The current NCCN treatment guidelines for ER+ breast cancer involves the use of approved agents such as fulvestrant, tamoxifen and aromatase inhibitors that either inhibit estrogen production or block estrogen receptor binding. While the initial treatment regimens with these selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs) is often successful, many women eventually relapse with more aggressive forms of endocrine-resistant disease. To begin to overcome some of the challenges associated with current therapies including exposure limitations and intramuscular administration, we have developed RAD1901, a novel, non-steroidal, orally available SERD. Preclinical studies with RAD1901 have demonstrated potent dose dependent ER degradation consistent with a SERD mechanism of action, as well as potent inhibition of proliferation in vitro in breast cancer cell lines. RAD1901 also demonstrated significant anti-tumor efficacy in vivo, and notably single agent regressions in both MCF7 and a primary patient derived xenograft models harboring an ESR1 mutations.

A phase 1 monotherapy study conducted in healthy postmenopausal female volunteers evaluated forty four subjects treated once daily with RAD1901 with doses ranging from 200 mg/day up to 1000 mg/day for 7 days. All dose levels were generally well tolerated and pharmacokinetic analysis demonstrated plasma exposures consistent with preclinical efficacy in ER+ breast cancer models. Furthermore, 18F-estradiol positron emission tomography (FES-PET) was also performed at baseline and after 7 days of RAD1901 treatment, to evaluate estrogen receptor engagement. Standardized uptake values (SUV) pre- and post-treatment with RAD1901 demonstrated complete attenuation of FES-PET signal in ER+ tissues such as the uterus from the 200 mg/day dose level. Taken together, these results provide strong preclinical and clinical rationale for the development of RAD1901 as a potent and selective oral SERD for the treatment of hormone driven and hormone resistant ER + metastatic breast cancers.

RAD1901-005 is a Phase 1 study currently enrolling ER+ advanced metastatic breast cancer patients. The study consists of two parts: a monotherapy dose escalation followed by a safety expansion at the maximum tolerated dose (MTD). The dose escalation will follow a standard 3+3 design with once daily dosing to establish, safety, tolerability, and PK. Once the MTD for RAD1901 has been established, the safety expansion will further evaluate the safety, tolerability, biomarkers and preliminary efficacy at the recommended phase 2 dose (RP2D) following a continuous once daily schedule. Key inclusion criteria include post-menopausal women aged 18 years or older, with advanced ER positive, HER2 negative breast cancer, who have received ≤ 2 prior chemotherapy regimens in the metastatic setting and > 6 months of prior endocrine therapy. Patient enrollment started in early 2015, and is currently ongoing. identifier: NCT02338349.

Citation Format: Harb W, Garner F, McDermott J, Zimmerman T, Williams G, Hattersley G, Purandare D. A phase 1 study of RAD1901, a novel, orally available, selective estrogen receptor degrader, for the treatment of ER positive advanced breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT2-01-10.