Abstract P4-22-02: Evaluation of veliparib (V) and temozolomide (TMZ) in a phase 2 randomized study of the efficacy and tolerability of V+TMZ or carboplatin (C) and paclitaxel (P) vs placebo (Plc)+C/P in patients (pts) with BRCA1 or BRCA2 mutations and metastatic breast cancer
Authors: Diéras V , Han HS , Robson ME , Palácová M , Marcom PK , Jager A , Bondarenko I , Citrin D , Campone M , Telli ML , Domchek SM , Friedlander M , Kaufman B , Ratajczak C , Coates A , Bonnet P , Qin Q , Qian J , Giranda VL , Shepherd SP , Puhalla S , Isakoff SJ 
Published: March 2017

Abstract
Background: V is a potent, poly(ADP-ribose) polymerase (PARP) inhibitor that obstructs DNA damage repair. BRCA1/2 tumors are defective in homologous recombination, which leads to more error-prone mechanisms of DNA repair and increased sensitivity to PARP inhibition. V enhances the antitumor activity of alkylating agents such as TMZ in preclinical models. In addition, V+TMZ showed promising activity in a single-arm phase 2 study in pts with BRCA1/2 mutations. This phase 2 trial (NCT01506609) investigated the efficacy and tolerability of V+TMZ (or V+C/P) compared to Plc+C/P in pts with locally recurrent or metastatic breast cancer harboring a BRCA1 or BRCA2 mutation. Results from the primary analysis for the V+TMZ arm vs Plc+C/P are presented, and the V+C/P vs Plc+C/P results will be presented separately.
Methods: Male and female pts aged ≥18 years with histologically confirmed locally recurrent or metastatic breast cancer were randomized 1:1:1 to: 1) V 40 mg BID D1–7 + TMZ 150–200 mg/m2 QD D1–5, 28-D cycle; 2) V 120 mg BID D1–7 + C AUC 6, D3 and P 175 mg/m2, D3, 21-D cycle; 3) placebo BID D1–7 + C/P. Key eligibility criteria included known deleterious BRCA1/2 mutation, ≤2 prior chemotherapies for metastatic disease, no prior platinum agent, and no CNS metastases. Randomization was stratified by hormone receptor status, prior cytotoxic therapy (yes vs no), and ECOG PS (0–1 vs 2). The primary endpoint was progression-free survival (PFS) per RECIST 1.1 by independent review. Overall survival (OS), objective response rate (ORR), and safety/tolerability were also evaluated.
Results: A total of 290 pts (284 BRCA+ per central lab) were randomized (V+TMZ, n=94 [91 BRCA+]). Baseline demographics and disease characteristics were comparable among treatment arms; 41.3% of pts had triple-negative breast cancer (TNBC) and 31.7% had received &gt;2 prior regimens. Median study drug exposure was 6 cycles for the V+TMZ arm and 10 cycles for the Plc+C/P arm. Median PFS, median OS (interim), and ORR for V+TMZ were inferior to Plc+C/P (PFS 7.4 vs 12.3 mo, OS 19.1 vs 25.0 mo, and ORR 28.6% vs 61.3%). In pts with TNBC, median PFS was 5.5 (3.1–8.5) mo; 8.4 (6.8–10.6) mo for pts with non-TNBC. Treatment-emergent adverse events (AEs) of interest occurring differentially with V+TMZ are shown in Table 1. Grade ≥3 AEs in ≥30% of pts in the V+TMZ arm were thrombocytopenia (48%) and neutropenia (37%).
Conclusions: V+TMZ provided durable responses, with less neutropenia, alopecia, and neuropathy than Plc+C/P; however, PFS, OS, and ORR were inferior in the TMZ arm compared to C/P.
Table 1Treatment-Emergent AEs, n (%)V+TMZ, n=93Plc+C/P, n=96Neutropenia46 (50)71 (74)Alopecia10 (11)55 (57)Peripheral neuropathy11 (12)56 (58)Thrombocytopenia73 (79)67 (70)Nausea70 (75)56 (58)
Citation Format: Diéras V, Han HS, Robson ME, Palácová M, Marcom PK, Jager A, Bondarenko I, Citrin D, Campone M, Telli ML, Domchek SM, Friedlander M, Kaufman B, Ratajczak C, Coates A, Bonnet P, Qin Q, Qian J, Giranda VL, Shepherd SP, Puhalla S, Isakoff SJ. Evaluation of veliparib (V) and temozolomide (TMZ) in a phase 2 randomized study of the efficacy and tolerability of V+TMZ or carboplatin (C) and paclitaxel (P) vs placebo (Plc)+C/P in patients (pts) with BRCA1 or BRCA2 mutations and metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-22-02.