Abstract OT2-03-01: heredERA Breast Cancer: Phase III study of first-line, fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection ± giredestrant (GDC-9545) for estrogen receptor+, HER2+ advanced breast cancer
Authors: Küemmel Sherko , Harper-Wynne Catherine , Park Yeon H. , Franke Fábio , De Laurentiis Michelino , Schumacher-Wulf Eva , Eiger Daniel , Heeson Sarah , Shivhare Mahesh , Restuccia Eleonora , O’Shaughnessy Joyce 
Published: March 2023

Abstract
BACKGROUND Giredestrant is a highly potent, nonsteroidal, oral selective estrogen receptor antagonist and degrader (SERD) that was found to be well tolerated and active as a monotherapy and in combination therapy in Phase I/II studies in early BC and pretreated locally advanced/metastatic BC (LA/mBC). Dual HER2 blockade with pertuzumab + trastuzumab (PH) + a taxane (induction therapy) followed by maintenance PH is the first-line standard of care for most patients (pts) with HER2+ LA/mBC. Despite HER2–ER blockade synergy, paucity of Phase III data evaluating maintenance PH + endocrine therapy (ET) vs. PH in pts with ER+/HER2+ LA/mBC leads to variable use of ET in this setting. Adding giredestrant to the maintenance phase could improve outcomes. TRIAL DESIGN This is a Phase III, randomized, two-arm, open-label, multicenter study evaluating the efficacy and safety of giredestrant + the fixed-dose combination of PH for subcutaneous injection (PH FDC SC) vs. PH FDC SC after induction therapy with PH FDC SC + a taxane in pts with ER+/HER2+ LA/mBC. In the induction phase, pts will receive 4–6 PH FDC SC cycles (1200 mg P/600 mg H in the first cycle, followed by 600/600 mg every 3 weeks) + a taxane (investigator choice of docetaxel/paclitaxel). Pts deriving clinical benefit may receive two additional cycles per investigator’s discretion. Pts completing ≥4 induction therapy cycles, achieving at least stable disease, and with a left ventricular ejection fraction (LVEF) ≥50% will be randomly assigned 1:1 to maintenance giredestrant 30 mg/day + PH FDC SC every 3 weeks or PH FDC SC only, until disease progression (PD). ET (aromatase inhibitor/tamoxifen) will be allowed in the PH FDC SC-only arm. Study treatment will continue until PD, limiting toxicity, death, or consent withdrawal. ELIGIBILITY Enrolled pts must have ER+/HER2+ LA/mBC, disease-free interval from completion of (neo)adjuvant non-ET ≥6 months, Eastern Cooperative Oncology Group performance status 0/1, LVEF ≥50%, and adequate organ function. Pts with prior SERD treatment or presence of symptomatic central nervous system metastases will be excluded. All men and pre-/perimenopausal women must be eligible for a luteinizing hormone-releasing hormone agonist. AIMS The primary endpoint is investigator-assessed, maintenance progression-free survival. Secondary endpoints include overall survival (OS), objective response rate, duration of response, clinical benefit rate, pt-reported outcomes, and safety. STATISTICAL METHODS The primary endpoint analysis will use a stratified log-rank test at an overall 0.05 significance level (two-sided). An interim OS analysis is planned, and an independent data monitoring committee will be in place. ACCRUAL The study is open for enrollment. Approximately 812 pts will be enrolled in the induction phase, to allow for approximately 730 pts to be randomized in the maintenance phase. CONTACT INFORMATION For more information or to refer a patient, email global.rochegenentechtrials@roche.com or call 1-888-662-6728 (USA only). Clinicaltrials.gov number: NCT05296798.
Citation Format: Sherko Küemmel, Catherine Harper-Wynne, Yeon H. Park, Fábio Franke, Michelino De Laurentiis, Eva Schumacher-Wulf, Daniel Eiger, Sarah Heeson, Mahesh Shivhare, Eleonora Restuccia, Joyce O’Shaughnessy. heredERA Breast Cancer: Phase III study of first-line, fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection ± giredestrant (GDC-9545) for estrogen receptor+, HER2+ advanced breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-03-01.