Abstract PD13-07: Activity and biomarker analyses from a phase Ia/b study of giredestrant (GDC-9545; G) with or without palbociclib (palbo) in patients with estrogen receptor-positive, HER2-negative locally advanced/metastatic breast cancer (ER+/HER2- LA/mBC)

Abstract Background A mainstay of ER+ BC treatment is to target ER activity and/or estrogen synthesis; however, during or after endocrine therapy (ET), many patients either relapse or develop resistance to such treatments due to several mechanisms, including ESR1 mutations which can be drivers of estrogen-independent transcription and proliferation. The majority of tumors remain dependent on ER signaling, and it is possible that patients will be responsive to second- or third-line ET after they have progressed on previous therapies. The highly potent, nonsteroidal oral selective ER antagonist and degrader G achieves robust ER occupancy and is active in patients with either ESR1-wildtype or -mutant tumors and in patients who had previously been treated with ET. G was well tolerated as a single agent and in combination with palbo, with antitumor activity shown in the nonrandomized, open-label, dose-escalation and -expansion, phase Ia/b GO39932 study (NCT03332797). We present updated activity and biomarker analyses in patients treated with 30 mg G monotherapy and those treated with 100 mg G + 125 mg palbo ± luteinizing hormone-releasing hormone (LHRH) agonists (clinical cutoff: Apr 16, 2021); 30 mg has since been selected as the dose in both the single agent and combination settings. Methods Eligible patients had ≤2 prior therapies for LA/mBC, disease recurrence, or progression while on adjuvant ET for ≥24 months and/or ET for LA/mBC, and tumor response or stable disease ≥6 months. All were postmenopausal (premenopausal women were allowed co-administered LHRH agonists with 100 mg G). Oral G was given daily on Days (D)1-28 of each 28-day cycle (C); 125 mg palbo, on a 21-day on/7-day off schedule. Modulation of ER signaling and proliferation of paired pre- and on-treatment (C2D8) tumor biopsies were assessed with immunohistochemistry for ER, progesterone receptor (PgR), and the proliferation marker Ki67, as well as with gene expression analysis of a predefined set of 38 ER target genes using the Illumina TruSeq RNA Access method. Plasma samples collected pre- and on-treatment (C1D15 and/or C2D1) were assessed for circulating tumor (ct)DNA using a digital PCR BEAMing assay detecting a total of 22 mutations across ESR1, AKT1, and PIK3CA. Results Objective response rates in patients with measurable disease at baseline were 20.0% in the 30 mg G group (6/30 patients) and 47.7% in the 100 mg G + palbo ± LHRH (combination) group (21/44). Clinical benefit rates were 55.0% (22/40 patients) and 81.3% (39/48), respectively. Overall, 21 pre- and on-treatment-paired tumor biopsies were collected in the 30 mg (n=13) and combination (n=8) groups. Consistent downregulation of ER, PgR, Ki67, and ER pathway activity was observed at C2D8, regardless of clinical benefit or baseline ESR1 mutation, demonstrating consistent on-target activity of G. Stronger Ki67, ER, and PgR suppression was seen with the addition of palbo to G. Of the 36 patients across both cohorts with a detectable ctDNA baseline ESR1 mutation, 16 had >1 baseline ESR1 mutation. Of the eight unique ESR1 mutations detected, none showed an association with response. At C2D1, 34 patients had a decrease in ESR1 ctDNA levels from baseline, of which 27 became undetectable for ESR1 ctDNA. Early changes in PIK3CA and AKT1 ctDNA levels, but not ESR1, trended with response. Conclusions Encouraging clinical activity was observed with single agent G at 30 mg and with G at 100 mg in combination with palbo. Biomarker analyses demonstrated consistent biologic activity of G, and largely consistent decreases of ESR1 ctDNA levels. Further updated activity and biomarker data, including PAM50 subtype classifications, will be presented. Citation Format: Nicolas C Turner, Sherene Loi, Heather M Moore, Ching-Wei Chang, Jennifer Eng-Wong, Aditya Bardia, Valentina Boni, Joohyuk Sohn, Komal L Jhaveri, Elgene Lim. Activity and biomarker analyses from a phase Ia/b study of giredestrant (GDC-9545; G) with or without palbociclib (palbo) in patients with estrogen receptor-positive, HER2-negative locally advanced/metastatic breast cancer (ER+/HER2- LA/mBC) [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 PD13-07.