Dora: A randomized phase II multicenter maintenance study of olaparib alone or olaparib in combination with durvalumab in platinum responsive advanced triple-negative breast cancer (aTNBC).

Abstract

TPS1113 Background: PARP inhibition (PARPi) with olaparib is approved in HER2-negative germline BRCA mutant (g BRCAm) metastatic breast cancer. Maintenance PARPi in relapsed platinum-sensitive ovarian cancer improves median PFS regardless of gBRCA mutation status. Preclinical work has shown that platinum response strongly correlates with olaparib response in breast cancer models; hence, maintenance therapy trials are underway in aTNBC. PARPi modulates immune responses and enhances immunogenicity in many preclinical models. We hypothesize that olaparib either alone or in combination with the PD-L1 inhibitor durvalumab will have clinical efficacy as maintenance therapy in aTNBC subjects who have responded to platinum-based chemotherapy. Methods: DORA is a randomized, international, multicenter, phase II study designed to explore the efficacy of olaparib or olaparib in combination with durvalumab as maintenance therapy in platinum-sensitive aTNBC. 60 subjects will be enrolled following a minimum of 3 cycles of treatment with platinum-based (cisplatin or carboplatin) chemotherapy as a single agent or combination therapy in the first or second-line setting. Subjects deriving clinical benefit (CR / PR / SD) from platinum-based therapy will be eligible and randomized in a 1:1 ratio. Patients in arm 1 will receive olaparib orally 300mg BID continuously and in arm 2 will receive olaparib orally 300mg BID continuously in combination with durvalumab 1500mg IV every 4 weeks. Assessment of tumor response will be done every 8 weeks. Primary endpoint: progression-free survival. Secondary endpoints: overall survival, clinical benefit rate, safety. Correlative analyses: pre-treatment archival/fresh biopsy samples are mandated. Post-treatment tissue biopsy is requested. Serial ctDNA will be collected at baseline, staging, and progression to correlate with response and track emerging genomic alterations in a platinum sensitive cohort under the pressure of PARP inhibition. Whole exome DNA sequencing, IHC for PDL-1 and TILs will be performed on tissue samples. ClincalTrials.gov Identifier: NCT03167619. (Moore K, et al "SOLO-1: Phase III trial of maintenance olaparib following platinum-based chemotherapy in newly diagnosed patients with advanced ovarian cancer and a BRCA1/2 mutation" ESMO 2018; Abstract LBA7-PR). Clinical trial information: NCT03167619.