Talazoparib Beyond BRCA Prospective Study Identifies the Sensitivity of gPALB2-Associated Breast Cancers to PARP Inhibition

A phase II clinical study of the PARP inhibitor talazoparib conducted in patients with solid tumours shows that the drug has activity in patients with breast cancer with mutations in other homologous recombination pathway genes beyond BRCA1 and BRCA2. Cohort B of the Talazoparib Beyond BRCA study was specifically assessed by either germline or somatic mutations in a panel of genes associated with homologous recombination pathway activity as entry criteria. The results demonstrate that this may be a useful strategy especially in patients with advanced HER2-negative breast cancer.

Patients with breast cancer with mutations beyond gBRCA1/2 had a 31% overall response rate (ORR), whereas no objective responses were observed in non-breast tumours. The responses of patients with breast cancer were driven, in part, by patients with germline mutations in PALB2 (gPALB2; encoding partner and localizer of BRCA2) and were correlated with high homologous recombination deficiency scores. The results are published by Dr. Melinda L. Telli of the Department of Medicine, Stanford University School of Medicine in Palo Alto, CA, US and colleagues on 17 October 2022 in the Nature Cancer.

Previous studies have suggested that other biomarkers beyond gBRCA1/2 may be associated with clinical responses to PARP inhibitors, but the data remain relatively sparse. Talazoparib Beyond BRCA phase II clinical study explored the hypothesis that triple-negative breast cancers with high homologous recombination deficiency scores (cohort A) or any solid tumour with germline or somatic mutations in homologous recombination deficiency-associated genes other than BRCA1 and BRCA2 (cohort B) could be used to select patients for talazoparib monotherapy. In an article published in the Nature Cancer, the study investigators report the results of 20 patients treated in cohort B who were enrolled based on identification of an homologous recombination pathway-associated mutation other than gBRCA1/2 on either germline or somatic next-generation sequencing testing.

Cohort B of the Talazoparib Beyond BRCA, an open-label phase II study, evaluated talazoparib in 13 patients with pretreated advanced HER2-negative breast cancer and 7 patients with other solid tumours with mutations in homologous recombination pathway genes other than BRCA1 and BRCA2. In patients with breast cancer, 4 patients had a partial response according RECIST (ORR 31%), and 3 additional patients had stable disease of ≥6 months (clinical benefit rate 54%).

All patients with germline mutations in PALB2 had treatment-associated tumour regression. Tumour or plasma circulating tumour DNA homologous recombination deficiency scores were correlated with treatment outcomes and were increased in all gPALB2 tumours. In addition, a gPALB2-associated mutational signature was associated with tumour response.

The authors commented that positive results were driven in large part by individuals with gPALB2 mutations, as 5 patients with breast cancers (and 1 patient with pancreatic cancer with gPALB2 and gBRIP1 mutations) had tumour shrinkage as the best response. The results were subsequently corroborated in the TBCRC 048 Olaparib Expanded study. In Talazoparib Beyond BRCA study, tumours with gPALB2 mutations had uniformly high HRD scores, which led to a positive correlation in cohort between high tumour homologous recombination deficiency scores and magnitude of tumour response to talazoparib in this setting.

In contrast, tumours with other mutations including gATM and gCHEK2 mutations had loss of heterozygosity, but not increased homologous recombination deficiency scores. One responding patient had combined mutations including gFANCA, gCHEK2 and sPTEN mutations (with loss of heterozygosity for FANCA), perhaps highlighting the role of FANCA in PARP inhibitor sensitivity. In the TBCRC 048 study, 9 of 11 patients with a gPALB2 mutation responded, although further genomic analyses are pending.

The authors commented that Talazoparib Beyond BRCA prospective study identified the sensitivity of gPALB2 breast cancers to PARP inhibition and highlighted the core role of PALB2 in BRCA1– and/or BRCA2-mediated homologous recombination DNA repair in human breast cancers. These results are currently being further evaluated in a multi-institutional study of talazoparib in PALB2 mutation associated advanced breast cancer.

Reference

Gruber JJ, Afghahi A, Timms K, et al. A phase II study of talazoparib monotherapy in patients with wild-type BRCA1 and BRCA2 with a mutation in other homologous recombination genes. Nature Cancer 2022;3:1181-1191.

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