So What Happened to the PARP Inhibitors in Breast Cancer Anyway? ASCO 2011

Many of you may recall that we described our studies with the small molecules BSI201 (iniparib) and AZD2281 (olaparib) (Nagourney, et al. ASCO 2011). Based upon the exciting Phase II data reported by Dr. Joyce O’Shaughnessy, first at the ASCO meeting, then in the NEJM, describing the remarkable efficacy of BSI201 (iniparib) combined with carboplatin and gemcitabine in triple negative breast cancer (TNBC), we initiated a study of both iniparib and olaparib in human breast cancer specimens. Our results were reported at the American Society of Clinical Oncology meeting.

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 inabirib with carboplatin plus gemcitabine was not proven superior.

So, what happened? Quite a few things.

It turned out that BSI201, 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, it was our group that originally reported the carboplatin plus gemcitabine combination in breast cancer, as a split-dose doublet in 2008 (Nagourney, Clin Breast Cancer Research, 2008). We 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 our concluding comments in that paper, we suggested 600mg/ml2. At 1000 mg/m2, Dr. O’Shaughnessy’s trial nearly doubled our recommended dose in this patient population.

While our abstract did not receive the fanfare of the clinical trial, it was, in fact, remarkably prescient. We, like other investigators, entered into our original studies of these molecules believing iniparib to be a PARP inhibitor. To our surprise, and, in retrospect, to our credit, a direct comparison of olaparib (AZD2281) to inapaprib (BSI201) revealed no correlation. We described this in our abstract, “Of interest, BSI201 & AZD2281 activity did not correlate in parallel analyses (R = 0.07, P > 0.5).”  Thus, our human tumor primary culture analysis scooped the ASCO investigators. Unfortunately, it appears they weren’t listening.

So, what have we learned? First, we’ve learned that iniparib is not a true PARP inhibitor.

Second, we learned that 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, we learned 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.

About Dr. Robert A. Nagourney
Dr. Nagourney received his undergraduate degree in chemistry from Boston University and his doctor of medicine at McGill University in Montreal, where he was a University Scholar. After a residency in internal medicine at the University of California, Irvine, he went on to complete fellowship training in medical oncology at Georgetown University, as well as in hematology at the Scripps Institute in La Jolla. During his fellowship at Georgetown University, Dr. Nagourney confronted aggressive malignancies for which the standard therapies remained mostly ineffective. No matter what he did, all of his patients died. While he found this “standard of care” to be unacceptable, it inspired him to return to the laboratory where he eventually developed “personalized cancer therapy.” In 1986, Dr. Nagourney, along with colleague Larry Weisenthal, MD, PhD, received a Phase I grant from a federally funded program and launched Oncotech, Inc. They began conducting experiments to prove that human tumors resistant to chemotherapeutics could be re-sensitized by pre-incubation with calcium channel blockers, glutathione depletors and protein kinase C inhibitors. The original research was a success. Oncotech grew with financial backing from investors who ultimately changed the direction of the company’s research. The changes proved untenable to Dr. Nagourney and in 1991, he left the company he co-founded. He then returned to the laboratory, and developed the Ex-vivo Analysis - Programmed Cell Death ® (EVA-PCD) test to identify the treatments that would induce programmed cell death, or “apoptosis.” He soon took a position as Director of Experimental Therapeutics at the Cancer Institute of Long Beach Memorial Medical Center. His primary research project during this time was chronic lymphocytic leukemia. He remained in this position until the basic research program funding was cut, at which time he founded Rational Therapeutics in 1995. It is here where the EVA-PCD test is used to identity the drug, combinations of drugs or targeted therapies that will kill a patient's tumor - thus providing patients with truly personalized cancer treatment plans. With the desire to change how cancer care is delivered, he became Medical Director of the Todd Cancer Institute at Long Beach Memorial in 2003. In 2008, he returned to Rational Therapeutics full time to rededicate his time and expertise to expand the research opportunities available through the laboratory. He is a frequently invited lecturer for numerous professional organizations and universities, and has served as a reviewer and on the editorial boards of several journals including Clinical Cancer Research, British Journal of Cancer, Gynecologic Oncology, Cancer Research and the Journal of Medicinal Food.

2 Responses to So What Happened to the PARP Inhibitors in Breast Cancer Anyway? ASCO 2011

  1. It is very encouraging to see that the parp inhibitor drug may be used to treat a wide variety of cancers. Small trials were very encouraging and they are now undertaking bigger trials, I am looking forward to seeing the results!

  2. Rich66 says:

    “we’ve learned that iniparib is not a true PARP inhibitor.”
    Perhaps in line with strangely attributed comment above, makes the agent potentially more broadly useful?

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

%d bloggers like this: