BRCA-targeting drug olaparib could offer hope for women with advanced breast cancer with inherited mutation

Breast cancer cells stained for DNA (red), NFkB (green), and a reactive oxygen species probe (blue) (photo: Julia Sero/the ICR)

We now know about a large number of genes linked to cancer, but none are more famous than the genes BRCA1 and BRCA2. Mutations in the DNA sequence of these genes can significantly increase a person’s risk of several cancers – most notably breast and ovarian cancer.

But there has been a major treatment breakthrough for cancer patients with BRCA mutations in the last few years. A new family of drugs called PARP inhibitors can kill cancer cells with faulty BRCA genes, while leaving healthy cells alone.

One such drug, olaparib, was approved on the NHS for patients with advanced ovarian cancer who carry BRCA mutations, after a phase II clinical trial showed the drug delayed progression for 8.4 months. 

The pharmaceutical company AstraZeneca issued a statement this week saying that an international phase III clinical trial shows that olaparib also significantly delayed progression of breast cancer for longer than standard chemotherapies.

This is potentially exciting news for patients, and also for us here at The Institute of Cancer Research in London. It was 20 years of research carried out here that underpinned the development of olaparib as the world’s first licensed treatment targeted against an inherited genetic fault.

How it works

Professor Alan Ashworth, a former Chief Executive of the ICR, Professor Andrew Tutt, Director of the Breast Cancer Now Research Centre at the ICR, and colleagues discovered that the protein produced by the BRCA2 gene plays a key role in repairing DNA. This means cancers with BRCA mutations are particularly vulnerable to DNA damage.  

Some years later, Professors Ashworth, Tutt and ICR Team Leader Dr Chris Lord were able to show in the laboratory that you could target this weakness, using drugs called PARP inhibitors to cause breaks in DNA that BRCA-defective tumours struggle to repair. Using PARP inhibitors, such as olaparib, caused BRCA defective tumour cells, but not normal cells, to die.

And these results translated into the clinic, where phase I trials of the PARP inhibitor olaparib – designed and led by ICR Professors Johann de Bono, Tutt and Stan Kaye at the ICR and The Royal Marsden NHS Foundation Trust – found that olaparib was effective against tumours with BRCA1 or BRCA2 mutations, and had fewer side-effects than many traditional chemotherapies.

What about breast cancer?

AstraZeneca issued a statement this week says that an international phase III clinical trial of 302 patients shows reached its trial ‘end point’ – its measure of success – by showing olaparib significantly delayed progression in women with breast cancer.

However, the detailed trial data has no yet been published and is not expected to be presented until later in the year. The data will then need to be reviewed by regulatory bodies in Europe and the US before it can be made available to patients.

Commenting on the announcement, Professor Tutt, said: “While we await the presentation of the detailed results of this study, it is exciting news that the BRCA mutation-targeting drug olaparib appears to delay progression of metastatic breast cancer in women who have inherited BRCA1 and BRCA2 mutations.

“Olaparib is already available for advanced ovarian cancer, and was the first drug to be approved that is directed against an inherited genetic mutation. This drug’s development was underpinned by science carried out at the ICR, and exemplifies the benefits in understanding germline and tumour genetics as a way of personalising treatment for cancer.

“I look forward to the publication of the full trial results with great interest.”

Not just female cancers

What is also exciting is that the benefits of PARP inhibitors may stretch beyond ovarian and breast cancer, and even beyond patients with inherited BRCA mutations.

A phase II trial, led in the UK by Professor de Bono at the ICR and The Royal Marsden, found that olaparib was also effective in men with advanced prostate cancer who have mutations in genes involved in DNA repair within their tumours. Trials of olaparib are currently under investigation in clinical trials for cancers of the pancreas, stomach, brain and lung.

It will be a little while longer before patients with cancer, other than those with ovarian cancer, benefit from PARP inhibitors. But we hope that these drugs will live up to their promise and improve the lives of cancer patients worldwide.