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 (gBRCA1/2) mutation; now a new research, recently published in Nature Cancer, shows benefits with talazoparib in patients with pretreated advanced HER2-negative breast cancer or other solid tumors with mutations in homologous recombination pathway genes other than BRCA1 and BRCA2.
The open-label phase II Talazoparib Beyond BRCA trial involved 13 patients with advanced breast cancer and 7 with other solid tumors, wild-type for BRCA1 and BRCA2 and with a median of two prior lines of therapy for advanced disease. All enrolled patients were treated with talazoparib monotherapy, 1 mg orally daily; the median time on therapy was 23.8 weeks, which was longer in the breast cancer subgroup compared to the non-breast cancer subgroup. Patients with breast cancer with mutations beyond gBRCA1/2 had a 31% overall response rate (four patients), whereas no objective responses were observed in non-breast tumors; three additional patients had stable disease of ≥6 months (clinical benefit rate, 54%). All patients with germline mutations in PALB2 had treatment-associated tumor regression. Tumor or plasma circulating tumor DNA homologous recombination deficiency scores were correlated with treatment outcomes and were increased in all gPALB2 tumors and a gPALB2-associated mutational signature was associated with tumor response. «The Talazoparib Beyond BRCA trial is a prospective study that identifies the sensitivity of gPALB2 breast cancers to PARP inhibition and highlights the core role of PALB2 in BRCA1- and/or BRCA2-mediated homologous recombination DNA repair in human breast cancers. The results are currently being further evaluated in a multi-institutional study, ‘Talazoparib monotherapy in PALB2 mutation associated advanced breast cancer’; these efforts may confirm a patient population that benefits from targeted therapy to improve patient outcomes and diminish toxicity associated with chemotherapies that are commonly used for these patients», authors conclude.