Aromasin, New Hormonal Agent, Approved for Breast Cancer

NEW YORK—Studies leading up to FDA approval last year of a new aromatase inactivator, exemestane tablets (Aromasin, Pharmacia & Upjohn), were reviewed at the Chemotherapy Foundation Symposium XVII.

A large multicenter randomized phase III trial in 769 postmenopausal women with metastatic breast cancer who had failed tamoxifen (Nolvadex) showed a survival advantage for exemestane over megestrol acetate (Megace), reported Stephen E. Jones, MD, director of breast cancer research, Sammons Cancer Center, Baylor University Medical Center, Dallas. Patients received exemestane, 25 mg daily, or the standard dose of megestrol acetate, 160 mg daily.

At the last report of the trial at ECCO 10 in Vienna, the median overall survival for the megestrol acetate group was 123.4 weeks, but, Dr. Jones said, the median has not been reached for patients treated with exemestane. “It is significantly different, compared to megestrol, which is interesting because there really are very few agents that have a survival advantage in these patients,” he said.

To calculate the survival advantage, the researchers estimated the 75% survival level. For the exemestane group, it was 74.6 weeks and for the megestrol cohort, 55 weeks. Based on Kaplan-Meier analysis, this represents a 36% survival advantage for the exemestane group. With Cox model analysis, the women receiving exemestane had a 23% longer survival than those on megestrol.

Overall disease control— a combined score of partial and complete responses and stable disease for 6 months or longer—was similar in the two groups: 37% of patients receiving exemestane and 35% of those on megestrol acetate.

The time to tumor progression, however, was significantly longer with use of exemestane, Dr. Jones said, a median of 4.7 months vs 3.8 months for megestrol. Further, the duration of response was significantly longer with exemestane (60.1 weeks vs 49.1 weeks).

In earlier trials, exemestane was tested as second- and third-line therapy. In a second-line study in which exemestane was given to 128 women who had failed tamoxifen, the overall disease control rate was 47%. “And these responses are really quite long,” Dr. Jones said. The median duration of response was 74 weeks.

Overall success, which includes stable disease, was 66 weeks. “This is well over a year for patients who are benefiting from the drug,” Dr. Jones said. “In fact, I’ve had a couple of patients in the trials who had responses longer than 2 years and one patient who had a 4½-year response.”

In two third-line studies of patients who had failed both tamoxifen and megestrol, one enrolling 91 women and the other 87, overall disease control averaged 30%. The median duration of overall success, Dr. Jones noted, was 34 and 39 weeks, respectively.

In another study of exemestane in 241 patients who had failed aromatase inhibitors as well as tamoxifen, objective responses were seen in only 7%, but 25% showed evidence of disease control, with a median duration of benefit of 58 weeks. “This is in patients failing aminoglutethimide or drugs like anastrozole [Arimidex],” Dr. Jones said. “This does suggest that there may be something very different about exemestane, compared to the aromatase inhibitors.”

While agents such as letrozole (Femara) and anastrozole inhibit aromatase, exemestane inactivates the enzyme, Dr. Jones explained. “It’s a permanent inactivator rather than an inhibitor,” he said. With a chemical structure similar to androstenedione, exemestane binds to a substrate of aromatase, he noted, while the nonsteroidal agents attach to the heme portion.

Few Side Effects

Like the aromatase inhibitors, exemestane has few side effects. “They’re usually menopausal, hot flashes and so on,” Dr. Jones said. “Less than 2% of patients in these trials went off study because of possible adverse effects.”

Based on the findings to date, studies to evaluate whether exemestane is effective in adjuvant therapy are planned, Dr. Jones said. In a study now underway in Europe, he said, patients treated with tamoxifen for 5 years will then be randomized to receive either placebo or exemestane for 2 years.

For now, Dr. Jones sees exemestane’s place in the clinical armamentarium as “a new well-tolerated hormonal agent for postmenopausal women with metastatic breast cancer who fail tamoxifen or who fail tamoxifen, megestrol, and aromatase inhibitors.” With exemestane, he added, responses have been seen in patients with visceral disease of the lung or liver as well as those with metastases only to bone.

Hormonal therapy in metastatic breast cancer is “clearly one of the best palliative tools we have,” Dr. Jones said. “It works best usually in slowly progressive disease.” Responses are also not rapid, he cautioned. Agents like exemestane, he added, might be considered cytostatic. “It may just stop the cancer growth or induce minimal regression,” he said, “but the patient won’t have symptoms, and that’s a very worthwhile effect.”