Michael Schweizer, MD, Fred Hutchinson Cancer Center, Seattle, Washington, discusses results from a dose-expansion study which demonstrated that the addition of mevrometostat to enzalutamide improved outcomes compared to enzalutamide alone among patients with metastatic castration-resistant prostate cancer (mCRPC). 

Dr Schweizer commented if ongoing phase 3 studies evaluating mevrometostat plus enzalutamide are positive, “the hope is that this would eventually become a reasonable standard of care for patients with early metastatic castrate-resistant prostate cancer.”

These results were presented at the 2025 ASCO Genitourinary Cancers Symposium in San Francisco, California. 

Transcript:  

Hi, my name is Mike Schweizer, I'm a medical oncologist and associate professor here at the University of Washington, Fred Hutch Cancer Center. This past ASCO GU, we presented research on the use of mevrometostat, an EZH2 inhibitor, in combination with enzalutamide for patients with metastatic castrate-resistant prostate cancer. 

Just as background, EZH2 is an epigenetic enzyme that is overexpressed in castrate-resistant prostate cancer and has been implicated in promoting lineage plasticity and resistance to androgen receptor pathway inhibitors in general. Mevrometostat inhibits EZH2 based on this data, showing that this was a potential target in prostate cancer. Prior dose exploration of mevrometostat plus enzalutamide showed that it had a generally manageable safety profile on target PD inhibition of EZH2 and showed preliminary evidence of clinical activity. At the past ASCO GU meeting, we presented results from a randomized dose-expansion part of this study, as well as data on the food effect on mevrometostat’s pharmacokinetic profile. 

In terms of the randomized dose-expansion study, we presented results testing mevrometostat in combination with enzalutamide versus enzalutamide alone. Patients had to have metastatic castrate-resistant prostate cancer that previously progressed on abiraterone, up to 1 line of prior chemotherapy was allowed, and all patients maintained on androgen deprivation therapy. Randomization again was to mevrometostat at a dose of 1250 mg by mouth twice daily on an empty stomach plus enzalutamide versus enzalutamide alone. The primary end points of the study were radiographic progression-free survival (rPFS) and safety. We also looked at objective radiographic responses and PSA50 responses, which is defined as a decline of 50% or more in PSA from baseline. In terms of the baseline characteristics on the study, these were generally well matched, although there were more patients with ECOG performance status 1 at baseline enrolled to the enzalutamide monotherapy arm. 

In terms of the primary objective of the study, we did see that there was a strong efficacy signal with the combination of mevrometostat plus enzalutamide, with a median radiographic progression-free survival with the combination at 14.3 months which compared favorably to what we saw with enzalutamide monotherapy which was only a median rPFS of 6.2 months. This equated to a 49% reduction in the risk of progression or death with the use of the combination. 

In terms of responses, the majority of patients with measurable disease at baseline responded to the combination of mevrometostat and enzalutamide with an objective radiographic response rate of 26.7%. Enzalutamide monotherapy on the other hand, was demonstrated to have an objective radiographic response rate of 14.3%. Likewise, the majority of patients also had declines in PSA with the combination with a PSA50 response rate of 34.1% compared to a PSA50 response rate of 15.4% with enzalutamide monotherapy. 

In terms of safety, we found that the majority of patients in both treatment arms had at least 1 treatment-emergent adverse events. There were more serious treatment-related adverse events with mevrometostat plus enzalutamide however, it's notable that almost nobody came off the study on either arm due to toxicity. Looking at the most common treatment-emergent adverse events, the combination was associated with more GI toxicity specifically including things like diarrhea, nausea, and decreased appetite. 

As part of this study, we also did a report on the food effect cohort, looking at treating with a lower dose of mevrometostat at 875 mg along with food as opposed to the higher dose of mevrometostat that was tested on an empty stomach in the randomized study I just discussed. Overall, we found that treating at lower dose with food resulted in comparable pharmacokinetic profile to the higher dose on an empty stomach but importantly, low dose mevrometostat with food was associated with better tolerability in general, specifically showing fewer GI adverse events. 

Overall, this study showed that mevrometostat plus enzalutamide has very promising anti-tumor effects with a 49% reduction in the risk of progression with the combo compared to enzalutamide alone. Overall, the 1250 mg dose on an empty stomach was tolerable, but importantly we found that using a lower dose of mevrometostat with food improved the safety profile in general and this is currently the dose that's being moved forward in pivotal phase 3 studies. 

In terms of the phase 3 trials that are ongoing, the MEVPRO-1 study is enrolling patients who previously progressed on abiraterone and randomizing between either mevrometostat plus enzalutamide or physician's choice of enzalutamide or docetaxel. The MEVPRO-2 study is enrolling patients who've not been exposed to a prior androgen receptor pathway inhibitor and randomization here is between either mevrometostat plus enzalutamide or enzalutamide monotherapy. Should these studies demonstrate efficacy in a larger patient population, the hope is that this would eventually become a reasonable standard of care for patients with early metastatic castrate-resistant prostate cancer. 

Source: 

Schweizer MT, Calvo M, Moreno V, et al. Mevrometostat (PF-06821497), an enhancer of zeste homolog 2 (EZH2) inhibitor, in combination with enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC): A randomized dose-expansion study. Presented at the 2025 ASCO Genitourinary Cancers Symposium. San Francisco, California. February 13-15, 2025. Abstract LBA138