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

Abstract

Three phase II studies were conducted to determine the efficacy and tolerability of liarozole fumarate (R85246; liarozole), a retinoic acid metabolism blocking agent (RAMBA) and aromatase inhibitor. Additionally, animal experiments in the MNU-induced rat mammary tumor model and in immature ovariectomized rats were conducted to further elucidate liarozole's mechanisms of action. Patients were postmenopausal with either: ER negative disease in first relapse (Group 1: 1n = 16); ER positive or unknown disease refractory to tamoxifen (Group 2; n = 16); ER positive, negative or unknown disease resistant or refractory to chemotherapy (Group 3; n = 27). Treatment was liarozole (150-300mg) twice daily orally until disease progression. Response rates were: 25% in group 1 (95% CI 11.0-52.3%: median duration (MD) 20 months; range 2-36.5); 25% in group 2 (95% CI 11.0-52.3%; MD 6.5 months: range 3.5-38): 11% in group 3 (95% CI 4.2-29.2%; MD 7 months; range 3-8.5). No significant improvement in quality of life scores (FLI-C) was noted. Toxicities observed were predominantly dermatological (skin disorders: 88%; dry mouth/eyes/lips: 69%). Plasma estradiol decreased from mean pre-treatment levels of 72.7 pM (9.1-1,839 pM) to below detection (9.2 pM) after 1 month. Liarozole, but not vorozole, partially inhibited estradiol induced uterine hypertrophy and demonstrated dose-dependent anti-tumor effects in the rats, only partially overcome by coadministration of estradiol. The clinical responses observed, together with our preclinical results, confirm liarozole's dual mechanism of action and provide a rationale for further evaluation of RAMBAs in the treatment of breast cancer.

• Authors: P E Goss, K Strasser, R Marques, M Clemons, A Oza, R Goel, M Blackstein, L Kaizer, E E Sterns, J M Nabholtz, R De Coster, M Crump, M Abdolell, S Qi
• Journal: Breast cancer research and treatment (Breast Cancer Res Treat) Vol. 64 Issue 2 Pg. 177-88 (Nov 2000) ISSN: 0167-6806 [Print] Netherlands
• PMID: 11194453 (Publication Type: Clinical Trial, Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Hormonal
• Imidazoles
• Receptors, Estrogen
• Tamoxifen
• Estradiol
• liarozole

Topics

• Administration, Oral
• Adult
• Aged
• Aged, 80 and over
• Animals
• Antineoplastic Agents, Hormonal (administration & dosage, pharmacology, therapeutic use)
• Breast Neoplasms (drug therapy, pathology)
• Disease Progression
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm
• Estradiol (blood)
• Female
• Humans
• Imidazoles (administration & dosage, pharmacology, therapeutic use)
• Mammary Neoplasms, Experimental (drug therapy)
• Middle Aged
• Neoplasm Metastasis
• Postmenopause
• Quality of Life
• Rats
• Receptors, Estrogen (analysis)
• Tamoxifen (pharmacology)
• Treatment Outcome