By Exemestane, a Novel Irreversible Aromatase Inhibitor, in Postmenopausal Breast Cancer Patients1

Vol. 4, 2089-2093, September 1998 Clinical Cancer Research 2089

In Vivo Inhibition of Aromatization by Exemestane, a Novel Irreversible Aromatase Inhibitor, in Postmenopausal Breast Cancer Patients1

Jfirgen Geisler, Nick King, Gun Anker, ation aromatase inhibitor AG3 has been used for breast cancer Giorgio Ornati, Enrico Di Salle, treatment for more than two decades (1). Because of substantial side effects associated with AG treatment, several new aro- Per Eystein L#{248}nning,2 and Mitch Dowsett matase inhibitors have been introduced in clinical trials. Department of Oncology, Haukeland University Hospital, N-502l Aromatase inhibitors can be divided into two major classes Bergen, Norway [J. G., G. A., P. E. L.]; Academic Department of Biochemistry, Royal Marsden Hospital, London, SW3 6JJ, United of compounds, steroidal and nonsteroidal drugs. Nonsteroidal Kingdom [N. K., M. D.]; and Department of Experimental aromatase inhibitors include AG and the imidazole/triazole Endocrinology, Pharmacia and Upjohn, 20014 Nerviano, Italy [G. 0., compounds. With the exception of testololactone, a testosterone E. D. S.] derivative (2), steroidal aromatase inhibitors are all derivatives of A, the natural substrate for the aromatase enzyme (3). The second generation steroidal aromatase inhibitor, 4- ABSTRACT hydroxyandrostenedione (4-OHA, formestane), was found to The effect of exemestane (6-methylenandrosta-1,4- inhibit peripheral aromatization by -85% when administered diene-3,17-dione) 25 mg p.o. once daily on in vivo aromati- by the i.m. route at a dosage of 250 mg every 2 weeks as zation was studied in 10 postmenopausal women with ad- recommended (4) but only by 50-70% (5) when administered vanced breast cancer. Aromatization was determined before p.o. Thus, a major disadvantage with this drug is that it has to be treatment and after 6-8 weeks on therapy by administering administered by the i.m. route to maximize its pharmacological a bolus injection of [3lllandrostenedione (500 aCl) and effect (6). [‘4C]estrone (5 pCi) followed by measurement of the isotope Exemestane (6-methylenandrosta-l,4-diene-3,17-dione) is ratio of urinary estrogens after high-performance liquid a third generation steroidal aromatase inhibitor developed for chromatography purification. In addition, plasma endoge- oral administration. Treatment with exemestane given p.o. has nous estrogens were measured with highly sensitive radio- been shown to be well tolerated, and chronic treatment was immunoassays after separation with high-performance liq- found to suppress plasma estrogen levels by about 85-95% wd chromatography. Treatment with exemestane when the drug was administered at a dose of 10 mg o.d. (7). suppressed whole body aromatization from a mean pretreat- Although this suggests exemestane to be a potent aromatase ment value of 2.059% to 0.042% (mean suppression of inhibitor, direct measurement of in vivo aromatase inhibition 97.9%). Plasma levels of estrone, estradiol, and estrone sal- during treatment with exemestane has not been conducted thus fate were found to be suppressed by 94.5%, 92.2%, and far. 93.2%, respectively. This is the first study revealing near In the present study, we measured in vivo aromatization total aromatase inhibition in vivo with the use of a steroidal before and during treatment with exemestane (25 mg o.d. by the aromatase inhibitor. The observation that exemestane is a oral route) by administering radiolabeled bolus injections of highly potent aromatase inhibitor, together with the fact [3H]androstenedione and [‘4C]estrone followed by determina- that the drug is administered p.o. and causes limited side tion of the isotope ratio in urinary estrogens. In addition, plasma effects, suggests that exemestane is a promising new drug for levels of E1, B2, and E1S were determined before and during the treatment of hormone sensitive breast cancer. treatment with exemestane.

INTRODUCTION PATIENTS AND METHODS Aromatase inhibition is a well-established therapeutic op- Patients. Postmenopausal women suffering from locally tion in postmenopausal breast cancer patients. The first gener- advanced or metastatic breast cancer failing on tamoxifen were eligible and were treated as part of a larger multicenter, Phase II study evaluating the clinical effects of exemestane 25 mg o.d. The associated biochemical study presented here was approved by the regional ethical committee, and the patients gave their Received 12/30/97; revised 6/9/98; accepted 6/10/98. written informed consent in addition to their consent for enroll- The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. I Supported by the Norwegian Cancer Society. J. G. is a research fellow of the Norwegian Cancer Society. 3 The abbreviations used are: AG, aminoglutethimide; o.d., once daily; 2 To whom requests for reprints should be addressed, at Department of E1, estrone; B2, estradiol; E3, estriol; E1S, estrone sulfate; A, andro- Oncology, Haukeland University Hospital, N-5021 Bergen, Norway. stenedione; HPLC, high-performance liquid chromatography; CI, con- Phone: 47-55-97-20-10; Fax: 47-55-97-20-46. fidence interval; RIA, radioimmunoassay; SBS, substrate binding site.

ment in the clinical study. Previous treatment was terminated at Table 1 Influence of treatment with exemestane on percentage of least 4 weeks before commencing treatment with exemestane, peripheral aromatization and no other anticancer treatment was allowed during the study Patient Pretreatment” Exemestane” % suppression period. A total number of 11 patients was enrolled in the I 2.095 0.174 91.7 biochemical study. 2 2.596 0.063 97.6 Study Protocol. Whole body aromatization was meas- 3 1.399 0.028 98.0 4 1.174 0.042 96.4 ured before treatment with exemestane and after 6 to 8 weeks on 5 1.531 0.051 96.7 treatment (8, 9). Exemestane was administered by the oral route 6 4.462 0.032 >99.1 at a dose of 25 mg o.d. The patients received their first dose of 7 1.445 0.015 99.0 exemestane after the completion of the first urine collection 8 3.989 0.028 >99.1 period. 9 1.893 0.091 95.2 10 2.052 0.020 99.0 Measurement of Whole Body Aromatization. Aroma- tization of A to E1 can be measured in vivo by either adminis- Ge o. mean” 2.059 0.042 97.9 CI (1.498-2.829) (0.025-0.071) (96.3-98.8) tration of a steady-state infusion or a bolus injection of A and E1 a Percentage of aromatization. labeled with different isotopes followed by determination of the b ceo. mean, geometric mean value. isotope ratio in plasma estrogens or urinary estrogens, respectively. In this study, we used a HPLC technique to measure the isotope ratio in urinary estrogens after a bolus injection of [3H]androstenedione (500 pCi) and [‘4C]estrone (5 p.Ci) dis- solved in 50 ml of saline containing 8% ethanol (w/w; Ref. 8). graphic system used for the purification of the steroids. The Aliquots of the isotopes in the injection mixture were taken to intra-assay coefficient of variation was < 10% for each estrogen. calculate the 3H: “C ratio. Urine was collected for a period of Statistical Methods. Previous studies by our group have shown plasma estrogen levels in postmenopausal women to be 96 h, pooled, and kept frozen (-20#{176}C) until processing. A recent assessment of the sensitivity of this method revealed that log-normal distributed (13). Thus, plasma estrogen levels as inhibition of whole body aromatization up to 99.1% is detects- well as aromatization levels obtained before and during treat- ble (10). ment with exemestane are given as their geometric mean value Hormone Measurements. Blood samples for hormone with 95% CI of the mean. For estrogen levels below the sensi- measurements were obtained immediately before the radiotracer tivity limit of the assays, the sensitivity limit was used for injections administered on day -4 and after 6-8 weeks on statistical analysis. treatment with exemestane. After an overnight fast, the blood samples were collected between 8 and 10 a.m. before intake of RESULTS the drug. Plasma was separated by centrifugation and stored at The percentage of aromatase inhibition could not be eval- -20#{176}Cuntil processing. Each plasma estrogen (E1, E2, and E1S) uated in one patient (patient 1 1). This patient received her was measured by RIAs after HPLC purification according to proper tracer dose, but although radioactivity was recovered methods currently developed in the laboratory of Di Salle et al. from the crude urine samples in both test situations, little radio- (7) to avoid possible nonspecific interactions that have been activity (‘4C and 3H) was recovered from the purified estrogen suspected in earlier reports of estrogen suppression with cx- fractions in the second test situation. Repeated measurements emestane therapy (7, 1 1, 12). The detection limits for E1, E2, and suggested that the reason for the low amount of radioactivity in E3S were 6.7, 2.6, and 22.2 pmol/liter, respectively. The results the urinary E1 and E3 fractions in this particular patient could obtained were corrected for mean recovery, which was deter- not be due to technical flaws. A major estrogen metabolite in the mined by passing 3H-labeled steroids through the chromato- urine is 2-hydroxyestrone (14). Enhanced 2-hydroxylation,

Table 2 Influen cc of treatmen t with exeme stane on plasma estrogen leve ls (pmol/liter) E1 B2 E1S

Patient Pretreat.” Exemestane % supp. Pretreat. Exemestane % supp. Pretreat. Exemestane % supp. 1 272.0 12.2 95.5 50.7 <2.6 >94.9 1824 178 90.3 2 125.8 7.0 94.4 26.1 <2.6 >90.1 1380 115 91.7 3 152.8 7.4 95.2 43.3 4.4 89.8 1554 130 91.7 4 94.0 <6.7 >92.9 24.2 <2.6 >89.4 662 63 90.5 6 142.5 1 1.5 91.9 26.1 <2.6 >90.1 781 63 91.9 7 174.3 8.9 94.9 27.5 <2.6 >90.7 1410 70 95.0 8 112.1 10.7 90.4 68.6 <2.6 >96.3 1166 48 95.9 9 407.4 11.8 97.1 76.7 2.9 96.2 5501 233 95.8 10 141.0 <6.7 >95.3 17.6 <2.6 >85.4 662 44 93.3 Geo. mean 162.4 8.9 94.5 35.6 2.8 92.2 1320 89 93.2 CI 114.5-230.5 7.3-10.9 92.8-95.8 24.1-52.7 2.4-3.2 88.7-94.7 798-2181 57-141 91.2-94.8

a itret., pretreatment value; % supp., percentage of suppression from baseline; Geo. mean, geometric mean value.

A second test situation, which left 10 patients evaluable for the NADPH, 2 NADP determination of in vivo aromatase inhibition (Table 1). One of these patients (patient 5) had plasma E2 levels below the detection limit and an E1 level close to the detection limit in the pretreatment situation, which left nine patients for the assessment of plasma E1, E2, and E1S suppression (Table 2). The percentage of total body aromatization was 2.059% A.ROMATASE before the initiation of treatment (geometric mean value; 95% COMPLEX CI, 1.498-2.829) and fell to a mean value of 0.042% (95% CI.

0.025-0.071) during treatment with exemestane. This corre- sponds to an aromatase inhibition of 97.9% (geometric mean value; 95% CI, 96.3-98.8). Thus, all but 1 of the patients experienced a suppression of total body aromatization by >95%, and 5 of 10 patients experienced suppression by at least B 98%. NADPH, 02 NADP The influence of exemestane therapy on plasma estrogen levels is shown in Table 2. Plasma E2 was suppressed from a mean level of 35.6 pmollliter (95% CI, 24. 1-52.7 pmollliter) before treatment to a mean of 2.8 pmollliter (95% CI, 2.4-3.2

EXEMESTANE pmol/liter) during exemestane therapy, whereas plasma levels of E1 fell from a mean pretreatment value of 162.4 pmollliter (95% CI, 1 14.5-230.5 pmollliter) to 8.9 pmol/liter (95% CI, 7.3-10.9 pmol/liter) during treatment with exemestane. In addition, plasma levels of E1S fell from a mean level of 1320 pmol/liter (95% CI, 798-2181 pmollliter) before treatment to 89 pmol/liter (95% CI, 57-141 pmol/liter). Accordingly, treatment with exemestane decreased plasma levels of E1, E,, and E1S by mean values of 94.5% (95% CI, 92.8-95.8%), 92.2% (95% CI, 88.7- C 94.7%), and 93.2% (95% CI, 91.2-94.8%), respectively. Corn- NADPH, 02 paring the percentage of plasma estrogen suppression with the percentage of aromatase inhibition in individual patients re-

vealed 0.403 :S R 0.477 for all of the three plasma estrogens. I EM LETROZOLE DISCUSSION The present trial reveals for the first time near total in vito aromatase inhibition by an aromatase inhibitor belonging to the

NCCCNCN steroidal class. Administered at a dose of 25 mg o.d. by the oral route (the dose currently recommended for clinical use), we found exemestane to inhibit aromatization by a mean of 97.9% in breast cancer patients. This aromatase inhibition is signifi- cantly better than that reported for the second generation steroi- Fig. 1 Mechanisms of action of steroidal (Type-I) and nonsteroidal dal aromatase inhibitor, formestane (4), and testololactone (2), (Type-Il) aromatase inhibitors at the aromatase complex. A, A occupies the SBS. B, the steroidal aromatase inhibitor exemestane occupies the the only other steroidal aromatase inhibitors for which in vito SBS and excludes A. Heme activity is required for the suicide inhibition aromatase inhibition has been determined. The findings also (inactivation) of the enzyme. The 6-methylene group of exemestane reveal exemestane to be pharmacologically more effective than probably sticks into one ofthe hydrophobic pockets (HP). C, the triazole first and second generation nonsteroidal inhibitors like AG (1), group of the nonsteroidal aromatase inhibitor letrozole coordinates the iron atom of the heme, occupies part of the SBS, and reversibly excludes A. rogletimide (17), and fadrozole (18) at their clinically used doses. The extent of whole body aromatase inhibition found during treatment with exemestane is comparable to what has recently been found for anastrozole and close to that found for which may be caused by, among other factors, dietary corn- letrozole, two highly potent arornatase inhibitors belonging to pounds (15), will increase the synthesis of this metabolite (and the triazole class (10, 19). Although the degree of aromatase other catechol estrogens also) with a similar drop in the excre- inhibition achieved with these drugs has not been compared in don of other estrogen metabolites. Because no antioxidant was randomized trials, all of these results were obtained in the same added to our solvent systems, all catechol estrogens would be laboratory within a limited time frame, which suggests that these destroyed during the purification procedures (16). Thus, one results may be reliably compared. possible explanation for the finding of little E1 and E3 could be Plasma estrogen measurements in patients on exemestane enhanced production of catechol estrogens in this patient in her treatment require HPLC purification before RIA analysis (7).

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J Geisler, N King, G Anker, et al.

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