Clinical development of aromatase inhibitors for the treatment of breast and prostate cancer

Abstract

Numerous aromatase inhibitors are under development for breast cancer treatment. The major aims are to obtain a drug which at its dose of maximum efficacy has no effect on other endocrine systems, has no clinical side-effects and is convenient to administer. During the early clinical stages of development detailed endocrine and pharmacokinetic analyses are a valuable aid in the establishment of a drug's selectivity and its optimum dose, route and frequency of administration. The optimal dose may be defined as the minimum that will achieve maximal and sustained suppression of aromatase activity. This has generally been measured indirectly by comparing the suppression of plasma oestrogen levels at a selection of dosages. This approach has major advantages in speeding dose selection for therapeutic clinical trials. However, it also has some disadvantages including the unproven assumption that clinical response has a direct relationship with the degree of oestrogen suppression. In addition there are technical difficulties of analysis, of wide variability in endocrine response between patients and of demonstrating oestrogen suppression to be equivalent between doses (necessary to show maximal suppression). The direct measurement of aromatase inhibition in vivo by isotopic infusion analysis provides support to these indirect estimates. Its value is shown by our recent results with CGS16949A. The additional value of collating pharmacokinetic and endocrine measurements is apparent from our investigations of 4-hydroxyandrostenedione (4-OHA) and pyridoglutethimide. A consideration of our experience with these inhibitors may be helpful in directing the development of future agents. Whilst the value of aromatase inhibition in breast cancer is established its value in prostatic cancer is in doubt: we have found that 4-OHA is only poorly efficacious in advanced prostatic cancer.