In a phase II study, The TRANSFORMER Trial (Testosterone Revival Abolishes Negative Symptoms, Fosters Objective Response and Modulates Enzalutamide Resistance), men with metastatic castration-resistant prostate cancer (mCRPC) who were previously treated with and failed Zytiga (abiraterone) were randomized to receive, as their subsequent therapy, either bipolar androgen therapy (BAT) or enzalutamide (Enza) to see if either treatment was superior at this stage of prostate cancer. Crossover was permitted.

Evaluating alternative therapies after the failure of Zytiga is an important research question since men who fail Zytiga often do not have a positive response or have a limited response to Enza. Therefore, we need to develop more effective therapies after Zytiga's failure.

BAT, or bipolar androgen therapy, involves rapid cycling back and forth between providing high dose androgen (testosterone) therapy through supplementation and then abruptly halting the testosterone and providing hormone therapy (ADT), creating a low testosterone environment. In other words, quickly adding testosterone and then abruptly ending it and starting ADT.

In this study comparing BAT to Enza after Zytiga failure, the researchers found a response of approximately 28%. BAT demonstrated a clinically superior activity level compared with Enza. It also was associated with the same progression-free survival and numerically more prolonged PSA progression-free survival and overall survival.

Furthermore, the sequence BAT→Enza was associated with significantly longer progression-free survival than the opposite sequence (28.2 vs. 19.6 months). This means that this study hints that after Zytiga failure using BAT and then Enza is superior to using Zytiga to Enza.

Since this study was a phase 2 study, we cannot yet call BAT ready for the clinic. Still, we can say that BAT vs. Enza may be a more effective therapy for men with mCRPC with progression on Zytiga. Further research is required for optimal clinical use and to identify biomarkers to predict treatment efficacy.

As a bit of icing on the cake, the trial also reported that the participant's quality of Life (QoL) was better for men on BAT than those on third line Enza therapy.

https://ascopubs.org/doi/10.1200/JCO.20.02759