Agent may modulate side effects of androgen therapy for treatment of prostate cancer

May 15, 2007

Improved survival of prostate cancer patients treated with androgen deprivation therapy has drawn attention to the side effects of androgen-dependent care.

Key Points

Orlando, FL-In the distant past, many men with prostate cancer who were assigned to hormone therapy had widespread metastatic disease and a relatively short life expectancy. Today, the majority of men who undergo hormone therapy do not have metastatic disease and can expect extended survival. However, improved survival has drawn attention to the side effects of androgen-dependent care, as Matthew R. Smith, MD, PhD, pointed out.

Dr. Smith, associate professor of medicine at Massachusetts General Hospital Cancer Center, Boston, noted that marked changes in patterns of care have made understanding and preventing the side effects of treatment more important. Research in recent years has identified previously unappreciated side effects, including osteoporosis and associated fractures and cardiovascular disease.

A new agent that modulates the estrogen receptor may help lower the risk of these adverse events, Dr. Smith reported at the Prostate Cancer Symposium here.

"We use the term 'androgen deprivation therapy,' but standard forms of hormone therapy for prostate cancer dramatically reduce levels of testosterone, the primary male hormone made by the testes, as well as estrogen, a major metabolite of testosterone."

The selective estrogen receptor modulator toremifene citrate (Acapodene), commonly used to treat women with advanced breast cancer, is a promising candidate for managing androgen deprivation therapy-related side effects, according to findings from two interim analyses by Dr. Smith and colleagues.

Bone, CV health studied

Both analyses were based on results of a large, prospective, randomized controlled trial of 1,392 men, age 50 years and older who received androgen deprivation therapy for advanced prostate cancer at several centers in the United States and Mexico. Men were randomly assigned to receive toremifene, 80 mg, or placebo daily for 2 years.

In the first abstract, toremifene was shown to significantly increase bone mineral density compared with placebo. The mean percentage changes in bone mineral density from baseline in men receiving toremifene were 1.6%, 0.7%, and .2% in the lumbar spine, total hip, and femoral neck, respectively, compared with –0.7%, –1.3%, and –1.3%, respectively, in men receiving placebo (p<.001, .001, and .009). The magnitude of the benefit compared to placebo was in line with, if not greater than, the benefit previously reported in large pivotal studies of selective estrogen receptor modulators in postmenopausal women.

"We believe this will translate into fracture reduction when the results of the final study become available later this year," Dr. Smith said.

In the second analysis, at 12 months, data for the first 197 men to complete follow-up indicate that compared with placebo, toremifene significantly improved the total cholesterol/HDL ratio (11.7%; p<.001); significantly decreased total (7.1%; p=.001) and LDL cholesterol (9.0%; p=.003) and triglycerides (20.1%; p<.009), and increased HDL levels (5.4%; p=.018). These benefits were seen in both statin and non-statin users. Consequently, toremifene's favorable effect on lipoprotein profiles may predict cardiovascular benefits in men, Dr. Smith said.

Potential clinical benefits

Commenting on Dr. Smith's presentation, Dean F. Bajorin, MD, an oncologist at Memorial Sloan-Kettering Cancer Center, New York, said the current data address the important issues of bone and cardiovascular health in men being treated with androgen deprivation therapy for prostate cancer.

"We need to see if the effects he reports in the lab tests, in the bone health, and in cardiac profiles will translate into benefits in patients," Dr. Bajorin explained to Urology Times. "Hopefully, these data will be forthcoming shortly. If this is the case, that can improve the quality of life in men with prostate cancer."

"I think the message here is that there is a need for therapies to prevent the side effects of androgen deprivation therapy," Dr. Smith concluded. "The results of these interim analyses suggest that toremifene may be part of that plan."

Dr. Smith has disclosed that he is a consultant to Amgen, GTX, Novartis, and Abbott Oncology, and that he has received research support from Novartis Oncology and Abbott Oncology.