Patients with breast cancer may derive greater treatment benefit by doubling the dose of the estrogen-receptor antagonist fulvestrant according to results from the international randomized, double-blind, phase 3 Comparison of Faslodex in Recurrent or Metastatic Breast Cancer (CONFIRM) trial.
Results from the trial, presented by Angelo DiLeo, MD, of the Hospital of Prato, Prato, Italy, showed that fulvestrant 500 mg (F500) was significantly more effective than fulvestrant 250 mg (F250) in in creasing time to disease progression in women with advanced estrogen receptor–positive breast cancer. "We anticipate that the 500-mg regimen will become the established dose for fulvestrant," he said.
The approved dose is 250 mg/month, but investigators hypothesized that outcomes might be further improved by increasing the dose to 500 mg (two 250-mg injections on days 1, 14, and 28, and every 28 days thereafter). They designed a phase 3 trial to determine whether the higher dosage might induce a more profound downregulation of the estrogen receptor without worsening side effects.
CONFIRM compared F250 with F500 in postmenopausal women with estrogen receptor–positive advanced breast cancer recurring or progressing after prior endocrine therapy. The study recruited 736 women from 128 centers in 17 countries, and randomized them to one of the two doses until disease progression.
The primary end point, time-to-progression, was significantly prolonged with F500—6.5 months versus 5.5 months with F250, corresponding to a 20% reduction in the risk of progression. Disease progression was observed in 82% versus 85.8%, respectively, and the differences were consistent across all predefined subgroups.
"It is clear that the 500-mg dose is more effective than 250 mg," DiLeo observed, emphasizing that the higher dose did not result in more toxicity and there was no evidence of dose-dependence for adverse events.
This was an interim analysis and only 50% of the patients have died. Although there was a trend for improved overall survival with F500, it did not reach statistical significance. Death occurred in 48.3% of the F500 group and 54.3% of the F250 group, corresponding to a 16% nonsignificant reduction in mortality risk with the higher dose.
"It is not statistically significant, but our impression is that patients on 500 mg are surviving longer," he added.
An exploratory analysis is currently seeking to identify a subgroup that may derive the most benefit from dose escalation and from hormonal therapy in general. "It is important to target the population that will benefit most from downregulation of the estrogen receptor," he said.