Treating BRCA breast cancer with PARP inhibition

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Published: 4 Jun 2017
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Dr Mika Sovak - AstraZeneca, Cambridge, UK

Dr Sovak speaks with ecancer at ASCO 2017 about the findings presented at an earlier press conference, in which olaparib showed effectiveness in treating breast cancer patients whose tumours contained BRCA mutations.

She describes the mechanism of actions of targeting DNA repair, and considers the wider application of PARP inhibitors across ovarian and prostate cancer.

For more on the OlympiAD trial, ecancer spoke with Dr Mark Robson, here.


The data from the OlympiAD study are really significant and really mean a lot for patients who have gBRCA breast cancer. Basically the data show that patients have a 42% reduction in the risk of disease progressing or death if they receive olaparib versus active chemotherapy, I think that’s a really important part of the study. It’s the first PARP inhibitor study really to compare a PARP inhibitor against active treatment and demonstrate a significant benefit for these patients with high unmet medical need.

Some of the questions that came to Dr Robson were focussed on the history of PARP inhibitors because there have been some attempts at using PARP inhibitors for BRCA before, I think it was niraparib or something similar before that didn’t quite meet expectations. But this one is proving effective. Can you tell us more about the mechanisms there?

The mechanism of the PARP inhibitor? Actually it’s a really interesting drug. A lot of targeted drugs interact with a very specific mutation but a PARP inhibitor is very different in that it really takes advantage of the cell’s ability to repair DNA. So it’s not targeting a specific defect, it’s targeting a cancer cell weakness. You have this weakness and you use the PARP inhibitor which also further impairs the cell’s ability to repair DNA and that basically results in the cell dying. So it’s a pretty unique mechanism of action. You’re right in saying there are multiple different PARP inhibitors out there, there are actually three that are approved in the US but olaparib is a best in class PARP inhibitor and is the only one that has demonstrated benefit in the gBRCA breast cancer patient population.

As was also mentioned during the press conference, unfortunately a lot of healthy cells tend to rely on DNA repair which then leads on to the problems of toxicity.

Yes, so theoretically there is definitely concern. There are patients who have a germline BRCA mutation, will have that mutation both in the cancer cells as well as in the normal cells. But it does seem that when we look at the actual toxicity profile in the patients that one thing that’s actually notable about olaparib is how well it is tolerated. Most of the adverse events are grade 1 and grade 2 and a lot of the adverse events, while not minimising them because they’re nausea, vomiting, anaemia, they are also ones that most oncologists are very comfortable in treating. So that’s really important to note when you look at the toxicity profile.

Olaparib is approved currently in ovarian cancer, as I mentioned, and one of the really significant parts about OlympiAD actually is that it’s the first time that we’ve demonstrated the benefit of a PARP inhibitor in a disease other than ovarian cancer. So now we have the idea of proof of concept is it’s not just in ovarian cancer, it’s also in breast cancer. We actually have an ongoing programme that is looking at multiple different tumour types. First we’re looking at earlier stages of disease of ovarian cancer and breast cancer. We’re also looking at whether this drug can provide benefit to patients with prostate cancer and then also pancreatic cancer, so areas of really high unmet medical need. As the discussant in today’s plenary said, it’s the end of the beginning for PARP inhibitors in breast cancer and you can extend that to multiple different diseases.

One of those is the OlympiA trial.

Yes, the OlympiA trial is looking at olaparib in the adjuvant setting. I definitely think that the OlympiAD study gives us hope that we’ll be able to demonstrate that olaparib also provides benefit to patients in that earlier line of disease.