DNA repair defects, PARP inhibitors and metastatic prostate cancer


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Johann de Bono1
1The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK

Abstract

Many cancers have DNA repair defects and these can be utilised in synthetic therapeutic lethal strategies to impart patient benefit. Preclinical and clinical studies have shown that PARP inhibitors have anti-tumour activity against tumours with defects in high fidelity homologous DNA repair. PARP inhibitors have impressive anti-tumour activity against cancers in BRCA carriers with evidence for clinical benefit to patients with ovarian, breast and advanced prostate cancer. Anti-tumour activity with PARP inhibitors has also been demonstrated against sporadic cancers with loss of HR DNA repair due to somatic cell genomic aberrations or repair gene promoter methylation. Data will be presented on the anti-tumour activity of PARP inhibitors against prostate cancer, with a particular focus on anti-tumour activity in sporadic castration resistant prostate cancer. Data from the investigator-initiated TO-PARP trial will be presented; this adaptive design is focused on identifying a biomarker panel that identifies PARP inhibitor sensitivity in this population. All the patients on the TO-PARP trial received olaparib at 400mg bid (tablets), had fresh CRPC biopsies pre-trial participation as well as after 2-4 weeks of olaparib. All patient fresh samples have undergone exome and transcriptome sequencing in efforts to elucidate which sporadic CRPC patients respond to PRP inhibition.