Letrozole Superior to Tamoxifen in Metastatic Breast Cancer

April 1, 2002

SAN ANTONIO-The aromatase inhibitor letrozole (Femara) should be considered for first-line hormonal therapy in postmenopausal women with advanced breast cancer, according to the final analysis of a pivotal phase III trial comparing the agent with tamoxifen (Nolvadex).

SAN ANTONIO—The aromatase inhibitor letrozole (Femara) should be considered for first-line hormonal therapy in postmenopausal women with advanced breast cancer, according to the final analysis of a pivotal phase III trial comparing the agent with tamoxifen (Nolvadex).

907 Women

The large multinational trial included 907 women randomized to receive letrozole 2.5 mg daily or tamoxifen 20 mg daily as first-line therapy for advanced disease.

Martine Piccart, MD, PhD, of Jules Bordet Institute, Brussels, Belgium, reported the findings at the 24th Annual San Antonio Breast Cancer Symposium (abstract 9) on behalf of lead author Henning Mouridsen, MD, of Rigshospitalet, Copenhagen, who could not attend the meeting.

Some of the study results have been previously reported (Mouridsen H et al: J Clin Oncol 19:2596, 2001). At the San Antonio conference, Dr. Piccart reported the 32-month follow-up that included the first survival figures for the randomized comparison.

Letrozole was shown to be significantly superior to tamoxifen in the primary endpoint of median time to progression: 9.4 months vs 6 months, for a 28% risk reduction (P = .0001), Dr. Piccart said.

"In addition to being statistically significant, these differences are also clinically relevant," she commented. "And there is a consistency of the results across all the subgroups of women in this trial. The superiority of letrozole is seen whether or not they received adjuvant tamoxifen or had hormone-receptor-positive tumors, and independently of the dominant site of disease."

The objective response rate was increased with letrozole vs tamoxifen, from 21% to 32%. This difference yielded an odds ratio of 1.78 in favor of letrozole (P = .0002). The clinical benefit rate (complete response plus partial response plus stable disease for 24 weeks or more) was 50% vs 38%, for an odds ratio of 1.62 (P = .0004), Dr. Piccart reported.

There were no statistically significant differences, however, in duration of response or duration of clinical benefit. Time to response was about 14 weeks in both arms.

Survival Rates

Letrozole and tamoxifen yielded similar survival rates, with a median survival of 34 months with letrozole and 30 months with tamoxifen. "However, a closer look at these curves clearly indicate that they nicely separate in the beginning and merge after approximately 36 months," she noted.

By Wilcoxen test, the survival differences approached statistical significance, with a P value of .079, she said.

In addition, the investigators performed a survival analysis by 6-month intervals and found that letrozole was associated with a survival benefit at all time points up to and including 24 months. For example, 18-month survival was 75% for letrozole and 65% for tamoxifen.

Diminution of the survival advantage, she suggested, may have been due to the study design that allowed patients to cross over from one drug to another upon disease progression. As of May 2001, 11% of patients remained on their initial first-line treatment, and 51% had crossed over to second-line hormonal therapy. Median time to crossover was 17 months for first-line letrozole and 13 months for tamoxifen.

"It is important to remember that crossover was an integral part of the trial. Crossover is a likely explanation for the later merge of the survival curves," Dr. Piccart remarked.