Pamiparib, an investigational PARP inhibitor, in patients with metastatic castration-resistant prostate cancer (mCRPC) and a circulating tumor cell (CTC) homologous recombination deficiency (HRD) phenotype or BRCA defects: A trial in progress.

person Simon Chowdhury Guy’s, King’s and St. Thomas’ Hospitals, and Sarah Cannon Research Institute, London, United Kingdom info_outline Simon Chowdhury, Joaquin Mateo, Mitchell Gross, Andrew J. Armstrong, Marcia Cruz-Correa, Josep M. Piulats, Jean-Yves Blay, Miao Li, Delcia Rivas, Luis Quintero, Henry Castro, Andong Nkobena, Mitch Raponi, Robert Pelham, Mark Landers, Robert B. Montgomery

Authors person Simon Chowdhury Guy’s, King’s and St. Thomas’ Hospitals, and Sarah Cannon Research Institute, London, United Kingdom info_outline Simon Chowdhury, Joaquin Mateo, Mitchell Gross, Andrew J. Armstrong, Marcia Cruz-Correa, Josep M. Piulats, Jean-Yves Blay, Miao Li, Delcia Rivas, Luis Quintero, Henry Castro, Andong Nkobena, Mitch Raponi, Robert Pelham, Mark Landers, Robert B. Montgomery Organizations Guy’s, King’s and St. Thomas’ Hospitals, and Sarah Cannon Research Institute, London, United Kingdom, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain, USC Westside Cancer Center, University of Southern California, Beverly Hills, CA, Duke Cancer Institute, Duke University, Durham, NC, The University of Puerto Rico and MD Anderson Cancer Center, San Juan, PR, Institut Català d’Oncologia-IDIBELL-CIBERONC, Barcelona, Spain, Centre Léon Bérard, Lyon, France, BeiGene (Beijing) Co., Ltd., Beijing, China, BeiGene USA, Inc., San Mateo, CA, Epic Sciences, Inc., San Diego, CA, University of Washington, Seattle, WA Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Background: Men with mCRPC who have a BRCA1/2 mutation ( BRCA1/2 mut ) or mutations in other genes resulting in HRD have a poor prognosis. A novel liquid biopsy test (EPIC Sciences) identifies CTCs with an HRD phenotype. Preliminary studies showed that these men may respond to treatment with a PARP inhibitor. Pamiparib, an investigational PARP1/2 inhibitor, has shown brain penetration and potent PARP–DNA complex trapping in nonclinical studies. In early phase clinical studies (NCT02361723; NCT03333915), pamiparib was generally well tolerated and showed preliminary antitumor activity; 60 mg orally twice daily (BID) was established as the recommended investigational dose. Methods: This open-label, global, phase 2 study (NCT03712930) evaluates the antitumor activity and safety/tolerability of pamiparib in mCRPC patients (pts) with CTC-HRD, assessed by the CTC-HRD assay, or deleterious germline/somatic mutations in BRCA1 /2. Patients must have progressed on/after ≥1 androgen receptor-targeted therapy, received ≥1 taxane-based therapy, and have prostate-specific antigen (PSA) progression per PCWG3 criteria. Four cohorts of pts will receive pamiparib 60 mg BID in 28-day cycles. Cohort 1 will include ~50 pts with CTC-HRD + +/- BRCA1/2 mut mCRPC with measurable metastatic disease; Cohort 2 will include ~30 pts with CTC-HRD + +/- BRCA1/2 mut mCRPC with bone-only disease; Cohorts 3 & 4 will include ~20 pts with CTC-HRD -/unk + BRCA1/2 mut mCRPC with measurable metastatic disease (Cohort 3), or bone-only disease (Cohort 4). Disease status will be assessed every 8 wks for 24 wks, then every 12 wks; PSA levels will be tested every 4 wks. Co-primary endpoints are radiographic ORR assessed by IRC (pts with measurable disease) and confirmed PSA response rate per PCWG3 criteria (pts +/- measurable disease). Secondary endpoints include ORR, time to PSA response/progression, duration of PSA response, time to symptomatic skeletal event, radiographic progression-free survival, overall survival, and safety. As of 05 December 2018, this study is actively enrolling. Clinical trial information: NCT03712930