Phase I study of the oral nonsteroidal aromatase inhibitor CGS 20267 in postmenopausal patients with advanced breast cancer.

A phase I study was performed of CGS 20267, an oral nonsteroidal, highly potent, and selective aromatase inhibitor, in 21 postmenopausal patients with advanced breast cancer. The patients were recruited in 3 successive groups of 7, receiving 0.1, 0.5, and 2.5 mg p.o./day, respectively. All patients had received at least one prior endocrine treatment (range, 1-4), and six patients had received prior chemotherapy. The treatment was very well tolerated, and no toxicity was seen at any of the three doses. There was a statistically significant suppression of estradiol (E2) and estrone (E1) levels by 74% and 79% from baseline levels, respectively (P < 0.0001). Suppression occurred in all three patient groups, with many patients having serum concentrations of estradiol and estrone, which were below the limit of detection of the assays (3 and 10 pM, respectively), which corresponds to a maximum measurable estrogen suppression of 86%. CGS 20267 had no significant effect on serum levels of follicle-stimulating hormone, luteinizing hormone, thyroid-stimulating hormone, cortisol, 17 alpha-hydroxyprogesterone, androstenedione, and aldosterone. Seven (33%, 95% confidence interval, 15-57%) of the 21 patients have responded to treatment (one complete remission, 6 partial remissions according to criteria of the Union Internationale contre le Cancer), and 6 are still responding to CGS 20267 (duration of response; 4+, 6+, 6+, 9+, 9, 12+, and 12+ months). Five have had stable disease for more than 3 months, and 9 had progressive disease. These results suggest that CGS 20267 is a very potent and specific aromatase inhibitor, and phase II studies are now required to confirm its clinical efficacy.

Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate.

PURPOSE: To compare two doses of letrozole and megestrol acetate (MA) as second-line therapy in postmenopausal women with advanced breast cancer previously treated with antiestrogens. PATIENTS AND METHODS: Five hundred fifty-one patients with locally advanced, locoregionally recurrent or metastatic breast cancer were randomly assigned to receive letrozole 2.5 mg (n = 174), letrozole 0.5 mg (n = 188), or MA 160 mg (n = 189) once daily in a double-blind, multicenter trial. Data were analyzed for tumor response and safety variables up to 33 months of follow-up evaluation and for survival up to 45 months. RESULTS: Letrozole 2.5 mg produced a significantly higher overall objective response rate (24%) compared with MA (16%; logistic regression, P = .04) or letrozole 0.5 mg (13%; P = .004). Duration of objective response was significantly longer for letrozole 2.5 mg compared with MA (Cox regression, P = .02). Letrozole 2.5 mg was significantly superior to MA and letrozole 0.5 mg in time to treatment failure (P = .04 and P = .002, respectively). For time to progression, letrozole 2.5 mg was superior to letrozole 0.5 mg (P = .02), but not to MA (P = .07). There was a significant dose effect in overall survival in favor of letrozole 2.5 mg (P = .03) compared with letrozole 0.5 mg. Letrozole was significantly better tolerated than MA with respect to serious adverse experiences, discontinuation due to poor tolerability, cardiovascular side effects, and weight gain. CONCLUSION: The data show letrozole 2.5 mg once daily to be more effective and better tolerated than MA in the treatment of postmenopausal women with advanced breast cancer previously treated with antiestrogens.

Open dose-finding study of a new potent and selective nonsteroidal aromatase inhibitor, CGS 20 267, in healthy male subjects.

The aim of this open, dose-finding study was to evaluate the effects of single dose CGS 20 267, a new oral nonsteroidal aromatase inhibitor, on the inhibition of estrogen production and also on the production of adrenal and testicular steroids in healthy male subjects. Nine dose levels ranging from 0.02-30 mg and placebo were tested, each dose being given to 3 subjects only. A total of 18 subjects were included; 12 of them received 2 single administration, the remaining 6 were exposed only once to one of the 2 highest dose levels. A reduction in serum estrogen levels when compared to baseline was already observed after 2 h, reaching maximum suppression between 10 and 48 h after administration. After 24 h, a suppression of estrone levels by 60-85% from baseline was achieved with all tested doses. A reduction in estradiol levels by about 30% from baseline was observed at the lowest dose (0.02 mg). This reduction was further enhanced dose dependently to a maximum of about 90% from baseline at 24 h after administration of the highest dose (30 mg). With the higher doses (10 and 30 mg), estrogen suppression was maintained up to 3 days. A dose-dependent increase of testosterone, LH, and FSH was observed and was most pronounced in the 10- and 30-mg dose groups, which can be considered as a consequence of the long-lasting aromatase inhibition achieved with these high doses. No effect on serum cortisol and aldosterone levels was observed up to the highest dose. No clinically relevant changes were observed in blood chemistry and hematology tests. The systemic and subjective tolerability of CGS 20 267 was good at all doses. This study has shown that CGS 20 267 is a well tolerated, potent, selective, and long-acting inhibitor of the aromatase enzyme after single administration.

Phase I study of the oral nonsteroidal aromatase inhibitor CGS 20267 in healthy postmenopausal women.

We have performed a phase I study of the effect of a single dose of CGS 20267, an oral nonsteroidal aromatase inhibitor, in 12 healthy volunteer postmenopausal women. Each subject received 2 single doses of CGS 20267 (0.1, 0.5, or 2.5 mg) or placebo separated by a washout period of at least 6 weeks. There was statistically significant suppression of serum estrone and estradiol at all three doses of CGS 20267 tested. Serum estrone and estradiol concentrations were maximally suppressed by 76% and 79% from baseline levels, respectively. Urinary excretion of estrone and estradiol was also suppressed, although this did not reach statistical significance. Serum concentrations of aldosterone, cortisol, 17 alpha-hydroxyprogesterone, androstenedione, testosterone, FSH, LH, and TSH were unaffected by CGS 20267. The drug was well tolerated, with no significant side-effects. This study has shown CGS 20267 to be a potent and specific aromatase inhibitor, and further studies are now needed to assess its clinical efficacy.

The effects of fadrozole hydrochloride on aldosterone secretion in healthy male subjects.

The aim of this double blind placebo-controlled cross-over study was to evaluate the effects of fadrozole, a new oral nonsteroidal aromatase inhibitor, on basal and stimulated cortisol and aldosterone secretion at a daily dosage of 4 mg given for 14 days to eight healthy men. After 2 weeks of treatment, fadrozole, compared with placebo, effectively suppressed plasma estrogen levels (P less than 0.05 at 0800 h), but did not affect glucocorticoid secretion either under basal conditions or after stimulation with ACTH. Basal plasma aldosterone levels were not significantly different with fadrozole treatment compared to those after placebo treatment. However, compared with pretreatment values, basal aldosterone secretion appeared impaired (P less than 0.05). A statistically significant blunting of the responses of plasma aldosterone to ACTH (P less than 0.01) and upright posture (P less than 0.01) after fadrozole compared with placebo treatment further indicated that fadrozole impaired basal aldosterone secretion. This attenuation of aldosterone secretion was accompanied by a rise of PRA in the basal condition (P = 0.05) and after stimulation by 40 mg furosemide (P less than 0.01) and upright posture (P less than 0.01). An increase in deoxycorticosterone was observed after fadrozole treatment compared with pretreatment values (P less than 0.01) and after stimulation with ACTH compared with placebo (P less than 0.05). This study confirms that fadrozole given in daily doses of 4 mg is an effective aromatase inhibitor which does not affect glucocorticoid secretion. However, this dose may induce an impairment of aldosterone secretion which is modest and revealed mainly under specific stimulatory conditions, and does not lead to clinical symptoms of hemodynamic dysregulation or a relevant disturbance of serum electrolytes.

Endocrine changes with the aromatase inhibitor fadrozole hydrochloride in breast cancer.

Fadrozole hydrochloride is a potent aromatase inhibitor with proven clinical effectiveness. However, its optimal dose and its effects on serum aldosterone levels/electrolyte balance have been disputed. To resolve these issues, a double-blind randomised endocrine study of three doses of fadrozole hydrochloride [0.5 mg twice daily (bd); 1.0 mg bd; 2.0 mg bd] was conducted in 80 (68 evaluable) postmenopausal patients with advanced breast cancer over a period of 3 months. There were substantial falls in the serum levels of oestradiol, oestrone and oestrone sulphate. For oestrone only, there was a significant effect of dose (on-treatment means: 0.5 mg, 38.0 pmol/l; 1.0 mg, 25.0 pmol/l; 2.0 mg, 23.9 pmol/l). All oestrogens showed a similar pattern in relation to time, with the 3-month mean being higher than those at 1 and 2 months, and this was significant for oestradiol (P = 0.012). There was an indication that complete suppression of oestradiol and oestrone was not maintained throughout the 12-h dosing period, but the data and its interpretation are complicated by a minor diurnal rhythm in these parameters. There were significant increases in 17-hydroxyprogesterone and androstenedione which may be due to a block of 11 beta-hydroxylase. There was a statistically non-significant fall in aldosterone levels (P = 0.06) during treatment (median pretreatment, 446 pmol/l; median decrease, 125 pmol/l). However, the concurrent significant fall in the plasma sodium: potassium ratio indicated that changes in aldosterone secretion did occur. None of these effects on adrenal pathways was of a degree which is likely to have clinically relevant consequences. It is concluded that fadrozole hydrochloride achieves near maximal suppression of oestrogens at 1 mg bd, and that its effects on aldosterone synthesis are unlikely to be of clinical significance.

Inhibition of estrogen biosynthesis and its consequences on gonadotrophin secretion in the male.

Of the gonadal steroids in the male, testosterone is the most important regulator of gonadotrophin secretion. However, whether testosterone affects gonadotrophin secretion directly or whether it must first be aromatized to estrogens is controversial. We have reported extensively on the endocrine and anti-tumor effects of the non-steroidal aromatase inhibitors CGS 16949A and CGS 20267 in adult female rats. In these animals, both inhibitors potently and selectively inhibit estrogen biosynthesis. Thus these agents can be effectively used in studying estrogen-dependent processes. CGS 16949A was administered for 14 days to adult male rats, over a dose range which in females suppresses estradiol and elevates LH. In male rats a suppression of estradiol was seen, however, there was no significant effect on either serum LH or on the weights of androgen-dependent organs. CGS 16949A, when administered to healthy men at a dose of 1 mg b.i.d. for 10 days, causes a significant fall in plasma estradiol and significant elevations of plasma FSH and testosterone. Dose-dependent suppression of serum estradiol and an increase in serum testosterone and LH are seen after administration of single oral doses of CGS 20267. These results indicate that in the male rat, inhibition of aromatization of testosterone to estrogens does not influence gonadotrophin secretion whereas in men the negative feedback exerted by testosterone on gonadotrophin secretion is dependent on the aromatization of testosterone to estrogens.

Clinical use of aromatase inhibitors in the treatment of advanced breast cancer.

The aim of endocrine therapy is to reduce the estrogenic stimulus for tumour growth. After failure of tamoxifen--the standard "first-line" hormonotherapy for advanced breast cancer (ABC)--the most frequently prescribed endocrine therapies are progestins and aromatase inhibitors (AIs) ("second-line" hormonotherapy). Estrogen deprivation through AIs provides effective treatment of hormone-dependent ABC in postmenopausal (PMP) women. Over the past few years, the goals of our research programme were to develop more potent, more selective and better tolerated AIs than our first AI, aminoglutethimide (AG). Lentaron (4-hydroxyandrostenedione, formestane), a highly selective steroidal compound was the first of the new AIs to be used in clinical trials. It is a substrate analogue, administered as an i.m. injection every 2 weeks. It is effective in the treatment of ABC with an objective response rate (ORR) similar to tamoxifen and megestrol acetate (MA) and is generally well tolerated; rare instances of injection site reactions have been reported. Afema (fadrozole HCl), a non-steroidal AI is active orally, and effectively suppresses estrogen levels in PMP women, but it is not completely selective for aromatase when administered at higher than therapeutic doses. At the therapeutic dose of 1 mg twice a day it has an anti-tumour efficacy similar to MA, a good tolerability and no clinically relevant effects on other hormones of the endocrine system. Letrozole is the fourth of our AIs in clinical development. It is a non-steroidal, achiral, orally active, potent and highly selective competitive AI. Clinical endocrine studies have shown that the dose of 0.5 mg a day is the lowest dose achieving maximum estrogen suppression. Over a wide dose range, a lack of clinically relevant effects on other hormones of the endocrine system has confirmed its high selectivity. In four phase Ib/IIa studies in PMP patients with ABC who failed previous therapy, letrozole produced ORRs of 9, 31, 33 and 36%. One phase IIb/III study has been completed and two others are ongoing, comparing two doses of letrozole with MA or AG to confirm the anti-tumour efficacy of letrozole in the treatment of ABC in PMP women after treatment with anti-estrogens. Preliminary results from the completed trial show that letrozole 2.5 mg is superior to 0.5 mg in terms of ORR, time to progression and time to treatment failure, and is superior to the standard dose of MA in terms of ORR and tolerability. Therefore letrozole 2.5 mg can be recommended as a first choice for the treatment of PMP patients with hormone receptor-positive or unknown ABC after anti-estrogen therapy.

Letrozole, a new oral non-steroidal aromastase inhibitor in treating postmenopausal patients with advanced breast cancer. A pilot study.

PURPOSE: To evaluate the endocrine effects as well as the pharmacokinetic parameters, efficacy and safety of letrozole, a new fourth-generation non-steroidal aromatase inhibitor. PATIENTS AND METHODS: Fourteen postmenopausal women with progressive metastatic breast cancer, previously treated with endocrine therapy and/or chemotherapy for advanced disease, were treated with 0.5 mg daily doses of letrozole, orally. Endocrine and pharmacokinetic measurements were made before treatment and on days 14, 28, 56, and 84 of therapy. RESULTS: Letrozole induced a >86% decrease in plasma estrone and a approximately 67% reduction in circulating estradiol from day 14 on. There was a statistically significant decrease in plasma cortisol, which appeared clinically irrelevant since all values remained within the normal range. No significant changes in aldosterone concentration were noted. One patient achieved a complete response (CR) and 4 patients a partial response (PR), with an objective response rate of 36% (95% CI 13% to 65%). Median duration of response was 24 months, ranging from 4 to 44 months. No toxic effects attributable to letrozole were noted in any patient. CONCLUSION: Letrozole appears to be a very promising new antiaromatase drug. The characteristics of the patients more likely to respond, taking into account prior systemic treatment, should be defined by future studies. Further phase II and phase III studies comparing letrozole to other available second or even first-line endocrine-therapy agents, are warranted.

Letrozole (CGS 20267), a new oral aromatase inhibitor for the treatment of advanced breast cancer in postmenopausal patients.

Letrozole is a new orally, active, potent, and highly specific non-steroidal aromatase inhibitor. Letrozole is about 200 and 10000 times as potent as aminoglutethimide (AG) in vitro and in vivo, respectively. Letrozole was tested in healthy men and postmenopausal women and in postmenopausal patients with advanced breast cancer (ABC). Levels of circulating estrogens decreased by more than 75 to 95% from pre-treatment levels have been observed in patients treated with daily doses of 0.1 to 5 mg letrozole. No clinically relevant changes in other hormones of the endocrine system were found. In four phase Ib/IIa trials, letrozole has shown anti-tumor activity in postmenopausal patients with ABC previously treated with hormonotherapy and/or chemotherapy. Letrozole was well tolerated. Phase IIb/III studies are on going to compare two doses of letrozole with megestrol acetate or AG in order to confirm the anti-tumor efficacy of letrozole in the treatment of ABC in postmenopausal patients who progressed/relapsed following treatment with anti-estrogens.

Letrozole (CGS 20267). A phase I study of a new potent oral aromatase inhibitor of breast cancer.

BACKGROUND: Letrozole (CGS 20267), a triazole derivative, is a new, once-daily, oral nonsteroidal inhibitor of aromatase activity. METHODS: In this Phase I trial, 23 heavily pretreated postmenopausal patients with metastatic breast cancer received letrozole at doses ranging from 0.1 to 5.0 mg once daily. RESULTS: No hematologic, biochemical, or significant clinical toxicity was encountered. Serial steroid measurements were determined in 19 of these patients. Letrozole at all doses tested produced a marked suppression of plasma estrone, estradiol, estrone sulfate, and urine estrone and estradiol. This was observed within 24 hours of the initial dose of letrozole and resulted in a greater than 90% suppression of plasma and urinary estrogen levels within 2 weeks. Letrozole appears to be highly selective in its action and does not compromise glucocorticoid or mineralocorticoid production or thyroid function. Of the 21 evaluable patients, there were 2 with partial responses and 7 with stable disease. CONCLUSIONS: Letrozole is a well tolerated, potent, and specific inhibitor of estrogen biosynthesis in postmenopausal patients with metastatic breast cancer.

Therapeutic effects of the aromatase inhibitor fadrozole hydrochloride in advanced breast cancer.

The endocrine and therapeutic effects of the aromatase inhibitor fadrozole hydrochloride have been assessed in 80 post-menopausal patients with recurrent breast cancer after tamoxifen failure. Treatment allocation was randomly 0.5, 1.0 or 2.0 mg orally b.d. Eight patients were not assessable for response. All patients were evaluated for toxicity (intent-to-treat analysis). In general, the patients' characteristics were well balanced between the three randomised groups. The endocrine data from this study previously reported suggest a dose-related suppression of oestrone, but not oestradiol or oestrone sulphate. The objective response rate was 17% (95% CI 8.9-27.3%) with no complete responders. Fifteen patients (21%) had stable disease (NC) and 45 patients (63%) had progressive disease (PD). The median duration of objective response was 36 weeks. The median time to treatment failure was 12.7 weeks. The log-rank test showed no statistical difference between the dosage groups. The main adverse events reported were mild to moderate severity: nausea in 11 patients (15%), hot flashes in four (5%) and somnolence in three (4%). No serious adverse events were reported. In conclusion, fadrozole is a clinically active aromatase inhibitor with a low incidence of side-effects and phase III clinical trials in post-menopausal women are currently under way.