Antiestrogen may have antitumor activity in prostate cancer, according to study

San Francisco-Two-year progression-free survival (PFS) improved significantly in men with castration-resistant prostate cancer treated with toremifene, researchers from the University of Washington, Seattle, have found.

Men treated with toremifene were almost 30% less likely to have PSA progression at 2 years compared with men given placebo. Though exploratory in nature, the results add to a growing volume of clinical and preclinical evidence that the selective estrogen receptor modulator (SERM) has activity in prostate cancer.

"Toremifene may have antitumor activity, as demonstrated by an improvement in 2-year PSA progression-free survival in men receiving androgen deprivation therapy who have a detectable PSA at baseline," said first author Daniel Lin, MD, associate professor of urology at the University of Washington.

Toremifene has agonist or antagonist effects on estrogen receptors, depending on factors that include dose, sex, and hormone levels. The drug lacks the steroid structure of estrogens but has a tertiary structure that facilitates binding to the estrogen receptor.

Multiple lines of evidence support a rationale for SERMs' potential antitumor activity in prostate cancer, noted Dr. Lin, who presented the results at the AUA annual meeting in San Francisco. Estrogen receptors are present in prostate and breast tissue. Toremifene (Fareston) and tamoxifen (Nolvadex) are approved for treatment of breast cancer. SERMs are antiestrogenic in the prostate and breast.

Of particular relevance to prostate cancer, toremifene and other SERMs have been shown to inhibit proliferation of prostate cancer cell lines and induce apoptosis. Toremifene prevents tumor development in the TRAMP (TRansgenic Adenocarcinoma Model of the Prostate) model of prostate cancer. Men with high-grade prostatic intraepithelial neoplasia had a lower incidence of prostate cancer when treated with toremifene compared with placebo.

Agent may prevent bone fractures

Toremifene also has bone-preserving properties that could apply to prevention of fractures and other adverse effects of androgen deprivation therapy (ADT) in prostate cancer. In a large, placebo-controlled clinical trial, prostate cancer patients treated with toremifene had more than a 50% reduction in new vertebral fractures during 2 years of follow-up.

Data from the fracture trial afforded an opportunity for an exploratory analysis of toremifene's effect on PSA progression. The analysis focused on patients who had baseline PSA values >0.1 ng/mL, identifying them as high risk for progression, which investigators defined as a rise in baseline PSA ≥25% and to >2.0 ng/mL.

The analysis comprised 174 patients treated with toremifene and 198 allocated to placebo. The men had a median age of 78 years, and the median time since diagnosis was 6.5 years in the toremifene group and 6.0 years in the placebo-treated patients. About 90% of both groups received an LHRH agonist for ADT, and the median time on ADT was 3 to 3.5 years.

The median baseline serum total testosterone was 20 ng/dL in both groups. More than 90% of men in both groups had castrate levels of testosterone (<50 ng/dL) at baseline. The median baseline PSA was 0.5 ng/mL in the toremifene group and 0.6 ng/mL in the placebo group.

After 2 years of treatment, 47 of 174 (27%) men in the toremifene group had progressed compared with 74 of 198 (37.4%) in the placebo group (p=.049).

Dr. Lin disclosed relationships with GTx Inc.