Drs. Hope Rugo and Nancy Davidson discuss the next generation of endocrine therapy in hormone receptor-positive breast cancer – SERDs, SERMs, CERANs, and PROTACs – and challenges relating to the optimal sequence of therapeutic options. TRANSCRIPT Dr. Hope Rugo: Hello, I'm Dr. Hope Rugo, your guest host of the ASCO Daily News Podcast today. I'm a professor of medicine and director of breast oncology and clinical trials education at the University of California San Francisco's Comprehensive Cancer Center. Hormone receptor-positive (HR+) breast cancer is the most common subset of this disease and breast cancer is the most common cancer diagnosed in women worldwide. Endocrine therapy (ET) is the cornerstone of management in hormone receptor-positive breast cancer and may involve suppressing estrogen production with aromatase inhibitors in the cancer cell itself, or directly blocking the estrogen receptor pathway through selective estrogen receptor modulators, such as tamoxifen, or the injectable selective estrogen receptor degrader, fulvestrant. However, despite the availability of these therapies, the largest unmet need lies in treatment of HR-positive HER-negative disease lies after progression on endocrine therapy. On today's episode, we'll be discussing the emerging generation of endocrine therapies in breast cancer, some of which were designed to overcome common mechanisms of endocrine resistance, and the challenges relating to the optimal sequence of therapeutic options. Today, I'm delighted to welcome the world-renowned breast cancer researcher, Dr. Nancy Davidson, to the podcast. She's a professor and the executive vice president for clinical affairs at the Fred Hutchinson Cancer Center and professor of medicine at the University of Washington as well as past president of ASCO and AACR. You'll find our full disclosures in the transcript of this episode and disclosures of all guests on the podcast can be found in our transcripts at asco.org/DNpod. Nancy, it's great to have you on the podcast today. Thanks so much for being here. Dr. Nancy Davidson: Thank you so much, Hope, for the opportunity. Dr. Hope Rugo:  You've done incredible work in the area of treating HR+ disease, but also in understanding some of the agents and pathways that are most important to our understanding of how we treat and really think about developing new drugs for HR+ breast cancer. The first generation of anti-estrogen drugs really included selective estrogen receptor modulators, but now we have a new generation of these anti-estrogen drugs. And there's also orally administered selective estrogen receptor degraders, so-called SERDs, that we hope someday will be an alternative with already one approved for the injectable SERD, fulvestrant. But there's a whole additional class of drugs, complete estrogen receptor antagonists, referred to as CERANs, and proteolysis targeting chimerics, PROTACs. These agents are all at various stages of development in both early and metastatic settings and really represent, I think, a confusing array of different treatments that are being studied, some of which of course are approved. Nancy, it would be great if you could tell us some about these exciting new agents, starting with our approved drugs and moving on to the agents that we're studying in clinical trials. Dr. Nancy Davidson: Hope, this is a terrific example of how basic science has really begun to inform clinical practice. For us as breast cancer practitioners, it was really easy for a long time because we only had tamoxifen. And then things like the aromatase inhibitors as a means of decreasing the estrogen ligand came into practice, as did fulvestrant, as you mentioned, a selective estrogen receptor degrader. Thanks though to a lot of understanding about estrogen receptor biology, and specifically, the discovery about a decade ago of estrogen receptor mutations, something that we didn't think exist ed for a long time, but which we now know exists in maybe a