RE-sensitizing With Supraphysiologic Testosterone to Overcome REsistance (The RESTORE Study)

Single-arm, single site, open label study of the effects of parenteral testosterone followed by enzalutamide, abiraterone or castration-only therapy in men with metastatic CRPC who previously progressed on one of these forms of therapy. The study will enroll four cohorts of patients: men with metastatic CRPC who have progressed on enzalutamide (Cohort A; n=30); men with metastatic CRPC who have progressed on abiraterone acetate (Cohort B; n=30); men with metastatic CRPC who have progressed on first line castration-only therapy (Cohort C; n=30); men with metastatic CRPC with inactivating somatic or germline mutations in ≥2 of the genes TP53, PTEN, or RB1 (Cohort D; n=20).

The trial will enroll up to 110 patients, 30 for each Cohorts A-C and 20 for Cohort D. Eligible patients will continue on androgen ablative therapy with LHRH agonist (i.e. Zoladex, Trelstar, Eligard or Lupron) if not surgically castrated to suppress endogenous testosterone production. Patients will also receive intramuscular injection with either testosterone cypionate or testosterone enanthate at a dose of 400 mg every 28 days. This dosing scheme was designed to produce rapidly fluctuating serum testosterone levels from the supraphysiologic to the near-castrate range (i.e. Bipolar Androgen Therapy \[BAT\]). Assessments for response to testosterone will be made approximately every 3 months. Upon displaying evidence of progression, patients will then go on to receive either abiraterone (Cohort B) or enzalutamide (Cohort A), whichever agent they had previously progressed on prior to study enrollment. Patients in Cohort C will remain on LHRH agonist therapy and receive no additional androgen ablative hormonal therapy while those in the mutation-positive Cohort D will receive enzalutamide regardless of prior therapy.