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Liarozole Fumarate (R85246): In the Treatment of ER Negative, Tamoxifen Refractory or Chemotherapy Resistant Postmenopausal Metastatic Breast Cancer

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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; n = 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 (150–300 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; 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 (9.1–1839 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.

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Authors and Affiliations

  1. Princess Margaret Hospital, Toronto

    Paul E. Goss, Kathrin Strasser, Ricardo Marques, Mark Clemons, Amit Oza, Michael Crump, Mohamed Abdolell & Shangle Qi

  2. Ottawa Regional Cancer Centre-Civic Division, Ottawa

    Rakesh Goel

  3. Mount Sinai Hospital, Toronto

    Martin Blackstein

  4. Credit Valley Hospital, Mississauga

    Leonard Kaizer

  5. Kingston General Hospital, Kingston, Ontario

    Ernest E. Sterns

  6. Cross Cancer Institute, Edmonton, Alberta, Canada

    Jean-Marc Nabholtz

  7. Janssen Research Foundation, Beerse, Belgium

    Roland De Coster

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  1. Paul E. Goss
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Goss, P.E., Strasser, K., Marques, R. et al. Liarozole Fumarate (R85246): In the Treatment of ER Negative, Tamoxifen Refractory or Chemotherapy Resistant Postmenopausal Metastatic Breast Cancer. Breast Cancer Res Treat 64, 177–188 (2000). https://doi.org/10.1023/A:1006480504790

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