TRANSFORMER: A Randomized Phase II Study Comparing Bipolar Androgen Therapy Versus Enzalutamide in Asymptomatic Men With Castration-Resistant Metastatic Prostate Cancer

Abstract

PURPOSE Prostate cancer (PCa) becomes resistant to androgen ablation through adaptive upregulation of the androgen receptor in response to the low-testosterone microenvironment. Bipolar androgen therapy (BAT), defined as rapid cycling between high and low serum testosterone, disrupts this adaptive regulation in castration-resistant PCa (CRPC). METHODS The TRANSFORMER (Testosterone Revival Abolishes Negative Symptoms, Fosters Objective Response and Modulates Enzalutamide Resistance) study is a randomized study comparing monthly BAT (n = 94) with enzalutamide (n = 101). The primary end point was clinical or radiographic progression-free survival (PFS); crossover was permitted at progression. Secondary end points included overall survival (OS), prostate-specific antigen (PSA) and objective response rates, PFS from randomization through crossover (PFS2), safety, and quality of life (QoL). RESULTS The PFS was 5.7 months for both arms (hazard ratio [HR], 1.14; 95% CI, 0.83 to 1.55; P = .42). For BAT, 50% decline in PSA (PSA50) was 28.2% of patients versus 25.3% for enzalutamide. At crossover, PSA50 response occurred in 77.8% of patients crossing to enzalutamide and 23.4% to BAT. The PSA-PFS for enzalutamide increased from 3.8 months after abiraterone to 10.9 months after BAT. The PFS2 for BAT→enzalutamide was 28.2 versus 19.6 months for enzalutamide→BAT (HR, 0.44; 95% CI, 0.22 to 0.88; P = .02). OS was 32.9 months for BAT versus 29.0 months for enzalutamide (HR, 0.95; 95% CI, 0.66 to 1.39; P = .80). 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 = .225). BAT adverse events were primarily grade 1-2. Patient-reported QoL consistently favored BAT. CONCLUSION This randomized trial establishes meaningful clinical activity and safety of BAT and supports additional study to determine its optimal clinical integration. BAT can sensitize CRPC to subsequent antiandrogen therapy. Further study is required to confirm whether sequential therapy with BAT and enzalutamide can improve survival in men with CRPC.

AR Splicing Variants and Resistance to AR Targeting Agents

“…CTC AR-V7 is associated with shorter PFS and OS on BAT and enzalutamide, but not predictive of treatment effects. [60,61] Nivolumab plus ipilimumab showed modest efficacy in CTC AR-V7(+) patients irrespective of enzalutamide addition. [51,52] CTC AR-V7 is not associated with PFS and OS after 177 Lu-PSMA-617 therapy.…”

“…In addition to these agents, bipolar androgen therapy (BAT) recently came under the spotlight as a new therapeutic intervention for CRPC [ 60 , 61 ]. As shown in earlier studies, androgens can be a double-edged sword for PCa growth [ 10 , 12 , 88 ].…”

“…BAT consisting of testosterone supplementation followed by a washout period targets this vulnerability of PCa by rapidly changing serum androgen concentrations between two polar extremes, which theoretically prevents the re-adaptation of CRPC to androgen concentration in microenvironments. BAT is showing promising results so far in terms of re-sensitization to enzalutamide [ 60 , 61 ]. BAT also led to the conversion from CTC AR-V7 positive to negative, but AR-V7 reverted back to positive after AR-targeted-therapy rechallenge in 83% of patients, indicating that BAT alone may not be enough to eradicate AR-V7 positive clones [ 60 ].…”

Titration of Androgen Signaling: How Basic Studies Have Informed Clinical Trials Using High-Dose Testosterone Therapy in Castrate-Resistant Prostate Cancer

“…Subsequent studies of BAT have been performed in CRPC patients progressing after treatment with enzalutamide, with 9 of 30 (30%) demonstrating a PSA response [ 22 ]. Building on this initial experience, a multicenter randomized trial of BAT has now been completed [ 23 ]. In this trial, men with metastatic CRPC previously treated with abiraterone, but without previous potent next-generation antiandrogen (e.g., enzalutamide) exposure, were randomized to enzalutamide versus high-dose intramuscular testosterone with crossover at progression.…”

“…A PSA decline of 50% was noted in 28% with BAT versus 25% with enzalutamide, demonstrating the activity of BAT in this setting. With the crossover design, it was also noted that BAT followed by enzalutamide did sensitize some patients to subsequent antiandrogen therapy [ 23 ].…”