Enzalutamide Improves Survival in Patients with Metastatic Prostate Cancer
In an international randomized phase III clinical trial, the hormone therapy enzalutamide (Xtandi®) extended survival in men with metastatic prostate cancer that had progressed during treatment with androgen deprivation therapy. Participants in the trial had not received chemotherapy.
New England Journal of Medicine, June 1, 2014. (See the journal article.)
Early in their development, prostate cancers need relatively high levels of male sex hormones (androgens) to grow. The testes are the main source of androgens, and treatments that stop the testes from producing male sex hormones—known as hormone therapy or androgen deprivation therapy (ADT)—are therefore a common treatment for androgen-sensitive prostate cancer. However, most prostate cancers eventually become castrate resistant—that is, they can grow even when androgen levels in the blood are very low. ADT does not block production of the small amount of androgen that is made by the adrenal glands and by prostate cancer cells themselves, and this low level is sufficient to fuel the growth of castrate-resistant prostate cancers.
Enzalutamide is among several hormone therapies that have been developed to prevent the androgen-fueled growth of castrate-resistant prostate cancers. This drug works by keeping androgens from binding to the androgen receptors on prostate cancer cells.
Treatments for castrate-resistant prostate cancer include chemotherapy with docetaxel (Taxotere®). Enzalutamide is approved by the FDA for the treatment of men with metastatic castrate-resistant prostate cancer that is no longer responding to chemotherapy. However, chemotherapy is not a treatment option for many men with pre-existing medical conditions or who cannot tolerate the side effects.
The randomized, double-blind PREVAIL trial enrolled 1,717 men with metastatic castrate-resistant prostate cancer who had few or no symptoms and had not received chemotherapy. The trial included patients from North America, Europe, Asia, and Australia.
Men in the trial were randomly assigned to receive 160 mg of enzalutamide or a placebo taken orally once daily.
The primary endpoints of the trial were overall survival (the time from random assignment to death from any cause) and radiographic progression-free survival (the time from random assignment to death or to the first evidence from imaging analysis, which was done regularly, that disease was progressing). Secondary endpoints included time to initiation of chemotherapy and time to the first skeletal-related event (such as bone fracture, spinal cord compression, or the need for radiation to treat bone-related symptoms).
In October 2013, on the basis of an interim analysis that showed a statistically significant reduction in the risk of death for men taking enzalutamide, an independent data safety and monitoring committee recommended stopping the trial early and allowing men who were assigned to the placebo group to begin taking enzalutamide.
Tomasz Beer, M.D., of the Oregon Health & Science University, led the trial. Medivation and Astellas Pharma, the companies that manufacture and market enzalutamide, funded the study.
At 12 months of follow-up, the rate of radiographic progression-free survival was 65 percent among men who took enzalutamide, compared with just 14 percent among men who took placebo. Not enough men in the trial’s enzalutamide group had experienced radiographic disease progression to establish a median radiographic progression-free survival; median radiographic progression-free survival in the placebo group was 3.9 months.
At the interim analysis (after a median follow-up of approximately 22 months), 28 percent of men in the enzalutamide group had died, compared with 35 percent of men in the placebo group. Men who received enzalutamide experienced a 29 percent reduction in the risk of death compared with those who received placebo.
The improvements in radiographic progression-free and overall survival with enzalutamide were seen in all subgroups of patients, including those with visceral disease, who have been excluded from other trials involving men with metastatic prostate cancer who have not received previous chemotherapy because of their poorer prognosis.
Enzalutamide showed a benefit with regard to all of the trial’s prespecified secondary endpoints, the authors reported, including an approximately 17 month improvement in the median time to initiation of chemotherapy and a reduced risk of a first skeletal-related event.
Many patients in both groups received additional therapies after their disease began to progress—40 percent of those in the enzalutamide group and 70 percent of those in the placebo group. The most common additional therapies were docetaxel and abiraterone (Zytiga®). (Abiraterone, another hormone therapy, prevents the production of testosterone by the adrenal glands and prostate cancer cells, as well as by the testes.)
The most common side effects among participants taking enzalutamide were fatigue, constipation, and back and joint pain. Hypertension was the most common serious (grade 3 or higher) side effect in the enzalutamide arm.
Enzalutamide delayed deterioration in the quality of life of trial participants compared with placebo, as measured by a questionnaire that assesses patient-reported health-related quality of life in men with prostate cancer.
Assessing the impact of enzalutamide on overall survival is complicated by the fact that many patients in the trial went on to receive treatments that have been proven to improve survival after their disease worsened, explained Bhupinder Mann, M.B.B.S., of NCI’s Division of Cancer Treatment and Diagnosis.
In the future, Dr. Mann noted, the population of patients with castrate-resistant prostate cancer who have not received docetaxel is likely to become smaller. That's because a large NCI-sponsored clinical trial recently showed that, in men with prostate cancer that is still androgen sensitive, treatment with docetaxel at the beginning of ADT substantially improves overall survival. The survival improvement in that trial was primarily seen in patients with more extensive metastatic disease.
"More patients will probably get docetaxel early on," he said, "so the PREVAIL trial results won't directly apply to them."
In men with metastatic prostate cancer, chemotherapy can improve overall and progression-free survival, the authors wrote. However, they continued, "many patients do not receive such therapy primarily because of pre-existing medical conditions or associated toxic effects. Thus, there is a need for effective, convenient, and less toxic therapies."
Dr. Mann agreed that enzalutamide would "provide another option for men with castrate-resistant prostate cancer prior to receiving chemotherapy" if the FDA were to approve it for this indication.
The finding that enzalutamide delayed deterioration in participant-rated quality of life suggests that "the treatment effects translated into patient-perceived benefits," the authors wrote.