Results Mixed for Veliparib Regimen in BRCA+ Breast Cancer

​The addition of the veliparib to carboplatin/paclitaxel demonstrated promising objective response rates and trends toward improvements in progression-free survival and overall survival in patients with advanced&nbsp;<em>BRCA</em>-positive breast cancer.

BRCA-positive breast cancer, according to findings from the phase II BROCADE trial presented at the 2016 San Antonio Breast Cancer Symposium.

Treatment with the PARP inhibitor plus chemotherapy elicited an ORR of 77.8%; however, PFS was not statistically signficiantly prolonged. The median PFS was 14.1 months (95% CI, 11.5-16.2) for the veliparib arm and 12.3 months (95% CI, 9.3-14.5) for the placebo group (HR, 0.789; 95% CI, 0.536-1.162; P= .231). The median OS was 28.3 months (95% CI, 26.9-NR) versus 25.9 months (95% CI, 20.4-31.8) with veliparib versus placebo, respectively (HR, 0.750; .503-1.117; P= 0.157), although these data were not fully mature.

“Although the improvements in progression-free and overall survival were not statistically significant, the study supports further investigation of veliparib in combination with chemotherapy as a potential treatment for this group of patient," lead study author Hyo Sook Han, MD, associate member at Moffitt Cancer Center, said when presenting the results. "The ongoing phase III BROCADE 3 clinical trial will provide more definitive answers as to whether this PARP inhibitor should become part of routine clinical care.”

The phase II BROCADE study included 290 women with histologically or cytologically confirmed locally recurrent or metastatic breast cancer who harbored a deleteriousBRCA1or BRCA2germline mutation. Patients were allowed to have received 2 or fewer prior lines of chemotherapy in the metastatic setting. Individuals with prior PARP inhibitor treatment or CNS metastases were ineligible.

The 3-arm trial randomized patients in a 1:1:1 ratio to veliparib (120 mg twice daily on days 1-7) plus carboplatin (AUC 6)/paclitaxel (175 mg/m2) every 3 weeks (n = 97); the same chemotherapy regimen plus placebo (n = 99); or veliparib (40 mg twice daily on days 1-7) plus temozolomide (150-200 mg/m2each day on days 1-5) every 4 weeks (n = 94).

Han reported the findings for the first 2 arms at the press briefing. In the placebo arm, the median patient age was 46 years (range, 24-66). Regarding hormone receptor status, 43.4% of patients were ER/PgR-negative and 56.6% of patients were ER and/or PgR-positive.

HER2neu-negative status was reported for 92.9% of patients and 42.4% of patients had triple-negative disease. The ECOG performance status was 0-1 for 93.9% of patients. The number of prior treatments received across all settings was 0, 1, 2, or >2, for 23.2%, 42.4%, 25.3%, and 9.1% of patients.

In the veliparib arm, the median patient age was 44 years (range, 25-65). The hormone receptor status was ER/PgR-negative for 41.2% of patients and ER and/or PgR-positive for 58.8% of patients.

HER2neu-negative status was reported for 96.9% of patients and 41.2% of patients had triple-negative disease. The ECOG performance status was 0-1 for 94.8% of patients. The number of prior treatments received across all settings was 0, 1, 2, or >2, for 19.6%, 48.5%, 24.7%, and 7.2% of patients.

Tumor response was assessed in patients with measurable disease, which included 72 patients in the veliparib arm and 80 patients in the placebo arm. The overall response rate was 77.8% (95% CI, 66.4-86.7) in the veliparib arm and 61.3% (95% CI, 49.7-71.9) in the placebo group.

The complete and partial response rates in the veliparib versus placebo arms were 5.6% (n = 4) versus 3.8% (n = 3) and 72.2% (n = 52) versus 57.5% (n = 46), respectively. The clinical benefit rate (progression-free rate at 18 weeks) was 90.7% versus 87.0%, respectively. The median duration of response was 11.7 months (95% CI, 8.5-14.1) in the veliparib arm and 11.1 months (95% CI, 9.5-15.7) in the placebo arm.

“We were pleased to see that adding veliparib to chemotherapy significantly improved the overall response rate among patients withBRCA-mutant breast cancer and did not increase adverse events,” said Han.

All-grade adverse events (AEs) occurred in 100% of the veliparib arm and 97.9% of the placebo arm. The most common nonhematologic AEs in the veliparib versus the placebo arm included alopecia (66.7% vs 57.3%), arthralgia (36.6% vs 32.3%), back pain (30.1% vs 22.9%), constipation (38.7% vs 29.2%), diarrhea (38.7% vs 28.1%), fatigue (50.5% vs 59.4%), headache (35.5% vs 32.3%), and peripheral neuropathy (68.8% vs 59.4%).

Common hematologic malignancies included anemia (57% with veliparib versus 51% with placebo), leukopenia (30.1% vs 28.1%), neutropenia (74.2% vs 74%), and thrombocytopenia (71% vs 69.8%). “The safety profile of veliparib plus carboplatin/paclitaxel was comparable to that of carboplatin/paclitaxel alone,” added Han.

Serious AEs occurred in 34.4% and 27.1% of the veliparib and placebo arms, respectively. Grade 3/4 AEs occurred in 78.5% and 83.3% of the 2 arms, respectively. The most common hematologic grade 3/4 AEs included anemia (17.2% vs 17.7%), febrile neutropenia (8.6% vs 3.1%), leukopenia (16.1% vs 11.5%), neutropenia (55.9% vs 55.2%), and thrombocytopenia (31.2% vs 26%). The most frequently reported nonhematologic grade 3/4 AEs were diarrhea (4.3% vs 7.3%), drug hypersensitivity (5.4% vs 0), fatigue (5.4% vs 8.3%), and peripheral neuropathy (7.5% vs 5.2%).

“The addition of veliparib did not increase the frequency of interruption, dose reduction, or discontinuation of veliparib/placebo, carboplatin, or paclitaxel due to adverse events,” said Han.

The results from the temozolomide arm will be presented later at the meeting. Han noted, however, that the data suggest that the veliparib/temozolomide regimen is inferior compared with the carboplatin/paclitaxel-alone arm.

Han HS , Diéras V, Robson M, et al. Efficacy and tolerability of veliparib (V; ABT-888) in combination with carboplatin (C) and paclitaxel (P) vs placebo (Plc)+C/P in patients (pts) with BRCA1 or BRCA2 mutations and metastatic breast cancer: a randomized, phase 2 study. Presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX. Abstract S2-05.