Enzalutamide prolongs survival in patients with metastatic castration-resistant prostate cancer after chemotherapy
Results from AFFIRM study validate androgen-receptor signalling as a key therapeutic target throughout the clinical spectrum of prostate cancer
- Date : 22 Aug 2012
- Topic : Genitourinary cancers
The results of a phase III clinical trial of enzalutamide (MDV3100), published as Online First on 15 August in the New England Journal of Medicine, show the drug extends survival by an average five months in the most advanced stages of prostate cancer. Enzalutamide targets multiple steps in the androgen-receptor signalling pathway, the major driver of prostate-cancer growth.
The phase III, double-blind, placebo-controlled study, known by the acronym AFFIRM, followed 1199 patients with castration-resistant prostate cancer after chemotherapy. Patients were randomly assigned in a 2:1 ratio, to receive oral enzalutamide at a dose of 160 mg per day (800 patients) or placebo (399 patients). The primary end point was overall survival.
The study was stopped after a planned interim analysis at the time of 520 deaths. Median overall survival for patients in the treatment arm of the trial was 18.4 months compared to 13.6 months for patients in the placebo arm (p < 0.001). In addition to prolonged survival, patients given enzalutamide showed meaningful improvements with respect to all secondary end points: the proportion of patients with a reduction in the prostate-specific antigen (PSA) level by 50% or more (54% vs. 2%), the soft-tissue response rate (29% vs. 4%), the quality-of-life response rate (43% vs. 18%), the time to PSA progression (8.3 vs. 3.0 months), radiographic progression-free survival (8.3 vs. 2.9 months), and the time to the first skeletal-related event (16.7 vs. 13.3 months).
Enzalutamide: An oral androgen-receptor signalling inhibitor
In this study, the researchers found that enzalutamide reduced the risk of death from any cause by 37% versus placebo. In a multivariate analysis, the survival benefit was seen in all patient subgroups, including those stratified according to age and Eastern Cooperative Oncology Group (ECOG) performance status score, the geographic location of the study centre, the extent of disease on diagnostic imaging, and biochemical measurements that included PSA and lactate dehydrogenase, even after adjustment for baseline factors.
The study data confirm the central role of the androgen receptor and androgen-receptor signalling in the progression of prostate cancer throughout the spectrum of disease. Castration-resistant disease was previously considered to be a hormone-refractory disease. The survival benefit in this study substantiates preclinical work showing that androgen-receptor signalling contributes to disease progression despite castrate levels of testosterone and previous conventional anti-androgen therapy. This result, coupled with the recent report of a survival benefit from abiraterone acetate plus prednisone, establishes that these tumours are not refractory to hormones, even after chemotherapy has been administered. Changes in the androgen receptor, including overexpression, not only are oncogenic in model systems but also are associated with growth-stimulatory effects from the available anti-androgen agents.
At the time that this placebo-controlled study was designed and initiated, no life-prolonging treatment was available for men with progressive prostate cancer after docetaxel therapy; however, during the study period, both cabazitaxel and abiraterone acetate plus prednisone were approved for use.
The median time to any initial adverse event of grade 3 or higher was 8.4 months longer in the enzalutamide group than in the placebo group (12.6 vs. 4.2 months). The most common adverse events that were reported more frequently in the enzalutamide group included fatigue, diarrhoea, and hot flashes. Although all men had castrate levels of circulating testosterone, further inhibition of androgen-receptor signalling in non-cancerous tissues probably explains some of these side effects. Treatment with enzalutamide did not result in an increase in the rate of cardiac disorders or hepatic dysfunction.
Seizure was reported in 5 of 800 patients (0.6%) receiving enzalutamide, several of whom had predisposing conditions or concomitant treatments. Convulsions are a dose-dependent toxic effect of enzalutamide, and seizures were seen in the phase I–II enzalutamide trial in each of the cohorts. Inhibition of the γ-aminobutyric acid–gated chloride channel is a hypothesised mechanism by which enzalutamide lowers the seizure threshold.
Enzalutamide should be used with caution when administering it to patients with a history of seizure or who have other predisposing factors, including underlying brain injury, stroke, brain metastases, or alcoholism, or to patients receiving concomitant medication that may lower the seizure threshold. In this study, enzalutamide was discontinued in patients who were reported to have had a seizure.
Enzalutamide, a once-daily oral hormonal treatment, is administered without the need for concomitant prednisone, which has been postulated to activate androgen-receptor signalling. Beyond establishing a new treatment for advanced prostate cancer, this study also helps to redefine hormone-refractory prostate cancer and proves that androgen-targeted treatments continue to be relevant later into the disease process than previously believed, including in patients who have received previous chemotherapy. Clinical trials of enzalutamide in earlier-stage prostate cancer are ongoing. It is a new, emerging drug and the challenge of the next five years is to discover how to best timely and potentially combine new agents.
The results were presented in part at the American Society of Clinical Oncology Genitourinary Cancers Symposium (San Francisco, February 2, 2012); the American Urological Association Annual Meeting (Atlanta, May 19–23, 2012); and the American Society of Clinical Oncology Annual Meeting (Chicago, June 1–5, 2012).
The study was supported by Medivation and Astellas Pharma Global Development.
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