A Phase II Pilot Study of Anti-PD-L1, Durvalumab, and a PARP Inhibitor, Olaparib in Patients With Metastatic Triple-Negative Breast Cancer With or Without Germline BRCA Mutation.

BACKGROUND: Immunostimulatory effects of PARP inhibitors could increase sensitivity to immune checkpoint inhibitors. The previous Phase II trial (MEDIOLA) reported clinical benefits of durvalumab and olaparib (D + O) in patients with germline BRCA-mutated (gBRCAm) HER2-negative metastatic breast cancer. Yet, the clinical activity of D + O in germline BRCA wild-type (gBRCAwt) triple-negative breast cancer (TNBC) remains unknown. METHODS: This single-arm Phase II study tested D + O in patients with metastatic TNBC. The primary objective was overall response rate (ORR). Secondary objectives were safety, disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Based on gBRCA status, patients were assigned to either gBRCAwt or gBRCAm cohort and were treated with D (1500 mg iv q4w) and O (300 mg twice a day orally). Pretreatment fresh tissues and serial blood samples were collected for correlative studies. RESULTS: Fifteen patients (12 gBRCAwt and 3 gBRCAm) were enrolled. gBRCAm and gBRCAwt cohorts are reported as a combined dataset because of small sample size due to COVID-19 and slow accrual. The median number of prior therapies was three (range 0-8). Among 14 RECIST-evaluable patients (11 gBRCAwt and 3 gBRCAm), ORR was 28.6% (3 gBRCAm and 1 gBRCAwt). DCR was 64.3% (3 gBRCAm and 6 gBRCAwt). The median PFS and OS were 3.6 months (95% confidence interval [CI]: 1.8-5.7) and 10.7 months (95% CI: 5.9-38.9), respectively. There is one gBRCAm patient with ongoing durable PR (67.4+ months). There was no new safety concern. CD83 expression on Types 1 and 2 conventional dendritic cells in blood at baseline was low in the patients with PFS ≥ 4 months compared to those with PFS < 4 months. CONCLUSION: Our study demonstrated modest clinical benefits of D + O with ORR of 28.6% in subsets of heavily pretreated TNBC. Further detailed classification of DCs to understand the predictive role of DCs and prospective validation in a large cohort is required. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02484404.