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Aromatase inhibition in the treatment of advanced breast cancer: is there a relationship between potency and clinical efficacy?

Aromatase inhibition in the treatment of advanced breast cancer: is there a relationship between... British Journal of Cancer (2004) 90, 1733 – 1739 & 2004 Cancer Research UK All rights reserved 0007 – 0920/04 $25.00 www.bjcancer.com Aromatase inhibition in the treatment of advanced breast cancer: is there a relationship between potency and clinical efficacy? ,1 R Sainsbury Department of Surgery, Royal Free and University College Medical School, Charles Bell House, 67 – 73 Riding House Street, London W1W 7EJ, UK Two-thirds of breast tumours are oestrogen-receptor positive and 60–70% of these tumours respond to interventions that reduce the effects of oestrogen. Until recently, tamoxifen was the drug of choice for the treatment of hormone-responsive early and advanced breast cancer. However, tamoxifen is associated with increased incidences of endometrial cancer and thromboembolic disease, and many tumours eventually become resistant to treatment with tamoxifen. Thus, there is a need for alternative therapies with different mechanisms of action. In postmenopausal women, aromatase inhibitors (AIs) suppress oestrogen levels by inhibiting oestrogen synthesis via the aromatase enzyme pathway. The third-generation AIs (anastrozole, letrozole and exemestane) are more potent than the earlier AIs (aminoglutethimide, formestane and fadrozole) with respect to both aromatase inhibition and oestrogen suppression. While the earlier AIs were unable to show any benefit over megestrol acetate or tamoxifen as second- and first-line therapy, respectively, in postmenopausal women with advanced breast cancer, third-generation AIs have shown significant benefits in both settings. Comparison of aromatase inhibition and oestrogen suppression between the third-generation AIs anastrozole and letrozole showed a small but significantly greater difference in the degree of suppression of oestrone and oestrone sulphate (but not oestradiol), with letrozole. In an open-label trial, there were no significant differences between letrozole and anastrozole for the clinical end points of time to progression (primary end point), time to treatment failure, overall survival, clinical benefit, duration of clinical benefit, time to response, duration of response or objective response rate in patients with confirmed hormone receptor- positive tumours. Together these data suggest that once a certain threshold of aromatase inhibition is reached, small differences in oestrogen suppression between the third-generation AIs do not lead to clinically significant differences in overall efficacy. British Journal of Cancer (2004) 90, 1733–1739. doi:10.1038/sj.bjc.6601731 www.bjcancer.com Published online 13 April 2004 & 2004 Cancer Research UK Keywords: anastrozole; aromatase inhibition; oestrogen suppression; potency; clinical efficacy Breast cancer is regarded world wide as a major cause of morbidity 1896), and many different treatment approaches are now available. and mortality in both pre- and postmenopausal women, and Although significant progress has been made over the past three currently comprises 18% of all female cancers (McPherson et al, decades in terms of both improved efficacy and tolerability of 2000). In the UK, breast cancer accounts for more than 14 000 endocrine treatments for breast cancer, many challenges still lie deaths each year (McPherson et al, 2000), while in Europe in 1995 ahead for both surgeons and oncologists in the treatment and it was responsible for the deaths of 124 000 women (Bray et al, management of all stages of the disease. 2002). However, between 1988 and 1998 mortality from the disease Until recently, and for more than 30 years, tamoxifen – a fell dramatically among women below the age of 70 years in selective oestrogen receptor modulator (SERM) – had been the Western (but not Eastern) Europe (Levi et al, 2001). Possible drug of choice for the treatment of hormone-responsive early and reasons for this improved mortality rate include the introduction advanced breast cancer. However, although tamoxifen is an of national breast screening programmes and new better treatment effective treatment, it has partial agonist activity. This is associated regimens (Blanks et al, 2000; Levi et al, 2001). with an increase in the incidence of endometrial cancer (Fisher It is recognised that two-thirds of breast tumours are oestrogen- et al, 1996) and of thromboembolic disease (Jaiyesimi et al, 1995; receptor positive and women who have hormone receptor-positive Fisher et al, 1996), and limits its use. In addition, most tumours tumours are suitable candidates for endocrine therapy (Forbes, eventually become resistant to tamoxifen and alternative treat- 1997). The use of endocrine therapy for the management of the ments are required. In recent years, a number of different classes disease has grown dramatically since the first pioneering report by of endocrine therapy have emerged as suitable alternatives in the Beatson in 1896 of a successful outcome in a premenopausal treatment of advanced breast disease. Although several new SERMs woman with breast cancer following ovarian ablation (Beatson, have been developed (e.g. raloxifene), they have not been shown to produce any clinically relevant effects in the treatment of tamoxifen-resistant tumours (Johnston, 2001). Thus, there is a *Correspondence: Mr R Sainsbury; E-mail: [email protected] need for new therapies with improved tolerability profiles that are Received 23 May 2003; revised 10 December 2003; accepted 15 January not cross-resistant with established endocrine therapies such as 2004; published online 13 April 2004 tamoxifen. The availability of endocrine agents with different Clinical Clinical Potency vs clinical efficacy of aromatase inhibitors R Sainsbury mechanisms of action to tamoxifen, such as the aromatase WHOLE-BODY OESTROGEN SUPPRESSION AND inhibitors (AIs), is an important step forward in the search to AROMATASE INHIBITION provide more efficacious and better-tolerated therapies. Comparison of first- and second- vs third-generation The AIs have been developed for the treatment of women with aromatase inhibitors: oestrogen suppression and breast cancer in whom ovarian function has ceased either due to aromatase inhibition the menopause or as a result of ovarian ablation, through oophorectomy or by ovarian irradiation. They prevent the Indirect comparisons of oestrogen suppression by the first- and formation of oestrogen from androgens in postmenopausal women second-generation AIs aminoglutethimide, formestane and fadro- through inhibition of the cytochrome P450 enzyme, aromatase, zole and the third-generation AIs anastrozole and exemestane that which catalyses the conversion of androgens to oestrogens in the were conducted in the same laboratory, have shown that third- fat, liver and muscle cells (Dowsett et al, 1995; Geisler et al, 1996) generation AIs are more potent than the earlier AIs (Figure 2). and breast tumour tissue itself (Bhatnagar et al, 2001; Geisler et al, These studies demonstrated that aminoglutethimide (1000 mg once 2001). In premenopausal women, the ovaries are the primary site daily (o.d.)) suppressed oestradiol levels by 75% (MacNeill et al, of oestrogen production and AIs are not able to completely block 1992), while formestane (250 mg o.d.) and fadrozole (1 mg twice ovarian oestrogen synthesis. daily) suppressed oestradiol by approximately 59% (Dowsett et al, Aminoglutethimide was the first AI to become available in the 1990; Lnning et al, 1991; Jones et al, 1992). Anastrozole (1 mg late 1970s (Wells et al, 1978) and the first to show efficacy as o.d.) and exemestane (10 mg o.d.) showed similar activities to each second-line therapy after tamoxifen in postmenopausal women other (84 vs 85%, respectively) and were more potent than with advanced hormone-responsive breast cancer. However, its aminoglutethimide, formestane and fadrozole (Geisler et al, 1996; toxicity and lack of selectivity for the aromatase enzyme, Johannessen et al, 1997). Similar differences between the agents necessitating concomitant corticosteroid supplementation (Wells were observed with respect to aromatase inhibition (Figure 2). An et al, 1978), prevented it from becoming a more widely used unrelated study comparing anastrozole (1 mg o.d.) with letrozole treatment. Formestane, a steroidal AI, became available in 1993. It (2.5 mg o.d.) (Geisler et al, 2002) showed that anastrozole was as was also effective for treatment of postmenopausal women with potent as letrozole in terms of oestradiol suppression (84.9 vs advanced breast cancer, but more selective than aminoglutethi- 87.8%, respectively, P¼ 0.1088), although the difference in mide, and therefore associated with fewer side effects. However, as aromatase inhibition between anastrozole and letrozole was a result of extensive first-pass metabolism, formestane cannot be significant (97.3 vs 499.1%, respectively, P¼ 0.0022) (Figure 2) given orally and has to be administered twice-monthly by (Geisler et al, 2002). intramuscular injection, leading to reports of local reactions in up to 17% of patients (Goss et al, 1986). Direct comparison of third-generation aromatase The newer third-generation AIs, which include the nonsteroidal inhibitors, anastrozole and letrozole: oestrogen agents, anastrozole, letrozole and fadrozole (Japan only) and the suppression steroidal compound, exemestane (Figure 1), are the most recent AIs to become available for use in postmenopausal women with The study in which anastrozole was directly compared with metastatic hormone-responsive breast tumours. These AIs show letrozole (Geisler et al, 2002) was a small-scale, randomised, increased potency with respect to both aromatase inhibition and double-blind, cross-over trial. In all, 12 postmenopausal women oestrogen suppression compared with the earlier AIs. Small but with oestrogen receptor-positive metastatic tumours suitable for statistically significant differences in potency have also been treatment with AIs were enroled into the study. Six patients reported between third-generation AIs (Geisler et al, 2002). received 6 weeks of anastrozole (1 mg o.d.) followed by 6 weeks of An important question is whether or not these differences in letrozole (2.5 mg o.d.), while the other six received 6 weeks of potency between the third-generation AIs lead to clinically relevant letrozole followed by 6 weeks of anastrozole. Compared with differences in efficacy and tolerability. This paper reviews current anastrozole, letrozole showed small but significantly increased published data on potency and clinical efficacy to determine if any suppression of oestrone and oestradiol sulphate concentrations such relationship exists. (Figure 3), but as discussed above, there was no difference in suppression of oestradiol (Geisler et al, 2002). N N N N CLINICAL EFFICACY Comparison of the third-generation aromatase inhibitors H C CH 3 with megestrol acetate and aminoglutethimide as second- line therapy for advanced breast cancer H C CH CN CN CN CN Several Phase III studies have compared the efficacy of the third- Anastrozole Letrozole generation AIs in postmenopausal women with advanced breast cancer who have progressed on tamoxifen, vs the previous standard treatments in this setting, megestrol acetate or amino- CH N glutethimide (Table 1). The efficacy of anastrozole (1 mg or 10 mg od) compared with CH N megestrol acetate [40 mg four times daily (qd)] has been assessed in two trials, one European (Jonat et al, 1996) and one North American (Buzdar et al, 1997), prospectively planned for combined analysis (Buzdar et al, 1996a). The results summarized in Table 1 are of the combined analysis. CH 2 After a median follow-up of 6 months, time to progression CN (TTP) and objective response (OR¼ completeþ partial response) Exemestane Fadrozole rate did not differ significantly for the 1 and 10 mg anastrozole Figure 1 Structures of anastrozole, letrozole, exemestane and fadrozole. groups compared with the megestrol acetate group (Table 1). The British Journal of Cancer (2004) 90(9), 1733 – 1739 & 2004 Cancer Research UK Potency vs clinical efficacy of aromatase inhibitors R Sainsbury Oestradiol suppression Aromatase inhibition >99.1* 97.9 97.3 96.7 90.5 87.9 85.4 90 84.8 84.9 84.0 82.4 75.7 58.8 58.9 Aminoglutethimide Formestane Fadrozole Anastrozole Exemestane** Anastrozole† Letrozole† (MacNeill et al, 1992) (Jones et al, 1992) (Dowsett et al, 1990. (Geisler et al, 1996) (Johannessen et al, (Geisler et al, 2002) (Geisler et al, 2002) 1996) Lønning et al, 1991) *P = 0.0022 for anastrozole vs letrozole. **Exemestane oestradiol suppression data is for 10 mg o.d. †Data for both drugs obtained from the same study Figure 2 Indirect comparison of oestradiol suppression and aromatase inhibition by first- and second- vs third-generation aromatase inhibitors (Dowsett et al, 1990; Lnning et al, 1991; Jones et al, 1992; MacNeill et al, 1992; Geisler et al, 1996; Johannessen et al, 1997; Geisler et al, 2002). *P¼ 0.0022 for anastrozole vs letrozole. **Exemestane oestradiol suppression data is for 10 mg o.d. Data for both drugs obtained from the same study. advantage for the higher dose of anastrozole, the data are consistent with, and supportive, of the findings observed with the clinically approved 1 mg dose. Oestradiol Oestrone Oestrone sulphate Two trials have investigated the efficacy of letrozole (2.5 or 78.1 18 17.2 80 425 422.8 0.5 mg o.d.) vs megestrol acetate 40 mg q.d. (Dombernowsky et al, 1998; Chaudri and Trunet, 1999; Buzdar et al, 2001) (Table 1). Results of the European trial (Dombernowsky et al, 1998) showed NS P = 0.019 P = 0.0037 the OR rate was significantly higher for patients receiving letrozole 2.5 mg than for letrozole 0.5 mg (P¼ 0.004) or megestrol acetate (P¼ 0.04) (24, 13 and 16%, respectively). Letrozole 2.5 mg was superior to letrozole 0.5 mg for TTP (P¼ 0.02), but not compared 27.6 14.8 2.6 12.3 2.1 with megestrol acetate. At a 51-month follow-up analysis for the 8.9 letrozole 2.5 mg arm (Chaudri and Trunet, 1999), letrozole did not 0 0 0 show significant survival benefit over megestrol acetate (Table 1). In the US trial (Buzdar et al, 2001), no significant differences were Pretreatment Anastrozole Letrozole reported for TTP (Table 1) or OR rate and, contrary to the first Assay detection limit trial, the efficacy of letrozole was not dose related. No significant survival benefit was seen for letrozole vs megestrol acetate Geisler et al, 2002 (Table 1). It has been speculated that these contradictory findings may be the result of an imbalance of prognostic factors in favour of Figure 3 Plasma oestrogen levels in postmenopausal women with megestrol acetate in the latter trial (Wischnewsky et al, 2002). advanced breast cancer (Geisler et al, 2002). In a further open-label trial, letrozole (2.5 and 0.5 mg o.d.) was compared with aminoglutethimide (250 mg, twice daily) (Gersha- novich et al, 1998) (Table 1). The higher dose of letrozole (2.5 mg overall median TTP was approximately 21 weeks and approxi- daily) was superior to aminoglutethimide for overall survival mately one-third of patients in each treatment group benefited (P¼ 0.002), TTP (Cox regression analysis, P¼ 0.008) and TTF (Cox from therapy (Buzdar et al, 1996a). After 31 months of follow-up regression analysis, P¼ 0.003). There were no significant differ- (Buzdar et al, 1998), anastrozole (1 mg) demonstrated a significant ences in OR seen in patients receiving letrozole 2.5 mg, letrozole survival advantage over megestrol acetate (Table 1). There was no 0.5 mg or aminoglutethimide. Letrozole 2.5 mg showed a signifi- significant difference for overall survival between anastrozole cant advantage over the letrozole 0.5 mg dose for survival 10 mg and megestrol acetate, although numerical advantages have (P¼ 0.04), but there was not a significant dose–response effect been shown in favour of anastrozole 10 mg, with longer median for letrozole in terms of TTP, in line with the results from the US time to death (25.5 vs 22.5 months for anastrozole 10 mg and trial of letrozole vs megestrol acetate (Buzdar et al, 2001). In megestrol acetate, respectively; P¼ 0.09) and lower death rate at 2 addition, a trial that assessed the impact of letrozole 2.5 and 0.5 mg years (45.4 vs 53.7%, respectively). Therefore, while there was no o.d. on peripheral aromatisation of androstenedione to oestrone & 2004 Cancer Research UK British Journal of Cancer (2004) 90(9), 1733 – 1739 −1 Plasma concentration (pmol l ) Inhibition (%) Clinical Clinical Potency vs clinical efficacy of aromatase inhibitors R Sainsbury Table 1 Overview of efficacy results from Phase III trials of second-line treatment of advanced breast cancer. Aromatase inhibitors vs megestrol acetate and aminoglutethimide in patients who have failed on tamoxifen (Buzdar et al, 1996a, b; 1998; Dombernowsky et al, 1998; Gershanovich et al, 1998; Chaudri and Trunet, 1999; Kaufmann et al, 2000; Buzdar et al, 2001) European & US combined analysis European trial US trial International trial International trial A MA L MA L MA L AG E MA Dose 1 mg o.d. 40 mg q.d. 0.5 mg o.d. 2.5 mg o.d. 40 mg q.d. 0.5 mg o.d. 2.5 mg o.d. 40 mg q.d. 0.5 mg o.d. 2.5 mg o.d. 250 mg b.d. 2.5 mg o.d. 40 mg (n¼ 263) (n¼ 253) (n¼ 188) (n¼ 174) (n¼ 189) (n¼ 202) (n¼ 199) (n¼ 201) (n¼ 192) (n¼ 185) (n¼ 178) (n¼ 366) q.d. (n¼ 403) Median 31 33 37 20 11 follow-up (months) Median TTP 4.8 4.6 5.1 5.6 5.5 6.0 3.0 6.0 3.3 3.4 3.2 4.7 3.8 (months) ns ns 0.5 mg vs MA, P¼ 0.044 2.5 mg vs AG, P¼ 0.008 P¼ 0.037 a a a Median 26.7 22.5 21.5 25.3 21.5 33 29 26 21 28 20 NR 28.4 survival (months) Po0.025 ns ns 2.5 mg vs AG, P¼ 0.002 P¼ 0.039 Survival data from an extended 51-month follow-up analysis. A¼ anastrozole; MA¼ megestrol acetate; L¼ letrozole; AG¼ aminoglutethimide; E¼ exemestane; o.d.¼ once daily; q.d.¼ four times daily; b.d.¼ twice daily; TTP¼ time to disease progression; NR¼ not reached; ns¼ nonsignificant. Table 2 Nonsteroidal aromatase inhibitors vs tamoxifen as first-line treatment TARGET study (Bonneterre N American study Combined study Letrozole study (Mouridsen et al, 2000) (Nabholtz et al, 2000) (Bonneterre et al, 2000) et al, 2001) A T ATAT L T n¼ 340 n¼ 328 n¼ 171 n¼ 182 n¼ 511 n¼ 510 n¼ 453 n¼ 454 TTP overall population 8.2 8.3 11.1 5.6 8.5 7.0 9.4 6.0 (months) NS P¼ 0.005 NS P¼ 0.0001 TTP HR+ve subgroup 8.9 7.8 NA 10.7 6.4 9.2 5.8 (months) NA P¼ 0.022 P¼ 0.0001 CB (%) 56.2 55.5 59.1 45.6 57.1 52.0 49.0 38.0 NA P¼ 0.0098 P¼ 0.1129 P¼ 0.001 OR (%) 32.9 32.9 21.0 17.0 29.0 27.1 30.0 20.0 NS NA NS P¼ 0.0006 HR+ve (%) 45 89 60 66 A¼ anastrozole; T¼ tamoxifen; L¼ letrozole; TTP¼ time to disease progression; NA¼ not available; HR+ve¼ hormone receptor-positive; CB¼ clinical benefit; OR¼ objective response; NS¼ not significant. has shown no differences between doses in inhibition of Overall, although there have been some differences in outcome aromatisation (Dowsett et al, 1995). All patients on the lower and the end points at which significant benefits have been dose showed 497% inhibition and on the higher dose showed observed, the newer-generation AIs have all proven more effective 498% inhibition. There was no evidence of any difference and better tolerated than the progestogen megestrol acetate, and between letrozole 2.5 and 0.5 mg in suppression of oestrone (80.8 letrozole has demonstrated superior efficacy to aminoglutethimide, and 82.0%, respectively) and oestradiol (68.1 and 84.1%, for the second-line treatment of patients with advanced breast respectively), but no formal statistical analysis was performed. cancer failing on tamoxifen. As a result, third-generation AIs are These results draw into question the dose–response effect seen for now established as the standard treatment in this patient letrozole in the European trial of letrozole vs megestrol acetate population. In contrast, the second-generation AIs formestane (Dombernowsky et al, 1998; Chaudri and Trunet, 1999). and fadrozole have shown no significant efficacy benefits over A large, randomised, double-blind trial has compared exemes- megestrol acetate in patients progressing on tamoxifen (Buzdar tane (25 mg o.d.) with megestrol acetate (40 mg q.d.) (Kaufmann et al, 1996b; Thu¨rlimann et al, 1997). et al, 2000). There was significant improvement in TTP for exemestane compared with megestrol acetate (Table 1), while OR Comparison of the third-generation aromatase inhibitors rate was not significantly different between groups. Exemestane with tamoxifen as first-line therapy for advanced breast also showed significant improvement in overall survival compared cancer with megestrol acetate (Table 1), although this was after a shorter median follow-up (11.4 months) compared with the anastrozole Results of the Phase III studies assessing the efficacy of the third- and letrozole studies. generation AIs vs tamoxifen as first-line therapy in postmenopau- British Journal of Cancer (2004) 90(9), 1733 – 1739 & 2004 Cancer Research UK Potency vs clinical efficacy of aromatase inhibitors R Sainsbury sal women with advanced breast cancer are summarised in Table 2. Table 3 Efficacy data in patients randomised to anastrozole or letrozole These data indicate the superiority of the third-generation (Rose et al, 2002) nonsteroidal AIs compared with tamoxifen in this patient ITT population population. The efficacy of anastrozole vs tamoxifen was assessed in two Anastrozole Letrozole Phase III trials, one European (the Tamoxifen and Arimidex (n¼ 357) (n¼ 356) P-value Randomized Group Efficacy and Tolerability (TARGET) trial) (Bonneterre et al, 2000) and one North American (Nabholtz et al, a Median TTP (months) 5.7 5.7 0.920 2000), which were identical in design and prospectively planned Median TTF (months) 5.6 5.6 0.761 for combined analysis. Anastrozole was shown to be at least as Median OS (months) 20.3 22.0 0.624 effective as tamoxifen as first-line treatment of postmenopausal Objective response (%) women with advanced breast cancer, although some variation in Total population 12.3 19.1 0.014 data was observed between the two individual Phase III trials HR+ve subgroup 16.8 17.3 NA (depending upon the proportion of patients whose tumours were Unknown receptor 8.4 20.8 NA hormone receptor-positive). In the North American trial, TTP and status subgroup clinical benefit (CB) rates were significantly better for anastrozole compared with tamoxifen (Table 2). In the TARGET trial, TTP: primary end point; ITT¼ intention to treat; TTP¼ time to disease progression; anastrozole was shown to be equivalent to tamoxifen in terms of TTF¼ time to treatment failure; OS¼ overall survival. TTP and OR rates (Table 2). The difference in outcome was attributed to differences in the proportion of patients with confirmed hormone receptor-positive tumours (89 vs 45% for the North American and TARGET trials, respectively). Analysis of population and the unknown receptor status subgroup, which were the subgroup that comprised only patients with hormone receptor- higher in the letrozole vs the anastrozole group (overall popula- positive tumours (45%) in the TARGET trial showed a similar tion: 19.1 vs 12.3%, odds ratio¼ 1.70, P¼ 0.014; unknown receptor separation of the Kaplan–Meier curves to that seen in the overall status subgroup: 20.8 vs 8.4%, respectively) (Rose et al, 2002). population in the North American trial (in which 89% of patients However, in patients with confirmed hormone receptor-positive had hormone receptor-positive tumours). The combined analysis tumours there was no difference in OR between anastrozole and of the two trials also showed anastrozole to be superior to letrozole (28/167 [16.8%] vs 30/173 [17.3%], respectively). As the tamoxifen for TTP in patients with hormone-sensitive advanced overall population included patients with unknown receptor breast cancer (Table 2) (Bonneterre et al, 2001). status, it is possible that in this unknown receptor group there In a single Phase III study in postmenopausal women with was a greater number of patients randomised to letrozole who had advanced breast cancer, letrozole was also found to be superior to hormone receptor-positive tumours and who would respond to tamoxifen for several efficacy end points (Mouridsen et al, 2001). letrozole. If this was the case, it could account for the higher OR Time to progression, CB and OR rates were significantly better for rate with letrozole in the overall population. Presently, the number letrozole (Table 2). In addition, TTF was significantly longer for of patients with unknown receptor status in each group has not letrozole compared with tamoxifen (median TTF: 9.2 vs 5.7 been published. Furthermore, no results for TTP in the hormone months, respectively, P¼ 0.0001). receptor-positive population have been published to date, so the Although no data from Phase III trials of exemestane are relative efficacy of anastrozole and letrozole for this end point is currently available, the results of a Phase II trial of exemestane uncertain. (25 mg o.d., n¼ 31) vs tamoxifen (20 mg o.d., n¼ 32) are promising (Paridaens et al, 2000). Median TTP was 8.9 vs 5.2 months for exemestane and tamoxifen, respectively, and OR rates SUMMARY were 42 vs 16%, respectively. A Phase III trial is ongoing. In contrast to the third-generation AIs, the second-generation The AIs have been developed for treatment of breast cancer in agents fadrozole and formestane have not shown any significant postmenopausal women with hormone receptor-positive tumours efficacy benefits over tamoxifen in the advanced disease setting and it is important that they are used to treat this group of (Perez Carrion et al, 1994; Falkson and Falkson, 1996). patients. Third-generation AIs (anastrozole, letrozole and exemes- tane) show improved potency with respect to suppression of aromatase activity and circulating oestrogen levels compared with Direct comparison of the third-generation aromatase the older-generation AIs (aminoglutethimide, formestane and inhibitors: anastrozole vs letrozole as second-line therapy fadrozole) (Dowsett et al, 1990; Lnning et al, 1991; Jones et al, Anastrozole (1 mg o.d.) and letrozole (2.5 mg o.d.) were compared 1992; MacNeill et al, 1992; Geisler et al, 1996). This increased as second-line treatment for advanced breast cancer with hormone potency correlates with improved clinical efficacy of the third- receptor-positive or unknown receptor status in postmenopausal generation AIs relative to the older drugs. Thus, while formestane women who had progressed on tamoxifen in a multicentre, open- and fadrozole, which inhibit aromatase by o85%, have shown no label, randomised Phase III–IV study (Rose et al, 2002). The benefits over megestrol acetate (Buzdar et al, 1996b; Thu¨rlimann primary end point was TTP and secondary end points included OR et al, 1997) or tamoxifen (Perez Carrion et al, 1994; Falkson and rate, response duration, duration of clinical benefit, TTF, time to Falkson, 1996) as second- and first-line therapy, respectively, response and overall survival (OS). third-generation AIs, which inhibit aromatase activity by 496%, A total of 713 postmenopausal patients were randomly allocated show significant clinical efficacy benefits over these standard to either letrozole 2.5 mg o.d. (n¼ 356) or anastrozole 1 mg o.d. second- and first-line comparators (Buzdar et al, 1996a, 1998, (n¼ 357). Patient characteristics were well balanced between 2001; Dombernowsky et al, 1998; Bonneterre et al, 2000; Kaufmann treatment groups (Rose et al, 2002). A total of 48% of patients et al, 2000; Nabholtz et al, 2000; Bonneterre et al, 2001; Mouridsen had hormone receptor-positive tumours (Rose et al, 2002). et al, 2001). Efficacy end points are shown in Table 3. In the overall population, In contrast, direct comparison of the third-generation AIs anastrozole was similar to letrozole for TTP (P¼ 0.920), TTF anastrozole and letrozole has shown that although letrozole (P¼ 0.761) and OS (P¼ 0.624). The only differences between suppresses aromatase activity, oestrone and oestrone sulphate anastrozole and letrozole were for OR rate in both the overall levels to a greater degree than anastrozole, these differences in & 2004 Cancer Research UK British Journal of Cancer (2004) 90(9), 1733 – 1739 Clinical Clinical Potency vs clinical efficacy of aromatase inhibitors R Sainsbury potency do not translate to clinically significant differences in the become apparent during longer-term treatment as these drugs efficacy of these agents for the second-line treatment of hormone- move into the adjuvant setting. sensitive advanced breast cancer (Rose et al, 2002). The fact that these marginal differences in potency between CONCLUSION anastrozole and letrozole do not appear to produce clinically relevant differences in efficacy suggests that there may be a The third-generation AIs are more potent inhibitors of the threshold effect for aromatase inhibition/oestrogen suppression aromatase enzyme and cause greater oestrogen suppression than beyond which no further improvements in clinical efficacy can be older agents such as aminoglutethimide, fadrozole and formestane. gained. Since the potency of formestane, aminoglutethimide and This is linked to an increase in the clinical efficacy of the third- fadrozole fall below this threshold, the third-generation AIs show generation AIs relative to the previous standard comparators in clinical efficacy benefits relative to these older agents. Of note, both the second- and first-line settings. 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J Clin Oncol 19: 2596 –2606 contradictory, clinical trials of letrozole versus megestrol acetate, for the Nabholtz JM, Buzdar A, Pollak M, Harwin W, Burton G, Mangalik A, treatment of advanced breast cancer. Breast Cancer Res Treat 76(Suppl Steinberg M, Webster A, von Euler M (2000) Anastrozole is superior to 1): S76 abstract 266 & 2004 Cancer Research UK British Journal of Cancer (2004) 90(9), 1733 – 1739 Clinical http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Cancer Springer Journals

Aromatase inhibition in the treatment of advanced breast cancer: is there a relationship between potency and clinical efficacy?

Sainsbury, R
British Journal of Cancer , Volume 90 (9) – Apr 13, 2004
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Springer Journals
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Copyright © 2004 by The Author(s)
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Biomedicine; Biomedicine, general; Cancer Research; Epidemiology; Molecular Medicine; Oncology; Drug Resistance
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0007-0920
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10.1038/sj.bjc.6601731
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Abstract

British Journal of Cancer (2004) 90, 1733 – 1739 & 2004 Cancer Research UK All rights reserved 0007 – 0920/04 $25.00 www.bjcancer.com Aromatase inhibition in the treatment of advanced breast cancer: is there a relationship between potency and clinical efficacy? ,1 R Sainsbury Department of Surgery, Royal Free and University College Medical School, Charles Bell House, 67 – 73 Riding House Street, London W1W 7EJ, UK Two-thirds of breast tumours are oestrogen-receptor positive and 60–70% of these tumours respond to interventions that reduce the effects of oestrogen. Until recently, tamoxifen was the drug of choice for the treatment of hormone-responsive early and advanced breast cancer. However, tamoxifen is associated with increased incidences of endometrial cancer and thromboembolic disease, and many tumours eventually become resistant to treatment with tamoxifen. Thus, there is a need for alternative therapies with different mechanisms of action. In postmenopausal women, aromatase inhibitors (AIs) suppress oestrogen levels by inhibiting oestrogen synthesis via the aromatase enzyme pathway. The third-generation AIs (anastrozole, letrozole and exemestane) are more potent than the earlier AIs (aminoglutethimide, formestane and fadrozole) with respect to both aromatase inhibition and oestrogen suppression. While the earlier AIs were unable to show any benefit over megestrol acetate or tamoxifen as second- and first-line therapy, respectively, in postmenopausal women with advanced breast cancer, third-generation AIs have shown significant benefits in both settings. Comparison of aromatase inhibition and oestrogen suppression between the third-generation AIs anastrozole and letrozole showed a small but significantly greater difference in the degree of suppression of oestrone and oestrone sulphate (but not oestradiol), with letrozole. In an open-label trial, there were no significant differences between letrozole and anastrozole for the clinical end points of time to progression (primary end point), time to treatment failure, overall survival, clinical benefit, duration of clinical benefit, time to response, duration of response or objective response rate in patients with confirmed hormone receptor- positive tumours. Together these data suggest that once a certain threshold of aromatase inhibition is reached, small differences in oestrogen suppression between the third-generation AIs do not lead to clinically significant differences in overall efficacy. British Journal of Cancer (2004) 90, 1733–1739. doi:10.1038/sj.bjc.6601731 www.bjcancer.com Published online 13 April 2004 & 2004 Cancer Research UK Keywords: anastrozole; aromatase inhibition; oestrogen suppression; potency; clinical efficacy Breast cancer is regarded world wide as a major cause of morbidity 1896), and many different treatment approaches are now available. and mortality in both pre- and postmenopausal women, and Although significant progress has been made over the past three currently comprises 18% of all female cancers (McPherson et al, decades in terms of both improved efficacy and tolerability of 2000). In the UK, breast cancer accounts for more than 14 000 endocrine treatments for breast cancer, many challenges still lie deaths each year (McPherson et al, 2000), while in Europe in 1995 ahead for both surgeons and oncologists in the treatment and it was responsible for the deaths of 124 000 women (Bray et al, management of all stages of the disease. 2002). However, between 1988 and 1998 mortality from the disease Until recently, and for more than 30 years, tamoxifen – a fell dramatically among women below the age of 70 years in selective oestrogen receptor modulator (SERM) – had been the Western (but not Eastern) Europe (Levi et al, 2001). Possible drug of choice for the treatment of hormone-responsive early and reasons for this improved mortality rate include the introduction advanced breast cancer. However, although tamoxifen is an of national breast screening programmes and new better treatment effective treatment, it has partial agonist activity. This is associated regimens (Blanks et al, 2000; Levi et al, 2001). with an increase in the incidence of endometrial cancer (Fisher It is recognised that two-thirds of breast tumours are oestrogen- et al, 1996) and of thromboembolic disease (Jaiyesimi et al, 1995; receptor positive and women who have hormone receptor-positive Fisher et al, 1996), and limits its use. In addition, most tumours tumours are suitable candidates for endocrine therapy (Forbes, eventually become resistant to tamoxifen and alternative treat- 1997). The use of endocrine therapy for the management of the ments are required. In recent years, a number of different classes disease has grown dramatically since the first pioneering report by of endocrine therapy have emerged as suitable alternatives in the Beatson in 1896 of a successful outcome in a premenopausal treatment of advanced breast disease. Although several new SERMs woman with breast cancer following ovarian ablation (Beatson, have been developed (e.g. raloxifene), they have not been shown to produce any clinically relevant effects in the treatment of tamoxifen-resistant tumours (Johnston, 2001). Thus, there is a *Correspondence: Mr R Sainsbury; E-mail: [email protected] need for new therapies with improved tolerability profiles that are Received 23 May 2003; revised 10 December 2003; accepted 15 January not cross-resistant with established endocrine therapies such as 2004; published online 13 April 2004 tamoxifen. The availability of endocrine agents with different Clinical Clinical Potency vs clinical efficacy of aromatase inhibitors R Sainsbury mechanisms of action to tamoxifen, such as the aromatase WHOLE-BODY OESTROGEN SUPPRESSION AND inhibitors (AIs), is an important step forward in the search to AROMATASE INHIBITION provide more efficacious and better-tolerated therapies. Comparison of first- and second- vs third-generation The AIs have been developed for the treatment of women with aromatase inhibitors: oestrogen suppression and breast cancer in whom ovarian function has ceased either due to aromatase inhibition the menopause or as a result of ovarian ablation, through oophorectomy or by ovarian irradiation. They prevent the Indirect comparisons of oestrogen suppression by the first- and formation of oestrogen from androgens in postmenopausal women second-generation AIs aminoglutethimide, formestane and fadro- through inhibition of the cytochrome P450 enzyme, aromatase, zole and the third-generation AIs anastrozole and exemestane that which catalyses the conversion of androgens to oestrogens in the were conducted in the same laboratory, have shown that third- fat, liver and muscle cells (Dowsett et al, 1995; Geisler et al, 1996) generation AIs are more potent than the earlier AIs (Figure 2). and breast tumour tissue itself (Bhatnagar et al, 2001; Geisler et al, These studies demonstrated that aminoglutethimide (1000 mg once 2001). In premenopausal women, the ovaries are the primary site daily (o.d.)) suppressed oestradiol levels by 75% (MacNeill et al, of oestrogen production and AIs are not able to completely block 1992), while formestane (250 mg o.d.) and fadrozole (1 mg twice ovarian oestrogen synthesis. daily) suppressed oestradiol by approximately 59% (Dowsett et al, Aminoglutethimide was the first AI to become available in the 1990; Lnning et al, 1991; Jones et al, 1992). Anastrozole (1 mg late 1970s (Wells et al, 1978) and the first to show efficacy as o.d.) and exemestane (10 mg o.d.) showed similar activities to each second-line therapy after tamoxifen in postmenopausal women other (84 vs 85%, respectively) and were more potent than with advanced hormone-responsive breast cancer. However, its aminoglutethimide, formestane and fadrozole (Geisler et al, 1996; toxicity and lack of selectivity for the aromatase enzyme, Johannessen et al, 1997). Similar differences between the agents necessitating concomitant corticosteroid supplementation (Wells were observed with respect to aromatase inhibition (Figure 2). An et al, 1978), prevented it from becoming a more widely used unrelated study comparing anastrozole (1 mg o.d.) with letrozole treatment. Formestane, a steroidal AI, became available in 1993. It (2.5 mg o.d.) (Geisler et al, 2002) showed that anastrozole was as was also effective for treatment of postmenopausal women with potent as letrozole in terms of oestradiol suppression (84.9 vs advanced breast cancer, but more selective than aminoglutethi- 87.8%, respectively, P¼ 0.1088), although the difference in mide, and therefore associated with fewer side effects. However, as aromatase inhibition between anastrozole and letrozole was a result of extensive first-pass metabolism, formestane cannot be significant (97.3 vs 499.1%, respectively, P¼ 0.0022) (Figure 2) given orally and has to be administered twice-monthly by (Geisler et al, 2002). intramuscular injection, leading to reports of local reactions in up to 17% of patients (Goss et al, 1986). Direct comparison of third-generation aromatase The newer third-generation AIs, which include the nonsteroidal inhibitors, anastrozole and letrozole: oestrogen agents, anastrozole, letrozole and fadrozole (Japan only) and the suppression steroidal compound, exemestane (Figure 1), are the most recent AIs to become available for use in postmenopausal women with The study in which anastrozole was directly compared with metastatic hormone-responsive breast tumours. These AIs show letrozole (Geisler et al, 2002) was a small-scale, randomised, increased potency with respect to both aromatase inhibition and double-blind, cross-over trial. In all, 12 postmenopausal women oestrogen suppression compared with the earlier AIs. Small but with oestrogen receptor-positive metastatic tumours suitable for statistically significant differences in potency have also been treatment with AIs were enroled into the study. Six patients reported between third-generation AIs (Geisler et al, 2002). received 6 weeks of anastrozole (1 mg o.d.) followed by 6 weeks of An important question is whether or not these differences in letrozole (2.5 mg o.d.), while the other six received 6 weeks of potency between the third-generation AIs lead to clinically relevant letrozole followed by 6 weeks of anastrozole. Compared with differences in efficacy and tolerability. This paper reviews current anastrozole, letrozole showed small but significantly increased published data on potency and clinical efficacy to determine if any suppression of oestrone and oestradiol sulphate concentrations such relationship exists. (Figure 3), but as discussed above, there was no difference in suppression of oestradiol (Geisler et al, 2002). N N N N CLINICAL EFFICACY Comparison of the third-generation aromatase inhibitors H C CH 3 with megestrol acetate and aminoglutethimide as second- line therapy for advanced breast cancer H C CH CN CN CN CN Several Phase III studies have compared the efficacy of the third- Anastrozole Letrozole generation AIs in postmenopausal women with advanced breast cancer who have progressed on tamoxifen, vs the previous standard treatments in this setting, megestrol acetate or amino- CH N glutethimide (Table 1). The efficacy of anastrozole (1 mg or 10 mg od) compared with CH N megestrol acetate [40 mg four times daily (qd)] has been assessed in two trials, one European (Jonat et al, 1996) and one North American (Buzdar et al, 1997), prospectively planned for combined analysis (Buzdar et al, 1996a). The results summarized in Table 1 are of the combined analysis. CH 2 After a median follow-up of 6 months, time to progression CN (TTP) and objective response (OR¼ completeþ partial response) Exemestane Fadrozole rate did not differ significantly for the 1 and 10 mg anastrozole Figure 1 Structures of anastrozole, letrozole, exemestane and fadrozole. groups compared with the megestrol acetate group (Table 1). The British Journal of Cancer (2004) 90(9), 1733 – 1739 & 2004 Cancer Research UK Potency vs clinical efficacy of aromatase inhibitors R Sainsbury Oestradiol suppression Aromatase inhibition >99.1* 97.9 97.3 96.7 90.5 87.9 85.4 90 84.8 84.9 84.0 82.4 75.7 58.8 58.9 Aminoglutethimide Formestane Fadrozole Anastrozole Exemestane** Anastrozole† Letrozole† (MacNeill et al, 1992) (Jones et al, 1992) (Dowsett et al, 1990. (Geisler et al, 1996) (Johannessen et al, (Geisler et al, 2002) (Geisler et al, 2002) 1996) Lønning et al, 1991) *P = 0.0022 for anastrozole vs letrozole. **Exemestane oestradiol suppression data is for 10 mg o.d. †Data for both drugs obtained from the same study Figure 2 Indirect comparison of oestradiol suppression and aromatase inhibition by first- and second- vs third-generation aromatase inhibitors (Dowsett et al, 1990; Lnning et al, 1991; Jones et al, 1992; MacNeill et al, 1992; Geisler et al, 1996; Johannessen et al, 1997; Geisler et al, 2002). *P¼ 0.0022 for anastrozole vs letrozole. **Exemestane oestradiol suppression data is for 10 mg o.d. Data for both drugs obtained from the same study. advantage for the higher dose of anastrozole, the data are consistent with, and supportive, of the findings observed with the clinically approved 1 mg dose. Oestradiol Oestrone Oestrone sulphate Two trials have investigated the efficacy of letrozole (2.5 or 78.1 18 17.2 80 425 422.8 0.5 mg o.d.) vs megestrol acetate 40 mg q.d. (Dombernowsky et al, 1998; Chaudri and Trunet, 1999; Buzdar et al, 2001) (Table 1). Results of the European trial (Dombernowsky et al, 1998) showed NS P = 0.019 P = 0.0037 the OR rate was significantly higher for patients receiving letrozole 2.5 mg than for letrozole 0.5 mg (P¼ 0.004) or megestrol acetate (P¼ 0.04) (24, 13 and 16%, respectively). Letrozole 2.5 mg was superior to letrozole 0.5 mg for TTP (P¼ 0.02), but not compared 27.6 14.8 2.6 12.3 2.1 with megestrol acetate. At a 51-month follow-up analysis for the 8.9 letrozole 2.5 mg arm (Chaudri and Trunet, 1999), letrozole did not 0 0 0 show significant survival benefit over megestrol acetate (Table 1). In the US trial (Buzdar et al, 2001), no significant differences were Pretreatment Anastrozole Letrozole reported for TTP (Table 1) or OR rate and, contrary to the first Assay detection limit trial, the efficacy of letrozole was not dose related. No significant survival benefit was seen for letrozole vs megestrol acetate Geisler et al, 2002 (Table 1). It has been speculated that these contradictory findings may be the result of an imbalance of prognostic factors in favour of Figure 3 Plasma oestrogen levels in postmenopausal women with megestrol acetate in the latter trial (Wischnewsky et al, 2002). advanced breast cancer (Geisler et al, 2002). In a further open-label trial, letrozole (2.5 and 0.5 mg o.d.) was compared with aminoglutethimide (250 mg, twice daily) (Gersha- novich et al, 1998) (Table 1). The higher dose of letrozole (2.5 mg overall median TTP was approximately 21 weeks and approxi- daily) was superior to aminoglutethimide for overall survival mately one-third of patients in each treatment group benefited (P¼ 0.002), TTP (Cox regression analysis, P¼ 0.008) and TTF (Cox from therapy (Buzdar et al, 1996a). After 31 months of follow-up regression analysis, P¼ 0.003). There were no significant differ- (Buzdar et al, 1998), anastrozole (1 mg) demonstrated a significant ences in OR seen in patients receiving letrozole 2.5 mg, letrozole survival advantage over megestrol acetate (Table 1). There was no 0.5 mg or aminoglutethimide. Letrozole 2.5 mg showed a signifi- significant difference for overall survival between anastrozole cant advantage over the letrozole 0.5 mg dose for survival 10 mg and megestrol acetate, although numerical advantages have (P¼ 0.04), but there was not a significant dose–response effect been shown in favour of anastrozole 10 mg, with longer median for letrozole in terms of TTP, in line with the results from the US time to death (25.5 vs 22.5 months for anastrozole 10 mg and trial of letrozole vs megestrol acetate (Buzdar et al, 2001). In megestrol acetate, respectively; P¼ 0.09) and lower death rate at 2 addition, a trial that assessed the impact of letrozole 2.5 and 0.5 mg years (45.4 vs 53.7%, respectively). Therefore, while there was no o.d. on peripheral aromatisation of androstenedione to oestrone & 2004 Cancer Research UK British Journal of Cancer (2004) 90(9), 1733 – 1739 −1 Plasma concentration (pmol l ) Inhibition (%) Clinical Clinical Potency vs clinical efficacy of aromatase inhibitors R Sainsbury Table 1 Overview of efficacy results from Phase III trials of second-line treatment of advanced breast cancer. Aromatase inhibitors vs megestrol acetate and aminoglutethimide in patients who have failed on tamoxifen (Buzdar et al, 1996a, b; 1998; Dombernowsky et al, 1998; Gershanovich et al, 1998; Chaudri and Trunet, 1999; Kaufmann et al, 2000; Buzdar et al, 2001) European & US combined analysis European trial US trial International trial International trial A MA L MA L MA L AG E MA Dose 1 mg o.d. 40 mg q.d. 0.5 mg o.d. 2.5 mg o.d. 40 mg q.d. 0.5 mg o.d. 2.5 mg o.d. 40 mg q.d. 0.5 mg o.d. 2.5 mg o.d. 250 mg b.d. 2.5 mg o.d. 40 mg (n¼ 263) (n¼ 253) (n¼ 188) (n¼ 174) (n¼ 189) (n¼ 202) (n¼ 199) (n¼ 201) (n¼ 192) (n¼ 185) (n¼ 178) (n¼ 366) q.d. (n¼ 403) Median 31 33 37 20 11 follow-up (months) Median TTP 4.8 4.6 5.1 5.6 5.5 6.0 3.0 6.0 3.3 3.4 3.2 4.7 3.8 (months) ns ns 0.5 mg vs MA, P¼ 0.044 2.5 mg vs AG, P¼ 0.008 P¼ 0.037 a a a Median 26.7 22.5 21.5 25.3 21.5 33 29 26 21 28 20 NR 28.4 survival (months) Po0.025 ns ns 2.5 mg vs AG, P¼ 0.002 P¼ 0.039 Survival data from an extended 51-month follow-up analysis. A¼ anastrozole; MA¼ megestrol acetate; L¼ letrozole; AG¼ aminoglutethimide; E¼ exemestane; o.d.¼ once daily; q.d.¼ four times daily; b.d.¼ twice daily; TTP¼ time to disease progression; NR¼ not reached; ns¼ nonsignificant. Table 2 Nonsteroidal aromatase inhibitors vs tamoxifen as first-line treatment TARGET study (Bonneterre N American study Combined study Letrozole study (Mouridsen et al, 2000) (Nabholtz et al, 2000) (Bonneterre et al, 2000) et al, 2001) A T ATAT L T n¼ 340 n¼ 328 n¼ 171 n¼ 182 n¼ 511 n¼ 510 n¼ 453 n¼ 454 TTP overall population 8.2 8.3 11.1 5.6 8.5 7.0 9.4 6.0 (months) NS P¼ 0.005 NS P¼ 0.0001 TTP HR+ve subgroup 8.9 7.8 NA 10.7 6.4 9.2 5.8 (months) NA P¼ 0.022 P¼ 0.0001 CB (%) 56.2 55.5 59.1 45.6 57.1 52.0 49.0 38.0 NA P¼ 0.0098 P¼ 0.1129 P¼ 0.001 OR (%) 32.9 32.9 21.0 17.0 29.0 27.1 30.0 20.0 NS NA NS P¼ 0.0006 HR+ve (%) 45 89 60 66 A¼ anastrozole; T¼ tamoxifen; L¼ letrozole; TTP¼ time to disease progression; NA¼ not available; HR+ve¼ hormone receptor-positive; CB¼ clinical benefit; OR¼ objective response; NS¼ not significant. has shown no differences between doses in inhibition of Overall, although there have been some differences in outcome aromatisation (Dowsett et al, 1995). All patients on the lower and the end points at which significant benefits have been dose showed 497% inhibition and on the higher dose showed observed, the newer-generation AIs have all proven more effective 498% inhibition. There was no evidence of any difference and better tolerated than the progestogen megestrol acetate, and between letrozole 2.5 and 0.5 mg in suppression of oestrone (80.8 letrozole has demonstrated superior efficacy to aminoglutethimide, and 82.0%, respectively) and oestradiol (68.1 and 84.1%, for the second-line treatment of patients with advanced breast respectively), but no formal statistical analysis was performed. cancer failing on tamoxifen. As a result, third-generation AIs are These results draw into question the dose–response effect seen for now established as the standard treatment in this patient letrozole in the European trial of letrozole vs megestrol acetate population. In contrast, the second-generation AIs formestane (Dombernowsky et al, 1998; Chaudri and Trunet, 1999). and fadrozole have shown no significant efficacy benefits over A large, randomised, double-blind trial has compared exemes- megestrol acetate in patients progressing on tamoxifen (Buzdar tane (25 mg o.d.) with megestrol acetate (40 mg q.d.) (Kaufmann et al, 1996b; Thu¨rlimann et al, 1997). et al, 2000). There was significant improvement in TTP for exemestane compared with megestrol acetate (Table 1), while OR Comparison of the third-generation aromatase inhibitors rate was not significantly different between groups. Exemestane with tamoxifen as first-line therapy for advanced breast also showed significant improvement in overall survival compared cancer with megestrol acetate (Table 1), although this was after a shorter median follow-up (11.4 months) compared with the anastrozole Results of the Phase III studies assessing the efficacy of the third- and letrozole studies. generation AIs vs tamoxifen as first-line therapy in postmenopau- British Journal of Cancer (2004) 90(9), 1733 – 1739 & 2004 Cancer Research UK Potency vs clinical efficacy of aromatase inhibitors R Sainsbury sal women with advanced breast cancer are summarised in Table 2. Table 3 Efficacy data in patients randomised to anastrozole or letrozole These data indicate the superiority of the third-generation (Rose et al, 2002) nonsteroidal AIs compared with tamoxifen in this patient ITT population population. The efficacy of anastrozole vs tamoxifen was assessed in two Anastrozole Letrozole Phase III trials, one European (the Tamoxifen and Arimidex (n¼ 357) (n¼ 356) P-value Randomized Group Efficacy and Tolerability (TARGET) trial) (Bonneterre et al, 2000) and one North American (Nabholtz et al, a Median TTP (months) 5.7 5.7 0.920 2000), which were identical in design and prospectively planned Median TTF (months) 5.6 5.6 0.761 for combined analysis. Anastrozole was shown to be at least as Median OS (months) 20.3 22.0 0.624 effective as tamoxifen as first-line treatment of postmenopausal Objective response (%) women with advanced breast cancer, although some variation in Total population 12.3 19.1 0.014 data was observed between the two individual Phase III trials HR+ve subgroup 16.8 17.3 NA (depending upon the proportion of patients whose tumours were Unknown receptor 8.4 20.8 NA hormone receptor-positive). In the North American trial, TTP and status subgroup clinical benefit (CB) rates were significantly better for anastrozole compared with tamoxifen (Table 2). In the TARGET trial, TTP: primary end point; ITT¼ intention to treat; TTP¼ time to disease progression; anastrozole was shown to be equivalent to tamoxifen in terms of TTF¼ time to treatment failure; OS¼ overall survival. TTP and OR rates (Table 2). The difference in outcome was attributed to differences in the proportion of patients with confirmed hormone receptor-positive tumours (89 vs 45% for the North American and TARGET trials, respectively). Analysis of population and the unknown receptor status subgroup, which were the subgroup that comprised only patients with hormone receptor- higher in the letrozole vs the anastrozole group (overall popula- positive tumours (45%) in the TARGET trial showed a similar tion: 19.1 vs 12.3%, odds ratio¼ 1.70, P¼ 0.014; unknown receptor separation of the Kaplan–Meier curves to that seen in the overall status subgroup: 20.8 vs 8.4%, respectively) (Rose et al, 2002). population in the North American trial (in which 89% of patients However, in patients with confirmed hormone receptor-positive had hormone receptor-positive tumours). The combined analysis tumours there was no difference in OR between anastrozole and of the two trials also showed anastrozole to be superior to letrozole (28/167 [16.8%] vs 30/173 [17.3%], respectively). As the tamoxifen for TTP in patients with hormone-sensitive advanced overall population included patients with unknown receptor breast cancer (Table 2) (Bonneterre et al, 2001). status, it is possible that in this unknown receptor group there In a single Phase III study in postmenopausal women with was a greater number of patients randomised to letrozole who had advanced breast cancer, letrozole was also found to be superior to hormone receptor-positive tumours and who would respond to tamoxifen for several efficacy end points (Mouridsen et al, 2001). letrozole. If this was the case, it could account for the higher OR Time to progression, CB and OR rates were significantly better for rate with letrozole in the overall population. Presently, the number letrozole (Table 2). In addition, TTF was significantly longer for of patients with unknown receptor status in each group has not letrozole compared with tamoxifen (median TTF: 9.2 vs 5.7 been published. Furthermore, no results for TTP in the hormone months, respectively, P¼ 0.0001). receptor-positive population have been published to date, so the Although no data from Phase III trials of exemestane are relative efficacy of anastrozole and letrozole for this end point is currently available, the results of a Phase II trial of exemestane uncertain. (25 mg o.d., n¼ 31) vs tamoxifen (20 mg o.d., n¼ 32) are promising (Paridaens et al, 2000). Median TTP was 8.9 vs 5.2 months for exemestane and tamoxifen, respectively, and OR rates SUMMARY were 42 vs 16%, respectively. A Phase III trial is ongoing. In contrast to the third-generation AIs, the second-generation The AIs have been developed for treatment of breast cancer in agents fadrozole and formestane have not shown any significant postmenopausal women with hormone receptor-positive tumours efficacy benefits over tamoxifen in the advanced disease setting and it is important that they are used to treat this group of (Perez Carrion et al, 1994; Falkson and Falkson, 1996). patients. Third-generation AIs (anastrozole, letrozole and exemes- tane) show improved potency with respect to suppression of aromatase activity and circulating oestrogen levels compared with Direct comparison of the third-generation aromatase the older-generation AIs (aminoglutethimide, formestane and inhibitors: anastrozole vs letrozole as second-line therapy fadrozole) (Dowsett et al, 1990; Lnning et al, 1991; Jones et al, Anastrozole (1 mg o.d.) and letrozole (2.5 mg o.d.) were compared 1992; MacNeill et al, 1992; Geisler et al, 1996). This increased as second-line treatment for advanced breast cancer with hormone potency correlates with improved clinical efficacy of the third- receptor-positive or unknown receptor status in postmenopausal generation AIs relative to the older drugs. Thus, while formestane women who had progressed on tamoxifen in a multicentre, open- and fadrozole, which inhibit aromatase by o85%, have shown no label, randomised Phase III–IV study (Rose et al, 2002). The benefits over megestrol acetate (Buzdar et al, 1996b; Thu¨rlimann primary end point was TTP and secondary end points included OR et al, 1997) or tamoxifen (Perez Carrion et al, 1994; Falkson and rate, response duration, duration of clinical benefit, TTF, time to Falkson, 1996) as second- and first-line therapy, respectively, response and overall survival (OS). third-generation AIs, which inhibit aromatase activity by 496%, A total of 713 postmenopausal patients were randomly allocated show significant clinical efficacy benefits over these standard to either letrozole 2.5 mg o.d. (n¼ 356) or anastrozole 1 mg o.d. second- and first-line comparators (Buzdar et al, 1996a, 1998, (n¼ 357). Patient characteristics were well balanced between 2001; Dombernowsky et al, 1998; Bonneterre et al, 2000; Kaufmann treatment groups (Rose et al, 2002). A total of 48% of patients et al, 2000; Nabholtz et al, 2000; Bonneterre et al, 2001; Mouridsen had hormone receptor-positive tumours (Rose et al, 2002). et al, 2001). Efficacy end points are shown in Table 3. In the overall population, In contrast, direct comparison of the third-generation AIs anastrozole was similar to letrozole for TTP (P¼ 0.920), TTF anastrozole and letrozole has shown that although letrozole (P¼ 0.761) and OS (P¼ 0.624). The only differences between suppresses aromatase activity, oestrone and oestrone sulphate anastrozole and letrozole were for OR rate in both the overall levels to a greater degree than anastrozole, these differences in & 2004 Cancer Research UK British Journal of Cancer (2004) 90(9), 1733 – 1739 Clinical Clinical Potency vs clinical efficacy of aromatase inhibitors R Sainsbury potency do not translate to clinically significant differences in the become apparent during longer-term treatment as these drugs efficacy of these agents for the second-line treatment of hormone- move into the adjuvant setting. sensitive advanced breast cancer (Rose et al, 2002). The fact that these marginal differences in potency between CONCLUSION anastrozole and letrozole do not appear to produce clinically relevant differences in efficacy suggests that there may be a The third-generation AIs are more potent inhibitors of the threshold effect for aromatase inhibition/oestrogen suppression aromatase enzyme and cause greater oestrogen suppression than beyond which no further improvements in clinical efficacy can be older agents such as aminoglutethimide, fadrozole and formestane. gained. Since the potency of formestane, aminoglutethimide and This is linked to an increase in the clinical efficacy of the third- fadrozole fall below this threshold, the third-generation AIs show generation AIs relative to the previous standard comparators in clinical efficacy benefits relative to these older agents. Of note, both the second- and first-line settings. 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Published: Apr 13, 2004

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