What is Fulvestrant used for?

Fulvestrant: Indication and Clinical Use

Fulvestrant is a selective estrogen receptor downregulator (SERD) used to treat hormone receptor-positive metastatic breast cancer in postmenopausal women, particularly after disease progression on prior endocrine therapy. 1, 2

Primary Indication

Fulvestrant is indicated for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-negative) advanced or metastatic breast cancer in postmenopausal women. 1, 3, 4

Mechanism of Action

• Fulvestrant competitively binds to estrogen receptors with much greater affinity than tamoxifen, causing complete downregulation of cellular ER protein levels and abrogation of estrogen-sensitive gene transcription. 3
• Unlike tamoxifen, fulvestrant has no known estrogen agonist effects, ensuring lack of cross-resistance with other hormonal agents. 3

Clinical Settings for Use

Second-Line Therapy (Most Common)

Fulvestrant 500 mg with a CDK4/6 inhibitor should be offered to patients with progressive disease during treatment with aromatase inhibitors (AIs) or who develop recurrence within 1 year of adjuvant AI therapy. 1

• This combination is recommended for patients with or without one line of prior chemotherapy for metastatic disease. 1
• The PALOMA-3 trial demonstrated median PFS of 9.5 months with palbociclib plus fulvestrant versus 4.6 months with fulvestrant alone (HR 0.46,95% CI 0.36 to 0.59). 1

First-Line Therapy (Selected Patients)

• Combination therapy with fulvestrant 500 mg plus a nonsteroidal AI may be offered to patients without prior exposure to adjuvant endocrine therapy, based on SWOG 0226 trial showing survival benefit in this specific population. 1, 2
• Fulvestrant combined with CDK4/6 inhibitors can be offered as first-line therapy in selected patients. 2

Single-Agent Therapy

• After progression on nonsteroidal AIs, single-agent fulvestrant 500 mg with loading dose is an option alongside exemestane or combination therapies. 1
• Fulvestrant 500 mg was superior to fulvestrant 250 mg, megestrol acetate, and anastrozole for PFS in postmenopausal women with advanced breast cancer after endocrine therapy failure. 1

Dosing Specifications

Fulvestrant must be administered at 500 mg intramuscularly with a loading schedule (500 mg on days 0,14, and 28, followed by 500 mg every 28 days thereafter). 1, 2

• The CONFIRM trial demonstrated improved overall survival with the 500 mg dose compared to the 250 mg dose, establishing this as the only appropriate dosing regimen. 1, 2
• Treatment should continue until unequivocal evidence of disease progression documented by imaging, clinical examination, or disease-related symptoms. 2

Special Populations

Premenopausal Women

• Fulvestrant should be combined with ovarian suppression (GnRH agonists) or ablation (oophorectomy) in premenopausal women with HR-positive metastatic breast cancer. 1, 2
• The PALOMA-3 subset analysis showed median PFS of 9.5 months with palbociclib plus fulvestrant versus 5.6 months with placebo plus fulvestrant in premenopausal women (HR 0.50,95% CI 0.29 to 0.87). 1

Male Patients

• For male patients with HR-positive metastatic breast cancer, fulvestrant should be combined with a gonadotropin-releasing hormone analog. 2

Safety Profile

• Fulvestrant is generally well tolerated with mostly mild to moderate adverse events. 3
• Main adverse effects include nausea, asthenia, pain, vasodilation, and headache. 3
• Treatment-related adverse events led to withdrawal in only about 1% of patients. 3
• No significant difference in vasomotor toxicity, arthralgia, or gynecological toxicities compared to other endocrine therapies. 5

Critical Clinical Pitfalls to Avoid

• Never use the outdated 250 mg dose - the 500 mg dose with loading schedule is the only evidence-based regimen. 1, 2
• Do not discontinue treatment prematurely - continue until unequivocal disease progression, not based on tumor markers or circulating tumor cells alone. 2
• Do not combine fulvestrant with chemotherapy - sequential therapy is preferred over combination with cytotoxic agents. 2
• Do not use fulvestrant as monotherapy in premenopausal women - always combine with ovarian suppression or ablation. 1, 2

Treatment Sequencing

Sequential hormone therapy should be used as long as the patient benefits from hormone treatment and does not show evidence of rapid progression with organ dysfunction. 1 New hormonal agents should not be added to existing therapy at disease progression. 1