Discussion
HNSCC, tumor, tumors, pembrolizumab
TUMOR, PROLIFERATION, DNA DAMAGE, TUMORS, CPS, PATHOLOGY
To the best of our knowledge, we report the first trial that evaluates the efficacy of olaparib alone or with C or with D in the preoperative setting in patients with operable HNSCC. Our data indicate that olaparib-based treatment enhances both antitumor and protumor features. Olaparib-induced DNA damage leads to decrease in proliferation (measured by Ki67), enhanced immune priming and induced adaptive upregulation of PD-L1 expression. This modulation in HNSCC TME results in increased levels of intratumoral macrophages (The primary endpoint of the study was to evaluate the percentage of patients in each arm that achieved a reduction of at least 25% in Ki67 posttreatment. Thirteen of 29 (45%) had a decrease of at least 25% whereas a decrease in proliferation was observed in the majority of treated samples (23/29, 79%). However, ΔKi67 was not associated with response (based on physical exam, imaging, or pathology). ΔKi67 may not be the preferred surrogate marker in HNSCC WOO trials. Change in tumor size rather than ΔKi67 was the preferred surrogate marker in a placebo-controlled window study of EGFR, Src, or combined blockade in operable HNSCC by Bauman and colleagues (Olaparib appears to demonstrate activity in HNSCC especially in tumors with alterations in genes involved in DNA repair or chromatin remodeling. The patient who attained pCR to olaparib had loss-of-function mutation of the AT-rich interactive domain 2 (Defects in DDR pathways result in accumulation of cytosolic DNA, triggering activation of STING and promoting type I immunity (PD-L1 expression (by CPS) increased after treatment in all three treated groups (C-Olaparib, Olaparib, and D-Olaparib) and was significantly higher in C-Olaparib (Through multi-omics profiling, we showed that olaparib-based treatment enhances both antitumor and protumor features and modulates the TME in HNSCC. An ongoing study will evaluate the efficacy of PARP/PD-L1 blockade (NCT04169841) and explore whether immunotherapy increases the duration of response to PARP inhibition in HNSCC or whether a third blocking agent such as a CSF1R inhibitor might be necessary to enhance innate and adaptive antitumor immunity and survival in patients with HNSCC.To conclude, at the current WOO study we found that preoperative olaparib-based treatment was safe in HNSCC and led to a decrease of Ki-67 of at least 25% in a substantial proportion of patients. Our biomarker results demonstrate that olaparib upregulates PD-L1 and M2 macrophages. Given that pembrolizumab is approved in first-line recurrent/metastatic setting either as monotherapy in those expressing CPS ≥ 1 or combined with chemotherapy, olaparib-PD-1 inhibitor combinations deserve further study. The immune stimulating effects of olaparib are antagonized by the upregulation of M2 macrophages and combinatorial approaches including macrophage/CSF1R-targeting therapies, anti-PD-L1, and olaparib may prove effective.