Toremifene Reduces Fractures and Hot Flashes From ADT in Prostate Cancer

Zosia Chustecka

March 06, 2008

March 6, 2008 — Toremifene has been shown to reduce the incidence of vertebral fractures and hot flashes in men with prostate cancer taking androgen-deprivation therapy (ADT) in a phase 3 clinical trial. The drug, a selective estrogen-receptor modulator (SERM), is being developed for the treatment of serious adverse effects related to ADT in prostate cancer by GTx, Inc. The company hopes to file a product-license application for this indication (under the trade name Acapodene) by summer 2008; it already markets toremifene (as Fareston) in the United States for use in metastatic breast cancer.

The results were announced in company press releases, and GTx says that the details will be presented at medical meetings later in the year. They come from a 2-year double-blind placebo controlled study of 1389 patients conducted at approximately 150 sites in the United States and Mexico.

The primary end point was new morphometric vertebral fractures, as shown on x-rays read by an independent third party. The estimated 2-year fracture rate in the placebo group was 6.2%. This is about 10 times greater than that seen in men of a similar age not receiving ADT, commented lead investigator Matthew Smith, MD, PhD, from the Massachusetts General Hospital Cancer Center and Harvard Medical School, in Boston.

In an intent-to-treat analysis, which included all patients randomized in the trial, toremifene 80 mg showed a 53% reduction in new morphometric vertebral fractures (P = .034), the company said. In prespecified subset analyses, study patients who were more than 80% compliant with treatment showed a reduction in fractures of 61% (P = .017).

A key secondary end point was the incidence of hot flashes. In a subset of patients who were experiencing 6 or more hot flashes per day and who were not being treated with megestrol acetate (Megace), toremifene reduced the number of hot flashes by an average of 4.7 per day, compared with the reduction of 1.6 per day seen with placebo (P = .03). This reduction in hot flashes with toremifene was durable for at least 12 months, the company said.

"Hot flashes are the most common and bothersome symptomatic side effect of ADT," Dr. Smith commented in the press release. "Up to 80% of men on ADT report being troubled by hot flashes, which are often cited as a cause of noncompliance with hormone therapy," he added.

In addition, when compared with the placebo group, men in the toremifene group had statistically significant increases in bone mineral density at the lumbar spine, hip, and femur skeletal sites (P < .0001 at each site). Toremifene also resulted in a decrease in total cholesterol (P = .011), low-density lipoprotein (LDL) cholesterol (P = .018), and triglycerides (P < .0001), and an increase in high-density lipoprotein (HDL) cholesterol (P = .001). There were also statistically significant improvements in gynecomastia (P = .003). These results on bone mineral density and lipid levels have been reported previously by Medscape Oncology. At the time, an independent expert said the effects seen to date were on surrogate markers, and it remained to be seen whether they would translate into clinically meaningful end points, such as reductions in fractures. With the latest results announced by the company, it appears that they have done so.

Toremifene 80 mg was well tolerated and showed a favorable safety profile, according to GTx. The most common adverse effects were joint pain (reported by 7.3% of patients on toremifene and 11.8% on placebo), dizziness (6.3% vs 5.0%), back pain (5.9% vs 5.2%), and extremity pain (5.0% vs 4.4%).

Venous thromboembolic events (VTE) occurred in 17 patients (2.4%) in the toremifene group and7 patients (1.02%) in the placebo group. The majority of these VTE occurred in men at high risk, including those older than 80 years, those with a history of VTE, and those with recent surgical procedures and immobilization, the company said. Of men without major risk factors for VTE, there were 3 events in the toremifene group and 2 in the placebo group. In addition, the most significant of these events occurred in the first year of treatment. During the second year of treatment, the VTE rate was similar in the toremifene and placebo groups.


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