Toremifene May Protect Against Side Effects of Androgen Rx

ORLANDO—In a phase III study, toremifene (Acapodene), a selective estrogen receptor modulator, increased bone mineral density (BMD) and improved lipid profiles in men receiving androgen deprivation therapy (ADT) for advanced prostate cancer, and may prove to be a useful adjunct to protect against the multiple serious adverse effects of ADT, Matthew R. Smith, MD, PhD, reported at the 2007 Prostate Cancer Symposium (abstracts 149, 150). "In previous studies, other agents, including bisphosphonates, have also been associated with significant improvements in BMD in men receiving ADT for advanced prostate cancer," said Dr. Smith, associate professor of medicine, Massachusetts General Hospital Cancer Center and Harvard Medical School. "However, our study results suggest that toremifene has the potential not only to reduce the risk of fractures in men receiving ADT, but also to improve lipid levels, addressing another significant side effect of the standard treatment for this disease."

ADT produces an average 9% increase in total cholesterol and 26% increase in triglycerides.

The ongoing multicenter study includes 1,392 men aged 50 and older receiving ADT for advanced prostate cancer at centers in the United States and Mexico. The men were randomly assigned to receive toremifene 80 mg/d or placebo by mouth daily for 2 years.

In the first planned interim analysis, BMD was measured in 200 of the men after they were on toremifene for 12 months. The men had been treated with ADT for at least 6 months prior to initiation of toremifene and were deemed to be at increased risk of fracture because they were 70 years or older, or had evidence of osteoporosis or osteopenia by baseline dual energy x-ray absorptiometry (DEXA), Dr. Smith said.

At 12 months, the study found that toremifene significantly increased BMD in the lumbar spine by 1.6%, in the hip by 0.7%, and in the femoral neck by 0.2%, whereas men randomized to placebo experienced decreases in BMD at these sites of 0.7%, 1.3%, and 1.3%, respectively.

In the second planned interim analysis, lipid levels were examined in 197 of the men after 12 months. Compared with placebo, toremifene significantly decreased total cholesterol by 7.1%, LDL cholesterol by 9.0%, and triglycerides by 20.1%, and increased HDL cholesterol by 5.4%. The effects were observed in both statin users and nonusers, he said.

"These are highly significant improvements in lipid profiles in men receiving ADT, exactly the pattern of good lipoprotein changes you would like to see and that we believe will predict improvement in cardiac outcomes. This outcome, as well as the BMD fracture endpoint, will be determined by the ongoing trial," he said. The trial is sponsored by GTx, Inc., Memphis, maker of Acapodene.