Study shows clinical benefits of iniparib in combination with standard chemotherapy f

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Dr. Joyce O’Shaughnessy reported Phase II data, first at the ASCO meeting, then in the NEJM, describing the efficacy of iniparib combined with carboplatin and gemcitabine in triple negative breast cancer (TNBC). Despite the enthusiasm that surrounded Dr. O’Shaughnessy’s initial observations, the confirmatory clinical trial using iniparib combined with carboplatin and gemcitabine, then compared with carboplatin and gemcitabine did not achieve statistical significance. That is, the trial was negative and the combo of iniparib with carboplatin plus gemcitabine was not proven superior.

Based on this, Dr. Robert Nagourney initiated a study of both iniparib and olaparib in human breast cancer specimens. His results were reported at the ASCO meeting. What happened? Quite a few things.

First, it turned out that iniparib, a member of the benzamine chemical family, at physiological concentrations achievable in humans is not a PARP inhibitor. This, in retrospect, should have been obvious because a full-dose PARP inhibitor, plus a potent combination of carboplatin plus gemcitabine would not likely be tolerable if PARP inhibition were achieved.

Second, the patients receiving the drug are probably not a homogeneous population. That is, some TNBC patients may be similar to the BRCA patients, while others may not have the DNA repair deficiencies associated with PARP inhibitor response.

Finally, Dr. Nagourney originally reported the carboplatin plus gemcitabine combination in breast cancer, as a split-dose doublet in 2008 (Nagourney, Clin Breast Cancer Research, 2008). He observed, in that original clinical trial, that even a lower starting dose of gemcitabine (i.e. 800mg/ml2 vs. the O’Shaughnessy 1000 mg/m2) resulted in significant toxicity and in his concluding comments in that paper, he suggested 600mg/ml2. At 1000 mg/m2, Dr. O’Shaughnessy’s trial nearly doubled his recommended dose in this patient population.

Dr. Nagourney, like other investigators, entered into his original studies of these molecules believing iniparib to be a PARP inhibitor. To his surprise, and in retrospect, a direct comparison of olaparib (AZD2281) to inapaprib (BSI201) revealed no correlation. He described this in his abstract, “Of interest, BSI201 & AZD2281 activity did not correlate in parallel analyses (R = 0.07, P > 0.5).” Thus, his human tumor primary culture analysis scooped the ASCO investigators.

What has been learned? First, iniparib is not a true PARP inhibitor. Second, the combination of platins plus gemcitabine in breast cancer is synergistic, highly active and can be toxic (particularly at the doses chosen for this trial). Finally, that TNBC, indeed all breast cancers, even more to the point, all cancers in general, are heterogeneous. That is precisely why the use of human tumor primary culture analyses are so instructive and should be incorporated into clinical trials for these and other targeted agents.

Source: Rational Therapeutics

Take Home Message: In retrospect, a direct comparision of olaparib to inapaprib revealed no correlation. Thus, human tumor primary culture analysis scooped the investigators. Iniparib is not a true PARP inhibitor.