. He lost about 8% of his body weight in the first 6 months and then he stabilized, and the anorexia continued, but he kind of increased his portion size and the weight loss stopped.

His marrow function was very, very high at the beginning, having never received any chemotherapy or any radium-223, and he did not develop any cytopenias whatsoever. In fact, he didn’t have any decline in his hemoglobin, which remained in the 14 to 15 range.

DR LOVE: That’s really interesting, though, the way you described the fact that he was losing weight, et cetera. Neeraj, we certainly have been hearing, it began with the gynecologic oncologists. I think they were really the first ones to get a lot of use, and you started to hear a lot about GI side effects. Some of them started to use preemptive antiemetics, et cetera. It’s always been kind of difficult for me to tease out when I talk to people, like, even this case. I don’t know, I guess, was it your thought this was a kind of GI toxicity, Emmanuel?

DR ANTONARAKIS: Yes, definitely.

DR LOVE: I’m just kind of curious, Neeraj, what your clinical experience has been. Have you seen younger patients like this have more GI issues, less cytopenias? Older ones the reverse? What kinds of problems have you encountered?

DR AGARWAL: I frankly have not really seen any outstanding side effects with this whole class of drug, which is PARP inhibitors. I think I agree fatigue is something which we see mostly Grade 1. Anorexia, or lack of appetite, I would rather use the word lack of appetite, again, very subtle. Nausea, vomiting not so much of a problem. Maybe nausea, but I rarely see Grade 2 vomiting with PARP inhibitors. I personally think it’s relative. It’s how we look at the overall side effects.

These patients, younger patients, if we talk about younger patients who have very high testosterone levels to begin with and they undergo castration therapy, already have a lot of fatigue. And then we add abiraterone on top of that, and then we add olaparib after that, how much extra fatigue they are going to feel beyond what they were already feeling. I think it’s relative. I think the cleanest situation would be to appreciate the side effects with those patients who have not received androgen deprivation therapy and see how much fatigue is actually being caused exclusively by PARP inhibitors.

DR LOVE: Emmanuel, I was just flashing on this meeting we did at Society of Gynecologic Oncology last year. We were talking about toxicity, and Rob Coleman from MD Anderson was there. He had just written this really great paper reviewing all the toxic­­­ities, and one of the things that he brought up biologically in the paper was something about PARP inhibitors and circadian rhythm.

And so I started asking the panel, have you seen insomnia? And everybody was saying yes. I didn’t think to ever ask you all, but Emmanuel, have you seen insomnia?

DR ANTONARAKIS: I missed that paper and I have not seen it, but I don’t typically ask it. Most of the insomnia that we get is from the prednisone that’s given together with the abi. But I can’t say that I remember any insomnia for my PARP inhibitor patients myself.

DR LOVE: They were actually speculating that maybe that was contributing to the fatigue, because they felt like they were seeing insomnia. Anyhow, sometimes stuff, these kinds of subtleties come out.

Oliver, any other thoughts about toxicity, and particularly in the older patient, the patient with a lot of bone mets, in terms of cytopenias? Any experience with PARP inhibitors in people with packed marrows?

DR SARTOR: Yes, the cytopenias have been an issue for me, and I don’t have experience to say if that’s in the packed marrow setting. I can’t really comment on that. But I can comment about some patients. In one of the cases that I’ll present, had some pretty extreme cytopenias coming into the use of olaparib. And what I’ll say is that I know it’s a side effect. I know it’s real and we have to monitor it, and I haven’t seen a lot of GI toxicity in my own experience.

And I wonder whether or not the patients with ovarian cancer may be a little bit of a different subset. A lot of abdominal disease in that setting, a lot of cisplatin use in that setting, which of course is very emetic. But I’ve had a little less trouble with GI, but more problems with the cytopenias and particularly in someone who started off with cytopenias in the first place.  

DR LOVE: Interesting. One other issue that comes up about PARP, Neeraj, and I don’t know how much data you have right now in prostate cancer. I’m not even sure how relevant it actually is, is the question of secondary cancers, particularly AML and MDS. I haven’t really heard a major signal coming out yet about that, but I have heard people voice theoretical concerns, Neeraj. Any comments on that?

DR AGARWAL: I’ve never seen this happening in my patients yet. One reason I always think about why we are not seeing so-called MDS and all marrow failure syndromes in our patients may be because our patients are much older than those younger patients with ovarian cancer or maybe even breast cancer. And if you look at the metastatic CRPC trajectory, we are talking about 3 years of overall survival after androgen deprivation therapy fails them, in sensitive setting. And that may not be a sufficient amount of time to allow marrow failure to develop. Having said that, from this perspective, I have never seen a single case of myelodysplasia or marrow failure in my patients.

Case (Dr Antonarakis): A man in his late 40s with metastatic hormone-sensitive PC and biallelic BRCA2 mutations receives PARP inhibitor monotherapy on a clinical trial

DR LOVE: Let’s go on, and we’re going to talk about another case here of Emmanuel’s, this 48-year-old man.

DR ANTONARAKIS: This second case might get in trouble, Neil, because I sometimes have the reputation of being an iconoclast, and I’m going to go out on a limb and propose something that might be a little bit crazy here, but here we go.

This is another real patient from my clinic, a European American man, non-Ashkenazi, who was diagnosed at the age of 48. So again, quite young. This gentleman was diagnosed from a screening PSA, actually. The year before it had been 1.2, and then the year after it was 35. Because of the PSA, he had a bone scan and CT scan. Bone scan showed fairly widespread, about 6 bone metastases. CT scan showed enlarged prostate, invasion of the bladder, but otherwise no lymphadenopathy, no visceral disease. He did undergo a prostate biopsy for diagnostic and genomic purposes. He had a Gleason score of 4 + 5 = 9, perineural invasion.

And again, in the family history, this gentleman had a sister who was diagnosed with advanced ovarian cancer at age 37. When I saw him, he had not had any genomic testing or germline testing. And at the time when I met him, despite the 6 metastases in the bone, he was completely asymptomatic. And because of his age and the importance of his sex life and other factors, he was extremely reluctant to begin any form of androgen deprivation therapy.

About 10 days after I saw him, we got the result of his Invitae test. This is a 20-gene panel. And as you can see here, he has a pathogenic BRCA mutation. Again, this is a frameshift mutation that leads to a premature truncation of the protein. And this was not surprising given his age and his sister’s history of ovarian cancer.

And we have a clinical trial at Johns Hopkins right now, which we call the TRIUMPH study. And this study is for men that have a germline HRD mutation who have newly diagnosed metastatic hormone-sensitive prostate cancer who are willing to forego or delay any ADT-based therapy. And these patients receive a PARP inhibitor, in this case rucaparib, as a noncastrating therapy without any androgen deprivation.

This gentleman enrolled in that study. And again, the remarkable thing about this study, which is why I think it’s a bit iconoclastic, is that we are not using any form of ADT. We had a lot of trouble getting this past the FDA, actually, when we were writing this, because, as we all know, ADT plus or minus docetaxel plus or minus abiraterone/enzalutamide/apalutamide is the standard of care. We had to write the consent in such a way that the patient had to check a box that he was actively declining the current best standard of care.

This person, as you can see here, his PSA was just about 35 when he enrolled on the study. He began the rucaparib 600 mg po BID without any antiandrogens.

That’s the name of the study with the NCT number, if you want to look at it. And over the course of the next 12 months, his PSA essentially became undetectable.

Now, again, the most remarkable thing about this case is, as part of the study, we had to do a somatic analysis. And as you would have anticipated by type of PSA trajectory, this patient did have a proven second hit in the tumor cell of the other BRCA2 allele. This is what we call biallelic inactivation. In other words, both copies of the BRCA2 gene were dysfunctional, so his HR function coming from BRCA2 was completely wiped out. And this person essentially had a complete response to the rucaparib as a monotherapy.

DR LOVE: My jaw is, like, down on the ground right now — like, really? Whoa! This is amazing. I don’t even know what to say. Oliver, I’ll turn to you. Any comments?

DR SARTOR: Wow!

DR LOVE: Really.

DR SARTOR: Pretty amazing, and hats off to Emmanuel for getting way ahead of the curve on this one. Hats off to you, Emmanuel.

Perspective on the potential use of PARP inhibitor monotherapy in the first-line setting for patients with hormone-sensitive PC and DNA repair gene mutations

DR LOVE: Any comments about this case, Emmanuel? What do you think it means in terms of future clinical research?

DR ANTONARAKIS: Just to play the devil’s advocate on my own study, there are some potential concerns here that we have not resolved. One is, when this patient eventually becomes rucaparib resistant, which he almost certainly will, is the fact that he had rucaparib first going to make him less hormone sensitive? That is a question that bothers me, and we have not resolved that.

We have data from our laboratory showing that if you give olaparib to prostate cancer cell lines that are BRCA2 deficient and you treat them long enough, one of the things that happens is, you change the nuclear localization of AR. And the AR basically moves from being predominantly nuclear to becoming cytoplasmic, without using any charcoal strip medium or androgen deprivation therapies or antiandrogens.

And we’ve only been able to do this with 1 cell line, and we have not replicated that yet. But part of me wonders whether at least some of the effect that we saw in this patient could potentially be an indirect effect on somehow inhibiting the AR. That is more speculative at this point in time, but if that is the case, it is possible that there might be some cross resistance with downstream AR regulation. Again, I’m just speculating.

The other thing I want to say, and I don’t want to give too much away, because hopefully we’ll publish this trial one day. We’ve enrolled 6 patients on this trial, Neil, and 5 of the 6 have had responses quite similar to this one. This is not a unique case. We are accepting all types of HRD germline mutations. It has to be germline.

We are not allowing people that have somatic only. The theory behind that is, we hypothesize that those patients that have a germline first hit are more likely to have a somatic second hit, whereas patients that have a somatic first hit may not always, and sometimes don’t have a somatic second hit. This is purely for germline-positive cases. The patient that did not respond, going back to the CHEK2, is a patient with a germline CHEK2. And all the patients that have responded have been BRCA2 or BRCA1.

The other thing that we’re doing is that we are doing a similar study using olaparib in patients that have a biochemical recurrence after local therapy, again, without ADT. And in that trial they’re getting olaparib for their nonmetastatic BCR — biochemical-recurrent prostate cancer. And in that study we have enrolled about 20 patients, and we’ve seen 6 responses.

Interestingly, that study was biomarker unselected. In other words, we were giving olaparib to all patients, and then we were retrospectively, after the patient was enrolled, going back to their primary prostatectomy tissue and sequencing that. And it turns out that in our first 20 patients on that study, which is a 50-patient trial, the 6 patients that responded all had BRCA2 mutations, and 1 had an ATM mutation. Again, this can be done in the hormone-sensitive setting, both in terms of radiographic metastatic disease like in the TRIUMPH study and in terms of biochemical-recurrent disease.

Again, the FDA has been very strict with us in both of those trials, and they have mandated that if we see more than 1 case of MDS or AML, the entire study will immediately shut down. They were appropriately concerned about exposing patients with a long life expectancy to drugs that might cause MDS or AML. The way that it was phrased, and we had to agree with it, was, if we see 1 case it could be just accidental, but if there’s 2 or more cases of MDS or AML in either of those 2 studies the study will permanently shut down.

DR LOVE: Wow squared. And sometimes people say a thing, and they kind of trigger memories that I have of people saying things to me, and this thing about maybe it’s working through AR, Oliver, I think I remember in the past people speculating that taxanes, docetaxel in some way were connected to AR. Is that the case?

DR SARTOR: There’s been some data that suggests that the translocation of AR from the cytoplasm to the nucleus may be inhibited by taxanes. And it turns out that there is some validity, in my mind, toward that data. There’s clearly an interaction between AR and PARP inhibitors that has been shown. And this is coming out of Jefferson, where some very nice papers have shown interactions between the AR and DNA repair pathway. So it’s an interesting and evolutionary time right now, where the PARP inhibitors may interact with a variety of other therapies. And, of course, we’re going to learn whether or not this is true, they are targeted agents because we have good prospective trials that are designed to ask that question.

DR LOVE: Emmanuel, did these men have decreased testosterone levels?

DR ANTONARAKIS: That’s a great question. We have been testing that, and so far we have not seen that. Their circulating testosterone does not decrease. We still don’t know what’s happening to testosterone localization in the cancer cell.

Tolerability of PARP-inhibitor monotherapy in the first-line setting

DR ANTONARAKIS: I want to go back to something Neeraj asked before, and it was almost like he was setting me up to answer this, which was, here we can test the independent side effects of PARP inhibition in the absence of ADT, but both in the biochemical recurrent study where we’ve now treated 29 patients and in the metastatic study where we’ve treated 6 patients. And what I can say is that even in these studies, fatigue is consistently the most common problem. I do believe that some degree of fatigue is still present even in patients who are noncastrate.

One interesting thing that I will point out, which I did not appreciate before, is that a lot of the PARP inhibitors, especially olaparib, in my opinion, when it’s given without castration, maybe with castration as well, induces a dry cough. Somehow in the patients that I’ve seen, and in a few cases it does produce the subjective feeling of slight breathlessness and a dry cough. And there have been a few cases of frank olaparib-induced pneumonitis. This is not a florid pneumonitis, but when you stop the drug for a week, the cough disappears. And then when you put them back on the drug at the same dose or the lower dose, the cough often comes back. And I’ve seen this about 5% of the time. And I have not seen this really being published or mentioned before, but it’s something that I’ve observed.

DR LOVE: Wow, that’s really interesting. What about this man in terms of rucaparib? Again, how did he tolerate it?

DR ANTONARAKIS: He got some fatigue. He did not have an appetite suppression or an anorexia. He had no cytopenias to begin with. He did not develop cytopenias. For him, actually, fatigue is really the only side effect. We are seeing him monthly for the trial, and we have to always ask. But other than fatigue, he did not report anything else.

DR LOVE: I’m just kind of curious, Emmanuel, where else in the world are people looking at PARP inhibitors in prostate cancer before androgen deprivation? Are there other trials doing that?

DR ANTONARAKIS: There’s only 4 in the world. Two are at Johns Hopkins, and the other 2 are neoadjuvant trials, where a PARP inhibitor is being given before radical prostatectomy to try to understand what is going on pharmacodynamically in the prostate gland after treatment. I have not looked recently, but when we were designing those studies there really weren’t that many other ones.

DR LOVE: Very interesting.

DR LOVE: Neeraj?

DR AGARWAL: Yes, so we do have 1 trial with rucaparib in patients with biochemical recurrence after definitive radiation or chemotherapy for patients who are selected for germline or somatic homologous recombination defect-related mutations. This trial was definitely inspired by Emmanuel’s trial, and we decided to just go ahead with selected patients as opposed to all patients, as you are doing.

DR LOVE: That’s fascinating. I’m just kind of curious, Neeraj, have you seen the cough/shortness of breath thing that Emmanuel was talking about?

DR AGARWAL: It’s amazing how much I learn when I talk to Emmanuel and Oliver, right? I’m thinking now, 1 of my patients did have cough. And the patient is still undergoing treatment, and we are using guaifenesin and codeine, actually, right now —

DR LOVE: Wow. Wow. Wow.

DR AGARWAL: — for the cough. And I will definitely try to stop the drug. Otherwise the patient is doing fantastically well, responding, PSA going down, single-agent rucaparib, no ADT onboard. And when I noticed this cough, like, 3 months ago, I never thought about possibility of the drug causing the cough. But definitely I will look into it.

DR ANTONARAKIS: I think it’s probably a chemical drug pneumonitis, but I can’t prove that. I don’t think it’s an immune related, although it certainly could be as well. I have never tried steroids for it.

Case (Dr Sartor): A man in his late 60s with metastatic CRPC (mCRPC) and a germline BRCA2 mutation receives olaparib

DR LOVE: All right, let’s talk about a couple more cases. Oliver, you had a 68-year-old man. Maybe you can talk about him.

DR SARTOR: This is a 68-year-old, and interestingly he showed up having already had a history of breast cancer and bone metastatic prostate cancer, and nobody had done any germline testing on him or any testing of his tumor. Which I was fairly amazed, because pretty much if you have a male with a breast cancer, it’s BRCA until proven otherwise, in my mind.

We tested him. He had a BRCA2 lesion. And he had already progressed. He progressed after ADT alone, and based in part on the experience that we had in the publication that we had about the germline BRCA2 responding in the majority of cases with docetaxel and carboplatin, we used docetaxel/carboplatin regimen and got a really, really nice response, and he tolerated it quite well.

The problem is, he developed a severe allergic reaction to the carboplatin and then subsequently began to have a PSA rise. We put him on abiraterone and prednisone, and he responded for about a year.

And then we were able to obtain olaparib for him and started him on the 300 mg BID dose. And he had had a little bit of myelosuppression with the prior platinum-based therapy. His blood counts actually stabilized. He had not had any significant declines. His PSA declined over 50%, and that’s really been persistent for over a year.

Here’s a guy who had platinum-based therapy and then went on to receive the olaparib, and he’s had a really, really nice response. Now he started to lose his response very recently, and I escalated him up to 400 mg po BID, and actually his PSA has declined, but he is continuing to tolerate the therapy well and again has had no trouble with his blood counts, which we’ve been watching very carefully. This is a very interesting case. Initially the germline testing being missed because of direct history of breast cancer, and good response to platinum-based regimen and then going on to the PARP inhibitor later. And he tolerated it extremely well, by the way.

Dosing and PARP trapping activity of PARP inhibitors

DR LOVE: That’s really interesting. I’m just kind of curious, I was actually thinking about that before, Emmanuel, when I was listening to your case with the GI problems. I was wondering, of course the patient’s doing well, maybe you’re not thinking too much about changing anything, but whether a dose adjustment is helpful in symptoms like GI toxicity or cytopenias? But also whether or not we know anything about the relationship between dose and efficacy. Can you escalate up, as happened in this case? I don’t know. Emmanuel, have you ever seen — it sounds like this patient responded to a dose escalation. Emmanuel, any comments about the issue of dose of PARP inhibitor in prostate cancer?

DR ANTONARAKIS: The best data that I’ve seen that may partially answer that is the TOPARP-B data. In the TOPARP-B trial, they were looking at 2 doses of the old formulation of olaparib, which was 300 mg BID, and then there was another cohort with 400 mg BID. And although the 2 cohorts were not directly compared, my impression of the data, which has now been published in Lancet Oncology by Mateo et al, is that both the efficacy was slightly improved with the 400 BID dose but also the toxicity, specifically the cytopenias, seem to be a little bit worse. And there were a great number of patients that were mandated to have a dose reduction in the 400 BID compared to the 300 BID of olaparib. 

DR LOVE: I think there are some data with talazoparib in terms of dose. Oliver went through the mechanism of action in what we know about the various PARP inhibitors that are being studied. And we know there’re differences in mechanisms, in particular this issue of PARP trapping. Can you talk a little bit, Emmanuel, about your vision about the difference between the various PARP inhibitors that are kind of being looked at right now? And also from a theoretical point of view what your thoughts are about combining it, particularly with androgen deprivation or endocrine therapy.

DR ANTONARAKIS: I have to admit, Neil, that the PARP trapping conversation might not go beyond the theoretical. There’s preclinical data showing that in addition to the enzymatic inhibition, or the catalytic inhibition of PARP1 and PARP2, some PARP inhibitors might also work by trapping the PARP enzyme on the DNA, and as the PARP is trapped and is not able to dissociate during the S-phase, synthesis phase of the cell cycle, it gets stuck there on the DNA. And this causes replication fork collapse, and it induces double-strand DNA breakage in the double helix.

It is not clear to me, Neil, whether the PARP trapping piece is relevant in humans with respect to the activity of these agents. But what we do know, or we think we know, is that talazoparib, from all the 5 PARP inhibitors that have been used in prostate cancer, probably is the most potent PARP trapper. And perhaps veliparib is the least potent PARP trapper.

There is not necessarily a correlation between the enzymatic inhibition and the PARP trapping. In other words, the best PARP trapper might not necessarily be the best enzymatic inhibitor. It turns out the talazoparib, actually, by chance perhaps, or maybe by design, is also a very potent PARP1 and PARP2 catalytic inhibitor as well as being a PARP trapper.

Case (Dr Agarwal): A man in his late 60s with progressive mCRPC is enrolled on the TALAPRO-2 trial of enzalutamide with or without talazoparib

DR LOVE: We’ll get more into this as we talk about some of the trials, but maybe we can talk about this 67-year-old man, Neeraj, that you took care of. What happened there?

DR AGARWAL: First of all, Neil, my cases are those patients who are enrolled on these combination clinical trials. This is a 67-year-old man, presented with right femur fracture without any obvious provoking event, in February 2016. As we can see, family history, past medical history is unremarkable. Enlarged prostate. PSA is very high at 500 ng/mL. Prostate biopsy shows Gleason score 4 + 4. Widespread lymphadenopathy. Bone metastases. And we diagnosed him to have metastatic castration-sensitive prostate cancer.

DR AGARWAL: He did not have any evidence of homologous recombination defect, either on germline testing or somatic comprehensive genomic profiling. Treated with — at that time the standard was docetaxel combined with bicalutamide/leuprolide. It was 2016, CHAARTED data was already available to us, and we started him on this combination therapy. Nice response, but then 2 and a half years after, the patient had disease progression. PSA was rising. And at that time, I had the option of enrolling the patient on the TALAPRO-2 trial, which is a registration Phase III trial of enzalutamide plus/minus talazoparib. And the patient was willing and was eligible and was finally enrolled on this trial.

DR LOVE: I’m just kind of curious as you sat down with this man to give him informed consent for the trial, can you talk a little bit about how you approached that discussion? How you would have treated him if he hadn’t been on a trial? And kind of what that discussion went like. Really interesting how he presented. 67-year-old man who presents out of the blue with a fracture in the femur and all of a sudden finds out he has metastatic prostate cancer initially. How did you discuss with him the option of the trial?

DR AGARWAL: It was not that difficult, Neil, because enzalutamide is the standard of care for these patients who have just been diagnosed to have metastatic CRPC in new onset. All I had to do was to discuss the prelim data, laboratory data, our own Phase I data, how did we come up with this combination dosing in this trial.

As we were alluding to in the previous discussion, like, how come we are using a lower dose of talazoparib in this trial. So basically talking about safety data and the data from the earlier part of this trial, and some prelim data, and the fantastic translation data published by the team from Hopkins, Mike Schweizer, Cancer Discovery paper, Emmanuel, you were on it, how BRCA function is supported by ER function and vice versa. ER assistance is associated with BRCA inactivation, which may make these cancer cells more sensitive to PARP inhibition.

Anyway, bottom line is, we also have abiraterone with olaparib Phase II data where radiographic progression-free survival was statistically significantly prolonged with the combination of abiraterone with olaparib versus abiraterone alone. These data were presented, like, 2 years ago in GU ASCO. I think we have enough sufficient amount of prelim data in the context of laboratory data in the form of Phase II clinical trial data. And this is not very difficult to explain to our patients why this strategy may be useful for that.

Finally, the patient got enrolled on the trial. This was a randomized, obviously placebo-controlled trial, so I’m not sure if the patient is receiving talazoparib or not. But certainly the patient is receiving enzalutamide.

DR LOVE: That’s a pretty good sign that you can’t tell whether they’re receiving the PARP inhibitor talazoparib or not.

Efficacy and tolerability of PARP inhibitors alone or in combination with endocrine therapy

DR LOVE: Oliver, what’s your take in terms of what’s been seen in terms of tolerability as well as efficacy with these strategies of combining endocrine manipulation or treatment with PARP inhibitors?

DR SARTOR: There’s some interesting data there. To me the most interesting data presented is from Noel Clarke, who presented unselected patients in an abiraterone/olaparib combination trial. And it was quite provocative. It actually looked positive. In terms of tolerability, it appeared to be quite high. There was, perhaps, a little less toxicity than I might have imagined.

Taken together, I think it’s a promising approach, and the good news is that large trials are now in progress. And we’re going to have a definitive answer on this approach for not only those who might have homologous recombination repair alterations but in all comers. I look forward to the clinical trial results.

DR LOVE: It’s always a challenge to talk to investigators in any tumor type and separate out differences within a class, including PARP inhibitors, and particularly in terms of tolerability. Often you don’t have direct comparisons. I am kind of curious in terms of the various PARP inhibitors being used alone and in combination, Emmanuel, whether you think there’s any difference in terms of cytopenias, in terms of GI? In breast we heard about some alopecia with talazoparib. I don’t know whether that’s been seen in men with prostate cancer. Emmanuel, any comments?

DR ANTONARAKIS: I think my answer is going to be brief. I broadly don’t see major differences. I have not used talazoparib. The one thing that I will say is, niraparib seems to cause more thrombocytopenia in my hands, and rucaparib and olaparib seem to cause more anemia. That’s 1 difference in the cytopenias that I’ve noticed.

DR AGARWAL: I would like to just add on this, all these Phase III trials have both cohorts of HRD-selected patients and unselected patients. I think we’ll have pretty nice data available, hopefully next 2 years or 2 and a half years, about how these combinations are doing not only in HRD-positive patients but also unselected patients.

DR LOVE: It’s interesting you mention the thrombocytopenia, Emmanuel, with niraparib, because what we saw in ovarian cancer was it was related to the weight of the patient. They first started to see a lot of thrombocytopenia, and then they adjusted their dosing based on the woman’s weight. And, like, it was 177 pounds they use a lower dose, anything below it. Platelet count, again, unless it was completely normal, they’d drop it down to 200. That, I don’t know if that really is what the issue is as opposed to the drug itself. Of course, all of these cause cytopenias.

Again, Neeraj, any comments about differential? Of course, trials like this you can’t really tell because they’re placebo controlled. Have you seen any alopecia? I’m not even sure it happens in breast cancer. I’ve heard it mentioned. Have you seen any different side effects with talazoparib compared to the other PARP inhibitors?

DR AGARWAL: Not in my experience. I have not been able to pick up any differential cytopenias, and I mostly use olaparib and talazoparib. And I think they are very similar from a side-effect perspective. Alopecia has not been any outstanding side effect, at least I have seen in my practice.

Just to give a comment on the thrombocytopenia, Neil. After chemotherapy in ovarian cancer patients, is it possible that those patients receive more chemotherapy because of higher body weight and they have higher myelosuppression because of the higher dose of chemotherapy? When they receive the PARP inhibitor, they have more cytopenia because of a higher degree of myelosuppression from prior chemotherapy. That’s something I was thinking about.

DR LOVE: Wow, I’ve never heard anybody bring that up. I gotta bring that back up to them and see what they think about it.

Response to PARP inhibitors in patients with PALB2, FANCA and RAD51 mutations; clinical care of patients with PC during the COVID-19 pandemic

DR LOVE: Emmanuel, yes?

DR ANTONARAKIS: I just want to make a brief comment about PALB2. Since many people consider me to be a genetics nerd, it stands for partner and localizer of BRCA2 — partner and localizer of BRCA2. Directly interacts with BRCA2. So it’s not a stretch of the imagination to believe this gene is going to be important. We’ve had 2 data sets now that suggest that PALB2 is going to respond more favorably to PARP inhibition than other genes like CHEK2 and CDK12. The first is the TOPARP-B data that Oliver mentioned. The second is the TRITON2 data presented by Wassim Abida in Clinical Cancer Research. In that study, using rucaparib as opposed to olaparib, there were also a number of patients, still less than 5, with PALB2 mutations, some of which had very dramatic and long-lived responses to rucaparib.

The other 2 genes to keep in mind that are very rare, but do induce profound responses or can induce, one is FANC-A, Fanconi anemia A, and the second is RAD51. There is emerging data on the non-BRCA HR genes that may respond well to PARP inhibition. CHEK2 does not appear to be one of them. CDK12 does not. ATM does not. But potentially PALB2 yes, FANC-A yes and RAD51 yes.

DR LOVE: Partner of localizer, is that it?

DR ANTONARAKIS: Partner and localizer of BRCA2.

DR LOVE: Partner — so the PAL is a partner and a localizer. I like it. I like it. Very intuitive.

But I did want to get back to this issue of the clinical scenario of a patient progressing on primary endocrine therapy. We had Oliver — his fantastic Phase III trial presented at ESMO last year looking at those patients. Of course this was not about BRCA, this was just prostate cancer, looking at those patients comparing cabazitaxel to a second form of endocrine therapy. Cabazitaxel did a lot better. Everybody started to switch their therapy. Again, putting aside the BRCA, more typical patient that doesn’t, Oliver, are you still moving towards, say, cabazitaxel in that situation right now with COVID going on?

DR SARTOR: I’m trying to diminish my chemotherapy patients. Not only is it immunosuppressive, potentially making them more susceptible to COVID, but having potential consequences with COVID infection, that would be worse. And in addition, the repetitive trips to the hospital, with the blood testing and the infusion unit. I’m trying to keep patients away from the clinic to the extent feasible. And absolutely you’re referring to the current study, a very nice study with cabazitaxel showing benefit as opposed to AR after AR inhibitor therapy. But nevertheless, today I’m trying to keep away from the myelosuppressive chemotherapies to the extent feasible because of the virus.

DR LOVE: Again, not to get too far off track, Emmanuel, but I’m curious how you’re approaching this. Are you incorporating AR-V7 assays into your clinical decision outside of a clinical trial? Any other comments about how you’re approaching this right now with COVID going on?

DR ANTONARAKIS: I think with COVID going on the goal is to keep people off chemotherapy as long as they’re not very symptomatic from bone disease. And I have to admit, with or without AR-V7 I am more likely to go from 1 AR therapy to another in this current climate than I was before, or to consider off-label therapy with drugs such as PARP inhibitors that are oral and not intravenous.