Top Line: Is bipolar androgen therapy (BAT) superior to enzalutamide for men with metastatic, castrate resistant prostate cancer (mCRPC) who progress on abiraterone?
The Study: Prostate cancer becomes castrate resistant by upregulating the production of androgen receptors (AR) in response to low testosterone levels. However, there is data suggesting these AR-upregulated CRPC cells are vulnerable to a sudden surge in testosterone. Some CRPC cells can be killed by administration of supraphysiologic testosterone while others down-regulate AR and can once again become castrate sensitive. This is called bipolar androgen therapy (BAT). The randomized, phase 2 TRANSFORMER trial sought to determine 1) if BAT was superior to enzalutamide for men with mCRPC that progressed on abiraterone and 2) if the sequence of AR antagonist and BAT (via treatment crossover) influenced outcomes. Patients in both arms were maintained on ADT, while those in the BAT arm received 400 mg IM testosterone every 28 days. Overall, there was no difference in median PFS between arms (5.7 months). However, on sub-group analysis, men with short (< 6 month) response to abiraterone seemed to do better (both PFS and OS) with BAT while those with a long response to abiraterone did better with enzalutamide. Time to progression was short in both arms (< 4 months), and 39.3% (BAT) and 47.6% (enz.) crossed-over to the alternate treatment. Among those, men who received BAT→ enzalutamide had better median OS (37.1 mo) than those who received BAT→ enzalutamide (30.2 mo) and those who didn’t cross-over to BAT (28.6 mo). In addition, the time to second progression was longer after BAT→ enzalutamide (28 months) than with enzalutamide→ BAT (20 months).
TBL: BAT is not superior to enzalutamide (although it appears comparable) for men with mCRPC that progresses on abiraterone, and sequencing BAT before enzalutamide may enhance response to the latter. | Denmeade, J Clin Oncol 2021