GDC-0927 / Roche - LARVOL DELTA

Dissecting the genomic landscape of ERD genes in alfalfa (Medicago sativa): the effect of melatonin and low selenium under salt stress. (PubMed, Funct Integr Genomics) - "Notably, the results indicated that MsERD2, MsERD15 and MsERD27 were significantly overexpressed in response to low selenium concentrations and salt stress mediated by melatonin pathways...This comprehensive genomic and expression study provides valuable insights into the molecular regulation of ERD genes in alfalfa. The findings underscore the potential roles of specific MsERD genes in abiotic stress tolerance and mineral homeostasis, highlighting potential targets for the genetic improvement of stress-resilient alfalfa cultivars."

Journal

Genomic profiles of renal cell carcinoma in a small Chinese cohort. (PubMed, Front Oncol) - "For ccRCC patients, mutations in VHL, PBRM1, BAP1, and SERD2 can reach 74%, 50%, 24%, and 18%, respectively, while for nccRCC patients, the most frequent mutation was FH (29%), MLH3 (24%), ARID1A (18%), KMT2D (18%), and CREBBP (18%)...Our study revealed that nccRCC is more heterogeneous than ccRCC. For nccRCC patients, the small panel shows a more clear profile of genetic characteristics by replacing MLH3, KMT2D, and CREBBP with ATM, MSH6, BRAF, and KRAS, which may help predict prognosis and make clinical decisions."

Journal • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Sarcoma • Solid Tumor • ARID1A • BAP1 • BRAF • CREBBP • KMT2D • KRAS • MSH6 • PBRM1 • RAD50 • SETD2 • TFE3 • VHL

An Open-label Phase I Study of GDC-0927 in Postmenopausal Women with Locally Advanced or Metastatic Estrogen Receptor–Positive Breast Cancer (Clin Cancer Res) - P1 | N=43 | NCT02316509 | Sponsor: Genentech, Inc. | "Forty-two patients received GDC-0927 once daily. The MTD was not reached. The most common adverse events (AE) regardless of causality were nausea, constipation, diarrhea, arthralgia, fatigue, hot flush, back pain, and vomiting....Following dosing, approximately 1.6-fold accumulation was observed, consistent with the observed half-life and dosing frequency. There were no complete or partial responses. Pharmacodynamics was supported by >90% reduction in FES uptake and an approximately 40% reduction in ER expression, suggesting ER degradation is not the mechanistic driver of ER antagonism. Twelve patients (29%) achieved clinical benefit; 17 patients (41%) showed a confirmed best overall response of stable disease."

P1 data • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

An open-label phase I study of GDC-0927 in postmenopausal women with locally advanced or metastatic estrogen receptor positive breast cancer. (PubMed, Clin Cancer Res) - "GDC-0927 appeared to be well-tolerated with pharmacokinetics supporting once daily dosing. There was evidence of target engagement and preliminary evidence of anti-tumor activity in heavily pretreated patients with advanced/metastatic ER+/HER2- breast cancer with and without ESR1 mutations."

Clinical • Journal • Metastases • P1 data • Back Pain • Breast Cancer • Cardiovascular • Constipation • Estrogen Receptor Positive Breast Cancer • Fatigue • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Musculoskeletal Pain • Oncology • Pain • Solid Tumor • Thrombosis • Venous Thromboembolism • ER • HER-2

An open-label phase I study of GDC-0927 in postmenopausal women with locally advanced or metastatic estrogen receptor positive breast cancer (Clin Cancer Res) - P1 | N=43 | NCT02316509 | Sponsor: Genentech, Inc. | "Forty-two patients received GDC-0927 once daily. The maximum tolerated dose was not reached....Following dosing, approximately 1.6-fold accumulation was observed, consistent with the observed half-life and dosing frequency. There were no complete or partial responses. Pharmacodynamics was supported by >90% reduction in FES uptake and a ~40% reduction in ER expression, suggesting ER degradation is not the mechanistic driver of ER antagonism. Twelve patients (29%) achieved clinical benefit; 17 patients (41%) showed a confirmed best overall response of stable disease. Baseline levels of ER and PR protein and mutant ESR1 ctDNA did not correlate with clinical benefit."

P1 data • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

Physiologically-based pharmacokinetic/pharmacodynamic modeling to predict tumor growth inhibition and the efficacious dose of selective estrogen receptor degraders in humans. (PubMed, Biopharm Drug Dispos) - "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. 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."

Journal • PK/PD data • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER

GDC-9545: A novel ER antagonist and clinical candidate that combines desirable mechanistic and pre-clinical DMPK attributes (SABCS 2018) - P1a/1b; "However, we find that therapeutic candidates that have recently emerged from prospective optimization of ER degradation, including GDC-0810 and GDC-0927, are not mechanistically equivalent. The highly potent in vivo efficacy of GDC-9545 likely arises due to the particular combination of high binding potency, full suppression of ER signaling, and an improved DMPK profile when compared to GDC-0927 and fulvestrant. GDC-9545 is currently being evaluated in Phase 1 clinical trials (ClinicalTrials.gov Identifier: NCT03332797). "

Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor

Endocrine resistance in metastatic breast cancer: Mechanisms and new therapeutic strategies (AACR 2018) - "...Most of the ESR1 mutations confer constitutive ligand-independent ER activity, causing resistance to estrogen deprivation (i.e., aromatase inhibitors) and reduced sensitivity to the selective ER modulator (SERM) tamoxifen and the selective ER downregulator (SERD) fulvestrant...While the therapeutic value of newly developed orally bioavailable SERMs/SERDs such as GDC-0810 and GDC-0927 for patients with tumors harboring ESR1 mutations is yet to be clinically proven, we anticipate that ongoing studies will address this open question. Additionally, the recent clinically potent CDK4/6 inhibitor palbociclib, in combination with fulvestrant, has shown promising therapeutic efficacy against tumors harboring ESR1 mutations...In addition, a more complete suppression of the levels and activity of ER, its co-activators, and alternative survival pathways may prove to be a better therapeutic strategy in effectively combating endocrine resistance. Effective therapeutic strategies may...&quo

HER2 Breast Cancer • Hormone Receptor Breast Cancer • Renal Cell Carcinoma

Not all SERDs are equal: Context-independent ER degradation and full ER antagonism define the next generation of ER therapeutics (AACR 2018) - "...Though the clinical activity of fulvestrant is believed to be limited by its poor drug-like properties, a recent study demonstrated superiority of fulvestrant over the aromatase inhibitor, anastrozole...GDC-0927 is in Phase I clinical studies, and like GDC-0810 and AZD9496 was optimized for ER degradation in MCF7 cells...Specifically, FRAP (fluorescence recovery after photobleaching) demonstrated that while partial agonists 4OH-tamoxifen and GNE-274 maintain high mobility of ER, the full antagonists fulvestrant and GDC-0927 profoundly decrease ER mobility, suggesting that the immobilization of ER is likely a general property of full antagonists...The observation that full ER antagonism invariably associates with ER degradation could be interpreted as degradation driving full antagonism. However, we have discovered that full antagonists can be distinguished from partial agonists prior to the loss of ER protein, suggesting that ER degradation may

IO Biomarker • Hormone Receptor Breast Cancer

Discovery and evolution of orally bioavailable selective estrogen receptor degraders for ER+ breast cancer: From GDC-0810 to GDC-0927 (AACR 2018) - "Endocrine resistant tumors often remain dependent on ER for growth and survival, as evidenced by their sensitivity to the selective estrogen receptor degrader (SERD), fulvestrant. Co-crystal structures of both GDC-0810 and GDC-0927 with ER will be shared. Subsequent optimization of GDC-0927 resulting in improved pharmacokinetic properties will also be highlighted."

Hormone Receptor Breast Cancer

Discovery and evolution of orally bioavailable selective estrogen receptor degraders forER+ breast cancer: From GDC-0810 to GDC-0927 (AACR 2018) - "There is no abstract associated with this presentation."

Hormone Receptor Breast Cancer

Discovery of a C-8 hydroxychromene as a potent degrader of estrogen receptor alpha with improved rat oral exposure over GDC-0927. (PubMed, Bioorg Med Chem Lett) - "The excellent potency underscores the possibility of replacing the presumed indispensable phenolic group at C-6 or C-7 of the chromene core. Co-crystal structures were obtained to highlight the change in key interactions and rationalize the retained potency."

Journal • Preclinical

Identification of novel OsCML16 target proteins and differential expression analysis under abiotic stresses in rice. (PubMed, J Plant Physiol) - "Interestingly, the in vitro peptide-binding assays manifested that OsERD2 could bind both OsCaM1 and OsCML16 whereas other five target proteins could specifically bind OsCML16 but not OsCaM1. Furthermore, Ca and TFP, a calmodulin (CaM) antagonist, were involved in the ABA-induced transcription of OsCML16 and its target genes, and they were also obviously induced by cold, drought, and salt stresses. Taken together, our new findings have provided the basis for the novel signaling pathways of OsCML16 in the abiotic stress response in rice."

Journal

[VIRTUAL] GDC-9545: A pure antiestrogen clinical candidate that immobilizes the estrogen receptor and profoundly alters chromatin accessibility in vivo (AACR-II 2020) - "Fulvestrant was first discovered as a “pure antiestrogen”, in contrast to earlier generation ER therapeutic ligands that exhibit weak agonistic activity, such as tamoxifen...Importantly however, we recently demonstrated that fulvestrant and other full ER antagonists (e.g. GDC-0927) dramatically slow the intranuclear mobility of ER [Cell 178:4 (2019)]...We speculate that this particular pattern of accessibility changes may reflect redistribution of FOXA1 upon GDC-9545 treatment, and we will further explore this hypothesis. These data provide further insights into the impact of ER immobilization by the latest generation of pure antiestrogens."

Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • FOXA1

A Study of GDC-0927 in Postmenopausal Women With Locally Advanced or Metastatic Estrogen Receptor Positive Breast Cancer (clinicaltrials.gov) - P1; N=90; Recruiting; Sponsor: Genentech, Inc.; Trial primary completion date: Dec 2018 ➔ Nov 2019

Trial primary completion date • Biosimilar • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor

[VIRTUAL] GDC-9545: Discovery of an oral estrogen receptor antagonist, degrader, and immobilizer for the treatment of ER+ breast cancer patients (AACR-I 2020) - "These endocrine resistant tumors often continue to depend on ERα for growth and survival, as evidenced by their sensitivity to the selective estrogen receptor antagonist and degrader, fulvestrant...We have reported previously of our first and second generations of orally available ERα ligands, GDC-0810 and GDC-0927 respectively...It is orally bioavailable and has high safety margins in preclinical species. GDC-9545 is currently in active clinical testing."

Clinical

A Study of GDC-0927 in Postmenopausal Women With Locally Advanced or Metastatic Estrogen Receptor Positive Breast Cancer (clinicaltrials.gov) - P1; N=43; Completed; Sponsor: Genentech, Inc.; Active, not recruiting ➔ Completed

Clinical • Trial completion • HER-2