Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Pfizer Limited, Ramsgate Road, Sandwich, CT13 9NJ, UK
Pharmacotherapeutic group: steroidal aromatase inhibitor; anti-neoplastic agent
ATC: L02BG06
Exemestane is an irreversible, steroidal aromatase inhibitor, structurally related to the natural substrate androstenedione. In post-menopausal women, oestrogens are produced primarily from the conversion of androgens into oestrogens through the aromatase enzyme in peripheral tissues. Oestrogen deprivation through aromatase inhibition is an effective and selective treatment for hormone dependent breast cancer in postmenopausal women. In postmenopausal women, Aromasin p.o. significantly lowered serum oestrogen concentrations starting from a 5 mg dose, reaching maximal suppression (>90%) with a dose of 10-25 mg. In postmenopausal breast cancer patients treated with the 25 mg daily dose, whole body aromatization was reduced by 98%.
Exemestane does not possess any progestogenic or oestrogenic activity. A slight androgenic activity, probably due to the 17-hydro derivative, has been observed mainly at high doses. In multiple daily doses trials, Aromasin had no detectable effects on adrenal biosynthesis of cortisol or aldosterone, measured before or after ACTH challenge, thus demonstrating its selectivity with regard to the other enzymes involved in the steroidogenic pathway.
Glucocorticoid or mineralocorticoid replacements are therefore not needed. A non dose-dependent slight increase in serum LH and FSH levels has been observed even at low doses: this effect is, however, expected for the pharmacological class and is probably the result of feedback at the pituitary level due to the reduction in oestrogen levels that stimulate the pituitary secretion of gonadotropins also in postmenopausal women.
In a multicentre, randomised, double-blind study (IES), conducted in 4724 postmenopausal patients with oestrogen-receptor-positive or unknown primary breast cancer, patients who had remained disease-free after receiving adjuvant tamoxifen therapy for 2 to 3 years were randomised to receive 3 to 2 years of Aromasin (25 mg/day) or tamoxifen (20 or 30 mg/day) to complete a total of 5 years of hormonal therapy.
After a median duration of therapy of about 30 months and a median follow-up of about 52 months, results showed that sequential treatment with Aromasin after 2 to 3 years of adjuvant tamoxifen therapy was associated with a clinically and statistically significant improvement in disease-free survival (DFS) compared with continuation of tamoxifen therapy. Analysis showed that in the observed study period Aromasin reduced the risk of breast cancer recurrence by 24% compared with tamoxifen (hazard ratio 0.76; p=0.00015). The beneficial effect of exemestane over tamoxifen with respect to DFS was apparent regardless of nodal status or prior chemotherapy.
Aromasin also significantly reduced the risk of contralateral breast cancer (hazard ratio 0.57, p=0.04158).
In the whole study population, a trend for improved overall survival was observed for exemestane (222 deaths) compared to tamoxifen (262 deaths) with a hazard ratio 0.85 (log-rank test: p=0.07362), representing a 15% reduction in the risk of death in favour of exemestane. A statistically significant 23% reduction in the risk of dying (hazard ratio for overall survival 0.77; Wald chi square test: p=0.0069) was observed for exemestane compared to tamoxifen when adjusting for the pre-specified prognostic factors (i.e. ER status, nodal status, prior chemotherapy, use of HRT and use of bisphosphonates).
52 month main efficacy results in all patients (intention to treat population) and oestrogen receptor positive patients:
| Endpoint | Exemestane | Tamoxifen | Hazard Ratio | p-value* |
|---|---|---|---|---|
| Population | Events/N (%) | Events/N (%) | (95% CI) | |
| Disease-free survivala | ||||
| All patients | 354/2352 (15.1%) | 453/2372 (19.1%) | 0.76 (0.67-0.88) | 0.00015 |
| ER+ patients | 289/2023 (14.3%) | 370/2021 (18.3%) | 0.75 (0.65-0.88) | 0.00030 |
| Contralateral breast cancer | ||||
| All patients | 20/2352 (0.9%) | 35/2372 (1.5%) | 0.57 (0.33-0.99) | 0.04158 |
| ER+ patients | 18/2023 (0.9%) | 33/2021 (1.6%) | 0.54 (0.30-0.95) | 0.03048 |
| Breast cancer free survivalb | ||||
| All patients | 289/2352 (12.3%) | 373/2372 (15.7%) | 0.76 (0.65-0.89) | 0.00041 |
| ER+ patients | 232/2023 (11.5%) | 305/2021 (15.1%) | 0.73 (0.62-0.87) | 0.00038 |
| Distant recurrence free survivalc | ||||
| All patients | 248/2352 (10.5%) | 297/2372 (12.5%) | 0.83 (0.70-0.98) | 0.02621 |
| ER+ patients | 194/2023 (9.6%) | 242/2021 (12.0%) | 0.78 (0.65-0.95) | 0.01123 |
| Overall survivald | ||||
| All patients | 222/2352 (9.4%) | 262/2372 (11.0%) | 0.85 (0.71-1.02) | 0.07362 |
| ER+ patients | 178/2023 (8.8%) | 211/2021 (10.4%) | 0.84 (0.68-1.02) | 0.07569 |
* Log-rank test; ER+ patients = oestrogen receptor positive patients;
a Disease-free survival is defined as the first occurrence of local or distant recurrence, contralateral breast cancer, or death from any cause;
b Breast cancer free survival is defined as the first occurrence of local or distant recurrence, contralateral breast cancer or breast cancer death;
c Distant recurrence free survival is defined as the first occurrence of distant recurrence or breast cancer death;
d Overall survival is defined as occurrence of death from any cause.
In the additional analysis for the subset of patients with oestrogen receptor positive or unknown status, the unadjusted overall survival hazard ratio was 0.83 (log-rank test: p=0.04250), representing a clinically and statistically significant 17% reduction in the risk of dying.
Results from the IES bone substudy demonstrated that women treated with Aromasin following 2 to 3 years of tamoxifen treatment experienced moderate reduction in bone mineral density. In the overall study, the treatment emergent fracture incidence evaluated during the 30 months treatment period was higher in patients treated with Aromasin compared with tamoxifen (4.5% and 3.3% correspondingly, p=0.038).
Results from the IES endometrial substudy indicate that after 2 years of treatment there was a median 33% reduction of endometrial thickness in the Aromasin-treated patients compared with no notable variation in the tamoxifen-treated patients. Endometrial thickening, reported at the start of study treatment, was reversed to normal (<5 mm) for 54% of patients treated with Aromasin.
After a median duration of therapy of about 30 months and a median follow-up of about 87 months, results showed that sequential treatment with exemestane after 2 to 3 years of adjuvant tamoxifen therapy was associated with a clinically and statistically significant improvement in DFS compared with continuation of tamoxifen therapy. Results showed that in the observed study period Aromasin significantly reduced the risk of breast cancer recurrence by 16% compared with tamoxifen (hazard ratio 0.84; p=0.002).
Overall, the beneficial effect of exemestane over tamoxifen with respect to DFS was apparent regardless of nodal status or prior chemotherapy or hormonal therapy. Statistical significance was not maintained in a few sub-groups with small sample sizes. These showed a trend favouring exemestane in patients with more than 9 nodes positive, or previous chemotherapy CMF. In patients with nodal status unknown, previous chemotherapy other, as well as unknown/missing status of previous hormonal therapy a non statistically significant trend favouring tamoxifen was observed.
In addition, exemestane also significantly prolonged breast cancer-free survival (hazard ratio 0.82, p=0.00263), and distant recurrence-free survival (hazard ratio 0.85, p=0.02425).
Aromasin also reduced the risk of contralateral breast cancer, although the effect was no longer statistically significant in this observed study period (hazard ratio 0.74, p=0.12983). In the whole study population, a trend for improved overall survival was observed for exemestane (373 deaths) compared to tamoxifen (420 deaths) with a hazard ratio 0.89 (log rank test: p=0.08972), representing an 11% reduction in the risk of death in favour of exemestane. When adjusting for the pre-specified prognostic factors (i.e. ER status, nodal status, prior chemotherapy, use of HRT and use of bisphosphonates), a statistically significant 18% reduction in the risk of dying (hazard ratio for overall survival 0.82; Wald chi square test: p=0.0082) was observed for exemestane compared to tamoxifen in the whole study population.
In the additional analysis for the subset of patients with oestrogen receptor positive or unknown status, the unadjusted overall survival hazard ratio was 0.86 (log-rank test: p=0.04262), representing a clinically and statistically significant 14% reduction in the risk of dying.
Results from a bone sub-study indicate that treatment with exemestane for 2 to 3 years following 3 to 2 years of tamoxifen treatment increased bone loss while on treatment (mean % change from baseline for BMD at 36 months: -3.37 [spine], -2.96 [total hip] for exemestane and -1.29 [spine], -2.02 [total hip], for tamoxifen). However, by the end of the 24 month post treatment period there were minimal differences in the change in BMD from baseline for both treatment groups, the tamoxifen arm having slightly greater final reductions in BMD at all sites (mean % change from baseline for BMD at 24 months post treatment -2.17 [spine], -3.06 [total hip] for exemestane and -3.44 [spine], -4.15 [total hip] for tamoxifen).
The all fractures reported on-treatment and during follow-up was significantly higher in the exemestane group than on tamoxifen (169 [7.3%] versus 122 [5.2%]; p=0.004), but no difference was noted in the number of fractures reported as osteoporotic.
After a median duration of therapy of about 30 months and a median follow-up of about 119 months, results showed that sequential treatment with exemestane after 2 to 3 years of adjuvant tamoxifen therapy was associated with a clinically and statistically significant improvement in DFS compared with continuation of tamoxifen therapy. Analysis showed that over the observed study period exemestane reduced the risk of breast cancer recurrence by 14% compared with tamoxifen (hazard ratio 0.86, p=0.00393). The beneficial effect of exemestane over tamoxifen with respect to DFS was apparent regardless of nodal status or prior chemotherapy.
Exemestane also significantly prolonged breast cancer-free survival (hazard ratio 0.83, p<0.00152), and distant recurrence-free survival (hazard ratio 0.86, p=0.02213). Exemestane also reduced risk of contralateral breast cancer; however, the effect was no longer statistically significant (hazard ratio 0.75, p=0.10707).
In the whole study population, overall survival was not statistically different between the two groups with 467 deaths (19.9%) occurring in the exemestane group and 510 deaths (21.5%) in the tamoxifen group (hazard ratio 0.91, p=0.15737, not adjusted for multiple testing). For the subset of patients with oestrogen receptor positive or unknown status, the unadjusted overall survival hazard ratio was 0.89 (log-rank test: p=0.07881) in the exemestane group relative to the tamoxifen group.
In the whole study population, a statistically significant 14% reduction in the risk of dying (hazard ratio for OS 0.86; Wald chi square test: p=0.0257) was observed for exemestane compared with tamoxifen when adjusting for the pre-specified prognostic factors (i.e. ER status, nodal status, prior chemotherapy, use of HRT and use of bisphosphonates).
A lower incidence of other second (non-breast) primary cancers was observed in exemestane-treated patients compared with tamoxifen only-treated patients (9.9% versus. 12.4%).
In the main study, which had a median follow-up in all participants of 119 months (0 – 163.94) and median duration of exemestane treatment of 30 months (0–40.41), the incidence of bone fractures was reported on 169 (7.3%) patients in the exemestane group compared with 122 (5.2%) patients in the tamoxifen group (p=0.004).
Efficacy Results From IES in Postmenopausal Women With Early Breast Cancer (ITT):
| No. of Events | Hazard Ratio | |||
|---|---|---|---|---|
| Exemestane | Tamoxifen | Hazard Ratio | p-value | |
| 30-Month Median Treatment and 34.5-Month Median Follow-Up | ||||
| Disease-free survivala | 213 | 306 | 0.69 (95% CI: 0.58-0.82) | 0.00003 |
| Breast cancer-free survivalb | 171 | 262 | 0.65 (95% CI: 0.54-0.79) | <0.00001 |
| Contralateral breast cancer | 8 | 25 | 0.32 (95% CI: 0.15-0.72) | 0.00340 |
| Distant recurrence-free survivalc | 142 | 204 | 0.70 (95% CI: 0.56-0.86) | 0.00083 |
| Overall survivald | 116 | 137 | 0.86 (95% CI: 0.67-1.10) | 0.22962 |
| 30-Month Median Treatment and 52-Month Median Follow-Up | ||||
| Disease-free survivala | 354 | 453 | 0.77 (95% CI: 0.67-0.88) | 0.00015 |
| Breast cancer-free survivalb | 289 | 373 | 0.76 (95% CI: 0.65-0.89) | 0.00041 |
| Contralateral breast cancer | 20 | 35 | 0.57 (95% CI: 0.33-0.99) | 0.04158 |
| Distant recurrence-free survivalc | 248 | 297 | 0.83 (95% CI: 0.70-0.98) | 0.02621 |
| Overall survivald | 222 | 262 | 0.85 (95% CI: 0.71-1.02) | 0.07362 |
| 30-Month Median Treatment and 87-Month Median Follow-Up | ||||
| Disease-free survivala | 552 | 641 | 0.84 (95% CI: 0.75-0.94) | 0.002 |
| Breast cancer-free survivalb | 434 | 513 | 0.82 (95% CI: 0.72-0.94) | 0.00263 |
| Contralateral breast cancer | 43 | 58 | 0.74 (95% CI: 0.50-1.10) | 0.12983 |
| Distant recurrence-free survivalc | 353 | 409 | 0.85 ((95% CI: 0.74-0.98) | 0.02425 |
| Overall survivald | 373 | 420 | 0.89 (95% CI: 0.77-1.02) | 0.08972 |
| 30-Month Median Treatment and 119-Month Median Follow-Up | ||||
| Disease-free survivala | 672 | 761 | 0.86 (95% CI: 0.77-0.95) | 0.00393 |
| Breast cancer-free survivalb | 517 | 608 | 0.83 (95% CI: 0.74-0.93) | 0.00152 |
| Contralateral breast cancer | 57 | 75 | 0.75 (95% CI: 0.53-1.06) | 0.10707 |
| Distant recurrence-free survivalc | 411 | 472 | 0.86 (95% CI: 0.75-0.98) | 0.02213 |
| Overall survivald | 467 | 510 | 0.91 (95% CI: 0.81-1.04) | 0.15737 |
CI = confidence interval; IES = Intergroup Exemestane Study; ITT = intention-to-treat.
a Disease-free survival is defined as the first occurrence of local or distant recurrence, contralateral breast cancer or death from any cause.
b Breast cancer-free survival is defined as the first occurrence of local or distant recurrence, contralateral breast cancer or breast cancer death.
c Distant recurrence-free survival is defined as the first occurrence of distant recurrence or breast cancer death.
d Overall survival is defined as occurrence of death from any cause.
In a randomised peer reviewed controlled clinical trial, Aromasin at the daily dose of 25 mg has demonstrated statistically significant prolongation of survival, Time to Progression (TTP), Time to Treatment Failure (TTF) as compared to a standard hormonal treatment with megestrol acetate in postmenopausal patients with advanced breast cancer that had progressed following, or during, treatment with tamoxifen either as adjuvant therapy or as first-line treatment for advanced disease.
After oral administration of Aromasin tablets, exemestane is absorbed rapidly. The fraction of the dose absorbed from the gastrointestinal tract is high. The absolute bioavailability in humans is unknown, although it is anticipated to be limited by an extensive first pass effect. A similar effect resulted in an absolute bioavailability in rats and dogs of 5%. After a single dose of 25 mg, maximum plasma levels of 18 ng/ml are reached after 2 hours. Concomitant intake with food increases the bioavailability by 40%.
The volume of distribution of exemestane, not corrected for the oral bioavailability, is ca 20000 l. The kinetics is linear and the terminal elimination half-life is 24 h. Binding to plasma proteins is 90% and is concentration independent. Exemestane and its metabolites do not bind to red blood cells.
Exemestane does not accumulate in an unexpected way after repeated dosing.
Exemestane is metabolised by oxidation of the methylene moiety on the 6 position by CYP3A4 isoenzyme and/or reduction of the 17-keto group by aldoketoreductase followed by conjugation. The clearance of exemestane is ca 500 l/h, not corrected for the oral bioavailability.
The metabolites are inactive or the inhibition of aromatase is less than the parent compound.
The amount excreted unchanged in urine is 1% of the dose. In urine and faeces equal amounts (40%) of 14C-labeled exemestane were eliminated within a week.
No significant correlation between the systemic exposure of Aromasin and the age of subjects has been observed.
In patients with severe renal impairment (CLcr <30 ml/min) the systemic exposure to exemestane was 2 times higher compared with healthy volunteers.
Given the safety profile of exemestane, no dose adjustment is considered to be necessary.
In patients with moderate or severe hepatic impairment the exposure of exemestane is 2-3 fold higher compared with healthy volunteers. Given the safety profile of exemestane, no dose adjustment is considered to be necessary.
Findings in the repeat dose toxicology studies in rat and dog were generally attributable to the pharmacological activity of exemestane, such as effects on reproductive and accessory organs. Other toxicological effects (on liver, kidney or central nervous system) were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
Exemestane was not genotoxic in bacteria (Ames test), in V79 Chinese hamster cells, in rat hepatocytes or in the mouse micronucleus assay. Although exemestane was clastogenic in lymphocytes in vitro, it was not clastogenic in two in vivo studies.
Exemestane was embryotoxic in rats and rabbits at systemic exposure levels similar to those obtained in humans at 25 mg/day. There was no evidence of teratogenicity.
In a two-year carcinogenicity study in female rats, no treatment-related tumours were observed. In male rats the study was terminated on week 92, because of early death by chronic nephropathy. In a two-year carcinogenicity study in mice, an increase in the incidence of hepatic neoplasms in both genders was observed at the intermediate and high doses (150 and 450 mg/kg/day). This finding is considered to be related to the induction of hepatic microsomal enzymes, an effect observed in mice but not in clinical studies. An increase in the incidence of renal tubular adenomas was also noted in male mice at the high dose (450 mg/kg/day). This change is considered to be species- and gender-specific and occurred at a dose which represents 63-fold greater exposure than occurs at the human therapeutic dose. None of these observed effects is considered to be clinically relevant to the treatment of patients with exemestane.
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