Introduction:

Tazemetostat (TAZ) is an oral small molecule inhibitor of enhancer of zeste homolog (EZH2) approved for the treatment of epithelioid sarcoma and relapsed/refractory follicular lymphoma. Androgen-signaling inhibitors (ASIs), such as abiraterone/prednisone (A/P) and enzalutamide (E), are standard-of-care therapies for patients with metastatic castration-resistant prostate cancer (mCRPC), but patients who develop resistance to these agents have limited treatment options. EZH2 inhibition may re-sensitize tumors to overcome resistance to ASIs. In preclinical prostate cancer models, TAZ + A/P or TAZ + E led to greater tumor growth reduction than either drug alone. We present an updated analysis of the phase 1b/2 global, open-label, randomized CELLO-1 study (NCT04179864) evaluating the safety and efficacy of TAZ + A/P and TAZ + E in patients with mCRPC at a median study follow-up of 17.4 months.

Methods:

Males aged ≥18 years with mCRPC who were previously untreated (phase 1b only) or whose disease progressed on treatment with a second-generation ASI were enrolled. The protocol allowed prior first-generation anti-androgen receptor therapy and no more than 6 cycles of prior docetaxel received for castration-sensitive disease. A modified 3 + 3 design was used to assess TAZ dosing. Patients received TAZ escalated to 800 mg twice daily (BID) with abiraterone 1000 mg once daily (QD) plus prednisone 5 mg BID, or E 160 mg QD with TAZ escalated to 1600 mg BID, for optimal exposure. The primary endpoints were safety, tolerability, and recommended phase 2 dose (RP2D) of TAZ for each combination. Secondary endpoints included prostate-specific antigen (PSA) decline of ≥50% (PSA50) and radiographic progression-free survival (rPFS).

Results:

As of June 11, 2022, 21 patients (TAZ + A/P, n=7; TAZ + E, n=14), with a mean age of 71.3 years and a median of 3 prior lines of therapy, were treated. Median durations of treatment exposure for TAZ + A/P and TAZ + E were 10.0 and 6.9 months, respectively. The most common treatment-emergent adverse events (TEAEs) occurring in >2 patients are summarized in the Table. Grade 3/4 TEAEs were reported in 10 (47.6%) patients. No dose-limiting toxicities occurred in phase 1b. With median follow-up times of 20.5 (TAZ + A/P) and 17.0 (TAZ + E) months, PSA50 was observed in 6/21 patients (TAZ + A/P, 1/7 [14.3%]; TAZ + E, 5/14 [35.7%]) (Figure); the median rPFS durations were 36.1 and 48.1 weeks, respectively. The RP2D for TAZ in combination with E, determined through analyses of safety and all available pharmacokinetic/pharmacodynamic data, was 1200 mg BID.

Conclusion:

The safety profile and clinical activity of TAZ + A/P and of TAZ + E were maintained and were consistent with the prior analysis of the phase 1b data. No new safety signals were identified. Preliminary efficacy data supported proceeding to the phase 2 portion of this study, which will assess the efficacy and safety of TAZ (1200 mg BID) + E vs monotherapy with E in patients with mCRPC who were previously treated with A/P, with a primary endpoint of rPFS. Phase 2 is actively recruiting and currently has 81 patients enrolled.

Funding: This study was funded by Epizyme, Inc. Astellas Pharma, Inc., provided the study drug enzalutamide.