As reported in the March 15 issue of The ASCO Post, a phase III trial of the novel agent iniparib failed to demonstrate a significant improvement in survival for women with metastatic triple-negative breast cancer. The “top-line” results were communicated in the spring via press releases from Sanofi-aventis and BiPar Sciences, but the full results were withheld until the ASCO Annual Meeting.

Iniparib provokes cell-cycle arrest in the G2/M phase and induces double-strand DNA damage but does not inhibit poly (ADP-ribose) polymerase (PARP) 1 and 2 at physiologic drug concentrations—though it is often referred to as a PARP inhibitor. In the previous randomized phase II study,¹ the addition of iniparib to gemcitabine/carboplatin therapy improved response rates, progression-free survival, and overall survival in 123 women with metastatic triple-negative breast cancer.  Overall survival, in fact, nearly doubled, from 7.7 months with gemcitabine/carboplatin to 12.3 months with the addition of iniparib.

The blockbuster-level findings fueled anticipation over the results of the phase III trial presented by Joyce O’Shaughnessy, MD, of Baylor Sammons Cancer Center, Texas Oncology, and US Oncology in Dallas.²

Study Data

The study randomly assigned 519 women with stage IV triple-negative breast cancer to gemcitabine/carboplatin or to gemcitabine/carboplatin/iniparib.  The coprimary endpoints were progression-free and overall survival, and the study was considered positive if either endpoint was met. Due to the use of two primary endpoints, P values of .04 for overall survival and .01 for progression-free survival were required to prove statistical significance.

The arms were well balanced except for a shorter disease-free interval after first-line treatment in the three-drug arm (9.5 vs 15.9 months), but the difference in disease-free interval between the two arms in the overall population was not significant. At the time of the primary analysis, 96% of the gemcitabine/carboplatin arm had crossed over to receive iniparib.

In the intent-to-treat population, median progression-free survival was 5.1 months in the gemcitabine/carboplatin/iniparib arm vs 4.1 months with gemcitabine/carboplatin (P = .027), which was a 21% reduction in risk that did not meet the prespecified alpha (P = .01). Median overall survival was 11.8 vs 11.1 months, for a 12% risk reduction (P = .28). Overall response rates were 34% vs 30%, and clinical benefit rates were 41% and 36%, respectively, Dr. O’Shaughnessy reported.

Fifty-one percent of patients received gemcitabine/carboplatin/iniparib treatment in the first-line setting, and an exploratory analysis of this subgroup mirrored the overall results. However, the iniparib-containing triplet given second- or third-line to 43% of patients reduced mortality risk by 35%, with a median overall survival of 10.8 months, up from 8.1 months with gemcitabine/carboplatin. Median progression-free survival was 4.2 vs 2.9 months, a 33% risk reduction.

Subgroup Analysis

“An exploratory analysis by prior therapy suggests there is a potential efficacy benefit among second- and third-line patients, though a confirmatory study is needed,” Dr. O’Shaughnessy said.

By using prespecified baseline factors in the multivariate Cox model, but replacing the time since diagnosis of metastatic disease with the disease-free interval from primary breast cancer surgery, the investigators found that patients receiving iniparib in the second- or third-line setting had their risk of progression reduced by 29% (P = .05) and mortality risk reduced by 29% (P = .031).

Dr. O’Shaughnessy also suggested the drug may work in some molecular subtypes of triple-negative breast cancer but not others. “Metastatic triple-negative breast cancer is highly heterogeneous on intrinsic subtyping. Biomarker analyses are underway to evaluate patient populations that may benefit from iniparib,” she said. ■

Financial Disclosure: Dr. O’Shaughnessy has received honoraria from sanofi-aventis.

References

1. O’Shaughnessy J, Osborne C, Pippen JE, et al: Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med 364:205-214, 2011.

2. O’Shaughnessy J, Schwartzberg LS, Danso MA, et al: A randomized phase III study of iniparib (BSI-201) in combination with gemcitabine/carboplatin in metastatic triple-negative breast cancer. 2011 ASCO Annual Meeting. Abstract 1007. Presented June 6, 2011.