A phase II study of durvalumab, a PD-L1 inhibitor and olaparib in recurrent ovarian cancer (OvCa)

Abstract

Background: The PARP inhibitor, olaparib (O) showed clinical activity in subsets of recurrent OvCa patients (pts). We hypothesized increased DNA damage by O may complement anti-tumor activity of immune checkpoint blockade, durvalumab (D) in recurrent OvCa. We previously reported the safety data and recommended phase 2 dose (RP2D) of D+O. Enrollment in the phase 2 OvCa cohort was completed April 2018 and results are presented here (NCT02484404). Methods: Eligible pts with PS 0-1, good end organ function and biopsiable disease received the RP2D (O 300 mg orally twice daily and D 1500mg IV) on day 1 of each 28- day cycle. The primary objective was to estimate clinical activity using RECIST v1.1 response rate (RR) and a 2-stage design targeting 35 evaluable pts. Safety was assessed by CTCAEv4.0. Tissue and blood samples were collected pre-treatment and on therapy (cycle 1 day 15 and cycle 3 day 1). Results: 35 pts received at least 1 cycle of treatment (median age 67 year-old [range 40- 85], 6 germline BRCA mutation carriers [gBRCAm; 17%]/29 BRCA wild type [BRCAwt; 83%]). 30 pts (86%) had platinum-resistant recurrent disease. Median number of prior therapy regimens was 3.5 (1-16). Among 34 evaluable pts (6 gBRCAm/28 BRCAwt), 5 PRs were observed (15% RR, median 11months [6.5-23]): 2 pts with gBRCAm (platinum-resistant [8.5months] and -sensitive disease [11+months]) and 3 pts with BRCAwt (platinum-resistant [2; 23 and 14+months] and -sensitive disease [6.5months]). 13 pts (3 gBRCAm/10 BRCAwt) had SD>=4months (median 6.5months [4-12.5]), yielding 53% disease control rate (PR+SD>=4months). Grade 3/4 adverse events include anemia (26%) and lymphopenia (14%). 3 pts required O dose reduction due to grade 3 anemia (1), grade 3 atrial fibrillation (1) and recurrent grade 2 nausea refractory to supportive care (1). PD-L1 expression/TIL by immunohistochemistry, DNA repair deficiency by a BROCA-HR panel, and immune subsets by flow cytometry will be presented. Conclusions: Our results suggested D+O was well-tolerated and had clinical activity in a subgroup of heavily pretreated BRCAwt OvCa pts. Biomarker evaluation is ongoing to further characterize the subset of pts who had benefit from D+O.