Advances in Aromatase Inhibition: Clinical Efficacy and Tolerability in the Treatment of Breast Cancer

Home , Antiestrogen, Aromatase, Aromatase inhibitor, Formestane, Vorozole

2620 Vol. 7, 2620–2635, September 2001 Clinical Cancer Research

Review Advances in Aromatase Inhibition: Clinical Efficacy and Tolerability in the Treatment of Breast Cancer

Aman Buzdar1 and Anthony Howell been the most widely used endocrine drug for the management Department of Breast Medical Oncology, M. D., Anderson Cancer of all stages of breast cancer in women with estrogen-dependent Center, University of Texas, Houston, Texas 77030 [A. B.], and tumors, irrespective of their age and menopausal status (7–9), Cancer Research Campaign Department of Medical Oncology, and, until recently, it has maintained an unrivalled position as Christie Cancer Research Campaign Research Centre, Christie the standard first-line endocrine therapy for postmenopausal Hospital National Health Services Trust, Manchester, United Kingdom [A. H.] women with advanced breast cancer. Aromatase inhibitors are endocrine agents which have a Introduction different mode of action against breast tumors in postmenopausal women from that of tamoxifen. The first clinically avail- The successful management of breast cancer remains a able aromatase inhibitor, aminoglutethimide, was introduced for major challenge to surgeons and oncologists in the 21st century. the second-line treatment of advanced breast cancer in the late Although the incidence of breast cancer varies throughout the 1970s (10). But despite proven efficacy in this setting, its world, the disease is universally perceived to be a major cause widespread use was limited by its overall toxicity and its lack of of morbidity and mortality in both pre- and postmenopausal selectivity for the aromatase enzyme, which necessitated con- women. comitant corticosteroid supplementation (11). This led to the It has long been established that estrogen is the major search for novel, more effective, and less toxic aromatase in- hormone involved in the biology of breast cancer (1). Endocrine hibitors. As a result, several aromatase inhibitors with a high agents have therefore been designed to affect the supply of degree of selectivity for aromatase and improved tolerability estrogens to the breast tumor, principally by blockade of estro- have become clinically available for the treatment of postmeno- gen activity at the receptor level or by inhibition of estrogen pausal women with advanced breast cancer: anastrozole (1 mg production (although the widely used antiestrogen, tamoxifen, is once daily); letrozole (2.5 mg once daily); fadrozole (1 mg twice known to have additional modes of action, such as via produc- daily; available in Japan only); formestane (250 mg i.m. every 2 tion of the inhibitory growth factor transforming growth factor weeks); and exemestane (25 mg once daily; Fig. 1; Refs. 12–22). ␤ (2, 3) and suppression of insulin-like growth factor 1 (4), a It is the aim of this review to evaluate the clinical efficacy potent mitogen for breast cancer. Drug resistance, however, and tolerability of these latest additions to this class of drugs in remains a significant problem in breast cancer treatment, and the management of advanced breast cancer in postmenopausal this has led to the development of a variety of endocrine agents women and to discuss their potential for use in the adjuvant to extend the treatment options for breast cancer patients with treatment of early disease. hormone-sensitive disease. The success of the approach to use different endocrine therapies sequentially is made evident by the fact that 25% of patients with advanced breast cancer who Pharmacology of Aromatase Inhibitors eventually progress after an initial response on primary treat- In postmenopausal women, ovarian estrogen production ment are known to respond to second-line therapy with another diminishes with age. In these women, estrogen concentrations endocrine agent (5). In a recent study, ϳ40% of patients with are maintained primarily via aromatase, a cytochrome-p450 advanced breast cancer failing after an initial response to ta- enzyme complex which acts at the final step in the estrogen- moxifen gained clinical benefit (clinical benefit ϭ CR2 ϩ PR ϩ synthesis pathway and catalyzes the production of the estrogens, SD Ն 24 weeks) from the second-line use of a second endocrine estrone and estradiol, by extraglandular conversion from the therapy (6). androgens, androstenedione, and testosterone, respectively (Fig. 2). Over the past 30 years, the antiestrogen, tamoxifen, has It is knowledge of this peripheral route of estrogen supply in postmenopausal women that has led to the development of the aromatase inhibitors. These drugs act by suppression of the supply of endogenous estrogens in fat, liver, and muscle cells Received 9/7/00; revised 3/30/01; accepted 6/1/01. and in breast tumor tissue itself. They can be divided into two The costs of publication of this article were defrayed in part by the classes: steroidal and nonsteroidal drugs (23). The steroidal payment of page charges. This article must therefore be hereby marked class (type I) comprises primarily formestane and exemestane, advertisement in accordance with 18 U.S.C. Section 1734 solely to and the nonsteroidal class (type II) comprises primarily the indicate this fact. imide, aminoglutethimide; the imidazole, fadrozole; and the 1 To whom requests for reprints should be addressed, at Department of Breast Medical Oncology, M. D., Anderson Cancer Center, University triazoles, anastrozole and letrozole. A third nonsteroidal tria- of Texas, Houston, TX 77030. zole, vorozole, has recently been withdrawn from clinical de- 2 The abbreviations used are: CR, complete response; PR, partial re- velopment. sponse; SD, stable disease; TTP, time to progression; OR, objective Method of Administration. The newer nonsteroidal response rate; TTF, time to treatment failure; UICC, Union International Contre Cancer; HR, hazard ratio; ER, estrogen receptor; PgR, proges- drugs, anastrozole and letrozole, are well absorbed after oral terone receptor; CI, confidence interval; ATAC, Arimidex, tamoxifen, administration, with long terminal half-lives, allowing for once- alone or in combination; ABCSG, Austrian Breast Cancer Study Group. daily dosing (14–16). In contrast, the first steroidal drug to Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2001 American Association for Cancer Research. Clinical Cancer Research 2621

Fig. 1 Chemical structures of all aromatase inhibitors under review.

(18, 24). Exemestane, the other steroidal drug, is p.o. bioavail- able and has a terminal half-life of ϳ24 h during chronic treatment (21), allowing once-daily therapy at a dose of 25 mg of drug (25, 26). Mechanism of Action. Steroidal and nonsteroidal aromatase inhibitors differ in their modes of interaction with, and their inactivation of, the aromatase enzyme. Steroidal inhibitors compete with the endogenous substrates, androstenedione and testosterone, for the active site of the enzyme, where they act as false substrates and are processed to intermediates that bind Fig. 2 Enzyme pathway for estrogen synthesis from androgens via irreversibly to the active site, causing irreversible enzyme inhi- aromatase inhibitors. bition. Nonsteroidal inhibitors also compete with the endogenous substrates for access to the active site, where they then form a coordinate bond to the heme iron atom. Therefore, they become clinically available, formestane (250 mg i.m. every 2 effectively exclude both the natural substrate and oxygen from weeks), is subject to high first-pass metabolism when given p.o., the enzyme. The coordinate bonding is strong but reversible, so and has a relatively short terminal half-life (ϳ2 h), and conse- that enzyme activity can recover if the inhibitor is removed; but quently has to be administered by i.m. injection every 2 weeks inhibition is sustained whenever the inhibitor is present. Al-

though both classes of aromatase inhibitor lead to potent sup- relevance of such changes is not yet clear; however, although pression of aromatase, the enzyme is capable of rapid regener- there may not be any clinical detriment in the metastatic setting, ation, and so it is doubtful whether or not the type of inhibition it would be important to monitor closely for the potential impact (i.e., reversible or irreversible) is of any clinical relevance. in the adjuvant setting, where these compounds are likely to be There are currently no clinical data that compare the relative administered for up to 5 years, and where tolerability assumes efficacy of each type of agent. Their different modes of action, greater importance in a patient who otherwise may be “cured” of however, allow for sequential use in patients with advanced disease. breast cancer, as described later. Estrogen Suppression and Aromatase Inhibition. Selectivity. The degree of selectivity of an aromatase Both steroidal and nonsteroidal aromatase inhibitors result in a inhibitor for the aromatase enzyme has a bearing on both the significant decrease in serum estrogen concentrations. Amin- ease of use and the tolerability profile of the drug. For instance, oglutethimide was the first nonsteroidal aromatase inhibitor to the lack of selectivity of the first-generation aromatase inhibitor demonstrate a high level of aromatase inhibition, but this was for aromatase, aminoglutethimide, led to concomitant suppres- not accompanied by a reduction in estrogen concentrations sion of the important corticosteroids, aldosterone and cortisol. comparable with that now seen with the third-generation non- As a result, in clinical use, it became necessary to coadminister steroidal aromatase inhibitors (23). An increase in potency was a corticosteroid, such as hydrocortisone, as replacement therapy found with the second-generation drug, fadrozole (22), but, (11). Although the second-generation aromatase inhibitor, again in comparison, the newer-generation triazole drugs, anas- fadrozole, was shown to be more potent and selective (23) than trozole and letrozole, both produce a much greater suppression aminoglutethimide, it nevertheless demonstrated a lack of se- of estrogens, to the limits of detection of current assays, and lectivity through its effect on 11-deoxycorticosterone and aldos- have demonstrated a high degree of consistency between the terone concentrations as well as on sodium and potassium levels inhibition of whole-body aromatase activity and estrogen sup- in animals (11, 27–30). pression (16, 18, 23, 47). The third-generation aromatase inhibitor, anastrozole, has a Recent data have been reported from a small, double-blind, high degree of selectivity for aromatase in clinical pharmacol- randomized, cross-over study in 12 postmenopausal women ogy studies, with no significant effects being observed on either with advanced breast cancer, comparing plasma estrogen sup- cortisol or aldosterone secretion at up to 10 times the daily pression by letrozole (2.5 mg daily) and anastrozole (1 mg daily; recommended dose after 28 days of exposure (31, 32) and also 48). This study showed that letrozole led to significantly greater ϭ ϭ when given for up to 3 months (33). Letrozole showed a similar suppression of E1 (P 0.019) and E1S(P 0.0037), but not of degree of enzyme selectivity after an exposure period of 28 E2, which is widely considered to be the most important estro- days, (34, 35) although in a study evaluating the dosing of gen in the etiology of breast cancer. When inhibition of whole- letrozole 0.5 mg over a period of 12 weeks, cortisol levels were body aromatase was examined (49), it was shown that letrozole reduced significantly at this dose after 2 months (36) while (Ͼ99.1%) achieved a greater inhibition of aromatase than did remaining within the limits of normality (37, 38). Additionally, anastrozole (mean, 96.9%). No statistical analyses of these data a more recent study has shown significant reductions in adre- have been presented to date, and the clinical relevance of such nocorticorticotropic hormone-stimulated cortisol (P ϭ 0.015) differences between drugs of this class in their effect upon and aldosterone (P ϭ 0.04) concentrations after a 3-month aromatase remains questionable. exposure to letrozole at the clinical dose of 2.5 mg daily (39). The injectable steroidal aromatase inhibitor, formestane, Vorozole is also selective for the aromatase enzyme, as also suppresses estrogen concentrations significantly, but to a seen from studies of 2.5 and 5 mg doses once daily, which lesser extent than anastrozole (50). Formestane is associated reported no effect on adrenal steroidogenesis (40, 41). However, with inconsistent suppression of serum estradiol (50, 51), in one study at the 5-mg daily dose, vorozole led to a reduction whereby estradiol levels begin to rise between the twice-weekly in cortisol, the clinical relevance of which was uncertain (42). i.m. doses. This was shown in a small, randomized, comparative The higher selectivity of anastrozole, letrozole, and vorozole for study, in which formestane (250 mg i.m. every 2 weeks; n ϭ 31) aromatase leads to improved tolerability, compared with earlier was compared with the nonsteroidal aromatase inhibitor, anas- drugs of this class, through an overall lack of adverse effect on trozole (1 mg once daily; n ϭ 29), over 4 weeks in postmeno- steroidogenesis. pausal women with advanced breast cancer (50). More effective, In the case of the steroidal aromatase inhibitors, both reliable and consistent estradiol suppression was found with formestane (43–45) and exemestane (26, 46) are selective for anastrozole than with formestane at the usual therapeutic doses aromatase and do not affect either cortisol or aldosterone con- (79% versus 58% reduction in estradiol levels, respectively; P ϭ centrations adversely. 0.0001). Estrone and estrone sulfate levels were also signifi- The available data on selectivity confirm that all of the cantly suppressed to a greater extent by anastrozole compared aromatase inhibitors developed since aminoglutethimide first with formestane (estrone, 85% versus 67%, P ϭ 0.0043; estrone became clinically available are far more selective than the sulfate, 92% versus 67%, P ϭ 0.0007; respectively; Ref. 50). prototype compound. More recent data from indirect clinical Recently available results indicate that the oral steroidal pharmacology studies, however, do show variations between the aromatase inhibitor, exemestane, at daily doses of 10–25 mg, different aromatase inhibitors. For anastrozole and letrozole, suppresses estrogen concentrations to 6–15% of pretreatment there seem to be differences in overall selectivity that, although levels, showing more pronounced activity than formestane and not seen after short-term administration, do become apparent comparable activity with that of the clinically available, nonste- after longer-term exposure, i.e., up to 3 months. The clinical roidal aromatase inhibitors, anastrozole and letrozole (52, 53).

Table 1 Efficacy results from Phase III second-line trials of anastrozole versus megestrol acetate (MA) in postmenopausal women with advanced breast cancer (6- and 31-months’ follow-up) European54 North American55 Combined (6 mo)58 Combined (31 mo)6 Anastrozole MA 40 Anastrozole MA 40 Anastrozole MA 40 Anastrozole MA 40 1 mg o.d. mg q.i.d. 1 mg o.d. mg q.i.d. 1 mg o.d. mg q.i.d. 1 mg o.d. mg q.i.d. Parameter (n ϭ 135) (n ϭ 118) (n ϭ 128) (n ϭ 130) (n ϭ 263) (n ϭ 253) (n ϭ 263) (n ϭ 253) OR ϭ CR ϩ PR (%) 10.4 10.4 10 6 10 8 12.6 12.2 Clinical benefit (%) 34.1 32.8 37 36 33 34 42.2 40.3 Median TTP (mo.) 4.3 3.9 5.6 4.7 4.8 4.8 4.8 4.6a Median survival 26.7 mo. 22.5b mo. 2-yr survival rate (%) 50.5 39.1 62.0 53.1 56.1 46.3 a Hormone receptor anastrozole versus MA 0.94 (P ϭ 0.49; 97.5% CI, 0.76–1.1). b Hormone receptor anastrozole versus MA 0.78 (P ϭ 0.0248; 97.5% CI, 0.6040–0.9996).

In another report, exemestane exhibited potent aromatase inhi- response were applied on the basis of a strict interpretation of bition in vivo and suppressed plasma levels of estrogens to the UICC guidelines (6, 57, 58). limits of detection of current assays (25). At a median follow-up of ϳ6 months, a combined analysis In conclusion, it appears that the most effective aromatase of the above two trials showed that approximately one-third of inhibitors can provide near maximal suppression of plasma patients who were treated with either anastrozole (1 mg or 10 estrogens, irrespective of their precise mode of inhibition of mg, once daily) or megestrol acetate (160 mg daily) derived aromatase. It is clear that the newer-generation aromatase in- clinical benefit from their treatment (58). There were no statis- hibitors, anastrozole, letrozole, and exemestane, provide greater tically significant differences among the three treatment arms in suppression of estrogens than the earlier aromatase inhibitors, terms of efficacy (tumor response or TTP) in either trial. The aminoglutethimide, fadrozole, and formestane. The clinical data data were too immature for an analysis of survival to be per- available for the newer aromatase inhibitors versus the previous formed at that time. standard therapies, megestrol acetate and tamoxifen (see below), Intent-to-treat analyses were subsequently performed on indicate that step-changes in estrogen suppression are clinically the mature combined data from the two trials (62% of patients important. However, the clinical relevance of the small differ- had died), when the median follow-up was 31.2 months (6). At ences in estrogen suppression between the newer aromatase the clinical dose of 1 mg daily, anastrozole demonstrated a inhibitors remains to be established. Ultimately, only direct statistically significant survival advantage over megestrol ace- head-to-head comparative clinical studies will provide the an- tate, with a HR of 0.78 (P Ͻ 0.025). The median duration of swers to these questions. survival was 26.7 months for the anastrozole 1 mg group compared with 22.5 months for the megestrol acetate group. The HR Clinical Efficacy indicated that patients treated with anastrozole 1 mg were 22% Second- and Third-line Therapy in Advanced Breast Cancer less likely to die over a given time period than patients treated with Nonsteroidal Aromatase Inhibitors with megestrol acetate. Patients receiving anastrozole 10 mg daily also showed a survival benefit compared with the patients Anastrozole versus Megestrol Acetate. In 1995, anastro- receiving megestrol acetate, with an HR of 0.83 and a median zole was the first of the newer-generation aromatase inhibitors ϭ to become clinically available for second-line therapy in post- duration of survival of 25.5 months (P 0.0951), but this menopausal women with advanced breast cancer failing on an difference was not statistically significant. The estimated 2-year antiestrogen, usually tamoxifen. This came after the results of survival rates from the combined analysis were 56.1%, 54.6%, two large, Phase III studies, which were performed in parallel, and 46.3% for patients receiving anastrozole 1 mg, anastrozole comparing oral anastrozole (1 mg or 10 mg, once daily) with 10 mg, or megestrol acetate, respectively. Clinical benefit was ϳ oral megestrol acetate (40 mg four times daily) in postmeno- seen in 40% of patients in all three groups (42.3% with pausal women with advanced breast cancer who had progressed anastrozole 1 mg). The data from the individual and combined on tamoxifen (54, 55). The designs of each trial [one conducted analyses of these trials are summarized in Table 1. predominantly in Europe (n ϭ 378) and the other in North The authors concluded that the combined analysis clearly America (n ϭ 386)] were identical and prospectively intended demonstrated that, after disease progression with tamoxifen, to allow the data to be combined to strengthen the overall anastrozole 1 mg provides a statistically and clinically signifi- statistical reliability of the trial results (56). Each trial was a cant advantage over standard treatment with megestrol acetate. multicenter, randomized, controlled, parallel group, double- There was no additional benefit observed for anastrozole 10 mg blind for each anastrozole arm and open-label for megestrol over anastrozole 1 mg in terms of any of the primary end points. acetate. The primary objectives were to compare the three These results confirmed the choice of the 1 mg dose for use in treatment groups in terms of TTP and OR (OR ϭ CR ϩ PR), clinical practice. and the secondary objectives were survival, time to TTF, and In an additional subgroup analysis of the above combined response duration. Rigorous criteria for assignment of objective trial data, it was shown that anastrozole was effective in patients

Table 2 An overview of efficacy results from Phase III trials of second-line treatment of newer aromatase inhibitors versus megestrol acetate (MA) in patients who have failed on tamoxifen European and US trials combined analysis6 European trial61 US trial62 International trial71 Aa 1mg MA 40 L 2.5 MA 40 E25 MA 40 o.d. mg q.i.d. mg o.d. mg q.i.d. L 2.5 MA 40 mg o.d. mg o.d. Dose (n ϭ 263) (n ϭ 253) (n ϭ 174) (n ϭ 189) mg o.d. mg q.i.d. (n ϭ 366) (n ϭ 403) Median follow-up (mo) 31 33 11 Median TTP (mo) 4.8 4.6 5.6 5.5 No data published 4.7 3.8 NS NS NS P ϭ 0.037 Median survival (mo) 26.7 22.5 25.3 21.5 No data published NR 28.4 P Ͻ 0.025 NS P ϭ 0.039 a A, anastrozole; L, letrozole; E, exemestane; NS, nonsignificant; NR, not reported.

with advanced breast cancer with visceral and liver metastases vanced breast cancer in postmenopausal women previously (59). The median duration of clinical benefit in patients with treated with an antiestrogen (61, 63). visceral metastases was 16.4 months with anastrozole 1 mg (n ϭ In contrast, however, in a second similar, randomized, 263) compared with 14.7 months for megestrol acetate (n ϭ controlled trial performed at the same time in North America, 253); for liver metastases, the median duration of clinical benefit which has not yet been published in full, letrozole did not show was 17.9 months with anastrozole 1 mg compared with 9.9 this dose-dependent antitumor activity. Furthermore, there were months for megestrol acetate. Furthermore, in a recent report, no statistically significant differences in terms of OR, TTP, or overall survival in patients with advanced breast cancer under survival with the 2.5-mg dose of letrozole compared with assessment in one of the large-scale, comparative Phase III trials megestrol acetate; however, the 0.5 mg dose showed improved described above (58) was examined in relation to response type, TTP over the progestin (64).3 i.e., the survival outcome based on whether patients demon- Letrozole versus Aminoglutethimide. In an open-label, strated either CR/PR or SD Ն24 weeks (termed “long SD”; Ref. randomized trial, oral, once-daily letrozole (2.5 mg and 0.5 mg) 60). For anastrozole (1 mg daily), there was no difference in was compared with aminoglutethimide (250 mg twice daily) in estimates of 2-year survival between patients having either 555 postmenopausal women with advanced breast cancer pre- CR/PR or long SD. A similar result was obtained with patients viously treated with antiestrogens (65). Patients in the amin- treated with megestrol acetate (40 mg p.o. four times daily). oglutethimide arm received daily oral glucocorticoid supple- These data confirmed the clinical value of long SD as an mentation (hydrocortisone 30 mg or cortisone acetate 37.5 mg). important end point in the measure of clinical efficacy in post- The primary end point was overall objective tumor response menopausal patients with advanced breast cancer, with predic- (CR ϩ PR). The secondary end points were TTP, TTF, and tive value for overall survival. duration of survival. Letrozole versus Megestrol Acetate. Two doses of oral Overall, no significant differences in OR were seen in letrozole (2.5 mg or 0.5 mg, once daily) were compared against patients receiving letrozole 2.5 mg or 0.5 mg or aminoglute- each other and against megestrol acetate (160 mg once daily) as thimide. The absence of a significant dose-response effect for second-line therapy in postmenopausal women with advanced the two letrozole doses (0.5 mg versus 2.5 mg) is in contrast to breast cancer previously treated with antiestrogen endocrine that found in the trial comparing the same two doses of letrozole therapy (61). The trial design was multicenter, randomized, (P ϭ 0.03) with megestrol acetate in a similar patient population controlled, double-blind, in 551 patients with locally advanced, (61, 63).3 Letrozole 2.5 mg was, however, statistically signifi- locoregionally recurrent, or advanced breast cancer. The pri- cantly superior to aminoglutethimide in terms of overall sur- mary efficacy end point was overall objective tumor response vival, TTP, and TTF in postmenopausal women with advanced (CR ϩ PR), assessed by UICC criteria (62). Secondary end breast cancer previously treated with antiestrogens. points included TTP, TTF, and overall survival time. Vorozole: Open-Label, Phase III Trials. In an open- A higher overall OR rate was obtained for letrozole 2.5 mg label, multicenter, parallel-group Phase III trial, a total of 452 compared with letrozole 0.5 mg (P ϭ 0.004) or megestrol postmenopausal women with advanced breast cancer failing on acetate (P ϭ 0.04). The clinical benefit in each letrozole arm tamoxifen were treated with either oral vorozole (2.5 mg once was Ͻ35% (61). For TTP, letrozole 2.5 mg (5.6 months) was daily) or megestrol acetate (40 mg four times daily; Ref. 66). found to be superior to letrozole 0.5 mg (5.1 months; P ϭ 0.02) The primary end point was overall response rate. No significant but not to megestrol acetate (5.5 months; P ϭ 0.07; Table 2). differences were found between the two groups for overall For overall survival, there was a significant dose effect for response rate, clinical benefit [CR ϩ PR ϩ NC (no change) in letrozole 2.5 mg (25.3 months; P ϭ 0.03) over letrozole 0.5 mg Ն6 months], TTP, or survival. It was concluded that vorozole (21.5 months), although letrozole 2.5 mg showed no significant and megestrol acetate had similar efficacy in the treatment of survival advantage over megestrol acetate, even at an updated analysis at a follow-up of 51 months (63). The authors concluded that letrozole 2.5 mg was superior to the 0.5 mg dose and more effective than megestrol acetate in the treatment of ad- 3 Internet address: http://fda.gov/ohrms/dockets/ac/backgrd/3671b_01.doc.

postmenopausal women with advanced breast cancer progress- sponse rates, SD (Ն6 months), or TTF (3.9 versus 3.7 months, ing on tamoxifen. respectively), and formestane was considered to be as effective In a second open-label, centrally randomized, multicenter as megestrol acetate in this patient population. A second open Phase III trial, postmenopausal women with advanced breast trial of formestane (250 mg i.m. every 2 weeks) versus meges- cancer failing on tamoxifen therapy were treated with either oral trol acetate (160 mg p.o. once daily) compared the efficacy and vorozole (2.5 mg once daily; n ϭ 211) or aminoglutethimide safety of the two drugs as second-line therapy in 547 receptor- (250 mg twice daily; n ϭ 213) until disease progression or death positive or receptor-unknown postmenopausal patients with ad- (67). The patients in the aminoglutethimide arm also received vanced breast cancer previously treated with tamoxifen (70). supplementary oral hydrocortisone (30 mg daily). There was a There were no significant differences between formestane and higher overall response rate for patients receiving vorozole megestrol acetate in terms of median TTF and overall survival. compared with aminoglutethimide (24% versus 17%; P ϭ 0.07); Formestane was considered a suitable alternative to progestins but in terms of duration of response, TTP, TTF, and survival in patients previously treated with tamoxifen. time, no differences were found between the two treatment Exemestane versus Megestrol Acetate. In a randomized, arms. It was therefore concluded that vorozole and aminoglute- double-blind Phase III trial, 769 postmenopausal women with thimide were equivalent with respect to clinical efficacy. advanced breast cancer refractory to tamoxifen were random- Although another open-label, comparative trial in post- ized to receive either exemestane (25 mg p.o. daily; n ϭ 366) or menopausal patients with advanced breast cancer showed that megestrol acetate (40 mg p.o. four times daily; n ϭ 403; Ref. vorozole (2.5 mg daily) appeared to be superior to aminoglute- 71). The overall median duration of follow-up was 48.9 weeks. thimide (250 mg twice daily) plus hydrocortisone (30 mg once At the time of data cutoff, median survival had not been daily), in terms of response rate and clinical benefit (CR ϩ PR reached, and 143 patients were still receiving study medication. ϩ NC Ն 6 months; P ϭ 0.07 and P ϭ 0.017, respectively; Ref. The study was designed to demonstrate equivalence between 68), none of the studies involving vorozole has shown a signif- treatment arms. The OR rate was similar in both groups, as was icant advantage over megestrol acetate or aminoglutethimide in the rate of overall success (CR ϩ PR ϩ SD Ն 24 weeks; 37.4% terms of either TTP or overall survival. Vorozole is no longer in for exemestane and 34.6% for megestrol acetate; not statistically clinical development. significant). Both median TTP (P ϭ 0.037) and median survival Fadrozole versus Megestrol Acetate. At present, fadro- (P ϭ 0.039), however, were significantly improved in those zole is only clinically available in Japan. Two prospective, patients receiving exemestane (Table 2). It was concluded that, randomized, double-blind Phase III trials of similar design were compared with megestrol acetate in postmenopausal women initiated to compare fadrozole with megestrol acetate in 683 with advanced breast cancer refractory to tamoxifen, exemes- postmenopausal women with advanced breast cancer, who had tane significantly delays tumor progression and significantly progressed on first-line or adjuvant hormonal therapy (69). The prolongs survival. primary efficacy end point was OR. Other efficacy end points Summary and General Conclusions. Anastrozole, were TTP and survival. letrozole, and exemestane have all demonstrated improved clin- In the first trial, 380 patients were randomized to receive ical efficacy over megestrol acetate in the second-line treatment either fadrozole (1 mg twice daily) or megestrol acetate (40 mg of postmenopausal women who have failed on tamoxifen. Al- four times daily), and in the second trial, 303 patients also though anastrozole and exemestane have both demonstrated received a similar regimen. Both treatment arms in each of the significantly improved survival over megestrol acetate, there has two trials received matching placebos. There were no differ- been no statistically significant survival benefit reported with ences in the response rates from either trial between fadrozole letrozole (63). All three aromatase inhibitors, anastrozole (1 mg, and megestrol acetate. The median survival time was longer in once daily), letrozole (2.5 mg, once daily) and exemestane (25 the fadrozole group than in the megestrol acetate group in the mg, once daily) have demonstrated clinical benefit in second- first trial (26.8 versus 22.8 months, respectively) and in the line use in postmenopausal with advanced breast cancer (6, 61, megestrol acetate group compared with the fadrozole group 71), and these newer-generation aromatase inhibitors are now (25.4 versus 27.5 months, respectively) in the second trial (69). established as the second-line agents of choice in this patient Neither trial showed any significant differences between the two population. treatments in terms of primary and secondary end points, confirming equivalence of fadrozole and megestrol acetate as sec- First-line Therapy in Advanced Breast Cancer with ond-line endocrine therapy in postmenopausal women with ad- Nonsteroidal Aromatase Inhibitors vanced breast cancer. Anastrozole. In a major, large-scale, clinical trial program, anastrozole (1 mg once daily) was compared with tamox- Second- and Third-Line Therapy in Advanced Breast ifen (20 mg once daily) as first-line therapy in postmenopausal Cancer with Steroidal Aromatase Inhibitors women with advanced breast cancer in two international, mul- Formestane versus Megestrol Acetate. In a prospective, ticenter trials involving a total of 1021 patients (72, 73). The two randomized, crossover Phase III trial, formestane (250 mg i.m. trials were performed in the United States/Canada (“North every 14 days) was compared with megestrol acetate (160 mg American” trial) and in Europe/South America/Australia (“Eu- p.o. daily) in 179 postmenopausal patients with advanced breast ropean” trial). They were randomized, double-blind, double- cancer who were failing on tamoxifen (24). The trial was dummy trials designed to determine whether or not the two planned to test differences in TTF. There were no significant treatments had equivalent efficacy in this patient population. differences between formestane and megestrol acetate in re- Patients had to be eligible for endocrine therapy and have either

Fig. 3 Kaplan-Meier curve for median TTP (anastrozole versus tamox- Fig. 4 Kaplan-Meier curve for median TTP (anastrozole versus tamoxifen; North American trial). ifen; European trial; receptor-positive patients).

ER-positive and/or PgR-positive tumors or tumors of unknown for the 45% of ER-positive patients in the European trial showed receptor status. The patients were either newly diagnosed with a median TTP of 8.9 months on anastrozole compared with 7.8 advanced disease or had progressed subsequent to diagnosis and months on tamoxifen (Fig. 4; Ref. 72). treatment for early disease. They may have received prior ad- A prospectively planned combined analysis was performed juvant endocrine therapy or chemotherapy; however, a drug-free on the efficacy and tolerability data from the total of 1021 period of at least 1 year was required for those who had received patients recruited into the two trials (74). The data obtained in adjuvant tamoxifen. this large patient population indicate that anastrozole is at least The primary end points of the trials were TTP, OR, and as effective as tamoxifen for the treatment of postmenopausal tolerability. There were nine prespecified adverse events for women with advanced breast cancer, with an observed advan- which a statistical analysis was performed. The secondary end tage in terms of TTP: median TTP was 8.5 months for anastro- points were TTF and survival. The studies were designed pro- zole and 7 months for tamoxifen (HR ϭ1.12; lower 95% CI, spectively to allow combined analysis of the data and were 1.00; Table 3). A total of 57% of patients on anastrozole showed “powered” for equivalence. clinical benefit compared with 52% on tamoxifen. In total, 353 patients from 97 centers in the United States A subgroup analysis was performed on the combined data and Canada were entered into the North American trial (anas- from the European and North American trials. These analyses trozole, n ϭ 171; tamoxifen, n ϭ 182) and followed for a confirmed that receptor status was a key factor affecting the median of 18 months (73). The two patient groups were well relative efficacy of anastrozole in relation to tamoxifen. Anas- balanced with respect to demographic data, and a positive tumor trozole showed a statistically significant advantage over tamox- ER status was confirmed in 89% of patients. Median TTP was ifen in median TTP (P ϭ 0.022; two-sided, retrospective anal- 11.1 months for anastrozole versus 5.6 months for tamoxifen ysis) in a combined analysis of 611 patients who were known to (P ϭ 0.005; two-sided; Fig. 3). be ER-positive/PgR-positive (75). On the basis of the derived HR of 1.44, at any given time The significance of whether or not prior adjuvant treatment point, patients receiving tamoxifen were 44% more likely to impacted treatment outcome was investigated in the combined progress than those treated with anastrozole. OR was 21% for first-line trial population. Overall, 14.2% of patients had re- anastrozole and 17% for tamoxifen. Clinical benefit rates were ceived prior hormonal therapy, 19.5% in the North American 59% for anastrozole and 46% for tamoxifen (P ϭ 0.0098; trial and 11.4% in the European trial.4 In 97% of cases, the prior two-sided retrospective analysis). These data suggest that anas- adjuvant hormonal therapy was tamoxifen. Although no formal trozole is superior to tamoxifen as a first-line treatment of statistical analyses within subgroups were carried out, the data advanced breast cancer in postmenopausal women. observed for TTP and OR rates in those patients not receiving In the second trial (European), 668 postmenopausal women prior adjuvant hormonal therapy were similar to those observed with advanced breast cancer (anastrozole, n ϭ 340; tamoxifen, in patients who did receive therapy, which in turn is similar to n ϭ 328) from 83 centers worldwide were recruited and fol- data for the overall patient population.4 lowed for a median of 19 months (72). The two patient groups These data on the efficacy of anastrozole in the first-line were again well balanced with respect to demographic data, but setting versus tamoxifen are supported by the results of a re- a positive tumor ER status was only reported in ϳ45% of cently reported, independent, prospective, randomized, first-line patients. In this trial, median TTP was 8.2 and 8.3 months, and study in which 238 postmenopausal women with hormone- OR was 32.9 and 32.6% in the anastrozole and tamoxifen arms, sensitive, ER-positive, metastatic breast cancer, who had not respectively, confirming that anastrozole was at least as effec- received previous therapy for advanced disease, were treated tive as tamoxifen in terms of the primary efficacy end points. with either anastrozole (1 mg once daily; n ϭ 121) or tamoxifen Clinical benefit rates were 56.2% for anastrozole and 55.5% for (40 mg daily; n ϭ 117) (76). At the time of data cutoff, 61% of tamoxifen. This difference in the TTP results between the two trials has mainly been attributed to the percentage of patients with confirmed positive tumor ER. An exploratory subgroup analysis 4 AstraZeneca; data on file.

Table 3 Overview of efficacy results from Phase III first-line trials of newer aromatase inhibitors versus tamoxifen in postmenopausal women with advanced breast cancer Anastrozole: combined US and European trials75 Anastrozole: Spanish trial76 Letrozole: US trial only77 Anastrozole Tamoxifen Anastrozole Tamoxifen Letrozole Tamoxifen Parameter 1 mg daily 20 mg daily 1 mg daily 20 mg daily 1 mg daily 20 mg daily Median TTP (mo) 8.5 7.0a 10.6 5.3 9.4 6.0 HRϩveb patients only 10.7 6.4 HR ϭ 0.77 P ϭ 0.0001 P ϭ 0.022 (95% CI 0.56–0.91; (two-sided) (two-sided) P Ͻ 0.05) Survival rate NMb 61% died 92% died NM HR ϭ 0.63; (95% CI 0.51–0.89; P Ͻ 0.05) a Not significant. b HRϩve, hormone receptor-positive; NM, data not yet mature.

patients had died in the anastrozole-treated group, compared with 92% in the tamoxifen-treated group (HR ϭ 0.63; 95% CI, 0.51–0.89; P Ͻ 0.05; Table 3). Median TTP was 10.6 months for anastrozole and 5.3 months for tamoxifen, with a higher risk of progression in the tamoxifen group, as indicated by the HR of 0.77 (95% CI, 0.56–0.91; P Ͻ 0.05) (79). It was the conclusion of all of these studies that anastrozole should now be considered as an alternative first-line treatment to tamoxifen in postmenopausal women with advanced breast cancer. Letrozole. Preliminary data have recently been reported from a large, multicenter, double-blind, first-line Phase III clin- Fig. 5 Kaplan-Meier curve for median TTF (fadrozole versus ical trial in postmenopausal women (n ϭ 907) with locally tamoxifen). advanced or metastatic breast cancer, which compared letrozole (2.5 mg once daily) with tamoxifen (20 mg once daily; Ref. 77). The primary end point was TTP and secondary end points included OR, TTF, time to response, and survival. A total of adjustment for prognostic factors; Fig. 5), although duration of 65% of patients had ER-positive/PgR-positive status. Statisti- response and survival were comparable in the two groups. cally significant superiority for letrozole was shown for the primary end point, TTP (median TTP, 9.4 months for letrozole First-line Therapy in Advanced Breast Cancer with versus 6.0 months for tamoxifen; P ϭ 0.0001; Cox regression; Steroidal Aromatase Inhibitors Table 3). Formestane. In a comparative trial of first-line therapy In contrast to the anastrozole trials, prior adjuvant tamox- for postmenopausal women with advanced breast cancer, the ifen in this trial was seen to impact upon subsequent response to steroidal aromatase inhibitor, formestane (250 mg i.m. every 2 treatment. For instance, after adjuvant tamoxifen, patients re- weeks), gave comparable results to those of tamoxifen (30 mg ceiving tamoxifen for metastatic disease were seen to have a low p.o. daily) for both efficacy and tolerability (43). In total, 409 response rate compared with letrozole (29% versus 8% for patients were randomized into two groups, well matched for letrozole and tamoxifen, respectively). Additional data and a full pretreatment characteristics, although there was a higher pro- publication from this trial are awaited. portion of patients with soft tissue metastases in the formestane- Fadrozole. In a Phase III randomized trial, fadrozole (1 treated group compared with the tamoxifen-treated group. Pa- mg twice daily) was compared directly with tamoxifen (20 mg tients were assessed for antitumor efficacy using UICC criteria. once daily) as first-line therapy in the treatment of 221 post- A total of 61 patients were not evaluable, either because they menopausal women with advanced breast cancer (78). The study were not eligible for the trial (mainly attributable to a lack of was not double-blind, and patients with disease progression or confirmation of postmenopausal status) or because they were an unacceptable level of toxicity were given the opportunity to nonevaluable for tumor response. There were no statistically cross over to the alternative drug where feasible. The two groups significant differences found between the two groups (n ϭ 348) were well balanced with respect to prognostic factors except for for OR, median duration of response, and survival. However, metastatic disease; patients in the fadrozole arm had signifi- results significantly favored tamoxifen compared with formes- cantly more visceral metastases and disease than those in the tane in terms of TTP (9.7 months versus 7.0 months, respec- tamoxifen arm. tively; adjusted P ϭ 0.003) and TTF (9.7 months versus 6.5 There was no significant difference between treatments in months; adjusted P ϭ 0.001) compared with formestane. terms of OR rate. TTF was longer with tamoxifen (8.5 months) Exemestane. A Phase II study was recently conducted in compared with fadrozole (6.1 months; P ϭ 0.05; P ϭ 0.09, after which exemestane (25 mg daily) was compared with tamoxifen

Table 4 Tolerability data: indirect comparison of newer aromatase inhibitors versus megestrol acetate in second-line trials Anastrozolea Letrozolea Exemestane71 Megestrol acetate Adverse event (%) 1 mg o.d.b 2.5 mg o.d.c 25 mg o.d.d 160 mg q.i.d. Headache 14 13 NA 9–13 Hot flushes 13 6 13 4–11 Nausea 18 11 9 5–23 Vomiting 10 8 3 5–7 Diarrhea 9 6 NA 3–11 Weight gain 3 6 8e 9–17 Rash 6 6 2 3–12 Dyspnea 11 9 1 3–28 Asthenia 18 NAf NA 7–20 Fatigue NA 11 8 10–22 a Adapted from Ref. 83. b Commonly reported adverse events, irrespective of causality. c Adverse experiences in Ͼ5% of patients, irrespective of causality. d Adverse events considered to be drug-related. e Incidence of weight gain from baseline. f NA Data not available in published literature.

(20 mg daily) as first-line treatment of metastatic breast cancer lower incidence of weight gain with exemestane (P ϭ 0.001), as in postmenopausal women (n ϭ 93; Ref. 79). Median TTP for would be anticipated when comparing aromatase inhibitors with exemestane (n ϭ 31) was 8.9 months compared with 5.2 months progestins in this patient population (71). However, the ob- for tamoxifen (n ϭ 32), and OR (CR ϩ PR) was 42% versus served value for grade 3–4 weight gain (excessive weight gain 16%, respectively. No statistical data from this Phase II study Ͼ10% of baseline weight) of 7.6% in patients receiving exemes- are available at the present time. It was concluded that exemestane is higher than that reported for the nonsteroidal aromatase tane had promising activity in the first-line treatment of meta- inhibitors, anastrozole and letrozole, in similar trials in a com- static disease and warranted a Phase III trial. parable patient population (Table 4; Refs. 55 and 61); this higher Conclusions. The results of the first-line Phase III com- value for exemestane probably reflects the androgenic nature of parative trials between anastrozole and tamoxifen now support the drug. Additionally, weight gain changes of Ն10% after the use of anastrozole in the first-line treatment of advanced exemestane were noted in 4% of overweight patients (71). disease in postmenopausal women. Notwithstanding earlier in- At higher than normal therapeutic doses of exemestane vestigations into the first-line use of the aromatase inhibitors (200 mg daily), androgenic events have been reported, such as fadrozole and formestane, compared with tamoxifen in ad- alopecia (10%), hypertrichosis (55), hoarseness (5%), and acne vanced breast cancer in postmenopausal women, this is the first (4%; Ref. 84). Exemestane has been reported to lead to statis- full report from a large-scale, randomized study of a newer- tically significant dose-dependent falls in plasma sex hormone generation aromatase inhibitor having superior efficacy to that binding globulin levels at the 25-mg dose level (52). At 200 mg of tamoxifen. Preliminary data have recently been reported daily, exemestane gave rise to a case of mild hirsutism after 52 showing a statistically significant advantage for letrozole versus weeks’ treatment. In a Phase II trial, symptoms which may have tamoxifen in terms of TTP in the first-line treatment of ad- been androgenic in nature were reported, again using the clinical vanced disease, and a full report of these data are awaited. dose of exemestane of 25 mg daily (two cases of grade 1 alopecia, one patient each with hypertrichosis and acne among Tolerability of Steroidal and Nonsteroidal 91 treated patients; Ref. 53). Aromatase Inhibitors In a Phase III trial comparing exemestane and megestrol Adverse Events. In clinical use, both steroidal and non- acetate, significantly more women receiving exemestane expe- steroidal aromatase inhibitors are generally well tolerated. The rienced hot flushes (12.0% versus 5.0%), nausea (9.2% versus main adverse events observed are hot flushes and gastrointesti- 5.0%), and vomiting (2.8% versus 0.8%) than did women re- nal events, i.e., nausea and vomiting, which are either antici- ceiving megestrol acetate, respectively. Significantly more pated via the pharmacological actions of aromatase inhibitors or women receiving megestrol acetate reported dyspnoea than did are the most commonly seen type of events with this class of women receiving exemestane (3.0% versus 0.3%, respectively; drug (18, 21, 43, 71, 72, 80–82). There are, however, certain Ref. 71). specific side effects observed with exemestane, but not anastro- In a first-line study comparing fadrozole with tamoxifen, a zole and letrozole, that relate to the androgenic nature of the 4% incidence in thromboembolic events was reported in the drug. tamoxifen group, whereas no events were observed in fadrozole- When compared with megestrol acetate in second-line treated patients (78). In the first-line studies comparing anastro- studies in advanced breast cancer, the nonsteroidal drugs, anas- zole with tamoxifen (72–75), anastrozole-treated patients had a trozole and letrozole, were associated with a significantly lower significantly lower incidence of thromboembolic events (com- incidence of weight gain (55, 61). When exemestane was combined analysis).4 With respect to other adverse events in these pared with megestrol acetate, there was also a significantly same trials, more patients treated with anastrozole had hot

flushes and vaginal dryness, whereas more patients treated with effects on in situ estrogen synthesis in 11 postmenopausal tamoxifen had vaginal bleeding and vaginal discharge, although women with large, primary, ER-positive breast tumors (89). Of the differences were not significant. Although gastrointestinal 10 tumors which showed evidence of in situ estrogen synthesis, disturbances are widely recognized as a class effect of aro- 9 displayed a significant decrease in activity after letrozole matase inhibitors, it should be noted that that the incidence of treatment (P ϭ 0.022 by sign test). It was concluded that gastrointestinal disturbances was similar in the cases of anas- letrozole brought about a decrease in endogenous levels of trozole and tamoxifen in each trial [24% anastrozole versus 28% estrogen within the breast tumors of postmenopausal women. tamoxifen, respectively (72) and 54% anastrozole versus 57% Letrozole (2.5 mg daily; n ϭ 12; 10 mg daily, n ϭ 12) was tamoxifen, respectively (73)]. Finally, despite its lack of estro- administered to 24 patients with ER-positive breast tumors as genic effect, anastrozole showed no increase in myocardial primary systemic therapy (90). The patients were monitored by infarction or fractures compared with tamoxifen. monthly ultrasound and change in tumor volume over a 3-month Overall, very few patients withdrew from first- or second- period. The resulting median reduction in tumor volume was line comparative Phase III trials because of drug-related adverse 81%. Fifteen patients who would have been considered for events with aromatase inhibitors (19, 54, 55, 61, 66, 72, 73). In mastectomy before letrozole therapy were found to be suitable the large-scale, randomized trials of anastrozole versus tamox- for breast conservation after 3 months’ treatment with the drug. ifen for first-line treatment, the incidence of withdrawals was In a double-blind, randomized, multicenter study, letrozole similar in both treatment groups, showing that anastrozole is at (2.5 mg daily) was compared with tamoxifen (20 mg daily) as least as well tolerated as tamoxifen (72, 73). No tolerability data neoadjuvant treatment of 337 postmenopausal women with ER- are available, as yet, from the first-line study comparing letro- positive primary breast cancer, over a 4-month period (91). All zole with tamoxifen (77). patients at baseline were not considered eligible for breast- The newer-generation aromatase inhibitors have the addi- conserving surgery. The primary end point was tumor response. tional advantage of simple, oral, once-daily dosing. This avoids Another important end point was the resultant impact of treat- such problems as local reactions (7–13%) at the site of injection, ment on the down-staging of the extent of surgery. OR rates which have been reported after the twice-weekly i.m. adminis- were 55% for letrozole (n ϭ 154) versus 36% for tamoxifen tration of the steroidal aromatase inhibitor, formestane, thus (n ϭ 170), a difference which was statistically significantly limiting the potential, long-term usefulness of this drug in the different (P Ͻ 0.001; Mantel-Haenszel low rank test). After 4 adjuvant setting (11, 12, 43, 85). months’ therapy, 45% of letrozole-treated patients underwent a lumpectomy/quadrantectomy versus 35% of tamoxifen-treated Neoadjuvant Therapy with Aromatase Inhibitors patients (P ϭ 0.022; Mantel-Haenszel). It was concluded that Anastrozole. A small, randomized, double-blind, single- letrozole was significantly superior to tamoxifen in terms of center study was performed in which anastrozole (1 mg and 10 tumor reduction, which resulted in a superior rate of breast- mg daily, for 3 months) was used as neoadjuvant therapy in 23 conserving surgery in the letrozole-treated group. postmenopausal women with newly diagnosed, ER-rich, locally Conclusions. From the results of the above studies, both Ͼ advanced, or large ( 3 cm), operable breast tumors (86). Anas- anastrozole and letrozole are shown to be effective as neoadju- trozole at the normal clinical dose of 1 mg daily was shown by vant therapy in postmenopausal women with large, operable ultrasound measurements to be effective in leading to a decrease breast tumors. Treatment for up to 3 months with either aro- in tumor volume in the great majority of patients (80.5%). This matase inhibitor led to a marked reduction in mastectomy rates. had a dramatic influence on subsequent breast surgery, in that, Results to date for letrozole versus tamoxifen, and from an of 17 patients who would have required mastectomy at the indirect comparison of anastrozole with tamoxifen as neoadju- initiation of treatment, 15 were found to be suitable for breast vant therapy in a similar patient population, indicate that these conservation after 3 months’ treatment with anastrozole. These newer-generation aromatase inhibitors appear to offer an advan- results suggest that anastrozole is highly effective as neoadju- tage over neoadjuvant therapy with antiestrogens, and additional vant therapy in postmenopausal women with ER-rich breast comparative studies between these two classes of endocrine tumors. In the same group of patients, anastrozole was shown to agents are under way. suppress effectively aromatase activity within the breast, thereby reducing endogenous estrogens (87). This observation is compatible with the known antitumor effects of anastrozole. Adjuvant Therapy with Aromatase Inhibitors In another small study in 12 postmenopausal women with Tamoxifen is the most widely used endocrine agent for the locally advanced (T3–T4) breast cancer, anastrozole 1 mg daily adjuvant therapy of early breast cancer in postmenopausal for 15 weeks was evaluated for its effects on plasma and tumor women (79). Nevertheless, tamoxifen does have limitations in tissue estrogen levels in the same patient group (88). Treatment use, most notably its recognized pharmacological properties and with anastrozole suppressed tumor tissue concentrations of es- side effects. For instance, tamoxifen has been associated with an tradiol, estrone, and estrone sulfate by 88.9%, 82.3%, and increased risk of both thromboembolic events and endometrial 73.4%, respectively, and plasma concentrations by 86.1%, changes, including endometrial cancer (9, 92). It is feasible, 83.9%, and 95.8%, respectively. It was concluded that anastro- therefore, that other endocrine drugs can provide at least equiv- zole is a potent suppressor of plasma and intratumoral estrogen alent, if not superior, efficacy, together with improved tolera- levels in patients with locally advanced breast cancer. bility, in patients with early disease. In this context, the newer- Letrozole. In a similar study, letrozole 2.5 mg daily for 3 generation aromatase inhibitors are now under investigation in months as primary medical therapy was investigated for its the adjuvant setting (Table 5).

Table 5 Key adjuvant studies with aromatase inhibitors (see Refs. 81, 82, 91, and 92) Adjuvant study Design ATAC Tamoxifen alone (20 mg daily, 5 yr) versus Tamoxifen (20 mg daily) ϩ anastrozole (1 mg daily, 5 yr) versus Anastrozole alone (1 mg daily 5 yr) ARNO Tamoxifen (20 mg daily, 2 yr) followed by tamoxifen (20 mg daily, 3 yr) versus Tamoxifen (20 mg daily, 2 yr) followed by anastrozole (1 mg daily, 3 yr) ABCSG Comparison of addition of aminoglutethimide to tamoxifen for 5 yr, followed by rerandomization to compare anastrozole with placebo for an additional 3 yr Tamoxifen (20 mg daily) versus anastrozole (1 mg daily) after 2-yr exposure to tamoxifen (20 mg daily) FEMTABIG Tamoxifen (20 mg daily, 5 yr) versus Letrozole (2.5 mg daily, 5 yr) versus Letrozole (2.5 mg daily, 2 yr) followed by tamoxifen (20 mg daily, 3 yr) versus Tamoxifen (20 mg daily, 2 yr) followed by letrozole (2.5 mg daily, 3 yr) MA.17 Tamoxifen (5 yr) followed by letrozole (5 yr) versus Tamoxifen (5 yr) followed by placebo (5 yr) ICCG Tamoxifen (20 mg daily, 2–3 yr) followed by either tamoxifen (20 mg daily) or exemestane (25 mg daily) for the remainder of the 5-yr period NSABP (B-33) Tamoxifen (5 yr) followed by either exemestane (25 mg daily) for 2 yr or placebo for 2 yr

Anastrozole. Anastrozole is currently being compared tinuous course of a single endocrine agent. The trial consists of directly with tamoxifen as initial adjuvant therapy in postmeno- an option of randomization into two single arms of either pausal women with early breast cancer (82, 93–95). The ATAC tamoxifen (20 mg daily) or letrozole (2.5 mg daily) for 5 years trial is a randomized, double-blind trial designed to compare the or randomization into a four-arm trial comprising either arm of efficacy and tolerability of 5 years of treatment with tamoxifen the first option above (two-arm trial); and a third arm of 3 years with that of anastrozole versus the combination of anastrozole of tamoxifen (20 mg daily) and then letrozole (2.5 mg daily) for and tamoxifen (92, 93). The primary end points are time to 2 years; and a fourth arm of letrozole (2.5 mg daily) for 3 years recurrence and safety. Other criteria for evaluation include time and then tamoxifen (20 mg daily) for 2 years (81, 82, 92). to distant metastases, survival, and occurrence of contralateral Another adjuvant trial, the MA.17 study, evaluates patients breast cancer. Separate subprotocols include assessments of from the National Cancer Institute of Canada Clinical Trials pharmacokinetics, endometrial status, bone mineral density, and Group (NCIC CTG) who are disease-free after initially being quality of life. The ATAC trial has now completed recruitment treated with 5 years of tamoxifen and then randomized to of over 9300 patients and is expected to report in the year 2001. receive either 5 years of placebo or 5 years of letrozole. This A second trial, the Arimidex-Nolvadex (ARNO) trial, be- trial also incorporates assessments of incidence of bone frac- ing conducted by the German Breast Cancer Group, involves the tures and bone mineral density measurements together with lipid randomization of patients who have received adjuvant tamox- profiles (81). ifen for 2 years to receive either anastrozole for 3 years or Exemestane. The steroidal aromatase inhibitor, exemes- tamoxifen for an additional 3 years (82, 92–94). The primary tane is also being studied in the adjuvant setting (81, 82, 92). In end points in this trial are overall survival, relapse-free survival, the International Collaboration Cancer Group (ICCG) trial, pa- tolerability, and quality of life. tients with early breast cancer are randomized to receive tamox- Two other adjuvant studies of endocrine therapy with aro- ifen (20 mg daily for 2–3 years) and then either tamoxifen (20 matase inhibitors in early breast cancer are in progress with the mg daily) or exemestane (25 mg daily) for the remainder of the ABCSG (95). The first study compares the addition of the 5-year period (92). In the National Surgical Adjuvant Breast and first-generation aromatase inhibitor, aminoglutethimide, to ta- Bowel Project (NSABP; B-33) trial, patients with early breast moxifen treatment in postmenopausal patients with hormone- cancer are being randomized to receive either exemestane or responsive, stage I and stage II breast cancer. After 5 years’ placebo for 2 years after a standard 5 years of tamoxifen therapy endocrine treatment in either arm, patients who are recurrence- (82). free are being rerandomized to compare anastrozole with pla- Conclusions. The above adjuvant trials of aromatase in- cebo for another 3 years. In the second ABCSG study, adjuvant hibitors versus tamoxifen in the treatment of early breast cancer tamoxifen for 3 years is being compared with adjuvant anastro- offer the opportunity for the measurement of parameters such as zole for 3 years after 2 years’ exposure to tamoxifen in post- disease recurrence, contralateral breast cancer occurrence, menopausal patients presenting with hormone-responsive, G1 disease-free survival, and overall survival. It is hoped that the and G2, stage I and stage II breast cancer. current trials with anastrozole, letrozole, and exemestane as Letrozole. The Femera-Tamoxifen Breast International adjuvant endocrine treatment in early breast cancer will be Group (FEMTABIG) trials of letrozole and tamoxifen are being beneficial in terms of efficacy, tolerability and quality-of-life conducted by the Breast International Group to compare letro- parameters in postmenopausal women. The data from the ATAC zole with tamoxifen over 5 years in postmenopausal women trial will be available in the near future, and the recent data from with ER-positive/PgR-positive early breast cancer and to com- the first-line comparative trials between anastrozole and tamox- pare a sequence of adjuvant endocrine therapies versus a con- ifen and letrozole and tamoxifen suggest that there is also

Table 6 Properties of aromatase inhibitors Aromatase Normal clinical dose and Phase III clinical data available inhibitor Class Type route of administration for second-line use versus: Anastrozole Nonsteroidal II: Inhibitor 1 mg daily p.o. Megestrol acetate6,54,55,58 Fadrozole Nonsteroidal II: Inhibitor 1 mg twice daily p.o. Megestrol acetate69 Letrozole Nonsteroidal II: Inhibitor 2.5 mg daily p.o. Megestrol acetate61–63 Aminoglutethimide65 Vorozole Nonsteroidal II: Inhibitor 2.5 mg daily p.o. Megestrol acetate66 Aminoglutethimide67,68 Exemestane Steroidal I: Inactivator 25 mg daily p.o. Megestrol acetate71 Formestane Steroidal I: Inactivator 250 mg twice weekly i.m. Megestrol acetate24,70

Table 7 First-line clinical trials of aromatase inhibitors Phase III clinical data available for first-line use in advanced breast cancer. Aromatase inhibitor Major findings Anastrozole vs. tamoxifen72–75 Anastrozole at least as effective as tamoxifen. Significant difference in favor of anastrozole for patients with ER-positive and/or PgR-positive tumors (P ϭ 0.022; two-sided). Fadrozole vs. tamoxifen78 Numerical (nonsignificant) advantage for tamoxifen over fadrozole in terms of TTF. No significant difference in terms of OR rate. Duration of response and survival comparable. Formestane vs. tamoxifen43 No statistically significant differences for OR, median duration of response, and survival. Results significantly favored tamoxifen compared with formestane in terms of TTP and TTF. Exemestane vs. tamoxifen79 Promising antitumor activity vs. tamoxifen in a Phase II study (n ϭ 97). A Phase III trial is planned. Letrozole vs. tamoxifen77 Preliminary data available showing significant superiority for letrozole over tamoxifen in terms of TTP. Vorozole No data available.

potential for aromatase inhibitors to provide an advantage over criteria and different methods of assessment in different patient tamoxifen in the adjuvant setting. populations (20, 80). As a result, such indirect comparisons between trials cannot possibly lead to a clear outcome in favor Overall Conclusions of any single drug. Some investigators even have attempted to The data for the second-line use of endocrine therapy with reach conclusions based on the degree of estrogen suppression steroidal and nonsteroidal aromatase inhibitors has fully estab- exhibited by aromatase inhibitors; but it should be noted that the lished this class of drugs as the new treatment of choice in net clinical relevance of plasma estrogen reduction still needs to postmenopausal women with advanced breast cancer failing on be carefully evaluated (81). prior treatment with an antiestrogen such as tamoxifen (20, 58, One major area of considerable interest for these newer- 61, 71). In terms of efficacy, anastrozole, letrozole, and exemes- generation aromatase inhibitors lies in their potential for lack of tane each have shown advantages over the standard second-line cross-resistance with other drugs of the same class, thereby therapy, megestrol acetate. Anastrozole was the first nonsteroi- allowing the possibility for an additional response to endocrine dal, newer-generation aromatase inhibitor to demonstrate a ma- therapy, even after progression on second-line treatment. This is ture efficacy and survival advantage over another second-line illustrated by the response of patients to anastrozole after pro- endocrine drug (58), although exemestane has now also been gression on second-line therapy with formestane (96); 9 of 12 reported to improve survival compared with megestrol acetate patients who had initially achieved either a PR or SD on form- (71). All of the newer-generation aromatase inhibitors are well estane before progressing showed additional SD on anastrozole. tolerated, with hot flushes and gastrointestinal disturbance being Seven of these nine responding patients had ER-positive tumors. the major adverse events reported in second-line comparative Similarly, exemestane produced CR in 3 patients and PR in 13 studies. The nonsteroidal aromatase inhibitors, anastrozole and patients when given to postmenopausal women with metastatic letrozole, both display a clear benefit in terms of weight gain breast cancer after progression on second-line therapy with the over megestrol acetate. nonsteroidal aromatase inhibitors, aminoglutethimide, anastro- The properties of aromatase inhibitors reviewed in this zole, letrozole, or vorozole (97). This lack of cross-resistance article are shown in Table 6. might be predicted when steroidal aromatase inhibitors are used Many reviewers have attempted to draw indirect compar- sequentially after nonsteroidal aromatase inhibitors and vice isons between drugs within this class of aromatase inhibitors in versa because of their different mechanisms of action on the an effort to identify the optimal aromatase inhibitor for the aromatase enzyme. second-line therapy of advanced breast cancer. This is fraught The neoadjuvant use of newer-generation aromatase inhib- with difficulties, because randomized, controlled trials involv- itors in women with ER-rich, locally advanced, or large opera- ing these agents have study designs with different response ble breast tumors gives rise to optimism because of their ability

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Aman Buzdar and Anthony Howell

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