Breast cancer is the most frequently diagnosed cancer among women and remains the second leading cause of cancer death in women. An estimated 70% of all breast cancers express estrogen receptor alpha (ERα); and endocrine therapies have validated ERα as a target for the treatment of breast cancer. Despite effective endocrine therapies, many patients eventually relapse and become resistant to standard of care treatments. Endocrine resistant tumors often remain dependent on ERα for growth and survival, as evidenced by their sensitivity to the selective estrogen receptor degrader (SERD), fulvestrant. However, fulvestrant may be limited in achieving maximal target occupancy due to pharmaceutical and pharmacokinetics properties which necessitates intramuscular route of administration. Consequently, SERDs with superior drug-like properties were sought to allow consistent and rapid achievement of maximal therapeutic exposure. GDC-0810 and GDC-0927 as first and second generation orally bioavailable SERDs were discovered through a prospective lead optimization on ERα degradation. The evolution from GDC-0810 to GDC-0927 will be described and provides new insights into ERα biology and biochemistry. By shifting away from the acrylic acid moiety in GDC-0810, GDC-0927 achieved increased potency and more consistent, complete suppression of ER signaling. Co-crystal structures of both GDC-0810 and GDC-0927 with ERα will be shared. Subsequent optimization of GDC-0927 resulting in improved pharmacokinetic properties will also be highlighted. Citation Format: Mehmet Kahraman, Steven P. Govek, Johnny Y. Nagasawa, Andiliy Lai, Celine Bonnefous, Karensa Douglas, John Sensintaffar, Nhin Lu, KyoungJin Lee, Anna Aparicio, Josh Kaufman, Jing Qian, Gang Shao, Rene Prudente, James D. Joseph, Beatrice Darimont, Daniel Brigham, Richard Heyman, Peter J. Rix, Jeffrey H. Hager, Nicholas D. Smith, Robert A. Blake, Jae Chang, Edna Choo, Anneleen Daemen, Lori S. Friedman, Jane Guan, Steven Hartman, Ellen Ingalla, James R. Kiefer, Tracy Kleinheinz, Sharada Labadie, Ciara Metcalfe, Vidhi Mody, Michelle Nannini, Deepak Sampath, Amy Young, Maia Vinogradova, Wei Zhou, Jun Liang, Xiaojing Wang. Discovery and evolution of orally bioavailable selective estrogen receptor degraders for ER+ breast cancer: From GDC-0810 to GDC-0927 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1648.