Fulvestrant — Drug Monograph

Brand names: Faslodex

Drug class: Hormonal Agent

Mechanism of Action

Fulvestrant is a selective estrogen receptor degrader (SERD) that binds the estrogen receptor-alpha (ERα) with approximately 100-fold greater affinity than tamoxifen. Upon binding, fulvestrant induces a unique conformational change in the ligand-binding domain that prevents co-activator recruitment, causes receptor dimerization failure, and targets the ER protein for ubiquitin-proteasome–mediated degradation, resulting in near-complete depletion of cellular ERα protein. Unlike tamoxifen, fulvestrant has no partial agonist activity and does not stimulate estrogen-responsive gene…

FDA Indications

• Hormone receptor-positive (HR+), HER2-negative advanced or metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy — approved 2002
• HR+/HER2- advanced or metastatic breast cancer in combination with palbociclib (CDK4/6i) in postmenopausal women with disease progression after endocrine therapy — approved 2016 (PALOMA-3 trial)
• HR+/HER2- advanced or metastatic breast cancer in combination with abemaciclib (CDK4/6i) — approved 2018 (MONARCH-2 trial)
• HR+/HER2- advanced or metastatic breast cancer in combination with ribociclib (CDK4/6i) — approved 2018 (MONALEESA-3 trial)

Common Side Effects

• Injection site reactions (pain, inflammation) (11-14%)
• Hot flush (13%)
• Nausea (26%)
• Fatigue (23%)
• Musculoskeletal pain (16%)
• Arthralgia (16%)
• Headache (15%)
• Back pain (14%)
• Vomiting (13%)
• Anorexia (12%)
• Peripheral edema (10%)
• Constipation (13%)

Clinical Pearl

ESR1 ligand-binding domain mutations (e.g., Y537S, D538G) arise in up to 40% of HR+ metastatic breast cancers after aromatase inhibitor therapy and confer relative resistance to fulvestrant; detection via circulating tumor DNA guides sequencing toward elacestrant or newer oral SERDs. The 500 mg loading regimen (days 1, 15, 29) is essential to achieve therapeutic steady-state plasma concentrations more rapidly, as the drug has a long half-life (~40 days). When combined with CDK4/6 inhibitors,…

Related Therapies & Mechanisms

• Anastrozole (Arimidex) — Hormonal Agent · Breast
• Exemestane (Aromasin) — Hormonal Agent · Breast
• Goserelin (Zoladex) — Hormonal Agent · Breast
• Imlunestrant (Inluriyo) — Hormonal Agent · Breast