4360s Vol. 7, 4360s-4368s, December 2001 (Suppl.) Clinical Cancer Research Are Differences in the Available Aromatase Inhibitors and Inactivators Significant? Paige E. Johnson and Aman Buzdar 2 extend the treatment options for breast cancer patients with Department of Breast Medical Oncology, The University of Texas hormone-sensitive disease. M. D. Anderson Cancer Center, Houston, Texas 77030 Aromatase inhibitors are endocrine agents that have a different mode of action than tamoxifen against breast tumors in postmenopausal women. Several aromatase inhibitors with a Abstract high degree of selectivity for aromatase and improved tolera- Aromatase inhibitors are endocrine agents with a differ- bility have become clinically available for the treatment of ent mode of action than tamoxifen against breast tumors. In postmenopausal women with advanced breast cancer (2-6). postmenopausal women, estrogen concentrations are main- tained primarily via aromatase, a cytochrome P-450 enzyme Pharmacology of Aromatase Inhibitors that acts at the final step in the estrogen synthesis pathway. The In postmenopausal women, ovarian estrogen production first clinically available aromatase inhibitor, aminoglutethim- diminishes with age. In these women, estrogen concentra- ide, was introduced for the second-line treatment of advanced tions are maintained primarily via aromatase, a cytochrome breast cancer in the late 1970s. Despite proven efficacy in this P-450 enzyme complex that acts at the final step in the setting, its widespread use was limited by its overall toxicity estrogen synthesis pathway and catalyzes the production of and its lack of selectivity for the aromatase enzyme. This led to estrogens estrone and estradiol by extraglandular conversion the search for novel, more effective, and less toxic aromatase from androgens androstenedione and testosterone, respec- inhibitors. As a result, several aromatase inhibitors with a high tively. These drugs act by suppression of aromatase activity degree of selectivity for aromatase and improved tolerability in fat, liver, and muscle cells and in breast tumor tissue itself. have become clinically available for the treatment of postm- They can be divided into two classes: (a) steroidal drugs; and enopausal women with advanced breast cancer: (a) anastro- (b) nonsteroidal drugs (Ref. 7; see Table 1). The steroidal zole; (b) letrozole; (c) fadrozole; (d) formestane; and (e) ex- class (type I) comprises primarily formestane and exemes- emestane. Of these, formestane and exemestane are steroidal tane, and the nonsteroidal class (type II) comprises primarily nonreversible aromatase inhibitors, also known as aromatase the imide aminoglutethimide, the imidazole fadrozole, and inactivators, whereas fadrozole, anastrozole, and letrozole are the triazoles anastrozole and letrozole. A third nonsteroidal nonsteroidal reversible aromatase inhibitors. These agents dif- triazole, vorozole, has recently been withdrawn from clinical fer in pharmacokinetics, selectivity, and potency, although all development. are more selective than aminoglutethimide. Some differences in adverse effect profile are also noticeable between and within these two classes of agents. The clinical significance of these Method of Administration differences is not yet evident but may well prove to be relevant Anastrozole and letrozole are well absorbed following oral in the long-term adjunctive setting. dosing, with long terminal half-lives, allowing for once-daily dosing [anastrozole, 1 mg; letrozole, 2.5 mg (3, 4)]. In contrast, formestane is subject to high first-pass metabolism when given Introduction p.o., has a relatively short terminal half-life (approximately 2 h), It has long been established that estrogen is the major and has to be administered by i.m. injection (250 mg) every 2 hormone involved in the biology of breast cancer (1). Endo- weeks (8). Exemestane is p.o. bioavailable and has a terminal crine agents have therefore been designed to affect the supply half-life of about 24 h during chronic treatment, allowing once- of estrogens to the breast tumor, primarily by blockade of daily therapy (25 mg) (9). estrogen activity at the receptor level or by inhibition of estrogen production. However, drug resistance remains a Mechanism of Action significant problem in breast cancer treatment, and this has Steroidal and nonsteroidal aromatase inhibitors differ in led to the development of a variety of endocrine agents to their modes of interaction with and inhibition of the aromatase enzyme. Steroidal inhibitors compete with the endogenous sub- strates androstenedione and testosterone for the active site of the enzyme, where they act as false substrates and are processed to 1 Presented at the First International Conference on Recent Advances intermediates that bind irreversibly to the active site, causing and Future Directions in Endocrine Therapy for Breast Cancer, June irreversible enzyme inhibition. Hence, they are sometimes 21-23, 2001, Cambridge, MA. termed aromatase inactivators. Nonsteroidal inhibitors also 2 To whom requests for reprints should be addressed, at Department of compete with the endogenous substrates for access to the active Breast Medical Oncology, The University of Texas M. D. Anderson site, where they then form a coordinate bond to the heine iron Cancer Center, 1515 Holcombe Boulevard, Box 424, Houston, TX 77030. Phone: (713) 792-2817; Fax: (713) 794-4385; E-mail: abuzdar@ atom. They effectively exclude, therefore, both the natural sub- notes.mdacc.tmc.edu. strate and oxygen from the enzyme. The coordinate bonding is Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2001 American Association for Cancer Research. Clinical Cancer Research 4361s Table 1. Structure of aromatase inhibitors, pharmacology, and the selectivity data Chemistry Arimidex Letrozole Exemestane Nonsteroidal Nonsteroidal Steroidal Structure o (,,~N 7 cH~ NC~ CN H3C~~ CH 3 NC-dfCH~ v CH~! CN Regulatory Approved Use Second line Yes Yes Yes First line Yes No No ~ Adjuvant use No (Data ahead of No No other AIs) Pharmacology Daily clinical dose 1 m8 qd 2.5 mg qd 25 m~ qd Monthly dose 30 m~53 75 mg 750 mg Time to steady state plasma 7 days 14-42 days 54 4 days 55 levels Half-life 48-50 hours ~5 2-4 days 54 27 hours 55'57 Inter-patient variability in ND 35% (1.65-fold ND steady state blood levels variation) 54 Time to maximal E2 3-4 days 12 2-3 days 56 7 days 63 suppression lntratumoral activity Yes 58 Yes 59 ND demonstrated Drug-Drug Interactions Interactions with Inhibits in vitro Metabolized by Metabolized by cytochrome P450 (CYP) CYP 1A2, 2C8/9 CYP3A4 and CYP CYP3A4 and and 3A4 but only 2A6. In vitro aldoketoreductase at relatively high letrozole strongly s. No inhibitory concentrations. No inhibits CYP2A6 action on activity on and moderately CYP 1A2, 2C9, CYP2A6 or 2D6. inhibits CYP2C 19. 2D6, 2El or 3A4. (US Arimidex) (US Femara) (US Aromasin) Clinical drug-drug Antipyrine and Pharmacokinetic Ketoconazole has interactions cimetidine clinical interaction study no influence on interaction studies with cimetidine exemestane PKs. indicate co- showed no No other formal administration with clinically drug-drug other drugs significant effect on interaction studies Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2001 American Association for Cancer Research. 4362s Aromatase Inhibitors Table 1 Continued unlikely to result in letrozole PKs. have been clinically Warfarin performed. significant interaction study However, a CYP450 mediated showed no possible decrease interactions. clinically of exemestane No evidence of significant effect of plasma levels by interaction in letrozole on inducers of patients treated warfarin PKs. CYP3A4 cannot with Arimidex and (US Femara) be excluded. other commonly (US Aromasin) prescribed drugs. (US Arimidex) Selectivity Androgenic properties No 60 No 60 Yes 60,32,61 Other endocrine effects in No 53,62 Yes (reduction of Yes (androgenic) addition to desired effects cortisol and 32,54,61 on estrogens aldosterone levels) 18,54 Effect on sex hormone Decreased Increased Decreased 28 binding globulin (SHBG) (p=0.003) 63 or no (p=0.0001) 54 change 64 Effect on basal cortisol No 53 No 63 No level or reduced (p<0.03) 18 Effect on basal aldosterone No 53 No 18or increased No level (p=0.025) 63 Effect on ACTH stimulated No 53 Reduced ND cortisol synthesis (p=0.015 )63 Effect on ACTH stimulated No 53 Reduced 63 (p=0.04) ND aldosterone synthesis Ratio dose affecting >10 53 1 i 8,63 >32 25 cortisol: clinical dose Ratio dose affecting >10 53 1 18,63 >32 25 aldosterone: clinical dose ND = No data available ~, First line studies recently completed and results should become available in the near future. strong but reversible, so that enzyme activity can recover if the tivity for aromatase of the first-generation aromatase inhibitor inhibitor is removed. Inhibition is sustained whenever the in- aminoglutethimide led to concomitant suppression of the im- portant corticosteroids aldosterone and cortisol. In clinical use, hibitor is present. it became necessary to concurrently administer a replacement Selectivity corticosteroid such as hydrocortisone. Although the second- The degree of selectivity of an aromatase inhibitor for the generation aromatase inhibitor fadrozole was shown to be more aromatase enzyme has a bearing on both the ease of use and the potent and selective (7), it demonstrated a lack of selectivity tolerability profile of the drug. For instance, the lack of selec- through its effect