ENDOCRINE AND CLINICAL EFFECTS OF EXEMESTANE (PNU-155971), A NOVEL STEROIDAL AROMATASE INHIBITOR, IN POSTMENOPAUSAL BREAST-CANCER PATIENTS - A PHASE-I STUDY

Clinical and endocrinological effects of exemestane (6-methylenandrost a-1,4-diene-3,17-dione; PNU 155971) were evaluated in an open Phase I study. Thirteen postmenopausal women suffering from advanced breast ca ncer received exemestane in escalating doses over a 12-week period. St arting on 5 mg once daily (o.d.), exemestane was subsequently escalate d at 2-week intervals to 10, 25, 50, 100, and 200 mg o.d. Each patient subsequently continued treatment on the highest tolerated dose until time of progression. One patient terminated treatment after 6 days due to diarrhea that was probably not related to drug therapy, although a relationship could not be excluded. Apart from this, no serious side effects were seen during the dose escalation period. Exemestane (10 mg o.d.) caused maximal suppression of plasma estradiol (E-2) and estron e (E-1) to a mean of 14.6 and 5.8% of pretreatment levels, respectivel y, whereas 25 mg of exemestane o.d. suppressed estrone sulfate (E1S) t o 8.9% of pretreatment levels. No fall in adrenal steroid levels was r ecorded, Exemestane (5 mg o.d.) suppressed urinary E-2 and E-1 to a me an of 11.9 and 12.2% of pretreatment levels, respectively. Administeri ng exemestane at doses of 50-200 mg o.d. caused no further suppression of urinary E-1, whereas urinary E-2 fell to 6-7% of pretreatment leve ls. Median time to progression was 63 weeks.