Phase II Window Study of Olaparib Alone or with Cisplatin or Durvalumab in Operable Head and Neck Cancer

Abstract

Purpose: We conducted a phase II randomized noncomparative window of opportunity (WOO) trial to evaluate the inhibition of cellular proliferation and the modulation of immune microenvironment after treatment with olaparib alone or in combination with cisplatin or durvalumab in patients with operable head and neck squamous cell carcinoma (HNSCC).

Experimental design: Forty-one patients with HNSCC were randomized to cisplatin plus olaparib (arm A), olaparib alone (arm B), no treatment (arm C) or durvalumab plus olaparib (arm D). The primary endpoint was to evaluate the percentage of patients in each arm that achieved a reduction of at least 25% in Ki67. Secondary endpoints included objective response rate (ORR), safety, and pathologic complete response (pCR) rate. Paired baseline and resection tumor biopsies and blood samples were evaluated for prespecified biomarkers.

Results: A decrease in Ki67 of at least 25% was observed in 44.8% of treated patients, as measured by quantitative immunofluorescence. The ORR among treated patients was 12.1%. pCR was observed in 2 patients. Two serious adverse events occurred in 2 patients.Programmed death ligand 1 (PD-L1) levels [combined positive score (CPS)] were significantly higher after treatment in arms A and D. Expression of CD163 and colony-stimulating factor 1 receptor (CSF1R) genes, markers of M2 macrophages, increased significantly posttreatment whereas the expression of CD80, a marker of M1 macrophages, decreased.

Conclusion: Preoperative olaparib with cisplatin or alone or with durvalumab was safe in the preoperative setting and led to decrease in Ki67 of at least 25% in 44.8% of treated patients. Olaparib-based treatment modulates the tumor microenvironment leading to upregulation of PD-L1 and induction of protumor features of macrophages.

Significance: HNSCC is characterized by defective DNA repair pathways and immunosuppressive tumor microenvironment. PARP inhibitors, which promote DNA damage and "reset" the inflammatory tumor microenvironment, can establish an effective antitumor response. This phase II WOO trial in HNSCC demonstrated the immunomodulatory effects of PARP inhibitor-induced DNA damage. In this chemo-naïve population, PARP inhibitor-based treatment, reduced tumor cell proliferation and modulated tumor microenvironment. After olaparib upregulation of PD-L1 and macrophages, suggests that combinatorial treatment might be beneficial.

Synopsis: Our WOO study demonstrates that preoperative olaparib results in a reduction in Ki67, upregulation of PD-L1 CPS, and induction of protumor features of macrophages in HNSCC.

FIGURE 1

Consort diagram.

FIGURE 2

A, Waterfall plot of Ki67 change (measured by QIF) compared with pretreatment values. B, Comparison of Ki67 distribution assessed by QIF pretreatment and posttreatment/second biopsy or surgery within study groups. Wilcoxon matched pairs signed-rank P values were calculated for each treatment group; Cisplatin-Olaparib (C-O), P = 0.266; Olaparib (O), P = 0.004; Control, P = 0.875; Durvalumab-Olaparib (D-O), P = 0.461.

FIGURE 3

Baseline (up) and after treatment (down) images in Patient A (Cisplatin-Olaparib arm) and B (Olaparib arm), respectively, showing dramatic tumor volumetric decrease. Both patients had SD on imaging based on RECIST. Representative immunofluorescence (IF) images at baseline (up) and after treatment (down), highlighting changes in Ki67 (red), PD-L1 (white), STING (magenta) in tumor. Nuclei (blue) and cytokeratin (green) are also shown. A posttreatment decrease in Ki-67 (measured by QIF) was noticed in both patients.

FIGURE 4

Differentially expressed genes (A) and gene signatures (B) in pre-olaparib–based treatment relative to post-olaparib–based treatment samples. The significance (P value, P and adjusted P value, P_adj) is represented relative to fold change (FC) in the x-axis. Annotated markers are highlighted with orange (increased) or green (decreased). C, “All Signatures” heat map shows relatedness among signature scores for each sample. D, Subgroup analysis looking at the 4 patients with CR (1), PR (2), and pCR (1) revealed an increase in “Genes Within Tumor Inflammation Signature (TIS)” score posttreatement.