Dose Fulvestrant Escalation Increase Breast Cancer Progression?

San Antonio

, TX

—Doubling the dose of fulvestrant (Faslodex) from 250 mg to 500 mg significantly increases the time to disease progression in the treatment of postmenopausal women with hormone receptor-positive breast cancer, according to data from a multinational randomized study.

“The time to progression improvement seems to be the consequence of an increase in the rate, and of a prolongation in duration, of disease stabilization,” said Angelo Di Leo, MD, PhD, lead investigator of the trial, known as CONFIRM (Comparison of Faslodex in Recurrent or Metastatic Breast Cancer). Dr Di Leo, head of the Sandro Pitigliani Medical Oncology Unit, Hospital of Prato, Italy, presented the data at the CTRC-AACR San Antonio Breast Cancer Symposium.

The approved dosage of fulvestrant is 250 mg per month, but previous preclinical and clinical research suggested that the tumor markers ER, PgR, and Ki67 were downregulated by fulvestrant in a dose-dependent manner and that 250 mg was not the maximally effective dose. These data provided the rationale for assessing a higher dosage of fulvestrant in CONFIRM, which included 736 women with estrogen receptor—positive advanced breast cancer that had recurred or progressed after previous endocrine therapy. The women were randomized to receive 250 mg or 500 mg of fulvestrant on days 1, 14, and 28, followed by 500 mg every 28 days thereafter.

Prior to randomization, 57.5% of the patients received anti-estrogen therapy and 42.5% were treated with an aromatase inhibitor. Approximately two-thirds of the women in each dosage group had visceral involvement.

The median time to progression, the primary endpoint of the study, was 6.5 months in patients randomized to 500 mg of fulvestrant compared with 5.5 months in those randomized to 250 mg, corresponding to a 20% reduction in the risk of progression (P = .006).

The treatment effect in favor of the 500-mg dose was consistent across all prespecified subgroups, including receptor status, visceral involvement, the type of endocrine therapy prior to fulvestrant, and the response to endocrine therapy prior to fulvestrant, said Dr Di Leo. The median duration of clinical benefit was also superior in the group assigned to 500 mg compared to the 250-mg group (16.6 mo vs 13.9 mo, respectively).

A trend toward improved survival was observed with the higher dosage: patients in the 500-mg dose group had a median overall survival of 25.1months compared with 22.8 months in the 250-mg dose group (P =.09). There was no difference between doses in the incidence or severity of adverse events.

A follow-up exploratory substudy using 150 primary tumor archival samples from CONFIRM is being conducted to identify cohorts with different levels of responsiveness to fulvestrant dose escalation, said Dr Di Leo.

Two other analyses of fulvestrant were reported here; one found no advantage to combining a 250-mg loading dose of fulvestrant with anastrozole (Arimidex) to treat first relapse in women with hormone-positive breast cancer. The other reported no improvement on tumor biomarkers associated with combining 500 mg of fulvestrant with anastrozole versus fulvestrant monotherapy as an adjuvant treatment in postmenopausal women with estrogen receptor—positive breast cancer. SABCS Abstracts 23-25.