Bipolar Androgen Therapy (BAT), which entails cycling between androgen deprivation therapy (ADT) and very high doses of testosterone (T) has had disappointing results. No one really understood why only 20-30% of castration-resistant (CRPC) men derived any benefit and why even that was usually short-lived and didn't increase survival.
Researchers at Johns Hopkins have now done extensive tissue analysis of men using BAT in the hopes of finding the molecular mechanism that would explain the results so far, and what might be done to make it more effective. They focussed on the protein called c-MYC, which is known to be upregulated in advanced prostate cancer. They found:
• High androgen receptor (AR) activity is required for BAT to work. Only about ⅓ of CRPC men have high AR activity.
• But AR inhibition first is needed for T to raise AR activity
• High AR activity downregulates c-MYC.
• High doses of testosterone (T) increases AR activity.
• Xtandi (but not Zytiga or other advanced antiandrogens) prevents acquired resistance to T because it upregulates the AR while it inhibits its activity.
• AR activity (requiring tumor biopsy) may be a valuable biomarker.
Sartor is my MO and has told me that I would be a good candidate for it due to my age, physical status and low PSA which became detectable again about a year ago. I plan on giving it a try before moving on to something like Lutetium when he feels it’s appropriate. He’s had good success with a number of patients and is very experienced with it. It doesn’t work forever but you can rechallenge with Xtandi when the BAT or High Testosterone therapy as he prefers to call it begins to fail, and he’s had a good number of patients where Xtandi has become effective again. He has had some patients who get a good long run on BAT and QOL benefits are excellent. He has told me that he’ll know after the first few months whether it will be effective or not, treatment can be stopped immediately if it appears that it is not working. To me it’s another way to keep kicking the can down the road before using the last few bullets.
"He has told me that he’ll know after the first few months whether it will be effective or not, treatment can be stopped immediately it it appears that it is not working."
Well, for ⅔ of the men it gives them a good break from continuous ADT. There is also a good opportunity for men with the right biomarkers (thus, the study).
Those odds are typical for most of the treatments prescribed once men reach the MCRPC stage and have failed most treatments. Even 1/3 of men who try Xtandi get zero benefit. Their PSA can rise dramatically too.
"Xtandi (but not Zytiga or other advanced antiandrogens) prevents acquired resistance to T because it upregulates the AR while it inhibits its activity.'
Really super interesting.
Thanks as always for bringing cutting edge research to our attention.
BAT has my interest and my following for quite some time. Have had discussion with my MO about it's possibilities as well. I see the data, and it doesn't dissuade me from the possibility of its use... Although my mind has some different approaches to it's use.
Not specific to this therapy, but all, the concept of "Adaptive Therapy" is very intriguing to say the least. Using effective therapies but alternating their use, not at failure, but before and moving on to another, then back or to a completely new therapy may be what this shows a path to. Yes, done in a controlled and monitored setting with an oncologist... Why the 3 month interval in an advanced and aggressive setting? Whats to lose trying something untried? Starting BAT while still HSPC and monitoring the swings, and even if the PCa wakes up with T levels, but is put back to sleep with the subsequent ADT, but there's no progression... Who says thats a bad thing? Keeping the cells confused and alternating food source and sensitivity could be a good thing, maybe. Key being constant alternation between therapies.
Even for BAT, all these cutting edge therapies introduced in an advanced setting, then when found effective, are loosened and allowed to be used in an earlier setting sometimes miss the fact it may work more in that setting than an advanced or progressed setting, ie, the CRPC... Why wouldnt they have a focus group as well for HSPC patients as well? Especially those with some of those suspicious markers (MYC)... I find it annoying, even though I've arrived (possible CRPC right now with climbing PSA in low T environment) that the newer paths are always introduced in such a hostile environment (advanced PCa).
Anyways, good food for thought! Stimulates the cranium's inner workings for sure.
Very interesting case study with BAT here: cancerhackerlab.com/prostat.... Bob Gatenby has some very interesting thoughts about the advantages of not taking treatments to failure.
Good Morning Benkaymel, just Zometa, which started simultaneously with the Lupron/Xtandi in November/December 2019 (had adverse event to the Zometa and refused further treatment). Holding steady on the Lupron/Xtandi combo , coming up on 3 years this November.
"Xtandi (but not Zytiga or other advanced antiandrogens) prevents acquired resistance to T because it upregulates the AR while it inhibits its activity."
Does this mean you should just automatically favor Xtandi over Zytiga?
Or is this more complicated and nuanced than that?
Even if BAT use, in a limited scope, is a way to resensitize the PCa cells to ADT, it would be advantageous to patients... Something we won't or would never know in a linear treatment line progression system using therapy to failure, then on to another, etc. (As it now exists). This course has a set progression expectation, but maybe not a set linear definement in time as some patients respond well to single therapy lines too.
How many treatment lines are used in what timeframe, for a typical PCa patient? (I know theres no true "typical" patient, forgive the label)...
BAT in this instance can be very useful, as resetting sensitivity to being able to reuse a treatment line, could extend what becomes so valuable to us all, ie, time! So BAT, and especially ADAPTIVE THERAPY PRINCIPAL seem to be cutting new ideological paradigms into SOC thinking in some circles, and thats a good thing! Triplet therapy not too long ago was such a no-no too! Lol... But yes, finding the right fit, patient genomic profile or PCa cell type more susceptible to the therapy ensures success, same should be done for all "drug" interactions IMO and not just throw drugs at the PCa to see what works. Again, this opens the door to individual stylized care. That might be problematic for tracking purposes, but I believe would be more beneficial on a per patient basis.
the original BAT protocol may have demonstrated a limited “proof of concept”, but was certainly not optimally designed with monthly T-cypionate 400mg. They never got to castrate T, so was not truly as bipolar.
The current crop of modified BAT trials are correcting that, such as XtremeBAT, and others. Using AR blockade during the castrate period is a better idea. As is shorter acting testosterones for faster clearance at end of high T phases.
Your analysis also shows why mBAT should and probably does work even better in HSPC. (As it is doing for me and for others who are reporting on this site.) Agree clinical trial participation is the way to go.
BAT got my attention since I have an extreme bad reaction to ADT. I might still have that (and likely would) side effect on BAT so I don't think it would be good for me.
However, based on the preliminary results of trials I wouldn't think it would be a good option for anyone. If someone wants to try it they need to understand the possible results for them personally. Putting my cell biology and chemistry hat on, I can only speculate why it would work in any case.
The body and individual cell reactions to testosterone does vary though and I suppose it might be possible it could help some individuals. The initial trial results seem to bear that out although coincidence does not indicate causality. If it does cause some large percent to speed up the cancer growth, it is playing Russian roulette with your life situation. That's a personal decision for each.
I agree. Way back in 2015 when I first became aware of it, I was enthusiastic and followed it closely. With a lack of empirical data, it seemed reasonable. But then as we learned more of the biochemistry involved, as in this study, it only made sense for a small minority of patients, and possibly only if they were given the right antiandrogen or possibly some of the new bromodomain inhibitors in trial now. This is not ready for prime time.
I note that some patients are trying it on their own, which is dangerous. They seem to think that they can monitor effectiveness based on PSA, without regard as to how BAT may affect PSA expression.
PSA has been shown to be an excellent way to monitor whether BAT will work or not. If your PSA has not gone down after 3 cycles, you switch to Xtandi.
This is not a treatment for "a small minority" of patients. It is a treatment where 1/3 benefit, 1/3 don't improve but don't get worse, and 1/3 get worse but may have the benefit of having Xtandi work again.
PSA has always been found to be a poor surrogate for overall survival and is never used in Phase 3 studies of mCRPC. RECIST 1.1 criteria are used, which are based on scans.
Well, what does the oncologist monitor? PSA... Even in other trials, PSA! Not many trials include the expense of imaging to track drug efficacy, unless it's a part of the trial (effectiveness of drug). And considering monthly interactions with the BAT protocol, the therapy can be stopped with the event of adverse reaction.
How different would a one month reaction be, than CRPC development not discovered until 3 or even 6 months later for some patients who do a follow up and discovered their PSA had risen!?
I don't find the alarmist mentality sufficiently supported in this example. Agree to do it with the assistance of an oncologist in your corner, for obvious reasons. But its my body, my decision, period! Lmao, how many cancer patients take supplements and DON'T tell their doctor!
Anyways... It does appear they have made some adjustments more recently to the protocol(s) which have effectively benefitted some patients. I know when I started following data on BAT in late 2018, there wasn't so much data, or active trials, etc. So they're on to something and following up and expanded their view(s).
Suggesting scans vs PSA monitoring makes no sense. Insurance/medicare doesn't pay for scans whenever you want them. And you can't just pick the scan you want if you want it covered by insurance or Medicare.
More importantly, subjecting yourself to high levels of radiation to see if BAT is working is dangerous. Secondary cancers and other serious health issues brought on by radiation are a real threat when life expectancies are as long as they are with PC.
It makes sense in a clinical trial which is the only way a patient who cares about his life should attempt BAT or any other experimental therapy. There's a reason it's experimental. In a clinical trial, patients have to sign that they have been informed of the risks.
These are men who have exhausted SOC so their life, which they definitely care about, is measured in months to a year or two. That's the whole reason they try experimental treatments--the available SOC options are undesirable.
And anyone who has a treatment that hasn't been fully informed of the risks by their MO needs to find a new doctor. You don't need a clinical trial for that.
MRIs kind of defeat your premise that you must use scans. Instead of an MRI /additional unnecessary radiation, just go the simple route and monitor PSA. Then add scans when PSA rises quickly or you feel worse.
I posted it because many others here who are on “ADT vacations” (IADT) do not consider it. Don’t worry, I will avoid replying on any further threads you post. Have a nice day.
TA has been quoting a study that gathered data of approx 200 men between 2015-2018 when he quotes it has "never been shown to lengthen survival". According to our doc, you are correct nuc1111.
“From April 2015 to April 2018, we randomly assigned 195 men to receive either BAT (94 patients) or enzalutamide (101 patients) across 17 sites in the United States (Fig 1). The data cutoff date for this report was November 2019; median follow-up time among patients who are alive is 31.9 months.”
That study proved the opposite of your assertion. The change in survival was not significant. "Median OS was not statistically different" How could they be more clear?
(BTW progression-free survival was also no different)
I'm aware. I am saying you have quoted in most of your posts that BAT has NEVER (my emphasis, your word) been shown to increase survival, and you are basing that strong assumption on the above older study of a few hundred men which ended data collection several years ago.
My point is that my husband (and I indirectly because I go to his appointments) has been very involved with BAT since Jan 2021. We have met with oncologists who are doing clinical trials involving high dose testosterone 20 times since that study ended. The knowledge base is much broader now. I'm saying I disagree that BAT never increases survival based on those 20 conversations with doctors actively using high T with their patients mostly via clinical trials.
If that is old news, please post the update. I assume there is nothing to post, or I would have seen it. And I'm sure you would have shared it, as I've asked you several times. The study I posted here was published this week and cites no evidence that shows a survival increase. If there is nothing peer-reviewed or even presented to peers at a major conference, it is not science, just someone's hope.
I'll let you have that last word. Most of us can get along just fine navigating the cancer maze of smoke and mirrors without having to consult a published study. In the real world of doctor appointments and prescriptions they don't change how we live our lives. We all die when we die. Who really cares if you live a few months longer on one treatment vs another as long as you have no regrets, have the best QOL you can have, enjoy the company of your loved ones and feel you've made a difference to others while you are here on Earth.
Fortunately, everyone can make the decisions about quality and quantity of life for himself. One can only make a decision based on available data.
Most of us rely on the institutions of science to provide us with the options for "navigating the cancer maze" rather than "smoke and mirrors."
Exactly. Don't forget the cost of BAT is a fraction of the cost of SOC in addition to all of the reasons you mention even if "it doesn't extend life" (which I don't believe is true in many cases), 100% of men feel better on BAT. Who wouldn't choose a treatment that makes you feel better and is reversible if it doesn't work?
We are huge proponents of BAT too
Husband had 10 cycles of BAT and felt incredible. The High T resensitized Xtandi so he was able to benefit from it again for 8 months. He then went back on BAT for 3 more months and is now rechallenging Zytiga. Next step (most likely) will be to try Darolutamide and hopefully get enough benefit to buy time so he can start Pluvicto without doing chemo.
We have been told there will be more studies with topical T (vs. injected) which will include men with painful bone mets. As I understand it, using T daily as a gel will allow MOs to better control pain flares until the testosterone works (and stop it faster if it doesn't work).
It appears you haven't read the study. Here are some quotes:
"We have previously described that BAT can produce clinical benefit and tumor regression for 20-30% of patients with CRPC, however predictors and mechanisms of response and resistance have been ill-defined...Clinically we have observed that most patients with CRPC who initially respond to BAT acquire secondary resistance after approximately 6-12 months of therapy... This is consistent with the measured PSA50 response rate to BAT of 24.3% among 173 patients with mCRPC across two clinical trials "
In fact, I keep my BAT file updated with every importan t study on the subject, and have since 2015. I doubt I have anything to learn from your cursory study, but if I do, please point it out:
Certainly. PSA is a first screener. If PSA increases markedly (PSA50) it is used as evidence that the therapy should be pursued in a more rigorous trial. Similarly, if PSA doubles (the way it has in BAT trials), it's an indicator that something bad is going on. When signals are mixed, the way it usually is in BAT trials, it's a signal that some biological patient characteristics may be driving outcomes.
Whichever way such a Phase 2 trial comes out, it's an indicator of whether or not a Phase 3 trial (using RECIST criteria) is appropriate. Most Phase 2 trials fail at Phase 3.
PSA is used as a screening device for further trials. It is appropriate for scientific researchers, not for patients. Because Google makes the results available to anyone, many patients, not understanding how research works, treat themselves based on erroneous understanding. The results can be tragic.
Clinical trials have to follow certain ethical standards, including informed consent. If an MO has an experimental therapy, it is unethical to test it on a patient without review by an independent review board. Here are the Helsinki protocols that all civilized nations have agreed to:
It means that dangerous, and possibly life threatening experiments cannot be practiced on a patient without written and informed consent. You may have heard of the Tuskeegee Study. If not, look it up.
It means that is if an MO practices any experimental protocol on a patient without IRB approval and written informed consent, he can lose his license and may face criminal charges. It also protects the MO from patients who may decide to sue down the road if things go awry.
I said that as plainly as possible:"It means that dangerous, and possibly life threatening experiments cannot be practiced on a patient without written and informed consent."
How do you get from a statement as clear as that to " So nothing to do with the desire for life or inferiority/superiority."?
I guess you don’t understand or won’t admit that a man may jeopardize his survival by undertaking an experimental treatment. Kudos to all those like our dear departed Javelin who heroically take that risk on behalf of all of us. Sadly some risk their lives blindly in a way that cannot benefit anyone else.
I warned Javelin that it is better to wait until his clinical trial advance to stage 3 rather than jump into a stage 1 clinical trial.
I advised him to extend his life with other proven treatments untill his potentially curative clinical trial gets to stage 3.
He replied that CAR-T is curative and ignored my warning. (Probably nobody properly explained him the risks involved taking part in a phase I clinical trial.)
I believe that it is a good tactics to extend your life as long as possible with proven treatments untill the cure will be available.
My intelligent ex wife said to me that my goal is to survive as long as possible until they find a cure.
Taking part in phase I clinical trials is not in that mindset for me.
Maybe I am too individualistic but I refuse to believe that they will not find a cure in my lifetime.
I am especially concerned with low volume cancer people who for years totally ignore that they are curable.
I always advise them to get a consult with Dana Farber or with any other center of excellence and ask them if their cancer is curable.
It seems that they ( Denmeade ++) now know the preconditions for a sucsessful implementation of BAT, that is AR Copy Number gain - amplification ref.: jci.org/articles/view/162396
If a test shows high AR activity the probability of a positive response is high, low or no AR indicate trying other options.
From the study I understand that high AR activity is measured/defined as a high ARAMW score . "Together, our results suggest that an ARAMW score greater than 0.6 is required for clinical benefit from BAT, and this gene expression score could function as a biomarker for patient selection if validated. A limitation to use of this biomarker is that it requires fresh tumor tissue, which can be difficult to obtain in some patients".
Not that easy to obtain in HSPCa, I believe. Or could there be a less refined but more practical way to define high AR activity?
They created the measurement for the clinical trial. It is based on IHC using stains for specific markers of AR activity. It is not available outside of Johns Hopkins, as far as I know.
It is another good reason to only do BAT on a clinical trial.
BAT is only tried for asymptomatic mCRPC. There are now a large array of medicines for mHSPC, so BAT is irrelevant for that.
Do you agree that some form of BAT is likely to be beneficial for those with BRCA2+? There are studies indicating good response on those who are DNA repair-deficient, like the one below.
------------------------
DOI: 10.1200/JCO.2021.39.6_suppl.127 Journal of Clinical Oncology - published online before print March 2, 2021
Molecular and clinical characterization of metastatic castration-resistant prostate cancer (mCRPC) patients achieving deep PSA responses to bipolar androgen therapy (BAT).
Mark Christopher Markowski, Sushant Kachhap, Angelo M De Marzo, Samuel R. Denmeade, Emmanuel S. AntonarakisShow More
Abstract Disclosures
• Abstract
127
Background: BAT is an emerging treatment strategy for men with mCRPC, whereby testosterone concentrations are cycled from supraphysiologic to castrate levels each month. BAT has been shown to be safe, and induces clinical responses in a proportion of patients, some of which are extreme.
.....
. Results: Next-generation somatic DNA sequencing was obtained on 15/22 (68%) pts. Of these 15 pts with sequencing data who achieved a >70% PSA response on BAT, 14/15 (93%) harbored a pathogenic mutation in TP53 and/or a homologous recombination DNA repair (HRD) gene.
------------
. Conclusions: We observed an enrichment of TP53 and/or HRD mutations in mCRPC pts with extreme PSA responses to BAT, with durability lasting about a year These data support the hypothesis that BAT may work best in DNA repair-deficient mCRPC pts.
mCRPC patients achieving >70% PSA reductions with BAT.
"whereby testosterone concentrations are cycled from supraphysiologic to castrate levels each month"
If I were you I would check and double check if the study is designed to actually achieve castrate levels each month. (I am not a doctor or even a pharmacist. So I can't check it myself.)
The other concern for me is if it is the best to cycle monthly.
As you can see i have concerns. Until more people are convinced to the BAT studies we don't really know.
If i were you I would wait with clinical trials until you run out of standard of care options.
Everyone should decide himself.
I just don't want to experiment with myself at this point of time.
• Median progression-free survival was 14.8 months if they were mutation-free vs. 7.5 months if they had the defects.
• PSA50 responses were seen in 7 of 15 (47%) patients with (44% if 2 who dropped out for progression are added) and 7 of 15 (47%) patients without an HRR mutation. (so having an HRR mutation makes no difference).
• 3 of 6 90+% progressors had DNA damage repair defects
Thank you, this is a very comprehensive review you have done.
The study I referred to pointed in the direction of BAT being more favorable for those with DNA-repair deficiency, with 14 out of 15 patients with >70% PSA reductions harboring such defects, see below. Would your response be that this is lower-level evidence than the phase 2 trial that you pointed to, and should be ignored?
"We identified N= 22/114 (19%) mCRPC pts who achieved >70% PSA reductions on treatment with BAT.
. Results: Next-generation somatic DNA sequencing was obtained on 15/22 (68%) pts. Of these 15 pts with sequencing data who achieved a >70% PSA response on BAT, 14/15 (93%) harbored a pathogenic mutation in TP53 and/or a homologous recombination DNA repair (HRD) gene.
Conclusions: We observed an enrichment of TP53 and/or HRD mutations in mCRPC pts with extreme PSA responses to BAT, with durability lasting about a year These data support the hypothesis that BAT may work best in DNA repair-deficient mCRPC pts".
That only speaks to the 15 of the 22 (19%) patients who responded to BAT. It doesn't include the other 81% of patients who were non-responders. Among the few responders, 41% had a BRCA or ATM mutation. What percent of the non-responders did? Based on that study, one cannot conclude that those with BRCA+ were better responders.
Thanks. One of the inclusion criteria is: Ongoing gonadal androgen deprivation therapy with gonadotropin-releasing hormone (GnRH) analogues, antagonists or orchiectomy. Patients who have not had an orchiectomy must be maintained on effective GnRH analogue/antagonist therapy
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T Therapy in men with APC
Testosterone therapy to... LOWER testosterone production?
