Fulvestrant (Faslodex)

Is an analog 17B- estradiol binds the estrogen receptor with a similar affinity as estrogen.

An analogue of estradiol that down-regulates the estrogen receptor by disruption of of estrogen- receptor dimerization and accelerating degradation of the unstable fulvestrant-estrogen receptor complex.

It is a selective estrogen receptor degrader (SERD).

Reduces cross-talk between estrogen receptor and estrogen independent growth factor signaling, delaying resistance to hormone treatment.

An estrogen receptor downregulator.

Approved for treatment of hormone receptor positive metastatic breast cancer in postmenopausal women with disease progression following endocrine therapy.

Approved as a front line indication as monotherapy for postmenopausal women with hormone receptor positive, HER 2 negative locally advanced or metastatic breast cancer that have not been previously treated with endocrine therapy.

It is approved in the first and second line settings for hormone receptor positive metastatic breast cancer as a single agent and then combination with aromatase inhibitor’s, CDK4/6 inhibitors, and phosphoinositide 3-kinase (PI3K)  inhibitor alpelisib.

Similar to tamoxifen, it binds competitively to the estrogen receptor but with a higher affinity.

Like Tamoxifen it works at the receptor level, and is as effective or slightly more effective than aromatase inhibitors.

Fulvestrant blocks estrogen sensitive gene transcription, resulting in no known agonist activity.

When binds to the estrogen receptor, the receptor is disrupted leading to increased receptor degradation and decreases the receptor half-life.

Unlike tamoxifen this agent blocks the effect of growth factor signaling via the estrogen receptor and has little agonist activity.

Inhibits ER dimerization and translocation to the nucleus and accelerates ER degradation, resulting in complete suppression of estrogen effects on breast tissue.

As active as tamoxifen when used as first line treatment for metastatic breast cancer, and as active as anastrozole when given to patients with progressive disease after receiving tamoxifen.

Aromatase inhibitor acts in breast cancer by down-regulating expression of estrogen receptors.

As a third line drug for patients with ER+ disease Fulvestrant can benefit 20-30% of patients who have failed tamoxifen or other aromatase inhibitors in the metastatic setting for 6-26 months.

Randomized trials comparing this drug with tamoxifen, anastrozole, and exemestane in breast cancer indicated equivalency.

With standard dosing of 250 mg/month intramuscularly it take 2-3 months to reach steady state.

A loading dose accelerates achievement of steady state plasma levels, whether this leads to an earlier time to response is not clear.

Time to response not significantly different from other endocrine therapies.

Tumor markers may increase during the first few months of treatment and it is suggested that therapy needs to be continued for a minimum of 3 months before considering a change in treatment.

EFECT trial demonstrated the equivalence of this agent and exemestane in estrogen receptor positive metastatic breast cancer that had progressed on aromatase inhibitors

Increasing the dose to 500 mg per dose is associated with a 20% improvement over the 250 mg dose in patients with advanced estrogen receptor positive breast cancer in a randomized trial involving 736 postmenopausal women: Clinical benefit in the 500 mg group was 45.6% versus 39.6% in the 250 mg group, the median duration of response was 16.6 months versus 13.9 months, the objective response rates were the same between both groups 9 and 10%, and the median overall survival was 25.1 months in the high-dose group versus 22.8 months in the low-dose group, toxicity was he same in each group (CONFIRM).

NEWEST (Neoadjuvant Endocrine Therapy for Women with Estrogen Sensitive Tumors) trial 500 mg/month significantly decreased Ki-67 scores and ER expression levels compared to 250 mg/month (Kuter I et al).

Combination of fulvestrant and aromatase inhibitor, as compared with either drug alone, delays development of resistance by down regulating signaling molecules involved in the development of resistance.

Adding fulvestrant to everolimus in postmenopausal women with advanced breast cancer results in a progression free survival of 10.4 months versus 5.1 months for fulvestrant alone.

Fulvestrant added to anastrozole is associated with increased long-term survival as compared with anastrozole alone: there was substantial crossover to fulvestrant after progression during therapy with anastrozole alone.

Most common adverse events associated include menopause-like symptoms such as hot flashes.

Leave a Reply

Your email address will not be published. Required fields are marked *