"Bipolar androgen therapy (BAT) is the cyclic administration of high dose testosterone as a novel treatment for metastatic castration resistant prostate cancer (mCRPC). We hypothesized that rapid testosterone cycling would promote improvements in body composition and these would be associated with improvements in lipid profiles, and quality-of-life."
. 2021 Mar 25. doi: 10.1111/bju.15408. Online ahead of print.
Reversing the effects of androgen deprivation therapy in men with metastatic castration resistant prostate cancer
Catherine H Marshall 1 , Jessa Tunacao 2 , Varun Danda 3 , Hua-Ling Tsai 1 , John Barber 4 , Rakhee Gawande 2 , Clifford Weiss 2 , Samuel R Denmeade 1 , Corinne Joshu 4
Affiliations expand
PMID: 33765326 DOI: 10.1111/bju.15408
Abstract
Background: Bipolar androgen therapy (BAT) is the cyclic administration of high dose testosterone as a novel treatment for metastatic castration resistant prostate cancer (mCRPC). We hypothesized that rapid testosterone cycling would promote improvements in body composition and these would be associated with improvements in lipid profiles, and quality-of-life.
Methods: Men from two completed trials with CT imaging at baseline and after 3 cycles of BAT were included. Cross sectional areas of psoas muscle, visceral and subcutaneous fat were measured at the L3 vertebral levels. FACIT-Fatigue and Short Form-36 were used to measure quality of life.
Results: Participants (n=60) lost a mean of 7.8% of subcutaneous fat (SD 8.2%) and 9.8% of visceral fat (SD 18.2%) and gained 12.2% muscle mass (SD 6.7%). Changes in subcutaneous and visceral fat were positively correlated with each other (Spearman's correlation coefficient 0.58; 95% CI 0.35-0.71), independent of effects of age, body mass index, and duration of androgen deprivation therapy. Energy, physical function, and measures of limitations due to physical health were all significantly improved at 3-months. The improvements in body composition were not correlated with decreases in lipid levels or observed improvements in quality of life.
Conclusions: BAT is associated with significant improvements in body composition, lipid parameters, and quality of life. This has promising implications for the long-term health of men with mCRPC.
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pjoshea13
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Patrick, Thanks for this. Boy, what I'd give for 12% more muscle mass.... pretty much anything but a rising PSA. I'm now 15 months into ADT and my personal nadir appear to be 0.7 (have been at that level for 9 months now) Good enough for me but not likely to trigger an ADT holiday. So, I'd welcome any evidence that I could keep my onco happy, whilst keeping my wife happy too. Is there a particular profile that BAT works especially well with, or is it a case of starting it and watching the numbers like a hawk?
This study was on mCRPC guys, but I maintain that the strength of BAT might be in the prevention (or substantial delay) of CRPC. And I believe that the earlier it is started, the greater the percentage of men who will respond.
I have been using testosterone [T] in different ways for 15+ years. When I tried to follow Denmeade's 28-day cycle (late 2018), I developed leg pain that was eventually linked to a small lesion at S1. I had to go to a 2-month cycle to revers this & I think that anyone trying BAT should start out that way.
My next PSA test will be on Wed 31st. One's protocol is only as good as the next test, so I'm not making predictions, but I have been content with the two-month approach (& pain free for 19 months) & my PSA has been falling. I only measure the cycle nadirs - I don't know how it climbs when T is high.
Pat, you are very correct. I am hormone sensitive at the moment, and my Drs are not doing anything to prevent CRPC. SPT and BAT are the only ways, as far as I have been able to see from studies.
When I asked my Dr about it, he said he would never do it for me, I believe he is referring to my pain levels that will go sky high.
If SPT is also detrimental to PCa, why would high T levels cause pain? Does anybody have experience on BAT with high bone mets burden, PCa?
You are hormone sensitive, but ADT is not controling pain? Or you expect a quick return to unacceptable pain after the testosterone cypionate injection?
An issue with T-cyp is that T in thigh muscle can keep T blood levels high for more than a week. Another approach is to use T patches, which have to be changed daily & can be quickly stopped. Serum T clears quickly.
The return of pain should be gradual & one might have good control of the situation with patches.
Something that should be discussed with a doctor, of course.
The downside of course, is that for half the men, their PC gets worse with testosterone. Even for those who stay on it, there is no survival increase (TRANSFORMER). This should NEVER be attempted outside of a clinical trial, and NEVER in symptomatic men.
Can you please state the source of "half the men, their PC gets worse with testosterone"? That is not what both of my husband's MOs have experienced nor what recent trial data shows. Our understanding is more like 10% do poorly. TRANSFORMER showed longer overall survival with the BAT arm (about 3 months, which is the same as most of the advanced treatments) and better PSA response. Plus, QOL is better and the treatment is much less expensive.
My husband has had 3 cycles of BAT outside of a clinical trial. PSA went from 30 to 34 after first T injection, then down to 25 after second one. We won't know 3rd shot results for another week or two.
My husband and his doctors respectfully disagree with your position that BAT is dangerous. As more info gets published, I think it will become more common as a treatment. Right now, many doctors believe as you do and are unwilling to try BAT even if the patient wants it.
Sorry, but you are misinterpreting the data entirely. Please read the link I provided - the data are there.
You are also misinterpreting TRANSFORMER when you claim it showed longer OS in the treatment arm. In fact, there was no statistically significant difference in OS.
Your husband may be part of the subset that does well with BAT. I hope so. I agree that it improves QOL more than intermittent ADT. I've followed the BAT trials for about 5 years, and was optimistic at first. But as more data poured in, less so. I reemain hopeful that the researchers at JH will be able to identify the half of men with asymptomatic mCRPC who will benefit.
As I said (and you can read in the link provided), about half the men fail so badly with it that they never make it to a second injection. Johns Hopkins, with their advanced genomic studies, are well-poised to find the answers.
This should never be done outside of clinical trials.
Hi TA. I disagree. Denmeade has stated very clearly that in their experience at johns hopkins and elsewhere that BAT has very low probability of adverse results. The proviso is that no symptoms (not tested). A 3 month run of BAT should at the worst case result in being where you would be if no action taken. At 3 months you can make a decision: more BAT or SOC. My experience is consistent with PJ's observation that some form of adaptive BAT is better.
Yet that is what Denmeade's data showed, whether you agree or not. I do think that having Denmeade closely monitoring progression is incredibly important. This is risky business.
• Markowski et al. reported that using a PSMA PET scan (DCFPyL) 3 months into BAT treatment revealed that half of them had already progressed to having new metastases.
• Sena et al. reported that in Arm C of the RESTORE trial (ADT only),
- PSA more than doubled in 52%, and increased markedly in 14% more.
- Only 14% had a reduction in their metastases. All of those had lymph node metastases only.
- Musculoskeletal pain was experienced by 40%. Other prevalent side effects were: hypertension (21%), breast tenderness (21%), leg swelling (17%), fatigue (14%), and difficulty breathing (10%). One patient died of a stroke.
- There weren't any discernable genomic determinants of response.
- There was no statistically significant difference in overall survival between those who went from Zytiga -> BAT -> Xtandi and those who went from Zytiga -> Xtandi
- Comparing BAT to Xtandi (before crossover), there were no significant differences in the time to clinical or radiographic progression (5.7 months in both groups) or reduction in PSA by ≥ 50% "PSA50" (28% and 25%)
The transformer trial showed that BAT alone (with continuing ADT)was as good as and maybe even slightly superior to enza after failure of abi. That is itself a major conclusion applicable to clinical practice. (ie BAT is the equal of the 2nd generation lutamide in effectiveness) The 2nd conclusion was even more relevant and something that many of the earlier trials did not address (perhaps explaining the appearance that BAT may not be so effective. ) That is, the resensitization of lutamide-like anti androgens or making them more effective in the first place.
There are 2 different things happening with BAT. First there is the primary effect of the BAT. In my case it was a reduction of PSA by about 30% lasting about 8 months. (disappointing in my view) The second effect becomes apparent when rechallenging with a previously failed lutamide (in my case bical but also shown for failed enza). In my case a PSA drop of 80% for a bit over a year. (this was a pleasant surprise) While I found that repeating the whole exercise became more and more difficult with each iteration. However at the end of it all it gave me 3-4 years more of bical even after it initially failed. That is 3-4 years that I would not have had otherwise. This was confirmed by radiological means (Ga PSMA). In the Transformer case it was that the crossover sequence BAT to enza was far superior to the sequence Enza to BAT and seemed to sensitise the cancer to Enza. (All this after failure of Abi.) Conclusion: even after BAT fails it is worth rechallenging with the previously failed lutamide and when starting enza for the 1st time it is worthwhile doing a sequence of BAT (perhaps 3 months) before starting enza. (note it does not work so well with abi)
We do not know exactly the circumstances in which BAT is most effective but we do know that it is a fairly safe (and easy and cheap) clinical practice and many of the earlier trials did comment that it was a relatively safe procedure. Safe is of course a relative term here because ANY treatment at our stage carries significant risks that each of us must evaluate.
So, even looking at some of the earlier trials ( sometimes which did not factor in the resensitization effect) there is a clear conclusion that done properly, with good monitoring and expert advice, that BAT is a safe clinical option in the right circumstances. For sure, more research needed to focus down on its best use. The same can be said for all treatments at our stage.
We can also learn much from the body building community, many of whom use continually supra levels of T up to 10 times that used in BAT. They show that careful monitoring and management of effects (eg judicious use of Arimidex) make it feasible and sustainable.
No- it showed that comparing BAT to Xtandi (before crossover), there were no significant differences in the time to clinical or radiographic progression (5.7 months in both groups) or reduction in PSA by ≥ 50% "PSA50" (28% and 25%). And OS was NOT significantly different for the sequence Zytiga -> BAT -> Xtandi and Zytiga -> Xtandi
Bit of selection there. Firstly you say that comparing BAT to enza gives no difference. Correct. But what does this mean? It means that BAT is as effective as one of our most used 2nd generation anti androgens. This is news.
Secondly your account of the crossover is misleading. Lets be clear what happened here. All participants failed zytiga. That was a requirement of the trial. Half then did BAT and half did enza until failure. They did a direct compare of BAT to enza. As I said above this showed BAT to be as effective a treatment as enza. However when these failed they crossed over ie those who did enza then got to do BAT and those who did BAT got to do enza. Big difference. Those who went enza to BAT did about as well as those who originally did BAT. However those who went BAT to enza did significantly better than those who did enza first. BAT seemed to sensitise the cancer to enza.
It is important to remember that men starting BAT are at the end of conventional options. Quickly rising PSA, progression found through scans (not PSA), and the other side effects are happening at this stage of progression with BAT or without BAT. These are not men in remission.In my husband's case, his PSA rise was much faster on Xtandi than it was after starting BAT. He hasn't reached >=50% PSA reduction from baseline and his PSA went up initially, but to us it is a success so far.
Another reason to try BAT is because Xtandi is rechallenged and often works again to lower PSA.
Finally, BAT does not cure mcrpc in most cases. It isn't a miracle treatment. Our doc said it should slow progression down for several months. It is like every other treatment: initially it either works or doesn't work, then once it fails you move on.
The reason to do BAT is to feel good and hopefully buy time by slowing progression. It is the same reason doctors suggest chemo once ADT, Casodex, zytiga, xtandi, Provenge, radiation, etc fail.
As Patrick and Nal have written, there will most likely be a day when BAT is given before castration resistance but it will require changing old school thinking that BAT is dangerous.
That is not true that "men starting BAT are at the end of conventional options." In fact, BAT has ONLY been used in asymptomatic men. Comparing BAT to Xtandi (before crossover), there were no significant differences in the time to clinical or radiographic progression (5.7 months in both groups) or reduction in PSA by ≥ 50% "PSA50" (28% and 25%). After crossover, PSA-progression-free survival was 11 months for Zytiga->BAT->Xtandi vs 4 months for Zytiga->Xtandi->BAT. However there was NO statistically significant increase in survival. So the benefit is paliative.
Its use will be accepted or not based on actual evidence of benefit, rather than changing "old school thinking" that you imagine is out there.
Are you defining asymptomatic as pain free? Not every PC presentation has pain. Men can be asymptomatic and have failed all/most conventional treatments.
Yes- BAT has not been given to any men who have painful metastases. I have never heard of a case of PC that did not have pain in the end. In what magical world does that happen?
I don't know, but in our unmagical world, my husband has little pain but has run through most of the conventional treatment options. He isn't end of life. The perfect time for BAT.
I disagree with the two previous answers to you. I have talked with and visited the doctors at Tulane doing BAT, and I think read all of the BAT clinical trial results, and there is near unanimity that roughly a third of CR men seem to be helped. Apologies that I am not as organized as some members here and unable to supply the links. Since I am not yet CR I like to think that Patrick and Nal are correct in expecting BAT to work better for the non-CR and have begun the two-month plan. My problem is that since I am undetectable, how do I assess the results? The only BAT trial I know of for non-CR was done by Schweizer at U. of Washington and did not conclude very much beyond finding that BAT was safe in that setting.
Just a reminder since this week is my 6th year anniversary of a TRUS confirming PCa that I KNEW I had from my PCP's DRE 8 months earlier feeling a huge lump in the right side >>>>
I BEGAN treatment with a bilateral orchiectomy then treated my Gleason 10 with Cryoablation *BUT IT WAS CONTAINED* and then 7 months later the *ONE-OFF* at the time immuno injection followed one month later with the start of TESTOSTERONE REPLACEMENT injections every other week of 1ml Cypionate. Shoots *T* to 1,600ng/dL NOT A SUPER HIGH and NO BUZZ FACTOR FELT but does help recovery from exercising (FREQUENT 100+ mile bicycle rides) plus eliminates all of the crappy *low/no testosterone* side effects.
GUYS -- I WILL NOT SUGGEST THIS AND AS OF RIGHT NOW *THIS VERY MOMENT* AM NOT AWARE IF I HAVE METS, BUT LIFE IS VERY GOOD AND I PLAN ON GOING OUT IN A BLAZE OF GLORY, NOT WASTING AWAY >> 👍👍 Will have to reconsider if/when METS happen.
Am I missing something? Gain of muscle mass and loss of fat would be expected with more testosterone with or without any associated cancer or cancer treatment. It does not address whether or not it increased or decreased life expectancy, Or impacted PSA or progression of the disease at all. Seems like a very strange study to me To not even address disease progression.
While it may seem self evident to many of us that gains often seen in continuous TRT for healthy men would also be seen in rapid testosterone cycling for men with PC, I think perhaps the point of the study is to establish this as fact, rather than merely as a reasonable assumption.
In other words, if the jury is still out and waiting for other studies to definitively establish benefit in terms of disease progression for some groups of men (and which groups, and why), this study can at least be definitive in terms of OTHER health benefits of cyclic T. Our health and QoL is not only about our cancers.
But yes, anecdotally I think we already "know" that even one dose of T can improve QoL for many men and logically stop or reverse, at least temporarily, some of the effects of having low T. And anecdotally it has been known for over sixty years that administration of testosterone CAN stop disease progression in SOME men. It could be some time before we establish precisely WHICH men.
So it is at least nice to know that even if cyclic T might not be giving you longer cancer-specific survival, it is at least offsetting some of the negative effects of continuous low-T (and low E2) that are effectively causing you to age more rapidly and potentially die sooner from non-cancer causes.
BAT cannot be a stand alone treatment and cannot replace ADT. There must also be a means to go back to castrate T levels at the end of each month, which at the least entails there must be at least ADT in place and continuing.
It's interesting at, at this point, whether this is a valid treatment option for castrate sensive men is "mere speculation." It's clearly further advanced than that.
I don't have a problem with our FDA erring on the side of caution. But the collective misery brought about by continous, or even IADT, should not be ignored.
To run a phase 3 trial they need much more than a bit of NIH funding. It is very expensive and really only possible with the resources available to big pharma. There is no incentive for them to do that.
SELECT was done purely with NIH funding. Who do you suppose paid for CHAARTED? PCF and other NGOs also fund research. .Biden will makes sure that cancer research gets priority funding, obviously.
A double blind global trial involving maybe 2000 patients is within the Johns Hopkins resources? Give me a break.
They are doing very well just taking bites out of the problem and exploring sequences. To run a phase 3 we need to know much more about what exactly we are trying to prove and by what means. eg they are also exploring the combination of BAT with a checkpoint inhibitor.
I think they are getting best "bang for buck" with a number of phase 2 trials and learning what works. Thing is, this management tool will be put to clinical use or not by the individual decisions of doctors as we learn more.
Phase 2 trials lead to phase 3 trials, if successful. It won't be put to clinical use until there is proof and patient selection criteria. Most doctors practice evidence-based medicine. It protects the patient and them.
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