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Pharmacokinetic and pharmacodynamic analysis of fulvestrant in preclinical models of breast cancer to assess the importance of its estrogen receptor-α degrader activity in antitumor efficacy.

Abstract：

PURPOSE:Fulvestrant is a selective estrogen receptor downregulator (SERD) that is approved for first- or second-line use as a single agent or in combination with cyclin dependent kinase or phosphatidylinositol 3-kinase inhibitors for the treatment of metastatic breast cancer. Fulvestrant exhibits exceptionally effective antitumor activity in preclinical models of breast cancer, a success that has been attributed to its robust SERD activity despite modest receptor downregulation in patient tumors. By modeling human exposures in animal models we probe the absolute need for SERD activity. METHODS:Three xenograft models of endocrine therapy-resistant breast cancer were used to evaluate the efficacy of fulvestrant administered in doses historically used in preclinical studies in the field or by using a dose regimen intended to model clinical exposure levels. Pharmacokinetic and pharmacodynamic analyses were conducted to evaluate plasma exposure and intratumoral ER downregulation. RESULTS:A clinically relevant 25 mg/kg dose of fulvestrant exhibited antitumor efficacy comparable to the historically used 200 mg/kg dose, but at this lower dose it did not result in robust ER downregulation. Further, the antitumor efficacy of the lower dose of fulvestrant was comparable to that observed for other oral SERDs currently in development. CONCLUSION:The use of clinically unachievable exposure levels of fulvestrant as a benchmark in preclinical development of SERDs may negatively impact the selection of those molecules that are advanced for clinical development. Further, these studies suggest that antagonist efficacy, as opposed to SERD activity, is likely to be the primary driver of clinical response.

journal_name

Breast Cancer Res Treat

journal_title

Breast cancer research and treatment

authors

Wardell SE,Yllanes AP,Chao CA,Bae Y,Andreano KJ,Desautels TK,Heetderks KA,Blitzer JT,Norris JD,McDonnell DP

doi

10.1007/s10549-019-05454-y

subject

Has Abstract

pub_date

2020-01-01 00:00:00

pages

67-77

issue

eissn

0167-6806

issn

1573-7217

pii

10.1007/s10549-019-05454-y

journal_volume

179

pub_type

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Pharmacokinetic and pharmacodynamic analysis of fulvestrant in preclinical models of breast cancer to assess the importance of its estrogen receptor-α degrader activity in antitumor efficacy.