Samuel R. Denmeade, MD of The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins discusses TRANSFORMER: A Randomized Phase II Study Comparing Bipolar Androgen Therapy Versus Enzalutamide in Asymptomatic Men With Castration-Resistant Metastatic Prostate Cancer.
Link to Publication –
https://ascopubs.org/doi/abs/10.1200/JCO.20.02759
Summary –
OBJECTIVE
Because of adaptive upregulation of the androgen receptor in response to the low-testosterone microenvironment, prostate cancer (PCa) becomes immune to androgen ablation. In castration-resistant PCa, bipolar androgen therapy (BAT), characterized as rapid cycling between high and low serum testosterone, disrupts this adaptive control (CRPC).
APPROACHES
The TRANSFORMER (Testosterone Revival Abolishes Negative Symptoms, Fosters Objective Response, and Modulates Enzalutamide Resistance) trial compared monthly BAT (n = 94) to enzalutamide (n = 101) in a randomized trial. Clinical or radiographic progression-free survival (PFS) was the primary endpoint, with crossover allowed at any time during the study. Overall survival (OS), prostate-specific antigen (PSA) and objective response rates, PFS from randomization to crossover (PFS2), protection, and quality of life were secondary end points (QoL).
OUTCOMES
Both arms had a PFS of 5.7 months (hazard ratio [HR], 1.14; 95 percent confidence interval [CI], 0.83 to 1.55; P =.42). Patients on BAT had a 50 percent reduction in PSA (PSA50) compared to 25.3 percent on enzalutamide. PSA50 response occurred in 77.8% of patients switching to enzalutamide and 23.4 percent of patients switching to BAT at the crossover. After abiraterone, the PSA-PFS for enzalutamide increased from 3.8 months to 10.9 months after BAT. BATenzalutamide had a PFS2 of 28.2 months compared to 19.6 months for enzalutamideBAT (HR, 0.44; 95 percent CI, 0.22 to 0.88; P =.02). BAT had a 32.9-month OS compared to enzalutamide’s 29.0-month OS (HR, 0.95; 95 percent CI, 0.66 to 1.39; P =.80). Patients who switched from BAT to enzalutamide lived 37.1 months longer than those who switched back (HR, 0.68; 95 percent CI, 0.36 to 1.28; P =.225). The majority of BAT side effects are grade 1-2. BAT consistently outperformed BAT in terms of patient-reported QoL.
FINAL REMARKS
This randomized trial establishes BAT clinical operation and safety, paving the way for more research to assess its best clinical integration. BAT will make CRPC more susceptible to antiandrogen therapy. Sequential therapy with BAT and enzalutamide can improve survival in men with CRPC, but more research is needed.