Abstract PD13-04: PD13-04 Exploratory subgroup and biomarker analyses of acelERA Breast Cancer: Phase II study of giredestrant (GDC-9545) vs physician’s choice of endocrine therapy for previously treated, estrogen receptor+, HER2– advanced breast cancer
Authors: Lim Elgene , Chavez Marianna , Bardia Aditya , Sohn Joo Hyuk , Moore Heather M. , Shivhare Mahesh , Martinalbo Jorge , Roncoroni Laura , Perez-Moreno Pablo D. , Martín Miguel 
Published: March 2023

Abstract
BACKGROUND Endocrine therapy (ET) is the mainstay for management of estrogen receptor (ER)+ advanced breast cancer (aBC). Giredestrant is a highly potent, nonsteroidal, oral selective ER antagonist and degrader (SERD) that achieves robust ER occupancy. The Phase II randomized, open-label acelERA BC study (NCT04576455) evaluated giredestrant vs physician’s choice of ET (PCET) in the second- or third-line ER+, HER2– aBC setting. While the study did not reach statistical significance for its primary endpoint of investigator-assessed progression-free survival (INV-PFS), the giredestrant arm demonstrated a numerical improvement vs the PCET arm, with a hazard ratio of 0.81 (95% confidence interval: 0.60, 1.10), and encouraging results for key secondary efficacy endpoints (clinical benefit rate [CBR]: 32% vs 21%, respectively; objective response rate [ORR]: 13% vs 7%, respectively). We report exploratory subgroup analyses of these efficacy endpoints by prior treatments and by baseline circulating tumor (ct)DNA biomarkers.
METHODS Patients were post- and pre- or peri-menopausal women, or men, with ER+, HER2– aBC who had progressed after 1–2 lines of systemic therapy in the advanced setting (≤1 targeted agent; ≤1 chemotherapy regimen; prior fulvestrant allowed). Randomization was 1:1 to giredestrant (30 mg oral daily) or PCET between fulvestrant or an aromatase inhibitor (AI), stratified by disease site (visceral vs non-visceral), prior CDK4/6 inhibitor, and prior fulvestrant. Biomarkers were assessed in baseline ctDNA isolated from plasma using the FoundationOne Liquid CDx or PredicineCARE assays. ESR1 mutations were defined as short variants with known or likely impact on ER protein function.
RESULTS Among the 303 patients enrolled, prior aBC therapies included CDK4/6 inhibitors (42%), fulvestrant (19%), and chemotherapy (32%). Overall, most baseline characteristics were balanced across arms in subgroups. Efficacy in key subgroups by prior treatment and in ESR1-mutated tumors is shown in the table. Efficacy by PCET (75% received fulvestrant; 25%, an AI) and by type of ESR1 mutation will be presented. Clinical benefit (INV-PFS, CBR, ORR) was most prominently observed with giredestrant in patients with ESR1-mutated tumors. In the baseline ctDNA-evaluable population (232/303 patients; 77%), ESR1 and PIK3CA were the most prevalent mutations overall (39% and 36%, respectively). The most common ESR1 mutations were D538G, Y537S, Y537N, and E380Q; 54% of baseline ctDNA samples classified as ESR1-mutated had multiple ESR1 mutations detected (range of 2–7 mutations), demonstrating clonal heterogeneity. Clinical benefit was also observed with giredestrant in patients expressing different ESR1 mutations. Updated data will be presented.
CONCLUSIONS Exploratory subgroup analyses showed favorable outcomes with giredestrant in terms of INV-PFS, CBR, and ORR across most key subgroups. The benefit was more pronounced in a) patients with ESR1-mutated tumors and b) patients who received prior fulvestrant (the majority of AI-treated patients in the PCET arm). Overall, these data support continued investigation of giredestrant to advance and improve treatment outcomes in hormone receptor+ BC.
Table 1: Exploratory subgroup analyses
Citation Format: Elgene Lim, Marianna Chavez, Aditya Bardia, Joo Hyuk Sohn, Heather M. Moore, Mahesh Shivhare, Jorge Martinalbo, Laura Roncoroni, Pablo D. Perez-Moreno, Miguel Martín. PD13-04 Exploratory subgroup and biomarker analyses of acelERA Breast Cancer: Phase II study of giredestrant (GDC-9545) vs physician’s choice of endocrine therapy for previously treated, 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 PD13-04.