Abstract OT2-1-10: RAD1901, a novel tissue-selective estrogen receptor degrader (SERD) demonstrates estrogen receptor engagement in a phase 1 clinical study
Authors: Hattersley Gary , David Frank , Harris Alan , Clarkin Marcie , Banks Kate , Williams Greg , Glaudemans Andor , Doorduin Janine , Koole Michel , de Vries Erik , Lyttle Rich 
Published: May 2015

Abstract
Despite advances in the treatment of metastatic breast cancer through modulation of estrogen receptor (ER) activity, after initial efficacy, the use of hormonal therapies is frequently followed by the development of de novo or acquired endocrine resistance. There therefore exists a potentially significant opportunity for new agents that can overcome endocrine resistance. One mechanism by which this could be achieved is through degradation of the estrogen receptor and thereby elimination of estrogen receptor mediated signaling. RAD1901 is a novel, non-steroidal small molecule that selectively binds and degrades the ER that is currently being evaluated for the treatment of metastatic breast cancer. RAD1901 has demonstrated good tissue selectivity in preclinical models, its does not stimulate the uterine endometrium, and it protects against bone loss in an ovariectomy-induced osteopenia rat model. In addition, we believe that RAD1901 has the ability to cross the blood-brain barrier. In vitro, treatment of tamoxifen-sensitive and resistant human breast cancer cell lines with RAD1901 resulted in a potent degradation of the ER (IC50 1.6nM in MCF7 cells) and inhibition of both basal and estradiol-stimulated proliferation. In a mouse xenograft tumor model with MCF7, oral dosing with RAD1901 resulted in a significant decrease in estradiol-stimulated tumor growth. An ongoing phase 1 clinical study in healthy volunteers is being conducted to evaluate the tolerability, safety and pharmacokinetics of RAD1901 at escalating doses. This study is also using 18F-estradiol positron emission tomography (FES-PET) to provide a pharmacodynamic assessment of estrogen receptor engagement/turnover. Following 6-days of daily treatment with RAD1901, at doses that were well tolerated, a complete suppression of FES-PET signal was observed, with standardized uptake values (SUV) comparable to background tissues. The relationship between PK and PD will be presented. To date, the maximum tolerated dose of RAD1901 has not been determined. In conclusion, RAD1901 is a novel SERD that we believe has the potential to be used for the treatment of hormone driven and hormone resistant metastatic breast cancers, including breast cancer brain metastasis. The proposed phase 1b study design in metastatic breast cancer will be outlined.
Citation Format: Gary Hattersley, Frank David, Alan Harris, Marcie Clarkin, Kate Banks, Greg Williams, Andor Glaudemans, Janine Doorduin, Michel Koole, Erik de Vries, Rich Lyttle. RAD1901, a novel tissue-selective estrogen receptor degrader (SERD) demonstrates estrogen receptor engagement in a phase 1 clinical study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT2-1-10.