Abstract OT3-05-03: MEDIOLA: An open-label, phase I/II basket study of olaparib (PARP inhibitor) and durvalumab (anti-PD-L1 antibody)–Additional breast cancer cohorts
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 a PARP inhibitor that alters the repair of single-strand DNA breaks. Durvalumab (Imfinzi®) is a monoclonal antibody against programmed cell death ligand 1 (anti-PD-L1) that promotes antitumor immune responses. MEDIOLA (NCT02734004) is a Ph I/II open-label, multicenter study enrolling patients (pts) across several tumor types (small-cell lung cancer, gastric cancer, germline BRCA-mutated [gBRCAm] BC, or platinum sensitive relapsed gBRCAm ovarian cancer). 34 pts with gBRCAm BC received olaparib 300 mg po bid for a 4-wk run-in, followed by olaparib 300 mg po bid and durvalumab 1.5 g IV q4 wks. Encouraging preliminary results support an expansion cohort in a BRCAm popn. Evidence suggests that mutations in other homologous recombination repair (HRR) genes may confer a BRCA-like phenotype, warranting an expansion of the study population beyond BRCAm.
Inhibition of vascular endothelial growth factor (VEGF) has been reported to enhance the efficacy of chemotherapy in TNBC. In addition, VEGF inhibition potentiates PARP inhibitor activity, particularly in pts who do not carry BRCAm. Combinations of immune checkpoint inhibitors and bevacizumab, an anti-VEGF-A antibody, have shown promising results in other tumor types. Thus, MEDIOLA will additionally explore the efficacy and safety of olaparib + durvalumab in combination with bevacizumab in TNBC pts.
Trial design: Pts in the additional MBC cohorts will receive combination olaparib and durvalumab with no olaparib run-in. Pts in the TNBC cohort will also receive concurrent bevacizumab 10 mg/kg q 2 wks. Tumor assessments will be performed at baseline and every 8 wks thereafter.
Eligibility criteria: Pts with histologically confirmed, locally advanced or metastatic HER2-neg BC, who are PARP-inhibitor and immunotherapy naïve. Prior anthracycline and/or taxane therapy in early or MBC is required. Prior platinum therapy is allowed, if there was no disease progression while receiving treatment and at least 12 mths has elapsed since the last dose. Pts will undergo BRCA and HRR mutation testing and will be assigned to a cohort based on their mutation status, as illustrated in Table 1.
Specific aims: Cohort-specific primary efficacy endpoint targets were calculated aiming for superiority to standard of care treatment (Table 1). Other primary outcomes are safety and tolerability. Secondary endpoints are PK, DCR at 24 wks, objective response rate, duration of response, progression-free survival and overall survival. Exploratory endpoints include the analysis of tumor-infiltrating lymphocytes and PD-L1 expression.
Statistical methods: The expansion cohort will have a single-stage statistical design. Bayesian predictive probability design will be used for the analysis of the HRRm and TNBC triplet cohorts.
Accrual: Accrual targets are shown in Table 1. First subject will be enrolled in Nov 2018.
New MEDIOLA BC cohortsCohort nameTarget accrualDrugsPopnPrimary endpointBreast BRCAm expansion80Olap+DurvHER2-neg, tBRCAmORR 70%Breast HRRm cohort29Olap+DurvHER2-neg, non BRCAm, HRRm-posDCR at 16 wks 80%TNBC triplet cohort30Olap+Durv+BevTNBC, non BRCAm, non HRRmDCR at 16 wks 80%Bev, bevacizumab; durv, durvalumab; olap, olaparib
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. MEDIOLA: An open-label, phase I/II basket study of olaparib (PARP inhibitor) and durvalumab (anti-PD-L1 antibody)–Additional breast cancer cohorts [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 OT3-05-03.