A phase Ia/Ib study of talazoparib in combination with tazemetostat in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Choudhury Atish Dipankar , Xie Wanling , Tewari Alok , Miyamoto David Tomoaki , Kochupurakkal Bose , Ellis Leigh , Bandel Matthew , Leisner Claire , Shapiro Geoffrey , D'Andrea Alan D. , Van Allen Eliezer Mendel , Freedman Matthew , Brown Myles , Taplin Mary-Ellen , Beltran Himisha 
Published: June 2022

TPS5098 Background: Enhancer of zeste homolog 2 (EZH2) is frequently overexpressed in metastatic castration-resistant prostate cancer (mCRPC), and is linked to lineage plasticity and therapy resistance. In pre-clinical studies, EZH2 directly regulates DNA damage repair (DDR) gene expression, and pharmacologic inhibition of EZH2 sensitizes prostate cancer cells to genotoxic stress as induced by poly-ADP ribose polymerase (PARP) inhibition. The PARP inhibitor talazoparib and EZH2 inhibitor tazemetostat are currently under study in mCRPC, and we are conducting a Phase 1 clinical trial of the combination. Methods: Phase 1a of the study will define the recommended phase 2 dose (RP2D) and Phase 1b will better assess safety and preliminary clinical activity of the combination at the RP2D. Eligible patients must have progressive disease after at least one secondary hormonal therapy and taxane-based chemotherapy (or felt not to be more appropriate for taxane), have disease evaluable for response (PSA ≥ 2 ng/ml or measurable disease by RECIST 1.1) and have a metastatic lesion amenable to biopsy adequate for next generation sequencing. In Phase 1a (n = 9-18), the starting doses are talazoparib 0.75 mg daily and tazemetostat 600 mg BID, with dose escalation/de-escalation of both agents by up to 2 dose levels [DLs] based on a 3+3 design. The RP2D is the maximum tolerated dose (MTD) or DL +2 (talazoparib 1 mg daily + tazemetostat 800 mg BID) if the MTD is not reached. After 6 patients are treated at the RP2D, phase 1b will enroll an additional 20 patients to an expansion cohort. The primary endpoint of safety and tolerability is based on incidence of dose-limiting toxicities [DLTs] and incidence and grade of adverse events [AEs] by CTCAE version 5.0. For the secondary endpoint of overall response rate (ORR; defined as PSA reduction by ≥ 50% OR radiographic response by RECIST 1.1), with a sample size of 26 (6 patients from dose escalation and 20 from expansion), we deem talazoparib+tazemetostat effective if ORR is ≥ 5/26 (19%). The probability of concluding that the treatment strategy effective is 0.11 if its true response rate is 10% and at least 0.93 if the true response rate exceeds 30%. Mandatory pre-treatment and on-treatment (8-week) biopsies will undergo targeted genetic sequencing, transcriptomic profiling, ChIP (Chromatin ImmunoPrecipitation)-seq, and immunohistochemistry (IHC) for DDR and differentiation markers; blood specimens will undergo circulating cell-free DNA and circulating tumor cell profiling – these studies will nominate possible predictive biomarkers for therapeutic response and serve as pharmacodynamic markers of combined PARP and EZH2 inhibition. The goal of this study is to expand treatment options in mCRPC through a novel approach to exploit EZH2 as a therapeutic target through co-targeting the DDR response. Enrollment began in July 2021. Clinical trial information: NCT04846478.