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

Joshua J. Gruber, Anosheh Afghahi, Kirsten Timms, Alyssa DeWees, Wyatt Gross, Vasily N. Aushev, Hsin Ta Wu, Mustafa Balcioglu, Himanshu Sethi, Danika Scott, Jessica Foran, Alex McMillan, James M. Ford, Melinda L. Telli

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

Abstract

Talazoparib, a PARP inhibitor, is active in germline BRCA1 and BRCA2 (gBRCA1/2)-mutant advanced breast cancer, but its activity beyond gBRCA1/2 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(gPALB2; 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 gPALB2 tumors. In addition, a gPALB2-associated mutational signature was associated with tumor response. Thus, talazoparib has been demonstrated to have efficacy in patients with advanced breast cancer who have gPALB2 mutations, showing activity in the context of HR pathway gene mutations beyond gBRCA1/2.

Original languageEnglish (US)
Pages (from-to)1181-1191
Number of pages11
JournalNature Cancer
Volume3
Issue number10
DOIs
StatePublished - Oct 2022

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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