SUO 2022: Bipolar Androgen Therapy in Advanced Prostate Cancer

( The 23rd Annual Meeting of the Society of Urologic Oncology held in San Diego, CA was host to a prostate cancer session, with Dr. Laura Anne Sena discussing the recent advances in the field of bipolar androgen therapy in advanced prostate cancer.

Dr. Sena began her talk by noting that the concept of testosterone supplementation causing a paradoxical suppression of castration-resistant prostate cancer cell growth is not necessarily a novel one. In 1967, Prout and Brewer demonstrated that testosterone supplementation in a castrate-resistant prostate cancer patient was associated with a significant decrease in tumor biomarker levels. Subsequent analysis published by Wolf et al. in 1991 showed that synthetic androgen suppresses the transformed phenotype in the human prostate cancer LNCaP cell line.

LNCaP cell line.jpg

As such, the concept of bipolar androgen therapy (BAT) for treatment of castrate-resistant prostate cancer is not a truly new one. BAT refers to the cyclical administration of high-dose testosterone, whereby patients maintained on an LHRH agonist receive testosterone cypionate injections every three months.

There are five unique features to BAT:

  1. Has an acceptable safety profile
  2. Can induce objective responses
  3. Can sensitize cancer cells to androgen receptor inhibition
  4. Can improve patient quality of life
  5. Is inexpensive
“BAT has an acceptable safety profile”:

BAT has been demonstrated to be safe among patients with asymptomatic metastatic prostate cancer, as demonstrated below in the safety profile table summary from the TRANSFORMER trial. As demonstrated below, the percentage of patients with Grade 3-4 adverse events was 28.1% in the BAT arm versus 35.1% in the enzalutamide arm.1

bipolar androgen therapy (BAT).jpg

“BAT can induce objective responses”

As demonstrated in the RESTORE,2 TRANSFORMER, and COMBAT trials, the objective response rate has ranged between 23.8% and 37.5%. The median progression-free survival in the BAT arm has been demonstrated to be 5.7 months (enzalutamide arm: 5.7 months, HR: 1.14, 95% CI: 0.83 to 1.55).

bipolar androgen therapy (BAT)-2.jpg

Use of BAT in patients with CRPC has been demonstrated to downregulate MYC activity, which may induce objective responses. The pre-treatment androgen receptor activity may act as a predictive biomarker, whereby patients with higher androgen receptor scores, may have better responses, as demonstrated below.

bipolar androgen therapy (BAT)-3.jpg

“BAT can sensitize cancer cells to androgen receptor inhibition”

In an analysis from the RESTORE trial, 29 patients with new CRPC were treated with BAT (RESTORE cohort C). Of these 29 patients, 16 patients with mCRPC were treated with abiraterone or enzalutamide as next line of therapy. Notably, the median PFS with this sequential approach was 37 months compared to 20 and 16.5 months, as seen with the PREVAIL and COU-AA-302 trials, respectively. The median overall survival was “not reached” after 58.5 months, compared to median OS of 35.3 and 34.7 months, respectively. This concept is being further evaluated in the STEP-UP (Sequential Testosterone and Enzalutamide Prevents Unfavorable Progression, NCT04363164) trial. 

“BAT can improve patient quality of life”

As demonstrated in the TRANSFORMER trial using the validated SF-36 questionnaire, quality of life was superior in the BAT arm (versus enzalutamide). Similarly, erectile function (IIEF score) was also consistently superior in the BAT arm as well.


“BAT is inexpensive”

Compared to Enzalutamide which costs approximately $85,000 for 6 months (using, BAT costs approximately $2,500 for 6 months. 


Dr. Sena concluded her talk by noting that there remain five questions for further development of BAT:

  1. What is the best use for BAT?
    1. Primer for AR inhibition for unselected patients with mCRPC?
    2. Monotherapy for patients with mCRPC with high ARA scores?
    3. Combination therapy (yet to be determined)?
  2. What are more accessible biomarkers for high ARA score?
  3. How does BAT affect tissues near and distant from tumor to modify cancer progression and quality of life?
  4. Why does BAT cause pain flares in some patients?
  5. How do we assure informed use of BAT in the community? 

Presented by: Laura Anne Sena, MD, PhD, Department of Medicine, Medical Oncology, Johns Hopkins University, Baltimore, MD

Written by: Rashid Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 23rd Annual Meeting of the Society of Urologic Oncology (SUO), Nov 30 – Dec 2, 2022. San Diego, CA. 


  1. Denmeade SR, et al. TRANSFORMER: A Randomized Phase II Study Comparing Bipolar Androgen Therapy Versus Enzalutamide in Asymptomatic Men With Castration-Resistant Metastatic Prostate Cancer. J Clin Oncol. 2021;39(12):1371-82.
  2. Markowski MC, et al. 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. Eur Urol. 2021;79(5):692-9.