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
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 7. 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
Table 7: 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)
||Cmin min (ng/mL)
|500 mg + AD1
|Multiple dose steady state2
|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 CONFIRM. The efficacy of FASLODEX 250 mg was compared to 1 mg
anastrozole in Studies 0020 and 0021. The efficacy of FASLODEX 500 mg was
compared to 1 mg anastrozole in FALCON. The efficacy of FASLODEX 500 mg in
combination with palbociclib 125 mg was compared to FASLODEX 500 mg plus
placebo in PALOMA-3.
Comparison Of FASLODEX 500 mg And FASLODEX 250 mg
A randomized, double-blind, controlled clinical trial
(CONFIRM, NCT00099437) 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
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 CONFIRM are summarized in Table 8. The
efficacy of FASLODEX 500 mg was compared to that of FASLODEX 250 mg. Figure 6
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 7 shows a Kaplan-Meier plot of the updated OS data.
Table 8: Efficacy Results CONFIRM: Intent-To-Treat
||Fulvestrant 500 mg
|Fulvestrant 250 mg
| Median (months)
|Hazard Ratio2 (95% CI3 )
|OS4 Updated Analysis5 (% patients who died)
|Median OS (months)
|Hazard Ratio2 (95% CI3)6
|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
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 6 : Kaplan-Meier PFS: CONFIRM ITT Population
Figure 7 : Kaplan-Meier OS (Minimum Follow-up Duration
of 50 Months): CONFIRM ITT Population
Comparison Of FASLODEX 500 mg And Anastrozole 1 mg
A randomized, double-blind, double-dummy, multicenter
study (FALCON, NCT01602380) of FASLODEX 500 mg versus anastrozole 1 mg was
conducted in postmenopausal women with ER-positive and/or PgR-positive,
HER2-negative locally advanced or metastatic breast cancer who had not
previously been treated with any hormonal therapy. A total of 462 patients were
randomized 1:1 to receive administration of FASLODEX 500 mg as an intramuscular
injection on Days 1, 15, 29 and every 28 (+/- 3) days thereafter or daily
administration of 1 mg of anastrozole orally. This study compared the efficacy
and safety of FASLODEX 500 mg and anastrozole 1 mg.
Randomization was stratified by disease setting (locally
advanced or metastatic), use of prior chemotherapy for advanced disease, and
presence or absence of measurable disease.
The major efficacy outcome measure of the study was
investigator-assessed progression-free survival (PFS) evaluated according to
RECIST v.1.1 (Response Evaluation Criteria in Solid Tumors). Key secondary
efficacy outcome measures included overall survival (OS), objective response
rate (ORR), and duration of response (DoR).
Patients enrolled in this study had a median age of 63
years (range 36-90). The majority of patients (87%) had metastatic disease at
baseline. Fifty-five percent (55%) of patients had visceral metastasis at
baseline. A total of 17% of patients had received one prior chemotherapy
regimen for advanced disease; 84% of patients had measurable disease. Sites of
metastases were as follows: musculoskeletal 59%, lymph nodes 50%, respiratory
40%, liver (including gall bladder) 18%.
The efficacy results of FALCON are presented in Table 9
and Figure 8.
Table 9: Efficacy Results (Investigator Assessment,
ITT Population) - FALCON
||FASLODEX 500 mg
|Anastrozole 1 mg
|Number of PFS Events (%)
|Median PFS (months)
|PFS Hazard Ratio (95% CI)
||0.797 (0.637 - 0.999)
|Number of OS Events
|Median OS (months)
|OS Hazard Ratio (95% CI)
||0.874 (0.629 - 1.216)
|Objective Response for patients with measurable disease
|Objective Response Rate (%, 95% CI)
||46.1% (38.9%, 53.4%)
||44.9% (37.8%, 52.1%)
|Median DoR (months)
|NR: Not reached
* Interim OS analysis with 61% of total number of events required for the final
Figure 8 : Kaplan-Meier Plot of Progression-Free
Survival (Investigator Assessment, ITT Population) - FALCON
Comparison Of FASLODEX 250 mg And Anastrozole 1 mg In Combined
Data (Studies 0020 and 0021)
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 0021, NCT00635713; the
other predominantly in Europe, Study 0020) 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 0021 was a double-blind, randomized trial in 400
postmenopausal women. Study 0020 was an open-label, randomized trial conducted
in 451 postmenopausal women. Patients on the FASLODEX arm of Study 0021
received two separate injections (2 X 2.5 mL), whereas FASLODEX patients
received a single injection (1 X 5 mL) in Study 0020. 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 10. 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 0021 and 24.4 months
in Study 0020.
Table 10: Efficacy Results
||Study 0021 (Double-Blind)
||Study 0020 (Open-Label)
| 1 mg
|Objective Tumor Response Number (%) of subjects with CR1 + PR2
|% 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)
|Hazard Ratio 6
||0.9 (0.7, 1.1)
||1.0 (0.8, 1.2)
|2-sided 95.4% CI
|Stable Disease for ≥24 weeks (%)
|Overall Survival (OS)
|Died n (%)
| Median Survival (days)
|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
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
PALOMA-3 (NCT-1942135) 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 disease
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 PALOMA-3.
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
PALOMA-3 are summarized in Table 11 and Figure 9. 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 11: Efficacy Results - PALOMA-3
(Investigator Assessment, ITT Population)
||FASLODEX plus palbociclib
|FASLODEX plus placebo
|Number of PFS Events (%)
|Hazard Ratio (95% CI) and
|Median PFS (months) (95% CI)
|N=number of patients.
Figure 9 : Kaplan-Meier Plot of Progression-Free
Survival (Investigator Assessment, ITT Population) - PALOMA-3