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 May;79(5):692-699. doi: 10.1016/j.eururo.2020.06.042. Epub 2020 Jul 2.


Background: Cyclic high-dose testosterone injections, also known as bipolar androgen therapy (BAT), is a novel treatment strategy for patients with metastatic castration-resistant prostate cancer (mCRPC). BAT has shown clinical activity in prior studies enrolling men with mCRPC and may potentially restore sensitivity to prior androgen receptor (AR)-targeted agents.

Objective: To evaluate the clinical activity of BAT in patients progressing on AR-targeted therapy as well as responses to abiraterone or enzalutamide upon rechallenge after BAT.

Design, setting, and participants: RESTORE is a multicohort phase II study enrolling asymptomatic mCRPC patients after abiraterone or enzalutamide at Johns Hopkins Hospital (NCT02090114). Participants (29 after abiraterone and 30 after enzalutamide) received 400 mg testosterone cypionate intramuscularly every 28 days, with ongoing luteinizing hormone-releasing hormone agonist/antagonist treatment (ie, BAT). Following progression on BAT, patients were rechallenged with their most recent AR-targeted therapy.

Outcome measurements and statistical analysis: Coprimary endpoints were >50% decline in PSA from baseline (PSA50) responses to BAT and following AR-targeted therapy rechallenge. Outcomes in the post-abiraterone cohort are presented, as well as updated results from the post-enzalutamide cohort and an exploratory AR-V7 analysis.

Results and limitations: No statistically significant difference in PSA50 response rates to BAT was observed (30% [post-enzalutamide cohort] vs 17% [post-abiraterone cohort], p = 0.4). However, PSA50 responses to AR-targeted therapy rechallenge were higher in the post-enzalutamide cohort (68% vs 16%, p = 0.001). The median time from enrollment to progression following rechallenge with AR-targeted therapy (ie, progression-free survival 2; PFS2) was longer in the post-enzalutamide versus post-abiraterone patients (12.8 vs 8.1 mo, p = 0.04). Outcomes were worse in patients with detectable AR-V7 in circulating tumor cells (median PFS2: 10.3 vs 7.1 mo, p = 0.005).

Conclusions: BAT shows clinical activity in mCRPC patients and may be more effective at resensitizing to enzalutamide versus abiraterone.

Patient summary: BAT is well tolerated in metastatic castration-resistant prostate cancer patients. The type of prior AR-targeted therapy might affect response to BAT as well as AR-therapy rechallenge. BAT followed by AR-targeted therapy rechallenge did not improve outcomes in AR-V7-positive patients.

Keywords: Androgen receptor–targeted therapy; Bipolar androgen therapy; Testosterone.

Publication types

  • Clinical Trial, Phase II
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgens
  • Androstenes / therapeutic use
  • Benzamides / therapeutic use
  • Humans
  • Male
  • Nitriles / therapeutic use
  • Phenylthiohydantoin / therapeutic use
  • Prostate-Specific Antigen
  • Prostatic Neoplasms, Castration-Resistant* / drug therapy
  • Receptors, Androgen
  • Testosterone / administration & dosage
  • Testosterone / therapeutic use*


  • Androgens
  • Androstenes
  • Benzamides
  • Nitriles
  • Receptors, Androgen
  • Phenylthiohydantoin
  • Testosterone
  • enzalutamide
  • Prostate-Specific Antigen
  • abiraterone

Associated data

  • ClinicalTrials.gov/NCT02090114