Emmanuel Antonarakis: Thank you, Oliver.
Oliver Sartor: We're going to talk about an interesting concept: bipolar androgen therapy. Some people call it BAT. There are other names as well. You've been involved with it for a long, long time. And I'm just curious, help people understand a little bit about what it is, and then we'll talk about what type of patient might be suitable, and some of the recent advances.
Emmanuel Antonarakis: Well, as you know, Oliver, for many years, we've been focusing on blocking the androgen receptor or reducing its ligand for a therapeutic gain in prostate cancer. Well, this is the exact opposite. This is where we take a man that has androgen pathway modulation resistant, previously called castration-resistant prostate cancer, and we are giving them supraphysiologic androgen, androgen levels that are higher than physiologic.
And, this is done through an intramuscular injection of a testosterone, either cypionate or enanthate. And this is done in the clinic once every four weeks by IM injection. We are achieving testosterone levels of around 1,500 nanograms per deciliter, and we are maintaining their medical or surgical castration at the same time.
Oliver Sartor: Now that seems a little bit paradoxical to me. So you've got high, you've got low. How do you kind of figure out what type of patient might be suitable for this unusual therapy?
Emmanuel Antonarakis: Right. So it is a paradox, and Johns Hopkins is known for many paradoxical discoveries. This was made by Dr. Sam Denmeade and John Isaacs at Hopkins. And we tested our first patient around 2014 to 2015. And the key thing here, Oliver, is that this is not for every patient. While we do see remarkable responses and remissions in 30 to 40% of patients, stable disease in maybe another 30%, unfortunately, there is an unpredictable 10% risk, I would say, of accelerating the disease.
And this is very important if this ever becomes deployed in clinical practice. It's not FDA approved yet in any indication, but let's imagine that it does become FDA approved one day. We do not want to be treating symptomatic patients, especially those with bone pain, or those with impending urinary tract obstruction, impending spinal cord compression.
And so, the ideal patient, to answer your question, is someone that has androgen pathway modulation resistant prostate cancer, medium to low burden of disease, luminal type androgen receptor driven. We're not trying to treat the neuroendocrine or AR negative cases. It will not work for those patients, and patients who are minimally symptomatic or asymptomatic, and certainly no one that's taking a narcotic analgesic for bone pain.
Oliver Sartor: Now you mentioned the APMR, and that can include any one of four agents here in the US. That'd be enzalutamide, apalutamide, darolutamide, abiraterone. Are there distinctions between which prior therapy might be important or not important?
Emmanuel Antonarakis: That is less clear. What is clear is that, because we are giving superphysiologic androgen, the target is the androgen receptor. So that must be present. And, it turns out the therapy works better when the androgen receptor is amplified or overexpressed. So, whatever prior therapy leads to the greatest degree of androgen receptor amplification will be the one that will generate, we think, the most sensitivity.
Oliver Sartor: Interesting. That's a little bit of an esoteric concept. We don't have any targeted therapies that depend on AR amplification, but you've introduced this. So how do you measure that?
Emmanuel Antonarakis: Well, in the clinic, there's not many ways to do so. One is through a clinical grade NGS assay, including a tumor biopsy or a circulating tumor DNA liquid biopsy. And as you know, Oliver, sometimes those biopsies report androgen receptor amplifications. Most of the clinical assays do not give you the number of amplicons. They don't say sixfold or tenfold or 50 fold or a hundredfold. They just say presence or absence.
We need to do better than that. I would love to see clinical assays that report the number of AR copies. We're not there yet. And there are research labs that are doing that.
Oliver Sartor: It's quite interesting. And recently, there was a presentation at ESCO helping to look at some of the molecular underpinnings that might predict response resistance. And I wonder if you might help to cover that. And by the way, there was a consortium effort, which I happened to be involved with as well as you, and a group from Brazil and others.
Emmanuel Antonarakis: So we conducted a consortium effort, as you said, about six or seven sites that were using bipolar androgen therapy off-label. Your site was one of them. My site, my old site, Hopkins, and my present site, Minnesota. And two sites in Brazil, actually, that have developed some experience with this.
We ended up gathering about 150 patients, not a small number, not huge. But the key was, these 150 or so patients were all treated with the once-monthly high dose testosterone, and they had some form of NGS testing done within one month of their first dose of bipolar androgen therapy.
Now, there was heterogeneity in the tumor testing. Some patients received a tumor biopsy. Some had a liquid biopsy. But the key was they all had it done within about 30 days. We looked for biomarkers of sensitivity and resistance. We focused on energy receptor. We confirmed that cases with AR amplification, when it was detected, had higher sensitivity.
Now a key important point there, the absence of an AR amplification does not necessarily mean that it wasn't there, could have been missed. And of course, this is especially challenging with liquid biopsies where, if you have low tumor content, you will miss and undercall AR amplifications.
The second one, perhaps paradoxical, but if you stop and think about it, maybe not. P53 mutations. I thought that was a little bit interesting, because in almost every other context of systemic therapy, p53 is bad. Here, it portended and improved PSA50 response and improved progression-free survival. I found that a little bit surprising.
Furthermore, in patients that had the combination of androgen receptor amplification and a pathogenic p53 mutation, that was about 20% of them, the enhanced sensitivity was the greatest. So, they had about a 70% chance of a PSA50 response, and they had a progression-free survival that was very significantly longer than patients without AR amplification and without p53 mutation.
Two more surprising things from that study. SPOP mutations. We've always thought about SPOP mutations being favorable in the context of androgen directed therapies. Here it was the opposite. Presence of an SPOP mutation was associated with increased resistance and shorter progression-free survival on bipolar androgen therapy. A bit paradoxical, and we haven't quite figured out why that is the case. It needs to be replicated first.
And finally, androgen receptor ligand binding domain mutations, ARLBD. The presence of those, again, associated with resistance to bipolar androgen therapy, perhaps because the androgen in those cases would not bind as well, or with high affinity to the mutated androgen receptor, thereby potentially causing resistance. So there we have a bit of a hypothesis.
Oliver Sartor: Let me go down that pathway just for a bit more, because we typically think 875, 878, but what about 702 mutation? Did that also seem to portend resistance?
Emmanuel Antonarakis: Yes, but less so.
Oliver Sartor: Less so. Okay. Got it. Well, this is really cool. Now let's jump ahead in a speculative way, if you don't mind. So, not having a patentable product is really a detriment when it comes to drug development. Are there possibilities that there could be something patented that would actually lead to a drug development plan with this type of approach?
Emmanuel Antonarakis: Yes. There's a small number of companies that have paid attention to this work. They've seen it, they've been intrigued by it. By the way, patients like it because they feel better. They have more energy. Sometimes their sexual function returns.
What if we could use an oral bioavailable androgen receptor agonist? Not an antagonist, an agonist. Still binds to the LBD, but stimulates the androgen receptor. And there are such efforts underway, too early to disclose what they are, what the names of the drugs might be. But I think that if we can do this in an oral fashion, and we can try to modulate the alternating superphysiologic testosterone alternating with castrate or near-castrate testosterone, using an oral short half-life bioavailable drug, we could mimic or maybe even improve the efficacy of bipolar androgen therapy.
Dirty little secret about the timing of the bipolar androgen therapy: it was empirically decided. And we made that empiric decision about 10 years ago in 2015 when we did our first trial. And then we kind of locked ourselves in, for better or for worse.
So now we will have the opportunity to look at alternative doses and schedules. Do we have to do it intermittently on and off? Would continuous androgen receptor stimulation be better or worse? Is a six-week cycle better than a four-week cycle? Is a two-week cycle better than a four-week cycle? These are questions that we can now answer without being locked into this historical intramuscular every four weeks dose.
Oliver Sartor: I think there are a couple of detriments on the every four-week dosing. Number one is once it's in with long-lasting supinate, it could be hard to reverse. With an oral, you could reverse it quickly.
And I'll just mention that we had actually published some time ago a little bit of transdermal continuous exposure to androgens, testosterone, and certainly it's capable of working there. So, could not agree more.
Dosing schedule, I think a little bit unknown. You're right. Walked in with some initial studies, but now we might have more freedom. I like the idea of an oral, short-acting, reversible compound. I think we could exploit the PK, exploit the circumstances quite well.
Emmanuel, any final words before we cut it off? But I'll simply say, fascinating topic.
Emmanuel Antonarakis: Just like to thank you, and it's been fun.