A phase Ia/Ib study of talazoparib in combination with tazemetostat in metastatic castration-resistant prostate cancer (mCRPC).

作者：Atish D. Choudhury, Wanling Xie, Alok K. Tewari, David T. Miyamoto, Bose Kochupurakkal, Leigh Ellis, Matthew Bandel, C. Leisner, Geoffrey I. Shapiro, Alan D. D’Andrea, Eliezer M. Van Allen, Matthew L. Freedman, Myles Brown, Mary‐Ellen Taplin, Himisha Beltran · 发表于：Journal of Clinical Oncology · 年份：2022 · DOI：10.1200/jco.2022.40.16_suppl.tps5098 · 被引用次数：1 · 研究领域：PARP inhibition in cancer therapy、Prostate Cancer Treatment and Research、Cancer Genomics and Diagnostics

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 ...