Abstract PD4-01: First-line veliparib plus carboplatin/paclitaxel in patients with HER2-negative advanced/metastatic gBRCA-associated breast cancer: Planned subgroup analysis from the phase 3 BROCADE3 trial
Authors: Arun Banu K. , Han Hyo S. , Kaufman Bella , Wildiers Hans , Friedlander Michael , Ayoub Jean-Pierre , Puhalla Shannon L. , Bach Bruce A. , Dudley Matthew , Ratajczak Christine K. , Maag David , Diéras Véronique 
Published: March 2020

Abstract
Background: BROCADE3 (NCT02163694) evaluated the PARP inhibitor veliparib in combination with carboplatin/paclitaxel (C/P) vs placebo + C/P in patients with HER2-negative locally advanced/metastatic breast cancer and a germline BRCA1/2 mutation. In the intent-to-treat (ITT) population, investigator-assessed median progression-free survival (PFS) was 14.5 months for veliparib vs 12.6 months for placebo (hazard ratio=0.71 [95% CI 0.57-0.88], p=0.002); 75th percentile PFS was 39.9 months for veliparib vs 20.7 months for placebo. In this preplanned analysis, we evaluated efficacy and safety of veliparib plus C/P in patients with no previous cytotoxic chemotherapy for metastatic disease.
Methods: Patients with ≤2 prior lines of cytotoxic chemotherapy for metastatic breast cancer were randomized 2:1 to C/P with veliparib or C/P with placebo. Veliparib (120 mg p.o. BID) or placebo was given on Days −2 to 5, C (AUC 6 mg/mL/min IV) on Day 1, and P (80 mg/m2 IV) on Days 1, 8, and 15 (21-day cycles). Patients who discontinued both C and P for toxicity or reasons other than disease progression could continue veliparib/placebo monotherapy until progression. Monotherapy dose was 300 mg BID, increasing to 400 mg BID if tolerated. Although randomization was not stratified by lines of prior cytotoxic chemotherapy, the treatment arms were well-balanced with respect to this baseline characteristic. The primary endpoint was PFS as assessed by investigator. Secondary endpoints included overall survival (OS), clinical benefit rate (CBR), and objective response rate (ORR). Adverse events were monitored throughout the study. Analysis of PFS in patients with no prior cytotoxic therapy for metastatic disease was pre-planned.
Results: In the ITT population, 337 patients (81% of the entire cohort) received treatment as first line and were randomized to veliparib plus C/P and 172 patients to placebo plus C/P. Most patients received prior cytotoxic chemotherapy in the neo-adjuvant/adjuvant setting (66%, placebo plus C/P; 70%, veliparib plus C/P). Among the 81% of patients in each arm who had no prior cytotoxic chemotherapy in the metastatic setting, median PFS was longer in patients receiving veliparib plus C/P compared to placebo plus C/P (16.6 mo vs 13.1 mo), and median PFS for both arms was over 1 year (Table). Proportion of patients with a serious AE was 30.9% for placebo plus C/P and 33.1% for veliparib plus C/P; proportion with an AE leading to study drug discontinuation was 10.8% for placebo plus C/P and 15.6% for veliparib plus C/P. Additional safety data will be presented.
Conclusions: In patients with HER2-negative advanced/metastatic breast cancer and a germline BRCA1/2 mutation who had no prior cytotoxic chemotherapy for metastatic disease, veliparib with C/P demonstrated an improvement in median PFS over C/P alone. This benefit was durable with 25% of patients alive and progression free at nearly 4 years.
Table. Efficacy in patients with no prior cytotoxic chemotherapy for metastatic disease.Veliparib + C/P, n=274Placebo + C/P, n=139mPFS per INV (mo, 95% CI)16.6 (13.4, 18.7)13.1 (11.4, 14.5)PFS HR (95% CI)0.69 (0.54, 0.88)PFS 75th percentile (mo, 95% CI)46.3 (29.3, NR)22.6 (16.5, 27.2)mPFS per ICR (mo, 95% CI)21.5 (18.7, 29.2)14.0 (12.5, 16.5)PFS HR (95% CI)0.63 (0.47, 0.84)PFS 75th percentile (mo, 95% CI)NR33.3 (19.7, NR)mOS (mo, 95% CI) [interim]36.0 (32.0, 43.1)29.9 (26.0, 39.3)OS HR (95% CI)0.92 (0.68, 1.2)CBR at 24 weeks (% [95% CI])92.8 (90.0, 94.9)93.4 (89.1, 96.0)ORR (% [95% CI])79.7 (74.0, 84.7)76.3 (67.4, 83.8)
C/P, carboplatin and paclitaxel; CBR, clinical benefit rate; HR, hazard ratio; m, median; mo, months; NR, not reached; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; INV, investigator; ICR, independent central review.
Citation Format: Banu K. Arun, Hyo S. Han, Bella Kaufman, Hans Wildiers, Michael Friedlander, Jean-Pierre Ayoub, Shannon L. Puhalla, Bruce A. Bach, Matthew Dudley, Christine K. Ratajczak, David Maag, Véronique Diéras. First-line veliparib plus carboplatin/paclitaxel in patients with HER2-negative advanced/metastatic gBRCA-associated breast cancer: Planned subgroup analysis from the phase 3 BROCADE3 trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD4-01.