Emma Foreman, The Royal Marsden NHS Foundation Trust
Enzalutamide is an effective and well-tolerated treatment for advanced prostate cancer that has become resistant to hormone therapy. Unfortunately however, enzalutamide can sometimes interact with other medicines that the patient is taking, altering their concentration in the blood-stream. Enzalutamide can do this in two ways: either by increasing the breakdown of a medicine, or by blocking a special protein, called p-glycoprotein, that pumps it out of the body. An example of a medicine whose breakdown is increased by enzalutamide is warfarin.
Warfarin is used to prevent, and treat blood clots that have formed in the deep veins of the legs (deep vein thrombosis or DVT) or have become lodged in blood vessels in the lungs (pulmonary embolism or PE). As enzalutamide is known to reduce the effect of warfarin, the manufacturer advises avoiding using the two medicines together. Instead, we can use a new class of medicines called the direct oral anticoagulants, or DOACs. DOACs have an additional advantage over warfarin in that they do not require regular monitoring with blood tests.
We, and other experts in the field believe that there may be a problem using DOACs and enzalutamide together however. Scientific evidence suggests that enzalutamide may stop the p-glycoprotein pump from working properly, and alter its ability to pump out a range of medicines. Other evidence suggests that under certain conditions, enzalutamide may actually increase the activity of P-glycoprotein, and reduce the concentration of other medicines in the bloodstream. However, there is no scientific evidence, or evidence from patients, that has looked directly at the combination of enzalutamide and DOACs together. Because no routine monitoring is carried out with DOACs, we are not sure of the extent of this problem, but the consequences of over or underdosing could be serious. We have recently generated some preliminary data in our laboratory which has the measured the extent of this interaction. But, we need to repeat these experiments before we can draw any firm conclusions from them.
In this pilot study, we would like to explore the potential interaction between enzalutamide and DOACs. First, we plan the measure the activity of DOACs in patients who are due to start treatment with enzalutamide using a simple, well established blood test. We would then repeat this blood test after the first month of treatment, along with regular blood tests, to determine if there has been a change in the effectiveness of the DOAC. Second, we aim to build upon our laboratory data, and examine whether brief, or prolonged exposure to enzalutamide affects the ability of p-glycoprotein to pump out DOACs.
Our aims are to 1) determine if enzalutamide interacts with DOACs in patients recruited from an advanced prostate cancer clinic, 2) understand in greater detail the nature of any interaction between enzalutamide and DOACs in the laboratory, and 3) assess the feasibility of expanding this study to generate sufficient evidence to make recommendations for clinical practice.
This project is running from March 2019 to February 2020.