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Enzalutamide for the treatment of prostate cancer.

ABSTRACT: The FDA approval of docetaxel for metastatic castration-resistant prostate cancer (mCRPC) in 2005 marked a major milestone, as it was the first approved agent for this disease that demonstrated a survival advantage in Phase III assessment of this disease. Since 2009, several other agents have been approved by FDA, including sipuleucel-T, abiraterone, cabazitaxel and enzalutamide . Enzalutamide, a potent antiandrogen that blocks nuclear translocation of the androgen receptor (AR), is the most recently approved of these agents.The clinical development of enzalutamide is discussed, with attention given as to how this agent will most appropriately be used among a growing list of agents for mCRPC. A MEDLINE search was conducted to identify all relevant published datasets pertaining to the drug. In addition, relevant ASCO and ESMO abstracts were searched.The current role and sequencing of enzalutamide may change drastically based on studies such as PREVAIL (a Phase III pre-chemotherapy assessment of enzalutamide) and planned studies to assess relevant combinations (i.e., enzalutamide with abiraterone). Outside of clinical efficacy, issues such as drug cost may ultimately dictate our utilization of agents such as enzalutamide for mCPRC. Although the development of biomarkers to guide therapy for mCRPC is ideal, there are inherent challenges in establishing biomarker-driven treatment.

SUBMITTER: Pal SK

PROVIDER: S-EPMC3845878 | biostudies-other | 2013 Apr

REPOSITORIES: biostudies-other

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Enzalutamide for the treatment of prostate cancer.

Pal Sumanta K SK Stein Cy A CA Sartor Oliver O

Expert opinion on pharmacotherapy 20130227 5

<h4>Introduction</h4>The FDA approval of docetaxel for metastatic castration-resistant prostate cancer (mCRPC) in 2005 marked a major milestone, as it was the first approved agent for this disease that demonstrated a survival advantage in Phase III assessment of this disease. Since 2009, several other agents have been approved by FDA, including sipuleucel-T, abiraterone, cabazitaxel and enzalutamide . Enzalutamide, a potent antiandrogen that blocks nuclear translocation of the androgen receptor ...[more]

PMID: 23441761

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Project description:Enzalutamide is an oral androgen receptor inhibitor that targets multiple steps in the androgen receptor signaling pathway. In the randomized phase III AFFIRM study, significant improvements in survival versus placebo were observed when enzalutamide was used as a treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) following prior treatment with docetaxel. Additional benefits included significant delay in time to first skeletal-related event, and improvement in several measures of pain and health-related quality of life. Treatment effects were consistent across all prespecified subgroups. The phase III PREVAIL study evaluated enzalutamide versus placebo in patients with mCRPC who had not received chemotherapy. Enzalutamide significantly decreased the risk of radiographic progression and death. There were also significant improvements in all secondary and prespecified exploratory endpoints, including delayed initiation of chemotherapy, reduction in risk of first skeletal-related event and a high percentage of patients with objective response compared with placebo. Enzalutamide was also studied in hormone naïve patients (as monotherapy) in a small, open-label phase II study in patients with prostate cancer who were eligible for androgen-deprivation therapy. A prostate-specific antigen (PSA) response, defined as ⩾80% decline in PSA level from baseline at week 25, was achieved in 92.5% of patients. Long-term follow up is ongoing. Despite differences between these three trials, enzalutamide displayed a favorable safety profile in all three patient populations. Similar rates of adverse events between the enzalutamide and placebo groups were observed in AFFIRM and PREVAIL, with fatigue, diarrhea, back pain and hot flashes being more common with enzalutamide than with placebo. Hypertension was reported at a higher rate in the enzalutamide group than in the placebo group in PREVAIL. Breast-related disorders associated with enzalutamide treatment were also reported in the Monotherapy trial. Few seizures were reported in any trial. Enzalutamide is being studied in several early disease state populations.

Project description:BackgroundEnzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer in whom the disease has progressed after chemotherapy. New treatment options are needed for patients with metastatic prostate cancer who have not received chemotherapy, in whom the disease has progressed despite androgen-deprivation therapy.MethodsIn this double-blind, phase 3 study, we randomly assigned 1717 patients to receive either enzalutamide (at a dose of 160 mg) or placebo once daily. The coprimary end points were radiographic progression-free survival and overall survival.ResultsThe study was stopped after a planned interim analysis, conducted when 540 deaths had been reported, showed a benefit of the active treatment. The rate of radiographic progression-free survival at 12 months was 65% among patients treated with enzalutamide, as compared with 14% among patients receiving placebo (81% risk reduction; hazard ratio in the enzalutamide group, 0.19; 95% confidence interval [CI], 0.15 to 0.23; P<0.001). A total of 626 patients (72%) in the enzalutamide group, as compared with 532 patients (63%) in the placebo group, were alive at the data-cutoff date (29% reduction in the risk of death; hazard ratio, 0.71; 95% CI, 0.60 to 0.84; P<0.001). The benefit of enzalutamide was shown with respect to all secondary end points, including the time until the initiation of cytotoxic chemotherapy (hazard ratio, 0.35), the time until the first skeletal-related event (hazard ratio, 0.72), a complete or partial soft-tissue response (59% vs. 5%), the time until prostate-specific antigen (PSA) progression (hazard ratio, 0.17), and a rate of decline of at least 50% in PSA (78% vs. 3%) (P<0.001 for all comparisons). Fatigue and hypertension were the most common clinically relevant adverse events associated with enzalutamide treatment.ConclusionsEnzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer. (Funded by Medivation and Astellas Pharma; PREVAIL ClinicalTrials.gov number, NCT01212991.).

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Enzalutamide for the treatment of prostate cancer.

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Enzalutamide for the treatment of prostate cancer.

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