Selective Estrogen Receptor Degrader May Help Patients With Resistant ER+ Breast Cancer

Presented by Dr. Maura N. Dickler MD Associate member of the Breast Medicine Service at Memorial Sloan Kettering Cancer Center and Weill Medical College of Cornell University in New YorMedicalResearch.com Interview with:
Presented by Dr. Maura N. Dickler MD
Associate member of the Breast Medicine Service at
Memorial Sloan Kettering Cancer Center and
Weill Medical College of Cornell University in New York

Medical Research: What is the background for this study?

This year, breast cancer will claim the lives of nearly 40,000 women in the United States, and up to half of these women will have a disease that is driven by the estrogen receptor.

  • Although medicines have been approved for the treatment of hormone receptor-positive breast cancer for decades, more treatment options are needed.
  • Resistance to endocrine therapies causes morbidity and mortality for women with metastatic estrogen receptor-positive (ER+) breast cancer as many patients relapse or develop resistance to available hormonal agents via estrogen-dependent and estrogen-independent mechanisms.
  • Dual-acting investigational Selective Estrogen Receptor Degrader (SERDs) could potentially lead to a new treatment option for people with hormone receptor-positive breast cancer and may help overcome resistance to current anti-hormonal medicines.
  • GDC-0810 is a dual-acting investigational next-generation oral SERD that works in a number of ways to prevent estrogen fueling tumor growth. It is not only designed to target the estrogen receptor (ER) as an antagonist, but also to cause degradation of the ER protein. In preclinical studies, GDC-0810 was shown to induce tumor regressions in both tamoxifen sensitive and tamoxifen resistant tumor models in vivo.

Medical Research: What are the main findings?

  • Clinical data from the dose-escalation portion of a Phase I/IIa study evaluating GDC-0810 appears to have an acceptable safety profile with encouraging anti-tumor activity in postmenopausal women with advanced breast cancer positive for the estrogen receptor (ER), all of whom were previously treated with standard endocrine therapy.
  • Promising anti-tumor activity was observed in 38% of patients on study for six months or longer. At all doses tested, there was robust engagement of the estrogen receptor by GDC-0810 as demonstrated by fluoroestradiol (FES) PET scans.  Overall, the most common adverse events of any grade related to GDC-0810 were diarrhea, nausea and fatigue.

Medical Research: What should clinicians and patients take away from your report?

  • SERDs could potentially lead to a new treatment option for women with hormone receptor-positive breast cancer and may help overcome resistance to current anti-hormonal medicines, such as tamoxifen, aromatase inhibitors, and fulvestrant.
  • We believe these investigational next-generation oral SERDs could one day redefine the standard of care for hormone receptor-positive breast cancer.
  • New therapies, like GDC-0810, that potentially have activity against treatment-resistant tumors are needed.
  • When some women become resistant to anti-hormonal medicines and see their disease return or worsen, preclinical and clinical data suggest that the cancer continues to be driven by the actual estrogen receptor (not by natural hormones).
  • We believe that when the SERDs bind to the estrogen receptor, they induce degradation and turnover of the estrogen receptor so that it is eliminated from the cell. So you could hypothesize that if the SERDs have the ability to eliminate the estrogen receptor from the cell altogether, this may circumvent the problem of resistance.
  • These small molecules have been rationally designed to enter the cell, change the shape of the estrogen receptor, and mark it for elimination.
  • Note: Philip Rosenberg from the NCI will present data at AACR reporting that the total number of breast cancer cases in the US is forecast to be 50% greater in 2030 than it was in 2011, when invasive and in-situ or screening-detected cancers are counted together, and this increase is driven mostly by a marked increase in cases of estrogen receptor (ER)–positive tumors and in women older than 70.

Medical Research: What recommendations do you have for future research as a result of this study?

  • In the Phase II portion of the study, we are evaluating GDC-0810 in patients previously treated with aromatase inhibitors and fulvestrant, including those with estrogen receptor mutations. We expect to enroll approximately 140 patients.
  • Randomized studies are being planned to compare GDC-0810 against other standard of care therapies.

Citation:

Presented at the 2015 American Association of Cancer Research meeting
April 19 2015

Abstract Number: 8953
Title: A first-in-human Phase I study to evaluate the oral selective estrogen receptor (ER) degrader GDC-0810

(ARN-810) in postmenopausal women with ER+ HER2-, advanced/metastatic breast cancer (BC)

Author Block: Maura Dickler1, Aditya Bardia2, Ingrid Mayer3, Eric Winer4, Peter Rix5, Jeff Hager5, Meng Chen6, Iris Chan6, Edna Chow-Maneval5, Carlos Arteaga3, Jose Baselga1. 1Memorial Sloan Kettering Cancer Center, New York, NY; 2Massachusetts General Hospital Cancer Center, Boston, MA; 3Vanderbilt-Ingram Cancer Center, Nashville, TN; 4Dana-Farber Cancer Institute, New York, NY; 5Seragon Pharmaceuticals, San Diego, CA; 6Genentech, Inc, South San Francisco, CA

MedicalResearch.com Interview with: Presented by Dr. Maura N. Dickler MD (2015). Selective Estrogen Receptor Degrader May Help Patients With Resistant ER+ Breast Cancer 

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