This week’s results offer a brand-new precision treatment option for a group of men with particularly aggressive forms of advanced prostate cancer.

Scientists in a lab
2 Oct 2019

Precision medicine is an exciting and effective approach to cancer care that uses information about the genetics of a man’s tumour to work out the best treatment for him.

New research presented at the ESMO conference this week is the final piece of the puzzle to show the drug olaparib (Lynparza) could be the first-ever precision medicine treatment for prostate cancer.

The drug is part of a class of drugs called PARP inhibitors, which target defects in cancer cells' ability to repair damage to their DNA. Recent results from a new study have shown that Olaparib could delay the progression of advanced prostate cancer for over four months. Crucially, the men who responded all had mutations in one of 15 genes in their prostate cancer, including BRCA. 

It marks a landmark achievement in treating advanced prostate cancer. But this breakthrough didn’t happen overnight. It's the result of two decades worth of research, funded by you, to unpick the genetics behind prostate cancer to create new precision treatments.

Here’s a deep dive into how we got to this incredible milestone.

Lab studies to lives saved: how you’ve helped create the first precision medicine for prostate cancer

1990s: Researchers discover BRCA genes increase cancer risk

The cells in our body undergo a daily cycle of DNA damage and repair. In a normal day, the DNA in each cell can be damaged between 1,000 and 1,000,000 times. Luckily, we've evolved ways to either repair the DNA or destroy the 'broken' cells.

In the mid-90s, researchers identified the genes BRCA1 and BRCA2, which are an important part of this repair process. Faults, or mutations, in these genes reduce cells’ ability to repair the daily onslaught of DNA damage. This means that mistakes can start to build up in the DNA, which increases the chances of the cell becoming cancerous.

Scientists knew that mutations in the BRCA genes were associated with increased risk of breast or ovarian cancers, but their influence in other cancers was unknown.

In 1999, an international group of researchers discovered that BRCA gene mutations also increased the risk of getting other cancers, including prostate cancer. Nobody knew how common these mutations were in men with prostate cancer, or how to find the men affected. 

2002: Investigating the scale of the problem

With your donations, we part-funded research carried out by Professor Ros Eeles and her team at the Institute of Cancer Research (ICR) in London, which gave us the first insight into the importance of BRCA mutations in prostate cancer. This revealed that two percent of men diagnosed with prostate cancer before the age of 55 had a BRCA gene mutation.

2009: Understanding the link between prostate cancer and BRCA 

With your support, we funded Professor Thomas Helleday at the University of Sheffield and Professor Freddy Hamdy at the University of Oxford to explore what effect BRCA mutations might have on prostate cancer cells. They found that a BRCA mutation disabled one method prostate cancer cells' use to repair damage to their DNA, meaning they resorted to another method using the PARP protein. This led scientists to realise that the drug Olaparib, which inhibits the PARP protein, could be an effective treatment for men with prostate cancer and a BRCA mutation. 

2012-2015: Shifting focus to advanced prostate cancer

In 2012, Professor Ros Eeles' group at ICR, again part funded by Prostate Cancer UK, showed that only 0.5 - 1 percent of all men newly diagnosed with prostate cancer at any age had an inherited BRCA gene mutation.

Then in 2015, an international team of researchers, led in the UK by Professor Johann de Bono at the ICR, discovered that if we looked for these mutations in men with advanced prostate cancer only, rather than any prostate cancer - BRCA, and other DNA damage repair mutations were far more common. In fact, over 19 percent of men with hormone-resistant prostate cancer that has spread around the body had a mutation in either a BRCA gene, or another DNA damage repair gene called ATM.

More importantly, by comparing the DNA in a man’s cancer with that in his blood, they were able to tell that not all of these mutations had been inherited. Many of them had developed spontaneously in the cancer. Together, these results meant that far more men than previously suspected were likely to benefit from treatment with a drug like Olaparib.

2014 - 2019: Finding the men who respond to Olaparib

A new trial called TOPARP was cleverly designed to test Olaparib in men with prostate cancer. The  first stage tested Olaparib in all men with advanced disease to see if enough responded to make it worth taking further. The result of that first stage was that around 30% of men seemed to get benefit from taking olaparib and so, together with The Movember Foundation, and the Medical Research Council we funded Dr Joaquin Mateo, a Clinical Training Fellow in Professor de Bono’s lab to do the crucial next stage of work.

Your funding was critical to build a platform that allowed testing of prostate cancer patients from across the UK. That was huge. This allowed us to start selecting patients who would benefit from treatment. It also allowed us to test different scenarios (for example tumour metastases, tumour biopsies, diagnostic biopsies, and plasma) to work out the best ways to test and select men in future.

- Dr Mateo

 

From that work Joaquin and Johann worked out that the men who responded were those who had certain mutations in DNA damage repair genes, including BRCA, as Professor Helleday's work had suggested. They then developed a test to find the men who had those mutations, the men most likely to respond to Olaparib.

2019: Making it global

The test developed by Joaquin and Johann, and funded by you, enabled a trial called TOPARP-B to trial Olaparib on a selection of men with advanced hormone-resistant prostate cancer, who also had a mutation in a DNA damage repair gene. This was the first precision medicine trial for men with prostate cancer in the world.

This trial revealed that Olaparib works better for men with certain DNA damage repair mutations. The results were positive enough to suggest that AstraZeneca, the pharmaceutical company that owns Olaparib, should test Olaparib in a Phase III trial. This type of large scale international clinical trial is big enough to provide the evidence that health regulators need to recommend a drug for widespread use. They’re also extremely expensive, so can normally only be run by pharmaceutical companies.

In this new international trial, called PROfound, doctors took biopsies from men with advanced prostate cancer across the world and tested the tumour for DNA damage repair gene mutations. The results, published last week, showed Olaparib to be effective in men with advanced prostate cancer who had one of 15 genetic mutations in their prostate cancer.

Thank you, for helping to make breakthroughs in treating prostate cancer possible

These results represent a giant leap forward for men with prostate cancer. A leap we’ve been building towards since 2014, with your support, through research funding and behind-the-scenes work.

With your help we’re moving from a one-size-fits-all approach to treating advanced prostate cancer to a much more effective approach where drugs target the genetic drivers of an individual’s cancer. Thanks to you Olaparib is ready to blaze a trail for future precision medicines of this kind.

This is by no means the end of the story. There’s still plenty of work to do to ensure that all the men who can benefit from drugs like Olaparib can get access. We will continue to champion the use of Olaparib, through working with the relevant pharmaceutical company, healthcare regulators, researchers and men to make sure this happens. 

Help develop our precision treatment programme by donating today.

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