In the first ever head-to-head comparative trial of a drug against anastrozole, the most common treatment for breast cancer, exemestane was not superior to anastrozole but comparable in its anticancer effects and likely better in terms of its side-effect profile," reported Study Chair Paul E. Goss, MD, PhD, of Massachusetts General Hospital, Boston. Dr. Goss presented the final analysis of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) MA.27 at the 33rd Annual San Antonio Breast Cancer Symposium.¹

Backbone for Novel Therapies

Dr. Goss believes the trial was positive in terms of a superior side-effect profile, particularly on bone density, something that he hopes further reports in 2011 will prove.

"We see this as providing a new option for 5 years of upfront adjuvant therapy. On the face of things, these may appear to be slightly 'ho hum' results. The aromatase inhibitors are coming off patent, and there is not much excitement over such results," he told The ASCO Post. "But remember these constitute the single most important class of anticancer drugs in breast cancer, and they form the backbone for novel therapies," he added.

"Exemestane is the third pony in the race because it started later, not because it is not a good runner. It's just as fast as the lead horse."

MA.27 is the first trial in hormone receptor-positive early breast cancer to compare a nonsteroidal and steroidal aromatase inhibitor. The nonsteroidal agent anastrozole is approved for monotherapy in the adjuvant setting, whereas the steroidal inhibitor exemestane is indicated only in sequence after an initial 2 to 3 years of tamoxifen.

According to Dr. Goss, the study investigators believed that exemestane might have greater efficacy and better end-organ safety than anastrozole because it is "irreversible and more potent, does not induce intratumoral aromatase, and through its mild androgenic activity may exert a second antitumor effect and a more favorable bone and lipid metabolism profile."

Excellent Disease-free Survival in Each Arm

MA.27 randomly assigned 7,576 patients to 5 years of treatment with anastrozole (1 mg/d) or exemestane (25 mg/d). No differences were observed between arms.

"Exemestane was not superior to anastrozole, which was the primary objective of the trial. The event-free survival curves were superimposable at 4.1 years of follow-up," Dr. Goss announced.

The disease-free survival rate was 91% in both arms of MA.27. Events (recurrence, new breast cancer, death) were observed in 9.2% of the exemestane arm and in 9.1% of the anastrozole arm (P = .85). About 4% per arm experienced distant metastases. All subset analyses were similar as well. The low event rates probably reflect "the low-risk population and improvements in breast cancer care," he said.

Dr. Goss prefers not to view the findings as "negative," he said. He noted that differences were observed in the end-organ effects for the two aromatase inhibitors, and these may be clinically important. Menopause-like symptoms occurred equally between the arms, although vaginal bleeding was slightly less common with exemestane.

Cardiovascular effects were similar and infrequent. Hypertriglyceridemia and hypercholesterolemia occurred less with exemestane, as did new diagnoses of osteoporosis, though clinical fracture rates were similar. By 3 years, approximately one-fourth of patients had discontinued treatment on both arms.

Differing Side-effect Profiles

"Because the side-effect profiles are somewhat different, if patients have symptoms on one drug they can try another one without doing harm. We now know that exemestane will not impair cancer outcomes," he continued.

Dr. Goss offered exemestane as perhaps the better choice for women with baseline osteoporosis, osteopenia, or lipid abnormalities, in whom breast cancer treatment may trigger the need for yet another pill to counteract the side effects.

MA.27 is a huge repository of data, and findings will continue to emanate from the study, he added. Additionally, Dr. Goss is heading up the NCIC CTG placebo-controlled MAP.3 trial that is evaluating exemestane for prevention in women with moderate breast cancer risk. "This will be a vehicle for determining if aromatase inhibitors are as powerful in preventing breast cancer as we think they are." ■

Reference

1. Goss PE, Ingle JN, Chapman J-AW, et al: Final analysis of NCIC CTG MA.27: A randomized phase III trial of exemestane versus anastrozole in postmenopausal women with hormone receptor positive primary breast cancer. 33rd Annual San Antonio Breast Cancer Symposium. Abstract S1-1. Presented December 9, 2010.