Abstract ES6-4: Parp inhibitors for brca1/2mutation associated breast cancer
Authors: Tutt ANJ 
Published: March 2022

Abstract
More than 15 years ago we and others showed the use of potent PARP1 inhibitors (PARPi), that both inhibit the catalytic activity of the PARP1 enzyme and trap PARP1 onto DNA, generate a “synthetic lethal” interaction with the malignant cell specific loss of function of genes crucial for homologous recombination (HR) gene function. This phenomenon has now been exploited with therapeutic intent in several contexts leading to approved single agent PARPi treatments for advanced forms of ovarian, prostate, pancreatic and breast cancers. These approvals have in large part been associated a biomarker requirement for evidence of loss of function of HR. Recently a number of trials have investigated PARPi in a (neo)adjuvant breast cancer treatment (NACT) setting in patients with (or enriched for) HR deficiency. These have included phase II neoadjuvant PARPi studies such as the NeoTALA study using single agent talazoparib in germline BRCA1 and BRCA2 mutation carriers and the combination chemotherapy and olaparib therapy studies GeparOLA and PARTNER, enriched for HR deficient breast cancer, that have reported important signals with regard efficacy and tolerability. Two recent phase III trials have influenced recent early breast cancer treatment guidelines. These are the BrighTNess trial in the neoadjuvant setting and OlympiA in the post-(neo)adjuvant setting. BrighTNess recruited patients with biologically heterogeneous triple negative breast cancer (TNBC) and used the weak PARP1 trapping PARPi veliparib and OlympiA restricted eligibility to patients with the germline “pathogenic” or “likely pathogenic” mutation in BRCA1 or BRCA2 but included patients with hormone receptor positive breast cancer. BrighTNess did not show convincing evidence of benefit to the addition of veliparib to standard of care in TNBC NACT but has shown the benefit to the addition of carboplatin to sequential paclitaxel-AC NACT with significant improvements in event free survival (HR 0.57 ) compared to sequential paclitaxel-AC alone. OlympiA has reported following an interim analysis showing 12 months of olaparib in the post-(neo)adjuvant chemotherapy setting improves both invasive disease free and distant disease free survival by approximately 40% with highly statistically significant hazard ratios of 0.58 and 0.57 respectively that met pre-specified early stopping boundaries. The publication of results for OlympiA has led to rapid updates of both genetic testing and treatment international guidelines for BRCA1 and BRCA2 mutation associated breast cancer to include use of olaparib in patients meeting the eligibility criteria for the trial. The lecture will both explore the data and the implications for practice of the adoption of these guidelines and some of the ongoing questions to be addressed by ongoing clinical trial and translational research initiatives.
Citation Format: ANJ Tutt. Parp inhibitors for brca1/2mutation associated breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr ES6-4.