FDA Safety Review of GnRH Agonists Used to Treat Prostate Cancer

Roxanne Nelson


May 04, 2010

May 4, 2010 — The US Food and Drug Administration (FDA) has announced that it is conducting an ongoing safety review of gonadotropin-releasing hormone agonists (GnRH) to address evidence that suggests an increased risk for diabetes and cardiovascular disease in men with prostate cancer who are treated with these drugs.

The "FDA became aware of the potential safety risk after several studies were published suggesting a small, statistically significant increase in the risk for diabetes, heart attack, stroke, and sudden death in men treated with one of the medications," explained Erica V. Jefferson, a press officer at the FDA. "As data emerged identifying these safety signals in this class of medications, the FDA believed it was important to conduct a review and communicate preliminary findings to the public."

The "FDA's review is ongoing, and we have not concluded that GnRH agonists increase the risk of diabetes and heart disease in patients receiving one of these medications to treat prostate cancer," she added. "After our review is complete, we will make a determination on next steps, which may include updates to the product labels."

Accumulating Evidence

The FDA review of these agents is not unexpected; a number of studies published over the past few years have shown suspected associations between these drugs and serious comorbidities. In February 2010, a joint advisory issued by the American Heart Association, the American Cancer Society, and the American Urological Association stated that "there may be a relationship" between androgen-deprivation therapy for prostate cancer and cardiovascular risk.

The purpose of the advisory is "strictly informative," according to its authors, and "should not be construed as dictating clinical practice or superseding the clinical judgment of physicians."

Although a causal relation between therapy with these agents and cardiovascular events "cannot be determined definitely at this point," the advisory states, "it is plausible."

Last year, findings from a large Swedish study, which were presented at the 2009 Congress of the European CanCer Organization and the European Society for Medical Oncology and were reported by Medscape Oncology at that time, showed that the risk is increased for all types of cardiovascular disease, including ischemic heart disease, myocardial infarction, heart failure, and cardiac arrhythmias.

Another recent study found that neoadjuvant hormone therapy was associated with a nearly 2-fold risk for death in prostate cancer patients who had a history of coronary artery disease (JAMA. 2009;302:866-873).

In an interview at the time that study was first published, lead author Akash Nanda, MD, PhD, from Brigham and Women's Hospital and the Dana-Farber Cancer Institute in Boston, Massachusetts, told Medscape Oncology that "our results suggest that for these men, either hormonal therapy not be used in the treatment of their prostate cancer, or their underlying heart disease be addressed by a primary-care physician and/or a cardiologist before they are considered for hormonal therapy."

The following GnRH agonists approved for the palliative treatment of advanced prostate cancer: leuprolide acetate (Lupron, Abbott; Viadur, Bayer; Eligard, Sanofi-Aventis; and generic formulations); triptorelin pamoate (Trelstar, Watson); histrelin acetate (Vantas, Endo); and nafarelin acetate (Synarel, Pfizer). Goserelin acetate (Zoladex, AstraZeneca) is approved for the palliative treatment of advanced prostatic cancer and, in combination with flutamide, for the management of locally confined stage T2b–T4 (stage B2–C) carcinoma of the prostate

Recommendations for Clinicians

For now, the FDA recommends that healthcare professionals:

  • Follow the recommendations in the drug label when prescribing GnRH agonists.

  • Carefully weigh the known benefits and risks of GnRH agonists when determining appropriate treatment for prostate cancer.

  • Monitor patients receiving GnRH agonists for diabetes and cardiovascular events.

  • Ensure that cardiovascular risk factors, such as blood pressure, cholesterol, blood sugar, weight, and smoking, are managed according to current clinical practice.

"While our review of these prostate cancer treatments is ongoing and there are some limitations to the data, the FDA believes it is important to tell patients and healthcare professionals that there may be an increased risk of serious side effects," said Robert Justice, MD, director of the Division of Drug Oncology Products in the FDA's Center for Drug Evaluation and Research, in a statement.

Some of the GnRH agonists are used in other populations and for other indications but, thus far, there are no known comparable studies that have evaluated the risk for diabetes and cardiovascular in women and children.


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