Approximately 1 in 8 men¹ will be diagnosed with prostate cancer, often at a late stage. Olaparib is a type of targeted cancer drug, known as a PARP inhibitor, and is used to treat patients with advanced prostate cancer who carry mutations in DNA repair genes, however, after a while the cancer becomes resistant to the treatment, and it continues to grow. The length of time that patients respond to this treatment varies greatly and there was little understanding as to why this is.  

Scientists based at the ICR have recently published their research looking for a way to use an understanding of treatment resistance to anticipate which prostate cancer patients will benefit from olaparib and for how long. The researchers identified two main mechanisms behind resistance to olaparib. First, they demonstrated that cancer cells can reverse mutations in their DNA repair genes, specifically BRCA2 or PALB2. This reversal restores the cells' ability to repair DNA, rendering them no longer sensitive to olaparib's effects. Second, they found that in some patients, a small subset of cancer cells without these mutations already exists. When the majority of cancer cells die off, this resistant population takes over. Remarkably, both of these resistance mechanisms can be detected in a patient’s blood by analysing circulating tumour DNA fragments and sequencing them.  

his breakthrough means that with the right technology, clinicians can monitor how well a patient is responding to treatment and predict when resistance begins to develop. This approach could lead to timely adjustments in treatment, avoiding unnecessary therapies and significantly improving patient survival and quality of life. 

This work was partly funded by the CRUK Convergence Science Centre through our strategic investment in the Drug Development Unit at the ICR and Royal Marsden Hospital. 

More information is on the ICR website. Read the full paper in Cancer Cell.

Image credit: Johann de Bono and Mateus Crespo