SAN ANTONIO – Combination therapy with anastrozole and fulvestrant might be a new first-line treatment option for postmenopausal women with hormone receptor–positive breast cancer.

Phase III trial results demonstrated a statistically significant progression-free survival benefit with the combination therapy, compared with anastrozole monotherapy, Dr. Rita S. Mehta reported at the San Antonio Breast Cancer Symposium. Tamoxifen-naive patients, in particular, appear to reap the most benefit.

Among the 694 patients analyzed in the Southwest Oncology Group (SWOG)-S0226 trial of anastrozole (Arimidex) vs. anastrozole plus fulvestrant (Faslodex), the median progression-free and overall survival rates of the 349 women randomized to combination therapy were longer by 1.5 months and more than 6 months, respectively, than in 345 women randomized to monotherapy, according to Dr. Mehta of the University of California, Irvine.

The combination therapy "is the first new treatment in more than a decade that gives women with hormone receptor–positive metastatic breast cancer an overall survival benefit," she said.

Further, in a subset analysis, tamoxifen-naive patients randomized to combination therapy survived more than 4 months longer without disease progression than those in the monotherapy group, Dr. Mehta said, noting that, among tamoxifen-pretreated women, the progression-free survival benefit was nearly the same as that observed in the overall study population.

All of the study patients, median age 65 years, were postmenopausal with estrogen or progesterone receptor–positive metastatic breast cancer, and none had been previously treated for metastatic disease, Dr. Mehta explained.

Women with a history of previous adjuvant aromatase inhibitor therapy or neoadjuvant or adjuvant chemotherapy were eligible for inclusion only if their prior treatment was completed more than 12 months prior, she said. Previous tamoxifen treatment was also allowed, but approximately 60% of the study population was tamoxifen-naive.

From 2004-2009, eligible patients were randomized to receive 1 mg of anastrozole daily, either alone or in combination with an intramuscular injection of fulvestrant, dosed as follows: 500 mg on the first day; 200 mg on days 14 and 28; and 250 mg monthly thereafter. The primary study end point was progression-free survival, Dr. Mehta said. Upon disease progression, patients randomized to monotherapy were encouraged to crossover to combination therapy, "unless they were candidates for immediate chemotherapy," she explained.

During the period of analysis, 287 of the monotherapy patients and 261 of the combination therapy patients experienced disease progression after a median 13.5 months and 15.0 months, respectively. Median overall survival was 41.3 months in the monotherapy group and 47.7 months in the combination group, reported Dr. Mehta.

Randomization was stratified by adjuvant tamoxifen to assess a possible differential benefit of fulvestrant in the two strata, Dr. Mehta said. In a subset analysis of the 414 tamoxifen-naive patients, median progression-free survival was 12.6 months for monotherapy and 17.0 months for combination therapy; median overall survival was 39.7 months and 47.7 months, respectively, she said.

Among the patients pretreated with tamoxifen, median progression-free survival was 14.1 months with monotherapy and 13.5 months with combination therapy; median overall survival was 44.5 months and 49.6 months, respectively. The observed survival benefit was independent of age, HER2 status, sites of metastasis, time since primary diagnosis, disease measurability, and adjuvant chemotherapy, Dr. Mehta stated.

Although it is possible that prior tamoxifen treatment may predict outcomes, "it’s too soon to say," according to Dr. Mehta. The findings require prospective validation, she noted: "We need to better understand other possible factors, because the prior tamoxifen factor could be a false lead from an unplanned analysis."

Treatment-related adverse events in the combination group included three deaths – two attributed to pulmonary embolism and one to cerebrovascular ischemia; one grade 4 pulmonary embolism; and one grade 4 neutropenia and lymphopenia, Dr. Mehta stated. Four patients in the monotherapy group experienced grade 4 toxicities, including thrombosis/embolism, arthralgia, thrombocytopenia, and dyspnea, she said.

Grade 3 toxicities, including musculoskeletal pain, fatigue, and gastrointestinal symptoms were reported in approximately 13% of the combination group and 11% of the monotherapy group, "but very few patients stopped treatment because of adverse events or side effects," she said.

The findings suggest that combination anastrozole and fulvestrant therapy amps up the anti-estrogen benefits of anastrozole alone in postmenopausal breast cancer when used as a first-line therapy, Dr. Mehta stressed.

This is in contrast, she noted, to previously reported first results from the randomized FACT study in which the combination therapy did not improve overall survival among postmenopausal women with hormone receptor–positive advanced breast cancer in first relapse.

"The next step for researchers will be to try the combination in even earlier stages of breast cancer to test whether long-term cures could be increased at those stages," Dr. Mehta concluded.

Dr. Mehta disclosed receiving grant and research support from AstraZeneca.

Fulvestrant Adds Punch to Anastrozole for HR+ Breast Cancer