We presented results from a randomised dose expansion part of a phase I study that was looking at treatment with mevrometostat, an EZH2 inhibitor, in combination with enzalutamide. In this randomised expansion part of the trial we compared that to enzalutamide monotherapy as the control arm.
What was the study design?
This, again, was a randomised controlled trial. We enrolled patients with metastatic castrate-resistant prostate cancer who had progressed on abiraterone previously. We did allow patients to receive up to one prior line of chemotherapy prior to enrolling. All patients who were eligible were maintained on androgen deprivation therapy then randomised 1:1 between either mevrometostat, 1250mg by mouth twice daily on an empty stomach, plus enzalutamide versus enzalutamide alone.
The primary endpoints were radiographic progression free survival and safety. We also looked at overall radiographic responses and also PSA50 responses which would be declines of PSA of 50% or greater from baseline.
What were the results of this study?
The bottom line is this was a positive trial. In terms of the primary efficacy analysis we saw that there was an improvement in radiographic progression free survival with the addition of mevrometostat to enzalutamide. Overall, the median rPFS with the mevrometostat plus enzalutamide was observed to be 14.3 months compared to only 6.2 months with the enzalutamide alone. This equated to a 49% reduction in the risk of progression or death.
What is the clinical significance of these results?
These results support preliminary efficacy for the combination of mevrometostat plus enzalutamide and have justified two pivotal phase III studies which are currently ongoing. MEVPRO-1 is a randomised phase III trial looking at treating with mevrometostat plus enzalutamide plus either enzalutamide or docetaxel based on the treating provider’s preference as well as the patient’s choice. This would be in a population who have already progressed on abiraterone.
The second study, MEVPRO-2, is evaluating mevrometostat plus enzalutamide versus enzalutamide in patients who have not been exposed to prior abiraterone or other androgen receptor pathway inhibitors.
Please discuss the safety data?
In terms of the safety of the combination, we did see that the majority of patients in both arms actually had at least one treatment emergent adverse event. There were more treatment related serious AEs in patients receiving the combo, however. When looking at the specific treatment emergent adverse events that occurred, a lot of them were actually due to GI toxicity, including things like diarrhoea, nausea and decreased appetite.
As part of the study we also conducted a food effect cohort analysis to look at the PK when lower dose mevrometostat was given along with food as opposed to the higher dose on an empty stomach that we tested in the randomised portion of the trial I just mentioned. Overall, we did find that mevrometostat at a lower dose, 875mg twice daily with food, had essentially identical pharmacokinetic profile to the higher dose on an empty stomach but, importantly, this showed better tolerability with decreased GI toxicity in general. Because of this analysis we’re using the lower dose of mevrometostat with food as the dose that’s being tested in our phase III trials.
