Clinical Pearls & Morning Reports
The median bone metastasis–free survival among men with nonmetastatic, castration-resistant prostate cancer ranges from 25 to 30 months. The risk of metastases is associated with an increasing prostate-specific antigen (PSA) level and a PSA doubling time of 10 months or less. Hussain et al. hypothesized that enzalutamide treatment would delay the development of metastases in men with nonmetastatic, castration-resistant prostate cancer and a rapid PSA doubling time. Read the latest Original Article here.
Q: How does the PSA doubling time guide treatment for nonmetastatic, castration-resistant prostate cancer in the United States?
A: In the United States, the current National Comprehensive Cancer Network guidelines for prostate cancer suggest observation if the PSA doubling time is 10 months or greater and treatment with additional lines of hormonal therapy if it is less than 10 months.
Q: What is the mechanism of action of enzalutamide?
A: Enzalutamide binds directly to the androgen receptor and inhibits the binding of androgens, androgen-receptor nuclear translocation, and androgen-receptor–mediated DNA binding. Its effect on overall survival has been shown in two international, phase 3 trials involving patients with metastatic, castration-resistant prostate cancer before and after the receipt of docetaxel.
A: In the trial by Hussain et al., among men with nonmetastatic, castration-resistant prostate cancer and a rapidly rising PSA value, the end points of the time to metastasis-free survival, the time to PSA progression, and the time to the first use of a subsequent antineoplastic therapy were significantly longer with enzalutamide treatment than with placebo (P<0.001 for all comparisons). Enzalutamide treatment was associated with a 71% lower risk of metastasis or death than placebo. A consistent benefit with regard to metastasis-free survival in favor of enzalutamide treatment was observed in all the prespecified subgroups. There was no decrease in quality of life associated with enzalutamide treatment. Although the median overall survival was not reached in either group, in the first of several prespecified interim analyses, the risk of death was 20% lower with enzalutamide treatment than with placebo. This result did not reach statistical significance.
A: The safety profile of enzalutamide was consistent with that reported in previous clinical trials involving men with castration-resistant prostate cancer. The most common adverse event in patients receiving enzalutamide was fatigue. Adverse events of special interest that occurred more frequently (by ≥2 percentage points) in the enzalutamide group than the placebo group, regardless of relatedness to the trial regimen, were hypertension (in 12% vs. 5%), major adverse cardiovascular events (in 5% vs. 3%), and mental impairment disorders (in 5% vs. 2%). Three patients in the enzalutamide group had convulsions, all of which were considered to be serious and drug-related and occurred within 180 days after the initiation of the trial drug. A higher percentage of patients receiving enzalutamide reported falls and nonpathologic fractures than did those receiving placebo (17% vs. 8%).