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Section 6
Faslodex®(fulvestrant): An estrogen receptor downregulator

OVERVIEW

Numerous phase III randomized clinical trials have demonstrated the efficacy of selective estrogen receptor modulators (SERMs) in women at increased risk for breast cancer, DCIS and invasive disease in the adjuvant and metastatic setting. Until recently, antiestrogens had minimal impact on patients progressing on tamoxifen, but Faslodex, a novel agent with a mechanism distinct from SERMs, has now demonstrated efficacy at least equivalent to anastrozole in tamoxifen-resistant patients. Faslodex is being compared to tamoxifen for advanced disease, and a new generation of trials will evaluate neoadjuvant and adjuvant therapy with this unique endocrine agent.

BIOLOGIC EFFECTS

Faslodex is a very interesting agent. I was a co-author on one of the very early Phase 1 studies looking at the mechanism of action. Surprisingly, as well as it being a pure antiestrogen, Faslodex is an estrogen receptor downregulator. It's an extraordinarily elegant molecule. Biologically, it's very attractive, because there's no other molecule that works as an estrogen receptor antagonist and downregulator, and also as an antiangiogenic agent.

-Michael Baum, ChM, FRCS

MECHANISM OF ACTION

If you look at the spectrum of drugs that interact with the estrogen receptor, estrogen is on one end of the spectrum, stimulating most genes under its control after binding to the estrogen receptor. Drugs like tamoxifen stimulate some genes and inhibit others, depending on the tissue and gene. At the far other end of the spectrum, drugs like Faslodex seem to have a pure antiestrogenic profile on all genes with none of the agonist qualities of tamoxifen.

There are several activation domains on the estrogen receptor protein - areas that seem to be important in activating transcription of genes. Tamoxifen blocks only one of these. The other is still active, which may give rise to the agonist qualities of tamoxifen. Faslodex, in contrast, blocks all of the activation domains - both AF-1 and AF-2. Faslodex also reduces the level of estrogen receptor in cells. In some cases, you can't measure any estrogen receptor after exposure to Faslodex. So, Faslodex doesn't have any agonist activity, blocks all transcription domains and gets rid of the estrogen receptor.

-C Kent Osborne, MD

Mode of action of estradiol (E)

1. E binds with high affinity to the estrogen receptor (ER) to form an E-ER complex.
2. The E-ER complex pairs with another E-ER complex (dimerizes) and localizes in the cell nucleus. The two transcription activation functions of ER, called AF1 and AF2, are both active.
3. The E-ER dimer binds to estrogen-sensitive genes at the estrogen response element (ERE).
4. The dimer activates transcription of the estrogen-sensitive gene. (AF1 and AF2 interact with coactivators to stimulate the transcription enzyme RNA polymerase II [RNA POL II].)

Mode of action of tamoxifen (T)

1. T binds to ER with low affinity compared with E.
2. The T-ER complex dimerizes and localizes in the cell nucleus, and AF1 (but not AF2) is active.
3. The T-ER dimer binds to the gene DNA at the ERE.
4. Transcription of the estrogen-sensitive gene is lessened because AF2 is inactive and coactivator binding is likewise attenuated. AF1 activity results in the partial agonist activity of T.

Mode of action of Faslodex (F)

1. F binds to ER with affinity similar to E.
2. F triggers rapid degradation of ER.
3. The F-ER complex results in reduced rate of dimerization and nuclear localization.
4. There is reduced binding of F-ER to ERE on the gene resulting in blocked transcription.

SECOND-LINE TRIALS FOR METASTATIC DISEASE: FASLODEX VERSUS ARIMIDEX

The European trial and the American trial are a little bit different in their structure and results. The American trial - which I think has a better design - was a double-blind study. Patients assigned to Arimidex received placebo injections. So, it's clearly blinded. Also, because the patients in both groups had to come to the clinic once a month, there was consistency with regard to the patient being seen.

The European trial was not double-blinded. The patients on Arimidex were seen every three months, while the patients on Faslodex were seen by someone every month. This design has the potential to have some bias in terms of identifying when the patient progresses. Patients in the Faslodex group of the European trial were seen more often, and conceivably progression would be identified a little earlier than in an Arimidex patient.

Having said that, the results show similar response rates between the two drugs, but in the American trial the response duration is about twice as long for Faslodex compared to Arimidex. We have to keep it in mind that aromatase inhibitors are very good agents in and of themselves, and in one of these new trials, Faslodex is at least as good as Arimidex, and in the other we see an advantage at least in one important parameter.

-C Kent Osborne, MD

In terms of efficacy, Faslodex was at least equal to treatment with a third-generation aromatase inhibitor, which currently is our best endocrine therapy for postmenopausal patients. There were also some hints that Faslodex might be a bit better, mainly in the North American trial, where the overall rates of objective response and clinical benefit were slightly higher for Faslodex, though not statistically significant. The duration of response in Trial 0021 was significantly better for Faslodex and was of a magnitude that is clinically and humanly worthwhile in the metastatic setting. These results suggest that perhaps this agent also might give an extra boost as adjuvant therapy which will be tested in clinical trials.

-Richard Elledge, MD

NONBREAST EFFECTS OF FASLODEX

This is a completely new class of antiestrogen. It differs from tamoxifen and other SERMS in that it increases degradation of the estrogen receptor, resulting in dramatic reductions in this protein. It also shuts down both AF1 and AF2 transcription functions, and it appears not to have any estrogenic activity. This agent may be one of the most important new developments in endocrine therapy.

The lack of estrogen agonistic properties would clearly be beneficial in terms of the endometrium. Thus far from available studies, Faslodex seems to have a neutral effect on bone or lipids, but we need more information about those systems.

Faslodex doesn't seem to cause hot flashes, probably because it is not thought to cross the blood-brain barrier. It is given by monthly intramuscular injection, which is well-tolerated. Patients in the metastatic setting don't seem to have a problem coming for the injection, because it provides more contact with the oncology nurse. In the adjuvant setting, if Faslodex proves to be more efficacious, I have no question that an injection once a month will not be a deterrent to patients receiving this agent.

We have identified a new endocrine therapy option for postmenopausal breast cancer patients, and it is exciting to now have a second antiestrogen, which is clinically active in patients who become tamoxifen-resistant. This is the first time we've ever seen an antiestrogen produce clinically significant response rates in a randomized trial in tamoxifen-resistant patients. That is really quite a significant event, and I think that these studies will change the concept of antiestrogen therapy in the same way the Arimidex-Megace studies changed concepts of endocrine therapy of breast cancer.

-John F Robertson, MD, FRCS

EFFECTS IN PREMENOPAUSAL PATIENTS

There's been some reservation about the use of Faslodex in premenopausal women, because the large randomized trials were in postmenopausal patients. In Trial 19 in premenopausal women about to undergo hysterectomy for fibroids, there was no increase in side effects compared to placebo. It was very well-tolerated. A number of biologic endpoints were measured and were unchanged. Unlike tamoxifen, estrogen levels did not significantly increase when Faslodex was given to premenopausal patients, and there's no biologic reason to think that it wouldn't be effective in these women. We used to think that tamoxifen wouldn't be effective in premenopausal patients, but the Overview demonstrates that tamoxifen has efficacy that's not measurably different than in postmenopausal patients.

-Richard Elledge, MD

INTRAMUSCULAR INJECTION

The good thing is that coming in every month and getting the injection is not a big problem. It's a 5 cc injection, which for some reason terrorized everybody in the beginning, and initially we actually gave it in split doses. But in fact, you can give 5 cc's or 2.5 cc's twice and neither of them cause much in the way of local problems at all. It's very well-tolerated. In the trials, we could not tell which were Faslodex injections and which we re the placebo injections. If this drug is move d into the adjuvant setting, that could be more of an issue, but in the metastatic setting it doesn't seem to be an issue for our patients at all. We've had some experience in the adjuvant setting using another injectable over a five-year period, and actually once you get the mechanisms in place to deliver the injection, it doesn't seem to be a big issue.

- Kathleen Pritchard, MD

SECONDARY EFFECTS

There is some data in animals suggesting that the effects of Faslodex on bone may be neutral or even slightly positive. This may relate to the types of estrogen receptor and tissue-specific effects. I believe that Faslodex downregulates both alpha and beta estrogen receptor, but there are co-regulators, and there could be a number of other more complicated things going on that may vary from one tissue to another. The whole area is very complex. We understand a lot about it, but like many issues in breast cancer, the more we understand, the more we have to ask. It's possible that a drug like Faslodex is not a pure antiestrogen at all, but rather a complex drug that interacts differently with receptors in bone and in some other tissues. Certainly, in the long term, osteoporosis and heart disease are issues that will have to be explored.

- Kathleen Pritchard, MD

COMBINING FASLODEX AND AN AROMATASE INHIBITOR

Conceptually, it's a very interesting compound, and I think it's going to be an exciting agent as we move forward. We participated in both trials of Faslodex versus Arimidex and Faslodex versus tamoxifen. It would be interesting to combine Faslodex with another agent with a different mechanism of action - perhaps an aromatase inhibitor. In the past, we had problems with tolerability when we combined endocrine agents. Now we have more selective compounds, and the idea of combining therapies is being revisited - for example, the ATAC trial where Arimidex is being combined with tamoxifen as adjuvant therapy.

Preclinically in animal models, Faslodex didn't have a uterotropic effect, so you didn't end up with endometrial hyperplasia. If the metastatic data look promising enough, it would be reasonable to look at that kind of compound in the adjuvant setting, but we would also need to evaluate the effects on the heart, bone, etc.

The monthly intramuscular injection doesn't seem to be much of a deterrent. For older patients where there may be a compliance question, the injection may be a plus. Also there are some patients where reimbursement may be more favorable for an injectable agent. Other patients may not like the idea of an injection or coming to the doctor's office once a month - they prefer a pill. Efficacy will be the key determining factor though, particularly if we move to the adjuvant setting.

- William Gradishar, MD

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