Vorozole results in greater oestrogen suppression than formestane in postmenopausal women and when added to goserelin in premenopausal women with advanced breast cancer

Abstract

The high potency and selectivity of new aromatase inhibitors has translated to greater efficacy and improved tolerability in comparison with established second-line hormonal agents for advanced breast cancer in phase III clinical trials. Two pharmacological studies are reported which assess the use of one of these inhibitors, vorozole, in combination or comparison with well-established methods of oestrogen deprivation in pre and postmenopausal patients. When combined with the gonadotrophin-releasing hormone agonist (GnRHa) goserelin in 10 premenopausal patients, vorozole markedly enhanced the suppression of serum levels of oestrone, oestradiol and, oestrone sulphate beyond that achieved by goserelin alone (by a mean 74%, 83%, and 89%, respectively). The combination was well-tolerated and had no significant effects on androgen levels. Vorozole was compared with formestane in 13 postmenopausal women and serum oestrone, oestradiol, and oestrone sulphate levels were suppressed by 47%, 30%, and 70%, respectively, more by vorozole than by the steroidal aromatase inhibitor. Again the tolerability was excellent. The plasma oestrogen levels in the postmenopausal patients on vorozole were lower than in the premenopausal patients on goserelin plus vorozole, indicating that ovarian oestrogen synthesis may be relatively resistant to aromatase inhibition, even during GnRHa treatment. Thus, in both pre and postmenopausal patients substantially greater suppression of oestrogen can be achieved by vorozole compared with alternative approaches. Existing clinical-pharmacological correlates suggest that these increases in pharmacological effectiveness may result in enhanced clinical effectiveness.

Impaired Tamoxifen Metabolism Reduces Survival in Familial Breast Cancer Patients

“…Importantly, aromatase inhibitors do not sufficiently inhibit ovarian estrogen synthesis to be a viable monotherapy in premenopausal women, and a high proportion of women with familial tumors will be premenopausal at presentation. Therefore, the use of luteinizing hormone-releasing hormone analogues, including goserelin, has been considered either alone or in combination with aromatase inhibitors in this patient group (44,45), and major international studies are under way to test this hypothesis (46). The results of our study suggest that in patients with BRCA2 mutations and low CYP2D6 activity, who are postmenopausal, an aromatase inhibitor would be the drug of choice.…”

Antitumour and biological effects of letrozole and GnRH analogue as primary therapy in premenopausal women with ER and PgR positive locally advanced operable breast cancer

“…Available data range from anecdotal reports to small phase II studies and include mainly the second-generation steroidal inhibitor formestane other than the non-steroidal inhibitors anastrozole and vorozole. In all reports, a further inhibition of oestradiol levels was observed after therapy with aromatase inhibitor (Dowsett et al, 1992(Dowsett et al, , 1999Celio et al, 1999;Forward et al, 2004). In our study, we evaluated the levels of oestradiol at different time points during the study to determine the hormonal status.…”

Estrogen suppression in premenopausal women following 8 weeks of treatment with exemestane and triptorelin versus triptorelin alone

“…In premenopausal women with advanced breast cancer, the AUC 0-t(last) = Area under the curve from predose to last detectable concentration; C last = Concentration at the last detectable level; C max = Maximum serum concentration; EX = Exemestane; P = Placebo; t max = Time of occurrence of C max ; T = Triptorelin a n = 13 combination of T with the aromatase inhibitor formestane has been shown to reduce plasma E 2 concentrations by approximately 70% more than T alone [17]. Similarly, the aromatase inhibitor vorozole, when combined with goserelin in premenopausal patients with advanced breast cancer, enhanced E 2 suppression by 77% beyond that achieved by goserelin alone [18]. In addition, there is evidence that in premenopausal women who have experienced disease progression while taking goserelin plus tamoxifen, a switch to the aromatase inhibitor anastrozole can reduce peripherally circulating estrogen by an additional 76%, with corresponding clinical benefit [19].…”