Abstract PD5-04: An open-label, phase II basket study of olaparib and durvalumab (MEDIOLA): Updated results in patients with germline BRCA-mutated (gBRCAm) metastatic breast cancer (MBC)
Authors: Domchek SM , Postel-Vinay S , Im S-A , Hee Park Y , Delord J-P , Italiano A , Alexandre J , You B , Bastian S , Krebs MG , Waqar S , Lanasa M , Angell HK , Tang M , Gresty C , Opincar L , Herbolsheimer P , Kaufman B 
Published: May 2019

Abstract
Background: Olaparib (Lynparza®) is approved for the treatment of gBRCAm HER2-negative MBC based on the OlympiAD study results. Olaparib-induced DNA repair defects may attract tumor-infiltrating lymphocytes, upregulate programmed cell death ligand-1 (PD-L1) and release tumor neo-antigens upon cell death. Here, the objective was to assess the efficacy and safety of olaparib in combination with durvalumab (Imfinzi), a PD-L1 agent, in gBRCAm HER2-negative MBC (NCT02734004).
Methods: Patients (pts) with HER2-negative, gBRCAm MBC were eligible; prior platinum therapy without disease progression was allowed. Pts received olaparib 300 mg tablet BID for a 4-wk run-in, followed by a combination of olaparib 300 mg BID and durvalumab 1.5 g IV q 4 wks. The combination was continued until progressive disease by RECIST 1.1. Tumor assessments were done at baseline, 4 wks, and every 8 wks thereafter. The primary endpoints were disease control rate (DCR) at 12 wks, safety and tolerability. The secondary endpoints included DCR at 28 wks, objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), overall survival (OS) and a biomarker analysis. A Bayesian predictive probability design was used for the statistical analysis of the primary endpoint.
Results: Thirty-four pts were included in the safety, and 32 pts in the efficacy analysis. At data cut-off (DCO) on 30 Mar 18, the 12-wk DCR was 81% (90% CI: 66%, 92%) and 28-wk DCR 47% (90% CI: 32%, 63%). The ORR for the overall cohort was 56% (95% CI: 38%, 74%), with 1 (3%) complete response (CR), 17 (53%) partial response (PR), 8 (25%) stable disease (SD), and 6 (19%) progressive disease (PD). Median DoR was 9.2 months (interquartile range, 5.5 to 12.9 months). First- and second-line pts showed higher response rates (70% and 73%, respectively) compared to pts with 3 or more lines of prior chemotherapy (27%) (Table 1). The median PFS for the overall cohort was 6.7 months (95% CI of 4.6, 11.7 months). With median follow-up of 14.5 months, the median OS has not been reached. At the time of DCO, 8 (25%) pts remained on combination therapy. The most common Grade 3 or 4 adverse events reported were anemia (11.8%), neutropenia (8.8%), and pancreatitis (5.9%). Efficacy and safety results with longer follow-up will be presented. Biomarker analysis on CD3, CD8 and
PD-L1 expression in the archival tissue and in paired biopsies obtained at baseline and after olaparib monotherapy run-in, will also be presented.
Conclusions: The addition of durvalumab to olaparib showed promising activity with the ORR in the early line gBRCAm MBC pts, comparing favorably with olaparib monotherapy (OlympiAD) (&gt;70% in 1–2L MEDIOLA vs 60% overall in OlympiAD). In addition, the median DoR appeared longer with the combination (9.2 months in MEDIOLA vs 6.4 months in OlympiAD). Approximately one-third of the pts in MEDIOLA were heavily pretreated (3L+) and as expected, the ORR was lower in these pts. Due to the small number of pts, these results warrant confirmation of activity in the early-line setting. Further MBC cohorts are in development.
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Citation Format: Domchek SM, Postel-Vinay S, Im S-A, Hee Park Y, Delord J-P, Italiano A, Alexandre J, You B, Bastian S, Krebs MG, Waqar S, Lanasa M, Angell HK, Tang M, Gresty C, Opincar L, Herbolsheimer P, Kaufman B. An open-label, phase II basket study of olaparib and durvalumab (MEDIOLA): Updated results in patients with germline BRCA-mutated (gBRCAm) metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD5-04.