Letrostad Mechanism of Action

Pharmacotherapeutic group: Enzyme inhibitors, Non-steroidal aromatase inhibitor (inhibitor of oestrogen biosynthesis); antineoplastic agent. ATC code: L02 BG04.
Pharmacological Properties: Pharmacodynamic properties: The elimination of oestrogen-mediated growth stimulation is a prerequisite for tumour response in cases where the growth of tumour tissue depends on the presence of oestrogens and where endocrine therapy is used. In postmenopausal women, oestrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens - primarily androstenedione and testosterone - to oestrone and estradiol. The suppression of oestrogen biosynthesis in peripheral tissues and the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme.
Letrozole is a non-steroidal aromatase inhibitor. It inhibits the aromatase enzyme by competitively binding to the heme of the aromatase-cytochrome P450, resulting in a reduction of oestrogen biosynthesis in all tissues where present.
In healthy postmenopausal women, single doses of 0.1, 0.5, and 2.5 mg Letrozole suppress serum oestrone and estradiol by 75-78% and 78% from baseline, respectively. Maximum suppression is achieved in 48-78 h.
In postmenopausal patients with advanced breast cancer, daily doses of 0.1 to 5 mg suppress plasma concentrations of estradiol, oestrone, and oestrone sulphate by 75-95% from baseline in all patients treated. With doses of 0.5 mg and higher, many values of oestrone and oestrone sulphate are below the limit of detection in the assays, indicating that higher oestrogen suppression is achieved with these doses. Oestrogen suppression was maintained throughout treatment in all these patients.
Letrozole is highly specific in inhibiting aromatase activity. Impairment of adrenal steroidogenesis has not been observed. No clinically relevant changes were found in the plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxy-progesterone, and ACTH or in plasma renin activity among postmenopausal patients treated with a daily dose of Letrozole 0.1 to 5 mg. The ACTH stimulation test performed after 6 and 12 weeks of treatment with daily doses of 0.1, 0.25, 0.5, 1, 2.5, and 5 mg did not indicate any attenuation of aldosterone or cortisol production. Thus, glucocorticoid and mineralocorticoid supplementation is not necessary.
No changes were noted in plasma concentrations of androgens (androstenedione and testosterone) among healthy postmenopausal women after 0.1, 0.5, and 2.5 mg single doses of Letrozole or in plasma concentrations of androstenedione among postmenopausal patients treated with daily doses of 0.1 to 5 mg, indicating that the blockade of estrogen biosynthesis does not lead to accumulation of androgenic precursors. In patients, plasma levels of LH and FSH are not affected by Letrozole, nor is thyroid function as evaluated by TSH, T₄ and T₃ uptake test.
Adjuvant therapy: A multicentre, double-blind study randomised over 8000 postmenopausal women with resected receptor-positive primary breast cancer, to one of the following arms: Option 1: A. Tamoxifen for 5 years.
B. Letrozole for 5 years.
C. Tamoxifen for 2 years followed by Letrozole for 3 years.
D. Letrozole for 2 years followed by Tamoxifen for 3 years.
Option 2: A. Tamoxifen for 5 years.
B. Letrozole for 5 years.
Data reflect results from the monotherapy arms of both randomisation options and data from the two switching arms up to 30 days after the date of switch. Analysis of monotherapy vs. sequential endocrine therapy will be performed when the required number of events have occurred.
Patients have been followed for a median of 26 months, 76% of the patients for more than 2 years, and 16% (1252 patients) for 5 years or longer.
The primary endpoint of the trial was disease-free survival which was assessed as the time from randomisation to the earliest event of loco-regional or distant recurrence (metastases) of the primary disease, development of invasive contralateral breast cancer, appearance of a second (non-breast) primary tumour or death from any cause without a prior cancer event.
Letrozole reduced the risk of recurrence by 19% compared with Tamoxifen (hazard ratio 0.81; P=0.003). The 5-year disease-free survival rates were 84.0% for Letrozole and 81.4% for Tamoxifen. The improvement in disease-free survival with Letrozole was seen as early as 12 months and was maintained beyond 5 years. Letrozole also significantly reduced the risk of recurrence compared with Tamoxifen whether prior adjuvant chemotherapy was given (hazard ratio 0.72; P=0.018) or not (hazard ratio 0.84; P=0.044).
For the secondary endpoint "overall survival" a total of 358 deaths were reported (166 with Letrozole and 192 with Tamoxifen). There was no significant difference between both treatments in overall survival rate (hazard ratio 0.86; P=0.15). The distant disease-free survival, a surrogate parameter for overall survival, differed significantly both in the overall patient population (hazard ratio 0.73; P=0.001) and in the predefined, stratified subgroups. Letrozole significantly reduced the risk of systemic failure by 17% compared with Tamoxifen (hazard ratio 0.83; P=0.02).
Although in favour of Letrozole non-significant difference was obtained in the occurrence of contralateral breast cancer (hazard ratio 0.61; P=0.09). Exploratory analysis of disease-free survival by nodal status showed that Letrozole was significantly superior to Tamoxifen in reducing the risk of recurrence (hazard ratio 0.71; 95% CI 0.59, 0.85; P=0.0002) in patients with node positive disease. No significant difference was apparent between the treatments in node negative patients (hazard ratio 0.98; 95% CI 0.77, 1.25; P=0.89). The reduced benefit in node negative patients was confirmed by exploratory interaction analysis (P=0.03).
Patients receiving Letrozole showed fewer secondary tumours compared with patients receiving Tamoxifen (1.9% vs. 2.4%). Particularly the incidence of endometrial cancer was lower with Letrozole compared to Tamoxifen (0.2% vs. 0.4%).
The median treatment duration (regarding the patient population assessed for safety) was 25 months; 73% of the patients were treated for more than 2 years and 22% of the patients for more than 4 years. The median duration of follow-up was 30 months for both Letrozole and Tamoxifen.
Adverse events causally related to the study medication were reported in 78% of the patients treated with Letrozole and 73% of the patients treated with Tamoxifen. The most common adverse events experienced with Letrozole were hot flushes, night sweats, arthralgia, weight gain and nausea. Of these only arthralgia occurred significantly more often with Letrozole than with Tamoxifen (20% vs. 13%). Treatment with Letrozole was associated with a higher risk of osteoporosis (2.2% vs. 1.2% with Tamoxifen). Overall, the number of cardiovascular/cerebrovascular events, irrespective of causality, reported at any time after randomisation was the same in both treatment groups (10.8% with Letrozole and 12.2% with Tamoxifen). Among these, thromboembolic events were reported significantly less often with Letrozole (1.5%) than with Tamoxifen (3.2%) (P<0.001), whereas cardiac failure was reported significantly more often with Letrozole (0.9%) than with Tamoxifen (0.4%) (P=0.006). In patients with baseline serum cholesterol levels within the normal range, increases in total serum cholesterol > 1.5 the upper limit of normal were observed in 5.4% of the patients of the Letrozole treatment arm compared to 1.1% of the Tamoxifen treatment arm.
Extended adjuvant therapy: In a multicentre, double-blind, randomised, placebo-controlled study, performed in over 5100 postmenopausal patients with primary breast cancer of positive or unknown receptor status, patients who had remained disease-free after completion of adjuvant treatment with Tamoxifen (4.5 to 6 years) were randomly assigned either Letrozole or placebo.
An updated analysis conducted at a median follow-up of around 39 months (70% of the patients being followed for at least 3 years) showed that Letrozole reduced the risk of recurrence by 44% compared with placebo (hazard ratio 0.56; P=≤0.00001). The statistically significant benefit in disease-free survival in favour of Letrozole was observed regardless of nodal status - node negative: hazard ratio 0.49; P=0.0004; node positive: hazard ratio 0.58; P=0.00007.
For the secondary endpoint overall survival (OS) a total of 224 deaths were reported (109 Letrozole, 100 placebo and 15 who switched from placebo to Letrozole). Overall, there was no significant difference between treatments in OS (hazard ratio 0.80; P=0.10).
At this update, results (median duration of follow-up was 3 years) from the bone mineral density (BMD) substudy (222 patients enrolled) demonstrated that, at 3 years, compared to baseline, patients receiving Letrozole were associated with greater decreases in BMD in the total hip (median decrease of 4% in hip BMD compared to a median decrease of 1.7% in the placebo group (P=0.131, adjusted for bisphosphonate use, P=0.645). Patients receiving Letrozole were associated with a greater decrease in lumbar spine BMD although not significantly different.
Concomitant calcium and vitamin D supplementation was mandatory in the BMD sub-study.
In the same update, results (median duration of follow-up was 47 months) from the Lipid substudy (310 patients enrolled) show no significant differences between the letrozole and placebo arms in total cholesterol or in any lipid fraction. In the updated analysis 7.7% of patients in the Letrozole arm reported cardiovascular adverse events during treatment compared with 6.1% in the placebo arm. These events included myocardial infarction (Letrozole 0.8%, placebo 0.6%); angina requiring surgical intervention (0.6% in each treatment arm), new or worsening angina (Letrozole 1.3% vs placebo 1.0%), thromboembolic events (Letrozole 0.6%, placebo 0.3%) and cerebrovascular accident (Letrozole 1.0% vs placebo 0.7%).
No significant differences in overall physical and mental scores were observed, indicating that overall, Letrozole did not worsen quality of life compared with placebo. Self-assessment by the patients' revealed treatment differences in favour of placebo, in particular for physical functions, bodily pain, vitality as well as sexual and vasomotor parameters. Although statistically significant, these differences were not considered clinically relevant.
First-line treatment: One controlled double-blind clinical study compared Letrozole with 20 mg Tamoxifen as first-line treatment in postmenopausal women with advanced breast cancer. In 907 women Letrozole was superior to Tamoxifen in time to progression (primary endpoint) and in overall objective tumour response, in time to treatment failure and in clinical benefit.
Time to progression was significantly longer and response rate significantly higher for Letrozole than for Tamoxifen in patients with both tumours of unknown and positive receptor status. Similarly, time to progression was significantly longer and response rate significantly higher for Letrozole, irrespective of whether adjuvant anti-oestrogen therapy had been given or not. Time to progression was also significantly longer for Letrozole irrespective of dominant site of disease. The median time to progression was almost twice as long for Letrozole in patients with soft tissue metastases only (median 12.1 months under Letrozole, 6.4 months under Tamoxifen) and in patients with visceral metastases (median 8.3 months for Letrozole, 4.6 months for Tamoxifen). The response rate was significantly higher for Letrozole in patients with soft tissue metastases only (50% vs. 34% for Letrozole and Tamoxifen respectively) as well as in patients with visceral metastases (28% vs. 17% for Letrozole and Tamoxifen, respectively).
Upon progression the study design allowed a switch (cross-over) to the other treatment or discontinuation from the study. Approximately 50% of all patients switched to the other treatment arm and cross-over was virtually completed after 36 months. The median time to cross-over was 17 months (from Letrozole to Tamoxifen) and 13 months (from Tamoxifen to Letrozole).
The median overall survival in the first-line treatment of advanced breast cancer was 34 months for Letrozole compared with 30 months for Tamoxifen (logrank test P=0.53, not significant). A better survival rate was associated with Letrozole up to at least 24 months. The survival rate after 24 months was 64% in the Letrozole group versus 58% in the Tamoxifen group. The absence of an advantage for Letrozole on overall survival could be explained by the cross-over design of the study.
The overall duration of endocrine treatment (time to chemotherapy) was significantly longer for Letrozole (median 16.3 months, 95% CI 15-18 months) than for Tamoxifen (median 9.3 months, 95% CI 8-12 months) (logrank test, P=0.0047).
Treatment after prior anti-oestrogen treatment (second-line treatment): Two controlled clinical studies were conducted comparing two letrozole doses (0.5 mg and 2.5 mg) with megestrol acetate and aminoglutethimide, respectively, in postmenopausal women with advanced breast cancer previously treated with anti-oestrogens.
Time to progression did not differ significantly between 2.5 mg letrozole and megestrol acetate (P=0.07). Statistically significant differences were observed in favour of 2.5 mg letrozole compared to megestrol acetate in response rate (24% versus 16%, P=0.04) and in time to treatment failure (P=0.04). Overall survival did not differ significantly between these two treatment arms (P=0.2).
In the second study, the response rate did not differ significantly between 2.5 mg letrozole and aminoglutethimide (P=0.06). Letrozole was statistically significantly superior to aminoglutethimide for time to progression (P=0.008), time to treatment failure (P=0.003) and overall survival (P=0.002).
Pharmacokinetic properties: Absorption: Letrozole is rapidly and completely absorbed from the gastrointestinal tract. Mean absolute bioavailability is 99.9%. Food slightly decreases the rate of absorption (median t_max: 1 hour fasted versus 2 hours fed; and mean C_max: 129 ± 20.3 nmol/L fasted versus 98.7 ± 18.6 nmol/L fed) but the extent of absorption (AUC) is not changed. The minor effect on the absorption rate is not considered to be of clinical relevance and therefore letrozole may be taken without regard to mealtimes.
Distribution: Plasma protein binding of letrozole is approximately 60%, mainly to albumin (55%). The concentration of letrozole in erythrocytes is about 80% of that in plasma. After administration of 2.5 mg ¹⁴C-labelled letrozole, approximately 82% of the radioactivity in plasma was unchanged compound. Systemic exposure to metabolites is therefore low. Letrozole is rapidly and extensively distributed to tissues. Its apparent volume of distribution at steady state is about 1.87 ± 0.47 L/kg.
Metabolism and elimination: Metabolic clearance to a pharmacologically inactive carbinol metabolite is the major elimination pathway of letrozole (CL_m= 2.1 L/h) but is relatively slow when compared to hepatic blood flow (about 90 L/h). The cytochrome P450 isoenzymes 3A4 and 2A6 were found to be capable of converting letrozole to this metabolite. Formation of minor unidentified metabolites and direct renal and faecal excretion play only a minor role in the overall elimination of letrozole. Within 2 weeks after administration of 2.5 mg ¹⁴C-labelled letrozole to healthy postmenopausal volunteers, 88.2 ± 7.6% of the radioactivity was recovered in urine and 3.8 ± 0.9% in faeces. At least 75% of the radioactivity recovered in urine up to 216 hours (84.7 ± 7.8% of the dose) was attributed to the glucuronide of the carbinol metabolite, about 9% to two unidentified metabolites, and 6% to unchanged letrozole.
The apparent terminal elimination half-life in plasma is about 2 days. After daily administration of 2.5 mg steady-state levels are reached within 2-6 weeks. Plasma concentrations at steady state are approximately 7 times higher than concentrations measured after a single dose of 2.5 mg, while they are 1.5 to 2 times higher than the steady-state values predicted from the concentrations measured after a single dose, indicating a slight non-linearity in the pharmacokinetics of letrozole upon daily administration of 2.5 mg. Since steady-state levels are maintained over time, it can be concluded that no continuous accumulation of letrozole occurs.
Age had no effect on the pharmacokinetics of letrozole.
Special populations: In a study involving 19 volunteers with varying degrees of renal function (24 hour creatinine clearance 9-116 mL/min) no effect on the pharmacokinetics of letrozole was found after a single dose of 2.5 mg. In a similar study involving subjects with varying degrees of hepatic function, the mean AUC values of the volunteers with moderate hepatic impairment (Child-Pugh grade B) were 37% higher than in normal subjects, but still within the range seen in subjects without impaired function. A comparison of the pharmacokinetics of letrozole following single oral administration to 8 male patients with liver cirrhosis and severe hepatic impairment (Child-Pugh grade C) with those of healthy volunteers (n=8) showed an increase in AUC and half-life of 95% and 187%, respectively. Thus, letrozole should be used with caution in these patients and after risk-benefit assessment.