Liarozole fumarate (R85246): In the treatment of ER negative, tamoxifen refractory or chemotherapy resistant postmenopausal metastatic breast cancer

Three phase II studies were conducted to determine the efficacy and tolerab ility of liarozole fumarate (R85246; liarozole), a retinoic acid metabolism blocking agent (RAMBA) and aromatase inhibitor. Additionally, animal exper iments in the MNU-induced rat mammary tumor model and in immature ovariecto mized rats were conducted to further elucidate liarozole's mechanisms of ac tion. Patients were postmenopausal with either: ER negative disease in firs t relapse (Group 1; n = 16); ER positive or unknown disease refractory to t amoxifen (Group 2; n = 16); ER positive, negative or unknown disease resist ant or refractory to chemotherapy (Group 3; n = 27). Treatment was liarozol e (150-300 mg) twice daily orally until disease progression. Response rates were: 25% in group 1 (95% CI 11.0-52.3%; median duration (MD) 20 months; r ange 2-36.5); 25% in group 2 (95% CI 11.0-52.3%; MD 6.5 months; range 3.5-3 8); 11% in group 3 (95% CI 4.2-29.2%; MD 7 months; range 3-8.5). No signifi cant improvement in quality of life scores (FLI-C) was noted. Toxicities ob served were predominantly dermatological (skin disorders: 88%; dry mouth/ey es/lips: 69%). Plasma estradiol decreased from mean pre-treatment levels of 72.7 pM (9.1-1839 pM) to below detection (9.2 pM) after 1 month. Liarozole , but not vorozole, partially inhibited estradiol induced uterine hypertrop hy and demonstrated dose-dependent anti-tumor effects in the rats, only par tially overcome by coadministration of estradiol. The clinical responses ob served, together with our preclinical results, confirm liarozole's dual mec hanism of action and provide a rationale for further evaluation of RAMBAs i n the treatment of breast cancer.