Phase I Study of the Oral Nonsteroidal Aromatase Inhibitor CGS 20267 in Postmenopausal Patients with Advanced Breast Cancer

A phase I study was performed of CGS 20267, an oral nonsteroidai, highly potent, and selective aromatase inhibitor, in 21 postmenopausal patients with advanced breast cancer. The patients were recruited in 3 successive groups of 7, receiving 0.1, 0.5, and 2.5 mg p.oJday, respectively. All patients had received at least one prior endocrine treatment (range, 1-4), and six patients had received prior chemotherapy. The treatment was very well tolerated, and no toxicity was seen at any of the three doses. There was a statistically significant suppression of estradiol (E2) and estrone (El) levels by 74% and 79% from baseline levels, respectively (P < 0.0001). Suppression occurred in all three patient groups, with many patients having serum concentrations of estradiol and estrone, which were below the limit of detection of the assays (3 and 10 pM, respectively), which corresponds to a maximum measurable estrogen suppression of 86%. CGS 20267 had no significant effect on serum levels of follicle-stimulating hormone, iuteinizing hormone, thyroid-stimulating hormone, cortisol, 17c~-hydroxyprogesterone, androstenedione, and aldosterone. Seven (33 %, 95% confidence interval, 15-57%) of the 21 patients have responded to treatment (one complete remission, 6 partial remissions according to criteria of the Union Internationale contre le Cancer), and 6 are still responding to CGS 20267 (duration of response; 4+, 6+, 6+, 9+, 9, 12+, and 12+ months). Five have had stable disease for more than 3 months, and 9 had progressive disease. These results suggest that CGS 20267 is a very potent and specific aromatase inhibitor, and phase II studies are now required to confirm its clinical efficacy. I N T R O D U C T I O N Approximately 30% of human breast cancers are sensitive to estrogen deprivation. Aminoglutethimide has been shown to be clinically effective in postmenopausal women with breast cancer, and its main action is inhibition of aromatase (the enzyme which catalyzes the conversion of androgens to estrogens), leading to a reduction in plasma estrogen levels (1-3). The clinical response rate to aminoglutethimide has been shown to be similar to that of surgical adrenalectomy (4) and tamoxifen (5). However, aminoglutethimide is poorly tolerated because of side effects including skin rash, drowsiness, and lethargy (5). Therefore, more potent aromatase inhibitors with improved specificity and fewer side effects have been sought. Aromatase, along with other steroidogenic enzymes such as the cholesterol side-chain cleavage enzyme, 21-hydroxylase, 11/3-hydroxylase, and 18-hydroxylase, form part of the superfamily of cytochrome P-450 enzymes. These enzymes are characterized by a heme group, the function of which is to attract molecular oxygen. Two classes of aromatase inhibitor exist: (a) competitive, nonsteroidal inhibitors (e .g . , aminoglutethimide), which act by binding to the heme group. Because of their mode of action these nonsteroidal inhibitors may bind to and thereby inhibit other members of the cytochrome P-450 superfamily listed above, which are involved in mineralocorticoid and glucocorticoid synthesis. (b) substrate analogues, which compete with the normal substrate (androstenedione) at the binding site of the aromatase enzyme and, in some cases (e .g . , 4-hydroxyandrostenedione), bind irreversibly to the enzyme (suicide substrates) (6). 4-Hydroxyandrostenedione was the first of the new aromatase inhibitors to be used in clinical trials (7-9). 4-Hydroxyandrostenedione is effective clinically by both the i.m. and oral routes (8, 10). However, first-pass hepatic metabolism means that much higher doses are required for effective oral treatment (10, 11). The i.m. route is therefore the preferred route, although this is complicated by local side effects, including sterile abscesses (8). The incidence of these local adverse events is less than with i.m. injection of medroxyprogesterone acetate. Use of 4-hydroxyandrostenedione 250 mg i.m. once every 2 weeks provides effective aromatase inhibition and minimizes the incidence of these local adverse events. Fadrozole hydrochloride, 2 a nonsteroidal competitive aromatase inhibitor, has been shown to suppress effectively estrogen levels in postmenopausal women (12, 13). It is well tolerated (14) and has been shown to be clinically effective in postmenopausal women with advanced breast cancer (15). However, at doses required to suppress estrogen synthesis (2 and 4 mg/day), fadrozole hydrochloride has been shown to cause a significant fall in serum aldosterone levels (16), which in one study was found to be associated with changes in electrolyte balance (13). In a different study fadrozole hydrochloride was found to cause a significant fall in serum aldosterone levels only at doses of 8 and 16 mg/day, and at these doses no change in electrolyte balance was detected (17). Nonetheless, it is clear there is still a need to develop a potent and specific aromatase inhibitor for use in postmenopausal women with breast cancer. CGS 20267 is a novel nonsteroidal agent, which has been shown in v i tro and in animal studies to be a potent, selective competitive aromatase inhibitor (18). In addition, in female rats bearing estrogendependent dimethylbenzanthracene-induced mammary tumors, CGS 20267 causes almost complete regression of tumors present at the start of treatment (18). We report here on the results of a phase I study of CGS 20267 in postmenopausal women with advanced breast cancer. PATIENTS AND M E T H O D S Patient Selection. Twenty-one postmenopausal patients with histologically or cytologically proven, locally advanced, or metastatic breast cancer at the Royal Marsden Hospital Breast Unit, Fulham Road, London, were entered into the study between March 1991 and December 1991. Demographic details are listed in Table 1. All patients had received at least one previous endocrine treatment, and their performance status was 0, I, or 2, according to WHO criteria (19). Postmenopausal status was defined as either (a) 5 years or more since a spontaneous menopause or (b) FSH and LH levels > 20 IU/liter if less than 5 years since spontaneous menopause or less than 55 years of age for 2 The abbreviations used are: Fadrozole hydrochloride, 4-(5,6,7,8-tetrahydroimidazoReceived 7/13/92; accepted 11/2/92. [l,5a]pyridin-5-yl)benzonitrile monohydrochloride (CGS 16949A); CGS 20267, 4,4'-(IHThe costs of publication of this article were defrayed in part by the payment of page 1,2,4-triazol-i-ylmethylene)-bis-benzonitrile; FSH, follicle-stimulating hormone; LH, charges. This article must therefore be hereby marked advertisement in accordance with luteinizing hormone; TSH, thyroid-stimulating hormone; CV, coefficient of variation; 18 U.S.C. Section 1734 solely to indicate this fact. IC5o, concentration of inhibitor required to inhibit enzyme activity by 50%; EDso, median i To whom requests for reprints should be addressed, effective dose.