Are Differences in the Available Aromatase Inhibitors and Inactivators Significant?

Home , Anastrozole, Aromatase inhibitor, Fadrozole, Formestane, Letrozole, Vorozole

4360s Vol. 7, 4360s-4368s, December 2001 (Suppl.) Clinical Cancer Research

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 maintained 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 substrates 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

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

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 important 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 on 11-deoxycorticosterone and aldosterone

concentrations, as well as on sodium and potassium levels in and tamoxifen, indicate that step-changes in estrogen suppres- animals (10-13). sion are clinically important. However, head-to-head clinical The third-generation aromatase inhibitor anastrozole has a trials are needed to analyze the differences in estrogen suppres- high degree of selectivity for aromatase in clinical pharmacol- sion by the newer aromatase inhibitors. ogy studies, and no significant effects were observed on either cortisol or aldosterone secretion at up to 10 times the daily Clinical Efficacy recommended dose after 28 days of exposure (14-16) and also Anastrozole. Phase III studies analyzed anastrozole as when given for up to 3 months (16). Letrozole showed a poorer second- and third-line therapy, comparing oral anastrozole (1 or degree of enzyme selectivity as compared with anastrozole (17). 10 mg, once daily) with oral megestrol acetate (40 mg, four The long-term effects of this difference have yet to be estab- times daily) in postmenopausal women with advanced breast lished. cancer who had progressed on tamoxifen (30, 31, 33). At 6 In the case of the steroidal aromatase inhibitors, both months, there were no statistically significant differences be- formestane (18-20) and exemestane (21) are selective for aro- tween anastrozole and megestrol acetate (32). However, at 31.2 matase and do not affect either cortisol or aldosterone concen- months, anastrozole at 1 mg daily demonstrated a statistically trations adversely. However, both have androgenic properties significant survival advantage over megestrol acetate, with a (22). median survival of 26.7 months versus 22.5 months for the megestrol acetate group (33). The combined analysis clearly demonstrated that after disease progression with tamoxifen, Estrogen Suppression and Aromatase Inhibition treatment with 1 mg of anastrozole provides a statistically and Both steroidal and nonsteroidal aromatase inhibitors result clinically significant advantage over standard treatment with in a significant decrease in serum estrogen concentrations. Ami- megestrol acetate. noglutethimide demonstrated a high level of aromatase inhibi- A further subgroup analysis of the above-mentioned trial tion, but there was not a reduction in estrogen concentrations data showed that anastrozole at 1 mg daily also had benefits comparable with that seen with the third-generation nonsteroidal among women with visceral and liver metastases compared with aromatase inhibitors (7). An increase in potency was found with megestrol acetate. The median clinical benefit for visceral me- the second-generation drug fadrozole (6), but, in comparison, tastases was 16.4 months with anastrozole versus 14.7 months the newer drugs anastrozole and letrozole both produce much with megestrol acetate; for liver metastases, it was 17.9 months greater suppression of estrogens (to the limits of detection of with anastrozole versus 9.9 months with megestrol acetate. current assays) and have demonstrated a high degree of consis- In a major North American and European randomized, tency between the inhibition of whole-body aromatase activity double-blind, double-dummy, clinical trial program, anastrozole and estrogen suppression (4, 7, 23). (1 mg, once daily) was compared with tamoxifen (20 mg, once Recent data have been reported from a small study in 12 daily) as first-line therapy in postmenopausal women with ad- postmenopausal women with advanced breast cancer, compar- vanced breast cancer (34, 35). The patients were either newly ing plasma estrogen suppression by letrozole and anastrozole diagnosed with advanced disease or had progressed following (24). This study showed that letrozole led to significantly greater diagnosis and treatment for early disease. suppression of estrone and estrone sulfate, but not of estradiol, In the North American trial, the median TTP 3 was 11.1 which is widely considered to be the most important estrogen in months for anastrozole versus 5.6 months for tamoxifen. Based on the etiology of breast cancer. When inhibition of whole-body the derived hazards ratio of 1.44, at any given time point, patients aromatase was examined (25), it was shown that letrozole receiving tamoxifen were 44% more likely to progress than those achieved a greater inhibition of aromatase than did anastrozole. treated with anastrozole. OR was 21% for anastrozole and 17% The clinical significance of these changes remains to be defined. for tamoxifen. Clinical benefit (CR + PR + SD) rates were 59% The injectable steroidal aromatase inhibitor formestane for anastrozole and 46% for tamoxifen. These data suggest that also suppresses estrogen concentrations significantly, but to a anastrozole is superior to tamoxifen as a first-line treatment of lesser extent than anastrozole (26). Formestane is associated advanced breast cancer in postmenopausal women (35). with inconsistent suppression of serum estradiol (26, 27), In the European trial, median TTP was 8.2 and 8.3 months in whereby estradiol levels begin to rise between the fortnightly the anastrozole and tarnoxifen arms, respectively, and OR was i.m. doses. 32.9% and 32.6% in the anastrozole and tamoxifen an'ns, respec- Recently available results indicate that the oral steroidal tively, confirming that anastrozole was as effective as tamoxifen in aromatase inhibitor exemestane, at daily doses of 10-25 mg, terms of the primary efficacy end points. Clinical benefit rates were suppresses estrogen concentrations to 6-15% of pretreatment 56.2% for anastrozole and 55.5% for tamoxifen (34). levels, showing more pronounced activity than formestane and A prospectively planned combined analysis was performed comparable activity with that of the clinically available nonste- on the efficacy and tolerability data from the total number of roidal aromatase inhibitors anastrozole and letrozole (28, 29). It is clear that the newer-generation aromatase inhibitors anastrozole, letrozole, and exemestane provide greater suppression of estrogens than the earlier aromatase inhibitors aminoglu- 3 The abbreviations used are: TTP, time to progression; OR, overall tethimide, fadrozole, and formestane. response; CR, complete response; PR, partial response; SD, stable The clinical data available for the newer aromatase inhib- disease; TTF, time to treatment failure; ACTH, adrenocorticorticotropic itors versus the previous standard therapies, megestrol acetate hormone.

patients recruited into the two trials (36). The data obtained in therapy in postmenopausal women with metastatic disease. TTP this large patient population indicate that anastrozole is at least and response rate were significantly superior in the letrozole as effective as tamoxifen for the treatment of postmenopausal arm of the study as compared with the tamoxifen arm of the women with advanced breast cancer, with an observed advan- study (37). In this study, the antitumor activity of tamoxifen was tage in terms of TTP: median TTP was 8.5 months for anastro- very low (8%) in patients previously exposed to tamoxifen. This zole and 7 months for tamoxifen. A total of 57% of patients on is in contrast to other studies in which tamoxifen had substan- anastrozole showed clinical benefit compared with 52% on tially higher antitumor activity in similar subgroups of this tamoxifen. population (34, 35). These data on the efficacy of anastrozole in the first-line Fadrozole. A double-blind study compared fadrozole setting versus tamoxifen are supported by the results of a re- (only available in Japan) to megestrol acetate in 683 postmeno- cently reported, independent, prospective, randomized, first-line pausal women with advanced breast cancer who had progressed study in patients with estrogen receptor-positive, metastatic on first-line or adjuvant hormonal therapy (44). There were no breast cancer who had not received previous therapy for ad- differences in the response rates from either trial between fadro- vanced disease and were treated with either anastrozole (1 mg, zole and megestrol acetate. The median survival time was longer once daily) or tamoxifen (40 mg, daily). At the time of data in the fadrozole-treated group than in the megestrol acetate- cutoff, 61% of patients had died in the anastrozole-treated treated group (44). Neither trial showed any significant differ- group, as compared with 92% of patients in the tamoxifen- ence between the two treatments in terms of primary and sec- treated group. Median TTP was 10.6 months for anastrozole and ondary end points. 5.3 months for tamoxifen, with a higher risk of progression in In a Phase III randomized trial, fadrozole (1 mg, twice the tamoxifen group, as indicated by a hazards ratio of 0.77. It daily) was compared directly with tamoxifen (20 rag, once was the conclusion of all of these studies that anastrozole should daily) as first-line therapy in the treatment of postmenopausal now be considered as an alternative first-line treatment to ta- women with advanced breast cancer (45). The study was not moxifen in postmenopausal women with advanced breast cancer double-blind, and patients with disease progression or an unac- (38). ceptable level of toxicity were given the opportunity to cross- Letrozole. Two doses of oral letrozole (2.5 or 0.5 mg, over to the alternative drug, when feasible. There was no sig- once daily) were compared against each other and against nificant difference between treatments in terms of the OR rate. megestrol acetate (160 mg, once daily) as second-line therapy in TTF was longer with tamoxifen (8.5 months) as compared with postmenopausal women with advanced breast cancer previously fadrozole (6.1 months), although duration of response and sur- treated with antiestrogen endocrine therapy (39). For overall vival were comparable in the two groups. survival, there was a significant dose effect for 2.5 mg of Formestane. In a prospective, randomized, cross-over letrozole (25.3 months) over 0.5 mg of letrozole (21.5 months), Phase III trial, formestane (250 mg i.m., every 14 days) was although 2.5 mg of letrozole showed no significant survival compared with megestrol acetate (160 mg p.o., daily) in post- advantage over megestrol acetate, even in an updated analysis at menopausal patients with advanced breast cancer progressing on follow-up of 51 months (40). It was concluded that 2.5 mg of tamoxifen (8). The trial was planned to test differences in TTF. letrozole was superior to the 0.5-mg dose and was more effec- There were no significant differences in response rates between tive than megestrol acetate in the treatment of advanced breast formestane and megestrol acetate. A second open-label trial of cancer in postmenopausal women treated previously with an formestane versus megestrol acetate compared the efficacy and antiestrogen (40, 41). However, in a second similar trial, letro- safety of the two drugs as second-line therapy in receptor- zole did not show this dose-dependent antitumor activity at the positive or receptor-unknown postmenopausal patients with ad- 0.5- or the 2.5-mg dose in comparison with megestrol acetate vanced breast cancer previously treated with tamoxifen (46). (41). The TTP and survival of patients treated with 2.5 mg of There were no significant differences between formestane and letrozole were similar to those of patients in the progestin arm of megestrol acetate in terms of median TTF and overall survival. the study. Patients treated with 0.5 mg of letrozole tended to Formestane was considered a suitable alternative to progestins have longer TTP and survival, which is consistent with anas- in patients previously treated with tamoxifen. trozole studies in which higher doses of anastrozole failed to In a comparative trial of first-line therapy for postmeno- show superiority over lower doses of the same drug. These pausal women with advanced breast cancer, formestane (250 mg disparate results raise the issue of what should be the appropri- i.m., every 2 weeks) gave results comparable with those of ate therapeutic dose of this drug. tamoxifen (30 mg p.o., daily) with regard to both efficacy and In a randomized trial, oral once-daily letrozole (2.5 and 0.5 tolerability (18). There were no statistically significant differ- rag) was compared with aminoglutethimide (250 mg, twice ences found between the two groups for OR, median duration of daily) among postmenopausal women with advanced breast response, or survival. However, results significantly favored cancer previously treated with antiestrogens (42). Overall, no tamoxifen over formestane in terms of TTP (9.7 versus 7.0 significant differences in OR were seen in patients receiving 2.5 months) and TTF (9.7 versus 6.5 months). mg of letrozole, 0.5 mg of letrozole, or aminoglutethimide. Exemestane. In a randomized, double-blind Phase III However, 2.5 mg of letrozole was significantly superior statis- trial, postmenopausal women with advanced breast cancer re- tically to aminoglutethimide in terms of overall survival, TTP, fractory to tamoxifen were randomized to receive either ex- and TTF in postmenopausal women with advanced breast can- emestane (25 mg p.o., daily) or megestrol acetate (40 mg p.o., cer previously treated with antiestrogens. (39, 40, 43). four times daily) to demonstrate equivalence between the drugs Letrozole has been evaluated against tamoxifen as initial (47). The overall median duration of follow-up was 48.9 weeks.

The OR rate and overall rate of success (CR + PR + SD > In a Phase III trial comparing exemestane and megestrol 24months) were similar in both groups. However, both median acetate, significantly more women receiving exemestane expe- TTP and median survival were significantly improved in pa- rienced hot flashes (12.0% versus 5.0%), nausea (9.2% versus tients taking exemestane. It was concluded that, compared with 5.0%), and vomiting (2.8% versus 0.8%) than did women re- megestrol acetate in postmenopausal women with advanced ceiving megestrol acetate, respectively. Significantly more breast cancer refractory to tamoxifen, exemestane significantly women receiving megestrol acetate reported dyspnea than did delays tumor progression and significantly prolongs survival. women receiving exemestane (3.0% versus 0.3%, respectively; A Phase II study was recently conducted in which exemes- Ref. 46). tane (25 mg, daily) was compared with tamoxifen (20 mg, daily) In a first-line study comparing fadrozole with tamoxifen, a as first-line treatment of metastatic breast cancer in postmeno- 4% incidence in thromboembolic events was reported in the pausal women (48). Median TTP for exemestane was 8.9 tamoxifen group, whereas no events were observed in fadrozole- months compared with 5.2 months for tamoxifen, and ORs (CR treated patients (45). In the first-line studies comparing anastro- + PR) were 42% versus 16%, respectively. It was concluded zole with tamoxifen (34, 35), anastrozole-treated patients had a that exemestane had promising activity in the first-line treatment significantly lower incidence of thromboembolic events (com- of metastatic disease and warranted a Phase III trial. bined analysis; AstraZeneca; data on file). With respect to other adverse events in these same trials, more patients treated with Sequential Utilization of Aromatase Inhibitors anastrozole had hot flushes and vaginal dryness, whereas more One major area of considerable interest for these newer- patients treated with tamoxifen had vaginal bleeding and vaginal generation aromatase inhibitors lies in their potential for lack of discharge, although the differences were not significant. Al- cross-resistance with other drugs of the same class, thereby though gastrointestinal disturbances are widely recognized as a allowing the possibility for a further response to endocrine class effect of aromatase inhibitors, it should be noted that that therapy, even after progression on second-line treatment. This is the incidence of gastrointestinal disturbances was similar in the illustrated by the response of patients to anastrozole following case of anastrozole and tamoxifen in each trial: in these trials, progression on second-line therapy with formestane (49); 9 of the incidence of gastrointestinal disturbance was 24% versus 12 patients who had initially achieved either a PR or SD on 28% (34) and 54% versus 57% (35) for anastrozole versus formestane before progressing showed further SD on anastro- tamoxifen. Finally, despite its lack of estrogenic effect, anastrozole. Seven of these nine responding patients had estrogen zole showed no increase in myocardial infarction or fractures receptor-positive tumors. Similarly, exemestane produced com- compared with tamoxifen, likely reflecting the short duration of plete response in 3 patients and PR in 13 patients when given to treatment and observation in these trials. postmenopausal women with metastatic breast cancer following In the large-scale randomized trials of anastrozole versus progression on second-line therapy with nonsteroidal aromatase tamoxifen for first-line treatment, the incidence of withdrawals inhibitor, aminoglutethimide, anastrozole, letrozole, or vorozole was similar in both treatment groups, showing that anastrozole (49). This lack of cross-resistance might be predicted when is at least as well tolerated as tamoxifen (34, 35). steroidal aromatase inhibitors are used sequentially following nonsteroidal aromatase inhibitors and vice versa because of their Overall Conclusions different mechanisms of action on the aromatase enzyme. The data for the second-line use of endocrine therapy with steroidal and nonsteroidal aromatase inhibitors have fully estab- Adverse Events lished this class of drugs as the new treatment of choice in In clinical use, both steroidal and nonsteroidal aromatase postmenopausal women with advanced breast cancer failing on inhibitors are generally well tolerated. The main adverse events prior treatment with an antiestrogen such as tamoxifen (32, 39, observed are hot flashes and gastrointestinal events, such as 47). In terms of efficacy, anastrozole, letrozole, and exemestane nausea and vomiting (18, 34, 46, 50-52). There are, however, have each shown advantages over the standard second-line certain specific side effects observed with exemestane, but not therapy, megestrol acetate. Anastrozole was the first nonsteroi- with anastrozole and letrozole, that relate to the androgenic dal, newer-generation aromatase inhibitor to demonstrate a ma- nature of the drug. ture efficacy and survival advantage over another second-line When compared with megestrol acetate in second-line endocrine drug (32), although exemestane has now also been studies in advanced breast cancer, the nonsteroidal drugs anas- reported to improve survival compared with megestrol acetate trozole and letrozole were associated with a significantly lower (47). All of the newer-generation aromatase inhibitors are well incidence of weight gain (31, 39). When exemestane was com- tolerated, with hot flashes and gastrointestinal disturbance being pared with megestrol acetate, there was also a significantly the major adverse events reported in second-line comparative lower incidence of weight gain with exemestane, as would be studies. There is a partial lack of cross-resistance between anticipated when comparing aromatase inhibitors with pro- steroidal and nonsteroidal aromatase inhibitors. Therefore, ste- gestins in this patient population (47). However, the observed roidal aromatase inhibitors can be used following progression value for grade 3-4 weight gain (excessive weight gain > 10% on nonsteroidal aromatase inhibitors. of baseline weight) of 7.6% in patients receiving exemestane is In the first-line therapy of advanced breast cancer, anas- higher than that reported for the nonsteroidal aromatase inhib- trozole and letrozole have now challenged the position of the itors anastrozole and letrozole in similar trials in a comparable long-established standard therapy, tamoxifen, showing signifi- patient population (31, 39). cant benefits in terms of TTP (36, 48). Both aromatase inhibitors

are very well tolerated, but anastrozole has shown fewer throm- Dr. Buzdar: Not aromatase inhibitors, but specifically the boembolic complications and instances of vaginal bleeding than second study of letrozole versus megestrol acetate. tamoxifen and is not associated with an increased risk of endo- Dr. Per Lonning: I have some concerns about the com- metrial cancer. bined analysis of the two anastrozole-tamoxifen studies. The There are differences in both the chemistry and the phar- American study is very well conducted with a very high per- macological properties of the newer-generation aromatase in- centage of ER-positive patients. More than 50% of the European hibitors. These differences appear to have an impact on the patients are ER unknown. When you look at the time-to- selectivity of the drugs for aromatase (e.g., effect on ACTH- progression curves for the total European study and then take stimulated cortisol levels) and may possibly affect the clinical the ER-positive subgroups, it doesn't change so much. So it's efficacy of aromatase inhibitors in the adjuvant setting on a likely that the bulk of the patient with ER unknown are ER long-term basis. Data on the adjuvant use of anastrozole, letro- positive. Zeneca should collect the blocks and do the estrogen zote, and exemestane wilt become available in the near future; receptor analysis retrospectively. data on anastrozole are expected to be the first reported. Dr. Buzdar: The point you're making is very valid: to do Whereas all of these aromatase inhibitors are generally well clinical studies, you need to have receptor status information. I tolerated in the metastatic setting, it will be their tolerability think it would be ideal to look at it and see that whether the profiles following long-term use in the adjuvant setting that will ER-positive patient distribution was similar between the groups ultimately determine whether or not tamoxifen is replaced as the with unknown and known receptor status. But the only thing you can compare are the patient populations for which you know the "gold standard" adjuvant treatment. It will be important to ER receptor information, and in the known receptor subgroup in determine whether there are any long-term effects on the endo- the European study, the data were consistent with North Amer- metrium, thromboembolic events, bones, and lipids and also ican trial findings. whether any differences in "selectivity" among these drugs have Dr. Paul Goss: The patients with ER-unknown tumors did clinical consequences. The ongoing clinical trial programs will better on tamoxifen than the patients with ER-positive tumors in provide the answers to many of these points, and the data are that study. So that again suggests that the populations are very awaited with great interest. similar. Dr. Osborne: I will never participate in any study that, Open Discussion number one, allows ER-negative or ER-unknown patients to be enrolled, and number two, does not collect the blocks. Dr. James Ingle: With the EORTC data in the premeno- Dr. Buzdar: The point you are making is absolutely true. pausal patient, are you still comfortable using tamoxifen or an The European philosophy for the longest time was that they did LHRH alone or ovarian ablation alone, given the superiority not believe the ER information-partly because the older com- shown for the combination? As we all know, the sample sizes in petitive assays were more cumbersome. With the immunohis- the premenopausal studies are incredibly low. Even in the meta- tochemistry, you can do it much easier, and the results are very analyses, they are not of a size that any of us would consider a reproducible. reasonable study. Dr. Ellis: There's a dose issue with letrozole that I think Dr. Buzdar: The question you are raising is whether using reflects the nature of the second-line endocrine therapy setting. combined tamoxifen and LHRH agonist in premenopausal pa- You get a lot of resistance and therefore a lot of noise, as well tients is showing survival advantage. I have serious reservations as the potential for imbalances between arms depending on how about the data. At our institute, we discuss and debate every many endocrine therapy-resistant patients ended up on each patient we see in that scenario. My bias is that until we see arm. If you look at the letrozole dose in the aminoglutethimide stronger data, I tend to use sequential endocrine therapy in studies, 2.5 mg is better than 0.5 mg. In one megestrol study, 2.5 metastatic settings. mg is better than 0.5 mg of letrozole, and then in another study Dr. Kathleen Pritchard: If you look through the meta- against Megace, it's the other way around. You see the same analysis as well, which I think has been put together as well as thing more or less in the Arimidex data with 10 mg being not as it can be, and how the toxicity data were collected in the good as 1 mg. individual papers, it's in a plus/minus fashion. I think the Dr. Buzdar: No, with anastrozole, the trend is consistently comment that toxicity is not different between the combination in the direction of 1 mg. There's no trial in which 10 mg looked and the single agents is based on very little data indeed, and I better than 1 rag. With the trial of 2.5 mg of letrozole versus 0.5 would really like to see more data in that area. mg versus aminoglutethimide, although there was a trend that Dr. Carlos Arteaga: Can you give us a sense of the was not statistically significant between 0.5 and 2.5 mg letro- proportion of patients in these trials that have seen prior chem- zole, the difference was highly significant against the aminoglu- otherapy? In your JCO study and in these other studies, how tethimide. heterogeneous was that factor? Could that perhaps explain the Dr. Angela Brodie: I would certainly support that view, difference between the United States and European trials? because all of the data we have in the animal models showed a Dr. Buzdar: We looked at all potential confounding fac- dose-response effect with letrozole; clinically, it correlates rea- tors that might skew the result. That's why it took so long to sonably in that direction, and the lack of statistical significance publish the data. probably is due to the population difference. Dr. Arteaga: So you looked at all these trials with aro- Dr. Anthony Howell: The studies we've done recently matase inhibitors? seem to be very big. But in fact, as pointed out, 60 of 100

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Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2001 American Association for Cancer Research. Are Differences in the Available Aromatase Inhibitors and Inactivators Significant?

Paige E. Johnson and Aman Buzdar

Clin Cancer Res 2001;7:4360s-4368s.

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