A PSB reader wrote in asking whether an update on the PARP inhibitors and the clinical trials would be possible. Following on from the last update in January that covered Sanofi’s negative iniparib phase III data in triple negative breast cancer and AstraZeneca’s decision in February not to pursue olaparib in hereditary BRCA1 and 2 positive breast cancers, it would be a good idea to see what’s left of this once highly promising class of compounds.
I first wrote about PARP inhibitors way back in 2006 and like many, I’m rather disappointed with the results we’ve seen so far. However, all is not lost. Abbott’s veliparib is going strong, while Pfizer (PF-01367338) and Cephalon (CEP-9722) are just getting started with their programs.
Iniparib was probably the weakest inhibitor of the class and perhaps not potent enough, since there was no increase in toxicities in the TNBC study (that can be a good and a bad thing), while olaparib has proven to be potent but challenging to combine with chemotherapy. It doesn’t mean that a different compound or clinical approach will be unsuccessful.
The saddest thing about the iniparib trial is the lack of BRCA1 and 2 testing, given the heterogeneous nature of triple negative breast cancer. We will likely never know which different subsets responded and why from that trial, it probably could have been better designed and included more rigorous biopsies for biomarker analysis, but once done it is too late. This is one of the dangers of applying old-style chemotherapy trial designs to targeted therapies – first know your molecular targets – or potential targets – and evaluate the biomarkers over time in response to therapy. Otherwise, it’s a bit like blindfolding an archer and asking him to hit a target s/he can’t even see.
I don’t think all is lost with AstraZeneca’s olaparib yet, but we will have to wait and see what the current ongoing studies bring in terms of answers. Certainly, both AstraZeneca and Abbott have a broad range of clinical trials that may yield some interesting results. We shall see.
I took a quick look at the clinical trials database and sifted through the available data for PARP inhibitors. This is what we have so far:
One trial I’m eagerly awaiting the results of is the ISPY2 trial in neoadjuvant breast cancer, which included veliparib as one of the treatment options in a molecular based approac,h much in the same way the BATTLE trial worked in lung cancer. For those interested in the background to this approach in breast cancer, you can find the details in an interview with Sue Desmond-Hellmann (UCSF), when the trial was first announced. It will be a while before we know the results, but one that is very eagerly awaited in the breast cancer community.