The oral selective estrogen receptor degrader GDC-0810 (ARN-810) in postmenopausal women with hormone receptor-positive HER2-negative (HR + /HER2 −) advanced/metastatic breast cancer
Tóm tắt
GDC-0810 (ARN-810) is a novel, non-steroidal, orally bioavailable, selective estrogen receptor degrader (SERD) that potentially inhibits ligand-dependent and ligand-independent estrogen receptor (ER)-mediated signaling. A phase Ia/Ib/IIa dose escalation, combination treatment with palbociclib or a luteinizing hormone-releasing hormone, and expansion study determined the safety, pharmacokinetics, and recommended phase 2 dose (RP2D) of GDC-0810 in postmenopausal women with ER + (HER2 −) locally advanced or metastatic breast cancer (MBC). Baseline plasma ctDNA samples were analyzed to determine the ESR1 mutation status. Patients (N = 152) received GDC-0810 100–800 mg once daily (QD) or 300–400 mg twice daily, in dose escalation, expansion, as single agent or combination treatment. Common adverse events regardless of attribution to study drug were diarrhea, nausea, fatigue, vomiting, and constipation. There was one dose-limiting toxicity during dose escalation. The maximum tolerated dose was not reached. GDC-0810 600 mg QD taken with food was the RP2D. Pharmacokinetics were predictable. FES reduction (> 90%) highlighting pharmacodynamic engagement of ER was observed. Outcomes for the overall population and for patients with tumors harboring ESR1 mutations included partial responses (4% overall; 4% ESR1), stable disease (39% overall; 42% ESR1), non-complete response/non-progressive disease (13% overall; 12% ESR1), progressive disease (40% overall; 38% ESR1), and missing/unevaluable (5% overall; 5% ESR1). Clinical benefit (responses or SD, lasting ≥ 24 weeks) was observed in patients in dose escalation (n = 16, 39%) and expansion (n = 24, 22%). GDC-0810 was safe and tolerable with preliminary anti-tumor activity in heavily pretreated patients with ER + advanced/MBC, with/without ESR1 mutations, highlighting the potential for oral SERDs. Clinical Trial and registration date April 4, 2013. NCT01823835 .
Tài liệu tham khảo
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90. https://doi.org/10.3322/caac.20107[published
Najim O, Seghers S, Sergoynne L et al (1872) 2019 The association between type of endocrine therapy and development of estrogen receptor-1 mutation(s) in patients with hormone-sensitive advanced breast cancer: a systematic review and meta-analysis of randomized and non-randomized trials. Biochim Biophys Acta Rev Cancer 2:188315. https://doi.org/10.1016/j.bbcan.2019.188315[published
Leal MF, Haynes BP, Schuster EF et al (2019) Early enrichment of ESR1 mutations and the impact on gene expression in pre-surgical primary breast cancer treated with aromatase inhibitors. Clin Cancer Res. https://doi.org/10.1158/1078-0432.ccr-19-1129[published
Lopez-Knowles E, Pearson A, Schuster G et al (2019) Molecular characterisation of aromatase inhibitor-resistant advanced breast cancer: the phenotypic effect of ESR1 mutations. Br J Cancer 120(2):247–255. https://doi.org/10.1038/s41416-018-0345-x[published
Sammons S, Shastry M, Dent S, Anders C, Hamilton E (2020) Practical treatment strategies and future directions after progression while receiving CDK4/6 inhibition and endocrine therapy in advanced HR(+)/HER2(-) breast cancer. Clin Breast Cancer 20(1):1–11. https://doi.org/10.1016/j.clbc.2019.06.017[published
Joseph JD, Darimont B, Zhou W et al (2016) The selective estrogen receptor downregulator GDC-0810 is efficacious in diverse models of ER+ breast cancer. Elife. https://doi.org/10.7554/eLife.15828[published
Lai A, Kahraman M, Govek S et al (2015) Identification of GDC-0810 (ARN-810), an orally bioavailable selective estrogen receptor degrader (SERD) that demonstrates robust activity in tamoxifen-resistant breast cancer xenografts. J Med Chem 58(12):4888–4904. https://doi.org/10.1021/acs.jmedchem.5b00054[published
Eisenhauer EA, Therasse P, Bogaerts J et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2):228–247. https://doi.org/10.1016/j.ejca.2008.10.026[published
Cheung KWK, Yoshida K, Cheeti S et al (2019) GDC-0810 pharmacokinetics and transporter-mediated drug interaction evaluation with an endogenous biomarker in the first-in-human Dose Escalation Study. Drug Metab Dispos 47(9):966–973. https://doi.org/10.1124/dmd.119.087924
Wang Y, Ayres KL, Goldman DA et al (2017) (18)F-fluoroestradiol PET/CT measurement of estrogen receptor suppression during a phase I trial of the novel estrogen receptor-targeted therapeutic GDC-0810: using an imaging biomarker to guide drug dosage in subsequent trials. Clin Cancer Res 23(12):3053–3060. https://doi.org/10.1158/1078-0432.ccr-16-2197[published
Turner NC, Kingston B, Kilburn LS et al (2020) Circulating tumour DNA analysis to direct therapy in advanced breast cancer (plasmaMATCH): a multicentre, multicohort, phase 2a, platform trial. Lancet Oncol 21(10):1296–1308. https://doi.org/10.1016/s1470-2045(20)30444-7[published
News in brief, no authors listed (2022) Novel SERD Has PFS Edge against Breast Cancer. Cancer Discov 12(2):281. https://doi.org/10.1158/2159-8290.CD-NB2021-406
Bardia A, Neven P, Streich G. Elacestrant. 2021 an oral selective estrogen receptor degrader vs investigator’s choice of endocrine monotherapy for ER+/HER2–advanced/metastatic breast cancer following progression on prior endocrine and CDK4/6 inhibitor therapy: Results of EMERALD phase 3 trial. Proceedings of the 2021 San Antonio Breast Cancer Symposium, San Antonio, TX, USA;8
Pagani O, Regan MM, Walley BA et al (2014) Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med 371(2):107–118. https://doi.org/10.1056/NEJMoa1404037[published
Turner NC, Ro J, André F et al (2015) Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med 373(3):209–219. https://doi.org/10.1056/NEJMoa1505270[published
van Kruchten M, de Vries EG, Glaudemans AW et al (2015) Measuring residual estrogen receptor availability during fulvestrant therapy in patients with metastatic breast cancer. Cancer Discov 5(1):72–81. https://doi.org/10.1158/2159-8290.cd-14-0697[published
Dehdashti F, Mortimer JE, Trinkaus K et al (2009) PET-based estradiol challenge as a predictive biomarker of response to endocrine therapy in women with estrogen-receptor-positive breast cancer. Breast Cancer Res Treat 113(3):509–517. https://doi.org/10.1007/s10549-008-9953-0
Kurland BF, Peterson LM, Lee JH et al (2017) Estrogen receptor binding (18F-FES PET) and glycolytic activity (18F-FDG PET) Predict progression-free survival on endocrine therapy in patients with ER+ breast cancer. Clin Cancer Res 23(2):407–415. https://doi.org/10.1158/1078-0432.ccr-16-0362
Guan J, Zhou W, Hafner M et al (2019) Therapeutic ligands antagonize estrogen receptor function by impairing its mobility. Cell 178(4):949–63.e18. https://doi.org/10.1016/j.cell.2019.06.026
Pinkerton JV, Goldstein SR (2010) Endometrial safety: a key hurdle for selective estrogen receptor modulators in development. Menopause 17(3):642–653. https://doi.org/10.1097/gme.0b013e3181c4f1d6
Garuti G, Cellani F, Centinaio G, Montanari G, Nalli G, Luerti M (2006) Prospective endometrial assessment of breast cancer patients treated with third generation aromatase inhibitors. Gynecol Oncol 103(2):599–603. https://doi.org/10.1016/j.ygyno.2006.04.004
Kahraman M, Govek SP, Nagasawa JY et al (2019) Maximizing ER-alpha degradation maximizes activity in a tamoxifen-resistant breast cancer model: identification of GDC-0927. ACS Med Chem Lett 10(1):50–55. https://doi.org/10.1021/acsmedchemlett.8b00414
Liang J, Zbieg JR, Blake RA et al (2021) GDC-9545 (Giredestrant): a potent and orally bioavailable selective estrogen receptor antagonist and degrader with an exceptional preclinical profile for ER+ breast cancer. J Med Chem 64(16):11841–11856. https://doi.org/10.1021/acs.jmedchem.1c00847
Kahraman M, Govek SP, Nagasawa JY et al (2018) Abstract 1648: discovery and evolution of orally bioavailable selective estrogen receptor degraders for ER+ breast cancer: from GDC-0810 to GDC-0927. Cancer Res 78(13 Supplement):1648–1748. https://doi.org/10.1158/1538-7445.am2018-1648
Dickler M, Villanueva R, Perez Fidalgo J et al (2018) A first-in-human phase I study to evaluate the oral selective estrogen receptor degrader (SERD) GDC-0927, in postmenopausal women with estrogen receptor positive (ER+), HER2-negative metastatic breast cancer (BC) cancer research. Cancer Res. https://doi.org/10.1158/1538-7445.SABCS17-PD5-10
Jhaveri K, Winer EP, Lim E et al (2020) Abstract PD7–05: a first-in-human phase I study to evaluate the oral selective estrogen receptor degrader (SERD), GDC-9545, in postmenopausal women with estrogen receptor-positive (ER+) HER2-negative (HER2-) metastatic breast cancer. Cancer Res 80(4 Supplement):PD7-05-PD7-05. https://doi.org/10.1158/1538-7445.sabcs19-pd7-05