A Randomized, Open-label, Presurgical, Window-of-Opportunity Study Comparing the Pharmacodynamic Effects of the Novel Oral SERD AZD9496 with Fulvestrant in Patients with Newly Diagnosed ER+ HER2− Primary Breast Cancer

Abstract

Purpose: Fulvestrant, the first-in-class selective estrogen receptor (ER) degrader (SERD), is clinically effective in patients with ER+ breast cancer, but it has administration and pharmacokinetic (PK) limitations. Pharmacodynamic (PD) data suggests complete ER degradation is not achieved at fulvestrant's clinically feasible dose. This pre-surgical study (NCT03236974) compared the PD effects of fulvestrant with AZD9496, a novel, orally bioavailable, non‑steroidal, potent SERD, in treatment‑naive patients with ER+ human epidermal growth factor receptor 2 negative primary breast cancer awaiting curative intent surgery. Methods: Patients were randomized 1:1 to receive AZD9496 250 mg twice daily from Day (D) 1 for 5-14 days, or fulvestrant 500 mg on D 1. On-treatment imaging‑guided core tumor biopsies were taken between D 5-14 and compared with pre‑treatment diagnostic biopsies. The primary objective was to compare the effects of AZD9496 and fulvestrant on ER expression. Secondary objectives included changes in progesterone receptor (PR) and Ki-67 PK/PD relationships and safety. Results: Forty-six women received treatment (AZD9496 n=22; fulvestrant n=24); 35 paired biopsies were evaluable (AZD9496 n=15; fulvestrant n=20). The least square mean estimate for ER H-score reduction was 24% after AZD9496 versus 36% after fulvestrant treatment (p=0.86). AZD9496 also reduced PR H-scores (-33.3%) and Ki‑67 levels (-39.9%) from baseline, but was also not superior to fulvestrant (PR: -68.7%, p=0.97; Ki‑67: ‑75.4%, p=0.98). No new safety findings were identified. Conclusion: This was the first pre‑surgical study to demonstrate that an oral SERD impacts its key biological targets. However, AZD9496 was not superior to fulvestrant at the dose tested.