I have hormone-sensitive PCa (HSPC) and want to switch from intermittent androgen deprivation therapy (IADT) and have a go at bipolar androgen therapy (BAT). I just met with a new (to me) MO here in Oklahoma with whom I discussed BAT. To my surprise, he expressed an interest in learning more about it and asked me to send him some studies and technical papers. He also wants to talk to an MO working in the USA who has experience administering individual BAT protocols. I'm considering sending him Dr. Denmeade's papers and trial results (Johns Hopkins), but I'm concerned about how my MO might react to his statements that BAT should be given only to castrate-resistant men. Any recommendations on papers and/or an MO he could speak with are greatly appreciated!
My new Oncologist needs learning curv... - Fight Prostate Ca...
My new Oncologist needs learning curve help!
BATMAN II: PSA provocation by bipolar androgen therapy may predict duration of response to first-line androgen deprivation: Updated results from the BATMAN study – PubMed
pubmed.ncbi.nlm.nih.gov/359...
a. Bipolar Androgen Therapy for Men with Androgen Ablation Naïve Prostate Cancer: Results from the Phase II BATMAN Study – PubMed
pubmed.ncbi.nlm.nih.gov/273...
b. Rationale for HSPC use. Androgen Receptor (AR) acquires an oncogene gain of function with regard to DNA replication licensing required for malignant cell proliferation and that during the subsequent progression during androgen ablation therapy to mCRPC: Rationale for bipolar androgen therapy (BAT) for metastatic prostate cancer
tandfonline.com/doi/full/10...
c. LNCaP starts as androgen sensitive (HSPC) but in an ADT environment “evolves” to CRPC forms: Establishment of the LNCaP Cell Line – The Dawn of an Era for Prostate Cancer Research | Cancer Research | American Association for Cancer Research aacrjournals.org/cancerres/...
d. ADT and SPA decreases growth of LNCaP and at least 5 days are required: Biphasic Effect of Androgens on Prostate Cancer Cells and Its Correlation With Androgen Receptor Coactivator Dopa Decarboxylase - Shao - 2007 - Journal of Andrology - Wiley Online Library
onlinelibrary.wiley.com/doi...
e. Includes discussion of BAT use on hormone sensitive PCa patients with the goal of reducing the probability of hormone resistance. A clinical trial of BAT for HSPC men was conducted. “BAT resulted in high rates of PSA suppression at the end of the study, with improvements in quality of life…it remains unclear if BAT would prove a viable treatment option in this clinical disease space…we have refocused our attention toward testing BAT in men with CRPC.”: Bipolar androgen therapy: Progress and future directions | oncology.medicinematters.com
oncology.medicinematters.coWhy m/prostate-cancer/androgen-deprivation-therapy/bipolar-androgen-therapy--progress-and-future-directions/15910622
f. LNCaP cells are widely used as a PCa model system. These cells have androgen receptors, are androgen sensitive, and express PSA. Cell growth is inhibited by SPA: Supraphysiological androgen levels induce cellular senescence in human prostate cancer cells through the Src-Akt pathway | Molecular Cancer | Full Text molecular-cancer.biomedcent...
g. DHT or R1881 (pure androgen often used as a DHT analog in research) applied to cells inhibits cloning in LNCaP and VCaP cells but not androgen insensitive Du145 cells. HSPC tumors are LNCaP phenotypes. Early CRPC has some LNCaP and some VCaP. As CRPC progresses, Du145 phenotypes become more dominant. This limits the effectiveness of the SPA phase. Transient exposure to androgens induces a remarkable self-sustained quiescent state in dispersed prostate cancer cells – PMC ncbi.nlm.nih.gov/pmc/articl...
h. Early upregulation of AR and steroidogenesis enzyme expression after 3 months of androgen-deprivation therapy | BMC Urology | Full Text
bmcurol.biomedcentral.com/a...
i. “Moreover, this cycled approach was hypothesized to target the heterogeneity and adaptability of prostate cancer cells present in metastases, some of which might be inhibited by high testosterone and others by low testosterone.”
The testosterone paradox of advanced prostate cancer: mechanistic insights and clinical implications - PMC
ncbi.nlm.nih.gov/pmc/articl...
j. Various BAT studies show radiographic response rate: HSPC 80%, CRPC 24.2%-50%
Also includes discussion of bromodomain/BET inhibitors, CBP/p300 inhibitors and dual inhibitors: ho0421IsaacsonVelho-1.pdf hematologyandoncology.net/f...
k. “PSA provocation by bipolar androgen therapy may predict duration of response to first-line androgen deprivation: Updated results from the BATMAN study
My MO is Sartor and it’s debatable who has more knowledge and experience with BAT, him or Denmeade. I don’t think he prescribes BAT unless someone is castrate resistant either. That said, I’d be hesitant to undergo BAT unless I was being monitored by someone who has experience with it. And I say that as someone who is pro-BAT, in fact now that I’m resistant it’s going to be my next line of therapy if SBRT becomes unable to keep my PSA in check like it is now. Sartor and I have already discussed this several times and he will coordinate with my local oncologist.
Ed
Sartor was not aware of BATMAN II. I sent him the study. Does he have the same opinion now about CRPC requirements?
Denmeade stated that he doesn't know if BAT would work for HSPC. He is going after CRPC approval because the bar to entry is lower.
My personal history is HSPC: I have used a modified BAT program for just over 2 years. Still HSPC with no mutations. TMB is now undetectable. However, I have two mets. Stable according to RECIST. Did BAT cause them, did it reduce the number I "would" have had, did it do nothing? I don't know.
Others have used modified BAT programs as long as me or longer (one guy over 14 years). I don't think that the conventional 1-month cypionate BAT is going to work for HSPC men. BATMAN II modified it to attain a true ADT condition during the cycles.
BATMAN II showed an 80% radiographic response rate in HSPC men.
Perhaps because you referred to it as BATMAN II instead of phase 2 BATMAN trial that he had never heard of it, because I don’t know of any trials the guy has never heard about, he’s normally all over them. I believe being castrate resistant is part of his criteria in order to administer BAT. He has many patients using it, other criteria are age, PSA, physical condition. He was one of the authors of the TRANSFORMER trial in which Denmeade was also a part of. So he is very well versed.
Ed
I was responding to a statement made my Sartor that there were no clinical trials that tested BAT on HSPC men.
I told him that there was. He professed ignorance and thanked me for bringing it to his attention. It didn't appear that the name was the reason for his statement.
Do you know if he has the same opinion now about CRPC requirements?
He's a smart guy but even a smart man can only cover so much ground. He has many interests. Not just BAT.
Funding is a problem for further HSPC BAT trials. The profit incentive for pharmaceutical companies is lower and, in some cases, negative.
PCaWarrior wrote -- " ... Funding is a problem for further HSPC BAT trials. The profit incentive for pharmaceutical companies is lower and, in some cases, negative. "
Been doing my own HSPC BAT since 2016 for my QUALITY of LIFE !!!
I started shortly after diagnosis. Not everyone is comfortable going outside of their MO. Trials might give more men an opportunity to do what we do.
I started not only for QoL but for quantity of life.
Thanks for the references. Do you have an MO helping with your BAT program? Would he or she be available to help my MO get up to speed?
I came up with the program and asked my MO to oversee my cancer progression. She seems happy with the progress and likes the program.
She wouldn't be able to help. I don't know of any MOs who do HSPC BAT. There are a few who are following guys who self-direct. Maybe Schweizer would help? Let me know if you find one.
Are you referring to Michael T. Schweizer at UW? If there aren't any MOs already doing HSPC BAT, it's going to be a tough sell for my MO to be the first and hard to find anyone willing write the necessary scripts outside of a trial. Or am I missing something?
Yes. Michael.
I know of 3 MOs doing HSPC BAT:
Mine - MO is following someone else's program.
One in Pennsylvania - MO is following someone else's program.
One in Norway - MO is following another person's program. The patient started CRPC but is now HSPC and is still following a modified BAT program.
I don't know how many others there are.
BATMAN II trial is publicly registered at clinicaltrials.gov. It was done on 29 HSPC men.
Even with BATMAN II it could be a hard sell depending on your MO. Most of the HSPC men who are doing BAT are doing it on their own with an MO overseeing their overall progress. It's early for most of them but so far, the results have been impressive.
I don’t know if it could be helpful for myself being on triplet therapy and metastatic, but it would be interesting to understand how much such study could cost. It is using already developed and approved products which are not even too expensive from what I understand. Could it be self funded by people on here? Maybe with some fund raising or crowdfunding?
Two prong approach:
1. A series of case studies. That avenue is being pursued. Putting out requests should help.
2. Clinical trials. Good clinical trials require huge sums. Funding from prostate organizations would be helpful. That route is being looked into. But there will likely be a shortfall even with help. Wrapping HSPC BAT up with pharmaceutical drugs is an option to get funding. That's a hard sell though since some of the drug use would be reduced. Getting a for-profit drug manufacturer to sponsor a trial that will cost them money...
Your suggestion is a good one.
BATMAN showed a particularly good response for HSPC men with mets. 80% radiographic response rate. Small trial though.
Maye it would be more "interesting" if used for mCRPC, just for the need of it?
could this be of any help?
youtu.be/2mvWaDaFeno?si=JIQ...
Russ was having internet issues. He sounded like a buffoon anyway... 
Honestly I don't know any of those guys, but it looked interesting! 
Antonarakis is saying that BAT is a "paradox". How can Testosterone that has been known for the last 60 years as a fuel for cancer, can do the exact opposite. Well, it doesn't take a university degree in mechanical engineering to know that too much fuel in any internal combustion engine will eventually drive it at a halt. No "paradox" Dr Antonarakis, only "ουκ εν τω πολλώ το ευ" that you should had known.
Well, I would not be so sure, your point would be completely valid if at the same time you stopped ADT, but they don't. To me it looks like it's the fluctuation between upper and lower limit that does not allow for a mutation to take over the "standard" cancer. It's more like keeping one foot on the clutch pedal (ADT) and giving gas to your car till the engine is super hot then pour ice cold water on it at the same time 😂😂
A short summary:
ADT doesn't drive testosterone levels. By itself it does nothing. You can completely override ADT if you introduce testosterone gel or injections.
Your testosterone = exogenous (e.g., injections) + endogenous (what your body makes)
ADT removes the endogenous part.
So now your testosterone = exogenous.
When we inject our testosterone goes high. When we stop injecting our testosterone decays to a low value.
Antonarakis says it is a paradox because the common belief is that testosterone "fuels the fire" of prostate cancer.
We have found that to be false. Testosterone fuels some cancer cells but some cells do not need the testosterone.
Antonarakis is aware of this and has been the head researcher on various studies that identify cell types and responses to various androgens and anti-androgens.
It's an extremely cool concept. Ten years ago the BATMAN trial showed an 80% radiographic response rate. The protocol was setup in a nice manner and a true ADT state was entered. It was done on HSPC men.
Since that time, we have swung off to CRPC for political and financial reasons. The protocol has been changed to address CRPC therapeutic needs and to allow for resensitization. The first CRPC clinicals showed about a 30% brute force BAT monotherapy response. Tremendous sequential therapy benefits were discovered and are now being explored.
The next slew of clinical trials are either exploring resensitization or combining BAT with other therapies. Some trials are taking a shot at sequential therapies.
In some of the combination trials we are seeing a 40%-60% response rate.
In some of the sequential therapy trials we are seeing 70%+. This is far better than anything we have today.
The trials are small but numerous. Larger trials are in process.
The hope is that PCa will have negligible impact on QoL or quantity of life. For some of us QoL will improve vs. pre-PCa and so will quantity of life.
Antonarakis is a very smart guy and knows this.
He's using the word paradox because many doctors and most patients have bought into some of Huggins' research. Huggins knew that high androgens could contain PCa. He termed it hormonal interference. There were several issues and we were stuck with half the equation. The bad half. Most people have forgotten about the other side of the equation.
Denmeade terms it the "apparent paradox". He is brilliant and knows that we have a hard time learning from history. So he carefully crafts his message to keep people comfortable as he introduces a "new" concept that threatens their reality.
As evidence piles up, therapy will change. In time we will look back at our present PCa medical treatments the same way we look back at the medical tech 200 years ago. Barbaric.
So some cancer fuels on testosterone and the other? Prolactin?
Four cell types:
A. Rely on external DHT to live. ADT easily treats these.
B. Rely on DHT to live but have upregulated and/or mutated ARs so that they are more efficient at collecting DHT. These cells have functioning ARs and can be controlled with SPA.
C. Rely on DHT to live but can produce it internally if needed. These cells might be able to convert adrenal androgens into DHT (DHEA, DHEAS, androstenedione delta 4). The cells have functioning ARs and can be controlled with SPA.
D. Do not need DHT to live (androgen independent). These cells are exceedingly difficult to control and can morph into NEPC and small cell varieties.
These things are known.
What isn't known is all of the fuel sources for all of the cell types (we don't even know all of the cell types - there are over 200).
I admit that if I weren't risking my life, the subject would be quite fascinating.
I read a lot about old studies claiming that prolactin is the key when it starts being testosterone independent, I even asked dr Kwon at Mayo (never got an answer)
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