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23
Sep 2022

When Too Much of a Bad Thing Can Be Good!

It’s fall of 2022. I’ve now been battling aggressive stage IV metastatic prostate cancer in my bones for 8.5 years. I’ve been on 13 completely different lines of drug therapy, including standard of care drugs, off label drugs, and clinical trial drugs. Genomic Sequencing of my cancer has opened the doors to so many new drug options, I would have never survived this long without these cutting-edge diagnostics to help guide my care. But this lucky number 13 deserves some attention because you won’t see it promoted from the pharmaceutical industry. In honor of Prostate Cancer Awareness Month, I wanted to share what I did in hopes that others may also benefit.

2021 and the first part of 2022 was rough for me. In June of this year I dropped out of a novel clinical trial that simply wasn’t working. Then I didn’t get the response I hoped for from seven rounds of Cabazitaxel + Carboplatin. My back was against the wall. My PSA (prostate specific antigen) rose to over 300. I had tumors all over the place in my bones, was losing weight and was getting weaker. If I didn’t catch a break soon, I wondered if I would see past 2022.

I had heard of BAT (Bipolar Androgen Therapy). I knew that Johns Hopkins had been running multiple clinical trials on BAT. I was fascinated with the idea. What man going through advanced prostate cancer therapy wouldn’t want to get a surge of testosterone again? But I was also very leery of this. I didn’t know a single advanced prostate cancer patient personally who had done it. Afterall, introducing testosterone back into my system could be like pouring gasoline on a fire. It would be a controversial, paradoxical move. However, could too much of a bad thing be good? Could your adversary be your ally? I dug into the Patient’s Guide to BAT that had been written by Johns Hopkins doctors. Here’s what I found out.

BAT is designed to repeatedly shock the prostate cancer cells, by alternating between polar extremes of high and low testosterone levels. Bipolar androgen therapy (BAT) is a new treatment concept for men whose prostate cancer has become resistant to standard hormone-blocking therapy.

Male hormones, including testosterone, are called androgens. Treatment to shut down male hormones is known as androgen deprivation therapy, or ADT. Antiandrogens are “second-generation” drugs that block the action of androgens in the prostate cancer cell, and these include Xtandi, Erleada, and Nubeqa. Zytiga is included in this group, although it works differently.

Androgens (testosterone) drive prostate cancer growth. The way they do that is by binding to a protein within the cells called the androgen receptor (also known as AR). Primary ADT like Lupron or Eligard work by stopping the production of testosterone, so the AR doesn’t have as much testosterone to bind to. Antiandrogens block any remaining androgens from binding by gumming up the receptor. Initially, primary ADT and second-generation antiandrogen therapies work great. But overtime, prostate cancer cells respond to the low testosterone conditions by markedly increasing the level of the AR to catch any testosterone that remains after therapy. This is basically a genomic alteration called ‘AR Copy Number Gain’ that allows the cancer cells to evolve by adding tons of androgen receptors (AR) and that enables it to grow again despite the low level of testosterone in the body.

So, are you an advanced prostate cancer patient? Your prostate cancer cells have evolved over the years. If ADT drugs don’t work for you anymore, you probably have bred a population of cancer cells that is able to function in an androgen deprived environment from years of ADT. Consider what might happen if you flooded the cancer cells with androgens (testosterone)? Your prostate cancer sure wouldn’t need all those extra androgen receptors that it acquired because it would see a ton of androgens floating around and could easily catch them with many fewer receptors.  Would the cancer potentially get confused by the flooding? Would the cancer shed the excessive amounts of AR and revert to a less lethal state?  Could you potentially reverse the evolutionary biology of your prostate cancer? Yes, it looks like this is possible.

What I learned from reading the BAT Patient Guide was that patients like me who were CRPC and had high levels of AR had a better chance of responding to this treatment. A patient can determine if he has high levels of AR (ie. ‘AR Copy Number Gain) by doing cancer genomic profiling from Tempus or Foundation Medicine. Turns out, I had this DNA alteration. I also had a P53 mutation and that mutation along with mutations in the genes BRCA2, or other DNA repair enzymes may be more likely to have a significant response to BAT. Then, I asked my oncologist Dr. Rana McKay at UCSD for support in getting the therapy. She reached out to the team at Johns Hopkins to get the protocol, which is basically an injection of 400mg of Depo Testosterone that I get every 6 weeks (the original JH study was every 4 weeks) while I stay on Lupron the whole time. I’m also adding Pembrolizumab (Keytruda) every 6 weeks as well, since there is some evidence that testosterone turns on immune functions in prostate cancer cells and we felt this could be an interesting combination.

Now, for the results.

I had an exceptional response. My PSA dropped from 307 to 5 after the first cycle. It continued to drop from 5 to 1.5 after the second cycle. I just had my 4th cycle on September 12th. When we look at imaging results (PSMA PET Scan) it’s remarkable. Significantly less disease. In addition, I feel amazing. All the nausea, appetite suppression and fatigue I was suffering from the previous toxic therapies is gone. I have much more energy, more muscle mass, and improved sexual function.

Here are three reasons why I wanted to get this story out.

BAT is super inexpensive and accessible. Depo Testosterone costs between $50-200 for each cycle. Compare that to any other prostate cancer therapy and it’s a huge bargain. It’s easy to get. However, there is no incentive for drug companies to promote this because it’s not a new drug and there’s no profits to be made for promoting the use of this. You won’t see any ads or promotion for this therapy. That means if you want to try this, you as the patient are going to need to get educated and make a case to your doctor for it.

BAT is very tolerable and improved my QOL (Quality of Life): I did have a temporary testosterone‐stimulated release of inflammatory factors that made bone pain significantly worse for about 4 days on my first cycle. This happened most likely because I already had some bone pain from cancer. In all honesty, I may have been excluded from the Johns Hopkins studies because of this. But we did it anyway, and I was able to alleviate the pain with a 5-day course of steroids. Also, there is some risk of stroke or heart attack for men with underlying congestive heart failure or cardiovascular challenges. But for me, as stated above, it was all upside.

BAT can restore sensitivity to hormone‐blocking therapy: I’m super excited about this. As you can read about in the Patient Guide, one of the Johns Hopkins trials had patients with CRPC who progressed on Xtandi get treated with BAT. Once BAT stopped working, the patients were retreated with the Xtandi. Remarkably, for the patients who received Xtandi then BAT and the Xtandi again, 70% had a PSA response to the rechallenge with Xtandi. In another study, for patients who received Xtandi directly after Zytiga, the PSA response was 25% and time to PSA progression was about 4 months. For those patients who received BAT directly after Zytiga and then received Xtandi after BAT, the PSA response was almost 80% with a time to PSA progression of about 11 months. The overall survival for patients who received BAT then Xtandi was about 37 months compared to about 29 months for those receiving Xtandi alone. This is like resetting the clock. It’s reversing the evolutionary biology of the disease.

In summary, is this going to work for every advanced CRPC prostate cancer patient? No. But Johns Hopkins feels that up to 35% of advanced prostate cancer patients could benefit from this. If you are an advanced metastatic prostate cancer patient who is running out of options and whose cancer has evolved in a similar way as mine, you might get a nice benefit. Have a conversation with your doctor about this potentially transformational therapy idea. Best of luck!

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