Evaluating the Efficacy and Safety of Fulvestrant Plus DNA Damage Repair Inhibitors After a CDK4/6 Inhibitor

Nearly 70% of breast cancers (BCs) express estrogen receptor and rely on estrogen binding for growth and promotion of tumourigenesis. Endocrine therapy (ET), such as aromatase inhibitors, are the mainstay initial therapy for hormone receptor-positive (HR+), human epidermal growth factor receptor two-negative (HER2-) BC. Recently, the combination of ET and cyclin-dependent kinase (CDK) 4/6 inhibitors has shown significant and meaningful clinical benefit and has become the standard of care in this setting. So far, three CDK4/6 inhibitors have been approved by both FDA and EMA(European Medicines Agency): palbociclib (Ibrance, Pfizer, USA), ribociclib (vissali, Novartis, Switzerland) and abemaciclib (Verzenio, Lilly, USA). All of these drugs are approved and are widely used in 1st-line treatment for metastatic HR+/HER2- BC in Korea. CDK4/6 inhibitors have revolutionized the treatment landscape of HR+ HER2- BC but intrinsic or acquired resistance is inevitable. Fulvestrant, a selective estrogen receptor degrader (SERD), is one of preferred agents as the 2nd line treatment after failure of an aromatase inhibitor. More data regarding treatment options and sequences after failure of CDK4/6 inhibitors and endocrine treatments are needed. This is an umbrella study of treatments according to the germline or somatic genetic alterations in this patient population. The main focus would include, but not be limited to, DNA damage repair (DDR) inhibitors plus fulvestrant combinations.