In a phase III trial reported in Journal of Clinical Oncology, Joyce O’Shaughnessy, MD, of Baylor Charles A. Sammons Cancer Center, Dallas, and colleagues found that the addition of iniparib to gemcitabine and carboplatin did not improve overall survival or progression-free survival in patients with metastatic triple-negative breast cancer.¹ An exploratory analysis showed improved overall survival and progression-free survival with the iniparib-containing regimen in patients receiving it as second- or third-line therapy.

Iniparib was originally identified and investigated as a poly(ADP-ribose) polymerase (PARP) inhibitor, with later studies indicating that it did not exhibit typical characteristics of these agents. An active metabolite of the drug appears to act by increasing production of reactive oxygen species to cytotoxic levels. Iniparib enhances the antiproliferative and cytotoxic effects of gemcitabine and carboplatin in triple-negative breast cancer models, and a randomized phase II study showed improved response rate, progression-free survival, and overall survival with the addition of iniparib to gemcitabine/carboplatin.

Study Details

In the open-label phase III trial, 519 patients with stage IV/locally recurrent triple-negative breast cancer who had received no more than two previous chemotherapy regimens for metastatic triple-negative breast cancer were randomly assigned between July 2009 and March 2010 to receive gemcitabine at 1,000 mg/m² and carboplatin at area under the curve of 2 (days 1 and 8) alone (n = 258) or with iniparib at 5.6 mg/kg administered intravenously on days 1, 4, 8, and 11 (n = 261) every 3 weeks. Randomization was stratified by the number of prior chemotherapies.

The coprimary endpoints were overall survival and progression-free survival in the intention-to-treat population, with predefined superiority P values of .04 for overall survival and .01 for progression-free survival for the iniparib group. Patients in the gemcitabine/carboplatin group were permitted to cross over to iniparib at disease progression.

The iniparib and control groups were generally balanced for age (median = 53 and 54 years, 65% in both ≥ 60 years), Eastern Cooperative Oncology Group performance status (0 for 57% and 53%, 1 for 41% and 45%), number of metastatic sites (2 in 34% and 26%, ≥ 3 in 58% and 60%), metastatic sites (lungs in 62% and 61%, liver in 38% and 44%, lymph nodes in 76% and 72%, bone in 33% and 30%, central nervous system in 8% in both), prior chemotherapy (89% and 90%), disease-free interval (≤ 18 months in 54% and 50%), and line of therapy (first in 57% and 58%).

Before crossover, patients in the iniparib group received a median of six cycles of study therapy, and those in the control group received a median of five. The median number of cycles after crossover was two.

No Survival Differences

Median overall survival was 11.8 months in the iniparib group vs 11.1 months in the control group (hazard ratio [HR] = 0.88, P = .28). Median progression-free survival was 5.1 vs 4.1 months (HR = 0.79, P = .027; did not meet P = .01 threshold). Objective response rates were 33.7% vs 30.2% (P = .395).

Exploratory Analysis

An exploratory analysis by line of therapy showed median overall survival of 12.4 vs 12.6 months (HR = 1.11, 95% confidence interval [CI] = 0.78–1.57) and median progression-free survival of 5.6 vs 4.6 months (HR = 0.88, 95% CI = 0.67–1.17) among those receiving first-line treatment. Among those receiving second- or third-line treatment, median overall survival was 10.8 vs 8.1 months (HR = 0.65, 95% CI = 0.46–0.91), and median progression-free survival was 4.2 vs 2.9 months (HR = 0.68, 95% CI = 0.50–0.92).

An updated overall survival analysis after 70% of patients had died showed median overall survival of 12.2 vs 11.1 months (HR = 0.85, 95% CI = 0.69–1.04), including 12.3 vs 13.9 months (HR = 1.07, 95% CI = 0.80–1.40) among those receiving first-line therapy and 12.1 vs 8.1 months (HR = 0.60, 95% CI = 0.45–0.82) among those receiving later-line therapy.

Toxicity

Grade 3 or 4 adverse events occurred in 89% of the iniparib group and 86% of the control group, with the most common being neutropenia (62% vs 53%) and thrombocytopenia (29% vs 24%). The most common nonhematologic grade 3 or 4 toxicity was fatigue (8% vs 6%).

Serious adverse events occurred in 38% vs 28%. Adverse events led to discontinuation of at least one component of treatment in 35% vs 29%. Adverse events led to death in four patients in the iniparib group, with one (upper gastrointestinal hemorrhage) considered related to treatment, and in two patients in the control group, neither of which was considered treatment-related.

The investigators concluded: “[I] niparib added to [gemcitabine/carboplatin] did not benefit the overall treated [metastatic triple-negative breast cancer] population. The suggestion of an improved survival outcome in second-/third-line patients warrants further evaluation of iniparib in combination with DNA-damaging chemotherapy in patient populations not restricted to [triple-negative breast cancer].” ■

Disclosure: The study was supported by Sanofi. Dr. O’Shaughnessy has served as a consultant or advisor for Sanofi. For full disclosures of the study authors, visit jco.ascopubs.org.

Reference

1. O’Shaughnessy J, Schwartzberg L, Danso MA, et al: Phase III study of iniparib plus gemcitabine and carboplatin versus gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer. J Clin Oncol.  32:3840-3847, 2014.