09 February 2016

By Dr Wendy Winnall - PCFA Research Team

There is good news for prostate cancer patients in a recent announcement. The US Food and Drug Administration has granted "breakthrough therapy designation" to a drug being tested for metastatic prostate cancer. The drug, known as Olaparib or LynparzaTM, is already being used to treat ovarian cancer patients. The breakthrough designation means that its assessment as a prostate cancer therapy will be fast-tracked through the FDA system. This designation has been granted due to the very promising results from phase II clinical trials of Olaparib in prostate cancer patients.

Men with metastatic castration-resistant prostate cancer (mCRPC) are unfortunately faced with limited treatment options. They are often prescribed drugs such as abiraterone or enzalutamide, but many patients develop resistance to them. New drugs for these patients are desperately needed. Olaparib, a drug used by ovarian cancer patients, targets cancer cells that have defective DNA-repair genes. Since many metastatic prostate cancers also have the same DNA-repair problems, Olaparib may a good treatment for these men.

The DNA in our cells is constantly being damaged during cell division and by the environment. To fix this damage, there is a continual process of DNA-repair going on inside each cell. A team of proteins scans the DNA, looking for damage and fixing it. It's common for this process to be faulty in cancerous cells. Defects in the DNA-repair process allows DNA damage to increase, which helps the cancer to change and evolve. This isn't helpful at all, it means the cancer can spread and become resistant to drugs.

The way by which Olaparib kills cells with defective DNA-repair is oddly counterintuitive. Olaparib inhibits the action of a protein called PARP. PARP actually repairs DNA defects. It scans the DNA double helix for mistakes, seen in the picture above. So why would we want to stop that process? It turns out that if you stop PARP working, you get so many breaks in the DNA that the cell cannot repair them and it dies. This only works in cells that already have DNA-repair defects, so the normal, non-cancerous cells are not badly affected. It's an ingenious and elegant way to target cancer cells whilst protecting normal cells.

A 2015 phase II clinical trial, called TOPARP-A, showed that many mCRPC patients who became resistant to the other drugs, responded to Olaparib. The drug clearly worked best in men whose cancers had defective DNA-repair genes. 88% of these men responded to Olaparib. Unfortunately all the men in the trial succumbed to their cancer, but those with defective DNA-repair genes that took Olaparib (after developing resistance to the other drugs) lived for an average of 14 months. Those who took Olaparib but did not have defective DNA-repair only lived for 7.5 months. Olaparib is a targeted therapy; it will only help those whose cancers have defective DNA-repair genes. In the TOPARP-A trial, this was 33% of the men who took part.

Olaparib will need to be tested in phase III clinical trials. These are large-scale trials on thousands of patients at multiple sites. This process is lengthy, but the breakthrough status is designed to make it faster. We are all hoping that Olaparib is as effective for prostate cancer as it is for ovarian cancer.