Pamiparib is a potent and selective PARP inhibitor with unique potential for the treatment of brain tumor

Abstract

Pamiparib, an investigational Poly (ADP-ribose) polymerase (PARP) inhibitor in clinical development, demonstrates excellent selectivity for both PARP1 and PARP2, and superb anti-proliferation activities in tumor cell lines with BRCA1/2 mutations or HR pathway deficiency (HRD). Pamiparib has good bioavailability and is 16-fold more potent than olaparib in an efficacy study using BRCA1 mutated MDA-MB-436 breast cancer xenograft model. Pamiparib also shows strong anti-tumor synergy with temozolomide (TMZ), a DNA alkylating agent used to treat brain tumors. Compared to other PARP inhibitors, pamiparib demonstrated improved penetration across the blood brain barrier (BBB) in mice. Oral administration of pamiparib at a dose as low as 3 mg/kg is sufficient to abrogate PARylation in brain tumor tissues. In SCLC-derived, TMZ-resistant H209 intracranial xenograft model, combination of pamiparib with TMZ overcomes its resistance and shows significant tumor inhibitory effects and prolonged life span. Our data suggests that combination of pamiparib with TMZ has unique potential for treatment of brain tumors. Currently, the combination therapy of pamiparib with TMZ is evaluated in clinical trial [NCT03150862].

From Laboratory Studies to Clinical Trials: Temozolomide Use in IDH-Mutant Gliomas

“…One target from the base-excision repair (BER) pathway is poly (ADP-ribose) polymerase 1 (PARP1), which facilitates DNA repair by binding to single-strand breaks and recruiting DNA repair proteins to the site of damage [ 77 ]. PARP inhibitors (PARPi), INO-1001 [ 78 ], NU1025 [ 79 ], ABT-888 (veliparib) [ 80 , 81 ] and pamiparib [ 82 ], restored sensitivity in TMZ resistant glioma cells and xenografts. Several PARPi in combination with TMZ in GBM have been registered for clinical trials [ 83 , 84 , 85 ].…”

The pharmacokinetics of pamiparib in the presence of a strong CYP3A inhibitor (itraconazole) and strong CYP3A inducer (rifampin) in patients with solid tumors: an open-label, parallel-group phase 1 study

“…Pamiparib (BGB-290) is an investigational, highly selective PARP1/2 inhibitor with potent PARP–DNA trapping and central nervous system penetrance in preclinical models [ 6 , 7 ]. Unlike other PARPi (olaparib, rucaparib, talazoparib, and veliparib), pamiparib is not a substrate of P-glycoprotein, which can significantly restrict delivery across the blood–brain barrier [ 7 ].…”

“…Pamiparib (BGB-290) is an investigational, highly selective PARP1/2 inhibitor with potent PARP–DNA trapping and central nervous system penetrance in preclinical models [ 6 , 7 ]. Unlike other PARPi (olaparib, rucaparib, talazoparib, and veliparib), pamiparib is not a substrate of P-glycoprotein, which can significantly restrict delivery across the blood–brain barrier [ 7 ]. A first-in-human study (NCT02361723; BGB-290-AU-002) found that pamiparib was well tolerated and showed preliminary anti-tumor activity in patients with high-grade epithelial non-mucinous ovarian cancer [ 8 ].…”

Human Mass Balance and Metabolite Profiling of [14C]‐Pamiparib, a Poly (ADP‐Ribose) Polymerase Inhibitor, in Patients With Advanced Cancer

“…In a BRCA1 mutant mouse xenograft model, pamiparib has shown strong antitumor activity and was more potent than olaparib 8 . Pamiparib has also demonstrated brain penetrance after oral administration in mice 9 . Results from a first‐in‐human dose‐escalation/dose‐expansion study (BGB‐290‐AU‐002; NCT02361723) demonstrated that pamiparib was generally well tolerated up to 60 mg with a linear pharmacokinetic (PK) profile across the tested dose range (2.5‐120 mg) and promising antitumor activity 10 .…”

“… 8 Pamiparib has also demonstrated brain penetrance after oral administration in mice. 9 Results from a first‐in‐human dose‐escalation/dose‐expansion study (BGB‐290‐AU‐002; NCT02361723) demonstrated that pamiparib was generally well tolerated up to 60 mg with a linear pharmacokinetic (PK) profile across the tested dose range (2.5‐120 mg) and promising antitumor activity. 10 This first‐in‐human study also established the recommended phase 2 dose (RP2D) of pamiparib as 60 mg orally twice daily.…”