Neoplasms

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Breast Neoplasms

Breast Diseases

Skin Diseases

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Fulvestrant

Anastrozole

Antineoplastic Agents, Hormonal

Estrogens

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormone Antagonists

Aromatase Inhibitors

Enzyme Inhibitors

Blinded: Fulvestrant 500mg intramuscular injection (2x250mg) plus dummy Anastrozole tablets

Blinded: Anastrozole 1mg tablets plus dummy Fulvestrant intramuscular injection (2x0mg)

2 x intramuscular injections at day 1, 14, 28 and every 28 days thereafter

faslodex 500mg

arimidex 1mg

faslodex dummy

arimidex dummy

Shankar S, MD

John Robertson, MD

Matthew Ellis, DM

The purpose of the study is to compare how treatment with Fulvestrant (FASLODEX) or Anastrozole (ARIMIDEX) effects disease progression for women with locally advanced or metastatic breast cancer who have not had prior hormonal treatment.

A Randomised, Double-blind, Parallel-group, Multicentre, Phase III Study to Compare the Efficacy and Tolerability of Fulvestrant (FASLODEX) 500 mg with Anastrozole (ARIMIDEX) 1 mg as Hormonal Treatment for Postmenopausal Women with Hormone Receptor-Positive Locally Advanced or Metastatic Breast Cancer Who Have Not Previously Been Treated With Any Hormonal Therapy.

A Global Study to Compare the Effects of Fulvestrant and Arimidex in a Subset of Patients With Breast Cancer.

A Randomised, Double-blind, Parallel-group, Multicentre, Phase III Study to Compare the Efficacy and Tolerability of Fulvestrant (FASLODEX) 500 mg With Anastrozole (ARIMIDEX) 1 mg as Hormonal Treatment for Postmenopausal Women With Hormone Receptor-Positive Locally Advanced or Metastatic Breast Cancer Who Have Not Previously Been Treated With Any Hormonal Therapy.

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

PFS was defined as the time from randomisation until objective disease progression according to Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1), surgery or radiotherapy to manage worsening of disease or death by any cause (in the absence of progression). Outcome measure is reported as median time from randomisation to PFS, calculated using the Kaplan-Meier technique.

OS was defined as the time from randomisation until death by any cause. The current OS data correspond to that of the final analysis and the outcome measure is reported as percentage of patients with events.

ORR was defined as the percentage patients with an objective response (i.e. those recording a partial response \[PR\] or complete response \[CR\]) at some point during the study, prior to disease progression. ORR was assessed in patients with measurable disease at baseline only. The determination of measurable disease at baseline was done using baseline RECIST data. CR was disappearance of all target lesions since baseline; was any pathological lymph nodes selected as target lesions (TL) to have a reduction in short axis to \<10 millimeter. PR was at least a 30% decrease in the sum of the diameters of TL, taking as reference the baseline sum of diameters.

DoR was defined only for patients who had an objective response, as the time in days from date of first documentation of response (CR/PR) until date of disease progression. CR was disappearance of all target lesions since baseline; any pathological lymph nodes selected as TL to have a reduction in short axis to \<10 mm. At least a 30% decrease in the sum of the diameters of TL, taking as reference the baseline sum of diameters.

EDoR was estimated using the formula EDoR = p Efp(x), where x = DoR, p = proportion of responders, and Efp(x) = mean duration of response for responders. The estimation was completed by using the maximum likelihood estimates of p and Efp(x), as described by Ellis (Ellis S et al. Analysis of duration of response in oncology trials, Contemp Clin Trials 2008; 29:456-65).

CBR was defined as the percentage of patients who had a clinical benefit (i.e. best objective response of CR, PR or stable disease), that was maintained for at least 24 weeks, prior to any evidence of progression. Note that a minimum duration of 22 weeks for CBR was applicable in the analysis (rather than 24 weeks) to allow for the protocolled window of +/-2 weeks.

DoCB was defined only for patients who had clinical benefit, as the time in days from date of randomisation until the date of disease progression.

EDoCB was estimated using the formula EDoCB = p Efp(x), where x = EDoCB, p = proportion of responders, and Efp(x) = mean duration of response for responders. The estimation was completed by using the maximum likelihood estimates of p and Efp(x), as described by Ellis (Ellis S et al. Analysis of duration of response in oncology trials, Contemp Clin Trials 2008; 29:456-65).

The Functional Assessment of Cancer Therapy - Breast (FACT-B) questionnaire was the instrument selected to assess HRQoL and comprised of following subscales: physical well-being (PWB), functional well-being (FWB), social well-being, emotional well-being, and breast cancer subscale (BCS). The main outcome measure from the FACT-B questionnaire was the Trial Outcome Index (TOI), which was a summary of the following subscales: PWB, FWB, and BCS. Outcome measure is reported as median time to deterioration, defined as the interval from the date of baseline of final analysis to the first assessment of worsened without an improvement in the next 12 weeks in FACT-B TOI, or the date of death (by any cause in the absence of symptom deterioration). Time to deterioration as measured by FACT-B total score was derived similarly and is also reported.

AstraZeneca

All-Cause Mortality: The ITT analysis set included all randomised patients. For serious adverse events and other (non-serious) adverse events: Safety population was defined as all patients who received at least 1 dose of randomised study medication. 2 patients in the Fulvestrant 500 mg arm did not receive treatment and were not included in the safety population.

Patients received fulvestrant (Faslodex™) 500 mg, administered as two 5 mL intramuscular injections, 1 in each buttock, at each visit on Days 0, 14 (±3), 28 (±3) and every 28 (±3) days thereafter. In order to support the double-blind, double-dummy design of the trial, each patient randomised to receive fulvestrant, also received placebo to match the anastrozole schedule (tablets, once daily).

Fulvestrant 500 mg

Patients received anastrozole (Arimidex™), administered orally as a single tablet at a dose of 1 mg/day from randomisation on Day 0 and once daily thereafter. In order to support the double-blind, double-dummy design of the trial, each patient randomised to receive anastrozole also received placebo to match the fulvestrant schedule (injections on Days 0, 14 \[±3\], 28 \[±3\] and every 28 \[±3\] days thereafter).

Anastrozole 1 mg

Total

Age, Continuous

Sex: Female, Male

Race/Ethnicity, Customized

The intention to treat (ITT) analysis set included all randomised patients.

Global Clinical Lead

If the true PFS HR for comparison of fulvestrant vs. anastrozole was 0.69 (likely to correspond to a 45% prolongation of PFS) the study had 90% power to demonstrate a statistically significant difference for PFS with a one-sided type 1 error of 2.5% (two-sided 5%).

The ITT analysis set included all randomised patients.

Comparison of Progression-Free Survival (PFS) in Patients Treated With Fulvestrant With Those Treated With Anastrozole

The ITT analysis set included all randomised patients. Date of death of 2 participants were unknown in the Anastrozole 1mg arm, hence they were censored for OS analysis.

Comparison of Overall Survival (OS) in Patients Treated With Fulvestrant With Those Treated With Anastrozole; Percentage of Patients With Events

Percentages for ORR were calculated based on the number of patients in the ITT analysis set (which included all randomised patients) who had measurable disease at baseline (n=193 for Fulvestrant arm and n=196 for Anastrozole arm).

Objective Response Rate (ORR) for Fulvestrant Treatment Versus Anastrozole Treatment

Only patients in the ITT analysis set (which included all randomised patients), who also had an objective response and had measurable disease at baseline were included in the DoR analysis (n=89 for Fulvestrant arm and n=88 for Anastrozole arm).

Duration of Response (DoR) for Fulvestrant Treatment Versus Anastrozole Treatment

EDoR analysis was based on the number of patients in the ITT analysis set (which included all randomised patients) who had measurable disease at baseline (n=193 for Fulvestrant arm and n=196 for Anastrozole arm).

Expected Duration of Response (EDoR) for Fulvestrant Treatment Versus Anastrozole Treatment

Clinical Benefit Rate (CBR) for Fulvestrant Treatment Versus Anastrozole Treatment

Only patients in the ITT analysis set (which included all randomised patients) who also had a clinical benefit were included in the DoCB analysis (n=180 for Fulvestrant arm and n=172 for Anastrozole arm).

Duration of Clinical Benefit (DoCB) for Fulvestrant Treatment Versus Anastrozole Treatment

Expected Duration of Clinical Benefit (EDoCB) for Fulvestrant Treatment Versus Anastrozole Treatment

Comparative statistical analysis for time to deterioration of TOI score is presented (fulvestrant versus anastrozole).

Comparative statistical analysis for time to deterioration of FACT-B total score is presented (fulvestrant versus anastrozole).

Time to TOI deterioration

Time to FACT-B total score deterioration

Comparison of the Effect of Fulvestrant Treatment Versus Anastrozole Treatment on Time to Deterioration of Health-Related Quality of Life (HRQoL)

Patients received fulvestrant (Faslodex™) 500 milligrams (mg), administered as two 5 milliliters (mL) intramuscular injections, 1 in each buttock, at each visit on Days 0, 14 (±3), 28 (±3) and every 28 (±3) days thereafter. In order to support the double-blind, double-dummy design of the trial, each patient randomised to receive fulvestrant, also received placebo to match the anastrozole schedule (tablets, once daily).

Spots Global Cancer Trial Database for arimidex dummy