Biologic Efficacy of Liarozole Confirmed in Metastatic Breast Cancer

March 1, 1997

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

Response to liarozole fumarate has been observed in patients with receptor-positivemetastatic breast cancer, as well as those with receptor-unknown disease,confirming the biologic efficacy of this agent. The first clinical studyof the role of liarozole in breast cancer was described by Dr. P. E. Gossand colleagues of The Toronto Hospital in Canada at the 19th Annual SanAntonio Breast Cancer Symposium. This ongoing study, which began in October1994 and concluded in February 1997, examined the effects of liarozolein postmenopausal patients.

A benzimidazole developed primarily for the treatment of prostate cancer,liarozole inhibits the P450-dependent enzyme systems that mediate bothretinoic acid catabolism and estrogen biosynthesis. The agent was administeredat a dosage of 150 mg PO bid and increased to 300 mg PO bid at 2 weeks,tolerability permitting, until disease progression. Response was assessedby International Union Against Cancer (UICC) criteria at 2-month intervals.

Patients enrolled in the study had estrogen receptor (ER)-negative diseasein first relapse, ER-positive or ER-unknown disease that was refractoryto tamoxifen (Nolvadex), ER-positive or ER-unknown disease resistant tohormonal therapy, or ER-positive or ER-negative metastatic disease primarilyrefractory or resistant to chemotherapy. All patients had an Eastern CooperativeOncology Group (ECOG) performance status of 0 to 3 and adequate hematologicand hepatic function.

Estradiol suppression occurred within 2 weeks of treatment and was maintainedbelow assay detection levels throughout the treatment period. There wasno blunting of cortisol or aldosterone response to adrenocorticotropichormone stimulation. Descriptive statistics showed an apparent downwardtrend in testosterone, dehydroepiandrosterone, and insulin-like growthfactor-1 levels within 2 months on treatment. No trend for follicle-stimulatinghormone or luteinizing hormone was noted. Inferential statistics on thesedata will be performed at the study's conclusion.

Data for 61 patients were validated at the time of the report, with10 patients responding and 10 showing stabilization of disease. Eight ofthe 10 responders and 6 of the 10 patients with stable disease had soft-tissuemetastases. Adverse events were mainly mild to moderate in severity andappeared primarily similar to a hypervitaminosis A syndrome (skin rash,pruritis, xerophthalmia, xerostomia, anorexia, nausea, alopecia, and peripheraledema), which is consistent with the agent's increase of endogenous levelsof retinoic acid.