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    over1year
    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 • P1 data • Journal • Metastases
    |
    HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PGR (Progesterone receptor)
    |
    ER positive • HER-2 negative • HER-2 mutation • ER mutation • ESR1 mutation
    |
    GDC-0927
    over1year
    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
    |
    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ARID1A (AT-rich interaction domain 1A) • PBRM1 (Polybromo 1) • BAP1 (BRCA1 Associated Protein 1) • KMT2D (Lysine Methyltransferase 2D) • MSH6 (MutS homolog 6) • VHL (von Hippel-Lindau tumor suppressor) • CREBBP (CREB binding protein) • SETD2 (SET Domain Containing 2, Histone Lysine Methyltransferase) • RAD50 (RAD50 Double Strand Break Repair Protein) • TFE3 (Transcription Factor Binding To IGHM Enhancer 3)
    |
    KRAS mutation • BRAF mutation • ATM mutation • ARID1A mutation • KMT2D mutation • PBRM1 mutation • BAP1 mutation • VHL mutation • RAD50 mutation • MLH3 mutation • TFE3 fusion
    |
    GDC-0927
    over1year
    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.
    PK/PD data • Journal
    |
    ER (Estrogen receptor)
    |
    giredestrant (GDC-9545) • GDC-0927
    almost5years
    A Study of GDC-0927 in Postmenopausal Women With Locally Advanced or Metastatic Estrogen Receptor Positive Breast Cancer (clinicaltrials.gov)
    P1, N=43, Completed, Genentech, Inc. | Active, not recruiting --> Completed
    Clinical • Trial completion
    |
    HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
    |
    ER positive • HER-2 negative
    |
    GDC-0927
    almost6years
    Phamacodynamic and circulating tumor DNA evaluation in a phase I study of GDC-0927, a selective estrogen receptor antagonist/ degrader (SERD) (SABCS 2018)
    We report here evidence of consistent reduction of ESR1 and PIK3CA ctDNA in patients treated with GDC-0927. ER pathway suppression was observed at both the transcript and protein level confirming pharmacodynamic activity of the SERD. 
    P1 data
    |
    ER (Estrogen receptor) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • CDH1 (Cadherin 1)
    |
    GDC-0927
    almost6years
    Prospective optimization of estrogen receptor degradation yields ER ligands with variable capacities for ER transcriptional suppression (SABCS 2018)
    However, the full clinical potential of fulvestrant is believed to be limited by poor bioavailability, spurring attempts to generate ligands capable of driving ER degradation but with improved drug-like properties.Here, we evaluate three ER ligand clinical candidates that recently emerged from prospective optimization of ER degradation – GDC-0810, AZD9496 and GDC-0927 - and show that they display distinct mechanistic features. This class of “always mobile” ER variants promotes an antagonist-to-agonist transcriptional switch for fulvestrant and GDC-0927, and simultaneously prevents ER degradation by these molecules, implying that ER immobilization is a key functional determinant of robust transcriptional suppression.We thus propose that ER degradation is not a driver of full ER antagonism, but rather a downstream consequence of ER immobilization, occurring after a suppressive phenotype has been established at chromatin. We additionally argue that evaluating the transcriptional output of candidate ER therapeutics, both pre-clinically and clinically, will be critical for the identification of ER ligands with best-in-class potential. 
    Clinical
    |
    ER (Estrogen receptor)
    |
    fulvestrant • AZD9496 • GDC-0927 • brilanestrant (GDC-0810)