TRANSFORMER - A Study Comparing Bipolar Androgen Therapy Vs Enzalutamide in mCRPC - Emmanuel Antonarakis

April 30, 2021

Emmanuel Antonarakis joins Charles Ryan highlighting the first randomized study to assess high-dose testosterone as a treatment for metastatic castration-resistant prostate cancer (mCRPC). TRANSFORMER (Testosterone Revival Abolishes Negative Symptoms, Fosters Objective Response and Modulates Enzalutamide Resistance) was led by Dr. Samuel R. Denmeade at Johns Hopkins School of Medicine – Sidney Kimmel Comprehensive Cancer Center. It provides evidence that bipolar androgen therapy (BAT) significantly disrupts adaptive upregulation of the androgen receptor in response to the low-testosterone microenvironment. While the trial did not meet its primary endpoint of clinical or radiographic progression-free survival, the trial does suggest that in post-abiraterone patients, the sequence of BAT followed by enzalutamide is better than the sequence of enzalutamide followed by BAT with lower toxicity and higher quality of life.


Emmanuel Antonarakis, MD, MBBCh, Professor of Oncology and Urology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD

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 today, I'm joined by Emmanuel Antonarakis, Professor of Oncology and Urology at the Johns Hopkins Sidney Kimmel Cancer Center. He's going to talk about a recent publication on a clinical trial that he did at Johns Hopkins regarding bipolar androgen therapy, a paradoxical approach for the treatment of mCRPC. Emmanuel, thank you for joining us.

Emmanuel Antonarakis: Thanks very much, Chuck, it's a pleasure to be here. I'm going to talk to you about something that is a little bit out of the box here. At Johns Hopkins, we take pride in doing things a little bit differently from others, in a good way, and I want to introduce you to this concept that Dr. Samuel Denmeade, who is another medical oncologist here, who is the godfather of this approach, which he calls bipolar androgen therapy, also known as supraphysiological testosterone, also known as high-dose testosterone.

So, how can high-dose testosterone cause prostate cancer regressions? This is the biggest paradox, probably, of the whole field. It turns out that in some cell lines, but not all when you give a castration-resistant prostate cancer cell line, such as LNCaP or VCap, high doses of androgen in the laboratory, can induce cell death. This occurs also in mouse models. We've been trying to wrap our head around this for the last 10, 15 years.

Two of the prevailing hypothesis as to how this works is that we now believe that this high-dose testosterone, in the context of a long-term prior castration, leads to double-strand DNA breaks, and these double-strand DNA breaks, they occur at sites where the androgen receptor binds. So you can think of the androgen receptor as being a transcriptional activator, it binds to DNA, and it binds to the promoters or enhancers of genes. And when the AR is super agonized by tons and tons of ligand it gets stuck on the DNA. So the agonist binds the receptor, the receptor binds to the DNA in the promoter and enhancer regions of the genes that it's supposed to control, and then it gets stuck. It can't dissociate because there is so much androgen. And during the cell cycle, during the DNA replication, the AR cannot dissociate, so these double-strand DNA breaks occur.

This is how we do it, in patients, and this is why we call it bipolar androgen therapy. It's not because our patients become bipolar, it's because we alternate between very high levels of serum testosterone, as you can see here, as high as 1,500 nanograms per deciliter, and then right back down to near castrate levels, let's say 20 or 50 nanograms per deciliter. We do this by intramuscular injections of testosterone once every 28 days, and we continue the LHRH agonist or antagonist along with it. That's how we achieve these two high and low poles, the bipolar.

In 2015, we were brave enough to do our first human study, and this was published in Science Translational Medicine. This is an example of a patient, as you can see, his PSA was 22 or so when he enrolled, he went up for the first few cycles, and then swiftly declined. He had a very large, as you can see there, pelvic lymph node, which began to shrink. We saw this time and time again, and this encouraged us that not just in the laboratory and not just in mice, but in humans, this might work.

Fast forward to 2020. This is the TRANSFORMER study. The PI of this and the brainchild, so to speak is Sam Denmeade, my colleague here at Hopkins, and here we asked the question, in a patient with metastatic castration-resistant prostate cancer who has progressed on abiraterone, can the bipolar androgen therapy beat enzalutamide in a head-to-head randomized study. And this was a bold study. This was a high bar. We wanted to beat a very active anti-androgen, so in retrospect, we were probably a little bit too ambitious. But, 195 patients were randomized. Now, the interesting thing is the randomization was 1:1, they either got enzalutamide until progression, or they got bipolar androgen therapy until progression, and then at the time of progression, there was an option of crossover. And this allowed us to study the treatment sequencing.

Now, the primary endpoint of this study was not met. It is really important to say that here. We had powered this for superiority in progression-free survival, and we did not see superiority. What we did see was equivalence with a median of 5.7 months in the BAT group and 5.7 months in the enzalutamide group. We also, unfortunately, did not see a difference in overall survival. There was a numerical improvement in the patients receiving BAT 33 months, versus 29 months in the enzalutamide arm, but as you can see the hazard ratio of 0.95, nobody will get. So excited about that.

But let me start showing you some of the interesting data here in the breakdown. These are the so-called forest plots for progression-free survival. On the left of the vertical line is the arm favoring bipolar therapy, and on the right is the arm favoring enzalutamide. Look at the green thing that I've circled there. In patients who had a prior response to abiraterone that lasted for less than 6 months, in other words, we would call these patients primary-resistant to Abi, these are the patients that paradoxically responded the best to BAT. And the patients that had a very long response to abiraterone, well, those were actually the patients that had a pretty good response to subsequent enzalutamide.

This we thought was important because it suggests, indirectly, that those patients who are on their way to developing a neuroendocrine type of prostate cancer or AR indifferent prostate cancer are perhaps the ones that respond the best to BAT, and this is frankly an unmet medical need because those patients are very, very hard to treat. Now, this was pretty exciting. This is the confirmed PSA responses for the 90-odd patients receiving BAT in blue, and the 90-odd patients receiving enzalutamide in red. Now, remember these were all post-abiraterone patients. The PSA response was equivalent. It favored BAT, but it was not statistically higher. It was numerically higher, 28% versus 25%. So this is exciting because about a quarter of patients may respond to this treatment.

Now, this is something that we did not expect. We thought that when we give high-dose testosterone to these patients, their androgen receptor level and expression would go up, not down. This is an example of one of our patients. What I'm showing on the left is a lymph node biopsy at baseline, and the brown staining is androgen receptor protein immunohistochemistry. First of all, this lymph node was packed with cancer, you can virtually see no benign lymphoid tissue there, but secondly, this cancer is packed with androgen receptor, both in the cytoplasm and in the nucleus. And on the right, this is the same lymph node that was biopsied after 3 months of BAT. What you can see, first of all, number one, there are way fewer tumor cells there, and number two, the androgen receptor staining is much fainter.

Angelo DeMarzo was the pathologist is this and he's been working on AR for about 30 years and he came to us and he said, "I've never seen anything like this in 30 years of my career, it was striking." And by the way, this was not a preconceived hypothesis. Our preconceived hypothesis was that something else might get better, but AR itself would go up. So it looks like, somehow, maybe through a negative feedback loop, we might be paradoxically, once again, decreasing AR protein expression. We are still doing some further studies to follow that up.

What I'm showing here is the response to the crossover. So as you remember, the patients that got BAT first upon progression could cross over to enzalutamide, and that is shown on the left, and the patients that started with enzalutamide could crossover to receive BAT. What the waterfall plot shows here is that in patients who fail abiraterone, then they received bipolar androgen therapy, and then they get enzalutamide on the backend, they have a 77.8% PSA response. And that is striking because patients that receive enzalutamide directly after abiraterone will have about a 25% PSA response.

So what does this teach us? This teaches us that, not only does bipolar androgen therapy in and of itself produce tumor remissions in about a quarter of patients, but furthermore, that it sensitizes to downstream additional AR blockade. And that, frankly, is fascinating. This is reflected on the PFS2 Kaplan-Meier curve. Now, PFS2, a couple of years ago, we didn't know what that was. Now, it's becoming a common language in most of these trials. PFS2 means the time from the randomization through the first progression to the second progression, in this case after crossover. And this was one of the only statistically significant differences in the trial.

What this suggests is that in post-abiraterone patients, the sequence of BAT followed by enzalutamide is better than the sequence of enzalutamide followed by BAT. So this suggests a sandwich approach, whereby you intercalate BAT between the conventional anti-androgens. And again, this shows PFS2 forest plot, and the same trend that we saw before with PFS1, is that the PFS2 favored the patients who, again, paradoxically had the worst responses to prior abiraterone, suggesting that we are perhaps reversing lineage plasticity or AR indifference by giving androgen back.

This is my last slide, but a very important slide, quality of life. All of our patients hate the way that they feel with androgen deprivation therapy, and even more so with enzalutamide. We did tons of quality of life metrics on this trial. These are just six that I pulled out here. The top left is the overall score on the SF-36 questionnaire, red is the BAT, blue is the enzalutamide. The top middle is physical functioning, the top right, is energy and fatigue, the bottom left is emotional wellbeing, the bottom middle is sexual desire, and the bottom right orgasmic function. And in each of these cases, you can clearly see that, compared to enzalutamide, not only was there less of a detriment in any of these QoL metrics, but there was in fact, an improvement, especially in the sexual function, erection, sexual desire, and orgasmic function. So not only are we producing remissions, but we are also improving quality of life. Thanks very much. I'd love to stop there and take questions.

Charles Ryan: Yeah. Great presentation, really fascinating data. The testosterone paradox. Great idea for a book too. One of the things that are striking is this idea that you are kind of pulling the tumor back into hormone sensitivity, on the one hand, and perhaps pulling it away from the ledge that it goes towards neuroendocrine. You don't really present proof on that, but it is a great concept. So, where are you going to go next with this?

Emmanuel Antonarakis: That's a great question. Before I answer that, I'm going to give you a little teaser on the neuroendocrine hypothesis. Maybe I should write a book about that. Just kidding.

Charles Ryan: [crosstalk 00:12:34].

Emmanuel Antonarakis: As you know, Chuck, there is a molecular signature that is not a perfect surrogate for neuroendocrine but predisposes to it, and that is when you have combined deficits in p53 and p10, or p53 plus Rb1, or Rb1 plus p10, two out of three tumor suppressor losses. We have a study right now at Johns Hopkins where we are specifically giving bipolar androgen therapy to mCRPC patients who have two out of three of those tumor suppressor losses. It's not published, we've not presented it yet, but the response rates and the duration of responses appear to be even greater in those patients. I'll just leave it at that. There does, at least in my mind, and it remains to be proven, of course, there does seem to be some evidence that we are potentially reversing or slowing lineage plasticity.

Where do we go next with this? I'm so glad you asked. One of the things that DNA damage causes, potentially, is immune activation. It turns out that when you damage double-strand DNA, these double-strand DNA fragments exit the nucleus and go into the cytoplasm, and these cytoplasmic DNA fragments are very, very immunogenic. They're not supposed to be there. They are recognized by this protein called GAS, and the protein called GAS stimulates another protein called STING, which stands as a stimulator of interferon genes. And this is the so-called cGAS-STING pathway, and the cGAS-STING pathway is a pathway that is stimulated by cytoplasmic DNA fragments that are not supposed to be there. This, in turn, upregulates PD-L1 and the PD1, PD-L1 in the tumor cell and PD1 in the microenvironment.

We just completed a study, which Dr. Rahul Aggarwal from UCSF was the co-investigator with us, and two other sites, which was called the COMBAT trial. The COMBAT trial was a study of 45 patients with mCRPC who got the combination of bipolar androgen therapy plus nivolumab.

Charles Ryan: Okay.

Emmanuel Antonarakis: This is how we did it. We did it as a sequenced approach. In the first 3 months, the patients got only bipolar androgen therapy, a monthly injection, and on the fourth month, as long as they did not have a radiographic or clinical progression of their disease, in other words, stable disease or remission, we added the monthly dose of nivolumab, the Q4 week dose of nivolumab, and we continued concurrently the BAT. So starting from cycle four, cycle five, cycle six, they would come in, they would get their injection of T and they would get their nivolumab.

We have submitted an ASCO abstract, and what I have to say is that the objective response rates that... I forgot to mention, we required soft tissue disease and we required baseline biopsies in all patients. So we have an objective response rate, not just a PSA response rate. The objective response rate is strikingly high. In fact, it is about double what we see with BAT alone, and it's about five times higher than we see with PD1 alone. It's only 45 patients and we are doing studies to prove whether STING is being activated or not from these, we have post-treatment biopsies on these patients. We actually have 38 matched biopsies of the 45 baselines and progression, which, in and of itself, is a remarkable feat, actually. So more to come on that, but there is really an interesting hypothesis that perhaps the addition of immunotherapy with BAT could be synergistic.

Charles Ryan: Wow. Amazing. Yeah, and immunotherapy, you also touched on DNA repair, as a mechanism by which BAT may exert some effect. I was struck by your picture, which showed a reduction in the AR expression, but clearly a change towards a nuclear expression of the androgen receptor. And I don't know that that is fully appreciated by everybody. So while we are seeing that, maybe less AR in total, what we are seeing is a more engaged androgen receptor. I really congratulate you and Sam on this work. It's something that will serve as a foundation and a basis for further study, and perhaps changes to our thinking about the disease, importantly, but also potentially our therapy of the disease. So really congratulations, wonderful work, and I always learn from hearing you explain these topics.

Emmanuel, one of the things that have been criticized about this approach is that you are going to give high-dose testosterone, and you're going to lead to urinary retention and spinal cord compression. But I don't hear that you're seeing that.

Emmanuel Antonarakis: Yeah, that's a realistic concern, Chuck, and that is a concern that we as clinicians also had. In the randomized studies, we did not see a higher prevalence of core complications or other extreme things like pathological fractures. Now, I do want to mention one thing. We were very careful in all of these studies, including in the phase 3 TRANSFORMER study, not to enroll people who had clinical signs or symptoms or radiographic signs or symptoms of impending core compression, nor did we allow people that had big bulky prostates with a urinary obstructive symptoms where we thought that there could be a complete obstruction of the bladder, nor did we enroll people who had symptomatic bone METS as defined by the requirement for narcotic analgesics. I do believe that was the right move.

What I will say, in all honesty, is, in approximately 15% of patients, we did cause a pain flare. In other words, they had a little bit of pain at the beginning, it was controlled by Tylenol, let's say, and they enrolled on the study, and they didn't respond, their PSA went up 2 or 3 consecutive months. And some of those patients, about 15%, did also have a worsening of their pain. So it is very important to be a good doctor here and to be a good clinician and to really ask about all the symptoms, because yes, on the one hand, a lot of patients do want to get this therapy because of all the hype that they've seen about it, and also, when they're sitting in the waiting room, talking to their other buddies who are on the trial and they are responding well, they all expect to have the miraculous response. But the last thing that we want to do is harm even 5% of these patients.

This is not ready for prime-time in routine clinical practice, I must say, and it pains me to say that because we have seen great benefits from it. The good clinical care of these patients is paramount, and we should not be ignoring any of these side effects and our patients should be encouraged to report even the smallest complication.

Charles Ryan: Thank you for saying that. It is a really important point. As encouraging as the data are, I don't think I'm going to start using it on a routine basis with my patients, although I am very closely going to follow the work that you subsequently do in this arena because I think there is something there. So, thank you again.

Emmanuel Antonarakis: Thanks very much, once again, for the invitation, Chuck.