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).
Michael T. Schweizer, Konstantin Penkov, Atish D. Choudhury, Emiliano Calvo, Richard C. Frank, Li Liu, Rajendar K. Mittapalli, Jessica Tougias, Claudia Andreu‐Vieyra, Timothy G. Bowler, Neelesh Soman, Benjamin Garmezy
Abstract
5061 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 (PSA 50 ), 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), PSA 50 , 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 PSA 50 (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 .