More men with advanced prostate cancer could be successfully treated with precision drug olaparib

• PARP inhibitor drugs, such as olaparib, have transformed treatment for some men with prostate cancers caused by BRCA1 and BRCA2 mutations in recent years

• New research shows they could be used to treat other groups of men with advanced prostate cancer who have lost DNA repair protein RNASEH2B in some of their cancer cells

• Study found RNASEH2B loss was common - 44 per cent of men had lost RNASEH2B in at least half of their cancer cells.

• Some patients with RNASEH2B loss who were treated with olaparib, benefitted from long relapse-free survival despite not having a BRCA1/2 mutation

Scientists have discovered a genetic aberration found in some prostate cancers that could allow more men to be successfully treated with an existing targeted drug.

A team from The Institute of Cancer Research, London found that cancer cells which have ‘lost’ DNA repair protein RNASEH2B are killed when treated with a type of drug called a PARP inhibitor, according to the findings of a study published in the Journal of Clinical Investigation.

The RNASEH2B gene plays a role in repairing certain forms of DNA damage and when it is deleted or ‘lost’ during cell division or replication, it no longer functions as it should.

The Institute of Cancer Research (ICR) team hope that the discovery will mean that olaparib, a type of PARP inhibitor, which has transformed the treatment of some men with prostate cancers caused by BRCA1 and BRCA2 and ATM mutations, could be used to treat other groups of men with advanced prostate cancer.

The research received funding from AstraZeneca, Prostate Cancer UK, Cancer Research UK, the Medical Research Council, Movember and the Prostate Cancer Foundation.

Prostate cancer is the second biggest cancer killer of men in the UK, taking around 12,000 lives a year. Up to 30 per cent of men with advanced disease have tumours with defects in repairing DNA, some of which respond well to PARP inhibitor drugs.

Earlier research has suggested that olaparib may be successful in treating more men with prostate cancer and identified the RNASEH2B gene as a possible target.

For this study, the researchers looked at biopsies from 124 patients with advanced prostate cancer. The results showed that RNASEH2B loss was common – 44 per cent of patients had loss in at least 50 per cent of their cancer cells. A fifth (20 per cent) of patients had RNASEH2B loss in 75 per cent of cancer cells.

The researchers also evaluated both pre- and post-treatment biopsy samples from patients without BRCA1 and BRCA2 mutations who had taken part in the TOPARP-A and TOPARP-B clinical trials, which were managed by the ICR’s Clinical Trials and Statistics Unit (ICR-CTSU) and led by clinical researchers from the ICR and The Royal Marsden NHS Foundation Trust.

They found that the number of cells with RNASE2B loss decreased in 13 out of 18 patients following PARP inhibitor treatment.

Six of these patients also saw a decline in their circulating tumour cells, known as CTCs, which can show whether someone is benefitting from treatment. Three of those patients benefitted from relapse-free survival of between eight and 22 months, despite not having a BRCA1 or BRCA2 mutation.

Scientists at the ICR were the first to demonstrate that cancer cells with mutations in BRCA1 or BRCA2 were highly susceptible to PARP inhibitors like olaparib. Researchers from the ICR and The Royal Marsden then led clinical trials that showed olaparib was effective against a range of cancers associated with BRCA1 or BRCA2 mutations.

These new findings should lead to further trials of olaparib in prostate cancer to explore whether this drug could be targeted at a larger patient population by identifying people with RNASEH2B aberrations.

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

“We have identified a genomic aberration that is found in some prostate cancers that makes them very vulnerable to a targeted cancer drug, called a PARP inhibitor, which comes in pill form and has much fewer side effects than chemotherapy.

“This is a substantial advance, building on earlier research that demonstrates that the number of patients that benefit from this class of novel treatments could be expanded, improving the overall survival and quality of life in a greater number of men. This is the first time this has been shown in prostate cancer. “Further research is urgently needed to validate these findings and the tests that would identify tumours sensitive to PARP inhibitors beyond BRCA gene mutations so we can provide a new treatment option for patients with advanced prostate cancer.”

Professor Kristian Helin, Chief Executive of The Institute of Cancer Research, London, said:

“Precision medicines targeted to specific genetic faults are transforming treatment for many cancers, including prostate cancer. However, we currently don’t yet have the full picture of who exactly will respond to a particular drug and who won’t.

“A lot of work is needed to try and find out what underpins that response. So, it is very exciting to see these results which are helping to identify a wider group of men with advanced prostate cancer, who may be able to benefit from longer relapse-free survival and better quality of life.”

Dr Hayley Luxton, Research Impact Manager at Prostate Cancer UK, said:

“Each man is unique – and so is his prostate cancer – which is why targeted treatments like PARP inhibitors are so important.  

“These drugs have already begun to revolutionise the way we treat cancer, moving us away from the old ‘one-size fits all’ approach, and what’s important now is to figure out exactly who will benefit the most.  

“We already knew that these drugs helped men with mutations in specific genes like BRCA, and this exciting research shows they could also benefit a completely different group of men whose cancer cells have lost a novel marker called RNASEH2B. 

“We’re proud of the role we played in funding this research, which is a result of a bespoke funding scheme we designed to deliver breakthroughs exactly like this one. “We now look forward to future research that will identify how we can test for this and make these life-extending drugs available to even more men.”