Dr. Yu on Rationale for the KEYNOTE-365 Study in mCRPC

Evan Y. Yu, MD
Published: Tuesday, Jul 09, 2019



Evan Y. Yu, MD, professor, Department of Medical Oncology, University of Washington School of Medicine, member, Clinical Research Division, Fred Hutchinson Cancer Research Center, and clinical trials core director, Genitourinary Medical Oncology, Seattle Cancer Care Alliance, discusses the rationale behind the KEYNOTE-365 trial, looking at pembrolizumab (Keytruda) plus olaparib (Lynparza) in patients with metastatic castration-resistant prostate cancer (CRPC) previously treated with docetaxel.

Patients with mCRPC previously treated with docetaxel are a molecularly unselected patient population, according to Yu. There’s strong rationale for olaparib, a PARP inhibitor, in patients who have DNA repair abnormalities, Yu says. There is also strong rationale for use of pembrolizumab in patients who have microsatellite instability-high tumors or mismatched repair alterations that are hypermutated, Yu adds.

In this molecularly unselected population, there are some data that show when patients are given a PARP inhibitor, PD-L1 expression can increase in the cells, according to Yu. Additionally, data show that a PARP inhibitor, even in non-BRCA–mutated cells, can have cytosolic DNA fragments that accumulate. This will lead to activation of the STING pathway, causing type 1 interferons to get upregulated, and increase cytokines in the microenvironment to facilitate T-cell infiltration in the tumor. This rationale lends credence to adding a PD-1 or PD-L1 antibody in the treatment of patients with mCRPC.
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Evan Y. Yu, MD, professor, Department of Medical Oncology, University of Washington School of Medicine, member, Clinical Research Division, Fred Hutchinson Cancer Research Center, and clinical trials core director, Genitourinary Medical Oncology, Seattle Cancer Care Alliance, discusses the rationale behind the KEYNOTE-365 trial, looking at pembrolizumab (Keytruda) plus olaparib (Lynparza) in patients with metastatic castration-resistant prostate cancer (CRPC) previously treated with docetaxel.

Patients with mCRPC previously treated with docetaxel are a molecularly unselected patient population, according to Yu. There’s strong rationale for olaparib, a PARP inhibitor, in patients who have DNA repair abnormalities, Yu says. There is also strong rationale for use of pembrolizumab in patients who have microsatellite instability-high tumors or mismatched repair alterations that are hypermutated, Yu adds.

In this molecularly unselected population, there are some data that show when patients are given a PARP inhibitor, PD-L1 expression can increase in the cells, according to Yu. Additionally, data show that a PARP inhibitor, even in non-BRCA–mutated cells, can have cytosolic DNA fragments that accumulate. This will lead to activation of the STING pathway, causing type 1 interferons to get upregulated, and increase cytokines in the microenvironment to facilitate T-cell infiltration in the tumor. This rationale lends credence to adding a PD-1 or PD-L1 antibody in the treatment of patients with mCRPC.



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Community Practice Connections™: 2nd Annual International Congress on Oncology Pathology™Aug 31, 20191.5
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