Abstract OT-09-06: Phase II neoadjuvant study of GDC-9545 + palbociclib (palbo) vs anastrozole (A) + palbo in postmenopausal women with estrogen receptor-positive, HER2-negative, untreated early breast cancer (ER+/HER2- eBC)
Authors: Hurvitz Sara A , Fasching Peter A , Park Yeon Hee , Quiroga Vanesa , Crnjevic Tanja Badovinac , Fresco Rodrigo , López-Valverde Vanesa , Steinseifer Jutta , Ye Chenglin , Bardia Aditya 
Published: February 2021

Abstract
Background
Endocrine therapies (ETs) are the mainstay of ER+ BC management; however, many patients (pts) have disease relapse or develop therapeutic resistance. CDK4/6 and aromatase inhibitors decrease Ki67 expression significantly and are potent in arresting the cell cycle in the neoadjuvant eBC setting. Ki67 is a proliferation biomarker with prognostic value in ER+ BC. Efficacy of ETs relies on induction of cell cycle arrest, and during neoadjuvant treatment, Ki67 scores reflect the ability of ETs to suppress proliferation. Selective ER degraders have also shown efficacy against these tumors. The highly potent, non-steroidal, oral selective ER degrader GDC-9545 has therefore been developed as a monotherapy or in combination with CDK4/6 inhibitors for ER+ BC. Preliminary phase Ib data in postmenopausal women with metastatic BC have shown that oral 100 mg once daily (PO QD) GDC-9545 is well tolerated as a monotherapy and with palbo, with encouraging antitumor activity (clinical benefit rates: 55% without palbo/81% with palbo; clinical benefit observed in pts with prior fulvestrant treatment and in pts with detectable ESR1 mutations at enrollment) (Lim et al. ASCO 2020; abstract 1023).
We present a phase II, randomized, open-label, two-arm, neoadjuvant study of GDC-9545 vs A in a window of opportunity (WoO) phase, followed by GDC-9545 + palbo vs A + palbo in a neoadjuvant phase, for postmenopausal women with ER+/HER2- untreated eBC (NCT04436744).
Trial design
Pts are randomized 1:1 to GDC-9545 or A. The WoO phase will last 14 days; and the neoadjuvant phase, 16 weeks (4 x 28-day cycles) before surgery. GDC-9545 will be given at 30 mg PO QD; A, at 1 mg PO QD. 30 mg GDC-9545 was selected as it is well tolerated with promising anti-tumor activity (Jhaveri et al. SABCS 2019; abstract PD7-05), and no improvement in efficacy is expected at doses &gt; 30 mg. During the neoadjuvant phase, pts will receive 4 x 28-day cycles of GDC-9545 + palbo (125 mg PO QD on days 1-21 of each cycle) or A + palbo.
Eligibility
Female pts ≥ 18 years with ECOG performance status 0-1, histologically confirmed invasive breast carcinoma, measurable disease (modified RECIST v1.1), primary tumor ≥ 1.5 cm in its longest diameter (tumor size category at presentation: cT1c [≥ 1.5 cm]-cT4a-c), and Ki67 score ≥ 5% stained nuclei.
Aims
The primary efficacy endpoint is mean relative Ki67 score change from baseline to week 2 during the WoO phase. Secondary efficacy endpoints are objective response rate and complete cell cycle arrest (CCCA) rate (proportion of patients with centrally assessed Ki67 scores ≤ 2.7% stained nuclei upon treatment at week 2) in the neoadjuvant phase. Exploratory efficacy endpoints are changes in Ki67 scores from baseline to surgery and from week 2 to surgery, CCCA rate (upon treatment at surgery or post-treatment biopsy), and pathologic complete response rate in the neoadjuvant phase. Safety and tolerability, pharmacokinetics, and biomarkers will also be assessed.
Statistical methods
Randomization is stratified by T status (cT1c-cT2 vs cT3-cT4 a-c), Ki67 score (&lt; 20% vs ≥ 20%), and progesterone receptor status (positive vs negative). Ki67 scores will be centrally assessed and measured in percentage scores. Mean relative change at week 2 will be summarized in original percentage scales for each arm, and corresponding 95% confidence intervals will be calculated by normal approximation. Change in mean score between arms will be compared via z-test. Patients with missing central scores at baseline and/or week 2 will be excluded.
Accrual
Target enrollment is 215 patients at ~90 sites globally once the study is open for enrollment.
Contact information
For more information or to refer a patient, email global.rochegenentechtrials@roche.com or call 1-888-662-6728 (USA only).
Citation Format: Sara A Hurvitz, Peter A Fasching, Yeon Hee Park, Vanesa Quiroga, Tanja Badovinac Crnjevic, Rodrigo Fresco, Vanesa López-Valverde, Jutta Steinseifer, Chenglin Ye, Aditya Bardia. Phase II neoadjuvant study of GDC-9545 + palbociclib (palbo) vs anastrozole (A) + palbo in postmenopausal women with estrogen receptor-positive, HER2-negative, untreated early breast cancer (ER+/HER2- eBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-09-06.