“With demonstration of efficacy in biomarker-selected BRCA-like phenotype triple-negative breast cancer, the results of this trial are a very positive step toward expanding the role of PARP inhibitors beyond germline BRCA in breast cancer."
Veliparib in combination with cisplatin led to a significant improvement in progression-free survival (PFS) in patients with BRCA-like triple-negative breast cancer (TNBC) and demonstrated a trend toward improved overall survival (OS) in the phase 2 SWOG S1416 trial (NCT02595905), which was presented at the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program.1
In the trial, 248 patients were classified into 3 groups: those with germline BRCA-positive disease (n = 37), those with BRCA-like disease (n = 101), and those with non–BRCA-like disease (n = 110); 75 patients could not be classified because of missing biomarker information.
Results showed that, in the BRCA-like group, the median PFS was prolonged with the addition of veliparib, at 5.9 months (95% CI, 4.3-7.8) in the combination arm versus 4.2 months (95% CI, 2.3-5.0) in the placebo arm (HR, 0.53; 95% CI, 0.34-0.83; 2-sided P = .006). Overall survival (OS) in the veliparib and placebo arms were 14.0 months (95% CI, 10.3–not estimable) and 12.1 months (95% CI, 9.0-15.2), respectively (HR, 0.60; 95% CI, 0.35-1.04; 2-sided P = .067).
In patients with germline BRCA-positive disease, the PFS was 6.2 months (95% CI, 2.3-10.6) in the veliparib arm versus 6.4 months (95% CI, 4.3-8.2) in the cisplatin/placebo arm (HR, 0.66; 95% CI, 0.30-1.44; 2-sided P = .29). Median OS was 14.2 months (95% CI, 8.1-12.0) with veliparib versus 14.6 months (95% CI, 12.5-19.5) with cisplatin alone (HR, 1.27; 95% CI, 0.57-2.82; 2-sided P = .56).
“In the germline BRCA group, even though the hazard ratio favored the veliparib arm, there was no difference in median PFS between the 2 arms,” said lead study author Priyanka Sharma, MD, professor of medicine at the University of Kansas Medical Center, in a presentation during the meeting. “The PFS of 6.4 months in the placebo arm is in line with what was noted with platinum monotherapy for BRCA carriers in the TNT trial [in patients with TNBC]. No difference in OS was observed between the veliparib and placebo arms.”
In the non–BRCA-like group and in the unclassified groups, no improvement in PFS was observed, said Sharma. The median PFS with veliparib/cisplatin and cisplatin/placebo in the non–BRCA-like group was 4.0 months (95% CI, 2.5-4.5) and 3.0 months (95% CI, 2.2-4.4), leading to an 11% reduction in the risk of disease progression or death (HR, 0.89; 95% CI, 0.60-1.32; 2-sided P = .56). In the unclassified group, the median PFS was 3.3 months (95% CI, 2.3-5.6) with the combination versus 2.3 months (95% CI, 1.7-4.1) with cisplatin alone (HR, 1.00; 95% CI, 0.59-1.70; 2-sided P = 1.00).
It is known that treatment with PARP inhibitors results in improved PFS compared with chemotherapy in patients with germline BRCA1/2-mutant metastatic breast cancer,2-4 and efficacy of this approach has been demonstrated beyond germline BRCA1/2 in patients with ovarian cancer.5-7Approximately 40% to 60% of patients with TNBC show homologous recombination deficiency (HRD) that leads to a BRCA-like phenotype8-9; however, PARP monotherapy has shown limited efficacy beyond those with germline BRCAmutations in this space, according to Sharma.
“A phase 1 trial has demonstrated that adequate doses of cisplatin can be delivered safely in combination with a near-maximal single-agent dose of veliparib in patients with metastatic TNBC,” said Sharma. “This trial tests whether the addition of veliparib to cisplatin is beneficial in BRCA-like germline TNBC.”
Patients with metastatic and/or locoregionally recurrent TNBC or those with BRCA1/2 germline mutation–associated HER2-negative metastatic breast cancer who received 0 to 1 prior cytotoxic chemotherapy for their metastatic disease were enrolled on the trial. Patients were randomized 1:1 to receive cisplatin at 75 mg/m2 on day 1 every 21 days plus either placebo or oral veliparib at 300 mg twice daily from day 1 to day 14 every 21 days.
The primary end point of the trial was PFS in the 3 prespecified groups: germline BRCA, BRCA-like, and non–BRCA-like. The secondary end points included OS, objective response rate, and clinical benefit rate.
“A HR of 0.57 favoring the veliparib arm was assumed for both the germline BRCA and BRCA-like groups to detect whether the combination would be superior. A smaller sample size and higher α was set for the germline BRCA group, since PARP inhibitor efficacy in germline BRCA carriers was already being addressed in several ongoing phase 3 trials at the time this trial was designed,” explained Sharma. “For the BRCA-like group, the study had 80% power with one-sided α of 0.05 to detect if the combination was superior to cisplatin alone, requiring the sample size of 86 randomized patients. No effect was expected with veliparib in the non–BRCA-like group.”
Post-randomization, germline testing, and tissue BRCA-like biomarker testing was conducted to assign patients into the prespecified groups, said Sharma. This testing was performed after randomization to enable the immediate start of randomized treatment.
First, investigators performed central germline BRCA testing. Patients with deleterious BRCA mutations were assigned to the germline BRCA group. Those without germline BRCA mutations underwent further biomarker testing to identify the BRCA-like phenotype group; this assessment included 4 markers: HRD genomic instability score of ≥42, somatic BRCA1/2 mutation, BRCA1 promoter methylation, and germline homologous recombination repair gene mutations, excluding BRCA1/2. For the 3 tissue-based biomarkers, primary tumor tissue was utilized and positivity on any 1 of the 4 markers placed a patient in the BRCA-like group, explained Sharma.
Patients were eligible for enrollment regardless of if they had measurable disease. Patients who received prior neoadjuvant or adjuvant carboplatin were permitted as long as the treatment had been completed >12 months prior to entering the study. Prior immunotherapy was also permitted. Notably, patients with known brain metastases were allowed to enroll if it was >14 days postoperative excision and/or radiation. To enroll, patients had to submit blood and primary tumor tissue.
Those who did not receive prior cisplatin or a PARP inhibitor were excluded from the trial, as well as those with grade 2 or higher hearing impairment, grade 1 or higher peripheral neuropathy, or those with a history of uncontrolled seizure disorder.
Additionally, there was no minimal time requirement with regard to the end of neoadjuvant or adjuvant chemotherapy and study entry, with the exception of carboplatin.
The initial overall sample size was based on the assumption that all randomized patients could be assigned to 1 of the 3 prespecified groups upon analysis of germline DNA in primary tumor tissue. However, investigators found that during the course of the trial, some patients could not be assigned to a group because of sample submission nonadherence or assay failure. As such, the sample size was adjusted to 324 in the amended study protocol.
A total of 335 patients were registered for the trial between July 2016 and June 2019, and 321 of those patients are included in the intent-to-treat (ITT) analysis. Fourteen patients did not meet the eligibility criteria and thus were not included.
Baseline patient characteristics were well balanced between the veliparib and placebo arms. The median age was 56.2 years and three-fourths of patients (76%) were white. More than half of patients (58%) had an ECOG performance status of 0, while 42% had a score between 1 and 2. Sixty-nine percent of patients had not received any prior lines of chemotherapy for metastatic disease. Of the 31% of patients who did receive prior chemotherapy, 10% received carboplatin and 4% received prior biologic or checkpoint inhibitor therapy.
Of the 321 total patients in the ITT population, germline BRCA testing was performed in 294 patients. Thirty-seven patients were found to be germline BRCA-mutant, while 257 patients were found to be negative. With only 37 patients, the germline BRCA group only reached 59% of initially planned accrual, noted Sharma. Among those without the mutation, biomarker assessment could not be performed in 48 patients due to insufficient tissue or assay failure. Among 209 patients who were able to undergo biomarker assessment, 99 were found to have aBRCA-like phenotype and 110 were designated to the non–BRCA–like group.
“These proportions are in line with the original trial assumptions where BRCA-like phenotype was expected in about 50% of patients with germline BRCA wild-type disease,” said Sharma.
Beyond the PFS findings, Sharma and colleagues also presented results from an exploratory efficacy analysis in patients who received first-line treatment within the BRCA-like group. Again, PFS was found to be significantly prolonged in the veliparib arm compared with the placebo arm. The 12-month PFS rates were 23% with veliparib versus 3% with placebo, and the 24-month OS rate was doubled with veliparib, at 43% versus 20% with placebo.
Investigators also evaluated the impact of HRD score on the efficacy of veliparib, which is independent of the 3 BRCA-like markers. The analysis included 75 patients assigned to the BRCA-like group and was based solely on the HRD score of ≥42. Results showed that PFS was significantly higher in the veliparib arm compared with placebo at 6.1 months versus 4.2 months (HR, 0.53; 95% CI, 0.31-0.89; 2-sided P = .016).
Regarding safety, veliparib was found to be associated with higher grade 3/4 hematologic toxicities compared with placebo, including anemia (23% vs 7%, respectively), neutropenia (46% vs 19%), leukopenia (27% vs 7%), and thrombocytopenia (19% vs 3%). Two treatment-related deaths were reported; 1 occurred on each arm, noted Sharma.
Several translational studies on biospecimens from this trial are planned, including the evaluation of tumor PD-L1 status, somatic mutations in homologous recombination genes, and PI3K pathway genes, as well as liquid biopsy and metastatic tissue sample analysis.
“With demonstration of efficacy in biomarker-selected BRCA-like phenotype TNBC, the results of this trial are a very positive step toward expanding the role of PARP inhibitors beyond germline BRCA in breast cancer,” concluded Sharma. “The combination of veliparib plus cisplatin warrants further evaluation in larger randomized trials for patients with BRCA-like phenotype TNBC.”