Faslodex, Pure Antiestrogen, Studied in Tamoxifen-Resistant Breast Cancer

MANCHESTER, UK—Prelim-inary experience with the pure antiestrogen faslodex (investigational) suggests the agent has activity in tamoxifen (Nolvadex)-resistant breast cancer while avoiding troublesome side effects such as hot flashes often observed with endocrine therapy, Dr. Anthony Howell said at the San Antonio Breast Cancer Symposium.

“Clearly, faslodex represents a new class of nonagonist antiestrogens based on the estrogen molecule,” said Dr. Howell, professor of medical oncology, University of Manchester.

The agent is distinct from tamoxifen, raloxifene (Evista), and other antiestrogens, he said. “Faslodex has demonstrated clinical activity in the important hard-to-treat situation of tamoxifen-resistant breast cancer. A first-line study comparing faslodex against tamoxifen is just getting under way.”

Faslodex, or ICI 182,780, evolved from a desire to “discover a novel antiestrogen that was devoid of the partial agonist, estrogen-like activity of tamoxifen and other antiestrogens,” he said. “It was thought that such a compound would have greater efficacy in breast cancer and absence of trophic effects on the endometrium.”

An initial clinical investigation assessed faslodex’s antitumor activity when given prior to surgery. A total of 56 patients received no presurgical therapy, 6 mg injections of faslodex given for 7 days before surgery, or 18 mg faslodex injections for 7 days before surgery (Cancer Res 54:408-414,1994). Faslodex dramatically suppressed estrogen-receptor (ER) expression, “substantiating in humans what had been observed in preclinical studies,” Dr. Howell said.

A subsequent evaluation compared the effects of presurgical faslodex, tamoxifen, or placebo on ER protein synthesis (Breast Cancer Res Treat 41:31-41,1996). The primary conclusion was that faslodex “appears to produce a greater inhibition of estrogen-induced transcriptional events than tamoxifen,” Dr. Howell said.

Faslodex also has been evaluated in a small group of patients who had relapsed after at least 2 years of tamoxifen therapy. In this study, seven patients had disease stabilization with faslodex, but the noteworthy finding was a median duration of response of 26 months. “At the time, we considered that a very long response and were quite excited,” Dr. Howell said. “Historically, we always felt there would be about a year’s response to second-line therapy.”

The investigators also were encouraged by findings related to faslodex tolerability, specifically hot flashes. Women who had a history of hot flashes at study entry experienced no change when they began faslodex, and the agent did not induce hot flashes in women who had no history of hot flashes. The incidence of vaginal dryness also did not increase during faslodex therapy.

Preclinical studies have suggested that faslodex does not cross the blood-brain barrier, which might explain the lack of hot flashes observed in women taking the drug, Dr. Howell said.

Analysis of endometrial thickening in five of the tamoxifen-resistant patients showed no adverse effect of faslodex. “All the women in the study had been on tamoxifen, so their endometrium was already thickened when they began faslodex,” he said. “During faslodex therapy, the endometrium stayed exactly the same. We interpret that to mean that we need more data.”

Faslodex had no effect on prolactin levels, sexual function, or lipid levels. There were no deaths and virtually no withdrawals for adverse events in faslodex-treated patients.

“You will find it extremely hard to find any side effects at all with this drug, aside from occasional injection-site reactions,” Dr. Howell said.

Investigators in the United States and Europe are comparing faslodex and the aromatase inhibitor anastrozole (Arimidex) in two randomized clinical trials of second-line therapy in postmenopausal patients with advanced breast cancer. The trials are statistically powered to detect superiority of faslodex, particularly in terms of the primary end point of time to progression, Dr. Howell said.

First-Line Therapy

A study of first-line therapy with faslodex has just begun, he added. Patients will be randomized to faslodex or tamoxifen. The agent also is being evaluated in women with uterine fibroids. Data from these studies should be available by the end of 1999 and should provide needed information on faslodex’s impact on bone resorption and lipids. “In some animal models, there is no apparent effect on bones, and in others, it appears faslodex does have an effect,” he said. “We need to know what is happening in women.”