Ceralasertib (cer) in combination with olaparib (ola) in patients (pts) with advanced breast cancer (BC): Results of phase I expansion cohorts
Dean, E. Krebs, Matthew G Im, S. A. Campone, M. Postel-Vinay, S. Arkenau, T. Lopez, J. Abida, W. Jodrell, D. Lee, K. W.
Dean, E.
Krebs, Matthew G
Im, S. A.
Campone, M.
Postel-Vinay, S.
Arkenau, T.
Lopez, J.
Abida, W.
Jodrell, D.
Lee, K. W.
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Abstract
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).
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Date
2021
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Meetings and Proceedings
Citation
Dean E, Krebs MG, Im SA, Campone M, Postel-Vinay S, Arkenau T, et al. Ceralasertib (cer) in combination with olaparib (ola) in patients (pts) with advanced breast cancer (BC): Results of phase I expansion cohorts. Cancer Research. 2021;81(4).