Response to liarozole fumarate has been observed in patients with receptor-positive
metastatic breast cancer, as well as those with receptor-unknown disease,
confirming the biologic efficacy of this agent. The first clinical study
of the role of liarozole in breast cancer was described by Dr. P. E. Goss
and colleagues of The Toronto Hospital in Canada at the 19th Annual San
Antonio Breast Cancer Symposium. This ongoing study, which began in October
1994 and concluded in February 1997, examined the effects of liarozole
in postmenopausal patients.
A benzimidazole developed primarily for the treatment of prostate cancer,
liarozole inhibits the P450-dependent enzyme systems that mediate both
retinoic acid catabolism and estrogen biosynthesis. The agent was administered
at a dosage of 150 mg PO bid and increased to 300 mg PO bid at 2 weeks,
tolerability permitting, until disease progression. Response was assessed
by International Union Against Cancer (UICC) criteria at 2-month intervals.
Patients enrolled in the study had estrogen receptor (ER)-negative disease
in first relapse, ER-positive or ER-unknown disease that was refractory
to tamoxifen (Nolvadex), ER-positive or ER-unknown disease resistant to
hormonal therapy, or ER-positive or ER-negative metastatic disease primarily
refractory or resistant to chemotherapy. All patients had an Eastern Cooperative
Oncology Group (ECOG) performance status of 0 to 3 and adequate hematologic
and hepatic function.
Estradiol suppression occurred within 2 weeks of treatment and was maintained
below assay detection levels throughout the treatment period. There was
no blunting of cortisol or aldosterone response to adrenocorticotropic
hormone stimulation. Descriptive statistics showed an apparent downward
trend in testosterone, dehydroepiandrosterone, and insulin-like growth
factor-1 levels within 2 months on treatment. No trend for follicle-stimulating
hormone or luteinizing hormone was noted. Inferential statistics on these
data will be performed at the study's conclusion.
Data for 61 patients were validated at the time of the report, with
10 patients responding and 10 showing stabilization of disease. Eight of
the 10 responders and 6 of the 10 patients with stable disease had soft-tissue
metastases. Adverse events were mainly mild to moderate in severity and
appeared primarily similar to a hypervitaminosis A syndrome (skin rash,
pruritis, xerophthalmia, xerostomia, anorexia, nausea, alopecia, and peripheral
edema), which is consistent with the agent's increase of endogenous levels
of retinoic acid.