Higher Dose Fulvestrant Ups Survival in Breast Cancer

Final overall survival results of a trial comparing fulvestrant doses found that postmenopausal women with metastatic, ER–positive breast cancer had a 19% lower risk of death when taking a 500-mg dose compared with a 250-mg dose.

The final overall survival results of a trial comparing two different doses of fulvestrant (Faslodex) found that postmenopausal women with metastatic, estrogen receptor–positive breast cancer benefited more from the higher 500-mg dose compared with the 250-mg dose. Women taking the 500-mg dose had a 19% lower risk of death from their breast cancer compared with those who took the 250-mg dose.

Women taking the 500-mg dose lived a median 4.1 months longer compared with those who took the 250-mg dose. The final median overall survival was 26.4 months in the 500-mg dose arm and 22.3 months in the 250-mg dose arm (hazard ratio [HR] = 0.81; P = .02).

The long-term results of the phase III CONFIRM (Comparison of Faslodex in Recurrent or Metastatic Breast Cancer) trial were published in the Journal of the National Cancer Institute.

Fulvestrant is an estrogen-receptor antagonist. Based on progression-free survival results of the CONFIRM trial, the 500-mg dose was approved in 2010 by the US Food and Drug Administration for postmenopausal women with hormone receptor–positive breast cancer who have had disease progression after anti-estrogen therapy.

The initial results published in 2010 showed that the 500-mg dose improved progression-free survival by 1.1 months compared with the 250-mg dose, from 5.4 months to 6.5 months (P = .006). The higher dose decreased the risk of disease progression by 20% compared with the 250-mg dose (HR = 0.8; P = .006). These results followed the deaths of 50% of the patients on the trial.

The current overall survival analysis by Angelo Di Leo, MD, PhD, of the Hospital of Prato, Piazza dell Ospedale in Prato, Italy, and colleagues, was planned after 75% of deaths on the trial occurred. The trial had randomized 736 women 1:1 to either 500 mg or 250 mg of fulvestrant given as an intramuscular injection every 14 days for the first 3 doses followed by a dose every 28 days. The median age of women on the trial was 61 years.

The initial analysis showed a median overall survival of 25.1 months for the women in the 500-mg dose group and 22.8 months in the 250-mg dose group-a 2.3-month difference (HR = 0.84; P = .09).

The best overall responses were two complete responses and 17 (7.4%) partial responses in the 500-mg dose group. No complete responses were seen in the 250-mg dose group, and 20 (8.4%) patients in this treatment arm had partial responses.

No new serious adverse events (SAEs) occurred during the longer-term follow-up. Thirty-five (9.7%) patients in the 500-mg dose group had at least one SAE compared with 27 (7.2%) in the 250-mg dose group. SAEs that were directly attributed to the fulvestrant treatment occurred in eight (2.2%) women in the 500-mg dose group and in four (1.1%) women in the 250-mg dose group. Deaths due to SAEs occurred in five (1.4%) patients and seven (1.9%) patients in the 500-mg and 250-mg dose groups, respectively. “There were no clinically important differences in the profiles of SAEs between the treatment groups, and no clustering of SAEs could be detected in either treatment group,” stated the authors in their results.

Whether the 500-mg fulvestrant dose is a better option than aromatase inhibitors as a first-line therapy for postmenopausal patients with advanced estrogen receptor–positive breast cancer is not clear. According to the authors, these results of the CONFIRM trial provide a rationale for the use of the 500-mg dose of fulvestrant in combination with nonendocrine therapies that target primary or secondary resistance pathways activated in patients. “Fulvestrant might be an ideal partner for future combination studies considering that its unique mechanism of action leads to estrogen receptor downregulation, thus preventing not only the estrogen receptor–mediated transcription of several genes but also the cross-talks between cytoplasmic estrogen receptor and several downstream effectors of molecular pathways involved in resistance to endocrine therapies.”