New data presented at the CTRC-AACR 33rd Annual San Antonio Breast Cancer Symposium, USA, suggest fulvestrant 500mg offers improved disease control compared with the aromatase inhibitor, anastrozole, when used as a first-line treatment for hormone receptor positive breast cancer. The follow-up data from the FIRST (Faslodex fIRst line Study comparing endocrine Treatments) trial – a randomised, open-label, phase II trial in postmenopausal women with locally advanced or metastatic disease – showed a 34% reduction in risk of progression with fulvestrant 500mg compared with anastrozole.
The main goal of advanced breast cancer treatment is to prevent disease progression whilst maintaining quality of life. This new analysis was undertaken when 80% of patients had discontinued study treatment, as only 36% had progressed in the primary analysis in 2008.1 The data revealed that women who received fulvestrant 500mg had significantly prolonged Time To disease Progression (TTP) (hazard ratio=0.66; 95% confidence interval 0.47, 0.92; p-value=0.01), corresponding to a median TTP of 10.3 months longer than for anastrozole 1mg (23.4 vs 13.1 months respectively).
These data are consistent with the findings of the primary analysis, which showed that women receiving fulvestrant 500mg experienced a clinical benefit rate of 73% compared with 67% for those receiving anastrozole 1mg (p=0.386).1 No new safety concerns were identified for fulvestrant 500mg, which was well tolerated, and patients who progress on either fulvestrant 500mg or anastrozole 1mg remain sensitive to subsequent endocrine treatments (41% vs 42% respectively).
Fulvestrant has a different mechanism of action from other endocrine therapies; in addition to blocking the action of estrogen at its receptor, it also disrupts estrogen signalling, leading to down-regulation of the estrogen receptors in the tumour as well as disruption of other cancer growth pathways. This distinct mechanism of action not only reduces the growth and spread of the cancer but may help to reduce or delay resistance to treatment.
These data add to an expanding body of clinical evidence including the CONFIRM (COmparisoN of Faslodex In Recurrent or Metastatic breast cancer) and NEWEST (Neo-adjuvant Endocrine therapy for Women with Estrogen-Sensitive Tumours) studies which reinforce the use of fulvestrant at its newly approved dose of 500mg. Most recently, CONFIRM showed that increasing the dose of fulvestrant 250mg to 500mg significantly prolongs disease control without compromising tolerability. Based on this evidence, fulvestrant 500mg was licensed in Europe for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following anti-estrogen therapy in March 2010 and by the FDA in the US in September 2010.
For over 30 years, AstraZeneca has played a pivotal role in breast cancer research and treatment. Throughout this time, scientists at AstraZeneca have researched and developed a range of endocrine therapies that have made significant contributions to the treatment of both early and metastatic breast cancer around the world.
Fulvestrant is an estrogen receptor antagonist with no known agonist effects used to treat postmenopausal women with hormone-receptor positive metastatic breast cancer. It has a distinct and different mode of action to other endocrine therapies and is the only treatment in this class of drugs. Findings from the clinical development programme (CONFIRM, NEWEST and FIRST) have suggested that fulvestrant 500mg enhances estrogen receptor down-regulation and efficacy compared with the currently approved 250mg dose. A dose of 500mg fulvestrant (2 x 250mg injections) is given intramuscularly (i.m.) on day 1, followed by a further dose of 500mg i.m. on day 14, a further dose of 500mg i.m. on day 28 and then 500mg once every 28 days thereafter. Please note it is not possible to formulate the fulvestrant 500mg dose as a single injection.
FIRST (Faslodex fIRst line Study comparing endocrine Treatments) was a randomised, open-label, phase II trial comparing fulvestrant 500mg with anastrozole in postmenopausal women with locally advanced or metastatic hormone receptor-positive cancer (n=205). FIRST demonstrated that fulvestrant 500mg was at least as effective as anastrozole in terms of clinical benefit, with a significantly longer time to progression.
NEWEST (Neoadjuvant Endocrine therapy for Women with Estrogen-Sensitive Tumours) was a randomised phase II trial of over 200 patients, comparing fulvestrant 500mg given as 16 weeks neo-adjuvant therapy for metastatic hormone receptor-positive breast cancer versus fulvestrant 250mg. The primary efficacy endpoint was assessed using levels of Ki67, an important marker of tumour cell growth and a specific indicator of treatment response. The study showed that fulvestrant 500mg significantly reduces levels of Ki67 and increases ER down-regulation compared with the 250mg dose, indicating a greater reduction in tumour cell growth.
CONFIRM (COmparisoN of Faslodex In Recurrent or Metastatic breast cancer) was a randomised double-blind, double-dummy phase III clinical trial comparing fulvestrant 500mg (n=362) with fulvestrant 250mg (n=374) in postmenopausal women with metastatic hormone receptor-positive breast cancer, after failure on one prior endocrine therapy. The primary endpoint was Time To disease Progression (TTP).The study showed that fulvestrant 500mg significantly improves disease control, without affecting tolerability, when compared with the currently approved 250mg dose.
AstraZeneca is a global, innovation-driven biopharmaceutical business with a primary focus on the discovery, development and commercialisation of prescription medicines. As a leader in gastrointestinal, cardiovascular, neuroscience, respiratory and inflammation, oncology and infectious disease medicines, AstraZeneca generated global revenues of US $32.8 billion in 2009.
Time to progression (TTP): A measure of time after a patient’s disease is treated until the disease starts to get worse.
Double dummy: In CONFIRM, all patients were given two monthly injections; either two active doses (fulvestrant 500mg as 2 x 250mg injections) or one active dose (fulvestrant 250mg) and one placebo. In this way blinding of the study was maintained for both physician and patient.
Patients eligible for the FIRST trial were postmenopausal women with hormone receptor-positive (ER+ and/or PgR+ve), locally advanced or metastatic breast cancer. Prior endocrine therapy for advanced disease was not permitted but patients could have received adjuvant therapy for early disease, provided it had been completed more than a year prior to randomisation. In total 153 (75%) of patients had received no prior endocrine therapy at all and the remaining 25% had completed adjuvant endocrine therapy more than 12 months previously.