48IN - Integrating novel endocrine therapies: Sequential or concomitant treatment?

Date 30 September 2012
Event ESMO Congress 2012
Session Re-inventing the medical treatment of advanced prostate cancer
Topics Cytotoxic agents
Prostate Cancer
Therapy
Biological therapy
Presenter Johann De Bono
Authors J.S. De Bono
  • Institute of Cancer Research Royal Marsden Hospital, SM2 5PT - Sutton/UK

Abstract

Prostate cancer progression is associated with continued androgen receptor (AR) activation despite treatment with castration and/or currently available anti-androgens. Abiraterone, a rationally- designed inhibitor of CYP17A1 has been recently approved for the treatment of docetaxel-treated castration-resistant prostate cancer (CRPC), is often effective, but requires co-administration with glucocorticoids to curtail side effects. Enzalutamide (MDV3100) is a novel AR antagonist that effectively blocks AR signaling when currently available AR antagonists are unable to do this and has shown impressive antitumor activity and a similar impact on overall survival as abiraterone. We now report that these two drugs in combination may be superior to either drug alone. We have hypothesized that progressive disease on abiraterone may occur secondary to glucocorticoid-induced activation of mutated AR. We also found that prednisolone plasma levels in CRPC patients were sufficiently high to activate mutant AR. Mineralocorticoid receptor antagonists, such as spironoloactone and eplerenone that are used to treat side-effects related to mineralocorticoid excess, also bound to and activated signaling through both wild-type and mutant AR. Activation of mutant AR was inhibited by MDV3100, bicalutamide or greater concentrations of abiraterone. Moreover, higher androgenic steroid concentrations resulted in decreased enzalutamide antitumour activity. Together, our findings provide a strong rationale for the clinical evaluation of combined CYP17A1 inhibition and AR antagonism by enzalutamide.

Disclosure

J.S. de Bono: I am an employee of The Institute of Cancer Research that has a commercial interest in abiraterone. I have served as an advisor for J&J, Medivation, Astellas and Takeda.