Denmeade states that "BAT should not be combined with Zytiga, Xtandi, Erleada, or Nubeqa (or with taxane chemotherapy)."
Does anyone know why? I would have thought that Zytiga would be good to use during the low T phase of BAT.
Denmeade states that "BAT should not be combined with Zytiga, Xtandi, Erleada, or Nubeqa (or with taxane chemotherapy)."
Does anyone know why? I would have thought that Zytiga would be good to use during the low T phase of BAT.
It could be that you have to turn the testosterone on and off abruptly, and these agents aren't so good at that?
I use T propionate for the first week of high T, then Androgel after that (split dose since half-lfie is 23 hours and you get massive peaks and valleys if you only dose once a day). Then when I stop I use Casodex for a week to block the ARs and get closer to a square wave for T.
Casodex has 5 day half-life. If you take 150 mg on the day before you go low T, 150 mg on the day you start low T, and then reduce to 50 mg/day you get a pretty good steady state concentration.
My guess would be that since they block the androgen receptors at the cellular level the high testosterone phase remains pointless.
I use casodex but only during the first week after high T for exactly this reason.
Zytiga is a cyp17 inhibitor. I use it only during the low T phase but I'm not sure why it couldn't be used continuously.
I completely agree about the lutamides. Blocking the ARs while trying to do high T would make the whole thing rather useless for PCa control.
I agree that it would be pointless to use BAT with a "lutamide" (which inhibits T binding to AR. Also, I can't think why anyone would want to combine BAT with a taxane.
But Abiraterone? ADT is considered to be an intrinsic part of BAT. Abi is ADT+. In fact, Abi could be used without classic ADT. So why not? Because that combo has not been tested?
Here is the full list of "pearls":
"5 BAT CLINICAL PEARLS
−BAT is given as an intramuscular injection of testosterone cypionate every 28 days.
−BAT should only be given to patients with castrate-resistant (NOT hormone-sensitive) prostate cancer.
−BAT should NOT be given to prostate cancer patients with cancer-related bone pain.
−BAT should not be given to patients with urinary obstruction due to enlarged prostate or prostate cancer.
−BAT should be given together with ongoing ADT or surgical castration.
−BAT may be continued despite PSA elevation, if there is clinical benefit and stable scans showing no progression.
−BAT should not be combined with Zytiga, Xtandi, Erleada, or Nubeqa (or with taxane chemotherapy).
−BAT may render CRPC patients sensitive to Zytiga or Xtandi after ADT or after prior progression on these drugs
−BAT should preferentially be administered in the context of a clinical trial, especially when being used in conjunction with other experimental therapies."
I disagree with that strict 28 days - I am on a 2-3 month cycle.
I disagree with the CRPC restriction. I am not yet CRPC & am using BAT to prevent CRPC.
I disagree with the idea that PSA elevation is OK. For many, PSA elevation can be countered by modifying the 28 day rule. That should be tried first. If PSA does not fall, by all means try BAT continuation - but how often does PSA rise & scans remain stable?
Looks like the "pearls" are CYA rules related to lack of studies. IMO
But Standard BAT uses a continuous ADT like Lupron while injecting 400 mgs every 28 days.I think you nixed this one. Synthetic Estrogens have never been discussed either, by those who do the trials-->like Denmeade.
I agree---a 2-3 month cycle of T without ADT followed by a month off using a lutimide to protect against the remaining cancer cells from the onslaught of the High T and DNA pieces of destroyed cancer cells. Or your situational use is not using an ADT while on High T. This whole BAT/BAT+ category is starting to get confusing. I am now having trouble outlining my plan if I needed to use T Injections. At this point thank God I do not have to make that decision.
BAT+. I'm going to steal that if you don't mind. Sounds better than mBAT or aBAT.
BAT+ is certainly complicated. When you're on the high T phase and helping yourself to nandrolone it's fun, to say the least. On the low T phase it's dreary.
"Looks like the "pearls" are CYA rules related to lack of studies. IMO" is my opinion also.
And I do a 2-3 month cycle that is driven by PSA.
I'm also hormone-sensitive and think that BAT might put off hormone resistance.
Hi Russ, how did you convince your MO to approve BAT while you are still hormone sensitive?
Have you ever measured your PSA on the high T phase of BAT? Mine goes close to 1 ng/ml at the end of the high T phase and then drops below 0.1 on the low T phase.
I know from the years I was doing 3 months T alternating with 3 months castrate that my PSA bounces back fast.
T-cyp lingers in my thigh muscle so PSA might continue to rise for what - 2-3 weeks? If I knew when it maxes I would test, out of curiosity.
I'm testing PSA once a week during this cycle just to get an idea of its movement.
The curve will change as time goes on so I'm not sure how actionable this exercise is. I guess the functionality is that it takes my mind off the blahs of low T - SARMs help but don't give me the same feeling.
Exactly, Patrick. Completely agree. Denmeade et all would not even have achieved any time at castrate testosterone with 28 day T-cypionate 400mg cycling. And ADT would make absolutely no difference until the exogenous was cleared. Takes longer than 28 days with t1/2 of 8 days. I proved that for myself, as RSH1 and you have found also. BAT as published was not actually BAT it appears.
In an interview Denmeade said that he'd like to use a gel. Cyp takes too long to clear. I'm not certain why he didn't choose propionate. It's not nearly as good as Androgel but much better than cyp.
Maybe cost and some guys find propionate injections painful.
The way it is now BAT is high T, moderately low T.
The goal of BAT was to restore sensitivity to the Zytiga or Xtandi by alternating high and low T. The T acts on the androgen receptor to restore it. You want the ARs to be intact, not blocked. In the RESTORE trial, patients failed one, cycled through BAT, then were given it again. It only seemed to work for Xtandi (not Zytiga). Similarly, the TRANSFORMER trial found that BAT prolonged Xtandi response but not so much Zytiga response. Even though it prolonged the response to Xtandi, it has not shown it can prolong life. Still, the ADT vacation is very nice.
Zytiga doesn't block the ARs. I understand why you don't want to use a lutamide and I understand why Zytiga might be wasted (and possibly even counterproductive) during the high T phase. I'm wondering why the bold statement was made. Perhaps it's just the fact that it hasn't been tested.
As you state, even if it doesn't prolong life, if you can get off of ADT for half the time, that changes your life.
It was found to have little or no effect on Zytiga sensitivity, only on Xtandi sensitivity (not "lutamides"). Zytiga interferes with tumor androgen synthesis, so its use would be counterproductive. Xtandi blocks the AR.
My MO and I think that the purpose of the low T phase of BAT is to simulate ADT. I discussed Zytiga with her and she didn't raise any concerns with the use of Zytiga on the low T phase of BAT.
I'm hoping that BAT allows me to use lutamides repeatedly. I'm not expecting much in the way of Zytiga resensitization.
Why do you want tumor androgen synthesis on the low T phase of BAT?
You and your MO seem to misunderstand BAT. It doesn't "simulate" ADT - patients stay on ADT throughout. That's what gives the bipolar effect as the injection of testosterone wears off. Zytiga cripples the AR because it inhibits intratumoral androgen synthesis. The goal is to alternate heavy androgen with castrate level.
I have no idea what you mean by "lutamides" - it is only used with enzalutamide - not bicalutamide or any other.
Correct. I stay on ADT. But I add large exogenous doses of androgens (T) during one phase of BAT. Essentially nullifying the androgen deprivation (unless you are specifically referring to endogenous vs. exogenous).
"lutamides" block the androgen receptors. Bicalutamide is one of the lutamides.
My question is not about whether or not Zytiga is or is not helpful on the high T phase of BAT. I am also not concerned with lutamides and whether or not they can be used to block androgen receptors. Casodex is not irreversible.
How does Zytiga cripple the androgen receptors? I thought that it was designed to inhibit CYP17. Thus, adrenal, testes, and intratumoral androgen synthesis but no effect on the exogenous testosterone activation of the ARs.
Do we know if Zytiga irreversibly prevents intratumoral androgen synthesis? How long is this "irreversibility?"
You misunderstand anti-androgens. They range from wimpy in effect to very powerful. No reason to group them. 'Lutamides" is a useless term.
I didn't say irreversible. But you can't stay on it when you are trying to use testosterone to drive the AR. You are simultaneously stimulating it and crippling it.
Maybe you shouldn't be trying to reinvent the wheel. More knowledgeable people than you have designed the protocol.
Lol! You can list them out if you want. I will continue calling them lutamides and assume that anyone who is interested will not assume that they are all identical in strength, dose, half-life, efficacy, binding affinity, time of action, biological activity, clearance time, etc.
I know that you did not say irreversible - I said it and was asking a question as a follow-up to your talking about a CYP17 inhibitor damaging the androgen receptors. I had never heard that before. You don't know the answer. That's fine.
I said many many many times that I DO NOT TAKE ZYTIGA ON THE HIGH T CYCLE. I do not know why anyone would.
Interesting. I found a lot of research stating that Zytiga is indeed an irreversible CYP17 inhibitor. One paper even concluded that it might act on the ARs. I think that they meant that in a roundabout way. I don't see the biology behind a direct action but will ask my MO.
Now I need to find out what irreversible really means. As you probably know, irreversible doesn't mean forever - limited by cellular structure turnover at a minimum and usually more limited than that. A very misleading term.
Until I can figure out the possible time I'm going to drop it from BAT+ for now.
They never actually achieved castrate levels on a 28 day cycle of T-cyp. It goes to over 1,000 ng/dL and has an ~8 day half life. Why did they not measure and publish testosterone levels at weeks 3 and 4? ADT will do nothing until the exogenous is cleared. I have checked this in myself, as some others here have also found.
Does Erleada block the AR?
Yes. It's a powerful AR inhibitor.
Apalutamide. In general, the drugs ending in "lutamide" are AR inhibitors or blocks.
(good site that my MO referred me to years ago)
Yes, very strongly. That's why it is foolish to group mild AR blockers like nilutamide or bicalutamide together with 2nd generation AR blockers like apalutamide. I don't know why some people on this site make such an ignorant mistake.
This is why my MO put me on Apalutamide with Lupron, incase I become castration resistant, starting a month ago. My RO, who was both RO/MO, until he hired an assistant, thinks I may be already resistant considering how I went from a single lesion (psa 0 .4) to multiple lesions (7.3) in just 3 months. Going in for blood work next week.
Thanks for this description
Sure. If you decided to do BAT it certainly requires some thought and isn't something to go into lightly. But, that same statement applies to pretty much every PCa treatment (maybe cleaning up a diet or exercising are the only no-brainers).
I wrote a free book and it is at: drive.google.com/drive/fold...
The first 13 BAT references give a pretty good overview of where we are now.
Def keeping BAT in my back pocket, so far MO knows little and advises against, but I know when the time comes I'm going to include it in my arsenal with or without my current MO (Fortunately I'm currently Lupron/Xtandi) BTW your book looks awesome, especially the pages on diet and other substances that may help keep the beast at bay. Thanks so much for the link !!! Regards, Matt
Sartor at Tulane studies BAT. The "official" use is for hormone resistant guys. If you look at the BATMAN study it appears that it might work for us hormone sensitive men too. And pjosh has been on it for a long time and is still hormone sensitive. If somehow our cancer was a digital beast and upregulated/mutated the ARs in a 0-100 type fashion the hormone resistant restriction might make sense. But it isn't digital.
I fashioned my own program, started it, labwork showed that PSA went from 0.17 to undetectable. I showed my MO the data and she's 100% on board with it. Show me the money!
My thought on diet and supplements: they can help setup good health so that we are better able to withstand the therapies we need to go through. And some of them might help reduce PCa progression.
Exercise is the big one. None of my doctors has ever mentioned exercise but if you look at clinical trials, government recommendations, biological mechanisms, studies, and research you find that it is critical.
Please read some of the studies and articles and decide what the goals of BAT are. I think that TA was talking about one of the nicer outcomes of BAT. That outcome is being pursued with RCTs but was not the only intent for BAT.
1. Bipolar androgen therapy (BAT): A patient's guide - Denmeade - - The Prostate - Wiley Online Library
2. How BAT Works and possible BAT/Xtandi repeats: How Bipolar Androgen Therapy Works | Prostate Cancer Foundation
3. Overview of studies as of 2022: PCa Commentary | Volume 161 | Bipolar Androgen Therapy (BAT)
4. Rapid Hormonal Cycling as Treatment for Patients with Prostate Cancer: The Men’s Cycle - Study Results - ClinicalTrials.gov
5. STEP-UP RCT. BAT, Enzalutamide, BAT, Enzalutamide, repeat... Sequential Testosterone and Enzalutamide Prevents Unfavorable Progression - Full Text View - ClinicalTrials.gov
6. RE-sensitizing With Supraphysiologic Testosterone to Overcome REsistance (The RESTORE Study) - Full Text View - ClinicalTrials.gov
7. RESTORE commentary: A Multicohort Open-label Phase II Trial of Bipolar Androgen Therapy in Men with Metastatic Castration-resistant Prostate Cancer (RESTORE): A Comparison of Post-abiraterone Versus Post-enzalutamide Cohorts - PubMed
8. Bipolar Androgen Therapy + Carboplatin in mCRPC - Full Text View - ClinicalTrials.gov
9. TRANSFORMER: Testosterone Revival Abolishes Negative Symptoms, Fosters Objective Response and Modulates Enzalutamide Resistance - Full Text View - ClinicalTrials.gov
10. TRANSFORMER commentary: A Randomized Phase II Study Comparing Bipolar Androgen Therapy Versus Enzalutamide in Asymptomatic Men with Castration-Resistant Metastatic Prostate Cancer – PubMed
11. Bipolar Androgen Therapy for Men with Androgen Ablation Naïve Prostate Cancer: Results from the Phase II BATMAN Study – PubMed
12. BAT might promote ADT resensitization: Effect of bipolar androgen therapy for asymptomatic men with castration-resistant prostate cancer: Results from a pilot clinical study - PMC
13. Bipolar androgen therapy: Progress and future directions | oncology.medicinematters.com
I wonder if starting and stopping the accompanied Prednisone is a good thing or not.
For the androgen blockers I think the problem is the time to effectively remove all traces of them. If you are trying to stress cells with an androgen the last thing you want is a systemic blocker of what you are trying to introduce. As regards docetaxel, I don't know but have a vague recollection of some small trial doing BAT with chemo. I think it was inconclusive.
Zytiga is an irreversible CYP17 inhibitor. I wasn't able to trace down what "irreversible" means in this case. The author of a recent study had the same question about the "irreversibility" of Zytiga and even used the same terminology. Zytiga has nothing to do with the ARs and does not "cripple" them in any way. I suspect that Denmeade was doing a CYA but, until we know how long this is (I suspect it varies), I think Zytiga is contraindicated.
Casodex is not irreversible. If you take 150 mg for two days 98.5% of it clears within 4 weeks. But Androgel (half-life 23 hours) clears so rapidly that I don't think a lutamide is needed outside of special cases (say if you want a really quick pulse of T).
I found this: "Pre-clinical data suggest that docetaxel and enzalutamide interfere with androgen receptor translocation and signalling (sic). The aim of this study is to assess the efficacy of their concurrent administration in the first-line treatment for metastatic castration-resistant prostate cancer (mCRPC)." practiceupdate.com/content/...
I think you may find these interesting, some of these articles are too complicated for me...
"However, the mechanism of CYP17A1 inhibition by abiraterone has not been fully characterized. Firstly, X-ray crystal structures and spectral ligand binding assays reported coordination of the C17 pyridine of abiraterone with CYP17A1 heme iron, indicating a potent but reversible type II interaction (DeVore and Scott, 2012). Garrido et al. (2014) postulated that abiraterone is a slowly reversible CYP17A1 inhibitor and demonstrated its tight-binding effect with jump dilution experiments. Furthermore, abiraterone was suggested to be a slow-binding inhibitor with enhanced inhibition upon preincubation with CYP17A1 (Jarman et al., 1998). Collectively, the apparent complexities in the inhibition kinetics of CYP17A1 by abiraterone allude to a potential slow-, tight-binding phenomenon (Fig. 1B). Consequently, both inhibitory potency (thermodynamic selectivity) and target occupancy (kinetic selectivity) by abiraterone against CYP17A1 must be explicitly considered when defining its in vivo drug activity."
"In conclusion, this study provides compelling evidence that abiraterone is a slow-, tight-binding inhibitor of steroidogenic CYP17A1. Our in vitro enzyme kinetic analyses provided quantitative description of pertinent kinetic parameters characterizing the two-step binding that are entirely consistent with the results of MD simulations. Cellular washout experiments provided further corroborative evidence for the protracted residence time of abiraterone on CYP17A1. In addition, MD simulations offered insights into the fast, reversible step preceding tight-binding that was not apparent from either X-ray crystallography or molecular docking simulations. The long dissociation t1/2 of both abiraterone and D4A reflects protracted residence time on CYP17A1, which in turn creates the awareness that the incorporation of residence time along with PK parameters is imperative in the mechanistic PK-PD modeling of abiraterone to optimize mCRPC pharmacotherapy."
"Recently, it has been demonstrated in mice and patients with PCa that abiraterone was converted into a more active metabolite Δ4-abiraterone (D4A), which blocks enzymes required for androgen synthesis including CYP17A1, 3βHSD, and SRD5A. As for abiraterone, D4A also inhibits AR with potency comparable to enzalutamide.86 The metabolite D4A has more potent antitumor activity against xenograft tumors than the parent drug abiraterone itself, and thus, direct D4A treatment may offer greater clinical and survival benefits.86"
fwiw, i've been on casodex, tamsulosin and finasteride for about 4 yrs, with a T level steady around 500 and undetectable PSA. My GL was 4+3, targeted in-bore by Siemens 3TmpMRI and xray so that only the lesion was sampled. My uro-onc and hemato-onc are drooling to get me radiation roasted but they can both take long walks off short piers.
Rarely do I miss doses but when I have, just one day off the cocktail brings back my libido + erection ability... which would indicate to me ADT is reversible as far as this aspect of tx is concerned. I'm 75 and live alone, so not waking up dead is a bit more important than sex. 🤪
Much like Matt the Fiddler (related to Mott the Hoople?), my MO also was not familiar with BAT when I informed him about it about 3 1/2 yrs ago. He said he would look into it, then never did; maybe it hadn't caught on back then?
The fact that my T is always around 500 but the ARs in my gland can't use it due to the bicalutamide's "mild, old generation" activity kind of dissuades me from trying other lutamides that may or may not work as well, or work TOO well and screw up the good thing I got going for me now. I always go with my gut instincts, no matter what. Also got at least one angel by my side and she agrees with me.
An incredibly adorable angel! You must be extremely proud.
The libido thing is also what I have experienced. A day or two off of Caso and boom. Thanks for the input.
Keep on doing what is working. My MO is a big proponent of limiting side effects and riding the horse that works for as long as you can. I wouldn't mess with BAT since what you are doing is working. I suspect that if you asked your MO now he will have at least heard of it. Most doctors are 10-30 years behind the times (I used to work for a medical company and can vouch for this) so chances are he'd be against anything new. They are slow to adopt new things and there are some good reasons for that, but also some really lame ones.
May you live a long time so that you can see your angel!
The way I understand it is that BAT is all about targeting cells that have covered themselves with testosterone receptors so even though you have negligible amounts in your blood, these ‘super-sensitive cancer cells’ can pick up enough to start wreaking havoc again. If any of the cells in your cancer learn to do this, being on ADT (or any drug that works by reducing testosterone) is not going to stop them so your PSA starts to go up as these evolved cells multiply. The theory behind BAT, is that you suddenly bombard the system with an overload of testosterone. The newly sensitive cells are overwhelmed and die, leaving only the original cancer cells, so ADT will then work again (since it is only the super-sensitive cells that had worked out a way to cope without normal levels of testosterone). So BAT is for people who have become resistant to hormone therapy and is only a short treatment. Zytiga, as I understand it, is a drug that metaphorically masquerades as testosterone (but isn’t, so the cancer can’t use it) so the body thinks there is plenty of testosterone in the system and doesn’t need to reallocate the job of making it to another gland. So Zytiga is taken with ADT to keep the real testosterone levels down to a negligible level.
Most applications for BAT are indeed meant to target cells with upregulated or mutated ARs. But the premise seems like a digital one (I was a medical engineer so loved the simplicity of the digital world but also had to deal with the messiness of the analog world). In this case, I think we are stuck with the messy analog world. If this is true the cells do not go from normal numbers of ARs to super ARs in a flash.
The BATMAN study was conducted on hormone-sensitive guys. BAT+ has worked for me for 9 months now. My PSA has gone from 0.17 to undetectable. PJosh has been using BAT for years and he is still hormone-sensitive. One of our theories is using BAT to stave off CRPC.
Zytiga is a CYP17 inhibitor. CYP17 is involved in testosterone synthesis in testes, adrenals, and cancer cells. Pretty cool! First, we had oral estrogen. Next were the GnRH agonists. The next step was the GnRH antagonists. And we have improved our capability of blocking the ARs and instead of only being able to block the 90% or so of T that is made in the testes we can stop it from the adrenals and cancer cells. We also have estrogen patches to work with. No longer a need for oral estrogens.
I think maybe you are referring to the lutamides as mock T. If we think of ARs as baseball gloves and T as baseballs, a lutamide is like a water balloon. The baseball player catches it but can't use it and isn't able to catch any real baseballs as long as the water balloon is in the glove.
Bipolar Androgen Therapy for Men with Androgen Ablation Naïve Prostate Cancer: Results from the Phase II BATMAN Study – PubMed
Dr Nat here in Perth for my Lu-PSMA-J591 treatments said he wants me to stay on high T phase throughout treatments. He said he wants the cancer cells to be “as active as possible” (Replication cycles and producing PSA and PSMA). Makes theoretical sense. Both for radiation and for chemotherapy cell division cycle is part of the mechanism to kill. And testosterone probably would help with dealing with chemo side effects. Have never heard it proposed before.
I started looking into it after reading one of your posts. It makes perfect sense to me. ADT weakens the AS cells. So why not high T to weaken AIS cells? And speed up the cell cycle. I read something from Denmeade about it.
You and I know that high T makes you strong. And you need strength to handle some of this crap.
That’s a good one Russ, and right on target. Thanks for finding that. What’s good for the castrate mice may be good for the ganders (us). Here’s to DSBs from SPT with a Lutetium chaser. Cheers!