Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1       Pharmacodynamic properties
Pharmacotherapeutic group: Endocrine therapy, Antiestrogens, ATC code: L02BA03 
Mechanism of action and pharmacodynamic effects
Fulvestrant is a competitive oestrogen receptor (ER) antagonist with an affinity comparable to estradiol. Fulvestrant blocks the trophic actions of oestrogens without any partial agonist (oestrogen- like) activity. The mechanism of action is associated with down-regulation of estrogen receptor protein levels.
Clinical studies in postmenopausal women with primary breast cancer have shown that fulvestrant significantly down-regulates ER protein in ER positive tumours compared with placebo. There was also a significant decrease in progesterone receptor expression consistent with a lack of intrinsic estrogen agonist effects. It has also been shown that fulvestrant 500 mg down-regulates ER and the proliferation marker Ki67, to a greater degree than fulvestrant 250 mg in breast tumours in postmenopausal neoadjuvant setting.


Clinical efficacy and safety in advanced breast cancer
Monotherapy
A Phase 3 clinical study 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. The study included 423 patients whose disease had recurred or progressed during antiestrogen therapy (AE subgroup) and 313 patients whose disease had recurred or progressed during aromatase inhibitor therapy (AI subgroup). This study compared the efficacy and safety of Faslodex 500 mg (n=362) with Faslodex 250 mg (n=374). Progression-free survival (PFS) was the primary endpoint; key secondary efficacy endpoints included objective response rate (ORR), clinical benefit rate (CBR) and overall survival (OS). Efficacy results for the CONFIRM study are summarized in Table 4.

Table 4 Summary of results of the primary efficacy endpoint (PFS) and key secondary efficacy endpoints in the CONFIRM study


Variable                   Type of          Faslodex     Faslodex     Comparison between groups estimate;        500 mg       250 mg       (Faslodex 500mg/Faslodex treatment        (N=362)      (N=374)      250mg) comparison
Hazard    95%CI        p-value ratio
PFS                        K-M median in months:
Hazard ratio


ALL Patients                                6.5          5.5          0.8       0.68, 0.94   0.006 AE subgroup (n=423)                         8.6          5.8          0.76      0.62, 0.94   0.013 AI subgroup    (n=313) a                    5.4          4.1          0.85      0.67, 1.08   0.195 

OSb                        K-M median in months:
Hazard ratio
ALL Patients                                26.4         22.3         0.81      0.69, 0.96   0.016c AE subgroup (n=423)                         30.6         23.9         0.79      0.63, 0.99   0.038c AI subgroup (n=313) a                       24.1         20.8         0.86      0.67, 1.11   0.241c Variable                  Type of           Faslodex      Faslodex     Comparison between groups estimate;         500mg         250mg        (Faslodex 500 mg/Faslodex treatment         (N=362)       (N=374)      250 mg) comparison
Absolute          95%CI
Difference in%
ORRd                      %of patients with OR;
Absolute difference in%


ALL Patients                                13.8          14.6         -0.8            -5.8,6.3 AE subgroup (n=296)                         18.1          19.1         -1.0            -8.2,9.3 AI subgroup (n=205) a                       7.3           8.3          -1.0            -5.5, 9.8 

CBRe                      %of patients with CB;
Absolute difference in%

45.6          39.6         6.0             -1.1, 13.3
ALL Patients                                52.4          45.1         7.3             -2.2, 16.6 AE subgroup (n=423)                         36.2          32.3         3.9             -6.1, 15.2 AI subgroup (n=313) a

 a Faslodex is indicated in patients whose disease had recurred or progressed on an antiestrogen therapy.
The results in the AI subgroup are inconclusive.
b OS is presented for the final survival analyses at 75% maturity.
c Nominal p-value with no adjustments made for multiplicity between the initial overall survival analyses at 50% maturity and the updated survival analyses at 75% maturity.
d ORR was assessed in patients who were evaluable for response at baseline (i.e. those with measurable disease at baseline: 240 patients in the Faslodex 500 mg group and 261 patients in the Faslodex 250 mg group).
e Patients with a best objective response of complete response, partial response or stable disease ≥24 weeks.
PFS:Progression-free survival; ORR:Objective response rate; OR:Objective response; CBR:Clinical benefit rate; CB:Clinical benefit; OS:Overall survival; K-M:Kaplan-Meier; CI:Confidence interval; 
AI:Aromatase inhibitor; AE:Antiestrogen.

A Phase 3, randomised, double-blind, double-dummy, multicentre study of Faslodex 500 mg versus anastrozole 1 mg was conducted in postmenopausal women with ER-positive and/or PgR-positive locally advanced or metastatic breast cancer who had not previously been treated with any hormonal therapy. A total of 462 patients were randomised 1:1 sequentially to receive either fulvestrant 500 mg or anastrozole 1 mg.


Randomisation was stratified by disease setting (locally advanced or metastatic), prior chemotherapy for advanced disease, and measurable disease.


The primary efficacy endpoint of the study was investigator assessed progression-free survival (PFS) evaluated according to RECIST 1.1 (Response Evaluation Criteria in Solid Tumours). Key secondary efficacy endpoints included overall survival (OS), and objective response rate (ORR).


Patients enrolled in this study had a median age of 63 years (range 36-90). The majority of patients (87.0%) had metastatic disease at baseline. Fifty-five percent (55.0%) of patients had visceral metastasis at baseline. A total of 17.1% of patients received a prior chemotherapy regimen for advanced disease; 84.2% of patients had measurable disease.


Consistent results were observed across the majority of pre-specified patient subgroups. For the subgroup of patients with disease limited to non-visceral metastasis (n=208), the HR was 0.592 (95% CI: 0.419, 0.837) for the Faslodex arm compared to the anastrozole arm. For the subgroup of patients with visceral metastasis (n=254), the HR was 0.993 (95% CI: 0.740, 1.331) for the Faslodex arm compared to the anastrozole arm. The efficacy results of the FALCON study are presented in Table 5 and Figure 1.


Table 5 Summary of results of the primary efficacy endpoint (PFS) and key secondary efficacy endpoints (Investigator Assessment, Intent-To-Treat Population) ─ FALCON study 

Faslodex 500 mg (N=230)              Anastrozole 1 mg
(N=232)
Progression-Free Survival

Number of PFS Events (%)               143 (62.2%)                    166 (71.6%) PFS Hazard Ratio (95% CI) and                              HR 0.797 (0.637-0.999) p-value                                                           p=0.0486 PFS Median [months (95% CI)]            16.6 (13.8, 21.0)             13.8 (12.0, 16.6) Number of OS Events*                    67 (29.1%)                    75 (32.3%) OS Hazard Ratio (95% CI) and                                HR 0.875 (0.629-1.217) p-value                                                           P=0.4277 ORR**                                   89 (46.1%)                    88 (44.9%) ORR Odds Ratio (95% CI) and                                 OR 1.074 (0.716-1.614) p-value                                                           P=0.7290 Median DoR (months)                     20.0                          13.2 CBR                                     180 (78.3%)                   172 (74.1%) CBR Odds Ratio (95% CI) and                                 OR 1.253 (0.815-1.932) p-value                                                           P=0.3045 *(31% maturity)-not final OS analysis
**for patients with measurable disease


Figure 1 Kaplan-Meier Plot of Progression-Free Survival (Investigator Assessment, Intent-To- Treat Population) ─ FALCON Study



Two Phase 3 clinical studies were completed in a total of 851 postmenopausal women with advanced breast cancer who had disease recurrence on or after adjuvant endocrine therapy or progression following endocrine therapy for advanced disease. Seventy seven percent (77%) of the study population had estrogen receptor positive breast cancer. These studies compared the safety and efficacy of monthly administration of Faslodex 250 mg versus the daily administration of 1 mg anastrozole (aromatase inhibitor). Overall, Faslodex at the 250 mg monthly dose was at least as effective as anastrozole in terms of progression-free survival, objective response, and time to death.
There were no statistically significant differences in any of these endpoints between the two treatment groups. Progression-free survival was the primary endpoint. Combined analysis of both studies showed that 83% of patients who received Faslodex progressed, compared with 85% of patients who received anastrozole. Combined analysis of both studies showed the hazard ratio of Faslodex 250 mg to anastrozole for progression-free survival was 0.95 (95% CI 0.82 to 1.10). The objective response rate for Faslodex 250 mg was 19.2% compared with 16.5% for anastrozole. The median time to death was 27.4 months for patients treated with Faslodex and 27.6 months for patients treated with anastrozole. The hazard ratio of Faslodex 250 mg to anastrozole for time to death was 1.01 (95% CI 0.86 to 1.19).


Effects on the postmenopausal endometrium
Preclinical data do not suggest a stimulatory effect of fulvestrant on the postmenopausal endometrium (see section 5.3). A 2-week study in healthy postmenopausal volunteers treated with 20 μg per day ethinylestradiol showed that, pre-treatment with Faslodex 250 mg resulted in significantly reduced stimulation of the postmenopausal endometrium, compared to pre-treatment with placebo as judged by ultrasound measurement of endometrium thickness.


Neoadjuvant treatment for up to 16 weeks in breast cancer patients treated with either Faslodex 500 mg or Faslodex 250 mg did not result in clinically significant changes in endometrial thickness, indicating a lack of agonist effect. There is no evidence of adverse endometrial effects in the breast cancer patients studied. No data are available regarding endometrial morphology.


In two short-term studies (1 and 12 weeks) in premenopausal patients with benign gynaecologic disease, no significant differences in endometrial thickness were observed by ultrasound measurement between fulvestrant and placebo groups.


Effects on bone
There are no long-term data on the effect of fulvestrant on bone. Neoadjuvant treatment for up to 16 weeks in breast cancer patients with either Faslodex 500 mg or Faslodex 250 mg did not result in clinically significant changes in serum bone turnover markers.


Paediatric population
Faslodex is not indicated for use in children. The European Medicines Agency has waived the obligation to submit the results of studies with Faslodex in all subsets of the paediatric population in breast cancer (see section 4.2 for information on paediatric use).


An open-label Phase 2 study investigated the safety, efficacy and pharmacokinetics of fulvestrant in 30 girls aged 1 to 8 years with Progressive Precocious Puberty associated with McCune Albright Syndrome (MAS). The paediatric patients received 4 mg/kg monthly intramuscular dose of fulvestrant.
This 12-month study investigated a range of MAS endpoints and showed a reduction in the frequency of vaginal bleeding and a reduction in the rate of bone age advancement. The steady-state trough concentrations of fulvestrant in children in this study were consistent with that in adults (see section 5.2). There were no new safety concerns arising from this small study, but 5-year data are yet not available.


The efficacy of FASLODEX 500 mg in combination with palbociclib 125 mg was compared to FASLODEX 500 mg plus placebo in PALOMA-3.


Combination Therapy

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.
FASLODEX 500 mg in Combination with Palbociclib 125 mg (PALOMA-3).


PALOMA-3 (NCT-1942135) was an international, randomized, double-blind, parallel group, multi- centers 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/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 and final OS data from the PALOMA-3 are summarized in Table 6



The relevant Kaplan-Meier plots are shown in Figures 2 and 3, respectively. Consistent PFS results were observed across patient subgroups of disease site, sensitivity to prior hormonal therapy, and menopausal status. After a median follow-up time of 45 months, the final OS results were not statistically significant.


Table 6: Efficacy Results in PALOMA-3 ─ (Investigator Assessment, ITT Population) FASLODEX plus palbociclib            FASLODEX plus placebo
Progression-Free Survival for                  (N=347)                             (N=174) ITT
Number of PFS Events (%)               145 (41.8%)                         114 (65.5%) Median PFS (months) (95%                  9.5 (9.2-11.0)                      4.6 (3.5-5.6) CI)
Hazard Ratio (95% CI) and                       0.461 (0.360-0.591) p p-value                                                   <0.0001

Objective Response for Patients                 N=267                               N=174 with Measurable Disease
Objective response rate1 (%,                24.6 (19.6-30.2)                    10.9 (6.2-17.3) 95% CI)


Overall Survival for ITT                        N=347                               N=174 population


Number of OS events (%)                       201 (57.9)                          109 (62.6) 

Median OS (months) (95% CI)                34.9 (28.8, 40.0)                   28.0 (23.6, 34.6) 

Hazard Ratio (95% CI) and p-                        0.814 (0.644, 1.029), p=0.08572,3 value


N=number of patients; PFS=progression-free survival; CI=confidence interval; ITT=Intent-to-Treat; OS=overall survival.
1. Responses are based on confirmed responses.
2. Not statistically significant at the pre-specified 2-sided alpha level of 0.047.
3. 2-sided p-value fromthe log-rank test stratified by the presence of visceral metastases and sensitivity to prior endocrine therapy per randomization.


Figure 2
Kaplan-Meier Plot of Progression-Free Survival (Investigator Assessment, ITT Population) - PALOMA-3



Figure 3

Kaplan-Meier Plot of Overall Survival (ITT Population) ─ PALOMA-3
FUL=fulvestrant; PAL=palbociclib; PCB=placebo

Pharmacokinetic Properties

5.2    Pharmacokinetic properties

Absorption:
After administration of Faslodex long-acting intramuscular injection, fulvestrant is slowly absorbed and  maximum plasma concentrations     (Cmax) are reached after about 5 days. Administration of Faslodex 500 mg regimen achieves exposure levels at, or close to, steady state within the first month of dosing (mean [CV]: AUC 475 [33.4%] ng. days/ml, Cmax 25.1 [35.3%] ng/ml, Cmin 16.3 [25.9%] ng/ml, respectively). At steady state, fulvestrant plasma concentrations are maintained within a relatively narrow range with up to an approximately 3-fold difference between maximum and trough concentrations. After intramuscular administration, the exposure is approximately dose-proportional in the dose range 50 to 500 mg.


Distribution:
Fulvestrant is subject to extensive and rapid distribution. The large apparent volume of distribution at steady state(Vdss) of approximately 3 to 5 l/kg suggests that distribution is largely extravascular.
Fulvestrant is highly (99%) bound to plasma proteins. Very low density lipoprotein (VLDL), low density lipoprotein (LDL), and high density lipoprotein (HDL) fractions are the major binding components. No interaction studies were conducted on competitive protein binding. The role of sex hormone-binding globulin (SHBG) has not been determined.


Biotransformation
The metabolism of fulvestrant has not been fully evaluated, but involves combinations of a number of possible biotransformation pathways analogous to those of endogenous steroids. Identified metabolites (includes 17-ketone, sulphone, 3-sulphate, 3- and 17-glucuronide 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 CYP3A4 is the only P450 isoenzyme involved in the oxidation of fulvestrant, however non-P450 routes appear to be more predominant in vivo. In vitro data suggest that fulvestrant does not inhibit CYP450 isoenzymes.


Elimination:
Fulvestrant is eliminated mainly in metabolised form. The major route of excretion is via the faeces with less than 1% being excreted in the urine. Fulvestrant has a high clearance, 11 ±1.7 ml/min/kg, suggesting a high hepatic extraction ratio. The terminal half-life (t1/2) after intramuscular administration  is governed by the absorption rate and was estimated to be 50 days.

Special populations:
In a population pharmacokinetic analysis of data from Phase 3 studies, no difference in fulvestrant's pharmacokinetic profile was detected with regard to age (range 33 to 89 years), weight (40-127 kg) or race.

Renal impairment
Mild to moderate impairment of renal function did not influence the pharmacokinetics of fulvestrant to any clinically relevant extent.


Hepatic impairment
The pharmacokinetics of fulvestrant has been evaluated in a single-dose clinical study conducted in women with mild to moderate hepatic impairment (Child-Pugh class A and B). A high dose of a shorter duration intramuscular injection formulation was used. There was up to about 2.5-fold increase in AUC in women with hepatic impairment compared to healthy subjects. In patients administered Faslodex, an increase in exposure of this magnitude is expected to be well tolerated. Women with severe hepatic impairment Child-Pugh class C) were not evaluated.


Paediatric population
The pharmacokinetics of fulvestrant has been evaluated in a clinical study conducted in 30 girls with Progressive Precocious Puberty associated with McCune Albright Syndrome (see section 5.1). The paediatric patients were aged 1 to 8 years and received 4 mg/kg monthly intramuscular dose of fulvestrant. The geometric mean (standard deviation) steady state trough concentration (Cmin,ss) and AUCss was 4.2 (0.9) ng/mL and 3680 (1020) ng*hr/mL, respectively. Although the data collected were limited, the steady-state trough concentrations of fulvestrant in children appear to be consistent with those in adults.


Drug-Drug Interactions:
Data from a clinical study 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.