Joumal of Clinical Oncology, Vol 16, No 2 (February), 1998: pp 453-461 453 Letrozole, a New Oral Aromatase Inhibitor for Advanced Breast Cancer: Double-Blind Randomized Trial Showing a Dose Effect and Improved Efficacy and Tolerability Compared With Megestrol Acetate By P. Dombernowsky, I. Smith, G. Falkson, R. Leonard, L. Panasci, J. Bellmunt, W. Bezwoda, G. Gardin, A. Gudgeon, M. Morgan, A. Fornasiero, W. Hoffmann, J. Michel, T. Hatschek, T. Tjabbes, H.A. Chaudri, U. Hornberger, and P.F. Trunet Purpose : To compare two doses of letrozole and megestrol acetate (MA) as second-line therapy in postmenopausal women with advanced breast cancer previously treated with antiestrogens. Patients and Methods : Five hundred fifty-one patients with locally advanced, locoregionally recurrent or metastatic breast cancer were randomly assigned to receive letrozole 2.5 mg (n = 174), letrozole 0.5 mg (n = 188), or MA 160 mg (n = 189) once daily in a double-blind, multicenter trial. Data were analyzed for tumor response und safety variables up to 33 months of follow-up evaluation und for survival up to 45 months. Results : Letrozole 2.5 mg produced a significantly higher overall objective response rate (24%) compared with MA (16%; logistic regression, P = .04) or letrozole 0.5 mg (13%; P = .004). Duration of objective response was significantly langer for letrozole 2.5 mg compared with MA (Cox regression, P = .02). Letrozole 2.5 mg ENDOCRINE THERAPY is an important option in the treatment of advanced breast cancer, with tamoxifen the most widely used first-line drug. Approximately 40% of patients who relapse after tamoxifen may achieve further clinically useful tumor control with second-line therapy, 11-14 but the optimum choice of second-line treatment has not yet been defined. Progestins and aromatase inhibitors (AIs) are both commonly used; progestins (megestrol acetate [MA] and medroxyprogesterone acetate) can cause edema, weight gain, vaginal bleeding, hypertension, and thromboembolic problems, 2 while aminoglutethimide, until recently the most commonly used AI, can cause rash, drowsiness, and lethargy. 2 Lately, more selective AIs 3-8 have been developed, including letrozole (CGS 20267), a new orally active, potent, highly selective, nonsteroidal competitive inhibitor of the aromatase enzyme. 9 It has been reported to be approximately 10,000 times as potent as aminoglutethimide in vivo, with no evidence of inhibition of progesterone or corticosterone synthesis at doses required to inhibit estrogen synthesis. 10 In animal models, it has been shown to lead to almost complete regression of estrogen-dependent dimethylbenzanthracene (DMBA)-induced mammary tumors. 10 Phase 1 studies have shown letrozole to be effective in suppressing estrone, estradiol, and estrone sulfate by more than 75% to 80% at doses of 0. 1 mg to 5 mg/d, with no clinically relevant was significantly superior to MA und letrozole 0.5 mg in time to treatment failure (P = .04 und P = .002, respectively). For time to progression, letrozole 2.5 mg was superior to letrozole 0.5 mg (P = .02), but not to MA (P = .07). There was a significant dose effect in overall survival in favor of letrozole 2.5 mg (P = .03) compared with letrozole 0.5 mg. Letrozole was significantly better tolerated than MA with respect to serious adverse experiences, discontinuation due to poor tolerability, cardiovascular side effects, and weight gain. Conclusion: The data show letrozole 2.5 mg once daily to be more effective und better tolerated then MA in the treatment of postmenopausal women with advanced breast cancer previously treated with antiestrogens. J Clin Oncol 16:453-46 1. © 1998 by American Society of Clinical Oncology. effects on other hormones of the endocrine system (including glucocorticoids, mineralocorticoids, and thyroid hormones). 11-14 Objective tumor response rates of approximately 25% have been obtained in postmenopausal patients with advanced breast cancer after failure of previous therapy. Tolerability was excellent, with minimal side effects. 13-16 This study reports the results of a multicenter, international, double-blind, randomized trial to compare the efficacy and safety of two doses of letrozole versus MA as second-line therapy in the treatment of women with advanced breast cancer previously treated with an antiestrogen. The dose of letrozole 0.5 mg was selected because it was the lowest dose to achieve maximal estrogen suppression. The dose of 2.5 mg was chosen because it was still selective and well tolerated and could perhaps achieve a higher degree of aromatase inhibition at the level of the tumor. The two doses differ by a factor of five to ensure that a dose effect, if present, could be detected. 17 From the Letrozole International Trial Group (AR/BC2). Submitted April 14, 1997; accepted September 25, 1997. Supported by a grant from Novartis Pharma AG. Address reprint requests to P.F. Trunet, MD, Novartis Pharma SA, 92506 Rueil-Malmaison Cedex, France. © 1998 by American Society of Clinical Oncology. 0732-183X/98/1602-0008$3.00/0