Finding ways around treatment resistance

Finding ways around treatment resistance

“My PSA had been going up a bit over a period of a few months, but then it started to jump up quite rapidly. That’s when we did the scan to check if the cancer had spread and it was clear that after five and half years that the abiraterone was no longer working for me.”

Alan Oliver regards himself as one of the lucky ones. Diagnosed at the age of 56 with advanced cancer, he was initially given hormone therapy and when that stopped working, his doctor offered him a brand-new drug for men in his situation – abiraterone.

Abiraterone is a wonder drug for some men, like Alan, but for others it can mean they lose vital months taking a treatment that isn’t working for them. That’s because most men’s cancers at that stage are either already resistant to the drug or quickly become so.

For the past ten years, we have been working to find out why this happens.

Researchers designed abiraterone to stop the production of the hormone testosterone, which encourages prostate cancer cells to grow by activating a protein known as the androgen receptor. A large-scale trial that showed it could reduce deaths by a third, led by Professor Johann de Bono.

We awarded a grant of £143,000 to Professor Johann de Bono in 2008, which discovered that resistance could develop in lab-grown cells through mutations in the androgen receptor. These mutations meant the receptor was activated by a wide range of hormones, not just testosterone – like damaging a lock so that a number of different keys can open it.

“The important thing for us is that if you understand what causes resistance, then you can also understand how to treat the patients who are progressing on abiraterone with better drugs,” says Professor de Bono. “We have many other drugs that we are testing that we can try when abiraterone is failing. By understanding what causes the resistance, we can get better at developing new treatments that can make a difference.”

The results from this early research suggested that treatment resistance could be overcome by combining abiraterone with another drug, enzalutamide, which also targets the androgen receptor. This combination approach is currently being tested in men as part of the STAMPEDE clinical trial.

After understanding what happens in cells grown in the lab, we provided another grant of £248,000 to this lab in 2009 to study samples from men who weren’t responding to abiraterone. Using blood samples, they developed a technique to extract tumour cells circulating in the bloodstream and sequence their DNA, known as a ‘liquid biopsy’.

Selecting the right men

This research helped to understand the changes that protect the cancer against the effects of abiraterone. By looking for these changes in the cancer’s DNA, the researchers hoped to predict the effect of abiraterone.

“We believe we have a better understanding of which patients will respond to abiraterone and which will not. And if we can confirm that in ongoing studies we believe that this will help us to select which patients should receive abiraterone and which shouldn’t. This will help us to understand how abiraterone works and who will benefit from it,” says Professor Johann de Bono. “Without the support of Prostate Cancer UK we wouldn’t be where we are today.”

In 2013, we awarded £246,000 to Dr Gerhardt Attard, who worked alongside Professor de Bono on abiraterone, to identify which men would benefit from the drug. He found that patients with changes to the androgen receptor are less likely to benefit from abiraterone.

He recalls one patient in particular: “His PSA level initially dropped over 90 per cent, but soon after that his disease rapidly started to get worse. He became very unwell and died shortly after, before he could have any other treatment. We collected blood samples from him as part of the study, and analysed them afterwards. We realised that he had one of the changes in the androgen receptor gene that meant he was resistant to abiraterone.”

That man was one of 97 patients that Dr Attard and his team studied to develop a blood test. This test checks cancer DNA that is circulating in the blood, which allows doctors to understand what is happening in each individual man’s cancer.

This research allowed him to narrow down their search to just two key changes to the androgen receptor. They found that men with either of these changes were five times less likely to have a good response to abiraterone treatment.

Currently, it can take 12 weeks to see if a man’s cancer is responding to treatment – time that a man with advanced cancer cannot afford to waste taking a drug that isn’t working for him. With this new test, we hope to buy more time for him.

Not only could this help men to avoid taking a drug that wouldn’t benefit them, it could also save money for the NHS. This test was designed to cost less than £50, compared to more than £2000 for a month of abiraterone.

This exciting blood test has recently received a lot of attention as it could allow – for the first time – a personalised, precision approach to treatment based on the genetic makeup of each man’s cancer.

Before this test can be used by doctors, it needs to be confirmed in a trial to see if it can help men to live longer by switching them to a more suitable treatment if they appear resistant to abiraterone. In 2016, we awarded £859,000 to Dr Attard to carry out this trial, known as PARADIGM.

If this is successful, Dr Attard hopes that by the end of the trial they will have collected all the scientific data necessary to persuade health regulators to make this test available to all men with hormone resistant prostate cancer, so that doctors can work out which treatment route would be most beneficial for them.