Bipolar androgen therapy sensitizes castration-resistant prostate cancer to subsequent androgen receptor ablative therapy

Published:December 29, 2020DOI:


      • Prostate cancer (PCa) adapts to low testosterone by upregulating the androgen receptor (AR).
      • High AR is a therapeutic vulnerability to bipolar androgen therapy (BAT).
      • This is a trial of BAT as first-line hormonal therapy for patients with castration-resistant PCa (CRPC).
      • BAT produced prostate-specific antigen and objective responses in a subset of patients.
      • BAT appeared to sensitise CRPC to subsequent androgen ablative therapy.



      Cyclical, high-dose testosterone administration, termed bipolar androgen therapy (BAT), can induce clinical responses and restore sensitivity to androgen signalling inhibition in patients with previously treated castration-resistant prostate cancer (PCa) (CRPC). This trial evaluated whether BAT is a safe and effective first-line hormonal therapy for patients with CRPC.

      Patients and Methods

      In cohort C of this single-centre, open-label, phase II, multi-cohort trial (RE-sensitizing with Supraphysiologic Testosterone to Overcome REsistance study), 29 patients with CRPC received first-line hormonal therapy with 400 mg of testosterone cypionate intramuscularly every 28 days concurrent with a luteinising hormone-releasing hormone agonist/antagonist. The primary end-point of the study was the PSA50 response rate to BAT treatment.


      After treatment with BAT, four of 29 patients (14%; 95% confidence interval [CI]: 4–32%) experienced a PSA50 response. The median radiographic progression-free survival to BAT was 8.5 months (95% CI: 6.9–15.1) for patients with metastatic CRPC. After progression on BAT, 17 of 18 patients (94%; 95% CI: 73–100%) achieved a PSA50 response and 15 of 18 patients (83%; 95% CI: 59–96) achieved a PSA90 response on abiraterone or enzalutamide. Twelve of 15 patients (80%; 95% CI: 52–96) with metastatic CRPC remain on abiraterone or enzalutamide with a median duration of follow-up of 11.2 months.


      As first-line hormonal treatment for CRPC, BAT was well tolerated and resulted in prolonged disease stabilisation. After progression on BAT, patients had favourable responses to second-generation androgen receptor–targeted therapy.

      Trial Registration NCT02090114

      Graphical abstract


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