Here's a treat - a review of BAT (Bipolar Androgen Therapy), actually written by Dr. Sam Denmeade [1].
In his intro, he makes a point of stressing that androgen receptor axis therapies are "highly effective palliative therapy, but they are not curative." A few years ago it was reported that an extraordinary percentage of men on ADT etc, hold the belief that there is a chance of a cure. I don't believe that magical thinking is helpful. Knowing that a therapy will fail is motivation to develop Plan B.
Denmeade introduces a much-needed new term: "complete androgen inhibition-resistant PCa". "However, the majority of PCas remain addicted to signaling through AR throughout the course of the disease." "Studies dating back nearly 30 years indicate that high expression of AR induced by prolonged castration becomes a vulnerability of CRPC cells in vitro and in mouse xenografts to supraphysiologic androgen (SPA), which induces cell death and growth arrest in this context."
Regarding BAT: "This rapid cycling is intended to disrupt the adaptive of AR regulation associated with chronic exposure to high or low levels of testosterone"
IMO, the disruption of adaptation is best started at the inception of AR-axis inhibition therapy, with the first testosterone boost occuring after 3 months, or so.
"Conclusions/Recommendations
"Our cumulative clinical experience over the past 10 years treating >250 CRPC patients establishes the meaningful clinical activity and safety of BAT and supports additional studies to determine its optimal clinical integration. Key findings from these clinical studies are that BAT (a) can be safely administered to asymptomatic patients with mCRPC; (b) does not produce symptomatic disease progression; (c) produces sustained PSA and objective responses in 30%-40% of patients; and (d) can re-sensitize and prolong response to subsequent antiandrogen therapy.34,36-40 While ADT for advanced PCa often produces debilitating sexual and metabolic side effects, another highly significant feature of this approach is that BAT can make men feel remarkably better by decreasing fatigue, increasing physical activity, and restoring libido and sexual function. BAT can also increase skeletal muscle tone and decrease visceral and subcutaneous fat.48 Thus, the incorporation of inexpensive, high-dose testosterone via BAT into the treatment paradigm for men with CRPC has the potential to improve quality of life (QoL) and minimize morbidity from the metabolic sequelae produced by androgen ablative therapies. Patients who are interested in more information on BAT can be referred to a recent review written for a lay audience.48
"Ongoing clinical trials are designed to assess the optimal way to sequence and combine BAT in PCa. Patients are encouraged to seek out and participate in such clinical trials when possible. For those without access to trials, there are 2 clinical settings in which BAT could be recommended based on the available clinical data. First, for asymptomatic patients who have initially progressed on ADT, BAT could be administered prior to starting an ARSI due to its marked ability to enhance subsequent response to these agents. Second, in men with CRPC progressing on abiraterone, BAT can be considered as part of sequential therapy with an antiandrogen based on results from the TRANSFORMER study. Importantly, BAT should always be given in conjunction with ongoing ADT. BAT is not to be used in patients with castration-sensitive disease outside of a clinical trial. BAT is also not currently recommended for use in patients with PCa bone pain as these patients are at risk for significant worsening of pain following testosterone injection. In those few patients who experienced pain flares in BAT clinical studies, we have observed that the flare usually occurs within 12-48 h post-testosterone injection. Pain can be treated with anti-inflammatory medications but may be severe enough to require narcotics. It typically resolves after ~1-week post-BAT, when the testosterone level begins to fall. For those patients who do develop a pain flare on the first dose of BAT that resolves by the end of a 28-day cycle, consideration can be given to continue BAT for a second cycle. We have observed pain improvement or resolution that did not return with subsequent cycles of BAT. For those patients who continue to have pain at the end of the first 28-day cycle, BAT should be discontinued."
Denmeade doesn't appear to be in a hurry to address the needs of men with castrate-sensitive PCa. I jumped the gun 18 years ago & remain castrate-sensitive. PCa is easier to manage if CRPC & complete androgen inhibition-resistant PCa can be avoided.
-Patrick
[1] Full Text: academic.oup.com/oncolo/adv...
