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

Mark C. Markowski, Hao Wang, Rana Sullivan, Irina Rifkind, Victoria Sinibaldi, Michael T. Schweizer, Benjamin A. Teply, Nduku Ngomba, Wei Fu, Michael A. Carducci, Channing J. Paller, Catherine H. Marshall, Mario A. Eisenberger, Jun Luo, Emmanuel S. Antonarakis, Samuel R. Denmeade

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)692-699
Number of pages8
JournalEuropean Urology
Issue number5
StatePublished - May 2021
Externally publishedYes

Bibliographical note

Funding Information:
Funding/Support and role of the sponsor: The project described was supported by the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins NIH grant P30 CA006973, R01 CA184012, and a PCF Young Investigator Award. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.

Publisher Copyright:
© 2020 European Association of Urology


  • Androgen receptor–targeted therapy
  • Bipolar androgen therapy
  • Testosterone

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't


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