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 ( 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.

Figure 1 – EPIC liquid biopsy CTC-HRD assay:

In this poster, Simon Chowdhury, MD presented an open-label, global, phase 2 study (NCT03712930) that aims to evaluate antitumor activity and safety of Pamiparib in mCRPC patients with CTCs with homologous recombination deficiency (regardless of  germline or somatic BRCA 1 or 2 mutations) or in patients harboring BRCA 1 or 2 mutations, regardless of their CTC with homologous recombination deficiency status. The primary objectives are to evaluate the efficacy of Pamiparib in terms of the objective response rate (ORR) and PSA response rate. Key secondary objectives include the duration of response; investigator assessed ORR, time to objective response, time to PSA response, the progression of PSA response, time to a symptomatic skeletal event, radiographic progression-free survival, overall survival (OS), and safety. The study design is shown in Figure 2.

Figure 2 – Study Design: 

For this trial, approximately 100 patients will be enrolled at 45 centers across Asia, Australia, Europe, and North America. Inclusion criteria are shown in table 1. The trial is currently enrolling with the first patient recruited in December 2018. Disease status will be assessed every eight weeks for 24 weeks, then every 12 weeks; PSA levels will be tested every four weeks.

We look forward to seeing the results of this trial.

Table 1 – Inclusion and exclusion criteria:
Table1 InclusionExclusionCriteria

Presented by: Simon Chowdhury, MD, Guy’s and St. Thomas Hospital, NHS Foundation Trust, London, UK

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, Twitter: @GoldbergHanan at the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium, (ASCO GU) #GU19, February 14-16, 2019 - San Francisco, CA