Aromatase Inhibitors ‘Roughly Similar’ in Metastatic Breast Cancer

October 1, 2002

ORLANDO-An open-label randomized study comparing letrozole (Femara) and anastrozole (Arimidex), the two US FDA-approved nonsteroidal aromatase inhibitors, found a higher overall response rate for letrozole as second-line therapy in women with metastatic breast cancer.

ORLANDO—An open-label randomized study comparing letrozole (Femara) and anastrozole (Arimidex), the two US FDA-approved nonsteroidal aromatase inhibitors, found a higher overall response rate for letrozole as second-line therapy in women with metastatic breast cancer.

Commentators, however, discounted the difference due to the high number of receptor-unknown patients, and the session discussant called the agents "roughly similar." In response, presenter Carsten Rose, MD, PhD, stressed that the study demonstrated a high response rate for both agents, and showed that letrozole is at least as good as anastrozole in the metastatic setting.

In his presentation at the 38th Annual Meeting of the American Society of Clinical Oncology (abstract 131), Dr. Rose, director of the Department of Oncology, Lund University Hospital, Lund, Sweden, said that for some third-generation, highly selective aromatase inhibitors, "we have shown very clearly that they have at least an activity that is the same as tamoxifen [Nolvadex]."

He suggested further that aromatase inhibitors should replace tamoxifen as the gold standard in metastatic breast cancer. Oral letrozole at 2.5 mg/d, Dr. Rose pointed out, has been shown to be consistently superior to tamoxifen as first-line therapy of hormone-sensitive advanced breast cancer in terms of time to progression, overall response rate, clinical benefit, and early survival. Relative to anastrozole, he said, letrozole has shown greater ability to inhibit aromatase in vitro, and to reduce production of estrone, estrone sulfate, and estradiol.

FEM-INT-01

The current multicenter, multinational trial (FEM-INT-01), sponsored by Novartis, included 713 postmenopausal women with hormone-receptor-positive or unknown metastatic breast cancer who had failed tamoxifen therapy. Participants were randomized to letrozole 2.5 mg or anastrozole 1 mg, both given once daily, with data collected to 30 months. Mean age was 63 years.

Dr. Rose noted that about 50% of patients in each group (51% letrozole, 53% anastrozole) were of unknown receptor status, which was normal trial practice at the time of the study inception outside of the United States and Canada.

More than 50% of patients had metastatic engagement in the lung and/or liver. Importantly, Dr. Rose said, the distribution of patients who had received adjuvant tamoxifen or who were receiving tamoxifen for metastatic disease was equivalent in the two groups.

Study Results

Dr. Rose reported that the primary endpoint, time to progression, was identical in the two groups at 5.7 months, as was time to treatment failure, at 5.6 months. Overall survival was similar at 22.0 months for letrozole vs 20.3 months for anastrozole (P = .624). Clinical benefit, duration of response, and duration of clinical benefit were also similar.

However, the overall response rate for letrozole, at 19.1% (complete response, 6.7%; partial response, 12.4%), was statistically superior (P = .013) to that for anastrozole at 12.3% (complete response, 3.6%; partial response, 8.7%), with an odds ratio of 1.7.

Adverse events occurring in more than 2% of patients were similar and low for the two agents, as were serious adverse events. Discontinuations for adverse events were 8% for both drugs.

He stressed that performance of an independent review is crucial in any open-label study. "In this case," he said, "a retrospective, independent, blinded review in responders found a concordance of 83%."

Dr. Rose concluded, "In this open-label randomized study involving more than 700 patients, letrozole produced significantly superior response rates, compared with anastrozole." These results, he said, are consistent with preclinical and in vivo data showing higher aroma-tase inhibition with letrozole, compared with anastrozole.

Conclusions Questioned

Audience respondents questioned Dr. Rose’s conclusions, pointing out the high percentage of patients with unknown receptor status (more than half) and that response rates were similar among those whose receptor status was known (17.3% for letrozole; 16.8% for anastrozole).

Discussant George Sledge, MD, Indiana University, addressing what he called "dueling aromatase inhibitors," urged future trialists to include only receptor-positive patients. "This clearly affects the interpretation of such trials," he said.

Dr. Sledge pointed out further, that in the study abstract, overall response rate had included stable disease in addition to complete and partial remission, and that under that analysis, differences between the agents were not significant.

While noting that both agents have real clinical benefit, Dr. Sledge observed that with overall response rates in the 10% to 20% range and times to progression less than 6 months, "neither one of these agents works particularly well in tamoxifen failures." He said also that resistance to aromatase inhibition and hormonal therapy in general remains a significant problem.

"Differences between the two agents are modest, at best," Dr. Sledge concluded. "I personally would view these agents as being roughly similar in terms of their activity in this group of patients."