Endocrine-Related Cancer (1999) 6 219-225 Role of aromatase inhibitors in advanced breast cancer

A U Buzdar

Department of Medical Oncology, The University of Texas, M D Anderson University Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA

Abstract A number of potent and selective non-steroidal aromatase inhibitors are now available for treatment of advanced breast cancer in postmenopausal women, of which anastrozole and letrozole, in particular, represent a significant advantage over the earlier agents in terms of both efficacy and tolerability. These agents are rapidly becoming established as the second-line therapy of choice in postmenopausal women with advanced disease, progressing on tamoxifen, and data on their efficacy as first-line treatment compared with tamoxifen will be available in the near future. Exemestane, a new, steroidal aromatase inhibitor which potentially lacks cross-resistance with non-steroidal agents is still in clinical development. The full potential of the new-generation aromatase inhibitors in the treatment of breast cancer is currently being investigated in a large program of clinical trials evaluating their use as adjuvant treatment following surgery in postmenopausal patients with early disease.

Endocrine-Related Cancer (1999) 6 219-225

Introduction whose disease has progressed or recurred whilst on tamoxifen treatment (Blamey 1997, Wyld et al. 1998). It is well established that at least one-third of all breast Aromatase inhibitors first became available for the cancers are estrogen dependent and will regress following treatment of advanced breast cancer in postmenopausal estrogen deprivation (Miller 1989). In the postmenopausal women in the early 1980s, with the introduction of woman, ovarian steroid production declines with age and aminoglutethimide. A number of studies have demon- the production of estrogens takes place mainly in the strated the efficacy of aminoglutethimide as first- or peripheral tissues, such as adipose tissue and the adrenal second-line treatment compared with tamoxifen or glands, where the adrenal steroid, androstenedione, is progestins in this patient population (Congdon et al. 1991, converted to estrone and, subsequently, estradiol Coombes et al. 1992, Garcia-Giralt et al. 1992, Gale et al. (Roseman et al. 1997, Brodie & Njar 1998). This 1994), but it is not specific for the aromatase enzyme and peripheral conversion is carried out by aromatase, an also inhibits the adrenal synthesis of both glucocorticoids enzyme complex consisting of a cytochrome P450 and mineralocorticoids, thus requiring the co-admin- hemoprotein and a flavoprotein, which catalyzes the istration of hydrocortisone (Roseman et al. 1997). This, conversion of androgens to estrogens via three enzymatic together with the significant side-effects associated with hydroxylations (Roseman et al. 1997). In addition to the standard daily dose of 1000 mg, e.g. lethargy, aromatase activity in peripheral tissues, approximately depression and morbilliform skin rash, has severely two-thirds of breast tumors also exhibit aromatase activity, limited its use (Garcia-Giralt et al. 1992, Brodie & Njar apparently providing a local source of estrogens within the 1998). A second, more selective, steroidal aromatase tumor itself (Bolufer et al. 1992). The inhibition of inhibitor, formestane (4-hydroxyandrostenedione), aromatase, therefore, is more likely to accomplish a became available in 1993. Whilst it has shown major ‘complete’ estrogen blockade than surgical removal of the advantages over aminoglutethimide in terms of both endocrine glands (Roseman et al. 1997), and the new- specificity for the aromatase enzyme and a more favorable generation aromatase inhibitors are rapidly becoming tolerability profile, formestane is administered as a established as the second-line therapy of choice in fortnightly intramuscular injection, which makes it postmenopausal women with advanced breast cancer, inconvenient to use and, furthermore, it has been

Endocrine-Related Cancer (1999) 6 219-225 Online version via http://www.endocrinology.org 1351-0088/99/006-219 © 1999 Society for Endocrinology Printed in Great Britain

Downloaded from Bioscientifica.com at 09/26/2021 05:49:36PM via free access Buzdar: Aromatase inhibitors in advanced breast cancer associated with injection-site reactions (Coombes et al. benefit from treatment (complete or partial response, or 1992). stable disease for at least 6 months). Both anastrozole and The late 1980s/early 1990s, therefore, saw a continued megestrol acetate were well tolerated but there was search for better-tolerated aromatase inhibitors with more significantly less weight gain in those patients treated with convenient dosage regimens. This resulted in the develop- anastrozole, at either dose (Buzdar et al. 1996a). In ment of the new-generation triazole analogues, which are addition, patients on megestrol acetate were continuing to orally active, non-competitive, selective inhib-itors of the gain weight at 9 months, whilst with both doses of aromatase enzyme. This class of drugs includes anastrozole bodyweight continued to remain at, or around, anastrozole (Arimidex), the first of these agents to become baseline values (Buzdar et al. 1998). A further safety commercially available as a treatment for advanced breast analysis after 12 months confirmed the favorable tolera- cancer in postmenopausal women, failing on tamoxifen bility profile of anastrozole compared with that of therapy; letrozole (Femara), also now commercially megestrol acetate (Buzdar et al. 1998). available; fadrozole (Afema), which is available only in Updated, mature results for this combined analysis are Japan; and vorozole (Rivizor) which has not progressed now available, with a median follow-up of 31 months beyond phase III clinical development. Over the past 2-3 (Buzdar et al. 1996b, 1998, Howell et al. 1997). Objective years, each of these drugs has been assessed versus tumor response data are summarized in Table 1. established endocrine treatment in large, randomized Although there were no statistically significant diff- clinical trials in patients failing on tamoxifen. The aim of erences between the three treatment arms, approximately this presentation is to review the available data on these 40% of patients in each group gained clinical benefit from new agents, with major emphasis on their clinical efficacy treatment. in the treatment of advanced breast cancer. There was, however, a significant improvement in both median survival and 2-year survival rates for anastro- zole (1 mg) compared with megestrol acetate in the Non-steroidal inhibitors combined analysis (hazard ratio 0.78; P<0.025). Two large phase III studies have been conducted to Additionally, the two studies were consistent when compare anastrozole (1 and 10 mg daily) with megestrol analysed individually, each demonstrating a lower risk of acetate (160 mg daily) as second-line therapy in post- death for anastrozole (both 1 and 10 mg) compared with menopausal women with advanced breast cancer, failing megestrol acetate. on tamoxifen. Each trial was of the same protocol design A subgroup analysis of the combined data compared which allowed a combined analysis to be performed on the 2-year survival in patients with complete or partial data from a total of 764 patients (Buzdar et al. 1996a). At response with that of those achieving stable disease for at a median duration of follow-up of 6 months, approx- least 24 weeks (Robertson & Lee 1997). This imately one-third of patients in each group showed clinical demonstrated that for each treatment arm, patients with

Table 1 Anastrozole vs megestrol acetate: objective tumor response data from the combined analysis of two independent phase III trials at a median follow-up of 31 months

Anastrozole Megestrol acetate 1 mg (n=263) 10 mg (n=248) (n=253) Objective response n (%) n (%) n (%)

Clinical benefit* 111 42.2 99 39.9 102 40.3

CR 11 4.2 10 4.0 11 4.3

PR 22 8.4 21 8.5 20 7.9

SD ≥ 24 weeks 78 29.7 68 27.4 71 28.1

SD < 24 weeks† 1 0.4 6 2.4 1 0.4

Progression 151 57.4 143 57.7 150 59.3

*Clinical benefit = complete response (CR) + partial response (PR) + stable disease (SD) ≥24 weeks. †Patients lost to follow-up. No identifiable patients were still on study with SD <24 weeks. The material quoted here was adapted from Buzdar et al. (1998).

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Downloaded from Bioscientifica.com at 09/26/2021 05:49:36PM via free access Endocrine-Related Cancer (1999) 6 219-225 stable disease of 24 weeks or longer had comparable although there was no significant difference in time to overall survival to those achieving an objective tumor progression (P=0.07) or overall survival (P=0.15). In response. The subgroup analysis, therefore, confirms the addition, patients receiving letrozole (2.5 mg) had clinical value of stable disease in this study and supports significantly fewer serious adverse events than those on previous findings with both megestrol acetate and megestrol acetate. tamoxifen that long-term stable disease is an important In a similar study comparing the same two doses of remission criterion in advanced breast cancer patients letrozole with aminoglutethimide (500 mg daily) in (Robertson et al. 1996). 555 postmenopausal advanced breast cancer patients Although the 10 mg dose of anastrozole did not (Gershanovich et al. 1998), letrozole (2.5 mg) was shown produce any additional clinical benefit compared with the to be superior to aminoglutethimide in terms of both time 1 mg dose, the tolerability profile was very similar, thus to progression (P=0.008) and overall survival (P=0.002), providing an excellent therapeutic margin for tolerability although there were no statistically significant differences and selectivity over the clinically recommended daily between treatments in objective response. As might be dose of 1 mg (Jonat 1997, Brodie & Njar 1998). Thus the expected, significantly more patients on amino- important survival benefit, together with the favorable glutethimide experienced drug-related adverse events than tolerability profile, further supports the role of anastrozole did those on letrozole (2.5 mg). Both of the phase III (1 mg) as a valuable replacement for progestin therapy as studies demonstrated a dose-effect relationship for second-line treatment in this patient population (Buzdar et letrozole and showed 2.5 mg to be the clinically superior al. 1998, Wyld et al. 1998). dose (Brodie & Njar 1998, Dombernowsky et al. 1998, Another of the new-generation aromatase inhibitors, Gershanovich et al. 1998). letrozole, is also becoming more widely available. The Anastrozole and letrozole, therefore, have both shown recent publication of phase III trial results comparing superiority in terms of efficacy and tolerability over letrozole (0.5 and 2.5 mg daily) with megestrol acetate existing endocrine agents as second-line therapy for (160 mg daily) in 551 postmenopausal women with postmenopausal women with advanced breast cancer and advanced disease reported a significant improvement in are rapidly becoming established as the treatments of both objective response rate (P=0.04) and duration of choice in such patients (Wyld et al. 1998). Currently there response (P=0.02) for letrozole (2.5 mg) over megestrol are no data available which directly compare the two acetate (Dombernowsky et al. 1998). Objective response agents. data are summarized in Table 2. When first reviewing the data, it may appear that the Letrozole (2.5 mg) was also superior to megestrol objective response rate of 23.6% observed for letrozole acetate in terms of time to treatment failure (P=0.04), (2.5 mg) in the study versus megestrol acetate

Table 2 Letrozole vs megestrol acetate: overall tumor response data at a median follow-up of 33 months

Letrozole Megestrol acetate 0.5 mg (n=188) 2.5 mg (n=174) (n=189) Objective response n (%) n (%) n (%)

Clinical benefit* 51 27.1 60 34.5 60 31.7 CR 6 3.2 12 6.9 8 4.2

PR 18 9.6 29 16.7 23 12.2

NC ≥ 6 months 27 14.4 19 10.9 29 15.3

Progression 105 55.9 93 53.4 106 56.1

Not assessable† 32 17.0 21 12.1 23 12.2

*Clinical benefit = complete response (CR) + partial response (PR) + no change (NC) ≥6 months.†Patients with incomplete documentation of tumor lesions, patients judged by peer review not to have evidence of malignant disease, or patients who had PRs or NC that was not confirmed at least 4 weeks later.The material quoted here was adapted from Dombernowsky et al. (1998).

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Table 3 Objective response data: indirect comparison of anastrozole (1 mg) vs megestrol acetate and letrozole (2.5 mg) vs megestrol acetate

Anastrozole Megestrol Letrozole Megestrol (1 mg) acetate (2.5 mg) acetate Objective response (n=263) (n=253) (n=174) (n=189) (CR + PR) 12.6% 12.2% 23.6% 16.4% CR 4.2% 4.3% 6.9% 4.2% PR 8.4% 7.9% 16.7% 12.2% SD/NC ≥ 24 weeks 29.7% 28.1% 10.9% 15.3% Clinical benefit* 42.2% 40.3% 34.5% 31.7% Progression 57.4% 59.3% 53.4% 56.1% *Clinical benefit = complete response (CR) + partial response (PR) + stable disease (SD)/no change (NC) ≥6 months. NB A small number of patients in each study was either lost to follow-up or not accessible for objective response. NA, not applicable The data on anastrozole compared with megestrol acetate were adapted from Buzdar et al. (1998) and the data on letrozole compared with megestrol acetate from Dombernowsky et al. (1998).

(Dombernowsky et al. 1998) is high alongside the 12.6% differences between treatment groups for objective response seen with anastrozole, in a similar study versus response, time to progression or survival, in either trial. the same comparator (Buzdar et al. 1998) (see Table 3). There were no statistically significant differences between The numbers of patients with progressive disease, groups in the incidence or severity of adverse events; however, are similar for both treatment groups in each however, weight gain, fluid retention and dyspnea were study. This suggests that the apparent differences in observed more frequently with megestrol acetate, whilst objective response may be explained by the different fadrozole was associated with a higher frequency of response criteria used in the two studies. Indeed, in the nausea and vomiting. anastrozole versus megestrol acetate study, the Two further trials have also investigated fadrozole as assignment of a partial response was not permitted for an alternative to tamoxifen as first-line therapy in patients with non-measurable disease, an important postmenopausal women with advanced disease (Falkson consideration as approximately 30% of patients in this & Falkson 1996, Thuerlimann et al. 1996). The larger study had disease which was not measurable (Buzdar et al. study (n=212) showed no significant differences between 1998). For these patients, any response other than treatments in terms of efficacy, although there was a trend complete tumor regression could only be categorized as in favor of tamoxifen for time to treatment failure. stable disease. In the study of letrozole (2.5 mg) versus Fadrozole, however, was significantly better tolerated, in megestrol acetate, however, patients with non-assessable, particular with respect to cardiovascular adverse events non-measurable lesions could be assigned a partial (Thuerlimann et al. 1996). A second, smaller study (n=38) response (Dombernowsky et al. 1998). Such differences had slightly conflicting conclusions; again, efficacy was in assessment of response emphasize the value of clinical similar for both treatments, but there were no differences benefit as an important criterion for advanced breast in either time to treatment failure or toxicity (Falkson & cancer patients (Robertson & Lee 1997). Falkson 1996). Overall, therefore, whilst fadrozole may Whilst anastrozole and letrozole have shown clear have tolerability advantages over existing endocrine evidence of benefit over existing agents, the data therapies, it has not shown the efficacy advantages of the regarding fadrozole and vorozole are more equivocal. other new-generation aromatase inhibitors as a second- Two large phase III trials of fadrozole (1 mg, twice daily) line therapy, or proven superior to tamoxifen as a first-line versus megestrol acetate (160 mg daily) as second-line agent (Cocconi 1996). treatment for advanced breast cancer, in a total of With regard to vorozole, it appears that this agent has 683 postmenopausal women failing on antiestrogen been withdrawn from clinical development in the US. therapy (Buzdar et al. 1996c), showed no significant Phase III trials versus both megestrol acetate (Goss et al.

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Table 4 Indirect comparison: adverse events with new-generation aromatase inhibitors in studies vs megestrol acetate

Anastrozole (1 mg)* Letrozole (2.5 mg)† Fadrozole Adverse event (n=263) (n=174) (n=196; n=152) Headache 14% 13% 7.7%, 15.1% Hot flashes 13% 6% 11.7%, 14.5% Nausea 18% 11% 21.9%, 36.2% Vomiting 10% 8% 9.2%, 18.4% Diarrhea 9% 6% 9.9%, 11.2% Weight gain 3% 2% NA Rash 6% 6% 5.6%, 11.8% Dyspnea 11% 9% 7.7%, 14.5% Asthenia 18% NA 6.6%, 11.2% Fatigue NA 11% 16.3%, 20.4% *Commonly reported adverse events, irrespective of causality. †Adverse experiences in >5% of patients irrespective of trial-drug relationship. Anastrozole data, see Buzdar et al. (1998); letrozole data, see Dombernowsky et al. (1998); fadrozole data, see Buzdar et al. (1996c).

1997) and aminoglutethimide (Houston 1997), as second- aromatase (Lonning et al. 1997), and may lack cross- line therapy for postmenopausal women with advanced resistance with the non-steroidal aromatase inhibitors disease, have not shown any statistically significant (Thuerlimann et al. 1997). At a dose of 200 mg daily, it differences in favor of vorozole for any of the clinical has shown promising activity as third-line therapy in endpoints studied, although it was shown to be superior to postmenopausal patients progressing on aminoglut- aminoglutethimide for quality of life (Houston 1997). ethimide, confirming the lack of cross-resistance when a Although anastrozole and letrozole remain the only steroidal aromatase inhibitor is sequenced after a non- new-generation, non-steroidal aromatase inhibitors to steroidal aromatase inhibitor (Thuerlimann et al. 1997). A have demonstrated significant efficacy benefits over second phase II study has investigated the much lower existing endocrine therapies, the tolerability profile of all dose of 25 mg daily as second-line therapy following these new agents appears to be fairly similar, the main tamoxifen (n=134) (Kvinnsland et al. 1997). The overall adverse events generally being those pharmacological objective response rate to exemestane was 22%, with an effects that might be anticipated as a result of estrogen additional 31% of patients achieving no change for at least withdrawal (Table 4). 24 weeks. The drug was well tolerated, the main adverse Although such detailed data are not available from the events being hot flashes and nausea. Exemestane is currently being evaluated in a large, double-blind phase III published literature for vorozole, the main adverse event study versus megestrol acetate in this patient population in the study versus megestrol acetate was reported to be (Kvinnsland et al. 1997). hot flashes (Goss et al. 1997).

Steroid inhibitors Conclusions In contrast to the new-generation, non-steroidal agents A number of potent and selective non-steroidal aromatase discussed above, exemestane is a second-generation inhibitors are now available, of which anastrozole and steroidal aromatase inhibitor, with the advantage of letrozole, in particular, represent a significant advantage improved oral activity over formestane (the latter over the earlier agents in terms of both efficacy and normally being given intramuscularly), allowing once tolerability. These agents are rapidly becoming estab- daily, oral dosing. Exemestane interacts covalently with lished as the second-line therapy of choice in post- the aromatase enzyme during the first oxidation cycle, menopausal women with advanced disease, progressing causing potent, selective, irreversible inhibition of on tamoxifen, and data on their efficacy as first-line

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