Pharmacology Watch

Dutasteride and Low-Risk Prostate Cancer

In this issue: New treatment for prostate cancer; avastin and breast cancer; new CMS disclosure rule; and FDA actions.

Adjunct to active surveillance?

Low-risk prostate cancers are nonpalpable, low-grade tumors associated with prostate-specific antigen (PSA) levels less than 10 ng/mL. For these patients, active surveillance is an option, allowing a period of observation to help decide who should be treated or not treated. Generally, this involves repeated biopsy sampling with the option to treat more aggressively if higher grade tumors are found. Active surveillance is more frequently utilized in Europe and Canada than in the United States, where more aggressive treatment is the norm. A new study from the U.S. and Canada investigates the safety and efficacy of the 5α-reductase inhibitor dutasteride on prostate cancer progression in men with low-risk disease. A total of 302 men ages 48-82 with low-volume Gleason score 5-6 prostate cancer were randomized to dutasteride 0.5 mg per day or placebo. Patients were followed for 3 years with prostate biopsies done at 18 months and 3 years with the primary endpoint being time to prostate cancer progression. After 3 years, 38% of men in the dutasteride group and 48% of men in the control group had prostate cancer progression (hazard ratio 0.62; 95% confidence interval [CI], 0.43-0.9; P = 0.009). Dutasteride was not associated with an increase in adverse events. There were no prostate cancer-related deaths and no incidence of metastatic disease in either group. The authors conclude that "dutasteride could provide a beneficial adjunct to active surveillance for men with low-risk prostate cancer" (Lancet published online January 23, 2012). An accompanying editorial points out the appeal of a safe oral drug that can prevent prostate cancer progression, but the author cannot recommend the drug based on this study due to several limitations — short duration, no evidence of mortality difference, and, most importantly, the risk that 5α-reductase inhibitors may decrease the volume of low-grade, but not high-grade, cancers (Lancet published online January 23, 2012). This study comes at a time when physicians are actively debating the pros and cons of screening for prostate cancer. The recently published PLCO trial showed that PSA screening does not lower the risk for death from prostate cancer while there is evidence of harm (J Natl Cancer Inst 2012;104:125-132). Some would argue that rather than treating low-grade prostate cancers, it may be better not to diagnose it at all. This issue is sure to be a topic of discussion at the FDA if GlaxoSmithKline requests approval for dutasteride (Avodart) for the management of low-risk prostate cancer.

More to the avastin/breast cancer story?

In November 2011, the FDA revoked the approval of Genentech's bevacizumab (Avastin) for the treatment of breast cancer. The somewhat controversial decision was based on lack of evidence of improved survival with the drug, even though several studies have shown improvement in progression-free survival. This has sparked a debate regarding surrogate clinical endpoints, such as progression-free survival or pathological complete response, which is the endpoint used in two new studies recently published in the New England Journal of Medicine. The first study from Germany randomly assigned 1948 women with medium-sized tumors to receive neoadjuvant epirubicin and cyclophosphamide, followed by doxetaxel with or without bevacizumab, in patients with HER2-negative breast cancers. Rates of pathological complete response were 14.9% without bevacizumab and 18.4% with the drug (odds ratio 1.29; 95% CI, 1.02 to 1.65; P = 0.04). Patients with hormone receptor-negative ("triple negative") tumors did better while patients with hormone receptor-positive tumors saw no improvement (N Engl J Med 2012;366:299-309). The other study, supported by the National Cancer Institute, looked at about 1200 patients with operable HER2-negative breast cancer. Patients were given neoadjuvant therapy with docetaxel plus capecitabine or paclitaxel plus gemcitabine followed by doxorubicin-cyclophosphamide. They were further randomized to receive bevacizumab for the first six cycles. Adding capecitabine or gemcitabine to docetaxel had no effect and increased toxicity; however, adding bevacizumab increased the rate of pathological complete reponse (28.2% without bevacizumab vs the 34.5% with bevacizumab, P = 0.02). Bevacizumab increased the rates of hypertension, left ventricular systolic dysfunction, hand-foot syndrome, and mucositis. The authors conclude that bevacizumab significantly increased the rate of pathological complete response (N Engl J Med 2012;366:310-320). An accompanying editorial points out that the ongoing controversy regarding bevacizumab for the treatment of breast cancer revolves around the issue of using surrogate endpoints in clinical trials as well as broader economic issues in the treatment of cancer. Although the study showed improvement in the surrogate endpoint of pathological complete response (defined as absence of residual tumor in the breast and nodes in the European study and a less stringent criteria of absence of residual tumor in the breast only in the American study), neither study was powered to show differences in survival — the criteria the FDA used to withdraw the approval for bevacizumab (N Engl J Med 2012;366:374-375). It is unlikely that either of these studies will influence the FDA to change its decision until more definitive survival data are available.

Disclosure rule open for comments

The Centers for Medicare and Medicaid Services is requesting comments on a proposed rule that would require drug and device companies to report all financial relationships with physicians. The new rule is part of the Affordable Care Act. It would require disclosure of payments for food, entertainment, gifts, consulting fees, honoraria, research funding for grants, education or conference funding, royalties or licenses, and insurable contributions. Physicians would also need to disclose stock ownership in pharmaceutical and device companies, with all this information provided on a public website. Failure to disclose this information would mean substantial fines for physicians. Comments will be accepted until mid-February with the final rule expected later in 2012.

FDA actions

Responding to concerns about increasing antibiotic resistance, the FDA has issued an order that prohibits the use of cephalosporins in cattle, swine, chickens, and turkeys effective April 15, 2012. This rule is intended to limit the indiscriminate use of cephalosporins and preserve the effectiveness of the drugs in humans.

The FDA has approved a once-weekly, extended-release formulation of exenatide for treatment of type 2 diabetes. The drug is a glucagon-like peptide-1 receptor agonist and is indicated as an adjunct to diet and exercise for improved glycemic control. It is the first once-weekly diabetes drug to be approved. The approval was based on the DURATION-5 trial, which compared once-weekly exenatide with twice-daily exenatide injection. Exenatide extended-release is approved with a Risk Evaluation and Medication Strategy (REMS) because of concerns regarding acute pancreatitis and the potential risk for medullary thyroid cancer, as well as concerns about QT prolongation and cardiovascular risk. Exenatide extended-release will be marketed by Amylin Pharmaceuticals and Alkermes plc as Bydureon.

The FDA has approved vismodegib to treat adult patients with advanced basal cell carcinoma who are not candidates for surgery or radiation, and for patients with metastatic disease. The drug was approved under the agency's priority review program and is the first approved drug for metastatic basal cell carcinoma. The once-a-day oral pill inhibits the Hedgehog pathway, a molecular pathway found in basal cell carcinomas but few other normal tissues. The approval was based on a single, multicenter trial of 96 patients in which 30% of patients with metastatic disease experienced a partial response and 43% patients with locally advanced disease experienced a complete or partial response. Vismodegib is marketed by Genentech as Erivedge.

This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5404. E-mail: