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The addition of the PARP inhibitor iniparib failed to improve OS or PFS when added to gemcitabine/carboplatin (GC) compared with GC alone in patients with metastatic TNBC.
Joyce O'Shaughnessy, MD
The addition of the PARP inhibitor iniparib failed to improve overall survival (OS) or progression-free survival (PFS) when added to gemcitabine/carboplatin (GC) compared with GC alone in patients with metastatic triple-negative breast cancer (TNBC). TNBC lacks estrogen receptors, progesterone receptors, and HER2 receptors—the most common targets for breast cancer treatments. Results of this randomized phase III study (BSI-201) were disappointing because a previous phase II trial suggested that iniparib plus GC was highly effective in this patient population.
Perhaps the explanation for the difference between the phase II and III studies lies in the heterogeneity of the TNBC population, suggested lead author Joyce O'Shaughnessy, MD, a medical oncologist at Baylor Charles A. Sammons Cancer Center in Dallas, Texas.
TNBC is biologically heterogeneous and can be classified as claudin-low, basal-like HER2-enriched, luminal A, and luminal B. To explore the possibility that heterogeneity within TNBC affected study results, the authors are analyzing molecular subtyping of specimens from 304 patients with regard to response to iniparib.
The randomized, open-label, phase III trial enrolled 519 patients treated with GC alone or GC plus iniparib (GCI). Cycles were given every 21 days until disease progression, and then patients in the GC arm were allowed to cross over to GCI (59% of patients did so). Baseline characteristics were well-balanced. About 57% received study therapy as first-line and 43% received it second-line; 30% received prior bevacizumab.
The median disease-free interval was 15 months for GC and 12 months for GCI. Prior to crossover, no major differences were seen between the 2 treatment arms for neutropenia, thrombocytopenia, and anemia. Deaths were uncommon; 1 treatment-related death was reported in the GCI arm.
N = 258
N = 261
HR (95% CI)
Median PFS, mo
Median OS, mo
GC indicates gemcitabine/carboplatin; GCI, gemcitabine/carboplatin plus iniparib; m, months; PFS, progression-free survival; OS, overall survival.
Adapted from from O'Shaughnessy et al. J Clin Oncol. 2011;29(suppl; abstr 1007).
PFS was 4.1 months for GC versus 5.1 months for GCI (hazard ratio [HR] = 0.079; P = .027). Median OS was 11.1 months versus 11.8 months, respectively (HR = 0.88; P = .284). Overall response rate was 30% versus 34%, respectively. No difference in PFS or OS was observed for either arm when patients were receiving first-line therapy. For those treated with secondor third-line therapy, an exploratory analysis suggested a possible benefit for the addition of iniparib (PFS, HR = 0.67; OS, HR = 0.65).
In a multivariate analysis of OS, adjusted for age, disease burden, line of therapy, race, and time since diagnosis, the adjusted HR favoring GCI was 0.81. When disease-free interval replaced time since diagnosis in the multivariate analysis, HR improved to 0.75 (P = .05) in favor of the addition of iniparib. The addition of iniparib was safe, without potentiating the toxicity of GC.
The formal discussant of this trial, Lisa Carey, MD, associate professor of medicine and medical director at the University of North Carolina Breast Center in Chapel Hill, said that the phase II trial of iniparib generated great enthusiasm and high expectations. However, the phase III results did not bear this out, even though the drugs were the same and the patient characteristics were the same.
Carey said that TNBC is biologically heterogeneous, and this may account for the difference between the phase II and III trials. “We will always be misclassifying some of these tumors,” she said. “The direction of effects was the same as the phase II trial, and the difference may be quantitative rather than qualitative.”
“It would be hard to argue that GCI is the preferred regimen for triple-negative breast cancer, but it is a regimen,” said Carey. “The role of iniparib is a work in progress.”
Iniparib may not be a true PARP inhibitor because it has 1000 times lower PARP activity compared with other PARP inhibitors. “There is a question mark about its mechanism of action,” she said. “It does not have additive toxicity, unlike others in its class.”
Future research will focus on the best partner and setting for iniparib, and improved understanding of the drug’s mechanisms of action.
O'Shaughnessy J, Schwartzberg LS, Danso MA, et al. A randomized phase III study of iniparib in combination with gemcitabine/carboplatin in metastatic triple-negative breast cancer. J Clin Oncol. 2011;29(suppl; abstr 1007).