This is a 3 part article on Bipolar Androgen Therapy (BAT) which may be useful for anyone thinking about it. Its interesting that they (the Denmeade crew) are exploring combinations of BAT with other treatments and that they are also looking at seeing how far you can keep repeatably doing it (ie BAT-rechallenge with lutamide-back to BAT-lutamide etc). In my sample of 1 experiment, I found I could do 4 iterations before it seemed to finally fail after over 3 years. It extended my use of bicalutamide from 1 year to 4 years. But I did each step to failure (ie BAT to failure, bical to failure) I think that was a mistake and you would probably get more mileage by stopping each step well short of failure. I am also not convinced that we have yet found the optimum sequencing and others here have tried longer exposure to supraphysiological T and to the following ADT - say 2 shots of T 2 weeks apart then 2 months of ADT before the next T shots rather than 1 month between T shots. One thing the article did not mention is that there is a bit of evidence (not conclusive) that those with BRCA2 will do a little better but as yet we do not really know what distinguishes those who do well and those who do average. Most people get some benefit especially in reactivating previously failed antiandrogens such as enzalutamide. Something else the article did not mention: it does not work so well with abiraterone. In my case I reasoned that the easiest, cheapest way to find out if it works for me was just do it. After 3 months you know and you are no worse off than when you started. Care and monitoring needed (watch/control estradiol) but really, pretty safe, simple and easy. Its good to see it is starting to be viewed as a potential adjunct to some SOC treatments. A few years ago if you mentioned it to your MO it would usually have brought out expressions of horror (T is fuel
New BAT article: This is a 3 part... - Advanced Prostate...
New BAT article
1. AR overexpression wjmh.org/DOIx.php?id=10.553...
2. CRPC drug resistance and possible explanation for resensitization advantage of Enzalutamide (Xtandi) pubmed.ncbi.nlm.nih.gov/257...
3. BRCA2 and ATM mutations are hyper-responder case study ncbi.nlm.nih.gov/labs/pmc/a...
4. TP53 and/or HRD mutations are hyper-responders sciencedirect.com/science/a...
5. Rapid Androgen Cycling as Treatment for Patients with Prostate Cancer | Clinical Cancer Research clincancerres.aacrjournals....
6. Breaking androgen receptor addiction of prostate cancer by targeting different functional domains in the treatment of advanced disease – ScienceDirect sciencedirect.com/science/a...
7. Rapid Hormonal Cycling as Treatment for Patients with Prostate Cancer: The Men’s Cycle - Study Results - ClinicalTrials.gov clinicaltrials.gov/ct2/show...
8. Rapid Androgen Cycling as Treatment for Patients with Prostate Cancer | Clinical Cancer Research clincancerres.aacrjournals....
9. Sci-Hub | Bipolar androgen therapy in men with metastatic castration-resistant prostate cancer after progression on enzalutamide: an open-label, phase 2, multicohort study. The Lancet Oncology, 19(1), 76–86 | 10.1016/S1470-2045(17)30906-3 sci-hub.se/10.1016/S1470-20...
10. Mathematical modeling of prostate cancer progression in response to androgen ablation therapy | PNAS pnas.org/content/108/49/19701
11. Sci-Hub | Strategies for Testosterone Therapy in Men with Metastatic Prostate Cancer in Clinical Practice: Introducing Modified Bipolar Androgen Therapy. Androgens: Clinical Research and Therapeutics, 1(1), 76–84 | 10.1089/andro.2020.0009 sci-hub.se/10.1089/andro.20...
12 Sequential Testosterone and Enzalutamide Prevents Unfavorable Progression clinicaltrials.gov/ct2/show...
13 Immunotherapy following BAT oncology.medicinematters.co... system
14 STEP-UP RCT. BAT, Enzalutamide, BAT, Enzalutamide, repeat.. Sequential Testosterone and Enzalutamide Prevents Unfavorable Progression - Full Text View - ClinicalTrials.gov clinicaltrials.gov/ct2/show...
1. 5ARIs perhaps not beneficial jme.bioscientifica.com/down...
2. Zytiga with 5Aris urotoday.com/center-of-exce...
3. Metformin for ADT phase ncbi.nlm.nih.gov/pmc/articl...
4. Statins lower intracellular testosterone healio.com/news/endocrinolo...
5. Use of high-dose estrogens for ADT
• ncbi.nlm.nih.gov/labs/pmc/a...
• cancernetwork.com/view/estr...
• pubmed.ncbi.nlm.nih.gov/126...
• nature.com/articles/ncponc0602
• bjui-journals.onlinelibrary...
• ncbi.nlm.nih.gov/labs/pmc/a...
6. Low estrogen replacement for ADT
• erc.bioscientifica.com/view...
• Con: pubmed.ncbi.nlm.nih.gov/177...
7. Use of reduction of estrogens, therapy for Pca ar.iiarjournals.org/content...
8. Mathematical modeling of prostate cancer progression in response to androgen ablation therapy | PNAS (pnas.org/content/108/49/19701)
9. Sci-Hub | Strategies for Testosterone Therapy in Men with Metastatic Prostate Cancer in Clinical Practice: Introducing Modified Bipolar Androgen Therapy. Androgens: Clinical Research and Therapeutics, 1(1), 76–84 | 10.1089/andro.2020.0009 (sci-hub.se/10.1089/andro.20...
10. FSH lower is better? urotoday.com/conference-hig...
11. Statins pubmed.ncbi.nlm.nih.gov/350...
8–24-hour Androgen stimulation is optimum? ncbi.nlm.nih.gov/labs/pmc/a...
oncotarget.com/article/2277...
WOW that is some reading list! Thanks. I have copied and will dip in over time.
Very nice. Thank you.
Russ, your personalized plate should read VeryThorough! Thanks again for your many shares with the group. I am ATM positive and 15 months into ADT. I like what Nalakrats has said over time about keeping PCa confused, not waiting for failure.I know you hv seen some PSA rise. Kaptank mentions he extended Bicalutamide from 1 out to 4 years. That should open him up for other 2nd Gen ADT I would hope for him?
Best,
Mike
Thanks Mike!
I agree with Nal. Keep it "confused". We know that ARs and other sources of cancer delight will be upregulated/mutated to thwart whatever we are doing. So switch up. Switching works with many body functions (diet, exercise). Drug holidays or cycles are an example of switching.
I also hope that Kap can use another AR drug when he needs to.
The adaptive BAT is working well. PSA goes up to 0.2 and then down to zero (until this cycle - it was still 0.2 after a week into the low cycle). The high/low T cycling isn't too bad I guess. But nowhere near as nice as the constant high T. I'm seriously considering RT. After RT I will allow my T to recover (if it doesn't go fast enough I'll give it a boost with TRT). Then live life and monitor it. I think that the reality is that my MO will once again take me out of RT. She always has good arguments and it's hard to disagree with someone who is reasonable, has data to back up their opinions, and is willing to answer all of your questions WITHOUT belittling you or hinting that you are stupid or ignorant.
Russ
Update: PSA went to zero.
I talked to my MO again. I'm going to start calling her Batgirl.
I'm currently on abiraterone + nirapaparib (MAGNITUDE trial). From my reading of the Denmeade experiences, BAT does not work with abi - or not enough to do it. I'm guessing it works with the lutamides, so at some future time I will revisit some form of BAT but abi directly followed by enza is not so good, I need another treatment between them (chemo?) to wipe out the resistant bastards.
Yes, its part 3 of the article. Its interesting as there are quite a few possible routes by which BAT and supra T work. This is another one. That makes it 9 or 10. Its not all just about ARs. Immune response may be a biggie. Another major route is double strand DNA breaks which supra T does with gusto.
Thanks. Lots of info there. I think if Enzalutamide comes into my life at some future time, BAT of some sort is very compelling. Here in Australia its still not well regarded. The onco I had when I started it (against her advice) actually sacked me! The onco I have now is a bit better informed but I am sure would not do it. Prescriptions of T for PCa patients will likely invite questions. He might tolerate me doing it with grey market T as used by body builders. Was it Planck who observed that paradigms only end when the last of their adherents die of old age?
Lol! Yes, it was Planck. Good saying and quite applicable. My MO is in her early 40s and is much more advanced-minded than the older docs that I have talked to.
BAT is hard to get in the states. I have a naturopath to write my scripts. My MO is on board with what I am doing but I don't know if she'd put her license on the line to write me scripts.
My same thoughts about Enzo. I'm going to prime the pump with my MO to see if she will switch me from Zytiga to Enzo if I want to at some time.
Thanks for the post. I can see BAT in my future
Research it to make sure it fits your situation. Its just a tool as we manage this bastard bug.
This past summer I met with a member of Denmeade's team at Johns Hopkins to discuss the possibility of BAT for me. It was not recommended for patients like me with rising PSA, and could make matters worse.
Its not for everyone especially anyone with pain or bone mets - can cause pain due to inflammation. Rapidly rising PSA needs to be brought under control by SOC. Best of luck.
My apologies to everyone. The 3 articles I referred to came from an outside organisation that we cannot link to. They came from the Prostate Cancer Foundation newsletter. If you go there and search BAT they should come up for those who want.
I have copied the text below. I hope that is OK. I think anyone thinking about BAT needs to do some research and these articles are a good start.
Could More Testosterone Be the Hidden Key to Fighting Prostate Cancer?
Researchers Drive Prostate Cancer “BATty” - Part One: The Concept of BAT
January 24, 2022 | By JANET FARRAR WORTHINGTON
Androgen deprivation therapy (ADT) has been the bedrock of treatment for advanced prostate cancer for more than half a century. But investigators at Johns Hopkins are rethinking it – in a way that sounds counterintuitive – and driving new approaches to tackle treatment resistance. They’re discovering that shaking up prostate cancer with high-dose testosterone makes it more vulnerable to other treatments.
ADT slows prostate cancer’s progress by shutting off testosterone. Eventually, however, cancer adapts to this new environment and PSA levels start to rise; this stage is called castrate-resistant prostate cancer (CRPC). ADT is not a curative treatment, and long-term ADT causes significant side effects, including fatigue, hot flashes, weight gain, and loss of sexual function.
Several years ago, medical oncologist Samuel Denmeade, M.D., Co-Director of the Johns Hopkins Prostate Cancer Program, and colleagues came up with a remarkable concept for attacking prostate cancer: alternating ADT with high-dose testosterone. “It had been known for a long time that something weird happened when you gave testosterone to prostate cancer cells,” says Denmeade. “Yes, with low doses you could get the cancer cells to grow – but plenty of reports said that paradoxically, at high doses the cancer cells don’t grow as well, or they die. Even Charles Huggins, who won the Nobel Prize for discovering hormonal therapy, said in his Nobel acceptance speech that another way to kill cancer would be to give too much hormone. I was always interested in that idea.”
About 10 years ago, Denmeade conducted a small study to test the concept of using testosterone against prostate cancer. “At the time, it seemed like all the data and literature suggested that the dose was really important; it had to be a high dose.” The hypothesis: Prostate cancer cells adjust to a very low-testosterone environment (created by ADT) by making very high levels of the androgen receptor (AR). And here, as he says, “too much of a bad thing can be a good thing.” These high levels of the AR now make cancer vulnerable to very high levels of testosterone. Cancer cells that survive this respond to high-dose testosterone by turning the AR back down – and making the cancer once again susceptible to very low testosterone.
“The idea is to screw up the cancer cell’s ability to adapt.” Denmeade and colleagues coined the term, Bipolar Androgen Therapy (BAT), “to capture these polar extremes of very high and very low. Not just making the testosterone high, but cycling between high and low.” It’s this cycling that seems to be the key to keeping the cancer off-balance, slowing its ability to flourish. In BAT, men experience high testosterone levels that decrease over a 28-day period, then bounce back up with the next testosterone injection.
In that early study, of just a handful of patients, “we were very cautious, because we didn’t want to make the disease worse. We built in all these safety parameters. But we were surprised: it didn’t seem we made anybody worse. It seemed very safe. The patients did very well, and some of them stayed on the testosterone for a year or more. Most of them felt really good. A number of them did not want to come off of it when it seemed they were progressing: they were just so happy to have more energy, and some of them could have sex again.”
Armed with this initial clinical data to show that BAT was safe and to show some response, Denmeade received funding for additional proof-of-concept studies from PCF, among other sources. Larger studies at Johns Hopkins have followed, including RESTORE, TRANSFORMER, and COMBAT. Other trials testing this concept have been completed or are under way at the University of Washington, University of Colorado, and in Australia, Brazil, and the Netherlands.
A trial of BAT has recently opened in the VA system for Veterans with certain types of metastatic CRPC. Please click here for more information about the trial, and talk to your doctor if you think it might be right for you.
Contact information:
Angel.FelipaGabriel@va.gov
Phone: (206) 762-1010 x67190
Dr. Bruce Montgomery
rbmontgo@uw.edu
Part2: How BAT Works
Several years ago, medical oncologist Samuel Denmeade, M.D., Co-Director of the Johns Hopkins Prostate Cancer Program, and colleagues came up with a remarkable concept for attacking prostate cancer: alternating ADT with high-dose testosterone.
Patients have asked Denmeade if this treatment, called Bipolar Androgen Therapy (BAT), could be used as initial therapy for metastatic cancer instead of androgen deprivation therapy (ADT), or even as primary therapy instead of prostatectomy or radiation. “No and no,” says Denmeade. “BAT was designed to work against castration-resistant prostate cancer (CRPC).”
In CRPC, the cancer’s environment is significantly different than it is in earlier- stage cancer. As CRPC cells learn to adapt to the lack of testosterone with ADT, “they crank up the androgen receptor (AR) to high levels,” and make themselves comfortable in the new environment. But with high levels of AR, the cancer cells are sitting ducks, vulnerable to the shotgun blast of a hefty dose of testosterone. “Flooding the prostate cancer cell with testosterone gums up the works: suddenly, the cancer cells have to deal with too much androgen (male hormone) bound to the receptor. This disrupts their ability to divide. They either stop growing or die.”
It’s all about creating chaos in the environment, so the cancer cells can’t thrive, and timing is critical. “ADT initially works because prostate cancer cells are suddenly deprived of testosterone, and most of them can’t survive this shock.” Cancer cells die by the thousands, PSA plummets, imaging scans show cancer shrinking, and symptoms improve. But prostate cancer, like the Road Runner, is elusive. Over time, the hardy band of surviving cells regroups, adapts to living in the low-testosterone environment, and begins to grow again. “BAT is a similar type of hormone shock – just in the opposite direction,” says Denmeade. “A key feature of BAT is the rapid change from a very high- to low-testosterone level.” Men remain on ADT, and receive monthly shots of high-dose testosterone, which gradually fades, then bumps back up again with the next monthly shot. That’s the bipolar part of Bipolar Androgen Therapy (see Figure). “The repeated shocks of BAT cycling don’t give the cancer cells time to adapt, “because the underlying environment is always changing.”
Testosterone Levels During BAT
So far, in four clinical trials at Hopkins, Denmeade and colleagues have given BAT to about 350 men with CRPC, most of whom have also received enzalutamide (Xtandi), abiraterone (Zytiga), or both. For men with CRPC whose disease is worsening on ADT or on AR-blocking drugs like enzalutamide or abiraterone, BAT is highly promising. In the recent TRANSFORMER study, “we compared BAT head-to-head with enzalutamide” in patients with CRPC who had progressed on ADT and abiraterone. “It was kind of a weird study, comparing a drug to its exact opposite: an androgen vs. an anti-androgen. I don’t know if anybody’s ever done a study like that. To our amazement, BAT and enzalutamide were nearly identical in terms of their effect.” PSA levels dropped in about 25 percent of men on either treatment, and for both treatments, the response lasted about six months.
However, the real difference between the treatment arms was seen after cross-over – when men on BAT were switched to enzalutamide or vice versa. “If we gave BAT first and then enzalutamide, almost 80 percent responded, and the response lasted almost a year. That’s quite an improvement in the rate of response and duration.” Among patients who received enzalutamide first, followed by BAT, the response rate to enzalutamide was only 23 percent.
This begs the question: Why stop after one round of BAT then enzalutamide? Why not just keep going? “We should be able to cycle back and forth over and over again,” says Denmeade. The STEP-UP trial, of 150 patients at Johns Hopkins and eight other centers nationwide, is looking at just this, “sequencing androgen and anti-androgen. There are two BAT treatment arms: in one, the patients just switch every two months – two months of testosterone, two months of enzalutamide. In the other, the men stay on testosterone until their PSA goes up, and then switch to enzalutamide, and stay on that until their PSA goes up,” then repeat. Cancer response is also monitored by regular CT and bone scans. Patients stop treatment if scans show cancer progression.
The BAT studies thus far have been small, Denmeade says. “We need a big phase 3 study; we’ve just been nipping at the edges.” For now, BAT remains investigational; positive results from larger randomized trials are needed for it to be considered standard of care. While not a cure for advanced prostate cancer, BAT may become an option for extending life and, importantly, improving quality of life.
Note: BAT is not recommended for men with symptomatic bone pain from metastatic prostate cancer, because it can make that pain worse. “This pain increase occurs within hours of testosterone injection, and resolves as testosterone levels in the blood decline over the first cycle of BAT,” says Denmeade. “The worsening pain is not due to rapid growth of prostate cancer, but more likely to testosterone-stimulated release of inflammatory factors.”
Part 3: BAT and immune system, combination treatments
Some men are exceptional responders to Bipolar Androgen Therapy (BAT). Its pioneer, medical oncologist Samuel Denmeade, M.D., Co-Director of the Johns Hopkins Prostate Cancer Program, has a few patients who have remained on BAT alone for several years. But for many men, the response is temporary; just a few months. Why? Could it have something to do with mutated genes? What about the immune system?
“One of the things observed in the lab by our colleague Dr. Sushant Kachhap is that when we give testosterone, the prostate cancer cells get stressed and turn on all these immune factors,” says Denmeade. “Testosterone activates immune pathways.” When three men who had participated in BAT trials later had “dramatic” responses to immunotherapy – 100-percent decreases in PSA, and one man remains in long-term remission – “we thought that might be the secret: androgen plus immunotherapy.”
COMBAT, a small, phase 2 study supported by PCF, co-led by Hopkins investigators Mark Markowski, M.D., Ph.D., and Emmanuel Antonarakis, M.D., (now Director of Genitourinary Oncology at the University of Minnesota) tested the combination of BAT and immunotherapy in 45 men with metastatic castration-resistant prostate cancer (mCRPC). The men were treated with BAT in combination with nivolumab (an immunotherapy agent). “We saw an impressive clinical response rate of 40 percent,” says Markowski. “We also observed a durable benefit, lasting over a year, in a few patients who had received extensive prior therapies.” The results suggested that BAT alone has significant efficacy, while nivolumab improves responses in some patients. The combination of BAT with nivolumab was safe and well tolerated by the participants. Markowski and Antonarakis are designing a randomized Phase 3 study to compare combined BAT plus nivolumab versus standard treatments for patients with mCRPC.
In the COMBAT trial, “we treated a group of incredible men who agreed to have tumor biopsies before and after three cycles of BAT,” says Denmeade. “We are studying the heck out of these biopsies,” looking for specific biomarkers or gene mutations that might help predict who will have the deepest and longest-lasting responses. The team is also performing additional studies of the interactions between BAT and the immune system to discover how this treatment can be improved.
The term has a proper use in history and philosophy of science but it has been hijacked by pop economists and their ilk.
Thanks Kaptank for sharing your personal human experiment. I’m convinced it is what we are all doing. In the future Men will look back and say these guys were the forerunners of what has become phase 2 of SOC.Best for continued success in the next phase. I am 15 mos into ADT but on Abi as Enza didn’t do much and let T rise w PSA 2 weeks behind. Also ATM positive which seems positive for mBAT.
Also just finished 5 rounds of image guided SBRT/SABR at MSKCC which I have read will cause PSA to rise because of excess dead PCa cells but should extend ADT success. I want to be early not late (at failure) to start mBAT.
Best to you and yours,
Mike
Denmeade did some early studies of BAT with enza or abi. The conclusion was that it did not work so well for abi - there was an effect but not worth following up. I suspect (that is all it is) that BAT would work with the lutamides including the most recent but that has not been confirmed (we know it works with enza and bicalutamide)
Can anyone tell me if a man who has had an orchiectomy can do BAT. I read some of the links but did not find the answer. Thanks.
I'm pretty sure an orchi is is quite OK. An orchi gets us to the same state as ADT so in each case, after the shot T declines to a castrate state. May not even need ADT drugs. You are right, not any papers on this. Anyone trying BAT should get T levels (including free T) before the shot, 2 days after the shot then at the end of the month. That is to give knowledge of how your body reacts and how long it takes to get back to castrate so you can adjust dosage.
Yes, my husband had an orchiectomy years ago and recently did 10 cycles of BAT. He started back on Xtandi a few months ago and his psa is now the lowest it’s been in years. BAT worked very well for him. He started BAT when his psa was 30, then over the course of treatment his psa went down to 6 before spiking back up to 17. At that point he went back on Xtandi and his psa is now 4. The curve is leveling off so he will probably see a rise in psa within a couple of months. He will then start BAT again.
BAT definitely bought him time, much better quality of life, and recharged Xtandi so it is working again nicely. So glad our doc is working with lots of patients on BAT and is figuring it out.
That is a terrific result. Our aim has to be to manage PCa as a chronic condition.
kaptank I was reading thru some posts about BAT from 4-5 years ago and I see that you tired it. Would you please update your profile with more detail as to your experience .ie: PSA, blood tests and what markers you paid attention to. Especially interested on your thoughts about Estradiol
This info will be extremely helpful to those of us that plan to try BAT on our own.
I ask that you put it in your profile as it is really hard to find relevant messages in the post guys make over time.
Thanks so much
Scout
BAT & Abiraterone / Enzalutamide resensitization
Cellular and Genetic Clues that Drive BAT effectiveness
BAT Question
BAT only for CRPC??
