Data on medroxyprogesterone and enzalutamide/enzalutamide in castration-resistant prostate cancer

This study focuses onMevrometosat (PF-06821497), a novel drug that acts as an enhancer of Zister homolog 2 (EZH2), and aims to evaluate its interaction withEnzalutamide/Efficacy and safety of enzalutamide (Enzalutamide) combination treatment in patients with metastatic castration-resistant prostate cancer cancer (mCRPC). The study is part of a larger Phase 1/2 clinical trial, specifically the randomized dose expansion portion, designed to gain insight into the role of Mevrometosat in these patients and compare it to standard treatment.

1. Experimental design

The study was designed using a randomized, dose-expansion approach to provide reliable data support when testing the combined effect of the EZH2 inhibitor Mevrometosat and enzalutamide. Patients were included in the study if they had progressed on prior abiraterone therapy, had clear evidence of disease progression, and were able to receive no more than one cycle of chemotherapy. Eligible patients were randomly assigned in a 1:1 ratio to receive either Mevrometosat (1250 mg, taken on an empty stomach) or the approved dose of enzalutamide, or a control group taking enzalutamide alone.

The study's primary endpoints include radiographic progression-free survival (rPFS) and safety. In addition, the study evaluated objective radiographic response rate and PSA50 response (i.e., a decrease in PSA of 50% or more). These endpoints were selected to comprehensively assess the efficacy and potential risks of Mevrometasat combined with enzalutamide.

2. Key findings

From the primary efficacy analysis, the study had positive results. In terms of radiographic progression-free survival, the median rPFS of Mevrometosat combined with enzalutamide was 14.3 months, which was significantly better than the median rPFS of only 6.2 months in the enzalutamide group. This result showed that the combination treatment was able to reduce the risk of progression or death by 49%, while bringing a significant benefit of an overall improvement in median rPFS of 8 months.

Additionally, studies have shown promising signs of efficacy in terms of objective radiographic response rates. Most acceptedPatients treated with Mevrometosat in combination with enzalutamide experienced a reduction in target lesion volume, with an objective radiographic response rate of 26.7%, compared with 14.3% in the enzalutamide group. At the same time, 34.1% of patients experienced a decrease in PSA levels of 50% or more after receiving combination therapy, which was better than the enzalutamide single-agent group, which provides more support for this new treatment option.

3. Security analysis

Regarding safety, patients in both groups experienced at least one treatment-related adverse event. A higher proportion of patients experienced serious adverse events in the combination group, but reassuringly, few patients discontinued treatment due to adverse events. The main adverse events observed were mostly related to the gastrointestinal tract, including diarrhea, nausea, and decreased appetite, and were more common in the mevastatin plus enzalutamide group.

It is also worth noting that this study also included a cohort that looked at the effect of food. The researchers looked at the impact of giving a lower dose of Mevrometosat (875 mg twice daily) with food. This strategy was better tolerated and reduced the incidence of gastrointestinal toxic events by approximately half compared with patients taking 1,250 mg on an empty stomach.

Taking into account the above study results,The combination treatment of Mevrometosat and enzalutamide has demonstrated good efficacy and acceptable safety, and is paving the way for further clinical development. Currently, the research team is conducting two Phase 3 clinical trials to continue testing the 875 mg food dosing regimen based on improved safety and similar pharmacokinetic (PK) characteristics.

References:https://www.urologytimes.com/view/michael-schweizer-md-shares-data-on-mevrometostat-plus-enzalutamide-in-mcrpc