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High-dose fulvestrant reduced risk for death in ER-positive breast cancer
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Fulvestrant in 500-mg doses reduced risk for death by 19% compared with 250-mg doses in women with locally advanced or metastatic, ER-positive breast cancer, according to the final analysis of a double blind, phase 3 study.
The CONFIRM trial included 736 women (median age, 61 years).
Researchers assigned 362 women to 500 mg fulvestrant (Faslodex, AstraZeneca) in two 5-mL intramuscular injections on days 0, 14 and 28, and every 28 days thereafter. The other 374 women were assigned 250 mg fulvestrant. They received one 5-mL dose of the study drug and one dose of placebo in the same dosing schedule.
Initial study analyses demonstrated improved PFS with 500 mg fulvestrant. The initial OS analysis of the study occurred after approximately 50% of the patients had died, and demonstrated a trend toward improved OS with the higher dose.
At the time of the final survival analysis, 554 patients (75.3%) had died.
Median OS was significantly longer in the 500-mg cohort compared with the 250-mg cohort (26.4 months vs. 22.3 months; HR=0.81; 95% CI, 0.69-0.96).
Researchers calculated a 19% reduction in the risk for death associated with the 500-mg dose.
Fulvestrant was well tolerated across both arms. In the 500-mg cohort, 35 (9.7%) patients experienced at least one serious adverse event during the study vs. 27 (7.2%) patients in the 250-mg cohort.
“Based on the final results of the CONFIRM trial, we suggest an OS benefit for fulvestrant 500 mg over 250 mg,” the researchers concluded. “Taking into account that the previously reported PFS results were statistically significantly in favor of fulvestrant 500 mg, we believe that whenever treatment with fulvestrant should be initiated, this should be at the dose of 500 mg, according to the same schedule of this trial.”
Disclosure: The researchers report employment, consultant, advisory or leadership positions with, research funding or honoraria from, and stock ownership in AstraZeneca, Novartis and Pfizer.
Perspective
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Stephen Y. Chui, MD
The CONFIRM study quite definitely establishes the superiority of the 500-mg dosing of fulvestrant over the 250-mg dosing of the same medication. Improvements are seen for the higher 500-mg dosing for hormone receptor-positive metastatic breast cancer in PFS, objective response rate, clinical benefit rate, duration of clinical benefit rate, and now OS — the latter outcome being notoriously difficult to demonstrate in metastatic breast cancer — in exchange for no additional toxicity other than injection site pain.
Initial randomized studies of fulvestrant 250 mg demonstrated equivalence to tamoxifen, anastrozole (Arimidex, AstraZeneca) and exemestane. With superiority seen for fulvestrant 500 mg over the 250-mg dosing, the question arises whether fulvestrant 500 mg can provide clinically meaningful benefits — including OS benefit — over tamoxifen and the aromatase inhibitors. If randomized studies eventually show real OS benefit for the higher dose of fulvestrant over oral anti-estrogen agents, the paradigm of utilizing oral agents first in the treatment of metastatic hormone receptor-positive breast cancer has the potential to shift to the pure ER antagonist fulvestrant in this setting.
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