SUO 2019: Bipolar AR Therapy

Washington, DC (  Since Huggins’ noble prize-winning work on the role of androgens in prostate cancer progression in 1940, hormonal suppression has been the mainstay of therapy for advanced malignancy. While a flurry of new targets have been discovered over the recent decade, with each sequential therapy, patients face diminishing response rates. Additionally, these medications are associated with a host of side-effects, including decreased focus, fatigue, obesity, decreased bone mass, and sexual dysfunction. Dr. Samuel Denmeade from Johns Hopkins presented a novel approach to castrate-resistant prostate cancer using testosterone to re-sensitize patients to hormonal therapy.

Dr. Denmeade began his talk by exploring the 3 phases of androgen inhibitions: initial shock, adaptation and resistance. Essentially, as testosterone is suppressed, androgen receptor protein is overexpressed with gene amplification and eventual mutations which then leads to androgen synthesis. Dr. Denmeade hypothesizes that by rapidly cycling of supraphysiologic and castrate testosterone levels (bipolar AR therapy—BAT) could disrupt the adaptive autoregulation of the androgen receptors and may re-sensitize castrate-resistant prostate cancer to androgen ablation.

To that end, Dr. Denmeade and colleagues are currently evaluating this strategy in the RESTORE study, a phase II study testing the ability to re-sensitize castrate-resistant men after ADT and 2nd line therapy with either abiraterone or enzalutamide. The initial results for the post-enzalutamide arm has been published in Lancet Oncology, demonstrating an objective response rate of 43% after 3 cycles of BAT. Furthermore, 71% of patients experienced a >50% decrease in PSA following re-treatment with enzalutamide. Final results for the post abiraterone arm are still pending.

Given, these promising preliminary results, Dr. Denmeade and his team is currently evaluating BAT versus enzalutamide following progression on ADT with abiraterone in a phase II randomized control trial with a cross over design (TRANSFORMER trial, trial schema below). Their initial results demonstrate that response rates were significantly higher when BAT was given prior to enzalutamide, as opposed to the medications given in the other order (8.1% vs 28.6%, p=0.045). Furthermore, BAT prior to 3rd line enzalutamide restored PSA responses and progression-free survival to the same rates seen when enzalutamide has been used as 2nd line therapy.

SUO 2019 transformer trial design

SUO 2019 PSA response

In conclusion, Dr. Denmeade provided an overview of an exciting new treatment strategy for men with advanced prostate cancer which has the potential to revolutionize classical thinking regarding androgens and prostate cancer. Final results of his group’s ongoing trials are eagerly anticipated.
Presented by: Samuel Denmeade, MD, Professor of Oncology and Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland 

Written by: Adrien Bernstein, MD, Society of Urologic Oncology Fellow, Fox Chase Cancer Center, Fox Chase Cancer Center, Philadelphia, PA at the 20th Annual Meeting of the Society of Urologic Oncology (SUO), December 4 - 6, 2019,  Washington, DC