Combination of PARP inhibitor olaparib, and PD-L1 inhibitor durvalumab, in recurrent ovarian cancer: a proof-of-concept phase 2 study
Mené sur 35 patientes atteintes d’un cancer de l’ovaire récidivant, cet essai de phase II évalue l’efficacité, du point de vue du taux de réponse globale, et la toxicité d’un traitement combinant olaparib et durvalumab, après l’échec de plusieurs lignes de traitements (nombre médian de thérapies précédentes : 4)
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 IFN? and CXCL9/CXCL10 expression, systemic IFN?/TNF? production, and tumor-infiltrating lymphocytes, indicating an immunostimulatory environment. Increased IFN? 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.