Bipolar Androgen Therapy for Castrate-Resistant Prostate Cancer

•Control disease progression (as measured by prostate specific antigen/PSA and PSMA PET scans) for a sustained period

•Restore sensitivity to androgen therapies (e.g., Xtandi)

•Improve quality of life and also improve other health markers. The clinical evidence supporting BAT is small-scale, and only for a portion of patients. It isn’t included early in the standard of care. It doesn’t have any pharmaceutical companies promoting its use since it depends on easily available, relatively inexpensive testosterone. Yet many advanced prostate cancer patients in our community who don’t have time to wait are trying BAT or seriously considering it. We have had three previous discussions of adaptive therapy (where treatments are tuned to a patient's biomarkers, e.g., PSA level) and BAT.

•Bob Gatenby, MD, from Moffitt Cancer Center, introduced adaptive therapy -- using evolutionary and game theory to inform cancer treatment strategy.

•Advanced prostate cancer patient Bryce Olson shared the story of his exceptional response to BAT and then Bob Gatenby commented on Bryce’s experience and strategy.

•Emmanuel Antonarakis, MD, spoke about using BAT for advanced prostate cancer. What Does It Take to Choose BAT?

•First, most patients and oncologists are not aware of or considering BAT as an option. Pharma won’t fund trials for this treatment because they would not return a profit.

•Second, the patient has to be brave enough – we have been taught for years that taking testosterone can be like throwing gasoline on the fire, feeding cancer growth.

•Third, the patient must find a doctor who is willing to support it or be willing to self- administer (typically with monitoring by an MO). “How I Am Running Experiments on Myself to Control My Prostate Cancer – Using Bipolar Androgen Therapy” About Russ Hollyer Super patient Russ Hollyer is uniquely qualified to share a patient's view on BAT. He has been self-administering BAT and has written a book about his experience. Russ is a "citizen scientist", applying his expertise in science (reviewing research papers, running experiments, accessing drugs, testing, monitoring progress) to his own treatment. Russ has advanced prostate cancer, Gleason 9, and was diagnosed in 2018. He had a radical prostatectomy (RP) later that year, estrogen/Zytiga androgen deprivation therapy (ADT) in 2019, followed by high testosterone, followed by do it yourself (DIY) BAT. Each BAT treatment involves the self-administration of hormonal ablation or hormonal extremes. During his work career, Russ worked as an electrical engineer for a medical company, an aerospace engineer for the government and contractors, and as a hedge fund manager. Most of his work was in the medical technology area and involved data gathering, quality screen design, computer programming, and test screening. Because of this he became very data-driven. He determined from experience that theories and hypotheticals are very frequently proven to be incorrect. Discussion Agenda 1.Description of BAT: how it works 2.Russ's experience: PSA, cancer progression, RBC, WBC, liver markers, bone density, libido, and fatigue during that time 3.How to improve BAT “How I Am Running Experiments on Myself to Control My Prostate Cancer – Using Bipolar Androgen Therapy” 1.Description of BAT: How does depriving then flooding cancer cells with hormones (androgen) control the prostate cancer population? Cancer cells in a prostate cancer (prostate cancer) patient’s tumor are heterogenous and can be categorized into four distinct cell types: A.Hormone (androgen) sensitive : These prostate cancer cells rely on an external form of testosterone (dihydrotestosterone - DHT) to live. These cells are easily treated by androgen deprivation therapy (ADT). B.Androgen sensitive and unresponsive to androgen deprivation therapy (ADT) : These cells rely on DHT to live, but have upregulated and/or mutated androgen receptors (ARs), so that these cells may be more efficient at collecting DHT, and don’t respond to androgen deprivation therapy (ADT). C.Androgen sensitive and unresponsive to ADT and produce testosterone internally : These cells rely on DHT to live but they have mutated to be able to produce DHT internally if needed. They might be able to convert adrenal androgens (Dehydroepiandrosterone - DHEA, dehydroepiandrosterone sulfate - DHEAS, androstenedione delta 4) into DHT. D.Androgen insensitive : These cells do not need DHT to survive and grow. They are very difficult to control and can morph into neuroendocrine prostate cancer (NEPC) and small cell varieties. When you use androgen deprivation therapy (ADT), your goal is to drive testosterone down as low as possible and starve the prostate cancer cells of their growth fuel. This process deprives androgen sensitive cells (type A) of that “fuel”. Initially this appears to be successful. Usually during the early stages of prostate cancer development, most cancer cells are androgen “How I Am Running Experiments on Myself to Control My Prostate Cancer – Using Bipolar Androgen Therapy” sensitive (type A), and most of them die when androgens are withheld. This is hormone sensitive prostate cancer (HSPC). However, as type A cells are killed off and decrease in number, type B and C cells mutate and begin to grow, and type D cells will also appear. Eventually, the patient’s prostate cancer is composed of cells that can live in low androgen conditions (called Castrate Resistant Prostate Cancer - CRPC). The change from HSPC to CRPC typically takes 1-4 years. When prostate cancer is castrate resistant or beyond, it becomes much harder to control. If you have CRPC, you can use hormones to shift the population of your prostate cancer back into type A prostate cancer cells. Clinical trials are showing us that by using bipolar androgen therapy (BAT), most patients can restore their sensitivity to androgen receptor blockers/androgen receptor signaling inhibitors (ARBs/ARSIs). The desire is to cause prostate cancer to become a chronic disease and not a killing disease. BAT has two parts: 1.Rapidly increase your androgen to a very high level ( Supraphysiological - SPA). This increase makes the upregulated ARs of type B cells a liability. Some of the mutations of type B cells also become liabilities. SPA also induces cellular DNA double strand breaks (DNA DSBs) and these cellular breaks serve to kill type A, B, and C prostate cancer cells. If cancer cells are exposed to SPA for too long, (A) begins to dominate (they are dominant in HSPC men and present in smaller amounts in CRPC men). Before this can happen, with BAT, the patient moves to part two of the BAT process. 2.We rapidly decrease the patient’s systemic androgens to a very low level. This changed environment controls cancer cells that require androgens for food (type A cells, and to a far lesser extent, type B and C cells). This is particularly effective for HSPC men. Note that this requires some type of medical or physical castration. ADT drugs are that chemical castration. Supraphysiological levels of androgen effectively inhibit growth of some CRPC cells but also inhibit growth of some HSPC cells. If a true ADT castration level is obtained in the second phase, inhibition is far greater in HSPC cells than in CRPC cells. The HSPC -> CRPC transition is not binary. We do not know where the threshold of supraphysiological repression lies. If you can prevent HSPC -> CRPC progression, prostate cancer might become a chronic disease. Almost a dozen trials (RCT) have been performed on CRPC men with results ranging from decent to very good. One trial was performed on HSPC men with good results. Note that this trial used 3 standard 1-month testosterone cypionate BAT cycles followed by 3 months of the ADT cycle. This trial was called “Batman.” “How I Am Running Experiments on Myself to Control My Prostate Cancer – Using Bipolar Androgen Therapy” The longer ADT can be delayed, the better. The quality of life (QOL) benefits of BAT argues for its use even if it isn’t as effective as ADT alone. 2. What has been Russ’s experience? Russ uses Lupron for his ADT cycle of BAT continuously in order to remove endogenous testosterone produced by the body. He uses testosterone propionate to achieve high levels of androgens. A true ADT level will not be attained by using the standard 400 mg testosterone cypionate injections during the 4-week cycles. Russ uses testosterone propionate instead, and by so doing, he attains a true desired ADT level. Russ monitors prostate specific antigen (PSA) with blood tests and uses the level of his PSA results to guide the termination of the ADT phase of BAT to begin a new supraphysiological androgen (SPA) phase. Using PSA is a crude marker of prostate cancer progression. Ideally, scans and genetic tests should be performed to monitor therapeutic progression of prostate cancer and the success of BAT. Sometimes PSA will increase but conversely radiological scans will show no growth nor regression. Along those lines, sometimes conversely increased bone met activity appears to occur for about 2-3 months before reductions begin to be seen. PSA might rise for a couple of months following the start of BAT. This does not necessarily mean that BAT is failing. Sometimes it requires time for BAT to begin working. Sometimes “How I Am Running Experiments on Myself to Control My Prostate Cancer – Using Bipolar Androgen Therapy” scans will be at odds with PSA blood testing. One should always rely upon the scans. What can be confusing is that sometimes a PSA will increase for a couple of months, and scans will simultaneously deteriorate. When this conflict occurs, then, it becomes a judgment call whether to continue the BAT procedure or terminate it. If bone pain occurs, it is probably caused from inflammatory factors and not from growth of the cancer. Pain can be tested by administering 300 mg of transdermal Androgel. If you have pain, Androgel will wash out in a few days. If muscle pain occurs, this can be reduced by taking NSAID meds such as Ibuprofen or Aleve. One might need to use high doses of these meds because both Ibuprofen (Motrin) have a very short half-life. Thus, the med dosing might need to be done every 3 or 4 hours. Aleve has a much longer half-life, and one might find that a single or second dose each day will help,to reduce the muscle pain. Russ’s PSA when he began BAT was 0.17 ng/dl. After a little more than a year, his PSA had dropped to 0.02. Russ had osteopenia for years, and it was becoming worse as time progressed. Transitioning into Osteoporosis appeared likely. During his first year of BAT, his bone mineral density (BMD) increased 5.20% as determined by a DEXA scan. Half a year later, he verified using a DEXA- FIT scan results had increased by 4.0%. His sexual libido did not exist during ADT. But his sexual libido returned during SPA and has continued during BAT, however not as “actively” as he was during the SPA phase of BAT. His muscle loss was reversed. He has noticed that he has more energy during the SPA phase of BAT. 3.How can BAT be enhanced? Statements have been made that BAT was used to treat CRPC men in clinical trials because guidelines to obtaining FDA standard of care (SOC) approval would be easier to achieve. But, other opinions acknowledge that BAT might be effective for HSPC patients too. However, the primary focus presently is for the treatment of CRPC patients. The BATMAN clinical trial was performed on HSPC men, and had very good results. An aromatase inhibitor such as ? can be used to remove intratumoral estrogens. Systemic estrogen can be replaced, as desired, during the ADT phase of BAT with ?. Various treatment combinations can be used in combination or in sequence with BAT. These include PARP inhibitors, immunotherapy, radiation therapy, and the meds Xtandi or Nubequa. For more “How I Am Running Experiments on Myself to Control My Prostate Cancer – Using Bipolar Androgen Therapy” Russ’s book with detailed explanations, references, and programs is at: Amazon.com: Adaptive Bipolar Androgen Therapy (BAT) for Prostate Cancer eBook : Hollyer, Russ: Kindle Store . Free for Kindle Unlimited. Otherwise the Amazon minimum charge of $2. The information and opinions expressed on this website or platform, or during discussions and presentations (both verbal and written) are not intended as health care recommendations or medical advice by Prostate Cancer Lab, its principals, presenters, participants, or representatives for any medical treatment, product, or course of action. You should always consult a doctor about your specific situation before pursuing any health care program, treatment, product or other course of action that might affect your health. “How I Am Running Experiments on Myself to Control My Prostate Cancer – Using Bipolar Androgen Therapy” Meeting Notes The information and opinions expressed on this website or platform, or during discussions and presentations (both verbal and written) are not intended as health care recommendations or medical advice by Prostate Cancer Lab, its principals, presenters, participants, or representatives for any medical treatment, product, or course of action. You should always consult a doctor about your specific situation before pursuing any health care program, treatment, product or other course of action that might affect your health. SUMMARY KEYWORDS adt, testosterone, androgen, bat, lupron, work, psa, cells, estrogen, good, hormone sensitive, trial, hormone, years, dht, sipping, therapy, prostate cancer, castrate, sensitive SPEAKERS Russ Hollyer (89%), Brian McCloskey (5%), Brad Power (3%), Jeffrey Dwyer (2%). Session Outline 1.Introduction to today’s episode. (0:00) 2.Hormone sensitive androgens. (4:39) 3.Batman’s mask is unveiled. (9:34) 4.Denmeade’s statements on castrate resistant vs. hormone sensitive men. (13:36) 5.Castrate resistant vs. ADT. (19:35) 6.How do you persuade your oncologist to consider BAT? (25:13) 7.How did you become interested in cancer and hormones? (29:48) 8.How do you measure testosterone? (35:05) 9.Monitoring your testosterone levels. (39:38) 10.Genetic determinants of PSA response. (44:46) 11.How to use Olaparib to treat prostate cancer? (50:42) 12.Radiotherapy and androgen deprivation therapy. (54:50) Brian McCloskey 0:00 Thanks everyone for joining the Prostate Cancer Lab. Today we have a special guest, Russ Hollyer. He's a member, and he is an expert in bipolar androgen therapy (BAT). He is an advanced prostate cancer patient and has really chartered new ground in terms of knowledge around bipolar androgen therapy. There's a lot of interest in bipolar androgen therapy from many of our patients that join our community, and Russ is truly an expert, and he's brought expert physicians to speak to us as recently, such as Emmanuel Antonarakis. Russ has a wealth of knowledge, and I know that you're going to get a lot from this session. Russ Hollyer 0:58 A little about me. I'm Gleason 9 as diagnosed five years ago - T3c N1M0. I'm still hormone sensitive. “How I Am Running Experiments on Myself to Control My Prostate Cancer – Using Bipolar Androgen Therapy” First, “What is prostate cancer?” Well, it has four main types of cells. We know of more than 200 different cell lines, and with mutations and up-regulations, there are perhaps billions in total of different varieties. For hormonal purposes we can place them into four different categories. “How I Am Running Experiments on Myself to Control My Prostate Cancer – Using Bipolar Androgen Therapy” A.Category A - Hormone sensitive prostate cancer (HSPC) - the androgen sensitive cells that can be treated using androgen deprivation therapy (ADT). B.Category B - They are androgen sensitive cells but are resistant to ADT. They upregulate or mutate their androgen receptors (ARs) so they can be more efficient, to get testosterone (DHT) a little easier. And what you can do with ADT, you can add in Xtandi or darolutamide. And that's going to lower the bar and make it harder for those guys to live. It lowers the bar for testosterone or androgens, and those guys have to upregulate their androgen receptors even more, which they will do. C.Category C - They are androgen sensitive cells that require testosterone (DHT), but they can produce it internally. That's where Zytiga comes in. It blocks internal production through Cyp17. We think these cells can produce DHT from other androgens instead of testosterone and a conversion of DHEA, DHEAs (which comes out of DHEA) and androstenedione. Again, Zytiga blocks all of those. D.Category D - CRPC androgen insensitive. The rub for category B cells is that, while Xtandi or darolutamide will take the threshold down, eventually the upregulation of androgen receptors (ARs) is going to be high enough to get around this. In a similar way, you can control category C: you can block those through Zytiga. But eventually, those cells are going to die off, and then the type B's and D’s are going to predominate. The D’s are very hard to control. They're androgen insensitive, and BAT doesn't control these cells. Doctors practice ADT, but the typical HSPC->CRPC change occurs in about one to four years. Some guys last only six months on it. Some guys last for four years, some guys last for over 10 years. As far as I know there is no good predictions of who's gonna last longer. So six months seems to be the maximum time that I'd want to be on ADT. I was on it for four and a half months. If you are CRPC, trials are showing us that we could potentially use BAT to reset sensitivity back to sort of a hormone sensitive phenotype where Xtandi is going to work or darolutamide or possibly even just ADT. “How I Am Running Experiments on Myself to Control My Prostate Cancer – Using Bipolar Androgen Therapy” BAT has two main parts.