Scientists at The Institute of Cancer Research (ICR) and The Royal Marsden Hospital, working with pharmaceutical company AstraZeneca, have completed a Phase I clinical trial demonstrating the great promise of a completely new type of cancer treatment. The results are announced today in The New England Journal of Medicine.
Patients with inherited forms of advanced breast, ovarian and prostate cancers – caused by mutations in the BRCA1 and BRCA2 genes – were treated with the new drug olaparib (a PARP inhibitor). Despite having previously received many standard therapies, in more than half of the patients tumours shrank or stabilised. One of the first patients to be given the treatment is still in remission after two years.
Olaparib targets the cancer cells but leaves healthy cells relatively unscathed. Importantly, patients experienced very few side-effects and some reported the treatment was “much easier than chemotherapy”.
Dr Johann de Bono, one of the ICR scientists who led the AstraZeneca/KuDOS-sponsored Phase I trial held at The Royal Marsden and the Netherlands Cancer Institute, said the positive results confirmed olaparib should be taken into larger patient trials.
“This drug showed very impressive results in shrinking patients’ tumours,” Dr de Bono says. “It’s giving patients who have already tried many conventional treatments long periods of remission, free from the symptoms of cancer or major side-effects.”
Olaparib is the first successful example of a new type of personalised medicine using “synthetic lethality”, in which the treatment works in combination with a patient’s own specific molecular defect. It was based on experiments conducted at the ICR and funded by Cancer Research UK and Breakthrough Breast Cancer showing that some cancers had an Achilles’ heel: If drugs – such as olaparib – are used to block an enzyme called PARP in the body, the tumour cells’ DNA breaks down and they die.
Cancer cells with the BRCA1 or BRCA2 mutations were the first discovered to be sensitive to PARP inhibitors, but there is evidence that olaparib will be effective in other cancers with different defects in the repair of DNA – this could include some non-inherited breast and prostate cancers and up to half of the most common type of ovarian cancer.
“This is a very important drug for the treatment of BRCA1/2-related cancer,” ICR scientist and joint lead researcher Professor Stan Kaye, who is supported by Cancer Research UK, says. “The next step is to test this drug on other more common types of ovarian and breast cancers where we hope it will be just as effective.”
Professor Alan Ashworth, Director of the Breakthrough Breast Cancer Research Centre at the ICR, developed the approach of targeting defects in DNA repair in cancer.
“We are delighted that the work we did in the lab has been translated so quickly into potential benefit for patients,” Professor Ashworth says. “This concept is now being tested in a variety of clinical trials across the world.”
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Notes to editors:
* BRCA mutations
Some types of breast, ovarian and prostate cancers have a strong hereditary component. Mutations in the BRCA1 or BRCA2 genes are the best understood cause of these hereditary cancers and are thought to be responsible for about five per cent of breast and ovarian cancers and about one to two per cent of early onset prostate cancers. Women with a BRCA mutation have an up to 85 per cent risk of developing breast cancer and up to 60 per cent risk of developing ovarian cancer during their lifetime. Men with a BRCA mutation have an up to 15 per cent lifetime risk of prostate cancer. These patients are at high risk of cancer because the genetic fault weakens their cells ability to repair any DNA damage.
* Drug action
The concept behind this new approach is called “synthetic lethality”. Normal cells have several different ways of repairing damage to their DNA. But BRCA tumours lack one of these pathways. The drug olaparib blocks a different pathway involving the enzyme PARP and normal cells can recover from this drug because they can use the BRCA genes. But when the drug is applied to BRCA tumours they have no way of repairing their DNA so they simply die. This is why the drug is so effective at killing cancer cells but normal cells appear not to be affected.
*The clinical trial
Olaparib was tested on 60 patients, including 23 BRCA1/2 mutation carriers, to make sure it was safe and well-tolerated. Two patients did not complete the trial and another two had tumours not typically related to BRCA-mutations. Of the remaining 19 BRCA-carrier patients, 12 (63%) derived clinical benefit from the drug by their tumour shrinking or stabilising for at least four months. Side-effects were largely mild and included nausea, fatigue and vomiting. However, the drug would still need to pass Phase II and III trials before it could become widely available to patients.
Note to patients:
Olaparib is not available on prescription and can only be taken as part of a clinical trial as more research is needed to ensure its safety and benefit. Trials are listed on www.cancerhelp.org.uk or www.clinicaltrials.gov but these will have strict eligibility criteria and may not be taking place in your location.