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Results of phase II and phase III trials with new aromatase inhibitors
%Breost (1996) 5,209-215 0 1996 Pearson Professional Ltd
ES0 TASK FORCE ARTICLE
Results of phase II and phase III trials with new aromatase inhibitors W. Jonat Universitiitsklinik, Klinik jiiir Frauenheilkunde, Kiel, Germany S U M MA R Y. The new generation of aromatase inhibitors represent convenient and well-tolerated treatments for advanced breast cancer in postmenopausal women. With the exception of fadrozole, the others, anastrozole, letrozole and vorozole are given once daily by oral administration and are highly selective for the aromatase enzyme. Phase II studies have demonstrated the clinical activity of these agents. The comparative studies involving anastrozole and megestrol acetate, have shown that the new generation aromatase inhibitors, as typified by anastrozole, are as effective as the standard second-line agent megestrol acetate, in the treatment of advanced breast cancer in postmenopausal women. Furthermore, the improved tolerability of anastrozole, particularly with respect to weight gain, provides a valuable alternative in the treatment of advanced breast cancer patients failing on tamoxifen. Promising results have been observed in the study comparing fadrozole and tamoxifen as first-line treatment for advanced disease, where no significant differences in efficacy or toxicity was observed. Further studies are, however, required before the new generation of aromatase inhibitors can be used in this setting. The good tolerability of these agents, coupled with the clinical activity seen to date, make the new generation of aromatase inhibitors excellent candidates for investigation in the adjuvant setting. Such studies are planned, and an anastrozole adjuvant study is due to be initiated during 1996.
INTRODUCTION
dose of 1000 mg (4 x 250 mg) daily is associated with a wide range of side-effects such as lethargy, depression and morbilliform skin rash.9 With the knowledge that aromatase inhibition was an effective treatment for advanced breast cancer in postmenopausal women, during the mid-to-late 1980s there has been a search for better tolerated aromatase inhibitors with more convenient dosing regimens. The outcome of this research led to formestane (4-hydroxyandrostenedione), a steroidal aromatase inhibitor, becoming available as treatment for advanced breast cancer in postmenopausal women in 1993. Whilst formestane (LentaronTM) was a major advance over aminoglutethimide with respect to specificity for the aromatase enzyme and superior tolerability, it is inconvenient to use, requiring administration as a fortnightly intramuscular injection and can be associated with injection site reactions.‘O Notwithstanding, the development of formestane, the major research effort has been put into identifying specific non-steroidal aromatase inhibitors that are effective when administered by the oral route. Four non-steroidal (third generation) compounds have been developed which are based on either the imidazole or triazole ring (see the Fig. for structures), each of these compounds is active when given by oral administration. Two of these compounds,
Approximately one-third of human breast cancers are oestrogen dependent and will regress following oestrogen deprivation.’ In postmenopausal women, the major mechanism for oestrogen production is peripheral conversion (by aromatase) of the adrenal steroid androstenedione to oestrone and subsequently to oestradiol.2 Additionally, about two-thirds of breast tumours show aromatase activity which appears to provide a local source of oestrogens within the tumour.3 Inhibition of aromatase therefore represents a promising method of treatment for postmenopausal women with breast cancer.4 Aromatase inhibitors have been available as treatments for breast cancer since the early 1980s aminoglutethimide being the first aromatase inhibitor to become widely available. A number of studies have shown aminoglutethimide to be as effective as progestins and tamoxifen as first and second-line treatments for advanced breast cancer in postmenopausal women.5-8 However, aminoglutethimide is not specific for the aromatase enzyme, inhibiting several enzymes involved in steroid synthesis; additionally the standard Address correspondence to: W. Jonat, Universit%tsklinik, Frauenheilkunde, Michaelisstr. 16. 24105 Kiel, Germany.
Klinik
tir
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letrozole (imidazole ring structure) and vorozole (triazole ring structure), are currently in phase III clinical development and are not yet commercially registered. Anastrozole (ArimidexTM), a triazole-based compound is registered in the UK and USA as a treatment for advanced breast cancer in postmenopausal women failing on tamoxifen treatment, and fadrozole (ArensinTM) an imidazole-based compound is available in Japan as a treatment for advanced breast cancer. The aim of this article is to review the available clinical data on anastrozole, letrozole, fadrozole and vorozole, with major emphasis on clinical efficacy in the treatment of advanced breast cancer. The pharmacology of the thirdgeneration aromatase inhibitors, including oestrogen suppressing ability, selectivity for the aromatase enzyme and in vivo aromatase inhibition are reported elsewhere in this issue.
RESULTS Clinical efficacy: phase II trials Fadrozole (CGS 16949A) Of the new aromatase inhibitors, fadrozole is by far the most widely tested, being shown to be a potent aromatase inhibitor” and an effective oestrogen suppressing agent.12 However, fadrozole interferes with adrenal steroidogenesis,
Anastroxole
(Arimidex”‘)
Fadrozde
(Arensin”)
with effects upon aldosterone being observed in a number of studies ‘3,14demonstrating it is not totally selective for the aromatase’ enzyme; it is, however, generally well tolerated in patients with advanced breast cancer. Fadrozole has been investigated in a number of phase II dose-ranging studies. The study involving the largest number of patients was that reported by Hoffken et al in 199215 where 423 patients were included in a randomised double-blind study comparing fadrozole 0.5 mg b.i.d., 1 mg b.i.d. and 2 mg b.i.d. Three hundred and fifty patients were assessable for response. Ninety-five per cent of patients had received tamoxifen for advanced breast cancer whilst 5% of patients had progression of disease during adjuvant tamoxifen. Objective responses of 17.5%, 18.2% and 13.1% were observed with fadrozole 1 mg, 2 mg and 4 mg daily respectively, with disease stabilization being observed in 33.3%, 30% and 26.3% respectively. There were no differences in duration of response, median duration of response being 15.4 months, 18 months and 15.4 months respectively. In a further study, 80 previously treated postmenopausal women with advanced breast cancer were randomized to either fadrozole 0.5 mg b.i.d. or 2 mg b.i.d.16 Objective responses were 24% and 22% for fadrozole 1 mg and 4 mg daily respectively, with a further 50% and 42% of patients showing disease stabilization for at least 2 months. Median time to treatment failure was 4.7 months and 3.7 months (not significantly different) for fadrozole 1 mg and 4 mg daily. No severe or life-threatening toxicity was observed. In 78 patients assessable for toxicity, mild-to-moderate toxicity documented was as follows: hot flushes in 22 patients, fatigue in six patients, nausea and vomiting in 10 patients and loss of appetite in four patients, there being no difference between the doses. In a study involving Japanese postmenopausal patients with advanced breast cancer, fadrozole at doses of 1 mg, 2 mg and 4 mg was given once daily to a total of 150 patients, 130 of whom were evaluable for response.r7 The objective responses observed were 13.6%, 22.0% and 13.3% and median duration of response was 276, 391, and 277 days for fadrozole 1 mg, 2 mg and 4 mg respectively. The median survival times were 902, 635 and 689 days respectively. An unusual finding in this study was that the response rate and duration of response were significantly greater with fadrozole 2 mg daily, whilst median survival was significantly greater with fadrozole 1 mg daily, however, since no details were given on prior treatment or patient base-line characteristics it is difficult to interpret fully these data. As in previous studies fadrozole appeared to be well tolerated, the incidence of side-effects being 11.9%, 7.5% and 13% for 1 mg, 2 mg and 4 mg respectively, 30 out of 33 symptoms being of mild severity. From these data it can be seen that fadrozole at doses
Results of phase II and phase III trials with new aromatase inhibitors ranging from 1 mg to 4 mg daily seems to be of similar clinical efficacy. This has led to a dose of 1 mg b.i.d being used in a phase III randomized comparative study versus tamoxifen as a first-line treatment for advanced breast cancer in postmenopausal women. Letrozole (CGS 20267) Letrozole, an imidazole-based compound has been shown to be a highly potent aromatase inhibitori that is selective for the aromatase enzyme’9,20 and highly effective in reducing serum oestrogen levels.‘9~2’ Letrozole has been investigated in a small number of phase I/II dose ranging efficacy studies involving postmenopausal women with advanced breast cancer. In a study involving 21 patients,19 letrozole at doses of 0.1 mg, 0.5 mg and 2.5 mg daily was given to three groups of seven patients; all patients had received at least one prior endocrine therapy and six patients had received prior chemotherapy. Seven of the 21 patients showed an objective response (1 CR + 6 PR) according to UICC criteria, with responses between 4+ months and 12 + months duration. Additionally, five patients had disease stabilization of greater than 3 months. Letrozole was well tolerated in this study, the main symptoms observed were headache (6 patients) and gastrointestinal (5 patients). In a phase II study undertaken in Japan” 64 postmenopausal patients with advanced breast cancer were randomized to letrozole 0.5 mg or 1 mg daily. Patients were well matched with respect to oestrogen receptor status, approximately 50% of these patients were oestrogen receptor positive. Objective tumour responses were reviewed independently and were 28% in the 0.5 mg group and 39% in the 1 mg dose group, with disease stabilization of more than 6 months observed in a further 19% and 29% respectively. As in other studies involving letrozole and the other new generation aromatase inhibitors, adverse events were low in this study, 6% of patients in both dose groups having side-effects which were all mild in severity (grade 1) with the exception of one event of grade 2 itching with the 1 mg dose group. Clinical activity was also observed in further two studies, both of which involved small numbers of postmenopausal patients with breast cancer who were heavily pre-treated. In a study reported by Lipton in 1993,23 of 19 evaluable patients who received letrozole 0.1 mg to 5 mg daily, two patients showed a partial response and further seven showed disease stabilization for 6, 7, 7, 7, 14, 16 and 17 months respectively. Toxicity was mild to moderate and included five patients with hot flushes, five with nausea and two with diarrhoea. In the second study letrozole 0.5 mg daily was investigated in 14 patients, five patients showed partial responses whilst further four showed disease stabilization.24 Based on the results of phase I and phase II studies com-
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parative phase III studies have been initiated using letrozole at doses of 0.5 and 2.5 mg daily. Vorozole (R83842) Vorozole was investigated initially in the form of its mixed enantiomer R767 13, with early publications describing both pre-clinical and clinical activity of this compound.25,26More recently all investigations have used the dextro-enantiomer (R83842) of the triazole derivative, R76713. It is the phase II clinical data of the R83842 derivative (hereafter named vorozole) that is described in this article. Like the other new-generation aromatase inhibitors described previously, vorozole has been shown to be potent inhibitor of the invivo conversion of androstenedione to oestrone2’ and to lead to significant suppression of serum oestrogens.‘R With respect to clinical activity, the most detailed publication to date is that reported by Goss et alZ9 who used vorozole 2.5 mg daily in 29 postmenopausal women with advanced breast cancer who had developed recurrence or progression with tamoxifen for early or advanced disease. Seventeen patients had received tamoxifen for advanced disease (having received tamoxifen for a median period of 14 months). Of the 29 patients, 25 were ER +, whilst 4 were ER unknown. Three out of 27 (11%) evaluable patients showed a PR of 14, 15 and 16 months respectively with a further 14 patients having disease stabilization for 7-24 months (median 12 months). Older women, those without bone metastases and those with a longer disease-free interval were the most likely to benefit from treatment. Possible treatment-related side-effects were mild and included malaise, anorexia, nausea and hot flushes. In a further study using vorozole 2.5 mg once-daily, Amoroso30 investigated the efficacy of vorozole as a secondline treatment to tamoxifen in 27 patients with ER +/ unknown advanced breast cancer. The patients included showed disease progression within 24 months of receiving adjuvant tamoxifen or had shown a response or disease stabilization for at least 6 months to tamoxifen for advanced disease. Response evaluation was performed according to UICC criteria after 2 months of treatment. Twenty-three patients were evaluable for response, of which 8 out of 23 (34.8%) showed PRs of median duration 5 months (range 2 - 13 + months) and five patients (21.8%) showed disease stabilization. The best responses were seen in those patients with soft-tissue disease. The only toxicities observed were somnolence in two patients, pruritus (1 patient) and dry mouth (1 patient). A final study investigating the clinical activity of vorozole 2.5 mg once daily was a trial coordinated by the EORTC Breast Group3’ which involved 27 patients with advanced breast cancer. Six patients had received prior adjuvant chemotherapy, three had prior adjuvant tamoxifen and 25 patients had rece’,ved tamoxifen for advanced disease. With
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a median duration of treatment of 8 months (1-18 months) there were two CRs (chest wall and supraclavicular lymph nodes), six PRs (3 soft tissue, 2 lung and 1 supraclavicular lymph nodes) and seven disease stabilizations. The median response duration was 10 months (6.6-12.8 months) with a response rate of 34%. Vorozole was well tolerated in this study; side-effects were very mild and consisted of anorexia (7 patients) and hot flushes (6 patients). Anastrozole (201033) Anastrozole, an achiral triazole derivative has been in development since the early 1990s pre-clinical and volunteer studies showing it to be a potent and highly selective aromatase inhibitor.32 More recently a randomized doubleblind study in breast cancer patients has shown anastrozole to produce maximal aromatase inhibition in vivo, this being accompanied by a large and consistent reduction in the serum oestrogens, oestradiol, oestrone and oestrone sulphate.33 There is little clinical data available for anastrozole in the phase II setting, oestradiol suppression was used as a surrogate endpoint on which the dose levels to be used in the phase III comparative studies were determined. In a single study where clinical activity was observed, 19 heavily pretreated postmenopausal women with advanced breast cancer, were given anastrozole 5 mg and 10 mg daily for 2-week periods, and thereafter at 10 mg daily until disease progression.34 Patients in this study had been previously treated for advanced disease, each patient receiving between two and three prior treatments (range l-5). Six patients exhibited disease stabilization for at least 12 months and four patients continued to receive anastrozole for a duration of 13-20 months.
Phase III comparative studies At the time of this review, whilst it is known that all of the new generation of aromatase inhibitors are undergoing or have completed phase III comparative trials, published data are only available for two of these, namely anastrozole and fadrozole. Anastrozole has been investigated in patients failing on tamoxifen for early or advanced disease in two independent comparative studies versus megestrol acetate, and fadrozole has been compared with tamoxifen as a firstline treatment for advanced breast cancer. The trial design and major findings from both these studies are described below. Anastrozole (201033) (ArimidexTM) Two independent prospective randomized trials were carried out comparing the efficacy and tolerability of anastrozole versus megestrol acetate in postmenopausal advanced breast cancer patients. The two trials, identical in design,
were carried out in Europe and the USA. The trials compared anastrozole at doses of 1 mg and 10 mg once daily (double-blind) with megestrol acetate 4 x 40 mg daily (open) in patients recurring or progressing after prior antioestrogen treatment. A total of 378 patients were randomizedd into the European study and 386 into the US study. The primary endpoints of the study were time to objective disease progression, objective response rate and tolerability. As the two studies were identical in design and showed reproducible results,35”7 an analysis of the combined data was carried out, thereby strengthening the interpretation of the data. It is the data from this combined analysis that are reviewed in this report. Seven hundred and sixty-four patients were included in the combined data analysis, 263 and 248 patients randomized to anastrozole 1 mg and 10 mg respectively and 253 patients randomized to megestrol acetate.38z39Patient baseline characteristics were similar, with approximately 50% of patients in each treatment group being ER+, similar numbers of patients had received tamoxifen as adjuvant treatment for early disease and for advanced disease. No significant differences in clinical efficacy were observed between either dose of anastrozole and megestrol acetate, the median time to progression being approximately 5 months in all groups. Approximately one-third of patients in each group benefited when disease stabilization for greater than 24 weeks was included. Clinical benefit (CR + PR + SD) was observed in 35.4% patients in the anastrozole 1 mg group, 31.5% in the 10 mg group and 34% in the megestrol acetate group. (See Table 1 for response data). Across all groups, and in common with the findings in the phase II studies, the best responses were observed in patients with soft tissue disease, objective responses being seen in 34%, 28% and 27% for anastrozole 1 and 10 mg and megestrol acetate respectively. Among all responders, 70% or more were without disease progression for at least 24 weeks. Both doses of anastrozole and megestrol acetate were generally well tolerated, however, significantly more patients on megestrol acetate had weight gain. More than 30% of patients on megestrol acetate had weight gain Table 1 Objective turnour response in patients in the anastrozole anastrozole 10 mg, and megestrol acetate groups Objective
response
Number Anastrozole 1 mg (n = 263)
Complete response Partial response Stable disease t 24 weeks Stable disease S 24 weeks* Progression
6 21 66 29 141
(2.3) (8.0) (25.1) (11 .O) (53.6)
1 mg,
of patients (%)
Anastrozole 10mg (n = 248)
Megestrol acetate (n = 253)
(1.6) 1;: 56 45 125
(7.3) (22.6) (18.1) (50.4)
(2.0) 1: 66 31 136
* Represents patients who had stable disease but had turnour assessments taken at less than 24 weeks at the time of data cut-off.
(5.9) (26.1) (12.3) (53.8)
Results of phase II and phase III trials with new aromatase inhibitors of greater than 5% and 10% of patients had weight gain of 10% or more. Patients who received megestrol acetate continued to gain weight over time. The main side-effects observed with anastrozole were gastrointestinal disturbance, hot flushes and nausea, the incidence of gastrointestinal disturbances being significantly higher with anastrozole 10 mg as compared to megestrol acetate. Withdrawal rate caused by adverse events was 3% for both doses of anastrozole and 4% for megestrol acetate. Based on the findings of this study, a product licence has now been granted for anastrozole 1 mg daily, and the product is now available in the UK and the USA as a treatment for advanced breast cancer in postmenopausal women failing on tamoxifen treatment.
Fadrozole (CGS 16949 A) (ArensinTM) Although fadrozole has been in clinical development since the late 1980s to date the results of only one phase III comparative trial have been published, these being the results of a comparative study versus tamoxifen.40 In this study fadrozole 1 mg b.i.d (n = 86) was compared with tamoxifen 20 mg once daily (n = 90) as first-line treatment for advanced breast cancer in postmenopausal women. Upon disease progression there was an option of cross-over to the alternate treatment. Sixty per cent of patients had ER + tumours and 30% had received prior adjuvant treatment. The two groups were comparable with the exception of a statistically significant imbalance of dominant metastatic site, where 53 fadrozole patients had visceral metastases compared to 35 tamoxifen treated patients (P = 0.001). Sixteen per cent (4 CR, 10 PR) of fadrozole treated patients showed an objective response compared with 24% (6 CR, 16 PR) of tamoxifen-treated patients, with a further 56% and 53% respectively showing disease stabilization. Median time to treatment failure was 4.9 months for fadrozole and 8.3 months for tamoxifen. Multivariate analysis showed no significant differences between efficacy endpoints although the authors concluded there was a trend for higher efficacy with tamoxifen. See Table 2 for details of response data. When tolerability was considered the most common side-effects observed with fadrozole were hot flushes (18 patients), and nausea and vomiting (6 patients). Whilst no significant differences in toxicity was observed, there was a trend for increased toxicity with tamoxifen.
DISCUSSION The new generation aromatase inhibitors represent convenient and well-tolerated treatments for advanced breast cancer in postmenopausal women. With the exception of fadrozole which is given twice daily and interferes with
Table 2 Objective tumour response and tamoxifen 20 mg groups Objective
Complete
response
response
in patients
Number
in the fadrozole
of patients
(%)
213 2 mg
P-value
Fadrozole (n = 86)
Tamoxifen (n = 90)
4
(4.7)
6
(6.7)
10 48 24 29
(11.6) (55.8) (28.0) (33.7) 4.9
16 48 20 22
(17.8) (53.3) (22.2) (24.4)
0.19 Partial reponse No change Disease progression Early failure (2 12 weeks) Median TTF (months)
8.3
0.20 0.10
adrenal steroidogenesis, each of anastrozole, letrozole and vorozole are given once daily by oral administration and appear to be highly selective for the aromatase enzyme. Compared to formestane and aminoglutethimide, the new generation aromatase inhibitors are much more potent, having far greater effect upon the suppression of plasma oestrogens, this being reflected in the dose levels required to achieve maximal aromatase inhibition and oestrogen suppression. The phase II clinical studies demonstrate the clinical activity of the new treatments in patients failing on previous treatments (mainly tamoxifen) for either early or advanced breast cancer’5,‘9and also in patients who have been heavily pre-treated. 23~24 In phase ii studies objective response rates varied considerably, as did indicators of durability of response (i.e. median duration of response, time to treatment failure, time to progression, median survival times, etc.). Furthermore, the majority of studies were not randomized or comparative without patient stratification, and used different endpoints for response assessment. Thus, it is not possible to draw conclusions regarding the relative merits of individual treatments on the basis of these data. Nevertheless it can be concluded that the new generation aromatase inhibitors are effective in the advanced disease setting and additionally are very well tolerated, the main side-effects being those related to oestrogen withdrawal. The most valuable information on the effectiveness of the new generation aromatase inhibitors was the data generated from the phase III comparative studies involving anastrozole and fadrozole. Anastrozole was compared with megestrol acetate in two independent studies involving large numbers of patients. Megestrol acetate is currently the treatment of choice in postmenopausal women relapsing on previous tamoxifen treatment in most countries. In this well-balanced study, anastrozole was shown to be as effective as megestrol acetate with respect to time to treatment progression and objective response rates and disease stabilization, over onethird of patients in each group deriving clinical benefit from treatment (CR + PR + SD). The primary endpoint assessed in the anastrozole study
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was time to progression (TTP); the TIP observed across all three treatment groups in this study was approximately 5 months, this comparing with other studies where TTP or TTF of 2-3.8 months with megestrol acetate,41A3 and of 2.2-4.3 months with aminoglutethimide44-46 have been reported. The results for ‘ITP indicated that all treatment groups were effective, showing activity consistent with that reported for megestrol acetate and aminoglutethimide. As TTP is an objective and reliable indicator of clinical activity, it is this endpoint which should be emphasized in future randomized studies involving endocrine treatments, including the new generation aromatase inhibitors. Both treatments were well tolerated, however, more patients on megestrol acetate had oedema, dyspnoea and weight gain. This represents an important benefit of anastrozole treatment compared to megestrol acetate, and is a feature which may be expected with the other new generation aromatase inhibitors. Whilst the anastrozole study investigated the efficacy of the new aromatase inhibitors in patients failing on tamoxifen treatment, the fadrozole study was a direct comparison with tamoxifen as the first treatment for advanced disease in postmenopausal women. In this single study there were no statistically significant differences between the two treatments with respect to TTF or objective response, although there was a trend to increased TTF with tamoxifen (fadrozole TTF being 4.9 months compared to 8.3 months with tamoxifen). It is possible that this difference was due to the significant difference in visceral lesions that was seen between the two groups, and emphasizes the importance of balanced patient stratification in randomized comparative studies. As with the anastrozole study, however, fadrozole was well tolerated, emphasizing the low toxicity profile of the new generation aromatase inhibitors. From this review, it can be seen that the new generation aromatase inhibitors are very well tolerated and are as effective (based on the anastrozole data) as the current secondline treatment megestrol acetate; the superior tolerability, particularly with respect to weight gain offers a valuable treatment alternative. The good tolerability offers the possibility of extending the use of such agents into the adjuvant setting.
Acknowledgement The European School of Oncology grant from Zeneca Pharmaceuticals
gratefully acknowledges an educational which made the meeting possible.
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aromatase inhibitor Arimidex (A) (ZD1033) versus megestrol acetate (MA) in the treatment of postmenopausal women with advanced breast cancer. The Breast 1995; 4, 256, abstr 104. Jonat W, Howell A, Blomqvist C P et al. A randomised trial of the new specific aromatase inhibitor Arimidex versus megestrol acetate (MA) in the treatment of postmenopausal women with advanced breast cancer. Proc ASCO 1995; 108, abstr 130. Jonat W, Howell A, Blomqvist C P et al. A randomised trial comparing two doses of the new selective aromatase inhibitor Arimidex (Anastrozole) with megestrol acetate in postmenopausal women with advanced breast cancer. Eur J Cancer. In press. Expected publication March 96. Buzdar A U, Jonat W, Howell A et al. Arimidex: efficacy and tolerability of Arimidex (Anastrozole) in two randomised comparative studies in postmenopausal women with advanced breast cancer. Breast Cancer Res Treat 1996; 37 (suppl 37) abstr 20. Buzdar A U, Jonat W, Howell A et al. Anastrozole (Arimidex), a potent and selective aromatase inhibitor versus megestrol acetate (Megace) in postmenopausal women with advanced breast cancer: Results of an overview of two phase III trials. J Clin Oncol. In press. Expected publication April 1996. Thurlimann B, Beretta K, Bacchi M et al. Fist line fadrozole Hcl (CGS 16949A) versus tamoxifen (Tam) in advanced breast cancer: prospective randomised study SAKK 20/88. Proc ASCO 1995; 14: 98, Abstr 90. Gill P G, Gebski V, Snyder R. Randomised comparison of the effects of tamoxifen, megestrol acetate, or tamoxifen plus megestrol acetate on treatment response and survival in patients with metastatic breast cancer. Ann Oncol 1993; 11: 580-585. Ingle J N, Ahmann D L, Green S J et al. Random&d clinical trial of megestrol acetate versus tamoxifen in paramenopausal or castrated women with breast cancer. Am J Clin Oncol 1982; 5: 155-160. Muss H B, Case L D, Capizzi R L et al. High-versus standard-dose megestrol acetate in women with advanced breast cancer: a phase III trial of the Piedmont Oncology Association. J Clin Oncol 1990; 8: 1797-1805.
44. Ingle J N, Green S, Ahmann et al. Randomised trial of tamoxifen alone or combined with aminoglutethimide and hydrocortisone in women with metastatic breast cancer. J Clin Oncol 1986; 4: 958-964.
Mercer P M, Ebbs S R, Fraser S C A, Coltart R S, Bates T. Trial aminoglutethimide vs hydrocortisone as second-line hormone treatment of advanced breast cancer. Eur J Surgery Oncol 1993; 19: 254-258. 46. Pronzato P, Rubagotti, Amoroso D et al. Second-line hormonotherapy for breast cancer. Usefulness of first-line continuation. Am J Clin Oncol 1993; 16: 522-525.
45.
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ES0 TASK FORCE ARTICLE
Results of phase II and phase III trials with new aromatase inhibitors W. Jonat Universitiitsklinik, Klinik jiiir Frauenheilkunde, Kiel, Germany S U M MA R Y. The new generation of aromatase inhibitors represent convenient and well-tolerated treatments for advanced breast cancer in postmenopausal women. With the exception of fadrozole, the others, anastrozole, letrozole and vorozole are given once daily by oral administration and are highly selective for the aromatase enzyme. Phase II studies have demonstrated the clinical activity of these agents. The comparative studies involving anastrozole and megestrol acetate, have shown that the new generation aromatase inhibitors, as typified by anastrozole, are as effective as the standard second-line agent megestrol acetate, in the treatment of advanced breast cancer in postmenopausal women. Furthermore, the improved tolerability of anastrozole, particularly with respect to weight gain, provides a valuable alternative in the treatment of advanced breast cancer patients failing on tamoxifen. Promising results have been observed in the study comparing fadrozole and tamoxifen as first-line treatment for advanced disease, where no significant differences in efficacy or toxicity was observed. Further studies are, however, required before the new generation of aromatase inhibitors can be used in this setting. The good tolerability of these agents, coupled with the clinical activity seen to date, make the new generation of aromatase inhibitors excellent candidates for investigation in the adjuvant setting. Such studies are planned, and an anastrozole adjuvant study is due to be initiated during 1996.
INTRODUCTION
dose of 1000 mg (4 x 250 mg) daily is associated with a wide range of side-effects such as lethargy, depression and morbilliform skin rash.9 With the knowledge that aromatase inhibition was an effective treatment for advanced breast cancer in postmenopausal women, during the mid-to-late 1980s there has been a search for better tolerated aromatase inhibitors with more convenient dosing regimens. The outcome of this research led to formestane (4-hydroxyandrostenedione), a steroidal aromatase inhibitor, becoming available as treatment for advanced breast cancer in postmenopausal women in 1993. Whilst formestane (LentaronTM) was a major advance over aminoglutethimide with respect to specificity for the aromatase enzyme and superior tolerability, it is inconvenient to use, requiring administration as a fortnightly intramuscular injection and can be associated with injection site reactions.‘O Notwithstanding, the development of formestane, the major research effort has been put into identifying specific non-steroidal aromatase inhibitors that are effective when administered by the oral route. Four non-steroidal (third generation) compounds have been developed which are based on either the imidazole or triazole ring (see the Fig. for structures), each of these compounds is active when given by oral administration. Two of these compounds,
Approximately one-third of human breast cancers are oestrogen dependent and will regress following oestrogen deprivation.’ In postmenopausal women, the major mechanism for oestrogen production is peripheral conversion (by aromatase) of the adrenal steroid androstenedione to oestrone and subsequently to oestradiol.2 Additionally, about two-thirds of breast tumours show aromatase activity which appears to provide a local source of oestrogens within the tumour.3 Inhibition of aromatase therefore represents a promising method of treatment for postmenopausal women with breast cancer.4 Aromatase inhibitors have been available as treatments for breast cancer since the early 1980s aminoglutethimide being the first aromatase inhibitor to become widely available. A number of studies have shown aminoglutethimide to be as effective as progestins and tamoxifen as first and second-line treatments for advanced breast cancer in postmenopausal women.5-8 However, aminoglutethimide is not specific for the aromatase enzyme, inhibiting several enzymes involved in steroid synthesis; additionally the standard Address correspondence to: W. Jonat, Universit%tsklinik, Frauenheilkunde, Michaelisstr. 16. 24105 Kiel, Germany.
Klinik
tir
209
210
The Breast
letrozole (imidazole ring structure) and vorozole (triazole ring structure), are currently in phase III clinical development and are not yet commercially registered. Anastrozole (ArimidexTM), a triazole-based compound is registered in the UK and USA as a treatment for advanced breast cancer in postmenopausal women failing on tamoxifen treatment, and fadrozole (ArensinTM) an imidazole-based compound is available in Japan as a treatment for advanced breast cancer. The aim of this article is to review the available clinical data on anastrozole, letrozole, fadrozole and vorozole, with major emphasis on clinical efficacy in the treatment of advanced breast cancer. The pharmacology of the thirdgeneration aromatase inhibitors, including oestrogen suppressing ability, selectivity for the aromatase enzyme and in vivo aromatase inhibition are reported elsewhere in this issue.
RESULTS Clinical efficacy: phase II trials Fadrozole (CGS 16949A) Of the new aromatase inhibitors, fadrozole is by far the most widely tested, being shown to be a potent aromatase inhibitor” and an effective oestrogen suppressing agent.12 However, fadrozole interferes with adrenal steroidogenesis,
Anastroxole
(Arimidex”‘)
Fadrozde
(Arensin”)
with effects upon aldosterone being observed in a number of studies ‘3,14demonstrating it is not totally selective for the aromatase’ enzyme; it is, however, generally well tolerated in patients with advanced breast cancer. Fadrozole has been investigated in a number of phase II dose-ranging studies. The study involving the largest number of patients was that reported by Hoffken et al in 199215 where 423 patients were included in a randomised double-blind study comparing fadrozole 0.5 mg b.i.d., 1 mg b.i.d. and 2 mg b.i.d. Three hundred and fifty patients were assessable for response. Ninety-five per cent of patients had received tamoxifen for advanced breast cancer whilst 5% of patients had progression of disease during adjuvant tamoxifen. Objective responses of 17.5%, 18.2% and 13.1% were observed with fadrozole 1 mg, 2 mg and 4 mg daily respectively, with disease stabilization being observed in 33.3%, 30% and 26.3% respectively. There were no differences in duration of response, median duration of response being 15.4 months, 18 months and 15.4 months respectively. In a further study, 80 previously treated postmenopausal women with advanced breast cancer were randomized to either fadrozole 0.5 mg b.i.d. or 2 mg b.i.d.16 Objective responses were 24% and 22% for fadrozole 1 mg and 4 mg daily respectively, with a further 50% and 42% of patients showing disease stabilization for at least 2 months. Median time to treatment failure was 4.7 months and 3.7 months (not significantly different) for fadrozole 1 mg and 4 mg daily. No severe or life-threatening toxicity was observed. In 78 patients assessable for toxicity, mild-to-moderate toxicity documented was as follows: hot flushes in 22 patients, fatigue in six patients, nausea and vomiting in 10 patients and loss of appetite in four patients, there being no difference between the doses. In a study involving Japanese postmenopausal patients with advanced breast cancer, fadrozole at doses of 1 mg, 2 mg and 4 mg was given once daily to a total of 150 patients, 130 of whom were evaluable for response.r7 The objective responses observed were 13.6%, 22.0% and 13.3% and median duration of response was 276, 391, and 277 days for fadrozole 1 mg, 2 mg and 4 mg respectively. The median survival times were 902, 635 and 689 days respectively. An unusual finding in this study was that the response rate and duration of response were significantly greater with fadrozole 2 mg daily, whilst median survival was significantly greater with fadrozole 1 mg daily, however, since no details were given on prior treatment or patient base-line characteristics it is difficult to interpret fully these data. As in previous studies fadrozole appeared to be well tolerated, the incidence of side-effects being 11.9%, 7.5% and 13% for 1 mg, 2 mg and 4 mg respectively, 30 out of 33 symptoms being of mild severity. From these data it can be seen that fadrozole at doses
Results of phase II and phase III trials with new aromatase inhibitors ranging from 1 mg to 4 mg daily seems to be of similar clinical efficacy. This has led to a dose of 1 mg b.i.d being used in a phase III randomized comparative study versus tamoxifen as a first-line treatment for advanced breast cancer in postmenopausal women. Letrozole (CGS 20267) Letrozole, an imidazole-based compound has been shown to be a highly potent aromatase inhibitori that is selective for the aromatase enzyme’9,20 and highly effective in reducing serum oestrogen levels.‘9~2’ Letrozole has been investigated in a small number of phase I/II dose ranging efficacy studies involving postmenopausal women with advanced breast cancer. In a study involving 21 patients,19 letrozole at doses of 0.1 mg, 0.5 mg and 2.5 mg daily was given to three groups of seven patients; all patients had received at least one prior endocrine therapy and six patients had received prior chemotherapy. Seven of the 21 patients showed an objective response (1 CR + 6 PR) according to UICC criteria, with responses between 4+ months and 12 + months duration. Additionally, five patients had disease stabilization of greater than 3 months. Letrozole was well tolerated in this study, the main symptoms observed were headache (6 patients) and gastrointestinal (5 patients). In a phase II study undertaken in Japan” 64 postmenopausal patients with advanced breast cancer were randomized to letrozole 0.5 mg or 1 mg daily. Patients were well matched with respect to oestrogen receptor status, approximately 50% of these patients were oestrogen receptor positive. Objective tumour responses were reviewed independently and were 28% in the 0.5 mg group and 39% in the 1 mg dose group, with disease stabilization of more than 6 months observed in a further 19% and 29% respectively. As in other studies involving letrozole and the other new generation aromatase inhibitors, adverse events were low in this study, 6% of patients in both dose groups having side-effects which were all mild in severity (grade 1) with the exception of one event of grade 2 itching with the 1 mg dose group. Clinical activity was also observed in further two studies, both of which involved small numbers of postmenopausal patients with breast cancer who were heavily pre-treated. In a study reported by Lipton in 1993,23 of 19 evaluable patients who received letrozole 0.1 mg to 5 mg daily, two patients showed a partial response and further seven showed disease stabilization for 6, 7, 7, 7, 14, 16 and 17 months respectively. Toxicity was mild to moderate and included five patients with hot flushes, five with nausea and two with diarrhoea. In the second study letrozole 0.5 mg daily was investigated in 14 patients, five patients showed partial responses whilst further four showed disease stabilization.24 Based on the results of phase I and phase II studies com-
211
parative phase III studies have been initiated using letrozole at doses of 0.5 and 2.5 mg daily. Vorozole (R83842) Vorozole was investigated initially in the form of its mixed enantiomer R767 13, with early publications describing both pre-clinical and clinical activity of this compound.25,26More recently all investigations have used the dextro-enantiomer (R83842) of the triazole derivative, R76713. It is the phase II clinical data of the R83842 derivative (hereafter named vorozole) that is described in this article. Like the other new-generation aromatase inhibitors described previously, vorozole has been shown to be potent inhibitor of the invivo conversion of androstenedione to oestrone2’ and to lead to significant suppression of serum oestrogens.‘R With respect to clinical activity, the most detailed publication to date is that reported by Goss et alZ9 who used vorozole 2.5 mg daily in 29 postmenopausal women with advanced breast cancer who had developed recurrence or progression with tamoxifen for early or advanced disease. Seventeen patients had received tamoxifen for advanced disease (having received tamoxifen for a median period of 14 months). Of the 29 patients, 25 were ER +, whilst 4 were ER unknown. Three out of 27 (11%) evaluable patients showed a PR of 14, 15 and 16 months respectively with a further 14 patients having disease stabilization for 7-24 months (median 12 months). Older women, those without bone metastases and those with a longer disease-free interval were the most likely to benefit from treatment. Possible treatment-related side-effects were mild and included malaise, anorexia, nausea and hot flushes. In a further study using vorozole 2.5 mg once-daily, Amoroso30 investigated the efficacy of vorozole as a secondline treatment to tamoxifen in 27 patients with ER +/ unknown advanced breast cancer. The patients included showed disease progression within 24 months of receiving adjuvant tamoxifen or had shown a response or disease stabilization for at least 6 months to tamoxifen for advanced disease. Response evaluation was performed according to UICC criteria after 2 months of treatment. Twenty-three patients were evaluable for response, of which 8 out of 23 (34.8%) showed PRs of median duration 5 months (range 2 - 13 + months) and five patients (21.8%) showed disease stabilization. The best responses were seen in those patients with soft-tissue disease. The only toxicities observed were somnolence in two patients, pruritus (1 patient) and dry mouth (1 patient). A final study investigating the clinical activity of vorozole 2.5 mg once daily was a trial coordinated by the EORTC Breast Group3’ which involved 27 patients with advanced breast cancer. Six patients had received prior adjuvant chemotherapy, three had prior adjuvant tamoxifen and 25 patients had rece’,ved tamoxifen for advanced disease. With
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a median duration of treatment of 8 months (1-18 months) there were two CRs (chest wall and supraclavicular lymph nodes), six PRs (3 soft tissue, 2 lung and 1 supraclavicular lymph nodes) and seven disease stabilizations. The median response duration was 10 months (6.6-12.8 months) with a response rate of 34%. Vorozole was well tolerated in this study; side-effects were very mild and consisted of anorexia (7 patients) and hot flushes (6 patients). Anastrozole (201033) Anastrozole, an achiral triazole derivative has been in development since the early 1990s pre-clinical and volunteer studies showing it to be a potent and highly selective aromatase inhibitor.32 More recently a randomized doubleblind study in breast cancer patients has shown anastrozole to produce maximal aromatase inhibition in vivo, this being accompanied by a large and consistent reduction in the serum oestrogens, oestradiol, oestrone and oestrone sulphate.33 There is little clinical data available for anastrozole in the phase II setting, oestradiol suppression was used as a surrogate endpoint on which the dose levels to be used in the phase III comparative studies were determined. In a single study where clinical activity was observed, 19 heavily pretreated postmenopausal women with advanced breast cancer, were given anastrozole 5 mg and 10 mg daily for 2-week periods, and thereafter at 10 mg daily until disease progression.34 Patients in this study had been previously treated for advanced disease, each patient receiving between two and three prior treatments (range l-5). Six patients exhibited disease stabilization for at least 12 months and four patients continued to receive anastrozole for a duration of 13-20 months.
Phase III comparative studies At the time of this review, whilst it is known that all of the new generation of aromatase inhibitors are undergoing or have completed phase III comparative trials, published data are only available for two of these, namely anastrozole and fadrozole. Anastrozole has been investigated in patients failing on tamoxifen for early or advanced disease in two independent comparative studies versus megestrol acetate, and fadrozole has been compared with tamoxifen as a firstline treatment for advanced breast cancer. The trial design and major findings from both these studies are described below. Anastrozole (201033) (ArimidexTM) Two independent prospective randomized trials were carried out comparing the efficacy and tolerability of anastrozole versus megestrol acetate in postmenopausal advanced breast cancer patients. The two trials, identical in design,
were carried out in Europe and the USA. The trials compared anastrozole at doses of 1 mg and 10 mg once daily (double-blind) with megestrol acetate 4 x 40 mg daily (open) in patients recurring or progressing after prior antioestrogen treatment. A total of 378 patients were randomizedd into the European study and 386 into the US study. The primary endpoints of the study were time to objective disease progression, objective response rate and tolerability. As the two studies were identical in design and showed reproducible results,35”7 an analysis of the combined data was carried out, thereby strengthening the interpretation of the data. It is the data from this combined analysis that are reviewed in this report. Seven hundred and sixty-four patients were included in the combined data analysis, 263 and 248 patients randomized to anastrozole 1 mg and 10 mg respectively and 253 patients randomized to megestrol acetate.38z39Patient baseline characteristics were similar, with approximately 50% of patients in each treatment group being ER+, similar numbers of patients had received tamoxifen as adjuvant treatment for early disease and for advanced disease. No significant differences in clinical efficacy were observed between either dose of anastrozole and megestrol acetate, the median time to progression being approximately 5 months in all groups. Approximately one-third of patients in each group benefited when disease stabilization for greater than 24 weeks was included. Clinical benefit (CR + PR + SD) was observed in 35.4% patients in the anastrozole 1 mg group, 31.5% in the 10 mg group and 34% in the megestrol acetate group. (See Table 1 for response data). Across all groups, and in common with the findings in the phase II studies, the best responses were observed in patients with soft tissue disease, objective responses being seen in 34%, 28% and 27% for anastrozole 1 and 10 mg and megestrol acetate respectively. Among all responders, 70% or more were without disease progression for at least 24 weeks. Both doses of anastrozole and megestrol acetate were generally well tolerated, however, significantly more patients on megestrol acetate had weight gain. More than 30% of patients on megestrol acetate had weight gain Table 1 Objective turnour response in patients in the anastrozole anastrozole 10 mg, and megestrol acetate groups Objective
response
Number Anastrozole 1 mg (n = 263)
Complete response Partial response Stable disease t 24 weeks Stable disease S 24 weeks* Progression
6 21 66 29 141
(2.3) (8.0) (25.1) (11 .O) (53.6)
1 mg,
of patients (%)
Anastrozole 10mg (n = 248)
Megestrol acetate (n = 253)
(1.6) 1;: 56 45 125
(7.3) (22.6) (18.1) (50.4)
(2.0) 1: 66 31 136
* Represents patients who had stable disease but had turnour assessments taken at less than 24 weeks at the time of data cut-off.
(5.9) (26.1) (12.3) (53.8)
Results of phase II and phase III trials with new aromatase inhibitors of greater than 5% and 10% of patients had weight gain of 10% or more. Patients who received megestrol acetate continued to gain weight over time. The main side-effects observed with anastrozole were gastrointestinal disturbance, hot flushes and nausea, the incidence of gastrointestinal disturbances being significantly higher with anastrozole 10 mg as compared to megestrol acetate. Withdrawal rate caused by adverse events was 3% for both doses of anastrozole and 4% for megestrol acetate. Based on the findings of this study, a product licence has now been granted for anastrozole 1 mg daily, and the product is now available in the UK and the USA as a treatment for advanced breast cancer in postmenopausal women failing on tamoxifen treatment.
Fadrozole (CGS 16949 A) (ArensinTM) Although fadrozole has been in clinical development since the late 1980s to date the results of only one phase III comparative trial have been published, these being the results of a comparative study versus tamoxifen.40 In this study fadrozole 1 mg b.i.d (n = 86) was compared with tamoxifen 20 mg once daily (n = 90) as first-line treatment for advanced breast cancer in postmenopausal women. Upon disease progression there was an option of cross-over to the alternate treatment. Sixty per cent of patients had ER + tumours and 30% had received prior adjuvant treatment. The two groups were comparable with the exception of a statistically significant imbalance of dominant metastatic site, where 53 fadrozole patients had visceral metastases compared to 35 tamoxifen treated patients (P = 0.001). Sixteen per cent (4 CR, 10 PR) of fadrozole treated patients showed an objective response compared with 24% (6 CR, 16 PR) of tamoxifen-treated patients, with a further 56% and 53% respectively showing disease stabilization. Median time to treatment failure was 4.9 months for fadrozole and 8.3 months for tamoxifen. Multivariate analysis showed no significant differences between efficacy endpoints although the authors concluded there was a trend for higher efficacy with tamoxifen. See Table 2 for details of response data. When tolerability was considered the most common side-effects observed with fadrozole were hot flushes (18 patients), and nausea and vomiting (6 patients). Whilst no significant differences in toxicity was observed, there was a trend for increased toxicity with tamoxifen.
DISCUSSION The new generation aromatase inhibitors represent convenient and well-tolerated treatments for advanced breast cancer in postmenopausal women. With the exception of fadrozole which is given twice daily and interferes with
Table 2 Objective tumour response and tamoxifen 20 mg groups Objective
Complete
response
response
in patients
Number
in the fadrozole
of patients
(%)
213 2 mg
P-value
Fadrozole (n = 86)
Tamoxifen (n = 90)
4
(4.7)
6
(6.7)
10 48 24 29
(11.6) (55.8) (28.0) (33.7) 4.9
16 48 20 22
(17.8) (53.3) (22.2) (24.4)
0.19 Partial reponse No change Disease progression Early failure (2 12 weeks) Median TTF (months)
8.3
0.20 0.10
adrenal steroidogenesis, each of anastrozole, letrozole and vorozole are given once daily by oral administration and appear to be highly selective for the aromatase enzyme. Compared to formestane and aminoglutethimide, the new generation aromatase inhibitors are much more potent, having far greater effect upon the suppression of plasma oestrogens, this being reflected in the dose levels required to achieve maximal aromatase inhibition and oestrogen suppression. The phase II clinical studies demonstrate the clinical activity of the new treatments in patients failing on previous treatments (mainly tamoxifen) for either early or advanced breast cancer’5,‘9and also in patients who have been heavily pre-treated. 23~24 In phase ii studies objective response rates varied considerably, as did indicators of durability of response (i.e. median duration of response, time to treatment failure, time to progression, median survival times, etc.). Furthermore, the majority of studies were not randomized or comparative without patient stratification, and used different endpoints for response assessment. Thus, it is not possible to draw conclusions regarding the relative merits of individual treatments on the basis of these data. Nevertheless it can be concluded that the new generation aromatase inhibitors are effective in the advanced disease setting and additionally are very well tolerated, the main side-effects being those related to oestrogen withdrawal. The most valuable information on the effectiveness of the new generation aromatase inhibitors was the data generated from the phase III comparative studies involving anastrozole and fadrozole. Anastrozole was compared with megestrol acetate in two independent studies involving large numbers of patients. Megestrol acetate is currently the treatment of choice in postmenopausal women relapsing on previous tamoxifen treatment in most countries. In this well-balanced study, anastrozole was shown to be as effective as megestrol acetate with respect to time to treatment progression and objective response rates and disease stabilization, over onethird of patients in each group deriving clinical benefit from treatment (CR + PR + SD). The primary endpoint assessed in the anastrozole study
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The Breast
was time to progression (TTP); the TIP observed across all three treatment groups in this study was approximately 5 months, this comparing with other studies where TTP or TTF of 2-3.8 months with megestrol acetate,41A3 and of 2.2-4.3 months with aminoglutethimide44-46 have been reported. The results for ‘ITP indicated that all treatment groups were effective, showing activity consistent with that reported for megestrol acetate and aminoglutethimide. As TTP is an objective and reliable indicator of clinical activity, it is this endpoint which should be emphasized in future randomized studies involving endocrine treatments, including the new generation aromatase inhibitors. Both treatments were well tolerated, however, more patients on megestrol acetate had oedema, dyspnoea and weight gain. This represents an important benefit of anastrozole treatment compared to megestrol acetate, and is a feature which may be expected with the other new generation aromatase inhibitors. Whilst the anastrozole study investigated the efficacy of the new aromatase inhibitors in patients failing on tamoxifen treatment, the fadrozole study was a direct comparison with tamoxifen as the first treatment for advanced disease in postmenopausal women. In this single study there were no statistically significant differences between the two treatments with respect to TTF or objective response, although there was a trend to increased TTF with tamoxifen (fadrozole TTF being 4.9 months compared to 8.3 months with tamoxifen). It is possible that this difference was due to the significant difference in visceral lesions that was seen between the two groups, and emphasizes the importance of balanced patient stratification in randomized comparative studies. As with the anastrozole study, however, fadrozole was well tolerated, emphasizing the low toxicity profile of the new generation aromatase inhibitors. From this review, it can be seen that the new generation aromatase inhibitors are very well tolerated and are as effective (based on the anastrozole data) as the current secondline treatment megestrol acetate; the superior tolerability, particularly with respect to weight gain offers a valuable treatment alternative. The good tolerability offers the possibility of extending the use of such agents into the adjuvant setting.
Acknowledgement The European School of Oncology grant from Zeneca Pharmaceuticals
gratefully acknowledges an educational which made the meeting possible.
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2 Muss H B. Endocrine therapy for advanced breast cancer: a review. Breast Cancer Res Treat 1992; 21: 15-26. 3. Bolufer P, Ricart E, Lluch A et al. Aromatase activity and oestradiol in human breast cancer: its relationship to oestradiol and epidermal growth factor. J Clin Oncol 1992; 10: 4384t6. 4. Santen R J. Clinical use of aromatase inhibitors in human breast carcinoma. J Steroid Biochem Mol Biol 1991; 40: 247-253. 5 Gale K E, Andersen J W, Tormey D C et al. Hormonal treatments for me&static breast cancer. An Eastern Cooperative Oncology Group phase III trial comparing aminoglutethimide to tamoxifen. Cancer 1994; 73: 354-361. 6. Congdon J, Green S, O’Sullivan J et al. Megestrol acetate (MA) and aminoglutethimidelhydrocortisone (Ag/HC) in sequence or combination as second-line therapy of oestrogen receptor positive metastatic breast cancer. Proc ASCO 1991; 10: 93 abstr 45. 7. Canney P A, Priestman T J, Griff~ths T, Latief T N, Mould J J, Spooner D. Randomised trial comparing aminogluthethimide with high-dose medroxyprogesterone acetate in therapy for advanced breast carcinoma. Articles 1988; 80: 1147-1151. 8. Garcia Giralt E, Ayme Y, Canon M et al. Second and third line hormonotherapy in advanced post-menopausal breast cancer: a multicenter random&d trial comparing medroxyprogesterone acetate with aminoglutethimide in patients who have become resistant to tamoxifen. Breast Cancer Res Treat 1992; 24: 139-145. 9. Johannessen D C, Lonning P E. Aromatase inhibitors in malignant disease and ageing. Drugs and Ageing 1992; 2: 530-545. 10. Hoffken K. Experience with aromatase inhibitors in the treatment of advanced breast cancer. Cancer Treat Rev 1993; 19: 374. 11. Jones A, Dowsett M, Lonning P E et al. In vivo assessment of the nonsteroidal aroma&e inhibitor CGS 16949A in postmenopausal women with breast cancer. Br J Cancer 1990; 62 (suppl XII), 19, abstr 067. 12. Santen R J, Demers L M, Lynch J et al. Specificity of low dose fadrozole hydrochloride (CGS 16949A) as an aromatase inhibitor. J Clin Endocrinol Metab 1991; 73: 99-106. 13. Dowsett M, Smithers D, Moore J et at. Endocrine changes with the aromatase inhibitor fadrozole hydrochloride in breast cancer. Eur J Cancer 1994; 3OA: 1453-1458. 14. Demers L M, Lipton A, Harvey H A, Hanagan H, Mulagha M, Santen R J. The effects of long term fadrozole hydrochloride treatment in patients with advanced stage breast cancer. J Steroid Biochem Mol Biol 1993; 44: 683685. 15. Hoffken K, Chacon R, Dombemowsky P et al. Fadrozole hydrochloride (CGS 16949A), a double blind dose-finding study in postmenopausal patients with advanced breast cancer. Ann Gncol 1992; 3 (suppl 5). 76, abstr 294. 16. Falkson G, Raats J I, Falkson H C. Fadrozole hydrochloride, a new nontoxic aromatase inhibitor for the treatment of patients with metastatic breast cancer. J Steroid Biochem Mol Biol 1992; 43: 161-165. 17. Tominaga T, Ohashi Y, Nomura R et al. Efficacy of fadrozole, CGS 16949A (a novel aromatase inhibitor) and prognostic significance of ‘long NC’ in patients with advanced breast cancer. Proc ASCO 1994; 80, abstr 124. 18. Dowsett M, Jones A, Johnston S R D, Jacobs S, Trunet P, Smith I E. In vivo measurement of aromatase inhibition by letrozole (CGS 20267) in postmenopausal patients with breast cancer. Clin Cancer Res 1995; 1: 1511-1515. 19. Iveson T J, Smith I E, Ahem J, Smithers D A, Tnmet P E, Dowsett M. Phase I study of the oral nonsteroidal aromatase inhibitor CGS 20267 in postmenopausal patients with advanced breast cancer. Cancer Res 1993; 53: 266-270. 20. Bhatnagar A S, Hausler A, Schieweck K, Lang M, Bowman R. Highly selective inhibition~of estrogen biosynthesis by CGS 20267, a new non-steroidal aromatase inhibitor. J Steroid Biochem Mol Biol 1990; 37: 1021-1027. 21. Demers L M, Lipton A, Harvey H A et al. The efficacy of CGS 20267 in suppressing estrogen biosynthesis in patients with advanced breast cancer. J Steroid Biochem Mol Biol 1993; 44: 687-691. 22. Tominaga T, Ohashi Y, Abe R et al. Phase II trial of letrozole (a
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