heredERA Breast Cancer: a phase III, randomized, open-label study evaluating the efficacy and safety of giredestrant plus the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection in patients with previously untreated HER2-positive, estrogen receptor-positive locally advanced or metastatic breast cancer

Abstract

Background: HER2-positive, estrogen receptor-positive breast cancer (HER2+, ER+ BC) is a distinct disease subtype associated with inferior response to chemotherapy plus HER2-targeted therapy compared with HER2+, ER-negative BC. Bi-directional crosstalk leads to cooperation of the HER2 and ER pathways that may drive treatment resistance; thus, simultaneous co-targeting may optimize treatment impact and survival outcomes in patients with HER2+, ER+ BC. First-line (1L) treatment for patients with HER2+ metastatic BC (mBC) is pertuzumab, trastuzumab, and taxane chemotherapy. In clinical practice, dual HER2 blockade plus a fixed number of chemotherapy cycles are given as induction therapy to maximize tumor response, with subsequent HER2-targeted maintenance treatment given as a more tolerable regimen for long-term disease control. For patients whose tumors co-express ER, maintenance endocrine therapy (ET) can be added, but uptake varies due to lack of data from randomized clinical trials investigating the superiority of maintenance ET plus dual HER2 blockade versus dual HER2 blockade alone. Giredestrant, a novel oral selective ER antagonist and degrader, shows promising clinical activity and manageable safety across phase I-II trials of patients with ER+, HER2-negative BC, with therapeutic potential in those with HER2 co-expression.

Methods: This phase III, randomized, open-label, two-arm study aims to recruit 812 patients with HER2+, ER+ locally advanced (LA)/mBC into the induction phase (fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection [PH FDC SC] plus a taxane) to enable 730 patients to be randomized 1:1 to the maintenance phase (giredestrant plus PH FDC SC or PH FDC SC [plus optional ET]), stratified by disease site (visceral versus non-visceral), type of LA/metastatic presentation (de novo versus recurrent), best overall response to induction therapy (partial/complete response versus stable disease), and intent to give ET (yes versus no). The primary endpoint is investigator-assessed progression-free survival. Secondary endpoints include overall survival, objective response rate, clinical benefit rate, duration of response, safety, and patient-reported outcomes.

Discussion: heredERA BC will address whether giredestrant plus dual HER2 blockade is superior to dual HER2 blockade alone, to inform the use of this combination in clinical practice for maintenance 1L treatment of patients with HER2+, ER+ LA/mBC.

Trial registration: ClinicalTrials.gov, NCT05296798; registered on March 25, 2022. Protocol version 3.0 (November 18, 2022).

Sponsor: F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124 4070, Basel, Switzerland.

Keywords: Breast cancer; Estrogen receptor-positive; Giredestrant; HER2-positive; Pertuzumab; Trastuzumab.

Fig. 1

Bi-directional crosstalk between the HER2 and ER pathways. E2: estradiol, ER: estrogen receptor, G: giredestrant, HER: human epidermal growth factor receptor, TF: transcription factor

Fig. 2

Combined treatment with giredestrant and HER2-targeted therapy (pertuzumab and trastuzumab) shows greater antiproliferative effect than either treatment alone (F. Hoffmann-La Roche Ltd. Personal communication, unpublished data). Cell growth rate inhibition of ‘1’ denotes no effect on growth whereas ‘0’ represents stasis of the cell population. ER+: estrogen receptor-positive, HER2+: human epidermal growth factor receptor 2-positive

Fig. 3

Participating countries. The heredERA BC study is being conducted across 224 sites in 24 countries. BC: breast cancer

Fig. 4

Study design. CR: complete response, ER+: estrogen receptor-positive, ET: endocrine therapy, HER2+: human epidermal growth factor receptor 2-positive, LA: locally advanced, mBC: metastatic breast cancer, OR: overall response, PD: disease progression, PH FDC SC: fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection, po: orally, PR: partial response, qd: once daily, q3w: once every 3 weeks, R: randomization, SD: stable disease. ^a Endocrine therapy (aromatase inhibitor/tamoxifen) will be allowed in the PH FDC SC arm. ^b Breast cancer that presents as stage IV disease at first diagnosis