Led by Dr. Samuel R. Denmeade and his team at Johns Hopkins School of Medicine – Sidney Kimmel Comprehensive Cancer Center, the PCCTC’s TRANSFORMER Trial (Testosterone Revival Abolishes Negative Symptoms, Fosters Objective Response and Modulates Enzalutamide Resistance (ClinicalTrials.gov identifier: NCT02286921)) is the first randomized study to assess high-dose testosterone as a treatment for  metastatic castration-resistant prostate cancer (mCRPC). Results published in the Journal of Clinical Oncology give evidence that bipolar androgen therapy (BAT)—rapid cycling between high and low serum testosterone—significantly disrupts adaptive upregulation of the androgen receptor in response to the low-testosterone microenvironment. Critically, the study produced potentially practice-changing outcome data suggesting BAT efficacy is at least as good as enzalutamide as the treatment of choice for men with mCRPC progressing on abiraterone, with lower toxicity and higher quality of life.

TRANSFORMER randomized asymptomatic men with progressive mCRPC post- treatment with abiraterone acetate 1:1 and stratified based on duration of prior abiraterone acetate therapy (≤6 months or >6 months). Patients randomized to Arm A (n = 94) received intramuscular injections with testosterone cypionate or testosterone enanthate at a dose of 400 mg every 28 day (i.e., BAT) while patients randomized to Arm B (n = 101) received a daily oral dose of 160 mg of enzalutamide; crossover was permitted at progression. The primary objective was to compare radiographic progression-free survival (rPFS) between arms while. Secondary endpoints included overall survival (OS), prostate-specific antigen (PSA) and objective response rates, PFS from randomization through crossover (PFS2), safety, and quality of life (QoL).

While no advantage was observed between arms in the primary endpoint of clinical or radiographic PFS—median PFS (5.7 months in both the arms)—at crossover, 50% PSA50 response occurred in 77.8% of patients crossing to enzalutamide and 23.4% to BAT and the PSA-PFS for enzalutamide increased from 3.8 months after abiraterone to 10.9 months after BAT. Moreover, OS was 37.1 months for patients crossing from BAT to enzalutamide versus 30.2 months for the opposite sequence (HR, 0.68; 95% CI, 0.36 to 1.28; P = 0.225). Patient-reported QoL also consistently favored BAT.

Dr. Denmeade, the principal investigator of the trial, is hopeful about the future potential for incorporation of BAT into the treatment paradigm for prostate cancer.  “TRANSFORMER demonstrates that BAT is a safe, inexpensive therapy with meaningful clinical activity with the potential to improve quality of life in to men with mCRPC.  More importantly, it suggests that sequential therapy with high dose testosterone and antiandrogens may overcome hormonal resistance to extend the duration of hormonal therapy with the potential to improve survival for these patients.”

Co-investigator Dr. Emmanuel S. Antonarakis is optimistic that TRANSFORMER will open the door to future studies examining BAT in CRPC. “We are excited to build on the success of BAT monotherapy, by combining this approach with other systemic treatments for advanced prostate cancer. For example, we have recently completed a trial (the COMBAT study) combining BAT with the PD1 inhibitor, nivolumab, with striking clinical results. Our next trial, called BAT-RAD, will explore the combination of BAT with radium-223. These are exciting times for our patients with advanced prostate cancer who are looking for an alternative to androgen deprivation.”

Denmeade SR, et al. TRANSFORMER: A Randomized Phase II Study Comparing Bipolar Androgen Therapy Versus Enzalutamide in Asymptomatic Men With Castration-Resistant Metastatic Prostate Cancer. J Clin Oncol. 2021 Feb 22:JCO2002759. doi: 10.1200/JCO.20.02759. Epub ahead of print. PMID: 33617303.