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.
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.
Disclosure: The researchers report consulting relationships with Genomic Health Inc., Enzon, Eisai, Roche, Genentech, Novartis, Bristol-Myers Oncology and Abraxis, as well as grants from NCI.