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For the more than 800,000 men undergoing androgen deprivation therapy (ADT) for prostate cancer, managing the side effects of ADT is nearly parallel to managing the disease. The most common treatment for men with advanced prostate cancer, ADT includes a variety of therapeutic methods that manipulate vital hormones to decelerate the disease. Yet, in that process, common side effects like bone fractures, hot flashes and lipid changes can seriously decrease patients’ quality of life. Currently there are no drugs approved by the U.S. Food and Drug Administration (FDA) for the multiple side effects of ADT. GTx, a local biopharmaceutical company, has been testing Acapodene® (toremifene citrate), a selective estrogen receptor modulator (SERM), as a treatment for such side effects.

In February the company released data on a Phase III clinical trial involving an 80-milligram dose of Acapodene, which showed a 50 percent reduction in bone fractures, suggesting there may be relief on the horizon. This is the first fraction prevention study in men receiving ADT for prostate cancer. Based on their findings with key endpoints including fractions and hot flashes, GTx plans to file a new drug application (NDA) with the FDA by this summer.

GTx is licensed to test toremifene citrate for all indications worldwide except breast cancer outside the United States. The company has been hit by falling stock prices due to less than stellar results on another study involving Acapodene 20-milligram for the prevention of prostate cancer in high risk men. While the 20-milligram Acapodene data has unmet statistical goals for the prevention of prostate cancer, the study is ongoing and researchers expect improved results for the final analysis next year. The good news for Acapodene is the 80-milligram trial showed late-stage positive results that may boost the company closer to an NDA for the compound.

Toremifene citrate in 60 milligram form (FARESTON®), has long proven useful for treatment of metastatic breast cancer in post menopausal women with ER positive and ER unknown tumors.

Further study into the possible benefits of the molecule motivated the 80-milligram trial to investigate its efficacy as a therapy to counteract the side effects of ADT; particularly bone fractures which can significantly decrease survival.

ADT is typically used in patients who are unable to have surgery or who cannot be cured by radiation. It’s also used in patients with a high risk of cancer recurrence and before surgery in an effort to make other treatments more effective. Types of ADT include orchiectomy (surgical castration) and a variety of non-surgical therapies including luteinizing hormone-releasing hormone (LHRH) analogs, luteinizing hormone-releasing hormone (LHRH) antagonists, and anti-androgens. All of these forms of ADT, particularly orchiectomy, can lead to side effects such as hot flashes, osteoporosis, anemia, muscle wasting, fatigue and decrease in HDL, among others.

Previous studies have shown that men on ADT are not only at increased risk for fractures, but ADT patients who develop a fracture have a 39-month shorter mean life expectancy. In addition, ADT patients are at higher risk for cardiovascular disease and death.

“Toremifene citrate is a weak estrogen that increases bone mineral density,” explained Dr. Gary Barnette, vice president of clinical research and development strategy for GTx. “(With this drug) we hope to improve the prognosis of these patients.”

“With a 50 percent reduction in fractures,” he continued, “we believe that this drug could have a very positive benefit in this patient population.”

Study results showed a significant decrease in hot flashes as well. Hot flashes are the most common and universally troublesome symptomatic side effect of ADT, reported by up to 80 percent of patients. Analysis of patients experiencing six or more hot flashes per day, who were not being treated with megestrol acetate, showed Acapodene treatment reduced the number of hot flashes by an average of 4.7 hot flashes per day, which endured for at least 12 months. Other key endpoints were met including improvements in bone mineral density, lipid profiles and gynecomastia.

Acapodene was well tolerated by study patients and has a favorable safety profile. According to study data, the most common adverse events were joint pain, dizziness, back pain and extremity pain.

“We hope to bring this important drug to the market quickly,” said Barnette. “This is an unmet medical need and we’re excited with this drug and data. We will submit to the FDA by the end of summer and will wait for their responses.”

For more information about Acapodene clinical trials, visit: www.gtxinc.com



June 2008

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