medwireNews: Use of veliparib during cisplatin chemotherapy may help improve progression-free survival (PFS) in patients with metastatic triple-negative breast cancer (TNBC) displaying biomarker characteristics similar to those seen in BRCA1/2 mutation-positive disease, suggest findings from a phase 2 trial.
“The combination of PARP inhibitors with platinum chemotherapy warrants further evaluation in larger randomised trials for patients with BRCA-like triple-negative breast cancer”, state Priyanka Sharma (University of Kansas Medical Center, Westwood, USA) and co-workers in The Lancet Oncology.
For the S1416 trial, 335 patients with TNBC who had previously received up to one line of prior chemotherapy for metastatic disease were given cisplatin 75 mg/m2 on day 1 of each 21-day cycle alongside either veliparib 300 mg twice daily or placebo on days 1–14, 320 of whom were eligible for efficacy evaluation
Overall, 37 of the participants carried a germline BRCA1/2 mutation. The patients without germline BRCA1/2 mutations were classified as having a BRCA-like (n=101) or non-BRCA-like (n=109) phenotype, according to genomic instability score, somatic BRCA1/2 mutations, BRCA1 methylation status and presence of non-BRCA1/2 homologous recombination repair germline mutations.
There were inadequate biomarker panel findings to classify the remaining 73 participants, the researchers say.
After a median follow-up of 11.1 months, median PFS among the patients with a BRCA-like phenotype was significantly longer with veliparib than placebo, at a median 5.9 versus 4.2 months and a hazard ratio (HR) of 0.57 in favour of the PARP inhibitor’s use.
“Furthermore, the combination of cisplatin and veliparib showed durability of efficacy” in this patient subgroup, the researchers say, with 18% of patients free from progression at 12 months.
But there was no significant PFS benefit with veliparib versus placebo for patients with a non-BRCA-phenotype (4.0 vs 3.0 months), nor among those with germline BRCA1/2 mutations (6.2 vs 6.4 months), although Sharma et al note that accrual in the latter subgroup was low and therefore the analysis was “underpowered”.
None of the patient subgroups derived an overall survival benefit with use of veliparib versus placebo.
The most common grade 3 or more severe treatment-related adverse events (TRAEs) with veliparib plus cisplatin were neutropenia (46 vs 20% of controls), leukopenia (27 vs 7%), anaemia (23 vs 8%) and thrombocytopenia (19 vs 3%).
Serious TRAEs were reported in 31% of the patients given veliparib and 36% of controls, with one sepsis death in the veliparib arm and one death from acute cisplatin-related kidney injury in combination with doxorubicin-related heart failure in the control arm.
“With demonstration of efficacy in BRCA-like triple-negative breast cancer, the results of S1416 provide a foundation for expanding the role of PARP inhibitors beyond germline BRCA1/2 mutation in breast cancer”, conclude Sharma and co-authors.
“Another PARP inhibitor, olaparib, has also been safely combined with platinum chemotherapy; thus, other PARP inhibitors in addition to veliparib could be considered for future chemotherapy combination studies in BRCA-like triple-negative breast cancer.”
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