Two-year carcinogenesis studies were conducted in rats and mice. Positive findings were observed in both species. Rats were treated at intramuscular doses of 15 mg/kg/30 days, 10 mg/rat/30 days and 10 mg/rat/15 days.
These doses correspond to 0.9-, 1.5-, and 3-fold (in females) and 0.8-, 0.8-, and 2-fold (in males) the systemic exposure [AUC0-30 days ] achieved in women receiving the recommended dose of 500 mg/month. An increased incidence of benign ovarian granulosa cell tumors and testicular Leydig cell tumors was evident, in females dosed at 10 mg/rat/15 days and males dosed at 15 mg/rat/30 days, respectively. Mice were treated at oral doses of 0, 20, 150 and 500 mg/kg/day. These doses correspond to 0, 0.8, 8.4 and 18-fold (in females) and 0.8-, 7.1- and 11.9- fold (in males), the systemic exposure (AUC0-30 days ) achieved in women receiving the recommended dose of 500 mg/month. There was an increased incidence of sex cord stromal tumors (both benign and malignant) in the ovary of mice at doses of 150 and 500 mg/kg/day. Induction of such tumors is consistent with the pharmacology-related endocrine feedback alterations in gonadotropin levels caused by an antiestrogen.
Fulvestrant was not mutagenic or clastogenic in multiple in vitro tests with and without the addition of a mammalian liver metabolic activation factor (bacterial mutation assay in strains of Salmonella typhimurium and Escherichia coli, in vitro cytogenetics study in human lymphocytes, mammalian cell mutation assay in mouse lymphoma cells and in vivo micronucleus test in rat).
In female rats, fulvestrant administered at doses ≥0.01 mg/kg/day (0.6% the human recommended dose based on body surface area [BSA in mg/m2 ]), for 2 weeks prior to and for 1 week following mating, caused a reduction in fertility and embryonic survival. No adverse effects on female fertility and embryonic survival were evident in female animals dosed at 0.001 mg/kg/day (0.06% the human dose based on BSA in mg/m2). Restoration of female fertility to values similar to controls was evident following a 29-day withdrawal period after dosing at 2 mg/kg/day (equivalent to the human dose based on BSA in mg/m2). The effects of fulvestrant on the fertility of female rats appear to be consistent with its antiestrogenic activity. The potential effects of fulvestrant on the fertility of male animals were not studied, but in a 6-month toxicology study, male rats treated with intramuscular doses of 15 mg/kg/30 days, 10 mg/rat/30 days, or 10 mg/rat/15 days fulvestrant showed a loss of spermatozoa from the seminiferous tubules, seminiferous tubular atrophy, and degenerative changes in the epididymides. Changes in the testes and epididymides had not recovered 20 weeks after cessation of dosing. These fulvestrant doses correspond to 1.3-, 1.2- and 3.5-fold the systemic exposure [AUC0-30 days ] achieved in women receiving the recommended dose of 500 mg/month.
The efficacy of fulvestrant 500 mg versus fulvestrant 250 mg was compared in CONFIRM. The efficacy of fulvestrant 250 mg was compared to 1 mg anastrozole in Studies 0020 and 0021. The efficacy of fulvestrant 500 mg was compared to 1 mg anastrozole in FALCON. The efficacy of fulvestrant 500 mg in combination with palbociclib 125 mg was compared to fulvestrant 500 mg plus placebo in PALOMA-3. The efficacy of fulvestrant 500 mg in combination with abemaciclib 150 mg was compared to fulvestrant 500mg plus placebo in MONARCH 2. The efficacy of fulvestrant 500 mg in combination with ribociclib 600 mg was compared to fulvestrant 500 mg plus placebo in MONALEESA-3.
Comparison of Fulvestrant 500 mg and Fulvestrant 250 mg (CONFIRM)
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 fulvestrant 500 mg (n=362) with fulvestrant 250 mg (n=374).
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. Fulvestrant 250 mg was administered as two 5 mL injections (one containing fulvestrant 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 years. 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 12. The efficacy of fulvestrant 500 mg was compared to that of fulvestrant 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 fulvestrant 500 mg vs. fulvestrant 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 12: Efficacy Results in CONFIRM (Intent-To-Treat (ITT) Population)
|Endpoint||Fulvestrant 500 mg (N=362)||Fulvestrant 250 mg (N=374)|
Hazard Ratio† (95% CI‡)
0.80 (0.68 to 0.94)
OS§ Updated Analysis¶
(% patients who died)
Median OS (months)
Hazard Ratio† (95% CI‡)#
0.81 (0.69 to 0.96)
ORRÞ (95% CI‡)
13.8% (9.7%, 18.8%)
14.6% (10.5%, 19.4%)
*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.
† Hazard Ratio <1 favors fulvestrant 500 mg.
‡ CI=Confidence Interval
§ OS=Overall Survival
¶ Minimum follow up duration of 50 months.
# Not statistically significant as no adjustments were made for multiplicity.
Þ ORR (Objective Response Rate), as defined as number (%) of patients with complete response or partial response, was analyzed in the evaluable patients with measurable 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 Fulvestrant 500 mg and Anastrozole 1 mg (FALCON)
A randomized, double-blind, double-dummy, multi-center study (FALCON, NCT01602380) of fulvestrant 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 fulvestrant 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 fulvestrant 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 to 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 13 and Figure 8.
Fulvestrant 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 OS analysis.
Figure 8 Kaplan-Meier Plot of Progression-Free Survival (Investigator Assessment, ITT Population) ─ FALCON
Comparison of Fulvestrant 250 mg and Anastrozole 1 mg in Combined Data (Studies 0020 and 0021)
Efficacy of fulvestrant 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 years. 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%; 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 fulvestrant 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 fulvestrant arm of Study 0021 received two separate injections (2 X 2.5 mL), whereas fulvestrant 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 14. The effectiveness of fulvestrant 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 fulvestrant 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 14: Efficacy Results in Studies 0020 and 0021 (Objective Response Rate (ORR) and Time to Progression (TTP))
|Study 0021 (Double-Blind)||Study 0020 (Open-Label)|
|Endpoint||250 mg N=206||1 mg N=194||250 mg N=222||1 mg N=229|
Objective Tumor Response Number (%) of subjects
with CR* + PR†
2–sided 95.4% CI¶
Time to Progression (TTP)
Median TTP (days)
2-sided 95.4% CI
Stable Disease for ≥24 weeks (%)
Overall Survival (OS)
Median Survival (days)
(2-sided 95% CI)
*CR = Complete Response
† PR = Partial Response
‡ FUL = Fulvestrant
§ ANA = Anastrozole
¶ CI = Confidence Interval
# Hazard Ratio <1 favors Fulvestrant
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
Fulvestrant 500 mg in Combination with Palbociclib 125 mg (PALOMA-3)
PALOMA-3 (NCT-1942135) was an international, randomized, double-blind, parallel group, multi-center study of fulvestrant plus palbociclib versus fulvestrant 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 fulvestrant plus palbociclib or fulvestrant 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/5 mL, 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 v.1.1.
Patients enrolled in this study had a median age of 57 years (range 29 to 88). The majority of patients on study 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 15 and Figure 9. Consistent results were observed across patient subgroups of disease site, sensitivity to prior hormonal therapy and menopausal status. The OS data were not mature at the time of the final PFS analysis (11% of patients had died). Patients will continue to be followed for the final analysis.
Table 15: Efficacy Results in PALOMA-3 (Investigator Assessment, ITT Population)
Fulvestrant plus Palbociclib
Fulvestrant plus Placebo
Progression-Free Survival for ITT
Number of PFS Events (%)
Median PFS (months) (95% CI)
9.5 (9.2 to 11)
4.6 (3.5 to 5.6)
Hazard Ratio (95% CI) and
0.461 (0.360 to 0.591)
Objective Response for Patients with Measurable Disease
Objective response rate * (%, 95% CI)
24.6 (19.6 to 30.2)
10.9 (6.2, 17.3)
N=number of patients.
Figure 9 Kaplan-Meier Plot of Progression-Free Survival (Investigator Assessment, ITT Population) — PALOMA-3
FUL=fulvestrant; PAL=palbociclib; PCB=placebo.
Fulvestrant 500 mg in Combination with Abemaciclib 150 mg (MONARCH 2)
MONARCH 2 (NCT02107703) was a randomized, placebo-controlled, multi-center study conducted in women with HR-positive, HER2-negative metastatic breast cancer with disease progression following endocrine therapy treated with fulvestrant plus abemaciclib versus fulvestrant plus placebo. Randomization was stratified by disease site (visceral, bone only, or other) and by sensitivity to prior endocrine therapy (primary or secondary resistance). A total of 669 patients received intramuscular injection of fulvestrant 500 mg on Days 1 and 15 of cycle 1 and then on Day 1 of cycle 2 and beyond (28-day cycles), plus abemaciclib or placebo orally twice daily. Pre/perimenopausal women were enrolled in the study and received the gonadotropin-releasing hormone agonist goserelin for at least 4 weeks prior to and for the duration of MONARCH 2. Patients remained on continuous treatment until development of progressive disease or unmanageable toxicity.
Patient median age was 60 years (range, 32 to 91 years), and 37% of patients were older than 65. The majority were White (56%), and 99% of patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Twenty percent (20%) of patients had de novo metastatic disease, 27% had bone only disease, and 56% had visceral disease. Twenty-five percent (25%) of patients had primary endocrine therapy resistance. Seventeen percent (17%) of patients were pre- or perimenopausal.
The efficacy results from the MONARCH 2 study are summarized in Table 16 and Figure 10. Median PFS assessment based on a blinded independent radiologic review was consistent with the investigator assessment. Consistent results were observed across patient stratification subgroups of disease site and endocrine therapy resistance. At the time of primary analysis of PFS, overall survival data were not mature (20% of patients had died).
Fulvestrant plus Abemaciclib
Fulvestrant plus Placebo
Number of patients with an event (n, %)
Median (months, 95% CI)
16.4 (14.4, 19.3)
9.3 (7.4, 12.7)
Hazard ratio (95% CI)
0.553 (0.449, 0.681)
Objective Response for Patients with Measurable Disease
Objective response rate* (n, %)
Abbreviations: CI = confidence interval.
*Complete response + partial response.
Figure 10: Kaplan-Meier Curves of Progression-Free Survival: Fulvestrant Plus Abemaciclib versus Fulvestrant plus Placebo (MONARCH 2)
Postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer for initial endocrine based therapy or after disease progression on endocrine therapy
Fulvestrant 500 mg in Combination with Ribociclib 600 mg (MONALEESA-3)
MONALEESA-3 (NCT 02422615) was a randomized double-blind, placebo-controlled study of fulvestrant plus ribociclib versus fulvestrant plus placebo conducted in postmenopausal women with hormone receptor positive, HER2-negative, advanced breast cancer who have received no or only one line of prior endocrine treatment.
A total of 726 patients were randomized in a 2:1 ratio to receive fulvestrant plus ribociclib or fulvestrant plus placebo and stratified according to the presence of liver and/or lung metastases and prior endocrine therapy for advanced or metastatic disease. Fulvestrant 500 mg was administered intramuscularly on Days 1, 15, 29, and once monthly thereafter, with either ribociclib 600 mg or placebo given orally once daily for 21 consecutive days followed by 7 days off until disease progression or unacceptable toxicity. The major efficacy outcome measure for the study was investigator-assessed progression-free survival (PFS) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
Patients enrolled in this study had a median age of 63 years (range 31 to 89). Of the patients enrolled, 47% were 65 years and older, including 14% age 75 years and older. The patients enrolled were primarily Caucasian (85%), Asian (9%), and Black (0.7%). Nearly all patients (99.7%) had an ECOG performance status of 0 or 1. First and second line patients were enrolled in this study (of which 19% had de novo metastatic disease). Forty-three percent (43%) of patients had received chemotherapy in the adjuvant vs. 13% in the neoadjuvant setting and 59% had received endocrine therapy in the adjuvant vs. 1% in the neoadjuvant setting prior to study entry. Twenty-one percent (21%) of patients had bone only disease and 61% had visceral disease. Demographics and baseline disease characteristics were balanced and comparable between study arms.
The efficacy results from MONALEESA-3 are summarized in Table 17 and Figure 11. Consistent results were observed in stratification factor subgroups of disease site and prior endocrine treatment for advanced disease. At the time of the PFS analysis, 17% of patients had died, and overall survival data were immature.
Table 17: Efficacy Results – MONALEESA-3 (Investigator Assessment, Intent-to-Treat Population)
Figure 11 Kaplan-Meier Progression Free Survival Curves – MONALEESA-3 (Investigator assessment)
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