Interesting for postM, ER+ HER2- mBC patients.

GDC-0810 (ARN-810, RG6046) is a selective estrogen receptor degrader (SERD) that is designed to bind to the estrogen receptor (ER) to limit its function. In addition, when SERDs bind to the ER, they may be able to change the shape of the receptor in such a way that the cell eliminates it by degradation.

Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT01823835
Study of ARN-810 (GDC-0810) in Postmenopausal Women With Locally Advanced or Metastatic Estrogen Receptor Positive Breast Cancer
Estimated Enrollment: 141
Study Start Date: December 2014
Estimated Study Completion Date: July 2017

Trials Locations: California, Connecticut, Massachusetts, Missouri, New York, North Carolina, Ohio, Tennessee, Washington,
South Korea (Seoul), Netherlands (Amsterdam, Groningen), Spain (Barcelona, Madrid, Valencia)

Technical mumbo jumbo: Recently, a series of orally bioavailable SERDs were identified and optimized by Genentech/Seragon. The lead compound GDC-0810 showed robust activity in degrading ER-α in MCF-7 cells, and demonstrated anti-cancer activity in both tamoxifen-sensitive and tamoxifen-resistant breast cancer models¹²⁹. Importantly, in phase I/IIa studies that include 41 postmenopausal patients, all of whom had advanced ER-positive breast cancer disease that had progressed after at least 6 months of endocrine therapy, GDC-0810 competed effectively with tracer to occupy the ER at all doses tested, even in patients with ESR1 mutations, suggesting robust target engagement (http://www.aacr.org/Newsroom/pages/News-Release-Detail.aspx?ItemID=711#.VmCWoOOfrRY). Although the mechanism of action by GDC-0810 is not completely clear at this point, it is suspected that certain E3 enzymes are activated upon ER-α engagement by the GDC compound, leading to its ubiquitination and degradation. Alternatively, SERD molecules might also behave as their SERM (Selective ER Modulators) counterparts, by changing the conformation of the α12 helix of ER, to expose hydrophobic residues that engage the quality control machinery to degrade the ER^130,131,132.

Source: March 2016 - http://www.nature.com/cr/journal/v26/n4/full/cr201631a.html