The American Food and Drug Administration (FDA)today approved abiraterone acetate (Zytiga?, Centocor Ortho Biotech, Inc) in combination with the steroid prednisone to treat patients with metastatic or late-stage castration-resistant prostate cancer who have received prior treatment with the chemotherapeutic drug docetaxel.

Metastatic castration-resistant prostate cancer or CRPC occurs when cancer has metastasized beyond the prostate and disease progresses despite serum testosterone below castrate levels. The prostate is a gland located under the bladder and around the urethra in men that produces part of the seminal fluid. In some cases, cancer of the prostate can grow slowly compared with other cancers. However, depending on factors including characteristics specific to the patient and the tumor, prostate cancer also can grow very quickly and spread widely.

Excluding skin cancer, prostate cancer is the most frequently diagnosed cancer in men in the United States. In 2010, more than 217,000 new cases of prostate cancer were estimated and more than 32,000 men died from the disease.

Androgens are hormones that promote the development and maintenance of male sex characteristics. However, in prostate cancer, testosterone stimulates prostate tumors to grow. Androgen production primarily occurs in the testes and adrenal glands; in men with prostate cancer, the tumor tissue is an additional source of androgens.

In patients with prostate cancer, drugs or surgery are used to reduce testosterone production or to block testosterone’s effects. However, sometimes prostate cancer can continue to grow even when testosterone levels are low. Men with these cancers are said to have castration-resistant prostate cancer.

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Abiraterone acetate is a pill that targets a protein called cytochrome P450 17A1 (CYP17A1) which plays an important role in the production of testosterone. The drug works by decreasing the production of this hormone that would stimulate cancer cells to continue growing.

The application was reviewed under the FDA’s priority review program, which provides for an expedited six-month review for drugs that may offer major advances in treatment, or provide a treatment when no adequate therapy exists. Abiraterone acetate is being approved ahead of the product’s June 20, 2011 regulatory goal date.

“Zytiga prolonged the lives of men with late-stage prostate cancer who had received prior treatments and had few available therapeutic options,” said Richard Pazdur, M.D., director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research.

“This FDA approval represents a welcome new option in the treatment of metastatic prostate cancer,” said Howard Scher, MD, Chief of the Genitourinary Oncology Service, Sidney Kimmel Center for Urologic and Prostate Cancers at Memorial Sloan-Kettering, and one of the co-lead investigators for the Phase III clinical study. “As a clinician, I believe the efficacy and safety profile of abiraterone acetate, as well as its oral, once-daily formulation, will help address the important need for additional therapeutic choices for men living with this serious disease.”

The drug?s safety and effectiveness were established in a clinical study of 1,195 patients with late-stage castration-resistant prostate cancer who had received prior treatment with docetaxel chemotherapy. Patients received either abiraterone acetate once daily in combination with prednisone two times a day or a placebo twice daily in combination with prednisone.

“In this Phase III study, treatment with abiraterone acetate plus prednisone showed a significant increase in median survival compared with placebo plus prednisone,” said Professor Johann S. de Bono, MD, FRCP, MSc, PhD, The Institute of Cancer Research, The Royal Marsden NHS Foundation Trust, and one of the co-lead investigators for the Phase III clinical study. “It’s an exciting time for men with prostate cancer, and I believe that abiraterone acetate will play an essential role in clinical practice.”

The study was designed to measure overall survival, the length of time from when the treatment started until a patient’s death. In this trial patients were randomized 2:1 to receive abiraterone acetate 1 gram daily in combination with prednisone 5 milligrams (mg) twice daily or placebo in combination with prednisone 5 mg twice daily (control arm).

Results of the pivotal Phase III, randomized, placebo-controlled, multicenter study showed that at pre-specified interim analysis, treatment with abiraterone acetate in combination with prednisone resulted in a 35% reduction in the risk of death (14.8 months vs. 10.9 months [hazard ratio (HR) = 0.646; 95% CI: 0.543, 0.768; p<0.0001]) and a 3.9 month difference in median survival compared to placebo plus prednisone. In an updated analysis, results were consistent with those from the interim analysis with a 4.6 month difference between the two arms in median survival (15.8 months vs. 11.2 months [HR = 0.74]).

The most commonly reported side effects in patients receiving abiraterone acetate included joint swelling or discomfort, low levels of potassium in the blood, fluid retention (usually of the legs and feet), muscle discomfort, hot flashes, diarrhea, urinary tract infection, cough, high blood pressure, heartbeat disorders, urinary frequency, increased nighttime urination, upset stomach or indigestion and upper respiratory tract infection.

At a predetermined number of events in the study, an interim analysis was conducted and it was determined that efficacy had been demonstrated. At that time, the study was unblinded at the recommendation of the Independent Data Monitoring Committee.
Abiraterone acetate was developed by Ortho Biotech Oncology Research & Development, a Unit of Cougar Biotechnology, Inc., and will be marketed by Centocor Ortho Biotech Inc. Marketing applications for abiraterone acetate have been filed with other regulatory authorities throughout the world.

For more information:
FDA: Office of Oncology Drug Products
FDA: Approved Drugs: Questions and Answers
NCI: Prostate Cancer

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