Bipolar androgen therapy sensitizes castration-resistant prostate cancer to subsequent androgen receptor ablative therapy. (February 2021)

• Record Type: Journal Article
• Authors: Sena, Laura A.; Wang, Hao; Lim ScM, Su J.; Rifkind, Irina; Ngomba, Nduku; Isaacs, John T.; Luo, Jun; Pratz, Caroline; Sinibaldi, Victoria; Carducci, Michael A.; Paller, Channing J.; Eisenberger, Mario A.; Markowski, Mark C.; Antonarakis, Emmanuel S.; Denmeade, Samuel R.
• Is Part Of: European journal of cancer. Volume 144(2021)
• Page Start: 302
• Page End: 309
• Publication Date: 2021-02
• Subjects: Castration-resistant prostate cancer -- Bipolar androgen therapy -- Testosterone -- RESTORE trial; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Cancer; Tumors; Electronic journals; Periodicals; Electronic journals; 616.994
• DOI: 10.1016/j.ejca.2020.11.043
• Languages: English
• ISSNs: 0959-8049

Abstract

Abstract: Background: 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. Results: 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. Conclusion: 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: ClinicalTrials.gov NCT02090114 Graphical abstract: Image 1 Highlights: 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.