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Drug Effective in 80% of Men With BRCA-mutant Prostate Cancer

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A pioneering gene-targeted drug already licensed for breast and ovarian cancer can benefit some men with prostate cancer, a major new clinical trial reports.

Some 80 per cent of men with prostate cancer whose tumours had mutations in the BRCA breast cancer genes responded to olaparib.

And even though men in the trial had advanced, heavily pre-treated prostate cancer, olaparib delayed progression of the disease in these patients for a median of 8.3 months, with 35 per cent free of progression for more than a year.

The phase II study, called TOPARP-B, was led by researchers at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, and involved several other institutions in the UK.

The results were presented at the American Association of Clinical Oncology (ASCO) Annual Meeting and show the benefits of olaparib for men with DNA repair defects in their tumours.

A phase III trial of the drug is under way and researchers hope the treatment will reach patients within the next two years.

Delayed cancer progression

Olaparib targets cancer cells that aren’t able to properly repair their DNA. The researchers wanted to look at how effective the drug was in men with mutations in any genes known to have a role in repairing DNA – including BRCA1 and 2.

Overall, 47 per cent of men with DNA repair defects in their tumours responded to olaparib, and the drug delayed progression for a median of 5.5 months – 2.7 months longer than previous trial TOPARP-A found in men with advanced prostate cancer who weren’t selected for treatment based on gene mutations.

The trial received funding from AstraZeneca, Cancer Research UK, the Prostate Cancer Foundation, Stand Up To Cancer, Prostate Cancer UK and the Movember Foundation. It was supported by the NIHR Biomedical Research Centre at The Royal Marsden and The Institute of Cancer Research (ICR), and the Experimental Cancer Medicine Centre (ECMC) network.

PALB2 mutations

The researchers initially screened the tumours of 592 men and found 27 per cent had alterations in one or more genes linked to repairing damaged DNA. After screening and evaluation, they enrolled 98 patients with DNA repair mutations onto the trial.

BRCA mutations were by far the most common mutation – found in 33 per cent of the tumours with a DNA repair mutation. Other common DNA repair mutations were the genes ATM, CDK12, CHEK2 and PALB2.

Some 57 per cent of patients with mutations in the PALB2 gene responded to olaparib – the next highest response after those with BRCA1 or BRCA2 mutations.

The trial results follow a recent announcement by the ICR of a £15 million fundraising drive to complete a new £75 million Centre for Cancer Drug Discovery focusing on overcoming cancer evolution and drug resistance.

The versatility of olaparib

Olaparib is the first of a new class of drugs called PARP inhibitors which are underpinned by the work of ICR scientists, who showed that the drugs work best in cancers with weaknesses in repairing their DNA.

Olaparib was the first cancer drug to reach the market targeted against an inherited genetic fault – initially licensed and approved by NICE for women with ovarian cancer who had inherited BRCA mutations, and now also licensed for breast cancer.

Studies have also shown it is effective against cells with different DNA repair defects, and not just in inherited mutations but also those in the tumour itself.

Professor Johann de Bono, Regius Professor of Cancer Research at The Institute of Cancer Research, London, and Consultant Medical Oncologist at The Royal Marsden, said:

“Our study is exciting because it shows just how powerful genetic targeting and precision medicine can be. We have shown that by testing for DNA repair mutations we can select those patients with a high chance of responding well and for a long time to the targeted drug olaparib.

“We were delighted to see such strong responses in men with very advanced cancers, where BRCA mutations and other faults in DNA repair genes were present within their tumours. The next phase of the trials is now under way and, if the results look as good as we hope, we should see olaparib starting to reach the clinic for men with prostate cancer in the next couple of years.”

Exciting new treatments for prostate cancer

Dr Nuria Porta, Principal Statistician on the TOPARP-B trial in the Clinical Trials and Statistics Unit at The Institute of Cancer Research, London, said:

“Our trial shows that PARP inhibitors could be effective in some men with prostate cancer – potentially widening out their use beyond ovarian and breast cancer.

“We also found that these drugs could be effective in men with several different DNA repair mutations, and in men with genetic faults in their tumours rather than just the smaller group of men with inherited mutations.

“We now very much look forward to the results of the phase III trial, which could pave the way to olaparib becoming the latest in a clutch of exciting new treatments for prostate cancer, and the first for the disease to be gene targeted in this way.”

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