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Phase III, Double-Blind, Controlled Trial of Atamestane Plus Toremifene Compared With Letrozole in Postmenopausal Women With Advanced Receptor-Positive Breast Cancer

Paul Goss, Igor N. Bondarenko, Georgiy N. Manikhas, Kelly B. Pendergrass, Wilson H. Miller, Jr, Peter Langecker, Dennis Blanchett

From the Department of Medicine, Massachusetts General Hospital, Boston, MA; Dnepropetrovsk State Medical Academy, Dnepropetrovsk, Ukraine; St Petersburg City Oncology Center, St Petersburg, Russian Federation; Kansas City Cancer Center, Kansas City, MO; McGill University, Montreal, Quebec, Canada; and Intarcia Pharmaceutics Inc, Emeryville, CA
Deceased

Address reprint requests to Paul Goss, MD, PhD, Harvard Medical School, 55 Fruit St, Lawrence House, LRH-302, Boston, MA 02114; e-mail: pgoss{at}partners.org

Purpose: To compare time to progression (TTP) with a steroidal aromatase inhibitor (AI) atamestane (ATA) combined with toremifene (TOR; complete estrogen blockade) versus letrozole (LET) in receptor-positive advanced breast cancer (ABC).

Patients and Methods: Eligibility included postmenopausal receptor-positive ABC and adjuvant hormonal therapy completed more than 12 months prior to study entry. Participants received daily ATA 500 mg with TOR 60 mg (ATA + TOR), or letrozole 2.5 mg (LET). The primary end point was TTP, whereas secondary objectives included objective response (OR), overall survival (OS), 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 LET population.

Results: A total of 865 patients were randomly assigned (434 to ATA + TOR and 431 to LET) in 60 centers in the United States, Canada, Russia, and Ukraine. Baseline characteristics were balanced. Median TTP was identical in the two arms at 11.2 months (P < .92). Median TTF was similar at 9.24 months (ATA + TOR) versus 10.44 months (LET). The hazard ratios (LET/ATA + TOR) were 1.00 (95% CI, 0.92 to 1.08) for TTP, 0.99 (95% CI, 0.92 to 1.06) for TTF, and 0.98 (95% CI, 0.87 to 1.11) for OS. OR occurred in 30% of patients receiving ATA + TOR and in 36% of patients receiving LET (P < .1). Adverse events (AEs) were similar for patients receiving ATA + TOR versus LET, and serious AEs were 10% v 11%, respectively.

Conclusion: TTP for patients receiving ATA + TOR was identical to that for patients receiving LET, representing the first endocrine therapy comparable to LET in ABC. Unlike in the Anastrozole, Tamoxifen, and Combined trial, addition of an antiestrogen did not decrease efficacy of the AI. Future studies of AIs in combination with more effective selective estrogen receptor modulators or selective receptor downregulators is warranted.

Supported by Intarcia Pharmaceutics Inc, Emeryville, CA.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.