FALCON Trial: Faslodex Spreads Its Wings, but Remains in the Shadows of Its Competition

By Emily Benesh, Ph.D., Analyst, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Ph.D., Vice President, Clinical & Scientific Assessment, Kantar Health




Faslodex® (fulvestrant, AstraZeneca) was approved in 2002 for the treatment of postmenopausal metastatic hormone receptor (HR)-positive breast cancer patients following prior anti-estrogen therapy. To date, utilization of Faslodex has favored second- and third-line settings for this indication, while aromatase inhibitors (AI) are generally favored in the first line for postmenopausal patients. Unlike AIs, which inhibit estrogen biosynthesis, Faslodex is an estrogen receptor antagonist (a selective estrogen receptor degrader (SERD)) that competes with estrogen to bind to estrogen receptors.  Since Faslodex acts through a different mechanism than AIs, it may represent an attractive treatment option in the first line for physicians concerned about bone loss caused by AIs. AstraZeneca previously marketed the AI Arimidex® (anastrozole), but since it lost patent protection in 2010 AstraZeneca has been looking to reestablish a branded agent (Faslodex) in the first-line postmenopausal setting. Indeed, AstraZeneca supported the FIRST trial, an open-label randomized Phase II study that evaluated Faslodex (500 mg) versus anastrozole (1 mg) as first-line hormone therapy in 205 women with postmenopausal HR-positive, locally advanced or metastatic breast cancer; notably, 72% and 78% of patients in each arm, respectively, have received no prior endocrine therapy. Faslodex was superior to anastrozole in both time to progression (23.4 versus 13.1 months; HR: 0.66, P=0.01) and overall survival (54.1 versus 48.4 months; HR: 0.70, P=0.04),1,2 prompting further evaluation of Faslodex in the first-line setting.

The objective of the Phase III FALCON trial was to confirm the superiority of Faslodex over anastrozole in postmenopausal HR-positive and HER2-negative patients with locally advanced/metastatic breast cancer who had not received prior endocrine therapy. FALCON was a double-blinded international trial that randomized patients to either Faslodex (500 mg subcutaneous injection on Day 0, 14 and 28, then every 28 days) or anastrozole (1 mg oral once daily).  The primary endpoint was progression-free survival (PFS), with several secondary endpoints including overall survival and objective response rate. Patients were included had WHO performance status of 2 or better and greater than one measurable or non-measurable lesion. Exclusionary criteria included prior endocrine therapy, systemic estrogen-containing hormone-replacement therapy use six months or less prior to randomization, presence of life-threatening metastatic visceral disease, and prior systemic treatment except one line of chemotherapy or radiotherapy.

AstraZeneca announced via press release in May 2016 that FALCON met its primary endpoint, but the data outcomes remained unknown until presented today at the 2016 European Society of Medical Oncology (ESMO) conference.3 Median PFS was improved by 2.8 months in favor of Faslodex (16.6 months for Faslodex versus 13.8 months for anastrozole; HR: 0.797, p = 0.0486). Overall survival was not significantly different between the arms (HR: 0.88, P=0.428), although the study had reached just 31% maturity. No significant differences were found in overall response rate, clinical benefit rate, or median time to deterioration by FACT-B total score. Immature duration of response endpoints showed promise (20.0 versus 13.2 months, Faslodex and anastrozole, respectively) as did duration of clinical benefit (22.1 versus 19.1 months, Faslodex and anastrozole, respectively); although statistical significance was not reported for these endpoints, the authors noted that they were trending toward significance. Overall safety profiles were generally similar between the two arms, with modestly higher signals in the Faslodex arm for arthralgia (16.7% versus 10.3%), myalgia (7.0% versus 3.4%), and ALT increase (7.0% versus 3.0%).

Interestingly, subgroup analysis found that PFS more strongly favored the Faslodex arm in patients lacking visceral metastatic disease. In the subpopulation of 208 patients, only 53.7% had a progressive event in the Faslodex arm, compared with 69.9% of patients in the anastrozole arm (22.3 months versus 13.8 months median PFS, respectively; HR: 0.592). No difference was observed in PFS between the Faslodex and anastrozole arms in patients with visceral metastatic disease. The generalizability of these findings was strengthened by similar PFS improvements in the Faslodex arms of the FIRST1,2 and CONFIRM4,5 trials.

Despite the fact that the FALCON trial met its primary endpoint, Faslodex will have hurdles to overcome in order to gain utilization in the front-line setting for this patient population. The largest hurdle faced by Faslodex in the first line is competition with the CDK 4/6 inhibitors. Ibrance® (palbociclib, Pfizer) is already U.S. FDA-approved in combination with letrozole in the first-line setting and in combination with Faslodex in AI-pretreated metastatic breast cancer, and a European approval is currently pending. Given the exemplary data that Ibrance/letrozole demonstrated in first line in comparison to letrozole alone (PFS: 24.8 versus 14.5 months, respectively, HR=0.58, p<0.000001)6, the 2.8-month benefit for Faslodex demonstrated in the FALCON trial in a very selective group of hormone-naïve first-line patients is not expected to unseat current use of the Ibrance/letrozole combination. Where Faslodex may find use in first-line is in those patients who don’t currently receive an Ibrance combination. Metastatic breast cancer patients with very indolent disease that has demonstrated strong sensitivity to endocrine therapy may be treated with a single agent hormone therapy upon first metastatic recurrence; the superiority that Faslodex demonstrated over anastrozole may support its use in first-line in some of these patients. However, that displacement may not be widespread given the small degree of benefit (2.8 months median PFS, PFS HR 0.797, and no overall survival benefit). Where Faslodex may find a niche role in first-line is in patients with bone-only disease (non-visceral), patients at risk for bone complications, or in patients who are not compliant with oral therapies.

The FALCON results suggest that for the vast majority of metastatic breast cancer patients, Faslodex will continue to play a strong role in the second- or third-line settings. Several Phase III trials in the relapsed setting that have combined Faslodex with targeted agents are underway, and indeed the Phase III PALOMA-3 trial has already reported impressive results for the combination of Faslodex plus Ibrance in AI-pretreated patients.7 Knowing that Ibrance plus Faslodex is superior to Faslodex alone in the second-line setting, there has been speculation that positive results in FALCON could spur use of this combination in the first-line setting. However, the small magnitude of benefit actually observed in FALCON will likely limit use of this combination in first-line in clinical practice.

The positive results from the FALCON trial will be viewed as an important advance for a select group of metastatic breast cancer patients (HR-positive, HER2-negative and endocrine therapy-naïve). While the FALCON results will allow Faslodex to take flight into first-line for this niche patient group, ultimately this bird of prey can’t out-compete a bird of peace8


  1. Robertson JF, Lindemann JP, Llombart-Cussac A, et al., “Fulvestrant 500 mg versus anastrozole 1 mg for the first-line treatment of advanced breast cancer: follow-up analysis from the randomized ‘FIRST’ study,” Breast Cancer Res Treat, 136(2): 503-11, 2012.
  2. Robertson JF, Llombart-Cussac A, Felti D et al., “Fulvestrant 500 mg versus anastrozole as first-line treatment for advanced breast cancer: Overall survival from the Phase II ‘FIRST’ study,” Abstract S6-04, SABCS, 2014.
  3. Ellis MJ, Bondarenko IM, Trishkina E, et al.; “FALCON: A phase III randomised trial of fulvestrant 500 mg vs. anastrozole for hormone receptor-positive advanced breast cancer;” Annals Oncol, 27 (s1):  Abstract LBA 14_PR, 2016.
  4. Di Leo A, Jerusalem G, Petruzelka, et al.; “Results of the CONFIRM Phase III Trial Comparing Fulvestrant 250 mg With Fulvestrant 500 mg in Postmenopausal Women With Estrogen Receptor–Positive Advanced Breast Cancer;” J Clin Oncol, 28 (30): 4548-4550, 2010.
  5. Di Leo A, Jerusalem G, Petruzelka L, et al., ” Final Overall Survival: Fulvestrant 500mg vs 250mg in the Randomized CONFIRM Trial,” J Natl Cancer Inst, 106 (1): djt337, 2013.
  6. Finn RS, Martin M, Rugo HS, et al.; “PALOMA-2: Primary results from a phase III trial of palbociclib (P) with letrozole (L) compared with letrozole alone in postmenopausal women with ER+/HER2– advanced breast cancer (ABC);” J Clin Oncol 34, 2016 (suppl; abstr 507).
  7. Turner NC, Ro J, Andre F, et al.; “Palbociclib in Hormone-Receptor–PositiveAdvanced Breast Cancer;” New  Engl J Med,  2015, DOI: 10.1056/NEJMoa1505270.
  8. PALOMA is derived from Latin “palumbus” which means Dove; a symbol of Peace.
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