Background Endocrine therapy, the therapeutic mainstay for estrogen receptor-positive breast cancer, targets estrogen receptor activity and/or estrogen synthesis. CDK4/6 inhibitors cause cell cycle arrest and significantly decrease expression of the proliferation biomarker Ki67 when used in conjunction with aromatase inhibitors such as anastrozole. Giredestrant, a highly potent, nonsteroidal, oral, selective estrogen receptor antagonist and degrader, achieves robust estrogen receptor occupancy, is well tolerated, and has encouraging antitumor activity as a monotherapy and in combination with the CDK4/6 inhibitor palbociclib in metastatic breast cancer. coopERA Breast Cancer (NCT04436744) is a phase II study investigating 2 weeks of giredestrant versus anastrozole in a window-of-opportunity phase, followed by 4 months of giredestrant plus palbociclib versus anastrozole plus palbociclib in a neoadjuvant phase in postmenopausal women with estrogen receptor-positive, HER2-negative, untreated early breast cancer. We will report the results of the primary analysis. Methods Eligible patients who had measurable cT1c (≥1.5 cm)-cT4a-c estrogen receptor-positive, HER2-negative, untreated early breast cancer and baseline Ki67 score ≥5% were randomized 1:1 to 1 mg oral, daily anastrozole or 30 mg oral, daily giredestrant on Days 1-14 (window-of-opportunity phase lasting 14 days) followed by daily dosing for four 28-day cycles in combination with 125 mg oral palbociclib on Days 1-21 (neoadjuvant phase lasting 16 weeks) before surgery. Patients were stratified according to T status, Ki67 score, and progesterone receptor status. The primary efficacy endpoint was centrally assessed geometric mean relative Ki67 score change from baseline to Week 2 during the window-of-opportunity phase, which is reflective of the ability of endocrine therapies to suppress tumor-cell proliferation, and is a surrogate marker for clinical outcomes. The secondary efficacy endpoint is complete cell cycle arrest rate (CCCA), defined as Ki67 score ≤2.7%, at Week 2. Safety was also assessed. Results Results of a previous interim analysis (including 83 of the planned 202 patients) demonstrated a greater relative reduction of Ki67 at 2 weeks with giredestrant (reduction from baseline to Week 2 geometric mean = 80%; 95% CI = -85%, -72%) compared with anastrozole (reduction from baseline to Week 2 geometric mean = 67%; 95% CI = -75%, -56%; P = 0.0222). Similarly, consistent Ki67 suppression was observed in patients with baseline Ki67 ≥20% (83% reduction with giredestrant versus 71% reduction with anastrozole) or <20% (65% versus 24% reductions). At Week 2, 25% of tumors exhibited CCCA with giredestrant versus 5.1% with anastrozole (a 20% difference; 95% CI = -37%, -3%). Safety results were consistent with the known safety profile for giredestrant. Fewer patients experienced adverse events (AEs) related to giredestrant (28%) than to anastrozole (38%), and no grade ≥3 AEs or serious adverse events were assessed as related to giredestrant. We will present the results of the primary analysis, which will include data from all enrolled patients, and will report the primary and secondary efficacy endpoints (including patients with Ki67 >20%), and updated safety. Conclusions The study will proceed to the primary analysis. We expect to see encouraging results based on the favorable interim analysis data that demonstrated the superior activity of giredestrant, an oral selective estrogen receptor antagonist and degrader, compared with anastrozole.

Citation Format: Sara A Hurvitz, Vanesa Quiroga, Yeon Hee Park, Aditya Bardia, Vanesa López-Valverde, Jutta Steinseifer, Tharu M Fernando, Gonzalo Spera, Cloris Xue, Peter A Fasching. Neoadjuvant giredestrant (GDC-9545) + palbociclib versus anastrozole + palbociclib in postmenopausal women with estrogen receptor-positive, HER2-negative, untreated early breast cancer: Primary analysis of the randomized, open-label, phase II coopERA breast cancer study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD13-06.