A Pharmacodynamic (Pd) Evaluation Of The Parp Inhibitor Olaparib (Azd2281) In A First-In-Human Phase I Trial Of Patients With Advanced Solid Tumours

Olaparib (AZD2281; KU-0059436) is a potent and well tolerated oral inhibitor of PARP. Olaparib offers a potential synthetic lethal strategy for treatment of cancers with homologous recombination deficiency (HRD). A first-in-human Phase I dose escalation trial of olaparib was conducted and pharmacokinetic (PK) and pharmacodynamic (PD) studies were performed (Fong et al ., 2008). The trial consisted of patients with enrichment for those with hereditary BRCA1 and BRCA2 germline mutations. Dose levels rose from 10 mg daily given for 2 out of 3 weeks to continuous bid dosing at 600mg. PK data indicated rapid absorption and elimination. PARP inhibition PD studies were conducted using immunoblotting and an electrochemiluminescent immunoassay which utilises a functional ex vivo activation assay for poly(ADP)-ribose (PAR) formation (Menear et al ., 2008) in surrogate peripheral blood mononuclear cell (PBMC) and tumour tissue cell lysates. Substantial PARP inhibition of over 90% could be observed in individual patients at doses above 60mg bid and mean inhibitions for each cohort did not increase at doses above 100mg bid. The formation of \#947;H2AX foci, a marker of DNA double strand breaks, was also evaluated using immunofluorescence confocal microscopy on plucked eyebrow hair follicles These PARP PD studies confirmed PARP inhibition in surrogate and tumour tissue. At these doses and schedules anti-tumour activity was seen in genetic BRCA1 and BRCA2 deficient-associated ovarian, breast and prostate cancers with 46% ovarian cancer patients demonstrating response (combined RECIST and GCIG CA-125 criteria). Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3601.