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Mechanism Of Action
Many breast cancers have estrogen receptors (ER) and the growth of these tumors can be stimulated by estrogen. Fulvestrant is an estrogen receptor antagonist that binds to the estrogen receptor in a competitive manner with affinity comparable to that of estradiol and downregulates the ER protein in human breast cancer cells.
In vitro studies demonstrated that fulvestrant is a reversible inhibitor of the growth of tamoxifen-resistant, as well as estrogen-sensitive human breast cancer (MCF-7) cell lines. In in vivo tumor studies, fulvestrant delayed the establishment of tumors from xenografts of human breast cancer MCF-7 cells in nude mice. Fulvestrant inhibited the growth of established MCF-7 xenografts and of tamoxifen-resistant breast tumor xenografts.
Fulvestrant showed no agonist-type effects in in vivo uterotropic assays in immature or ovariectomized mice and rats. In in vivo studies in immature rats and ovariectomized monkeys, fulvestrant blocked the uterotrophic action of estradiol. In postmenopausal women, the absence of changes in plasma concentrations of FSH and LH in response to fulvestrant treatment (250 mg monthly) suggests no peripheral steroidal effects.
In a clinical study in postmenopausal women with primary breast cancer treated with single doses of FASLODEX 15-22 days prior to surgery, there was evidence of increasing down-regulation of ER with increasing dose. This was associated with a dose-related decrease in the expression of the progesterone receptor, an estrogen-regulated protein. These effects on the ER pathway were also associated with a decrease in Ki67 labeling index, a marker of cell proliferation.
The single dose and multiple dose PK parameters for the 500 mg dosing regimen with an additional dose (AD) at Day 15 are reported in Table 5. The additional dose of FASLODEX given two weeks after the initial dose allows for steady state concentrations to be reached within the first month of dosing.
Table 5: Summary of Fulvestrant Pharmacokinetic
Parameters [gMean (CV%)] in Postmenopausal Advanced Breast Cancer Patients
after Intramuscular Administration 500 mg + AD Dosing Regimen
|C max (ng/mL)||C min (ng/mL)||AUC (ng•hr/mL)|
|500 mg + AD1||Single dose||25.1 (35.3)||16.3 (25.9)||11400 (33.4)|
|Multiple dose steady state2||28.0 (27.9)||12.2 (21.7)||13100 (23.4)|
|1 Additional 500 mg dose given on Day 15
2 Month 3
The apparent volume of distribution at steady state is approximately 3 to 5 L/kg. This suggests that distribution is largely extravascular. Fulvestrant is highly (99%) bound to plasma proteins; VLDL, LDL and HDL lipoprotein fractions appear to be the major binding components. The role of sex hormone-binding globulin, if any, could not be determined.
Biotransformation and disposition of fulvestrant in humans have been determined following intramuscular and intravenous administration of 14C-labeled fulvestrant. Metabolism of fulvestrant appears to involve combinations of a number of possible biotransformation pathways analogous to those of endogenous steroids, including oxidation, aromatic hydroxylation, conjugation with glucuronic acid and/or sulphate at the 2, 3 and 17 positions of the steroid nucleus, and oxidation of the side chain sulphoxide. Identified metabolites are either less active or exhibit similar activity to fulvestrant in antiestrogen models.
Studies using human liver preparations and recombinant human enzymes indicate that cytochrome P-450 3A4 (CYP 3A4) is the only P-450 isoenzyme involved in the oxidation of fulvestrant; however, the relative contribution of P-450 and non-P-450 routes in vivo is unknown.
Fulvestrant was rapidly cleared by the hepatobiliary route with excretion primarily via the feces (approximately 90%). Renal elimination was negligible (less than 1%). After an intramuscular injection of 250 mg, the clearance (Mean ± SD) was 690 ± 226 mL/min with an apparent half-life about 40 days.
In patients with breast cancer, there was no difference in fulvestrant pharmacokinetic profile related to age (range 33 to 89 years).
Following administration of a single intravenous dose, there were no pharmacokinetic differences between men and women or between premenopausal and postmenopausal women. Similarly, there were no differences between men and postmenopausal women after intramuscular administration.
In the advanced breast cancer treatment trials, the potential for pharmacokinetic differences due to race have been evaluated in 294 women including 87.4% Caucasian, 7.8% Black, and 4.4% Hispanic. No differences in fulvestrant plasma pharmacokinetics were observed among these groups. In a separate trial, pharmacokinetic data from postmenopausal ethnic Japanese women were similar to those obtained in non-Japanese patients.
There are no known drug-drug interactions. Fulvestrant does not significantly inhibit any of the major CYP isoenzymes, including CYP 1A2, 2C9, 2C19, 2D6, and 3A4 in vitro, and studies of co-administration of fulvestrant with midazolam indicate that therapeutic doses of fulvestrant have no inhibitory effects on CYP 3A4 or alter blood levels of drug metabolized by that enzyme. Although fulvestrant is partly metabolized by CYP 3A4, a clinical study with rifampin, an inducer of CYP 3A4, showed no effect on the pharmacokinetics of fulvestrant. Also results from a healthy volunteer study with ketoconazole, a potent inhibitor of CYP 3A4, indicated that ketoconazole had no effect on the pharmacokinetics of fulvestrant and dosage adjustment is not necessary in patients co-prescribed CYP 3A4 inhibitors or inducers [see DRUG INTERACTIONS]. Data from a clinical trial in patients with breast cancer showed that there was no clinically relevant drug interaction between fulvestrant and palbociclib when the two drugs were co-administered.
The efficacy of FASLODEX 500 mg versus FASLODEX 250 mg was compared in Study 1. The efficacy of FASLODEX 250 mg was compared to anastrozole in Studies 2 and 3. The efficacy of FASLODEX 500 mg in combination with palbociclib 125 mg was compared to FASLODEX 500 mg plus placebo in Study 4.
Comparison of FASLODEX 500 mg and FASLODEX 250 mg (Study 1)
A Phase 3 randomized, double-blind, controlled clinical trial (Study 1) was completed in 736 postmenopausal women with advanced breast cancer who had disease recurrence on or after adjuvant endocrine therapy or progression following endocrine therapy for advanced disease. This trial compared the efficacy and safety of FASLODEX 500 mg (n=362) with FASLODEX 250 mg (n=374).
FASLODEX 500 mg was administered as two 5 mL injections each containing FASLODEX 250 mg/5mL, one in each buttock, on Days 1, 15, 29 and every 28 (+/- 3) days thereafter. FASLODEX 250 mg was administered as two 5 mL injections (one containing FASLODEX 250 mg/5mL injection plus one placebo injection), one in each buttock, on Days 1, 15 (2 placebo injections only), 29 and every 28 (+/- 3) days thereafter.
The median age of study participants was 61. All patients had ER+ advanced breast cancer. Approximately 30% of subjects had no measurable disease. Approximately 55% of patients had visceral disease.
Results of Study 1 are summarized in Table 6. The efficacy of FASLODEX 500 mg was compared to that of FASLODEX 250 mg. Figure 4 shows a Kaplan-Meier plot of the Progression Free Survival (PFS) data after a minimum follow-up duration of 18 months demonstrating statistically significant superiority of FASLODEX 500 mg vs. FASLODEX 250 mg. In the initial Overall Survival (OS) analysis after a minimum follow-up duration of 18 months, there was no statistically significant difference in OS between the two treatment groups. After a minimum follow-up duration of 50 months, an updated OS analysis was performed. Figure 5 shows a Kaplan-Meier plot of the updated OS data.
Table 6: Efficacy Results Study 1: Intent-To-Treat
|Endpoint||Fulvestrant 500 mg
|Fulvestrant 250 mg
|Hazard Ratio2 (95% CI3 )||0.80 (0.68-0.94)|
|OS4 Updated Analysis5|
|(% patients who died)||261 (72.1%)||293 (78.3%)|
|Median OS (months)||26.4||22.3|
|Hazard Ratio2 (95% CI3)6||0.81 (0.69-0.96)|
|ORR7 (95% CI3)||13.8% (9.7%, 18.8%) (33/240)||14.6% (10.5%, 19.4%) 38/261)|
|1 PFS (Progression Free Survival) = the time
between randomization and the earliest of progression or death from any cause.
Minimum follow-up duration of 18 months.
2 Hazard Ratio < 1 favors FASLODEX 500 mg.
3 CI=Confidence Interval
4 OS=Overall Survival
5 Minimum follow up duration of 50 months.
6 Not statistically significant as no adjustments were made for multiplicity.
7 ORR (Objective Response Rate), as defined as number (%) of patients with complete response or partial response, was analyzed in the evaluable patients with measureable disease at baseline (fulvestrant 500 mg N=240; fulvestrant 250 mg N=261). Minimum follow-up duration of 18 months.
Figure 4 : Kaplan-Meier PFS: Study 1 ITT Population
Figure 5 : Kaplan-Meier OS (Minimum Follow-up Duration
of 50 Months): Study 1 ITT Population
Comparison Of FASLODEX 250 mg And Anastrozole 1 mg In Combined Data (Studies 2 and 3)
Efficacy of FASLODEX was established by comparison to the selective aromatase inhibitor anastrozole in two randomized, controlled clinical trials (one conducted in North America, Study 2; the other predominantly in Europe, Study 3) in postmenopausal women with locally advanced or metastatic breast cancer. All patients had progressed after previous therapy with an antiestrogen or progestin for breast cancer in the adjuvant or advanced disease setting.
The median age of study participants was 64. 81.6% of patients had ER+ and/or PgR+ tumors. Patients with ER- /PgR- or unknown tumors were required to have demonstrated a prior response to endocrine therapy. Sites of metastases occurred as follows: visceral only 18.2%; viscera – liver involvement 23.0%; lung involvement 28.1%; bone only 19.7%; soft tissue only 5.2%; skin and soft tissue 18.7%.
In both trials, eligible patients with measurable and/or evaluable disease were randomized to receive either FASLODEX 250 mg intramuscularly once a month (28 days + 3 days) or anastrozole 1 mg orally once a day. All patients were assessed monthly for the first three months and every three months thereafter. Study 2 was a double-blind, randomized trial in 400 postmenopausal women. Study 3 was an open-label, randomized trial conducted in 451 postmenopausal women. Patients on the FASLODEX arm of Study 2 received two separate injections (2 X 2.5 mL), whereas FASLODEX patients received a single injection (1 X 5 mL) in Study 3. In both trials, patients were initially randomized to a 125 mg per month dose as well, but interim analysis showed a very low response rate, and low dose groups were dropped.
Results of the trials, after a minimum follow-up duration of 14.6 months, are summarized in Table 7. The effectiveness of FASLODEX 250 mg was determined by comparing Objective Response Rate (ORR) and Time to Progression (TTP) results to anastrozole 1 mg, the active control. The two studies ruled out (by one-sided 97.7% confidence limit) inferiority of FASLODEX to anastrozole of 6.3% and 1.4% in terms of ORR. There was no statistically significant difference in overall survival (OS) between the two treatment groups after a follow-up duration of 28.2 months in Study 2 and 24.4 months in Study 3.
Table 7: Efficacy Results
|Endpoint||Study 2 (Double-Blind)||Study 3 (Open-Label)|
|Objective Tumor Response Number (%) of subjects with CR1 + PR2||35 (17.0)||33 (17.0)||45 (20.3)||34 (14.9)|
|% Difference in Tumor Response Rate (FAS3-ANA4) 2-sided 95.4% CI5||0.0 (-6.3, 8.9)||5.4 (-1.4, 14.8)|
|Time to Progression (TTP) Median TTP (days)||165||103||166||156|
|Hazard Ratio6 2-sided 95.4% CI||0.9 (0.7, 1.1)||1.0 (0.8, 1.2)|
|Stable Disease for ≥ 24 weeks (%)||26.7||19.1||24.3||30.1|
|Overall Survival (OS)|
|Died n (%)||152 (73.8%)||149 (76.8%)||167 (75.2%)||173 (75.5%)|
|Median Survival (days)||844||913||803||736|
|Hazard Ratio6(2-sided 95% CI)||0.98 (0.78, 1.24)||0.97 (0.78, 1.21)|
|1 CR = Complete Response
2 PR = Partial Response
3 FAS = FASLODEX
4 ANA = anastrozole
5 CI = Confidence Interval
6 Hazard Ratio < 1 favors FASLODEX
FASLODEX 500 mg in Combination with Palbociclib 125 mg (Study 4)
Patients with HR-Positive, HER2-Negative Advanced Or Metastatic Breast Cancer Who Have Had Disease Progression On Or After Prior Adjuvant Or Metastatic Endocrine Therapy
Study 4 was an international, randomized, double-blind, parallel group, multicenter study of FASLODEX plus palbociclib versus FASLODEX plus placebo conducted in women with HR-positive, HER2-negative advanced breast cancer, regardless of their menopausal status, whose diseased progressed on or after prior endocrine therapy.
A total of 521 pre/postmenopausal women were randomized 2:1 to FASLODEX plus palbociclib or FASLODEX plus placebo and stratified by documented sensitivity to prior hormonal therapy, menopausal status at study entry (pre/peri versus postmenopausal), and presence of visceral metastases. Palbociclib was given orally at a dose of 125 mg daily for 21 consecutive days followed by 7 days off treatment. Fulvestrant 500 mg was administered as two 5 mL injections each containing fulvestrant 250 mg/5mL, one in each buttock, on Days 1, 15, 29 and every 28 (+/- 3) days thereafter. Pre/perimenopausal women were enrolled in the study and received the LHRH agonist goserelin for at least 4 weeks prior to and for the duration of Study 4.
Patients continued to receive assigned treatment until objective disease progression, symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first. The major efficacy outcome of the study was investigator-assessed PFS evaluated according to RECIST 1.1.
Patients enrolled in this study had a median age of 57 years (range 29 to 88). The majority of patients in each treatment arm were White (74%), all patients had an ECOG PS of 0 or 1, and 80% were postmenopausal. All patients had received prior systemic therapy and 75% of patients had received a previous chemotherapy regimen. Twenty-five percent of patients had received no prior therapy in the metastatic disease setting, 60% had visceral metastases, and 23% had bone only disease.
The results from the investigator-assessed PFS from Study 4 are summarized in Table 8 and Figure 6. Consistent results were observed across patient subgroups of disease site, sensitivity to prior hormonal therapy and menopausal status. Confirmed overall response rate in patients with measurable disease as assessed by the investigator was 24.6% in the FASLODEX plus palbociclib and was 10.9% in the FASLODEX plus placebo arm. Duration of response was 9.3 months in the FASLODEX plus palbociclib arm compared with 7.6 months in the FASLODEX plus placebo arm. At the time of final analysis of PFS, OS data were not mature with 29% of events.
Table 8: Efficacy Results - Study 4
(Investigator Assessment, ITT Population)
|FASLODEX plus palbociclib
|FASLODEX plus placebo
|Number of PFS Events (%)||145 (41.8%)||114 (65.5%)|
|Hazard Ratio (95% CI) and||0.461 (0.360-0.591)|
|p-value||p < 0.0001|
|Median PFS (months) (95% CI)||9.5 (9.2-11.0)||4.6 (3.5-5.6)|
|N=number of patients.
Figure 6 : Kaplan-Meier Plot of Progression-Free
Survival (Investigator Assessment, ITT Population) - Study 4
Last reviewed on RxList: 3/9/2016
This monograph has been modified to include the generic and brand name in many instances.
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