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.

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.

Physiologically-based pharmacokinetic/pharmacodynamic modeling to predict tumor growth inhibition and the efficacious dose of selective estrogen receptor degraders in humans.

GDC-9545 (giredestrant) is a highly potent, nonsteroidal, oral selective estrogen receptor antagonist and degrader that is being developed as a best-in-class drug candidate for early-stage and advanced drug-resistant breast cancer. GDC-9545 was designed to improve the poor absorption and metabolism of its predecessor GDC-0927, for which development was halted due to a high pill burden. This study aimed to develop physiologically-based pharmacokinetic/pharmacodynamic (PBPK-PD) models to characterize the relationships between oral exposure of GDC-9545 and GDC-0927 and tumor regression in HCI-013 tumor-bearing mice, and to translate these PK-PD relationships to a projected human efficacious dose by integrating clinical PK data. PBPK and Simeoni tumor growth inhibition (TGI) models were developed using the animal and human Simcyp V20 Simulator (Certara) and adequately described each compound's systemic drug concentrations and antitumor activity in the dose-ranging xenograft experiments in mice. The established PK-PD relationship was translated to a human efficacious dose by substituting mouse PK for human PK. PBPK input values for human clearance were predicted using allometry and in vitro in vivo extrapolation approaches and human volume of distribution was predicted from simple allometry or tissue composition equations. The integrated human PBPK-PD model was used to simulate TGI at clinically relevant doses. Translating the murine PBPK-PD relationship to a human efficacious dose projected a much lower efficacious dose for GDC-9545 than GDC-0927. Additional sensitivity analysis of key parameters in the PK-PD model demonstrated that the lower efficacious dose of GDC-9545 is a result of improvements in clearance and absorption. The presented PBPK-PD methodology can be applied to support lead optimization and clinical development of many drug candidates in discovery or early development programs.

UGT1A4 Polymorphism is not Associated with a Clinically Relevant Change in Giredestrant Exposure.

PURPOSE: Giredestrant is a potent, orally bioavailable, small-molecule selective estrogen receptor antagonist and degrader (SERD) that is being developed for the treatment of patients with estrogen receptor (ER)-positive breast cancer. In vitro, giredestrant was primarily metabolized by UGT1A4. The goal of this study was to investigate if UGT1A4 polymorphism had a clinically relevant impact on giredestrant exposure. METHODS: Genotyping and pharmacokinetic data were obtained from 118 and 61 patients in two clinical studies, GO39932 [NCT03332797] and acelERA Breast Cancer [NCT04576455], respectively. RESULTS: The overall allelic frequencies of UGT1A4*2 and UGT1A4*3 were 3.3% and 11%, respectively. Giredestrant exposure was consistent between patients with wild-type UGT1A4 and UGT1A4*2 and *3 polymorphisms, with no clinically relevant difference observed. In addition, haplotype analysis indicated that no other UGT1A4 variants were significantly associated with giredestrant exposure. CONCLUSION: Therefore, this study indicates that UGT1A4 polymorphism status is unlikely a clinically relevant factor to impact giredestrant exposure and giredestrant can be administered at the same dose level regardless of patients' UGT1A4 polymorphism status.

First Approval of Elacestrant as a Selective Estrogen Receptor Degrader for the Treatment of Metastatic Breast Cancer.

Elacestrant was approved by the US FDA on January 27, 2023, for treating postmenopausal women or adult men with estrogen receptor (ER)-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression prior to using at least one line of endocrine therapy. In this short perspective, physicochemical properties, dosage and administration, mechanism of action, pharmacodynamics, pharmacokinetics, drug interaction, and treatment-related adverse reactions of elacestrant are summarized.

Latest generation estrogen receptor degraders for the treatment of hormone receptor-positive breast cancer.

INTRODUCTION: The selective estrogen receptor degrader (SERD) and full receptor antagonist provides an important therapeutic option for hormone receptor (HR)-positive breast cancer. Endocrine therapies include tamoxifen, a selective estrogen receptor modulator (SERM), that exhibits receptor agonist and antagonist activity, and aromatase inhibitors that block estrogen biosynthesis but which demonstrate acquired resistance. Fulvestrant, the only currently approved SERD, is limited by poor drug-like properties. A key focus for improving disease management has been development of oral SERDs with optimized target occupancy and potency and superior clinical efficacy. AREAS COVERED: Using PubMed, clinicaltrials.gov, and congress websites, this review explored the preclinical development and clinical pharmacokinetics from early phase clinical studies (2015 or later) of novel oral SERDs, including giredestrant, amcenestrant, camizestrant, elacestrant, and rintodestrant. EXPERT OPINION: Numerous oral SERDs are in clinical development, aiming to form the core endocrine therapy for HR-positive breast cancer. Through property- and structure-based drug design of estrogen receptor-binding, antagonism, degradation, anti-proliferation, and pharmacokinetic properties, these SERDs have distinct profiles which impact clinical dosing, efficacy, and safety. Assuming preliminary safety and activity data are confirmed in phase 3 trials, these promising agents could further improve the management, outcomes, and quality of life in HR-positive breast cancer.