Update on PARP inhibitors including olaparib, iniparib and veliparib

Now that the dust has settled on the news from sanofi-aventis yesterday that iniparib did not achieve it’s primary survival endpoints in the phase III trial in newly diagnosed triple negative breast cancer (TNBC), it’s time to take stock of this class.

Yesterday was another major snow shovelling day in New Jersey so I missed the AstraZeneca year end conference call. A Pharma Strategy Blog reader kindly filled me in with some relevant information – the company discontinued the development of their PARP inhibitor, olaparib, in BRCA breast cancer – scroll down to the discontinued section to see the note.

Our source also listened to the Q+A and in response to questions on olaparib from the analysts, Martin Mackay, the Head of R&D observed that:

“We decided to focus on serious ovarian cancer, and really focus our attention to that in the first instance and wait to see how those results play out in Phase III. Then we’ll revisit… breast cancer.”

This raises some interesting questions about PARP inhibitors in general.

Yesterday, we noted the fine line that needs to be trod between potency/efficacy and tolerability. Last ASCO we saw how challenging it was to manage the toxicities with olaparib in combination with chemotherapy. Iniparib doesn’t appear to add to the adverse event profile in combination, but missed its efficacy endpoints.

Meanwhile, Abbott’s PARP inhibitor, veliparib, is being tested in the I-SPY breast cancer trial, so while it will be a while before we see any data, it will be interesting to see how it pans out given that it is also more potent than iniparib. Pfizer, BMS and Merck are also potential players in the PARP class, but their inhibitors are in earlier stage development. Based on the latest news with iniparib and olaparib it will be fascinating to see what they decide to do.

The latest developments in triple negative breast cancer also raise other critical issues:

Was the olaparib decision based on toxicities, lack of efficacy or being behind iniparib, since they recently announced their phase II results?
How will neliparib fare in the neoadjuvant setting and what toxicities might be expected?
TNBC are mainly basal cell histology so many will also be BRCA1 or 2 positive – did these women do better in the olaparib trial?
Will the Pfizer and Merck compounds have a better risk:benefit profile?
What biomarkers will emerge to indicate subsets or predict response to therapy?
If (5) does evolve, how will this develop from a diagnostics perspective?
What will happen in ovarian, lung and prostate cancers, all of which have a very small proportion of people who have the BRCA1 or 2 mutation.

The current situation with iniparib and olaparib raises more questions than answers, so it will be interesting to see what learnings emerge from the data and whether the once promising class is salvageable or dead.

All in all, 2011 is turning out to be an interesting year and we have yet to get past January.

Adam Bristol

Sally,
Nice posts. You and your readership may have noticed that Myraid Genetics suffered a bit today as collateral damage to the iniparib failure because of the hope that BRCA testing could be used to identify patients for treatment with PARP inhibitors. In an interview reported by Bloomberg, Myriad’s CEO Pete Meldrum clarified that BRCA testing was not used in the iniparib trial, but is being used on some patients in the trials of neliparib and olaparib trials by Abbott and AstraZeneca, respectively. Recall that at ASCO 2009 and later in NEJM, Johann de Bono reported significant antitumor activity of AZ’s olaparib in patients with BRCA1/2 mutations, so while the PARP hype officially ended yesterday, there is still hope.

http://pharmastrategyblog.com maverickny

Hi Adam, Excellent point on the collateral, although I’m somewhat dismayed if the iniparib women weren’t tested for BRCA1 or 2, that essentially means we have wasted a trial and missed a valuable opportunity since that subset analysis likely won’t be available. I certainly do recall the De Bono presentation, as the BRCA1/2 connection was suggested in the earlier olaparib data as well. AZN have consistently sought to test olaparib where the mutations are present, which makes a lot of sense.

The real losers with the negative iniparib data are women with triple negative breast cancer who don’t have many options at present and poorer outcomes

fish

BRCA status was captures in the iniparib trial. Also, Abbott’s PARPi is “veliparib.”

Adam B.

You’re right, ABT-888 or veliparib, is Abbot’s PARP1 inhibitor. And you might be right re: BRCA testing in the iniparib trial. I was simply responding to this story:

“Myriad CEO Says Sanofi Didn’t Use BRCA Screening in Parp Trial
By Rob Waters
Jan. 28 (Bloomberg) — Myriad Genetics Inc.’s lab test for breast cancer patients with the BRCA mutation wasn’t used by Sanofi-Aventis SA in a trial of the French drugmaker’s so-called parp inhibitor medicine that failed to meet its study goals.
Sanofi’s drug, called BSI-201, might have worked in that trial if Myriad’s testing had been used to identify patients who could benefit, Myriad Chief Executive Officer Pete Meldrum said in a telephone interview today.
Abbott Laboratories and AstraZeneca Plc will use Myriad’s BRCA test in their trials of similar medicines to limit study enrollment to patients who have the BRCA mutation, Meldrum said.”

http://pharmastrategyblog.com maverickny

Well, since Myriad own the test rights to BRCA1/2 mutation testing, this makes things somewhat confusing as to whether or not they did indeed do the testing. I will see if I can find out from sanofi.

http://pharmastrategyblog.com maverickny

Oops, good catch. I’m sure I typed veliparib but the iphone may have autocorrected it and I didn’t notice. Will fix the typo.

Alejaszo

I hope the BRCA status was really captured. That data will be critical to better understand the class.
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http://pharmastrategyblog.com maverickny

Update: the BRCA status wasn’t captured, so the Myriad statement was correct. Sanofi just looked at triple negative breast cancer patients as an allcomer group, however this is a heterogeneous defined by what it isn’t rather than a specific homogenous subset.