Effect of veliparib with or without cisplatin in breast cancer: results of SWOG S1416

The Southwest Oncology Group (SWOG) 1416 phase II trial was designed to compare the efficacy of the PARP inhibitor veliparib plus cisplatin versus cisplatin alone in patients with metastatic and/or locally recurrent triple-negative breast cancer (TNBC) or BRCA1 or BRCA2 germline mutation–associated HER2-negative metastatic breast cancer. Priyanka Sharma, MD, of the University of Kansas Medical Center, presented the results of this trial during the ASCO20 Virtual Scientific Program [1].

Eligible patients were randomly assigned 1:1 to receive either treatment with cisplatin 75 mg/m² on day 1 combined with veliparib 300 mg orally twice daily (BID) on days 1 to 14 (21-day cycle) or cisplatin 75 mg/m² on day 1 plus placebo BID on days 1 to 14 (21-day cycle). Dr. Sharma noted that the veliparib 300 mg BID dose in this trial is much higher than that used in other studies such as BROCADE 3 [2].

After being randomly assigned, all patients were tested for germline BRCA (gBRCA). Specimens from patients who were gBRCA negative underwent additional biomarker analysis, including homologous recombination deficiency (HRD) genomic instability score 42 or greater, somatic BRCA1 or BRCA2 mutation, BRCA1 promoter methylation, and germline HR repair genes mutation. Based on the test results, patients were assigned to one of following prespecified groups: 1) positive for gBRCA; 2) BRCA-like (positivity on any of the additional biomarker assays); or 3) non–BRCA-like. The primary endpoint was progression-free survival (PFS) in the three groups.

A total of 335 patients were randomly assigned, with 321 (95.8%) included in the intent-to-treat analysis (161 cisplatin/veliparib [50.2%] and 160 cisplatin/placebo [49.8%]). For all patients, the mean age was 56, 95% had TNBC, 76% were white, and 69% had not received prior therapy. The groups included 110 non–BRCA-like (34.3%), 99 BRCA-like (30.8%), and 75 (23.4%) unclassified; 37 (11.5%) were gBRCA positive, 59% of the initially planned accrual for this group.

Improved PFS with veliparib was observed in the BRCA-like group, with a median PFS of 5.9 months (95% CI [4.3, 7.8]) vs. 4.2 months (95% CI [2.3, 5.0]) in the placebo group (HR 0.53, 95% CI [0.34, 0.83]; p = 0.006). No improvement in PFS was seen in the gBRCA positive group, the non–BRCA-like group, or the unclassified group. In an exploratory analysis, significantly better outcomes were seen with veliparib for patients in the BRCA-like group receiving first-line treatment: PFS 6.1 months (95% CI [3.7, 10.3]) versus 4.2 months (95% CI [2.2, 5.6]; HR 0.49, 95% CI [0.29, 0.83]; p = 0.008) and overall survival 17.8 months (95% CI [10.1, not estimated]) versus 10.3 months (95% CI [8.9, 14.9]); HR 0.53, 95% CI [0.28, 0.99]; p = 0.048). Additionally, the 75 patients from the BRCA-like group with HRD 42 or greater had better PFS with veliparib (6.1 months; 95% CI [4.4, 10.2]) versus placebo (4.2 months; 95% CI [2.2, 6.1]; HR 0.53, 95% CI [0.31, 0.89]; p = 0.016).

“With demonstration of efficacy in biomarker-selected BRCA-like phenotype TNBC, [SWOG] 1416 results are a very positive step toward expanding the role of PARP inhibitors beyond gBRCA in breast cancer,” Dr. Sharma said.

Certain grade 3/4 adverse events occurred at significantly higher frequencies with veliparib compared with placebo: neutropenia (46% vs. 19%), anemia (23% vs 7%), leukopenia (27% vs. 7%), and thrombocytopenia (19% vs. 3%; all p < 0.001).

“Toxicity of veliparib plus cisplatin was manageable, and no new toxicity signals were noted,” Dr. Sharma said.

“This was an impressive study in terms of biomarker testing,” said Discussant Catherine M. Kelly, MBBCh, BAO, MSc, FRCPI, of Mater Misericordiae University Hospital, Dublin. Dr. Kelly suggested that a multivariate analysis including all subgroups may have led to a more straightforward interpretation of the trial results. She also noted that there is conflicting evidence in the predictive value of HRD in early and metastatic TNBC.

“Methods to identify HRD in tumors are varied and controversial,” Dr. Kelly said. “Further research is needed to identify the optimal HRD biomarkers critical in the early treatment-naive and in the advanced treatment-exposed disease settings.”

1. Sharma P, et al. ASCO Virtual Meeting, 29-31 May 2020, Abstract 1001.
2. Dieras VC, et al. Ann Oncol. 2019;30(suppl_5):v851-v934.

Posted on 8 September, 202027 March, 2024