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Published on: August 12, 2015
A Phase II Pilot Study of Anti-PD-L1, Durvalumab, and a PARP Inhibitor, Olaparib in Patients With Metastatic
Takeo Fujii1, Ashley Cimino-Mathews2, Stanley Lipkowitz1
1Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
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.
Insights
This study investigated durvalumab and olaparib combination therapy in metastatic triple-negative breast cancer (TNBC). The treatment showed modest overall response rates, suggesting potential benefits in heavily pretreated patients.
Area of Science:
- Oncology
- Immunotherapy
- Genetics
Background:
- PARP inhibitors (PARPi) may enhance immune checkpoint inhibitor (ICI) efficacy.
- Previous trials showed durvalumab and olaparib (D + O) benefit in BRCA-mutated (gBRCAm) HER2-negative metastatic breast cancer.
- Clinical activity of D + O in germline BRCA wild-type (gBRCAwt) triple-negative breast cancer (TNBC) was previously unknown.
Purpose of the Study:
- To evaluate the clinical activity and safety of D + O in patients with metastatic TNBC.
- To assess overall response rate (ORR) as the primary endpoint.
- To explore secondary endpoints including disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).
Main Methods:
- Single-arm, Phase II study enrolling patients with metastatic TNBC.
- Patients were assigned to gBRCAwt or gBRCAm cohorts.
- Treatment involved durvalumab (D) and olaparib (O); correlative studies analyzed baseline biomarkers.
Main Results:
- Fifteen patients (12 gBRCAwt, 3 gBRCAm) were enrolled.
- Combined ORR was 28.6% (1 gBRCAwt, 3 gBRCAm) among 14 evaluable patients.
- Median PFS was 3.6 months, median OS was 10.7 months; one gBRCAm patient achieved durable response.
- Low baseline CD83 expression on dendritic cells correlated with longer PFS.
Conclusions:
- D + O demonstrated modest clinical benefits in heavily pretreated metastatic TNBC.
- Further research is needed to classify dendritic cell subtypes and validate their predictive role.
- Prospective validation in larger cohorts is required to confirm findings.
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