A phase 1 dose escalation study of RAD1901, an oral selective estrogen receptor degrader, in healthy postmenopausal women

Estrogen and the estrogen receptor (ER) are known to be prominent drivers of breast tumourigenesis and breast cancer progression. Hormonal agents that target the ER such as selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs) are routinely used for the management for ER+ breast cancer. Fulvestrant is currently the only SERD approved for the treatment of ER-positive metastatic breast cancer, however, despite its clinical efficacy, the utility of fulvestrant has been limited by the amount of drug that can be administered in a single injection, the reduced bioavailability and the development of resistance in some patients. To overcome some of the challenges associated with current endocrine therapies there is a need for more durable and more effective ER-targeted therapies.RAD1901 is a novel, non-steroidal, orally bioavailable SERD. Preclinical studies demonstrated a favorable tissue selectivity profile, dose dependent ER degradation and potent inhibition of in vitro breast cancer cell proliferation. Significant tumor regression was consistently observed with RAD1901 treatment, compared to Tamoxifen or Fulvestrant in MCF7 and patient derived xenograft models, including those harboring ESR1 mutations. Here we describe a Phase 1 clinical study that was conducted in 52 healthy postmenopausal female volunteers. Cohorts of 10 subjects (2 placebo, 8 RAD1901 treated) were dosed with 200 mg, 500 mg, 750 mg or 1000 mg for 7 days. Additional subjects were enrolled to an 18F-estradiol positron emission tomography (FES-PET) cohort to evaluate the 200 mg (n=7 subjects) and 500 mg (n=6 subjects) dose levels. All dose levels were generally well tolerated with a total of 43/52 subjects completing the study. Pharmacokinetic analysis demonstrated good plasma exposure with dose proportional increases. FES-PET was performed at baseline and after 7 days of treatment with RAD1901, to assess estrogen receptor engagement. Standardized uptake values (SUV) pre- and post-treatment demonstrated a complete attenuation of FES-PET signal in ER-rich tissues such as the uterus at the 500 mg/day dose level, whereas almost 80% reduction in the signal was observed at the 200 mg/day dose level. Based on these preclinical and clinical results, RAD1901 is currently being investigated in a Phase 1 study for the treatment of hormone driven and hormone resistant metastatic breast cancers