SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 246,660 new cases of invasive breast cancer will be diagnosed in 2016 and 40,450 women will die of the disease. Estrogen Receptor (ER) positive breast cancer cells are driven by estrogens. Approximately 60-65% of breast tumors express Estrogen Receptors and/or Progesterone Receptors and this is a predictor of response to endocrine therapy. These patients are often treated with anti-estrogen therapy as first line treatment. In premenopausal woman, the ovary is the main source of estrogen production, whereas in postmenopausal women, the primary source of estrogen is the Aromatase enzyme mediated conversion of androstenedione and testosterone to estrone and estradiol, in extragonadal/peripheral tissues. NOLVADEX® (Tamoxifen) is a nonsteroidal Selective Estrogen Receptor Modulator (SERM) and works mainly by binding to the Estrogen Receptor and thus blocks the proliferative actions of estrogen on the mammary tissue. ARIMIDEX® (Anastrozole), FEMARA® (Letrozole) and AROMASIN® (Exemestane) are Aromatase Inhibitors (AIs) that binds to the Aromatase enzyme and inhibit the conversion of androgens to estrogens in the extra-gonadal tissues. FASLODEX® (Fulvestrant) is an estrogen antagonist and like NOLVADEX®, binds to estrogen receptors (ERs) competitively, but unlike NOLVADEX® causes rapid degradation and loss of ER protein (ER downregulator), and is devoid of ER agonist activity.
The superiority of ARIMIDEX® over NOLVADEX® was first established in the year 2000 following the publication of the results of a North American Multicenter Randomized Trial. In this study, ARIMIDEX® as first-line treatment in postmenopausal women with advanced breast cancer resulted in a significant increase in Time To Progression and a lower incidence of thromboembolic events and vaginal bleeding, compared to NOLVADEX®. In a previously reported phase II study (FIRST trial), first-line treatment with FASLODEX® significantly improved Time To disease Progression and Overall Survival compared with ARIMIDEX®, in patients with hormone receptor (HR) positive advanced breast cancer.
The FALCON trial is a phase III study conducted to confirm findings from the FIRST trial. This study included 462 postmenopausal women, with locally advanced or metastatic hormone receptor positive, HER2-negative, endocrine-therapy naive breast cancer. Patients were randomized to receive FASLODEX® IM at 500 mg on days 0, 1, and 28 and then every 28 days (N=230) or ARIMIDEX® 1 mg PO daily (N=232). Treatment was continued until disease progression or unacceptable toxicity. The primary endpoint was Progression Free Survival (PFS), and secondary endpoints included Overall Survival, Objective Response Rate, Clinical Benefit Rate, Duration of Response, health-related Quality of Life, and safety.
It was noted that FASLODEX® provided better disease control with a median PFS of 16.6 months compared to 13.8 months with ARIMIDEX® (P=0.048). Subgroup analysis showed that FASLODEX® was markedly superior to ARIMIDEX® in patients with non-visceral disease with a median Progression Free Survival of 22.3 months compared with 13.8 months for ARIMIDEX®. There was no significant improvement in the Overall Response Rate between the treatment groups. However, the median Duration of Response was 20.0 months with FASLODEX® compared to 13.2 months with ARIMIDEX®. Expected Duration of response and expected Duration of Clinical Benefit were in favor of FASLODEX® (11.4 vs 7.5 months; P=0.001) and (21.9 vs 17.5 months; P=0.001), respectively. There was no difference in Overall Survival at the time of this analysis. Rates of adverse events were similar in both treatment groups.
The authors concluded that FASLODEX® was superior to ARIMIDEX® as initial treatment of hormone receptor positive, endocrine therapy naive, advanced breast cancer. Patients with non-visceral and low volume disease, as well as elderly patients, may benefit the most with FASLODEX®, as this therapy is well tolerated with a low toxicity profile. FALCON: a phase III randomised trial of fulvestrant 500 mg vs. anastrozole for hormone receptor-positive advanced breast cancer. Ellis MJ, Bondarenko I, Trishkina E, et al. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA14.