Effect of a Reduced Dose Enzalutamide in Frail (m)CRPC Patients on Cognitive Side Effects
Status:
Recruiting
Trial end date:
2021-12-01
Target enrollment:
Participant gender:
Summary
Prostate cancer is the most commonly diagnosed cancer among men in Western countries. When
the disease recurs as castration-resistant prostate cancer (CRPC) it is associated with a
median overall survival of approximately 2 years with significant decrement in quality of
life due to additional cancer-specific and treatment-induced morbidity. Palliative agents
currently used in the CRPC setting include the 2nd generation hormonal agents abiraterone
acetate and enzalutamide but also radium-223, docetaxel and cabazitaxel. Choices for
treatment strategies are based on multiple factors such as age, co-morbidity and drug
toxicity profile. The side effect profile of enzalutamide is associated with central nervous
system (CNS side effects) such as fatigue and depression. The mechanism for these side
effects is not yet fully understood, but it was shown in rodent studies that enzalutamide and
its active metabolite penetrate into the CNS. This might cause the CNS side effects that were
later seen in the phase 1 study where fatigue was found to be a dose-dependent adverse event.
After dose reductions the symptoms resolved. This was also found in a retrospective study of
Japanese metastatic CRPC (mCRPC) patients (n=345) in which the side effects malaise and
nausea decreased remarkably after dose reduction. However, no exposure-response relation was
observed in the study of Gibbons et al. Additionally, based on the data of the phase 1 trial
of enzalutamide it can be suggested that a minimum trough concentration of 5.0 mg/L could be
considered as a target for exposure to enzalutamide. In particular, frail (m)CRPC patients
are more prone to develop CNS side effects on enzalutamide. The investigator's hypothesis is
that dose reduction to 75% (120mg) can be safely done to treat (m)CRPC in these patients with
preserving optimal efficacy and less CNS side effects.