EXAMESTANE IS DIFFERENT

December 14, 2009 (San Antonio, Texas) — New results coming from 2 mature trials with exemestane (Aromasin, Pfizer) suggest that this aromatase inhibitor differs slightly from the other 2 available products, letrozole (Femara, Novartis) and anastrozole (Arimidex, AstraZeneca).

Although all 3 are aromatase inhibitors, exemestane is a steroidal product that binds irreversibly to the estrogen receptor; the other 2 products are both nonsteroidal and are reversible inhibitors.

Concerning breast cancer recurrence, exemestane appears to be less effective at preventing early events, although it is effective at preventing later events, and it now appears that most of these events are in the bone, according to data presented here at the 32nd Annual San Antonio Breast Cancer Symposium (SABCS).

The first finding comes from 5-year final results from the TEAM (Tamoxifen Exemestane Adjuvant Multinational) study, which involved 9775 postmenopausal women with estrogen-receptor (ER)-positive early breast cancer. They were assigned to initial treatment with either exemestane or tamoxifen; after 2.5 to 3 years, the tamoxifen group was switched to exemestane.

The final results show no difference in efficacy between the 2 groups, measured as disease-free survival, time to recurrence, and overall survival, Daniel Rea, MD, senior lecturer in medical oncology at the University of Birmingham, United Kingdom, told the meeting.

This finding is out of line with the other aromatase inhibitors, said John Forbes, MD, from the University of Newcastle, in New South Wales, Australia, who moderated the session. Both of the other agents have demonstrated superiority over tamoxifen in significantly reducing the risk for breast cancer recurrence — letrozole in the Breast International Group (BIG)-1-98 trial and anastrozole in the Arimidex, Tamoxifen Alone or in Combination (ATAC) study.

"The finding from the TEAM study of no significant difference from tamoxifen is not consistent with the results of the other 2 aromatase inhibitors," Dr. Forbes told Medscape Oncology in an interview. "But a possible explanation for this is that the TEAM trial design targets particular early events (within the first 2.5 to 3 years), and that exemestane may be less effective at preventing these early events than letrozole or anastrozole," he said.

Approached for independent comment by Medscape Oncology, Kimberly Blackwell MD, from Duke University in Durham, North Carolina, said: "Exemestane does appear to be different from letrozole and anastrozole in [that it has] a less documented benefit when used immediately after diagnosis."

She reiterated the point that Dr. Forbes had made. Both of the other aromatase inhibitors have shown an improvement in progression-free survival when compared directly with tamoxifen and used as monotherapy immediately after diagnosis (data from the ATAC and BIG-1-98 studies), she said. These data have led to approval of letrozole and anastrozole as superior to tamoxifen, she added.

"We do not have that data for exemestane," Dr. Blackwell noted. The first part of the TEAM trial compares exemestane with tamoxifen directly, and as monotherapy after diagnosis, and it showed no difference, she pointed out. Exemestane is approved for use only after 2 to 3 years of tamoxifen, Dr. Blackwell explained, which is how it was used in the International Exemestane Study (IES).

Preventing Later Events

Dr. Forbes said that IES showed exemestane to be significantly better than tamoxifen at preventing later events. That study involved 4724 women with early breast cancer; the majority of the women were ER positive or their ER status was not known (97%), but 3% were ER negative, so not expected to respond. All of the trial participants received tamoxifen for 2 to 3 years, and women who remained disease-free were then randomized to receive either exemestane or tamoxifen.

Results from the IES have been published (Lancet. 2007;369:559-570), and show that exemestane was significantly better than tamoxifen in both disease-free and overall survival.

The new data presented here in at the SABCS come from an updated and more exploratory analysis, Judith Bliss, MD, from the Institute of Cancer Research Clinical Trials and Statistics Unit in Sutton, United Kingdom, told the meeting. She said this analysis was carried out only on the women who were ER positive or who had unknown ER status. "The women who were ER negative would have never been included in this trial if this had been known at the time that the trial started," she said.

Results are now out to 8 years and show an absolute difference of 4.4% for disease-free survival and 2.5% for overall survival between the 2 treatment groups, she said. "There is no evidence that the benefit is lost with time," she noted.

The finding was significant for all breast cancer events, which included death, breast cancer recurrence, and nonbreast secondary cancer.

An "unexpected finding" was that an analysis of the site of the first reported distant recurrence suggested that the reduction in distant recurrences was largely confined to events in the bone, she said. "This is highly speculative and is hypothesis-generating," she explained, and it is unclear whether these events are really distant recurrences or new primaries in the bone. "This is an unexpected finding, and we don't have an explanation for this," Dr. Bliss said.

Dr. Forbes told Medscape Oncology that this was an interesting finding. "IES targets later events, after 2 to 3 years, in a good-prognosis population, and has previously reported an advantage for exemestane over tamoxifen. The news today is that this advantage appears to be largely confined to a reduction in the risk of breast cancer recurrence in bone," he said.

Both exemestane studies, TEAM and IES, were funded by the manufacturer, Pfizer. Dr. Rea reports receiving research funding from Pfizer, and acting as a speaker and consultant for Pfizer and AstraZeneca. Dr. Forbes reports serving as a speaker for AstraZeneca and Novartis. Dr. Blackwell reports receiving honoraria from Genentech and GlaxoSmithKline, and consulting for Genentech. Dr. Bliss reports receiving research funding from Sanofi-Aventis and Pfizer.

32nd Annual San Antonio Breast Cancer Symposium (SABCS): Abstracts 11 and 12. Presented December 10, 2009.