Phase 3 study of atamestane + toremifene vs. letrozole in advanced breast cancer

LBA525 Background: This study addresses the principle of “complete estrogen blockade” by combining atamestane, an investigational steroidal aromatase inhibitor (AI) with toremifene, an approved first line therapy. The primary objective was to assess whether atamestane + toremifene could improve on the time to disease progression achieved with letrozole alone. Methods: This was a multinational randomized, double blind, double dummy phase 3 clinical trial. Eligible women were postmenopausal with advanced breast cancer (ABC), estrogen and/or progesterone receptor positive. Prior adjuvant hormonal therapy was permitted only if completed >12 months prior to enrollment. Subjects received either atamestane 500 mg per day with toremifene 60 mg per day (A+T), or letrozole 2.5 mg per day (L). The primary endpoint was time to progression (TTP), log-rank test comparison on all randomized patients. Secondary objectives included objective response (OR), overall survival, and time to treatment failure (TTF). The study had 80% power to detect a 25% increase in TTP assuming a TTP of 9.4 months in the L population. Results: 865 patients with locally advanced (9%) or metastatic disease (91%) were randomized: 434 to A+T and 431 to L. Baseline characteristics were: mean age 64 years (S.D. = 9); ECOG Status 0 = 30%, 1 = 60%, 2 = 10%; prior adjuvant hormonal therapy 13%; prior adjuvant chemotherapy 20%. Sites of metastases and number of sites were well balanced between arms. The median TTP was identical in the two arms: 11.2 months (p < .92, log-rank chi square). The hazard ratio (L/A+T) for TTP was 1.00 (0.92–1.08, Cox proportional hazards 95% CI); for TTF was 0.99 (0.92–1.06) and for overall survival was 0.98 (0.87–1.11). OR occurred in 30% of patients on A+T and 36% of patients on L (p < 0.1, likelihood ratio chi square). Most frequent AEs (A+T vs L) were asthenia (11% vs 12%), increased weight (12% vs 10%), and hot flushes (10% vs 11%). Serious AEs were 10% vs 11%. Conclusions: While our study did not demonstrate increased TTP for A+T compared with L, this is the first endocrine therapy to be equally effective as letrozole as first line therapy in ABC. Both treatments were equally well tolerated. Unlike the ATAC trial, addition of an anti-estrogen did not decrease the efficacy of the AI. Further study of combination AI + SERM is warranted. [Table: see text]

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