Genetic clues foretell olaparib resistance for prostate cancer patients
Researchers have devised a way to predict how long advanced prostate cancer patients will respond to olaparib.
A team from The Institute of Cancer Research (London, UK) has developed an approach to predict resistance to the PARP inhibitor Lynparza® (olaparib) for metastatic castration-resistant prostate cancer patients. This deepened understanding of the mechanism of olaparib resistance combined with the ability to foresee its effectiveness, could enable clinicians to switch to alternative therapies sooner.
PARP inhibitors have transformed treatment for advanced prostate cancer, however, the length of time that patients respond to them varies widely. The drug will eventually stop working for all patients, resulting in recurrence.
Previous research has demonstrated that reversion mutations, the process of restoring function back to the already mutated genes so they can repair DNA, may be the mechanism by which resistance to olaparib is developed.
In this study, researchers analyzed circulating tumor DNA (ctDNA) from blood samples of 25 metastatic castration-resistant prostate cancer patients who partook in the Phase II TOPARP-B trial and uncovered a clear link between the number of reversion mutations a patient had and how long they survived.
It was observed that after just 4 months of olaparib treatment patients who with a high number of reversion mutations had an average survival time of 13.9 months, compared to 21.4 months for those with a lower number of these mutations.
The team also uncovered an intriguing link between resistance and BRCA genes. Those patients who initially were missing BRCA2 gene, regained this gene after olaparib treatment, swiftly resulting in resistance to olaparib.
Lead author, Johann de Bono commented: “PARP inhibitors have transformed advanced prostate cancer care, but we need to stay one step ahead to prevent resistance developing.(…) In time, I expect to see the development of drugs targeting these tumor adaptations, so that we can personalize treatment to patients and give them longer and better-quality lives.”