Hormonal therapies that target androgen are the focus of several ongoing clinical trials for the treatment of advanced prostate cancer, and as more data accrues, clinicians are gaining valuable insight as to how these drugs can best be used to manage the disease.
Robert Dreicer, MD, MS, chairman of the Department of Solid Tumor Oncology at the Taussig Cancer Institute at the Cleveland Clinic and professor of Medicine at the Cleveland Clinic Lerner College of Medicine in Ohio, discussed important clinical trials concerning these agents at the 6th Annual Interdisciplinary Prostate Cancer Congress, held on March 16, 2013, in New York, NY.
Dreicer explained that the understanding of prostate cancer has changed dramatically in a relatively short period of time. Novel therapies have emerged rapidly, and while they have been helpful in the treatment of advanced prostate cancer, Dreicer said that challenges still remain in determining the optimum use of these drugs.
Abiraterone acetate (Zytiga), an androgen synthesis inhibitor, was approved by the FDA in 2011 for the treatment of patients with metastatic castration-resistant prostate cancer after they had received treatment with docetaxel. In the pivotal phase III COU-AA-301 trial, 1195 patients who had previously received docetaxel were randomly assigned to receive 5 mg of prednisone twice daily with either 1000 mg of abiraterone acetate (n=797) or placebo (n=398). After a median follow-up of 12.8 months, patients who received abiraterone achieved higher overall survival (OS) than those in the placebo-prednisone group (14.8 months vs. 10.9 months; hazard ratio [HR] = 0.65; 95% CI, 0.54 - 0.77; P
An updated analysis demonstrated a median OS of 15.8 months for patients who received abiraterone acetate versus 11.2 months for those who received placebo (HR = 0.740; 95% CI, 0.638 - 0.859), according to the website of the National Cancer Institute
“What we learned very quickly is that this is an important drug,” Dreicer said.
Abiraterone acetate received an expanded approval from the FDA last year for use in patients with advanced prostate cancer who have not yet received chemotherapy after positive results obtained from the COU-AA-302 trial. In that study, 1088 chemotherapy- naïve, asymptomatic or mildly symptomatic patients with metastatic castration-resistant prostate cancer (mCRPC) were randomized to receive either 1000 mg of abiraterone acetate once daily plus 5 mg of prednisone twice daily or a placebo plus 5 mg of prednisone twice daily.
According to the results, the median radiographic progression-free survival (rPFS) was 16.5 months with abiraterone acetate compared with 8.3 months in the control arm (HR = 0.53; 95% CI, 0.45, 0.62; P
< .001). The study also found that the median time to initiate chemotherapy was 25.2 months in the abiraterone acetate arm compared with 16.8 months for placebo (HR = 0.580; 95% CI, 0.487, 0.691; P
Antiandrogrens represent another promising class of drugs, although Dreicer explained that this was not necessarily the case when first-generation antiandrogen drugs such as bicalutamide were being tested in clinical trials. They had a weak binding to the androgen receptor. However, these agents have received renewed interest with the continued development of next-generation antiandrogen agents. Last year, enzalutamide (Xtandi) was approved by the FDA to treat mCRPC. Enzalutamide is a small-molecule androgen receptor antagonist that binds directly to the androgen receptor with high affinity.
The drug was approved in 2012 based on the results of the phase III AFFIRM trial, which enrolled 1199 men with mCRPC and randomized them in a 2:1 ratio to receive either once-daily, oral enzalutamide monotherapy or placebo. The median overall survival in the enzalutamide arm was 18.4 months (95% CI, 17.3 to not yet reached), compared with 13.6 months in the placebo arm (95% CI, 11.3–15.8; HR = 0.63; 95% CI, 0.53–0.75; P
Dreicer said that enzalutamide is being explored in a number of clinical trials that could expand its use, depending on what these studies find. In the phase III PREVAIL trial, 1680 mCRPC patients who have not received docetaxel will be randomized to receive enzalutamide or a placebo.
“There are also efforts to take enzalutamide into earlier stages of disease,” Dreicer said. “Adjuvant studies and studies in the non-metastatic setting are in phase II trials.”
Dreicer explained that even with these successes, numerous challenges still remain, such as determining the optimal timing of these drugs, the role of combining these therapies, and the optimal dose of the steroids that are required to accompany these therapies. These questions may be answered as more of these therapies enter clinical trials.
“The questions are, 'Are these better drugs? Do they have advantages over others? Do we need next-generation antiandrogens? Those are going to be important questions,” Dreicer said.