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(Drug information on 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.