Fulvestrant

Medical uses

Fulvestrant is used for the treatment of hormone receptor positive metastatic breast cancer or locally advanced unresectable disease in postmenopausal women; it is given by injection. A 2017 Cochrane review found it is as safe and effective as first line or second line endocrine therapy.

It is also used to treat HR-positive, HER2-negative advanced or metastatic breast cancer in combination with palbociclib in women with disease progression after first-line endocrine therapy.

It should not be used in women with kidney failure or who are pregnant.

Due to the medication having a similar chemical structure to estrogen, it can interact with immunoassays for blood estradiol concentrations and show falsely elevated results. This can improperly lead to discontinuing the treatment.

Adverse effects

Very common (occurring in more than 10% of people) adverse effects include nausea, injection site reactions, weakness, and elevated transaminases. Common (between 1% and 10%) adverse effects include urinary tract infections, hypersensitivity reactions, loss of appetite, headache, blood clots in veins, hot flushes, vomiting, diarrhea, elevated bilirubin, rashes, and back pain.

Pharmacology

Fulvestrant is a selective estrogen receptor degrader (SERD).

It works by binding to the estrogen receptor and making it more hydrophobic, which makes the receptor unstable and misfold, which in turn leads normal processes inside the cell to degrade it.

Fulvestrant is slowly absorbed and maximum plasma concentrations (Cmax) are reached after about 5 days and the terminal half-life is around 50 days. Fulvestrant is highly (99%) bound to plasma proteins includiung very low density lipoprotein, low density lipoprotein, and high density lipoprotein. It appears to be metabolized along the same pathways as endogenous steroids; CYP3A4 may be involved, but non-cytochrome routes appear to be more important. It doesn't inhibit any CYP450 enzymes. Elimination is almost all via feces.

Chemistry

Fulvestrant is a steroid; an alkyl-sulfinyl moiety was added to the endogenous estrogen receptor ligand, 17β-estradiol.

It was discovered through rational drug design, but was selected for further development via phenotypic screening.

Society and culture

It was the first selective estrogen receptor degrader to be approved, and was approved in the US in 2002 and in Europe in 2004.

NICE evaluation

The U.K. National Institute for Health and Clinical Excellence (NICE) said in 2011 that it found no evidence Faslodex was significantly better than existing treatments, so its widespread use would not be a good use of resources for the country's National Health Service. The first month's treatment of Faslodex, which starts with a loading dose, costs £1,044.82 ($1,666), and subsequent treatments cost £522.41 a month. In the 12 months ending June 2015, the UK price (excluding VAT) of a month's supply of anastrozole (Arimidex), which is off patent, cost 89 pence/day, and letrozole (Femara) cost £1.40/day.

Patent extension

The original patent for Faslodex expired in October 2004. Drugs subject to pre-marketing regulatory review are eligible for patent extension, and for this reason AstraZeneca got an extension of the patent to December 2011. AstraZeneca has filed later patents. There is no generic Faslodex available. A later patent for Faslodex expires in January 2021.

Research

Fulvestrant was studied in endometrial cancer but results were not promising and as of 2016 development for this use was abandoned.

Because fulvestrant is a steroid and cannot be given orally, efforts have been made to develop SERD drugs that can be taken by mouth, including brilanestrant and elacestrant. The clinical success of fulvestrant also led to efforts to discover and develop a parallel drug class of selective androgen receptor degraders (SARDs).