ASCO GU 2019: A Phase II Trial in Progress: Pamiparib, an Investigational PARP Inhibitor, in Patients with mCRPC and a Circulating Tumor Cell Homologous Recombination Deficiency Phenotype or BRCA Defects
San Francisco, CA (UroToday.com) Prostate cancer is one of the leading causes of cancer deaths in men. Patients with metastatic castration-resistant prostate cancer (mCRPC) who have a BRCA1/2 mutation or mutations in other homologous recombination deficiency genes have aggressive disease and a worse prognosis. Poly (ADP-ribose) polymerase (PARP) proteins are a family of proteins involved in DNA repair, genome stability, and programmed cell death. Inhibition of PARP proteins allows for the accumulation of unrepaired single-strand breaks, which are converted to double-strand breaks during cell division and can lead to apoptosis/cell death. DNA repair can be compromised by the absence of homologous recombination components such as BRCA1 or BRCA2.
Pamiparib (BGB-290) is a selective PARP1/2 inhibitor that demonstrated brain penetration, PARP-DNA complex trapping, and antitumor activity in preclinical models. Determination of homologous recombination mutational status is highly challenging using standard approaches in metastatic castration-resistant prostate cancer patients. Circulating tumor cells (CTCs) are shed from primary tumors during carcinogenesis and can be collected via liquid biopsy for further analysis.
The EPIC liquid biopsy test is a novel assay that can identify CTCs with homologous recombination deficiency (Figure 1). Preliminary data (NCT02361723; NCT03333915), have shown that Pamiparib is generally well-tolerated and showed initial antitumor activity as a single agent. 60 mg orally twice daily was established as the recommended investigational dose.