Regulatory Decision Summary for Faslodex

A pivotal study and a supportive study were submitted in this SNDS to demonstrate the efficacy and safety of the proposed indication of Faslodex in the treatment of locally advanced or metastatic breast cancer in postmenopausal women not previously treated with endocrine therapy.

The pivotal study FALCON was a randomised, double-blind, double-dummy, multicentre study comparing the efficacy and tolerability of fulvestrant with anastrozole in postmenopausal women with ER-positive and/or progesterone receptor (PR)-positive, HER2-negative locally advanced or metastatic breast cancer, who had not previously been treated with any endocrine therapy. A total of 462 patients were randomized 1:1 to receive fulvestrant 500 mg as intramuscular injection on Days 0, 14, 28 and every 28 (± 3) days thereafter or daily administration of anastrozole (an aromatase inhibitor) 1 mg orally. 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 study has fulfilled its primary objective, which was to demonstrate the superior progression-free survival (investigator assessed and evaluated according to RECIST v.1.1) of patients treated with fulvestrant vs. anastrozole. There was a statistically significant improvement in progression-free survival (PFS) in the fulvestrant arm (HR = 0.797; 95% CI: 0.637 - 0.999; p-value 0.0486), with median PFS which was 2.8 months longer in patients treated with fulvestrant (16.6 months) compared to patients treated with anastrozole (13.8 months). This difference is considered non-trivial given that the primary goal for therapy in advanced breast cancer is disease stabilisation and to provide patients with a reasonable period of disease control in order to maintain quality of life. Importantly, the improvement in PFS was demonstrated against an active comparator (anastrozole) which is a standard of care for this patient population.

There was a large number of patients with important protocol deviations in the study (45.2% in the fulvestrant arm and 33.6% in the anastrozole arm) which were mainly due to an incorrect stratification factor (ie. mis-stratification) and by RECIST timing issues. There was also a large number of patients who were censored in the PFS analysis early on in the study (at >12 weeks before data cut off). This number was higher in the fulvestrant arm compared to the anastrozole arm (11.7% vs. 8.6% of patients). The robustness of the study, however, is supported by a number of sensitivity analyses on the PFS data. Although there was some variability in the hazard ratios and p-values reported for the individual sensitivity analyses above and below those values reported for the primary analysis, overall an approximate 20% reduction in risk of disease progression (or death) was consistently observed. Importantly, this reduction was demonstrated against an active comparator.

In the subgroup analysis of PFS, the treatment effect observed was largely consistent with the primary analysis across the subgroups with the exception of those subgroups that had few patients and in the subgroup with visceral metastasis at baseline. The hazard ratio for the subgroup of patients with visceral metastasis was 0.993 with a median PFS of 13.8 months for the fulvestrant arm compared to 15.9 months for the anastrozole arm. For the subgroup of patients with non-visceral metastasis, the hazard ratio was 0.592 with a median PFS of 22.3 months for the fulvestrant arm compared to 13.8 months for the anastrozole arm. Given that the treatment effect in the visceral population was comparable in patients in the fulvestrant and anastrozole treatment arms as the hazard ratio was less than 1 and the safety profile of fulvestrant in the visceral subgroup was generally consistent with the overall population, limiting the proposed indication to patients with non-visceral disease is not considered necessary. The results of the subgroup analysis for the patients with visceral and non-visceral disease have been included in the Clinical Trials section of the product monograph (PM).

In terms of the key secondary efficacy endpoints, there was no statistically significant difference in overall survival (OS) between the treatment arms in this interim analysis. In patients with measurable disease at baseline, objective response rate (ORR) was also not statistically different between the treatment arms. However, expected duration of response was significantly improved in the fulvestrant arm (11.4 months) compared with the anastrozole arm (7.5 months), albeit not under strict alpha control as this secondary endpoint was not included in the multiple testing procedure. The study failed to detect a difference in health-related quality of life between the treatment arms.

The supportive study FIRST was a smaller randomised, open-label, parallel-group, multi-centre, phase II study comparing the efficacy and tolerability of fulvestrant 500 mg with 1 mg anastrozole as first-line hormonal treatment for postmenopausal women with ER+ and/or PR+ advanced breast cancer. The study population in FIRST was similar but not identical to that in FALCON, the main difference being it included some patients who had received prior hormone therapy (28.5% in the fulvestrant arm and 22.3% in the anastrozole arm) in the adjuvant or neo-adjuvant setting. However, this must have been completed more than 12 months prior to randomization, while patients in the FALCON study did not receive any prior endocrine therapy.

The primary efficacy endpoint was clinical benefit rate (CBR) defined by modified RECIST, and the observed results did not show any difference between the fulvestrant arm and the anastrozole arm (72.5% vs. 67.0%, respectively). The results demonstrated that fulvestrant offers a CBR that is at least as good as anastrozole. No statistically significant difference was observed in the secondary efficacy endpoint of ORR between the two treatment arms.

In the primary analysis of the secondary endpoint of time to progression (TTP, which was equivalent to PFS as it included death from any cause), treatment with fulvestrant resulted in a significantly longer TTP compared to treatment with anastrozole (hazard ratio = 0.6266, p-value = 0.0496), similar to what was observed for PFS in the FALCON study. Overall, the results from the FIRST study are considered to be supportive of the data in the FALCON study.

The adverse event profile observed was generally consistent with the known safety profile of fulvestrant. In the FALCON study, the percentage of patients with at least one adverse event (AE) was similar in both treatment arms (72.8% in the fulvestrant arm and 74.6% in the anastrozole arm), though more patients in the fulvestrant arm reported a Grade 3 AE compared to the anastrozole arm (18 % vs. 13.4%). The most commonly reported AEs in the fulvestrant arm were: arthralgia, hot flush, fatigue, nausea, back pain, myalgia, alanine aminotransferase increased, hypertension, insomnia, diarrhoea, constipation, pain in extremity, aspartate aminotransferase increased and cough.

Joint disorders and back pain group terms were pre-defined as AEs of special interest in the FALCON study. These were reported more often in the fulvestrant arm compared to the anastrozole arm: arthralgia (16.7% vs.10.3%), myalgia (7.0% vs. 3.4%), musculoskeletal pain (4.8% vs.2.2%), and back pain (9.2% vs. 6.0%). The sponsor considers that there is a reasonable possibility of a causal relationship between fulvestrant and joint and musculoskeletal pain. The frequencies of these adverse drug reactions (ADRs) have been captured in the Clinical Trial Adverse Drug Reactions section of the PM. Inclusion of a warning for joint and musculoskeletal pain in the PM is not warranted at this time given that most of the events were mild or moderate in severity.

In the supportive study FIRST, the percentage of patients with at least one AE was approximately 70% in both arms, which is similar to what was observed in the FALCON study. The most commonly reported AEs are similar to those reported in the FALCON study.

A Periodic Benefit-Risk Evaluation Report was submitted. No new safety issues were identified for Faslodex and standard monitoring is recommended.

The safety profile of Faslodex remains unchanged and there were no new adverse drug reactions observed from the studies in this submission.

In terms of labelling, the proposed indication has been recommended to be revised to specify the hormone receptor status of the indicated patient population. The indication should be limited to patients with ER-positive instead of a broader indication for hormone receptor-positive breast cancer because the majority (~95%) of the patients studied in the pivotal and the supportive trial were ER-positive while there were very few patients who were ER-negative and progesterone receptor (PR)-positive. Furthermore, substantial evidence of efficacy of fulvestrant in patients with ER-negative and PR-positive breast cancer is lacking.

Based on the data reviewed, the benefit-harm-uncertainty assessment is considered to be positive. Efficacy has been demonstrated and toxicity is considered tolerable and manageable. The use of Faslodex represents a beneficial addition to the currently approved therapeutic options for the treatment of ER-positive, HER2-negative locally advanced or metastatic breast cancer in postmenopausal women not previously treated with endocrine therapy.

No new clinical studies were submitted to support the proposed extension of the second-line indication to include patients who have progressed after aromatase inhibitors. The second-line indication remains as previously approved. The benefit-harm profile for the use of fulvestrant in patients who have progressed on anti-estrogen therapy remains unchanged.