PARP Inhibitors in Triple-negative Breast Cancer

PARP inhibitors are of significant interest to those who treat breast and gynecologic cancers, as they have shown such promise in BRCA-mutation related cancers.

One class of agents that has been of significant interest to those of us who treat breast and gynecologic cancers are the poly(ADP-ribose) polymerase (PARP) inhibitors, which have shown such promise in BRCA-mutation related cancers. It turns out that some features of BRCA-mutation related breast cancers share biologic features in common with a specific and aggressive breast cancer that is ER, PR and HER-2/neu negative (triple-negative breast cancers). Given this similarity, it was hypothesized that PARP inhibitors coupled with chemotherapy may improve the outcomes in women with triple-negative breast cancer (TNBC).

In 2009 O'Shaugnessy presented preliminary data at the American Society of Clinical Oncology meeting (ASCO) on a phase II randomized trial of an intravenous PARP inhibitor, BSI-201, given with carboplatin and gemcitabine, compared to the same combination chemotherapy but with placebo. The results as presented at ASCO were very exciting as were the final results presented in 2010 at the European Society of Medical Oncology (ESMO) meeting. The final results showed a 5 month gain in overall survival for the group who received BSI-201 and a 40% improvement in the progression free survival. On the basis of this data, all had much anticipation for the results of the phase III study, which if positive, would finally get a PARP inhibitor on the market for breast cancer.

Flash forward to January 31, 2011. The results of the larger (and confirmatory) phase III study of carboplatin and gemcitabine with or without BSI-201 in TNBC has been released and unfortunately, it is negative. The use of BSI-201 did not improve the survival in women with metastatic disease. This result has been met with shock in the breast cancer community, especially given the encouraging results seen in the phase II study. While the final results have been released, however, a peer review of the trial results has yet to take place and we await an opportunity to better understand this data and why it was so divergent from the phase II results.

Still, it emphasizes the importance of formal phase III evaluations in oncology. Many drugs show promise in phase II studies which in a larger trial are not borne out. In the process of trying to improve the outcomes for women with cancer this should serve as an important reminder of the caution needed when promise is seen in early development and to not put all of our proverbial eggs in one basket.

I look forward to reviewing the results in greater detail, once they become available. Stay tuned!