Background: Veliparib (Vel) is a potent PARP1/2 inhibitor with demonstrated antitumor activity when administered alone or combined with carboplatin and paclitaxel (C/P). The phase 3 randomized, double-blind, multicenter BROCADE3 study (NCT02163694) evaluated the efficacy and safety of Vel + C/P treatment compared with placebo (Pbo) + C/P treatment in patients (pts) with germline BRCA1/2 mutations and HER2-negative metastatic or locally advanced breast cancer (BC). Vel + C/P significantly prolonged progression-free survival (PFS) compared with Pbo + C/P treatment (14.5 months [mo] vs 12.6 mo, hazard ratio [HR]=0.71 [95% CI: 0.57, 0.88]; P=0.002). Previous studies have identified increased acute hematologic toxicity in response to chemotherapy in pts with BC carrying BRCA1 mutations compared with BRCA2 mutations or wildtype BRCA1/2. Herein we report a subgroup analysis of the efficacy and safety of Vel + C/P treatment in pts with BRCA1- or BRCA2-positive BC.

Methods: Pts ≥18 years of age who received ≤2 prior lines of cytotoxic chemotherapy for metastatic disease were randomized 2:1 to receive Vel + C/P or Pbo + C/P: Vel (120 mg PO BID) or Pbo on days -2 to 5, C (AUC 6 IV) on day 1, and P (80 mg/m2 IV) on days 1, 8, and 15 in 21-day cycles. Pts who discontinued C/P in the absence of disease progression could continue receiving Vel or Pbo monotherapy (300-400 mg BID continuous). Subgroup analysis of PFS stratified by BRCA1/2 status was preplanned. The primary endpoint was investigator-assessed PFS. Adverse events (AEs) were graded according to NCI CTCAE version 4.0. Ten pts with both BRCA1 and BRCA2 mutations were excluded from the analyses presented here.

Results: In the intent-to-treat population, 256 pts had BRCA1 mutations and 243 pts had BRCA2 mutations. The proportion of as-treated pts with BRCA1 or BRCA2 mutations was comparable between the Vel + C/P (51.4% BRCA1, 48.6% BRCA2) and Pbo + C/P (50.9% BRCA1, 49.1% BRCA2) study arms. Investigator-assessed PFS for the Vel + C/P and Pbo + C/P arms was 14.2 mo vs 12.6 mo, respectively, in the BRCA1 subgroup (HR=0.75 [95% CI: 0.55, 1.03]; P=0.073) and 14.6 mo vs 12.6 mo, respectively, in the BRCA2 subgroup (HR=0.69 [95% CI: 0.50, 0.95]; P=0.021). Safety data in the as-treated population are presented in the Table. Regarding any grade AEs, thrombocytopenia and anemia were slightly more frequent in pts in the BRCA1 subgroup compared with the BRCA2 subgroup, whereas pts in the BRCA2 subgroup experienced slightly more frequent nausea, fatigue, and neuropathy.

Conclusions: Globally, there was no clinically relevant difference in toxicity between BRCA1 and BRCA2 subgroups. Comparisons between treatment arms were generally consistent with findings in the overall study population, with more frequent thrombocytopenia and anemia of any grade reported in the Vel + C/P arm within both the BRCA1 and BRCA2 subgroups. Vel + C/P treatment improved PFS similarly in both BRCA1 and BRCA2 subgroups over C/P alone.

BRCA1-Positive Subgroup (n=253)BRCA2-Positive Subgroup (n=241)
Vel + C/P (n=168)Pbo + C/P (n=85)Vel + C/P (n=159)Pbo + C/P (n=82)
Any grade AE [≥50% of pts], n (%)  
Any event 167 (99.4) 85 (100) 158 (99.4) 82 (100) 
Neutropenia 151 (89.9) 78 (91.8) 140 (88.1) 74 (90.2) 
Thrombocytopenia 140 (83.3) 66 (77.6) 124 (78.0) 54 (65.9) 
Anemia 139 (82.7) 64 (75.3) 122 (76.7) 52 (63.4) 
Nausea 118 (70.2) 49 (57.6) 119 (74.8) 58 (70.7) 
Alopecia 89 (53.0) 43 (50.6) 89 (56.0) 41 (50.0) 
Fatigue 79 (47.0) 37 (43.5) 87 (54.7) 48 (58.5) 
Peripheral sensory neuropathy 69 (41.1) 37 (43.5) 82 (51.6) 49 (59.8) 
Any grade ≥3 AE [≥30% of pts], n (%)  
Any event 164 (97.6) 82 (96.5) 152 (95.6) 77 (93.9) 
Anemia 73 (43.5) 31 (36.5) 67 (42.1) 35 (42.7) 
Leukopenia 54 (32.1) 20 (23.5) 44 (27.7) 25 (30.5) 
Neutropenia 136 (81.0) 72 (84.7) 131 (82.4) 67 (81.7) 
Thrombocytopenia 72 (42.9) 30 (35.3) 59 (37.1) 18 (22.0) 
Serious AEs, n (%) 58 (34.5) 26 (30.6) 56 (35.2) 22 (26.8) 
AEs of special interest, n (%)  
Infections within 14 days of neutropenia 64 (38.1) 34 (40.0) 59 (37.1) 25 (30.5) 
Hemorrhages within 14 days of thrombocytopenia 14 (8.3) 5 (5.9) 17 (10.7) 7 (8.5) 
Any AE leading to study drug discontinuation not due to disease progression, n (%) 16 (9.5) 5 (5.9) 15 (9.4) 4 (4.9) 
Any AE leading to study drug interruption, n (%) 153 (91.1) 77 (90.6) 139 (87.4) 67 (81.7) 
Any AE leading to study drug reduction, n (%) 28 (16.7) 6 (7.1) 27 (17.0) 7 (8.5) 
Any AE leading to death with reasonable possibility related to study drug, n (%) 0 (0) 0 (0) 0 (0) 0 (0) 
BRCA1-Positive Subgroup (n=253)BRCA2-Positive Subgroup (n=241)
Vel + C/P (n=168)Pbo + C/P (n=85)Vel + C/P (n=159)Pbo + C/P (n=82)
Any grade AE [≥50% of pts], n (%)  
Any event 167 (99.4) 85 (100) 158 (99.4) 82 (100) 
Neutropenia 151 (89.9) 78 (91.8) 140 (88.1) 74 (90.2) 
Thrombocytopenia 140 (83.3) 66 (77.6) 124 (78.0) 54 (65.9) 
Anemia 139 (82.7) 64 (75.3) 122 (76.7) 52 (63.4) 
Nausea 118 (70.2) 49 (57.6) 119 (74.8) 58 (70.7) 
Alopecia 89 (53.0) 43 (50.6) 89 (56.0) 41 (50.0) 
Fatigue 79 (47.0) 37 (43.5) 87 (54.7) 48 (58.5) 
Peripheral sensory neuropathy 69 (41.1) 37 (43.5) 82 (51.6) 49 (59.8) 
Any grade ≥3 AE [≥30% of pts], n (%)  
Any event 164 (97.6) 82 (96.5) 152 (95.6) 77 (93.9) 
Anemia 73 (43.5) 31 (36.5) 67 (42.1) 35 (42.7) 
Leukopenia 54 (32.1) 20 (23.5) 44 (27.7) 25 (30.5) 
Neutropenia 136 (81.0) 72 (84.7) 131 (82.4) 67 (81.7) 
Thrombocytopenia 72 (42.9) 30 (35.3) 59 (37.1) 18 (22.0) 
Serious AEs, n (%) 58 (34.5) 26 (30.6) 56 (35.2) 22 (26.8) 
AEs of special interest, n (%)  
Infections within 14 days of neutropenia 64 (38.1) 34 (40.0) 59 (37.1) 25 (30.5) 
Hemorrhages within 14 days of thrombocytopenia 14 (8.3) 5 (5.9) 17 (10.7) 7 (8.5) 
Any AE leading to study drug discontinuation not due to disease progression, n (%) 16 (9.5) 5 (5.9) 15 (9.4) 4 (4.9) 
Any AE leading to study drug interruption, n (%) 153 (91.1) 77 (90.6) 139 (87.4) 67 (81.7) 
Any AE leading to study drug reduction, n (%) 28 (16.7) 6 (7.1) 27 (17.0) 7 (8.5) 
Any AE leading to death with reasonable possibility related to study drug, n (%) 0 (0) 0 (0) 0 (0) 0 (0) 

AE, adverse event; BRCA, breast cancer susceptibility gene; C/P, carboplatin plus paclitaxel; Pbo, placebo; pts, patients; Vel, veliparib.

Citation Format: Hans Wildiers, Jean-Pierre Ayoub, Michael Friedlander, Bella Kaufman, Banu K. Arun, Hyo S. Han, Shannon L. Puhalla, David Maag, Dai Feng, Christine K. Ratajczak, Bruce A. Bach, Véronique Diéras. Safety and efficacy of veliparib plus carboplatin/paclitaxel in patients with HER2-negative metastatic or locally advanced breast cancer: A subgroup analysis of germline BRCA1 or BRCA2 mutations from the phase 3 BROCADE3 trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-03.