Negative PARP inhibitor trial raises questions and dampens hope

There have been few drugs that have received more hype and coverage than PARP inhibitors. These work in a very elegant way – by inhibiting one of the mechanisms of DNA repair and appearing to exert the greatest effect on cancer cells that already have defects in another mechanism of DNA repair. (CURE's "A New Hope," about PARP inhibitors, was published in Fall 2010.)The BRCA gene encodes a double-strand DNA repair protein and when mutated, causes familial breast and ovarian cancers that appear to respond particularly well to PARP inhibitors. "Triple-negative" (estrogen, progesterone and HER2 receptor-negative) breast cancers encompass those associated with DNA-repair deficiency. In advanced cancers of this type, the addition of the PARP inhibitor iniparib (also known as BSI-201) to chemotherapy yielded significant improvements in time to progression and overall survival. These results were even more dramatic than had been seen with Herceptin over 10 years ago, and had the rather sedate oncology community in a buzz. Then why did the larger confirmatory phase 3 trial, which was supposed to lead to rapid FDA approval of this drug, not meet its endpoint? This rather shocking news was announced in a press release on Jan. 27 by sanofi-aventis, the company that now owns BiPar, the small start-up that discovered and initially developed this drug and moved it into a phase 3 trial with lightning speed.There are many possible reasons for this. We really don't know exactly why clinical trials of the same design do not give us consistent results, but it does happen quite often. It might be just the play of chance, as from a statistical standpoint, any experiment can only give you a certain level of probability that the result reflects reality. We accept a 95% probability as sufficient proof – but what happens if another trial falls just short of that mark – is it really a conflicting result? We are also realizing that the behavior of cancer and response to specific treatments can vary among the different subtypes that we are just starting to discern with sophisticated molecular tools. An imbalance of these subtypes among the treatment arms might go undetected, but could alter the findings. Whatever the reasons, the road ahead for PARP inhibitors is unclear. For iniparib, the timing of the FDA approval, the population that should be treated and the need for further studies will be decided shortly. For olaparib, AstraZeneca recently announced that ovarian cancer and not breast cancer will be the future focus of study. There is also evidence that the several PARP inhibitors in clinical development are not the same and may have different targets, mechanisms of action and side effects. Most scientists and clinicians agree that these drugs are a big step forward. In fact, it is important to recognize that the iniparib phase 3 trial did in fact show a big improvement in patients receiving second- and third-line therapy, and this needs to clearly be pursued. It is just very hard to know exactly how this will all unfold.