Arzoxifene as therapy for endometrial cancer

Arzoxifene, an orally active third-generation selective estrogen-receptor modulator (SERM), opposes the action of estrogen on the breast and endometrium but exerts an estrogen-agonist effect on bone and the lipid profile. Since this is an appealing combination for hormonal therapy of estrogen-related cancers, we initiated testing the potential of arzoxifene in women with treatment-refractory endometrial cancer.

Two phase I studies were conducted to evaluate the safety and pharmacokinetics of single and multiple doses of arzoxifene. In addition, two multi-institutional phase II trials have been completed on 100 women with metastatic or recurrent endometrial cancer.

No serious adverse events were observed in the single-dose phase I study, the principal side effect being hot flashes in 5/15 healthy volunteers. In the second phase I study, conducted in 32 women with metastatic breast cancer, one patient had a serious, possibly drug-related adverse reaction (pulmonary embolism). The two multi-institutional trials demonstrated significant activity at 20 mg/day in patients with metastatic or recurrent endometrial cancer. Observed clinical response rates were 25 and 31%, with a median response duration of 19.3 and 13.9 months, respectively. Progression of the disease was stabilized in a substantial number of women. Toxicity was mild, except for two cases of pulmonary embolism that might have been drug related.

Further investigation is warranted to verify these preliminary response rates and the clinical significance of the stable disease cases, to compare clinical outcomes with those in progestin-treated women, and to elucidate the mechanisms of SERM action in this disease.