I was looking at BAT-related studies involving Dr. Schweizer. The first was as lead author for Denmeade (2015).
Most BAT research has been performed on men with CRPC [Castrate-Resistant Prostate Cancer]. The U.S. statistics for 2022 were 268,490 new cases, with 34,500 deaths. The deaths being largely among men with metastatic CRPC. Historically, there have been very few options remaining once resistance to castrate therapy occurs. It's appropriate that researchers should be drawn to the condition. Those men need options.
PCa deaths are running at less than 13% of cases. Most men with PCa will not progress to a metastatic state. But as Schweizer writes:
"Targeting androgen receptor (AR) axis signaling by disrupting androgen-AR interactions remains the primary treatment for metastatic prostate cancer. Unfortunately, all men develop resistance to primary castrating therapy and secondary androgen deprivation therapies (ADTs). Resistance develops in part because castration-resistant prostate cancer (CRPC) cells adaptively up-regulate AR levels through overexpression, amplification, and expression of ligand-independent variants in response to chronic exposure to a low-testosterone environment."
A man with mets will likely still start out on AR-axis therapy, and that treatment will fail. (Schweizer said it and that's what I was reading back in 2004. The occasional anecdotal case of a man on Lupron for over 20 years is irrelevant for treatment decision making, imo.)
I retired from an actuarial consulting company. I remember seeing remarkable gains in male life expectancy tables for clients. (Not a good thing when it comes to pension plan funding. lol) In 1948, my birth year, a man with PCa (it would likely have been caught late when symptomatic) might be grateful for an added couple of years. Huggins deserved his Nobel prize. But when I was diagnosed at age 56, I might otherwise have been looking at another 20 years or more of quality life. Castration therapy, with CRPC before 60, say, seemed singularly unattractive.
The years go by and Denmeade continues on with his CRPC-BAT research, but who is looking at BAT in terms of CRPC-prevention? I began using testosterone after my failed surgery and salvage radiation. I began with the intent to (a) delay ADT & (b) reverse adaptations to ADT when forced to begin ADT. I have metastatic PCa but it seems to be under control. I am coming up to 19 years since diagnosis. I am an anecdotal case & might otherwise be dismissed as an outlier, but I set out with the intent to manage the cancer with testosterone, so I feel that I have established proof of concept.
From the 2015 paper:"Although all men showed eventual PSA progression, four men {out of 10} remained on BAT for ≥1 year."
The bad news being that the BAT benefit isn't durable in the CRPC setting. The good news is that 40% gained at least a year. Recall that:
... from de Bono, NEJM, 2011 [2] "After a median follow-up of 12.8 months, overall survival was longer in the abiraterone acetate–prednisone group than in the placebo–prednisone group (14.8 months vs. 10.9 months ..."
... a gain of 3.9 months for Abi was considered to be a really big deal in the CRPC world. The FDA certainly thought so:
"Abiraterone acetate was approved by the United States Food and Drug Administration on 28 April 2011 for mCRPC. The FDA press release made reference to a phase III clinical trial in which abiraterone acetate use was associated with a median survival of 14.8 months versus 10.9 months with placebo; the study was stopped early because of the successful outcome." [3] The FDA acted before before most had a chance to read the NEJM paper.
The 2015 paper came out 4 years later & suggested that >12 months (three times as much as 3.9 months) might be achieved by 40% of CRPC men.
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CRPC studies can be very attractive. There is good accrual and short duration. (a very dark LOL)
A BAT study on men with metastatic PCa, with the aim of preventing CRPC should be at least 10 years, imo. And much longer than that to report on overall survival. Who would fund such a study?
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The 2015 study is notable for using Etoposide.
It is thought that Etoposide mostly works via DNA damage. Denmeade aims for supraphysiological testosterone [T], in the belief that a T of ~2,000 ng/dL may lead to DNA double strand breaks.
"An additional feature of this trial that sets it apart from past studies using systemic testosterone was the incorporation of etoposide during the first three cycles of therapy. Etoposide showed minimal activity against prostate cancer in a previous study and is not used routinely as a treatment for prostate cancer. However, as outlined in this report, etoposide may increase and/or stabilize testosterone-induced DSBs, thus providing the motivation to combine BAT and etoposide."
"the substantial toxicity associated with etoposide has tempered our enthusiasm for combining it with BAT"
Skip the Etoposide!
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"... although this is not the first study to test the effect of systemic testosterone in men with prostate cancer, it is designed to evaluate the effects of systemic testosterone administration according to a dose and schedule that produce rapid cycling from supraphysiologic to near-castrate serum testosterone levels over a 28-day cycle."
In the context of hormone-sensitive PCa, the purpose of a BAT-like protocol would be to extend the duration of ADT. BAT acts as a periodic reset for ADT sensitivity.
The 28-day cycle ends with "near-castrate serum testosterone". There is no ADT phase. Denmeade's BAT doesn't even require castrate T (below 20 ng/dL - or even old-style 50 ng/dL)..
A few of us use a much longer cycle. I aim for 3 months. To avoid confusion with the Denmeade model, I'll call it long-BAT.
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Quite rightly, Denmeade wants to avoid dealing with patients who experience pain after the restoration of testosterone.
But pain is a personal issue. If it can be endured or controled, the long-BAT protocol might be adjusted so that pain is eventually not part of the cycle.In addition, since testosterone cypionate does not clear quickly from muscle, it might be a good idea to start out with a daily application of T, for better control.
-Patrick
[1] ncbi.nlm.nih.gov/pmc/articl...
BAT therapy/muscle pain.
