Dr. Yu on Combining Pembrolizumab and Olaparib in mCRPC

Evan Y. Yu, MD, professor, Department of Medicine, Division of Oncology, University of Washington, Seattle Cancer Care Alliance, discusses the combination of pembrolizumab (Keytruda) and olaparib (Lynparza) in metastatic castration-resistant prostate cancer (mCRPC).

At the 2019 ASCO Annual Meeting, Yu presented the results from cohort A of the phase Ib/II KEYNOTE-365 trial combining the PD-1 inhibitor pembrolizumab and the PARP inhibitor olaparib in a molecularly unselected group of patients with mCRPC. Yu notes there is clear rationale to explore PARP inhibitors in patients with DNA repair abnormalities and PD-1 inhibitors in patients with microsatellite instability—high tumors, but researchers wanted to test the efficacy in an unselected population. In these patients, previous data have suggested that PARP inhibition can increase PD-L1 expression.

Moreover, data show that a PARP inhibitor, even in non-BRCAness cells, can have cytosolic DNA fragments that accumulate, leading to activation of the STING pathway. Type 1 interferon gets upregulated, potentially increasing the cytokines in the microenvironment to facilitate T-cell infiltration in the tumor. This is the rationale to add a PD-1 antibody, Yu concludes.