The State of Bipolar Androgen Therapy in Prostate Cancer - Emmanuel Antonarakis

May 24, 2022

Joining Charles Ryan is Emmanuel Antonarakis to detail the present state of bipolar androgen therapy (BAT) and where the field going.  


Emmanuel Antonarakis, MD, Clark Endowed Professor of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota

Charles J. Ryan, MD, the President and Chief Executive Officer of The Prostate Cancer Foundation (PCF), the world’s leading philanthropic organization dedicated to funding life-saving prostate cancer research. Charles J. Ryan is an internationally recognized genitourinary (GU) oncologist with expertise in the biology and treatment of advanced prostate cancer. Dr. Ryan joined the PCF from the University of Minnesota, Minneapolis, where he served as Director of the Hematology, Oncology, and Transplantation Division in the Department of Medicine. He also served as Associate Director for Clinical Research in the Masonic Cancer Center and held the B.J. Kennedy Chair in Clinical Medical Oncology.

Read the Full Video Transcript

Charles Ryan: Hello from ASCO GU in San Francisco, 2022. I'm joined by Emmanuel Antonarakis, who is my colleague from the University of Minnesota, where he is the Clark Professor of Oncology and a Medical Oncologist in the Division of Hematology, Oncology, and Transplantation. Emmanuel, thanks for joining us.

You've been doing for a long time some great work on bipolar androgen therapy. It's really caught a lot of people's attention because of the interesting, positive, and somewhat paradoxical findings, I think. Bring us up to speed on where you are with the present state of knowledge of bipolar therapy and where you see yourself and the field going with it.

Emmanuel Antonarakis: Thanks, Chuck. It's nice to see you again. This is the paradox of BAT, bipolar androgen therapy. So, what is this? We've known for a long time that androgens stimulate prostate cancer, and we've spent the last 70 years figuring out ways to block androgen production or the androgen receptor. But now it turns out that, in certain scenarios, in certain men with castration-resistant prostate cancer, giving these patients super physiological, super high doses of... in this case, intramuscular testosterone, can be used as a therapy for castration-resistant prostate cancer. And it is a paradox because we are going to the polar extreme, from very, very low testosterone levels to very, very high testosterone levels. But instead of stimulating cancer, which is what some people thought we might do, we are actually inducing remissions in a reasonable proportion of patients.

Charles Ryan: What proportion of patients, and who are the patients who you consider to be eligible for BAT therapy?

Emmanuel Antonarakis: The high dose testosterone idea, which has gone by many names, and the one that has stuck is this bipolar androgen therapy, it was coined by John Isaacs and Sam Denmeade from Johns Hopkins, my old institution. It seems to work in about 35% of men with castration-resistant prostate cancer.

We've done about five prospective clinical trials in the last eight years, starting from about 2013/14 up until the present moment. Along the way, we've learned a number of things. We learned a lot from our most recent randomized phase two study, which was called, TRANSFORMER. This was the first time that we actually dared to compare bipolar androgen therapy against an active drug, in this case, enzalutamide. So let's review that and then I'll tell you about some of the biomarker learnings from that study.

TRANSFORMER, which is now published in the JCO, was a study of about 200 patients, and these were all men with metastatic castration-resistant prostate cancer who had received and progressed on abiraterone. So they were mCRPC post-ABI. Then they were randomized one to one. About a hundred patients got enzalutamide directly after abiraterone, and a hundred patients got bipolar androgen therapy. The way that we administer this in the clinic is it's an intramuscular injection of testosterone cypionate, which is actually FDA-approved for men that have hypogonadism. It's an FDA-approved drug that is used on an off-label indication, of course.

The primary endpoint of that study, we were foolish enough to think that we might be superior to enzalutamide. We designed this as a superiority study with progression-free survival being the primary endpoint. What we saw in both arms was a PFS of about six months in the post-abiraterone mCRPC population. The trial was technically negative, but at least we were equivalent to or non-inferior to enzalutamide although it wasn't designed as a non-inferiority study.

One of our hypotheses going into the trial in those days also stems from my own interest in these androgen receptor splicing variants. And I had hypothesized that the bipolar androgen therapy might be preferentially sensitizing these ARV-7-positive patients relative to enzalutamide. In that TRANSFORMER study, we collected baseline ARV-7 samples in all patients and then at some follow-up time points.

The bottom line, which was very disappointing to me, and which did not prove our hypothesis was that the ARV-7 marker did not appear to be a predictive marker. It was a prognostic marker for both groups and both groups did worse when ARV-7 was present at baseline; both the bipolar therapy group and the enzalutamide group. That didn't seem to be the answer.

Charles Ryan: I mean, you might have predicted that because if you have a faulty androgen receptor blocking it that's autonomous, blocking with enzalutamide isn't going to work, adding ligand isn't going to work either, it's this self-functioning motor at this point in time. Right?

Emmanuel Antonarakis: That's right. But we were hoping to have a low-hanging fruit there. We then decided to do some additional studies after the TRANSFORMER focusing on biomarkers. In one of our recent studies, which is called the COMBAT trial, we actually intended to combine bipolar androgen therapy with nivolumab, a PD-1 inhibitor. We had some hypotheses behind this. One of which was that one of the mechanisms that we think BAT works by is by inducing double-strand DNA damage. That double-strand DNA actually exits the nucleus and goes into the cytoplasm, and these DNA fragments in the cytoplasm, they actually stimulate a process called STING, and the STING pathway can be pro-immunogenic. We thought, "Well, we're activating STING with these double-strand breaks and now we are adding the PD-1 inhibitor."

But the interesting thing about the trial, in the end, was actually not the combination with the PD-1 inhibitor per se. It was that we had a lead-in phase, and the lead-in phase was three monthly injections of high-dose testosterone. And then after the third month, we added the nivolumab and we continued the high-dose testosterone. But during that lead-in phase, we had matched metastatic mCRPC biopsies from 24 paired patients, again, before the nivolumab was ever given.

And we designed it in that way so we can understand what changes, what pharmacodynamic changes induced by BAT, irrespective of the PD-1 inhibitor, actually portend or correlate with outcomes. And we found some very interesting things from that study, most of which are not published, but I just want to share the high level. One of which is that even though we are giving an androgen receptor agonist, an androgen receptor binder, we are actually diminishing AR protein both in the cytoplasm and in the nucleus.  If you compare immunohistochemistry, the staining, and we can do this quantitatively, and our pathologist, Angelo DeMarzo has worked out a very beautiful quantitative AR stain.  The AR, actually at the protein, the level goes down when you give BAT. That was another paradox.

Charles Ryan: Well, we've known for two decades that if you deplete androgens and suppress the androgen receptor effectively over time, what you potentiate is androgen receptor amplification, an outgrowth of androgen receptor amplified cells. So really you're just doing the opposite of that, aren't you? Aren't you un-amplifying the androgen receptor [crosstalk].

Emmanuel Antonarakis: Right. It's a break in the feedback loop in a way. The second thing that Angelo DeMarzo was very excited about was the MYC story. We've known that this oncogene, MYC is amplified or overexpressed in many castration-resistant prostate cancers, and bipolar androgen therapy really decreases MYC protein and MYC transcript in a big way. The patients who had MYC protein and RNA transcript reductions actually had longer progression-free survival. There seems to be an MYC effect with bipolar androgen therapy.

And then the other interesting thing, which may or may not be surprising is we can measure proliferation using the Ki-67 index. There was a strong correlation between the post-BAT reduction in Ki-67 and subsequent efficacy. So, three interesting findings from that study: one that AR itself goes down, more so in the responders; that MYC, that the protein and RNA level goes down; and that Ki-67 goes down. And that correlates with the objective responses and the PFS.

Now, a few other things that we are following up on, and let's go back to this DNA damaging concept. If it is true that BAT induces double-strand DNA damage in certain prostate cancer cells, then you might hypothesize that prostate cancers that have homologous recombination repair deficiencies, for example, BRCA2 mutations, may do better.

We have shown in a retrospective fashion, this was not prospectively defined when we amalgamated all the DNA sequencing data from all of our previous four trials in a post hoc fashion... in fact, we did show that those patients that happen to have homologous recombination deficiencies, especially BRCA2 and ATM, were preferentially sensitive to BAT.

Another interesting, and again, we've used the word paradoxical three times already.

Charles Ryan: It's one of my favorite words.

Emmanuel Antonarakis: The BAT paradox. It was that patients with p53 mutations that always portend a worse prognosis to basically all therapies that we have, including chemotherapies as well, actually, those men with p53 somatic mutations are more sensitive to BAT. They do better with BAT.

Charles Ryan: They have more of a response because they don't have a repair mechanism for their genomes. You're inducing genomic stress of some kind, right? Is that sort of the overarching idea?

Emmanuel Antonarakis: That's the overarching idea. There is a second idea, which is even more intriguing but remains to be proven. And that is... You are familiar with the concept of lineage plasticity, where an AR-positive or addicted cell over time, under the influence of hormonal therapy pressures, becomes more AR indifferent or less AR sensitive. And there has been a lot of data that tumors with a combination of p53 and RB1 mutations, these sort of double tumor suppressor, loss tumors, are more prone to lineage plasticity.

The hypothesis that I think needs to be proven, but at least I can entertain is, that BAT might be reversing lineage plasticity, not in those terminally AR indifferent cancers where the AR is lost, like the pure small cells, because in the pure small cells, if the AR protein is gone, the BAT has no target. But in those who are sort of on their way to becoming AR indifferent, whereas the AR is still operant but less so, it shifts them back the other way towards a more AR addicted phenotype.

Charles Ryan: I mean, you're basically taking... if I can use the term, the evolutionary biology of prostate cancer and just reverting it, because what you are saying is all of the progression and death from prostate cancer is because we starve, starve, starve the testosterone, the androgens, and cancer evolves, whether it's neuroendocrine or p53 emerges, et cetera. And you're just saying, "Don't give them that opportunity or revert that." In a way, it's almost convincing the cells that they are happy with the testosterone on board and they won't progress to these lineage plasticity-type events.

Emmanuel Antonarakis: Yeah. That's-

Charles Ryan: That's a paradox.

Emmanuel Antonarakis: That's the hypothesis. I just want to mention two other things so we can put a plug in for our fellows who became faculty members. We had a fellow, Michael Schweizer, who is, of course now at the University of Washington in Seattle. Dr. Schweizer has done a study, it's been presented at ESMO but not yet published; a single-arm study, no control group, where patients got bipolar androgen therapy plus the PARP inhibitor, olaparib.

In that study, the combination of BAT plus olaparib produced a PFS, a radiographic PFS that was more than 12 months, which was longer than we had previously seen with BAT monotherapy. Now, this was not a controlled study with a control group, but that 12 plus month PFS was very intriguing. I have not yet seen the breakdown by HRR status because, in that trial, he allowed both the HRR deficient and proficient, but you may have your own hypothesis.

Then a fellow from Brazil, Pedro Isaacson, who actually is now an assistant professor back in Brazil, was working with us at Hopkins for about three years. He has designed a study which is called BATRAD, which is the combination of BAT plus radium-223, again, using this concept of combined double-strand DNA damaging therapies to accentuate the efficacy.

Charles Ryan: A lot of plans moving forward, you have a lot of great ideas and hypotheses that are directed at additional combination approaches seizing on this idea that you are inducing this genomic stress and capitalizing on that with other therapies.

Final question, this is out there, patients love it, I'm told, and the data support this, that there is a quality of life potential benefit. I know that there are physicians out there who are thinking of doing this off study. What is your advice to them?

Emmanuel Antonarakis: Yeah, this is tricky. My comfort with off study BAT is increasing over time, my personal comfort. Having said that, we have treated now collectively about 500 patients. The lessons are that there are certain patients that you should not give this to. The concern is that you may cause a disease flare, because while in 30% to 40% of people, you see a benefit, in 50% you see a neutral effect, in 10% you do see a disease flare. And this is important for anyone in the community thinking about using this.

All of our trials excluded patients who had painful bone metastases. All of our trials excluded people with large osseous lesions in weight-bearing bones or joints like the femur, or lumbar spine. Anything that might increase the risk of an imminence cord compression should be avoided. And in patients who have a bulky primary disease or bulky pelvic lymphadenopathy where a flare might clip one of their ureters, or obstruct their bladder, you may want to think twice.

The ideal patient, if you were to do this in the community because the testosterone can be prescribed, it's available, would be someone who has metastatic castration-resistant prostate cancer. This is not indicated for men with hormone-sensitive prostate cancer, only for CRPC. And it should be someone ideally who is asymptomatic from a bone pain perspective who is not taking, for sure, narcotic analgesics for bone pain, someone who does not have a bulky primary, and someone who is not at risk of a pathological fracture or a spinal cord compression.

The other lesson is you will know within three months if that patient is responding, and PSA is a good surrogate. We have almost never seen objective responses or long-term progression-free survivals in the absence of a PSA reduction by the third month. It may not happen in the first month. In some patients, you see an increase in month one followed by a subsequent decrease in the second and third months, but after 12 weeks of therapy, which is three cycles, if the PSA isn't beginning to drop, usually it is not going to work. You don't lose that much time. And again, not for your symptomatic patients.

Charles Ryan: Right. Well, that's great advice, very sound, and also just speaks to the expertise that is required to do this. There's a lot written about it. You've published a lot on it, so if people are interested, they can look up your papers and look at the protocols that you followed. And I think that is really sound advice.

Thank you very much for joining us. Really exciting stuff, actually. And I love the idea of the biological paradox because you are moving this disease back along a spectrum that we are trying to prevent it from. It's going one way and you are trying to prevent it from going there. And that's really intriguing and exciting, and I wish you well. Thank you for joining us.

Emmanuel Antonarakis: Thanks again for the invitation.