Abstract 586P
Background
TAZ, an enhancer of zeste homolog (EZH2) inhibitor, is approved for use in patients with epithelioid sarcoma or relapsed/refractory follicular lymphoma. Inhibition of EZH2 has been proposed to overcome resistance to the androgen signaling inhibitors (ASIs) A and E. In preclinical prostate cancer models, TAZ + E or TAZ + A/P led to greater tumor growth reduction than each drug alone. This phase Ib/II global, open-label, randomized study (NCT04179864) is evaluating the safety and efficacy of TAZ + A/P and TAZ + E in mCRPC.
Methods
The phase Ib segment enrolled adults with mCRPC following a modified 3 + 3 design. The protocol allowed prior E, A, first-generation anti-androgen receptor therapy, or short course chemotherapy. Pts received TAZ escalated to 800 mg twice daily (BID) with A 1000 mg once daily (QD) + P 5 mg BID or E 160 mg QD with TAZ escalated to 1600 mg BID. The primary endpoints were safety, tolerability, and recommended phase II dose (RP2D) of TAZ for each combination. Disease control rate (DCR) was assessed at 6 months. In phase II, those treated with A/P will be randomized 1:1 to TAZ (at RP2D) + E or to E alone.
Results
As of Feb 2021, 21 pts (TAZ + A/P, n=7; TAZ + E, n=14) were enrolled. Median (range) age: 74 (53-85) years; ECOG PS: 0 (n=11, 52.4%) or 1 (n = 10, 47.6%). Serious treatment-emergent adverse events (TEAEs; any grade) occurred in 3/21 (14.3%) pts; in the TAZ + A/P arm, 1/7 (14.3%) had pneumonia and/or hyperglycemia; in the TAZ + E arm, 1/14 (7.1%) had urinary tract infection and hydronephrosis. Treatment-related TEAEs attributable to either study agent in each group occurred in 17 pts (TAZ + A/P, n=7; TAZ + E, n=10). No dose-limiting toxicities occurred in phase Ib. The RP2D for TAZ was 1200 mg BID + E or A/P. Prostate-specific antigen reduction ≥50% was observed in 7/20 pts (TAZ + E, 6/13 [46%]; TAZ + A/P, 1/7 [14%]). DCR through data cutoff was 47%.
Conclusions
In phase Ib, events observed with TAZ + A/P were consistent with known AEs of each drug or related to underlying conditions, and preliminary efficacy results indicate a response across cohorts. Phase II is enrolling pts to assess the efficacy and safety of TAZ at 1200 mg BID + E.
Clinical trial identification
NCT04179864.
Editorial acknowledgement
Claire Jarvis, PhD, and Duprane Young, PhD, of Peloton Advantage, an OPEN Health company, and funded by Epizyme, Inc.
Legal entity responsible for the study
Epizyme, Inc.
Funding
Epizyme, Inc.
Disclosure
W. Abida: Financial Interests, Personal and Institutional, Other, Honoraria: CARET; Financial Interests, Personal and Institutional, Advisory Role: Clovis Oncology; Financial Interests, Personal and Institutional, Advisory Role: Janssen; Financial Interests, Personal and Institutional, Advisory Role: MORE Health; Financial Interests, Personal and Institutional, Advisory Board: ORIC Pharmaceuticals; Financial Interests, Personal and Institutional, Funding: AstraZeneca (Inst); Financial Interests, Personal and Institutional, Funding: Clovis Oncology (Inst); Financial Interests, Personal and Institutional, Funding: GlaxoSmithKline (Inst); Financial Interests, Personal and Institutional, Funding: Zenith Epigenetics (Inst); Financial Interests, Personal and Institutional, Other, Travel, Accommodations, Expenses: Clovis Oncology; Financial Interests, Personal and Institutional, Other, Travel, Accommodations, Expenses: GlaxoSmithKline; Financial Interests, Personal and Institutional, Other, Travel, Accommodations, Expenses: ORIC Pharmaceutical. E. Kocabas Argon: Financial Interests, Personal and Institutional, Stocks/Shares: Epizyme, Inc.; Financial Interests, Personal and Institutional, Full or part-time Employment: Epizyme, Inc. L. Appleman: Financial Interests, Personal and Institutional, Funding: Acerta Pharma (Inst); Financial Interests, Personal and Institutional, Funding: Agensys (Inst); Financial Interests, Personal and Institutional, Funding: Astellas Pharma (Inst); Financial Interests, Personal and Institutional, Funding: AVEO (Inst); Financial Interests, Personal and Institutional, Funding: Bayer (Inst); Financial Interests, Personal and Institutional, Funding: Bristol-Myers Squibb (Inst); Financial Interests, Personal and Institutional, Funding: Calithera Biosciences (Inst); Financial Interests, Personal and Institutional, Funding: Eisai (Inst); Financial Interests, Personal and Institutional, Funding: Genentech/Roche (Inst); Financial Interests, Personal and Institutional, Funding: Inovio Pharmaceuticals (Inst); Financial Interests, Personal and Institutional, Funding: Lilly (Inst); Financial Interests, Personal and Institutional, Funding: Merck (Inst); Financial Interests, Personal and Institutional, Funding: Novartis (Inst); Financial Interests, Personal and Institutional, Funding: Peloton T (Inst)herapeutics; Financial Interests, Personal and Institutional, Funding: Pfizer (Inst); Financial Interests, Personal and Institutional, Funding: Seattle Genetics (Inst); Financial Interests, Personal and Institutional, Funding: Tokai Pharmaceuticals (Inst). N. Michaud: Financial Interests, Personal and Institutional, Full or part-time Employment: Epizyme, Inc.; Financial Interests, Personal and Institutional, Stocks/Shares: Epizyme, Inc.; Financial Interests, Personal and Institutional, Stocks/Shares: AstraZeneca; Financial Interests, Personal and Institutional, Royalties: Pfizer; Financial Interests, Personal and Institutional, Royalties: AstraZeneca; Financial Interests, Personal and Institutional, Royalties: Epizyme, Inc. A. Rajarethinam: Financial Interests, Personal and Institutional, Full or part-time Employment: Epizyme, Inc.; Financial Interests, Personal and Institutional, Stocks/Shares: Epizyme, Inc. D. Adib: Financial Interests, Personal and Institutional, Full or part-time Employment: Epizyme, Inc.; Financial Interests, Personal and Institutional, Advisory Role: Epizyme, Inc. D.R. Saltzstein: Financial Interests, Personal and Institutional, Funding: Epizyme, Inc. All other authors have declared no conflicts of interest.