PARP Inhibitors: One of These Things (Iniparib) Is Not Like the Others
The progression of PARP inhibitors through clinical trials has been much anticipated because of their widely touted selectivity (at least in the laboratory) for cells with homologous recombination defects – particularly cancers with BRCA1 or BRCA2 mutations.
There are a number of PARP inhibitors currently being assessed in clinical trials by biotech and pharma companies and their collaborating academic investigators for their activity against various cancers. However, the clinical development pathway has been rather rocky to date.
Recent Disappointing Clinical Trial Results for Iniparib
Perhaps the biggest hiccup so far has been the less than impressive results with the drug iniparib in a Phase III randomized clinical trial comparing gemcitabine/carboplatin plus iniparib to gemcitabine/carboplatin alone in the setting of metastatic triple-negative breast cancer.
However, there is more to this story than might be immediately apparent. As PARP inhibitors are being watched closely by both BRCA1 and BRCA2 carriers and the physicians who care for them, we thought it might be important to mention two recently published papers taking a close look at iniparib as they have important implications.
Is It A Drug Class Effect?!
Regardless of Sanofi-Aventis’ rationale for going broadly after triple-negative breast cancer rather than focusing on BRCA1- and BRCA2-associated cancers, the iniparib trial results have had a negative halo effect on the perceived likelihood of success of the entire drug class. But it is important to ask…is this fair?
In other words, do the iniparib results suggest that PARP inhibitors in general are unlikely to be successful in triple-negative breast cancer and perhaps even other settings where they are being tested?
An important first step in answering this question is to assess whether iniparib and PARP inhibitors in general are acting in the same way within the cell to kill cancer cells. In other words, do they have the same mechanism of action? To the best of our knowledge, until last month, there were no published studies in which iniparib’s putative PARP inhibition has been compared head-to-head with other PARP inhibitors in clinical development, like veliparib and olaparib, for example.
Two Recently Published Research Papers Show That Iniparib Does Not Seem to Act Via the Same Mechanism as Other PARP Inhibitors Currently Being Developed for Use in the Clinic
Given the disappointing clinical trial results for iniparib and also iniparib’s not entirely clear relationship to other PARP inhibitors (in terms of whether their mechanisms of action are the same or similar), and the slowing of the clinical development of several PARP inhibitors, there has been intense interest over the last year in trying to clarify whether iniparib, olaparib, veliparib and other PARP inhibitors are likely to behave similarly in the clinic, or whether, alternatively, disappointing clinical trial results with iniparib are unlikely to be relevant to the prospects of the PARP inhibitor class as a whole.
Last month, a research paper (see reference below) from Abbott Laboratories – which is pursuing the clinical development of veliparib – was published in the journal Clinical Cancer Research. This paper described work by Xuesong Liu, Alexander Shoemaker, and colleagues that aimed to determine whether iniparib has similar biological activities to veliparib and similar compounds. In this study, both iniparib and its key metabolite, 4-iodo-3-nitrosobenzamide, were studied and compared in a number of assays (tests) to veliparib and a number of compounds that are similar to veliparib chemically.
In short, veliparib and the similar compounds behaved just as would be expected for a PARP inhibitor. Without going too much into the biochemistry for this audience, while veliparib inhibited PARP enzyme activity in several types of laboratory tests, iniparib and its metabolite clearly did not. Likewise, when the inhibitory effects of the compounds on breast cancer cells in vitro (i.e., effects on cell lines established from breast cancers that are growing in a dish) were tested, veliparib and similar compounds significantly inhibited growth of BRCA1-mutant cells (but not those of a breast cancer without a BRCA1/2 mutation); iniparib and its metabolite did not significantly inhibit the growth of either cell type in this test. The group had similar results in mouse xenograft models (which look at inhibition of human cancer cells growing in vivo in mice), including one with a BRCA2-deficient pancreatic cancer cell line. Clearly, in all of these tests, iniparib does not seem to be behaving like veliparib (or like a PARP inhibitor would be expected to behave based on what is known about the mechanism of action).
In the second recent study, which was also published in Clinical Cancer Research online, a team from Mayo Clinic and Laval University Medical Center led by Dr. Scott Kaufmann pursued an overlapping strategy that provided further evidence generally consistent with the conclusions of the study discussed above. Briefly, they compared iniparib and PARP inhibitors veliparib and olaparib in a number of laboratory tests including a close look at their ability to inhibit growth of and kill cells with defective “homologous recombination” – a cellular defect in BRCA1/2-related tumors. As with the study by Shoemaker and colleagues at Abbott, iniparib did not behave in these tests like the PARP inhibitors that were assessed. This study provides further evidence that while iniparib does appear to have some ability to be cytotoxic (i.e., to kill cells), it does not seem to be acting as a specific PARP inhibitor.
It’s nice to see this similar evidence coming from a different group (and one that also is not an industry lab with a horse in the race), and I think it should make everyone feel increasingly comfortable that iniparib should not be thought of as a PARP inhibitor.
Bottom Line – Iniparib is Not a True PARP Inhibitor
Iniparib does not appear to be a true PARP inhibitor. Although it does have properties that result in toxicity to tumor cells, its mechanism of action does not appear to result in the remarkably specific toxicity for BRCA-deficient cells that has been reported for PARP inhibitors.
Disappointing Iniparib Clinical Trial Results are Irrelevant to the Prospects of Bona Fide PARP Inhibitors in the Clinic
It’s important to view the disappointing results reported from the Phase 3 trial of iniparib in triple-negative breast cancer last year in isolation. They are relevant to iniparib, but not more broadly to bona fide PARP inhibitors – like veliparib, olaparib and others. Therefore, although the pathway to moving along the clinical development of bona fide PARP inhibitors is complex, it is really important that we do not let the iniparib trial results cast a pall over the perceived prospects of the entire drug class! PARP inhibitors may or may not work in the clinic for BRCA1 and BRCA2 carriers with cancer, but we’ve got to go through the process and do the clinical trials to find out the answer.
Potential Implications for BRCA1/BRCA2 Carriers with Cancer
1. There has been significant risk that the clinical development of the entire class of PARP inhibitor drugs could be slowed down by the disappointing iniparib results. Although significant regulatory and economic challenges remain for the development of these drugs for BRCA1 and BRCA2 carriers specifically, hopefully, the clear demonstration in these two new papers that the mechanism of action of iniparib is distinct from bona fide PARP inhibitors will at least help mitigate against the perception that PARP inhibitors may not merit all of the previous enthusiasm.
2. Not surprisingly, many of the current PARP inhibitor trials exclude people who have been on a PARP inhibitor previously. Hopefully, these new studies may lead to iniparib being removed from the list of prior drugs that are part of the exclusion criteria for bona fide PARP inhibitor clinical trials.
How We Know This:
Patel AG, De Lorenzo S, Flatten K, Poirier G, Kaufmann SH. Failure of iniparib to inhibit poly(ADP-ribose) polymerase in vitro. Clinical Cancer Research 2012 (published online ahead of print January 30 2012)
Liu X, Shi Y, Maag DX, et al. Iniparib nonselectively modifies cysteine-containing proteins in tumor cells and is not a bona fide PARP inhibitor. Clinical Cancer Research 2012; 18:510-23.
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