Abstract PS11-18: Ceralasertib (cer) in combination with olaparib (ola) in patients (pts) with advanced breast cancer (BC): Results of phase I expansion cohorts

Background: Alterations in BRCA1/2 are associated with ~9% of all BCs. Ola (a poly ADP-ribose polymerase inhibitor [PARPi]) is approved for treating pts with HER2-negative metastatic BC with germline BRCA mutation (gBRCAm), demonstrating an improvement in progression-free survival (PFS). Ceralasertib (an ataxia telangiectasia and Rad3-related protein ATR inhibitor) targets DNA damage repair and cell cycle regulation. Preclinical studies show synergistic antitumor effects of ola+cer vs ola monotherapy supporting the clinical evaluation of this combination. Methods: Study 4 is a modular multicenter Phase I study of cer combinations (NCT02264678). Module 2 established the Recommended Phase 2 Dose of ola+cer as ola 300 mg bid daily + cer 160 mg qd D1-7 q 28d. We report the results of two expansion cohorts testing ola+cer in pts with triple negative breast cancer with no alterations in homologous recombination repair (HRR)-related genes (HRR wt group), and pts with advanced HER2- BRCAm BC (BRCAm group), with a data cut-off of 19th June 2019. Eligible pts had to have received 1-2 prior lines of chemotherapy for metastatic disease, and were PARPi naive. Patients may have enrolled directly based on a local BRCAm test result, but all pts submitted a tumor specimen for central confirmation of a deleterious (or suspected deleterious) germline or somatic BRCA1/2 mutation. The primary objective was to investigate the safety and tolerability of the combination; secondary objectives included assessment of objective response rate by RECIST 1.1. Results: Twenty-five pts were enrolled in the HRR wt group: median age 53 (31-75), ECOG PS 0/1 13 (52%)/12 (48%), median number of prior chemotherapy lines 2 of which 8 pts (32%) had received prior platinum. Thirty-seven pts enrolled in the BRCAm group: median age 51 (24-69), ECOG PS 0/1 20 (54%)/17 (46%), median number of prior chemotherapy lines 1 of which 19 pts (51%) had received prior platinum. The most frequent all causality Adverse Events (AEs) were nausea 43 (69%), anemia 36 (58%), diarrhea 20 (32%) and vomiting 20 (32%); CTCAE ≥ Grade 3 AEs included anemia 15 (24%), neutropenia 6 (10%) with few patients discontinuing treatment. In the HRR wt group, no responses were observed, 12 (48%) pts achieved a best response of stable disease and 13 (52%) had disease progression. The median PFS was 3.1 months (80%CI 2.0,3.9). In the BRCAm group, 13 (35%) pts achieved a confirmed response (including 1 complete response), 17 (46%) stable disease and 7 (19%) pts disease progression. The median PFS in pts with a centrally confirmed BRCAm was 11.5 months (80%CI 5.8-14.8, n=30), 7.7 months (80%CI 5.8-11.4, n=37) in all pts enrolled in the BRCAm group. Eleven of the 13 responders in the BRCAm group were on study treatment for a longer duration than their treatment immediately prior to enrollment. As of 18th June 20, preliminary data shows 10 pts are still ongoing with a treatment duration ranging 20 to 35 months. Conclusion: In pts with HER2- BRCAm breast cancer, clinical efficacy was observed with durable radiological response despite adverse prognostic features in this Phase I population. The observations in this study are currently being tested in a global multicenter open-label randomised Phase 2 study: VIOLETTE (NCT03330847). Citation Format: Emma Dean, Matthew G Krebs, Seock-Ah Im, Mario Campone, Sophie Postel-Vinay, Tobias Arkenau, Juanita Lopez, Wassim Abida, Duncan Jodrell, Keun-Wook Lee, SunYoung Rha, Irene Kang, Rebecca Roylance, Graeme Parr, Claire Smith, Andrew Goldwin, Elhan Sanay, Natasha Lukashchuk, Alan Lau, Andrew Pierce, Bienvenu Loembe. Ceralasertib (cer) in combination with olaparib (ola) in patients (pts) with advanced breast cancer (BC): Results of phase I expansion cohorts [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-18.