Initial testing (stage 1) of the PARP inhibitor BMN 673 by the pediatric preclinical testing program: PALB2 mutation predicts exceptional in vivo response to BMN 673

Abstract

Introduction BMN 673 is a potent inhibitor of poly-ADP ribose polymerase (PARP) that is in clinical testing with a primary focus on BRCA-mutated cancers. BMN 673 is active both through inhibiting PARP catalytic activity and by tightly trapping PARP to DNA at sites of single strand breaks. Methods BMN 673 was tested in vitro at concentrations ranging from 0.1 nM to 1 μM and in vivo at a daily dose of 0.33 mg/kg administered orally twice daily (Mon-Fri) and once daily on weekends (solid tumors) for 28 days. Results The median relative IC50 (rIC50) concentration against the PPTP cell lines was 25.8 nM. The median rIC50 for the Ewing cell lines was lower than for the remaining cell lines (6.4 versus 31.1 nM, respectively). In vivo BMN 673 induced statistically significant differences in EFS distribution in 17/43 (39.5%) xenograft models. Three objective regressions were observed: a complete response (CR) in a medulloblastoma line (BT-45), a maintained CR in a Wilms tumor line (KT-10), and a maintained CR in an ependymoma line (BT-41). BMN 673 maintained its high level of activity against KT-10 with a 3-fold reduction in dose. KT-10 possesses a truncating mutation in PALB2 analogous to PALB2 mutations associated with hereditary breast and ovarian cancer that abrogate homologous recombination (HR) repair. Conclusions The PPTP results suggest that single agent BMN 673 may have limited clinical activity against pediatric cancers. Single agent activity is more likely for patients whose tumors have defects in HR repair.

Synergistic Activity of PARP Inhibition by Talazoparib (BMN 673) with Temozolomide in Pediatric Cancer Models in the Pediatric Preclinical Testing Program

“…Both combinations and single agents were evaluated against a select group of non-Ewing xenografts, including: models deficient in MGMT (GBM2 glioblastoma, Rh28 rhabdomyosarcoma) andhence known to be sensitive to single agent temozolomide (31); a Wilms tumor xenograft (KT-10) shown previously to respond to single-agent talazoparib (25); and two additional alveolar rhabdomyosarcoma models (Rh30 and Rh41), Figure 2. As anticipated, both GBM2 and Rh28 xenografts regressed completely following temozolomide treatment.…”

“…As Combination B showed activity that was comparable to Combination A and as it reflects the preferred treatment strategy for clinical evaluation because of its low alkylating agent dose, it was further evaluated against 19 additional models including glioblastoma, neuroblastoma, osteosarcoma and ALL xenografts that have been characterized for sensitivity to temozolomide (31) and talazoparib (25). Results are summarized in Supplemental Table V (and Supplemental Table II).…”

“…Relative I/O% values range between 100% (no treatment effect) to −100% (complete cytotoxic effect), with a Relative I/O% value of 0 being observed for a completely effective cytostatic agent. The 10 nM talazoparib concentration selected for combination testing is a biologically active concentration based on its effects against the most sensitive cell lines in the PPTP in vitro cell line panel, but it is below the rIC 50 for most of the PPTP cell lines facilitating analysis of the combination testing results (25). …”

“…The Pediatric Preclinical Testing Program (PPTP) evaluated talazoparib as a single agent against its in vitro cell line and in vivo tumor panels (25). The median relative IC 50 (rIC 50 ) for talazoparib against the PPTP cell lines was 26 nM, with a trend for lower rIC 50 values for the Ewing cell line panel compared to the non-Ewing lines (6 nM versus 31 nMol/L, p=0.057).…”

“…Despite the in vitro sensitivity of the Ewing cell lines to talazoparib, the agent showed minimal in vivo activity against Ewing xenografts. Among the 35 solid tumor xenografts tested against single agent talazoparib, the two xenografts showing objective responses were a Wilms tumor xenograft and a medulloblastoma xenograft, both of which also showed maintained complete responses (MCR) to cisplatin(25). …”