MANCHESTER, UKPrelim-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 faslodexs 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.
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 years 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.
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 faslodexs 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.