Key study points:
1. Signaling through the androgen receptor plays a key role in the progression of prostate cancer including “castration-resistant” prostate cancer
2. Enzalutamide, an inhibitor of the androgen-receptor signaling pathway, has a significant survival benefit for patients with metastatic castration-resistant prostate cancer
Primer: Prostate cancer is the second most common cancer in men worldwide. There is a wide spectrum of disease that ranges from microscopic, clinically insignificant disease to highly morbid, metastatic disease that leads to death. Given the broad spectrum of disease, the appropriate management and treatment of prostate cancer is primarily based upon risk stratification, especially with consideration of clinical staging. For example, clinically localized disease can generally be treated with radiation therapy or radical prostatectomy.
With metastatic disease, the standard treatment is androgen deprivation therapy (ADT) via surgical or medical orchiectomy because prostate cancer is dependent on androgen signaling for growth. Patients who progress despite ADT are thought to have castration-resistant prostate cancer, which was traditionally thought to be resistant to hormonal therapies. The chemotherapeutic option for these patients is taxane chemotherapy (e.g. docetaxel). Recently, an array of new therapies has been shown to be effective in these patients with metastatic castration-resistant prostate cancer, namely Sipuleucel-T (immunotherapy), abiraterone and cabazitaxel plus prednisone (see background reading).
Enzalutamide is an agent that inhibits nuclear translocation of the androgen receptor, DNA binding and co-activator recruitment. As it has been shown in phase 1 and phase 2 trials to have significant antitumor activity, this trial was designed to test its effectiveness for patients with metastatic castration-resistant prostate cancer.
This [phase 3, randomized controlled] study: 1199 patients were randomly assigned in a 2:1 ratio to receive enzalutamide or a placebo treatment. Patients were eligible for the study with confirmed diagnosis of prostate cancer, castrate levels of testosterone, prior docetaxel therapy, and progressive disease defined by predetermined criteria. The primary end point was overall survival, while secondary end points included PSA levels, quality of life, time to PSA or radiographic progression, and time to adverse skeletal events.
The study was terminated after an interim analysis after 520 deaths. The median survival among the enzalutamide group and placebo group was 18.4 months and 13.6 months, respectively. Enzalutamide resulted in a 37% reduction in the risk of death compared to placebo (p<0.001). The superiority of enzalutamide was seen in all secondary end points (p<0.001). The rate of adverse events for patients in the enzalutamide group was comparable to the placebo group; the most common side effects for enzalutamide patients were fatigue, diarrhea and hot flashes. Of note, five patients in the enzalutamide group had seizures compared to none in placebo
In sum: Recent studies including this trial have discounted the previously-held notion that castrate-resistant patients had prostate cancer independent of androgen pathway activity. Enzalutamide acts as an inhibitor on the androgen-receptor signaling pathway, and the results of this well-designed phase 3 randomized controlled study convincingly indicates its effectiveness. Reinforcing this notion, the drug showed statistically significant improvement relative to placebo in the primary end point as well as all secondary endpoints. Thus, enzalutamide should be considered as another viable treatment for metastatic castration-resistant prostate cancer along with taxane chemotherapy, Sipuleucel-T immunotherapy, abiraterone and cabazitaxel/prednisone. Since there are no studies comparing these therapies against each other, the appropriate choice for patients with metastatic castration-resistant prostate cancer should be tailored uniquely to each patient.
Looking forward, results are pending from a phase 3 trial enzalutamide in patients without prior history of docetaxel chemotherapy (patients in this trial had all had a history of docetaxel therapy), and there are ongoing clinical trials that are investigating the use of enzalutamide in earlier stages of prostate cancer.
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