A Combination Study of Durvalumab Plus Olaparib in an Unselected Population with Metastatic Castrate-Resistant Prostate Cancer
Technical Report,01 Aug 2018,31 Jul 2019
The Geneva Foundation Tacoma United States
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Data suggest that 25 percent-30 percent of sporadic metastatic castration-resistant prostate cancers mCRPC have defects in DNA repair pathways that may confer sensitivity to PARP inhibition. Next generation sequencing NGS has identified recurrent mutations and genomic alterations in mCRPC that are potentially clinically actionable, including mutations in DNA damage response factors BRCA2, BRCA1 ATM andor CHK2. Recent data indicate that DNA damage plays an important role in priming a type I interferon IFN response, where DNA damage results in enhanced production of type I IFNs via the cytosolic DNA sensor STING, which can prime the innate and adaptive immune system for an amplified response. While programmed cell death protein ligand 1 PD-L1 inhibition has shown antitumor effects in bladder and non-small cell lung cancers and melanoma, immune checkpoint blocking antibodies have had limited success in mCRPC. It is likely that immune combination strategies are required to improve response rates in prostate cancer beyond the less than 10 percent seen with immune checkpoint inhibitors alone. We hypothesize that increased DNA damage by the PARP inhibitor olaparib will complement the antitumor activity of durvalumab, an anti-PDL-1 antibody, in an expansion cohort of a phase II study of men with mCRPC in the post-enzalutamide andor abiraterone setting.
- Medicine and Medical Research