A phase II study of talazoparib monotherapy in patients with wild-type BRCA1 and BRCA2 with a mutation in other homologous recombination genes

Talazoparib, a PARP inhibitor, is active in germline BRCA1 and BRCA2 (g BRCA1 / 2 )-mutant advanced breast cancer, but its activity beyond g BRCA1 / 2 is poorly understood. We conducted Talazoparib Beyond BRCA ( NCT02401347 ), an open-label phase II trial, to evaluate talazoparib in patients with pretreated advanced HER2-negative breast cancer ( n = 13) or other solid tumors ( n = 7) with mutations in homologous recombination (HR) pathway genes other than BRCA1 and BRCA2 . In patients with breast cancer, four patients had a Response Evaluation Criteria in Solid Tumors (RECIST) partial response (overall response rate, 31%), and three additional patients had stable disease of ≥6 months (clinical benefit rate, 54%). All patients with germline mutations in PALB2 ( g PALB2 ; encoding partner and localizer of BRCA2) had treatment-associated tumor regression. Tumor or plasma circulating tumor DNA (ctDNA) HR deficiency (HRD) scores were correlated with treatment outcomes and were increased in all g PALB2 tumors. In addition, a g PALB2 -associated mutational signature was associated with tumor response. Thus, talazoparib has been demonstrated to have efficacy in patients with advanced breast cancer who have g PALB2 mutations, showing activity in the context of HR pathway gene mutations beyond g BRCA1 / 2 .