5398 - A phase II window of opportunity study of preoperative olaparib (O) with cisplatin (C) or durvalumab (D) or olaparib alone in in patients with operable squamous cell head and neck carcinoma (HNSCC) (OPHELIA)

Background

There is substantial evidence that tumors use PARP to repair platinum- induced DNA damage and escape apoptosis. In addition, unifying model emerges with DNA Damage Response/Repair (DDR/R) and immune response systems being activated in concert.

Methods

OPHELIA is phase II trial in which pts are randomized 3:3:3:1 to C 60 mg/m2 on d1 followed by O 75mg d 1-5, O 300 mg bid for 21-28 days, D 1500 mg on d1 followed by O 600mg daily for 21-28 days and no treatment. The D arm will be activated in 9/2018. PBMCs were isolated from blood obtained from pts at diagnosis as well as 24h and 3 weeks following treatment. Double Stranded Brakes/Repair (DSB/R) was measured using phosphorylation of histone H2AX by immunofluorescence and confocal laser microscope analysis, and/or comet assay while Nucleotide Excision Repair (NER) efficiency was measured by southern blotting.

Results

The study continues to recruit pts. Characteristics of 23 enrolled pts were: median age 61.2 years, tobacco use 87%, cT1 (n = 4), cT2 (n = 4), cT3 (n = 2), cT4 (n = 11), cTx (n = 2) and cN0/1 (n = 15), cN2 (n = 8).12 pts were randomized to O, 8 pts to C+O, and 3 pts to no treatment. Preliminary results have demonstrated: 1) No serious study drug-related adverse events or unexpected surgical delays/complications, 2) 4 pts (17%), 3 in O arm and 1 in C+O arm with clinical or pathologic downstaging. 1 pt on O arm had pCR. 15 pts had SD post treatment, 2 pts had PD and 1 had PR. Results are not yet available for 2 pts. 3. Significantly increased ongoing spontaneous DNA damage was obtained in PBMCs from untreated pts compared to healthy controls. Differences in C-induced DNA damage levels were found among pts. Similar formation of monoadducts was found at 3-h ex-vivo C treatment of PBMCs from untreated pts; thereafter, their levels were decreased, with removal capacity being higher in healthy controls than in pts.

Conclusions

Neoadjuvant O with or without C was well tolerated and induced promising antitumor responses. Higher levels of spontaneous ongoing DNA damage were noted in HNSCC pts compared to controls; this feature may serve as a candidate biomarker for response to immunotherapy in HNSCC.

Clinical trial identification

NCT02882308 First posted: August 29, 2016.

Legal entity responsible for the study

Hellenic Cooperative Oncology Group.

Funding

AstraZeneca.

Editorial Acknowledgement

Disclosure

A. Psyrri: Advisory board: AstraZeneca; Honoraria: AstraZeneca. G. Fountzilas: Research funding: AstraZeneca. All other authors have declared no conflicts of interest.