Phase 10 scoring5/31/2023 PARP inhibitors, including talazoparib and olaparib, are currently approved for the treatment of HER2-negative advanced breast cancer in patients who harbor a genomic BRCA1 and/or BRCA2 (g BRCA1/ 2) mutation 1, 2. 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. In addition, a g PALB2-associated mutational signature was associated with tumor response. Tumor or plasma circulating tumor DNA (ctDNA) HR deficiency (HRD) scores were correlated with treatment outcomes and were increased in all g PALB2 tumors. All patients with germline mutations in PALB2 (g PALB2 encoding partner and localizer of BRCA2) had treatment-associated tumor regression. 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%). 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. 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.
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