Phase Ia/b Study of Giredestrant ±Palbociclib and ±Luteinizing Hormone-releasing Hormone Agonists in Estrogen Receptor-positive, HER2-negative, Locally Advanced/Metastatic Breast Cancer

Giredestrant is an investigational next-generation oral selective estrogen receptor antagonist and degrader for the treatment of estrogen receptor-positive (ER+) breast cancer. We present the primary analysis results of the phase Ia/b GO39932 study (NCT03332797).Patients with ER+, HER2-negative locally advanced/metastatic breast cancer previously treated with endocrine therapy received single-agent giredestrant (10, 30, 90, or 250 mg), or giredestrant (100 mg) ±palbociclib 125 mg ±luteinizing hormone-releasing hormone (LHRH) agonist. Detailed cardiovascular assessment was conducted with giredestrant 100 mg. Endpoints included safety (primary), pharmacokinetics, pharmacodynamics, and efficacy.As of January 28, 2021, with 175 patients enrolled, no dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. Adverse events (AEs) related to giredestrant occurred in 64.9% and 59.4% of patients in the single-agent ±LHRH agonist and giredestrant +palbociclib ±LHRH agonist cohorts, respectively (giredestrant-only related grade 3/4 AEs were reported in 4.5% of patients across the single-agent cohorts and 3.1% of those with giredestrant +palbociclib). Dose-dependent asymptomatic bradycardia was observed, but no clinically significant changes in cardiac-related outcomes: heart rate, blood pressure, or exercise duration. Clinical benefit was observed in all cohorts (48.6% of patients in the single-agent cohort and 81.3% in the giredestrant +palbociclib ±LHRH agonist cohort), with no clear dose relationship, including in patients with ESR1-mutated tumors.Giredestrant was well tolerated and clinically active in patients who progressed on prior ET. Results warrant further evaluation of giredestrant in randomized trials in early- and late-stage ER+ breast cancer.