Phase 1 trial of mevrometostat (PF-06821497), a potent and selective inhibitor of enhancer of zeste homolog 2 (EZH2), in castration-resistant prostate cancer (CRPC).
Authors: Schweizer Michael Thomas , Penkov Konstantin , Choudhury Atish Dipankar , Calvo Emiliano , Frank Richard C. , Liu Li , Mittapalli Rajendar K. , Tougias Jessica , Andreu-Vieyra Claudia , Bowler Timothy Geoffrey , Soman Neelesh , Garmezy Benjamin 
Published: June 2024

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Background: Mevrometostat (M; PF-06821497) is a potent and selective small molecule inhibitor of EZH2. Dose exploration of M in combination with enzalutamide (E) plus androgen deprivation therapy showed a manageable safety profile and preliminary evidence of objective response (OR), decline in prostate-specific antigen (PSA) to ≥50% of baseline (PSA50), and peripheral pharmacodynamic (PD) modulation in patients (pts) with CRPC in part 2A of a phase 1/2 study (NCT03460977; Schweizer, ESMO 2022, 488P). We report longer term follow up from the dose escalation cohort of M+E in CRPC. Methods: This is an open-label, phase 1/2 study of M (orally, 150-1250 mg twice daily) + E (160 mg daily) in adult pts with CRPC who had received prior abiraterone (A) and/or E and had evidence of cancer progression per Prostate Cancer Working Group 3 (PCWG3) criteria at entry. The primary endpoint was safety. Pharmacokinetics, radiographic progression-free survival (rPFS), PSA50, and OR by PCWG3 were also assessed. Dose/response relationship of M on-target H3K27Me3 PD modulation in whole blood and tumor biopsies and circulating tumor DNA mutational profiling were exploratory endpoints. Results: As of November 2, 2023, 47 pts had received ≥1 dose of study treatment. Median (interquartile range) duration of follow up was 9.7 (2.0-22.8) months (mo). Median (range) age was 70 (53-87) years. Overall, 57.4% of pts had received prior A, 74.5% had received prior E and 48.9% had received prior taxane therapy. As of data cut, 18 events were observed (14 progression events and 4 deaths). Median (95% CI) rPFS was 17.0 (6.3, not estimable [NE]) mo in the total population; 17.1 (6.2, NE) mo for pts who received prior A (without E) (n=12), and 11.7 (4.2, NE) mo for pts who received prior E (± A) (n=35). Confirmed PSA50 (95% CI) was observed in 14.9% (7.0, 31.4) of pts. In 22 pts with baseline measurable disease, OR rate (95% CI) was 27.3% (10.7, 50.2), including 1 complete and 5 partial responses. Geometric mean (95% CI) H3K27Me3 reduction was -75% (-93, -11) for M+E at 1250 mg M (twice daily) in tumor-paired biopsies (n=6). Durable antitumor activity was observed in both post-A (without E) and post-E (± A) pts with and without androgen receptor and/or TP53 mutations. Adverse events (AEs) led to treatment discontinuation in 9 (19.1%) pts. The most common treatment-emergent AEs (TEAEs) considered related to M were diarrhea (42.6%), dysgeusia (42.6%), and anemia (36.2%). Grade ≥3 TEAEs considered related to M were reported in 17.0% of pts. Serious TEAEs related to M were observed in 6.4% of pts. No treatment-related deaths were observed. Conclusions: M+E shows promising activity in both post-A (without E) and post-E (± A) pts with CRPC with evidence of tumor PD modulation and with a manageable AE profile. Further investigation of M+E in pts with CRPC is warranted. Clinical trial information: NCT03460977 .