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Combination of PARP inhibitor olaparib, and PD-L1 inhibitor durvalumab, in recurrent ovarian cancer: a proof-of-concept phase 2 study.

PURPOSE:

Preclinical studies suggest PARP inhibition (PARPi) induces immunostimulatory micromilieu in ovarian cancer thus complementing activity of immune checkpoint blockade. We conducted a phase 2 trial of PARPi olaparib and anti-PD-L1 durvalumab and collected paired fresh core biopsies and blood samples to test this hypothesis.

EXPERIMENTAL DESIGN:

In a single-center, proof-of-concept phase 2 study, we enrolled women aged ≥18 with recurrent ovarian cancer. All patients were immune-checkpoint inhibitor naïve and had measurable disease per RECISTv1.1, ECOG performance status 0-2, and adequate organ and marrow function. Patients received olaparib 300mg twice daily and durvalumab 1500mg intravenously every 4 weeks until disease progression, unacceptable toxicity, or withdrawal of consent. Primary endpoint was overall response rate (ORR). Secondary objectives were safety and progression-free survival (PFS). Translational objectives included biomarker evaluation for relationships with clinical response and immunomodulatory effects by treatment.

RESULTS:

35 ovarian cancer patients (median 4 prior therapies [IQR 2-5.5], predominantly platinum-resistant [86%], BRCA wild-type [77%]) received at least one full cycle of treatment. ORR was 14% (5/35;95%CI,4.8%-30.3%). Disease control rate (PR+SD) was 71% (25/35;95%CI,53.7%-85.4%). Treatment enhanced IFNγ and CXCL9/CXCL10 expression, systemic IFNγ/TNFα production, and tumor-infiltrating lymphocytes, indicating an immunostimulatory environment. Increased IFNγ production was associated with improved PFS (HR:0.37[95%CI,0.16-0.87], p=0.023) while elevated VEGFR3 levels were associated with worse PFS (HR=3.22[95%CI,1.23-8.40], p=0.017).

CONCLUSIONS:

The PARPi and anti-PD-L1 combination showed modest clinical activity in recurrent ovarian cancer. Our correlative study results suggest immunomodulatory effects by olaparib/durvalumab in patients and indicate that VEGF/VEGFR pathway blockade would be necessary for improved efficacy of the combination.

Related Products

Cat.No. Product Name Information
S1060 Olaparib (AZD2281) Olaparib (AZD2281, KU0059436) is a selective inhibitor of PARP1/2 with IC50 of 5 nM/1 nM in cell-free assays, 300-times less effective against tankyrase-1. Olaparib induces significant autophagy that is associated with mitophagy in cells with BRCA mutations.

Related Targets

PARP