Metastatic prostate cancer is a challenging and complicated disease to treat. The first line treatment for metastatic prostate cancer is androgen ablation therapy, which is designed to decrease serum testosterone levels to <50ng/dL.1 This can be accomplished surgically by orchiectomy, or pharmacologically with gonadotropin releasing hormone (GnRH) agonists or GnRH antagonists. Augmented therapy has become prevalent in metastatic prostate cancer and is accomplished by adding an antiandrogenic medication to androgen ablation therapy. Bicalutamide or flutamide may be added; which work as competitive androgen receptor inhibitors. Drugs that suppress adrenal androgen synthesis, such as abiraterone or ketoconazole, may also be utilized.2 Metastatic prostate cancer has a propensity to progress to castration-resistant prostate cancer, which is less dependent on androgen to proliferate. Evidence suggests that the competitive androgen receptor inhibitors may act as androgen receptor agonists in castrate-resistant prostate cancer, thus necessitating discontinuation of those agents when resistance develops. Patients that progress to castration-resistant prostate cancer become very challenging to treat and more advanced options, such as cytotoxic chemotherapy, become necessary.3 A new drug, enzalutamide (formerly MDV3100, Xtandi® Astellas Pharma/Medivation) is a competitive androgen receptor signaling inhibitor, but unlike flutamide and bicalutamide, it has no agonistic properties. In addition to the antiandrogenic properties, it prevents nuclear translocation of the androgen receptor, which eventually leads to cell cycle arrest and apoptosis.4,5
The AFFIRM (A Study Evaluating the Efficacy and Safety of the Investigational Drug MDV3100) study evaluated the use of enzalutamide in men with castration-resistant metastatic prostate cancer who had previously received cytotoxic chemotherapy.4 This phase 3, double blind, placebo controlled trial randomized 1199 men in a 2:1 ratio to receive 160mg of enzalutamide by mouth daily or placebo, respectively. The participants had progressive prostate cancer with a testosterone level < 50ng/dL and had received prior therapy with docetaxel; they were stratified using their pain intensity and Eastern Cooperative Oncology Group Performance (ECOG) score. Participants were evaluated for overall survival as the primary endpoint with secondary endpoints including prostate specific antigen (PSA) levels, quality of life, progression free survival, and time to the first skeletal event. All endpoints were assessed using intent to treat analysis.4
An interim analysis, planned after 250 deaths, found significant benefit in the enzalutamide group and the researchers unblinded all participants and offered enzalutamide to all subjects. Individuals receiving enzalutamide had a substantial increase in overall survival of 4.8 months compared to the placebo group (median overall survival of 18.4 months versus 13.6 months, respectively). Enzalutamide therapy resulted in a 37% reduction in the risk for death (p<0.0001). The secondary endpoints all showed significant reductions in risk for patients treated with enzalutamide versus placebo. The enzalutamide group experienced more fatigue, diarrhea and hot flashes, but had a longer time until an adverse effect than the placebo group (12.6 months versus 4.2 months, respectively).4
The authors concluded that the significant benefit from enzalutamide suggests that castration-resistant metastatic prostate cancer retains substantial reliance on androgens to proliferate. Enzalutamide provides a significant survival benefit in these patients and is easy to use as once daily therapy given by mouth and does not require concomitant use of corticosteroids. The benefits may far outweigh the risks for use in patients with castrate-resistant metastatic prostate cancer who originally had only the option to use cytotoxic chemotherapy.4 Results from this phase 3 trial show great promise in the treatment options for castration-resistant metastatic prostate cancer, which was previously thought to be impervious to androgen ablation therapy and suggests that there is still substantial androgen sensitivity. Enzalutamide is a new treatment that can prolong survival and further extend the time before patients require cytotoxic chemotherapy. ...