PCa Commentary | Volume 173 – January 2023

Posted by Edward Weber | January 2023


Bipolar Androgen Therapy (BAT) has been validated as an effective, but likely underused, option in the sequence of treatments for metastatic castration-resistant prostate cancer (mCRPC). 

What is BAT and Where Does It Fit In?

BAT is the monthly cyclic elevation of testosterone to supraphysiologic levels (1500-3000 ng/dL) by injections of testosterone while continuing ADT. The regimen leads to a durable PSA and objective response in 30-40% of patients (Peinette et. al. JCI, 12,2020). BAT was first described in the literature by Dr. Michael Schweizer (Sci Transi Med. 2015) and has been tested in numerous trials since. In the original report BAT was given over six cycles to asymptomatic patients with low to moderate burden mCRPC. The PSA50 response rate was 28%. (PSA50 indicates a PSA drop of >50% below baseline.) 

In two later trials the PSA50 with BAT was ~24.3%. Dr. Schweizer’s research substantiated that prostate cancer adapts to low testosterone levels by upregulating the AR. In the setting of elevated AR levels BAT therapy resensitizes the AR to inhibiting agents such as Xtandi to which resistance developed in prior exposure. The androgen receptor (AR) is the key cellular molecule that orchestrates PSA response and cancer growth and is inhibited by diminished testosterone.

This essentially is the basis of BAT’s effectiveness.

The PCa Commentary presented a BAT update in Vol.161, January 2022.   https://www.prostatecancerfree.org/pca-commentary-161 

[control+click link to follow or visit https://www.prostatecancerfree.org/pca-commentary]

Dr. Denmeade, a prominent researcher along with other colleagues from Johns Hopkins published the very informative “Bipolar androgen therapy (BAT): A Patient’s Guide” Prostate, May 15, 2022 https://pubmed.ncbi.nlm.nih.gov/35357024/ [control+click link to follow]

The Paradox:

Lowering serum testosterone (T) to the desired 20 to 30 ng/mL with Lupron or related agents is standard anti-prostate cancer therapy. A suppressed T inhibits a cell’s androgen receptor (AR) signaling, which in turn lowers PSA and suppresses prostate cancer growth. It is counter intuitive – and a paradox, that supraphysiologic T levels are toxic to the AR when AR levels are high — the setting in which the BAT is effective. The key point to understand about BAT therapy is that BAT suppresses the AR when abnormally high. During Xtandi therapy (and to a lesser extent with Zytiga) AR levels become elevated. This is the basis of monthly cycling between supra- physiologic androgen levels and low testosterone as fully discussed in “A Patient’s Guide,” and suggests a new regimen of therapy.

The TRANSFORMER TRIAL (NCT02286921) Demonstrating that  BAT Sensitizes the AR to Xtandi

This trial enlisted asymptomatic men with mCRPC progressing on Zytiga and then randomizing the men to next receive either BAT or Xtandi, both continued to progression. Those men receiving Xtandi had a PSA50 response of 25%, a response duration of 4 months and an overall survival of 29 months. “For those patients who received BAT first [after progressing on Zytiga] then received Xtandi, the PSA50 response was almost 80% with a time to PSA progression of about 11 months” … and an overall survival of 33 months. (Denmeade, ibid) 

This finding might suggest a potential sequencing scheme: Treat mCRPC to progression with Zytiga, initiate BAT to progression then follow with Xtandi. Or cycle between BAT and Xtandi each month. (see below)

  • Benefits and Adverse Effects of BAT: Nicely discussed in Patient’s Guide (section 2.9).

Benefits of BAT therapy: “Significant improvement was observed in areas of physical function, emotional well-being, and fatigue.” Quality of life was improved in relation to sexual function, sexual desire and sexual satisfaction, restoring erectile function in men who had been competent prior to initial therapy. Fat loss and muscle mass gains were reported; improvement in cholesterol and lipid levels occurred.

Adverse effects of BAT therapy: Generalized musculoskeletal pain and achiness, lower leg swelling, breast tenderness and tissue enlargement, hot flashes, and fatigue (30%). BAT may cause fluid retention; caution should be taken in use with men with underlying congestive heart failure. BAT should not be used in men with symptomatic bone metastases.

  • BAT — The Future: Rapid Recycling Between BAT and Xtandi

Over a 6-month period of BAT treatment resistance develops. A potentially more effective regimen is being tested in men with asymptomatic mCRPC to overcome resistance: alternate BAT and Xtandi in monthly cycles as set forth in NCT04363164, “STEP-UP”, Sequential Testosterone and Enzalutamide Prevents Unfavorable Progression.” Trialists are men progressing on ADT alone or ADT/Zytiga.

Other trial regimens include BAT with a checkpoint inhibitor, BAT with the PARP inhibitor Olaparib and BAT combined with Xofigo (Radium-223). BAT has already been found increasingly effective in men with BRCA-type mutations.

Caution: BAT should not be used in men with hormone sensitive prostate cancer, urinary obstruction due to prostatic enlargement, or in simultaneous combination with Zytiga, Xtandi or chemotherapy. It is advisable that BAT be supervised by an oncologist familiar with the BAT regimen since the interpretation of PSA response is not obvious. 


BAT increases the effectiveness of subsequent Xtandi therapy and is a promising option in asymptomatic men with mCRPC.

Your comments and requests for information on a specific topic are welcome e-mail ecweber@nwlink.com.
Please also visit https://prostatecancerfree.org/prostate-cancer-news for a selection of past issues of the PCa Commentary covering a variety of topics.

“I want to thank Dawn Scott, Staffperson, Tumor Institute Radiation Oncology Group, and Mike Scully, Librarian, Swedish Medical Center, for their unfailing, timely, and resourceful support of the Commentary project. Without their help this Commentary would not be possible.”


Edward Weber, MD, is a retired medical oncologist living in Seattle, Washington. He was born and raised in a suburb of Reading, Pennsylvania. After graduating from Princeton University in 1956 with a BA in History, Dr. Weber attended medical school at the University of Pennsylvania. His internship training took place at the University of Vermont in Burlington.

A tour of service as a Naval Flight Surgeon positioned him on Whidbey Island, Washington, and this introduction to the Pacific Northwest ultimately proved irresistible. Following naval service, he received postgraduate training in internal medicine in Philadelphia at the Pennsylvania Hospital and then pursued a fellowship in hematology and oncology at the University of Washington.

His career in medical oncology was at the Tumor Institute of the Swedish Hospital in Seattle where his practice focused largely on the treatment of patients experiencing lung, breast, colon, and genitourinary cancer and malignant lymphoma.

Toward the end of his career, he developed a particular concentration on the treatment of prostate cancer. Since retirement in 2002, he has authored the PCa Commentary, published by the Prostate Cancer Treatment Research Foundation, an analysis of new developments in the prostate cancer field with essays discussing and evaluating treatment management options in this disease. He is a regular speaker at various prostate cancer support groups around Seattle.