BACKGROUND: Poly (ADP-ribose) polymerase inhibitors (PARPi) prevent 
single-stranded DNA repair. Olaparib is a PARPi approved for the treatment of 
BRCA mutant ovarian and breast carcinoma. Emerging clinical data suggest a 
benefit of combining olaparib with immunotherapy in prostate cancer patients 
both with and without somatic BRCA mutations.
METHODS: We examined if olaparib, when combined with IgG1 antibody-dependent 
cellular cytotoxicity (ADCC)-mediating monoclonal antibodies (mAbs) cetuximab 
(anti-EGFR), or avelumab (anti-PD-L1), would increase tumor cell sensitivity to 
killing by natural killer (NK) cells independently of BRCA status or mAb target 
upregulation. BRCA mutant and BRCA wildtype (WT) prostate carcinoma cell lines 
were pretreated with olaparib and then exposed to NK cells in the presence or 
absence of cetuximab or avelumab.
RESULTS: NK-mediated killing was significantly increased in both cell lines and 
was further increased using the ADCC-mediating mAbs. Pre-exposure of NK cells to 
recombinant IL-15/IL-15Rα further increased the lysis of olaparib treated tumor 
cells. In addition, olaparib treated tumor cells were killed to a significantly 
greater degree by engineered high-affinity NK cells (haNK). We show here for the 
first time that (a) olaparib significantly increased tumor cell sensitivity to 
NK killing and ADCC in both BRCA WT and BRCA mutant prostate carcinoma cells, 
independent of PD-L1 or EGFR modulation; (b) mechanistically, treatment with 
olaparib upregulated death receptor TRAIL-R2; and (c) olaparib significantly 
enhanced NK killing of additional tumor types, including breast, non-small cell 
lung carcinoma, and chordoma.
CONCLUSIONS: These studies support the combined use of NK- and ADCC-mediating 
agents with correctly timed PARP inhibition.