AbbVie’s PARP inhibitor veliparib failed two key endpoints in a Phase II study of metastatic breast cancer with BRCA1 or BRCA2 mutations.
Investigators, including Heather Han from Moffitt, turned up at the San Antonio Breast Cancer Symposium to report that the progression-free survival rate of veliparib combined with carboplatin and paclitaxel chemotherapy was 14.1 months, an improvement but not a statistically significant advance when you compared the 12.3-month PFS rate in the group that substituted a placebo for veliparib. The overall survival rate — 28.3 months versus 25.9 months — also failed to sufficiently diverge.
The PARP race has been attracting considerable attention this year, especially after Pfizer stepped in to buy Medivation and its late-stage PARP in a $14 billion deal. Just weeks ago AstraZeneca whet investors appetites when it said its Phase III study has produced solid supporting data. Tesaro and Clovis, meanwhile, are also racing for an approval.
AbbVie’s rival, though, is much further back in the pack, and won’t get many people talking with data like this. Han said that the problem with the Phase II study is that it wasn’t designed to carefully track nondramatic differences. There’s a Phase III underway now that they believe will come up with the goods.
I asked AbbVie how the company expects to emerge on top given a busy field of advanced contenders and the failed Phase II. Dr. Vince Giranda, project director, AbbVie Oncology Development, answered as follows:
I would first like to provide an explanation of the current clinical trials design. The phase 2 trial was designed as a signal generation trial. The ongoing phase 3 trial was designed to be adapted to the size of the signal we have observed in phase 2, essentially to ensure the number of patients in the phase 3 trial is sufficient to test the hypothesis. The positive trends in OS, PFS and ORR observed in the phase 2 trial were of sufficient magnitude to warrant continuation of the phase 3 trial. If we had designed the phase 2 trial to be statistically significant it would have been a pivotal trial, and there would be no need to start the ongoing phase 3 trial.
In instances where a novel agent (e.g. veliparib) is combined with an active agent (e.g. carboplatin) a randomized, blinded, and placebo controlled trial is one of the best methods by which to determine if addition of a novel agent provides a benefit. The results of the small phase 2 trial are then assessed to determine if there is a signal of potential activity. In addition, if the potential signal is observed, it provides the basis for determining the appropriate size of the phase 3 trial.
Directly responding to your question, our research on veliparib is focused on use in combination with platinum based chemotherapy, which appears to produce high response rates in BRCA-associated breast cancers. This is the first Phase 2 randomized study to show that a PARP inhibitor has the potential to enhance the efficacy of platinum chemotherapy. This focus is distinct from other late-stage clinical PARP inhibitors that are focused on treating BRCA breast cancer without addition of platinum-based chemotherapy.
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