Mevrometostat Plus Enzalutamide Improves rPFS vs Enzalutamide in Metastatic CRPC

The combination of enzalutamide (Xtandi) and the selective EZH2 inhibitor mevrometostat (PF-06821497) improved radiographic progression-free survival (rPFS) outcomes vs enzalutamide alone in patients with metastatic castration-resistant prostate cancer (CRPC), according to data from the dose-expansion portion of a phase 1 study (NCT03460977).1

“[In] the primary efficacy analysis after a median follow-up of 9.6 months [IQR, 3.1-14.5], mevrometostat plus enzalutamide….[vs enzalutamide alone yielded] an 8-month improvement in median rPFS or a 49% reduction in the risk of progression or death,” lead study author Michael Thomas Schweizer, MD, said in a presentation of the data at the 2025 Genitourinary (GU) Cancers Symposium. Schweizer is an associate professor in the Clinical Research Division at Fred Hutch Cancer Center in Seattle, Washington.

Patients who received 1250 mg of mevrometostat twice daily on an empty stomach with enzalutamide(n = 41) achieved a median rPFS of 14.3 months (95% CI, 7.5-not estimable) compared with 6.2 months (95% CI, 4.1-13.9) among those treated with enzalutamide monotherapy (n = 40; HR, 0.51; 90% CI, 0.28-0.95) in the early-phase trial. The objective response rate (ORR) in evaluable patients who received the combination at the same dosing (n = 15) was 26.7% (95% CI, 7.8%-55.1%) compared with 14.3% (95% CI, 1.8%-42.8%) among those who received the monotherapy (n = 14). In the combination and monotherapy arms all objective responses were partial; 73.3% vs 21.4% of patients experienced stable disease, respectively, and no patients had disease progression on the doublet whereas 50% experienced progression on enzalutamide alone.

Efficacy findings presented were for patients treated with 1250 mg of mevrometostat on an empty stomach. However, pharmacokinetic data showed that plasma exposure with the drug at 875 mg given with food was similar to the 1250-mg dose with an improved safety profile. As such, the 875-mg dose is moving forward as the recommended phase 3 dose.

“Patients treated with mevrometostat 875 mg with food had an improved safety profile, including better gastrointestinal tolerability, compared with mevrometostat 1250 mg on an empty stomach,” Schweizer noted.

Examining Enrollment Criteria and Patient Characteristics

As EZH2 is overexpressed in CRPC and is associated with a poor prognosis, investigators examined the EZH2 inhibitor mevrometostat plus enzalutamide in the open-label study. Findings from the dose exploration portion of the trial were previously presented at the 2024 ASCO Annual Meeting. Patients enrolled were previously treated with abiraterone acetate (Zytiga) and no more than 1 regimen of prior chemotherapy in any setting. Additionally, patients were receiving androgen deprivation therapy and had evidence of disease progression per modified Prostate Cancer Working Group 3 criteria.

Following 1:1 random assignment and stratification by prior chemotherapy receipt, patients received mevrometostat at 1250 mg orally twice daily on an empty stomach with or without 160 mg of oral enzalutamide once daily. The trial’s primary end points were rPFS by investigator assessment and safety. ORR, decline in prostate-specific antigen levels of 50% or greater (PSA50), and pharmacokinetics served as secondary end points.

Patients in the doublet arm were a median age of 70.0 years (range, 48-86) and were 71.5 years (range, 50-86) in the monotherapy arm. Most patients were White (75.6% vs 75.0%) and had a Gleason score of at least 8 (63.4% vs 75.0%), and less than half of patients received a prior taxane (43.9% vs 45.0%), respectively. Lesions at baseline were present in the bone (87.8% vs 95.0%), lymph nodes (29.3% vs 40.0%), liver (7.3% vs 5.0%), and lung (7.3% vs 5.0%), and notably, ECOG scores varied in the arms: Patients had ECOG scores of 0 (63.4% vs 37.5%) or 1 (36.6% vs 62.5%), respectively.

Further Efficacy and Safety Findings From the Phase 1 Study

Additional data revealed that as of the September 2, 2024, data cutoff, the confirmed PSA50 response rate was 34.1% (95% CI, 20.1%-50.6%) among those who received mevrometostat plus enzalutamide vs 15.4% (95% CI, 6.0%-31.3%) with enzalutamide alone.

Regarding safety with the 1250-mg dose, any-grade treatment-emergent adverse effects (TEAEs) occurred in the doublet vs monotherapy (97.6% vs 92.5%) arms, respectively, as did grade 3 or higher TEAEs (53.7% vs 42.5%). Serious TEAEs (34.1% vs 27.5%) and TEAEs leading to dose reduction (36.6% vs 7.5%) and study discontinuation (2.4% vs 5.0%) occurred, respectively. The most common TEAEs experienced by at least 30% of patients in either arm were asthenic conditions, diarrhea, decreased appetite, anemia, nausea, dysgeusia, and alopecia. Notably, no treatment-related serious TEAEs led to death.

Phase 3 trials currently examining mevrometostat in patients with metastatic CRPC include the MEVPRO-1 study (NCT06551324) in those who previously received abiraterone and MEVPRO-2 (NCT06629779) in those who have not received an androgen receptor pathway inhibitor.2,3

References

1. Schweizer M, 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. J Clin Oncol. 2025;43(suppl 5):LBA138. doi:10.1200/JCO.2025.43.5_suppl.LBA138
2. A study to learn about the investigational medicine called PF-06821497 (mevrometostat) in men with mCRPC who were previously treated with abiraterone acetate for prostate cancer (MEVPRO-1). (MEVPRO-1). ClinicalTrials.gov. Updated January 28, 2025. Accessed February 20, 2025. https://clinicaltrials.gov/study/NCT06551324
3. A study to learn how PF-06821497 (mevrometostat) works in men with metastatic castration-resistant prostate cancer. ClinicalTrials.gov. Updated January 27, 2025. Accessed February 20, 2025. https://www.clinicaltrials.gov/study/NCT06629779