CHICAGO—The addition of iniparib to gemcitabine/carboplatin (GC) did not meet prespecified criteria for significance for co-primary endpoints of overall survival (OS) and progression-free survival (PFS) in patients with metastatic triple-negative breast cancer (mTNBC), according to results of a study presented at the American Society of Clinical Oncology’s 2011 Annual Meeting.

A previous randomized Phase 2 study in mTNBC suggested that iniparib, an anticancer agent with Poly ADP ribose polymerase (PARP) inhibitory activity, improved OS when added to GC without potentiating GC toxicity. The confirmatory study was performed to evaluate the safety and efficacy of GC with or without iniparib in a similar mTNBC patient population.

This randomized, open-label Phase 3 study enrolled patients ≥18 years with mTNBC, measurable disease, and ≤2 prior cytotoxic regimens for mTNBC. Patients were stratified based on having 0 vs. 1–2 prior metastatic therapies and were randomized (1:1) to GC alone or GC + iniparib (GCI). Gemcitabine 1000mg/m2 IV and carboplatin AUC 2 IV were given on Days 1 and 8, and iniparib 5.6mg/kg IV on Days 1, 4, 8, and 11 every 21 days. Upon central confirmation of disease progression on GC, crossover to GCI was permitted. Co-primary endpoints were OS and PFS (ie, the study would be considered positive if either endpoint was met) while secondary endpoints were objective response rate, safety, tolerability, and pharmacokinetics of GCI.

Joyce O’Shaughnessy, MD, Baylor Sammons Cancer Center, Texas Oncology, US Oncology, Dallas, and colleagues studied 519 randomized patients between July 2009 and March 2010. Patient characteristics were balanced between the two arms. The study did not meet the criteria for significance for co-primary endpoints of OS and PFS. See Table.

Objective response rates were 30% in the GC group and 34% in the GCI group. Clinical benefit rate (defined as complete response, partial response, and stable disease (>6 months) was 36% in the GC roup and 41% in the GCI group. At the time of the primary analysis, 96% (n=152) of patients crossed over from GC to receive GCI following disease progression.

Exploratory analysis conducted with the first-line population (57% of patients) resulted in a median PFS of 5.6 months for the GCI population and 4.6 months for the GC group; for OS, it was 12.4 months and 12.6 months (HR=0.65 [0.46–0.91]), respectively. Among the 43% of patients treated in the second- or third-line setting, median PFS was 4.2 months for the GCI group and 2.9months for the CG group; OS was 10.8 months and 9.1 months (HR=1.1 [0.78–1.56]), respectively. Analysis suggests a potential efficacy benefit of GCI in previously treated patients; however, a confirmatory study is needed.

Most frequently occurring grade 3/4 adverse events included neutropenia (53% GC vs. 61% GCI), anemia (22% vs. 18%), and thrombocytopenia (24% vs. 28%) Overall, the addition of iniparib did not significantly add to the toxicity profile of GC alone.

Dr. O’Shaughnessy et al. concluded that although this study failed to meet the prespecified criteria for significance for co-primary endpoints, it did demonstrate a consistent safety profile to that of the prior Phase 2 study. Biomarker analyses are underway to evaluate patient populations that may benefit from iniparib.