Fulvestrant significantly improves PFS versus anastrozole in advanced breast cancer

Fulvestrant demonstrated superior efficacy over anastrozole for postmenopausal women with hormone-receptor positive (HR+) ABC, this year’s European Society for Medical Oncology Congress was told. Dr Matthew Finn, Director of the Lester and Sue Smith Breast Center, Baylor College of Medicine, US, revealed that the results were more impressive in patients with non-visceral disease.

Current first-line therapies for postmenopausal women with HR+ ABC include either tamoxifen or endocrine therapy with an aromatase inhibitor, such as anastrozole. Fulvestrant is a competitive oestrogen receptor (ER) antagonist that downregulates ER protein levels. It is currently approved for HR+ ABC with disease progression after prior anti-oestrogen therapy.

“The effect was modest but particularly striking in the non-visceral patient population.”
Dr Matthew Ellis, Director of the Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas, US

The phase III study Dr Ellis presented, ‘FALCON’, aimed to confirm the superiority of fulvestrant compared to anastrozole. Patients included in the study had ER+ and/or progesterone-receptor positive (PgR+), HER2 negative locally advanced or metastatic breast cancer, a WHO performance status of 0-2 and ≥1 measurable and/or non-measurable lesions. A total of 462 patients were randomised 1:1 to fulvestrant (500 mg at days 0, 14, 28 then every 28 days) or anastrozole (1 mg daily).

The study met its primary endpoint, demonstrating a significant increase in median PFS; 16.6 months with fulvestrant versus 13.8 months with anastrozole (hazard ratio (HR) 0.797, 95% confidence interval (CI) 0.637-0.999, p=0.0486). PFS was measured using RECIST criteria (version 1.1).

Although the increase in PFS was modest, Dr Ellis reflected, it “was interesting to think about historically, because that’s about the same benefit that led us to move from tamoxifen to third-generation aromatase inhibitors in similar patient populations.”

While there were no significant differences between groups, “there was one subgroup that everyone’s discussing,” he said, “it’s the visceral versus non-visceral comparison.” Dr Ellis proceeded to explain that “in the non-visceral group, fulvestrant looked convincingly better than anastrozole, reaching a median PFS of over 22 months versus 13-14 months.”

“Whereas,” he continued, “in the visceral group, the two drugs looked much more equivalent.” For this reason, a further look into using fulvestrant in non-visceral patient populations is warranted.

FALCON secondary endpoint data

Based on Reck M, Rodríguez-Abreu D et al. KEYNOTE-024: Pembrolizumab (pembro) vs platinum-based chemotherapy (chemo) as first-line therapy for advanced NSCLC with a PD-L1 tumor proportion score (TPS) ≥50% (LBA8_PR). Presented on Sunday 9 October 2016.

Secondary endpoint	Fulvestrant (n=230)	Anastrozole (n=232)
Overall survival maturity (% deaths)	29.1%	32.3%	HR 0.88, 95% CI 0.63-1.22, p=0.428
Objective response rate	46.1% (n=89)	44.9% (n=88)	Odds ratio (OR) 1.07, 95% CI 0.72-1.61, p=0.729
Median duration of response	20.0 months	13.2 months
Expected duration of response	11.4 months	7.5 months	Ratio 1.52, 95% CI 1.23-1.89, p<0.001
Clinical benefit rate	78.3% (n=180)	74.1% (n=172)	OR 1.25, 95% CI 0.82-1.93, p=0.305
Complete response	3.0% (n=7)	3.4% (n=8)
Partial response	37.4% (n=86)	35.3% (n=82)
Stable disease at ≥24 weeks	37.8% (n=87)	35.3% (n=82)
Median duration of clinical benefit	22.1 months	19.1 months
Estimated duration of clinical benefit	21.9 months	17.5 months	Ratio 1.26, 95% CI 1.13-1.39, p<0.001

Overall survival results, which are not yet mature, “will be a key endpoint to look at,” Dr Ellis said, “because an earlier open-label phase II trial hinted at the possibility that front-line fulvestrant could produce long-term survival benefits over anastrozole.”

Most common adverse events reported from treatment with fulvestrant or anastrozole were arthralgia (16.7% vs 10.3%, respectively) and hot flushes (11.4% vs 10.3%). The effect of treatment on health-related quality of life was similar in both arms of the study.

“The main take-home message is that FALCON was a positive trial with an improvement in PFS over anastrozole, in a well-conducted trial unbiased by endocrine therapy. The effect was modest but particularly striking in the non-visceral patient population.” Dr Ellis believes that more discussion surrounding this finding will certainly be important for future care.

Based on Ellis M, Bondarenko I et al. FALCON: A phase III randomised trial of fulvestrant 500 mg vs. anastrozole for hormone receptor-positive advanced breast cancer (LBA14_PR). Presented on Friday 7 October 2016.

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