NEW YORKStudies 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 longerwas
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, Ive 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.
Its 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.
Theyre 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 exemestanes 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
wont have symptoms, and thats a very worthwhile