The combination of anastrozole and fulvestrant extended median survival
of women with hormone-receptor–positive metastatic breast cancer when
compared with standard therapy of either anastrozole alone or sequential
anastrozole and fulvestrant, according to study results.
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In prior studies, anastrozole (Arimidex, AstraZeneca) exhibited the
ability to suppress estrogen production, while fulvestrant (Faslodex,
AstraZeneca) demonstrated high efficacy in a low-estrogen environment.
In addition, the combination of fulvestrant and an aromatase inhibitor —
compared with either agent alone — delayed the development of
resistance by down-regulating several signaling molecules involved in
the development of resistance.
To determine whether the combination of anastrozole and fulvestrant
would be superior to anastrozole alone as first-line therapy for
metastatic breast cancer, Rita Mehta, MD, and colleagues from the UC
Irvine Medical Center conducted a phase 3 randomized trial of 694
postmenopausal women with previously untreated metastatic disease from
June 1, 2004, to July 1, 2009.
During the study, patients were randomly assigned to receive either 1
mg of anastrozole orally once daily in combination with injections of
fulvestrant — given in sequential dosing on the first day, every 2
weeks, and then once every 28 days after the first month — or 1 mg of
anastrozole orally once daily, with possible crossover to fulvestrant
alone following disease progression.
Median PFS was 15 months for patients who received the anastrozole
and fulvestrant combination vs. 13.5 months for patients who received
anastrozole alone, according to study results. The combination was
observed to be generally more effective than anastrozole alone in all
subgroups, with no significant interactions.
In addition, median OS was longer among patients assigned to the
combination therapy (47.7 months vs. 41.3 months), despite the fact that
41% of the patients in the anastrozole group crossed over to
fulvestrant after progression.
“The improvement in overall survival that was observed in our study
has not been seen in other trials of first-line hormonal therapy for
HR-positive metastatic breast cancer,” the researchers wrote.
“Specifically, in the trials comparing aromatase-inhibitor therapy with
tamoxifen therapy, the benefit from aromatase inhibitors with respect to
progression-free survival failed to translate into a benefit with
respect to overall survival, a finding that was attributed to the
crossover of some patients in the tamoxifen group to an aromatase
inhibitor.”
Three deaths that were possibly associated with treatment occurred
in the combination group. Toxic effects of grade-4 or higher were
observed in four patients who received anastrozole alone (1.2%) and in
five patients who received combination therapy (1.4%; P=1.00). The four
observed grade-4 toxic effects among patients who received anastrozole
alone included thrombosis or embolism, joint pain, thrombocytopenia and
dyspnea. Two patients in the combination group experienced grade 4-toxic
effects. One experienced thrombosis or embolism, and the other
experienced neutropenia or lymphopenia.
“The results of our study suggest that trials of adjuvant therapy
should be performed in which the combination of an aromatase inhibitor
and high-dose fulvestrant is compared with an aromatase inhibitor alone
or high-dose fulvestrant alone in patients with
estrogen-receptor–positive tumors for whom chemotherapy is not
necessary,” the researchers concluded.
The Wall