A phase 1b/2 study of the BET inhibitor ZEN-3694 in combination with talazoparib for treatment of patients with TNBC without gBRCA1/2 mutations.
Authors: Aftimos Philippe Georges , Oliveira Mafalda , Punie Kevin , Boni Valentina , Hamilton Erika P. , Gucalp Ayca , Shah Payal D , de Miguel Maria J. , Sharma Priyanka , Bauman Lisa , Campeau Eric , Attwell Sarah , Snyder Margo , Norek Karen , Johnson Emily , Silverman Michael H. , Lakhotia Sanjay , Domchek Susan M. , Litton Jennifer Keating , Robson Mark E. 
Published: June 2022

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Background: Metastatic triple negative breast cancer (mTNBC) is an aggressive and heterogeneous cancer with limited therapeutic options. PARP inhibitors (PARPi), approved to treat patients with HER2- breast cancer with a germline BRCA1/2 (gBRCA1/2) mutation, have not shown efficacy in homologous recombination repair (HRR) proficient tumors. In pre-clinical models, the BET inhibitor (BETi) ZEN-3694 sensitizes wild-type (WT) BRCA1/2 tumors to PARPi through downregulation of HRR gene expression, providing a rationale for combination therapy. We previously reported results from the Ph 1b portion of the trial evaluating the combination of ZEN-3694 plus talazoparib, in TNBC patients without gBRCA1/2 mutations; here we present results from the completed Ph 1b/2 study. Methods: A Ph 1b dose finding portion (n = 15) was followed by a single arm Ph 2 Simon 2-stage portion (n = 17+20 (37)). The primary endpoint of the Ph 1b portion of the study was safety and recommended Ph 2 dose (RP2D). The secondary endpoints were pharmacokinetics (PK), pharmacodynamics (PD), and clinical benefit rate (CBR = confirmed objective response rate (ORR) + stable disease > 16 weeks). Ph 2 measured CBR as the primary endpoint, ORR and duration of response (DOR) as key secondary endpoints. Eligibility criteria for Ph 1b included TNBC (ER/PR < 10%, HER2-), WT gBRCA1/2, and > 1 prior cytotoxic regimen for mTNBC, and in the Ph2 portion ER/PR < 1% and < 2 prior cytotoxic regimens for mTNBC. Patients were dosed daily in continuous 28 day cycles until disease progression or unacceptable toxicity. Adverse events, PK, and PD in whole blood and tissue biopsies were assessed. Response endpoints were assessed per RECIST 1.1 every 2 cycles. Results: RP2D was determined to be 48mg qd ZEN-3694 plus 0.75mg qd talazoparib. The most common AE for the Ph 1b/2 study was thrombocytopenia (TCP) (55% any grade, 34% G3/4), which was managed with dose holds and reductions. Dose intensity analysis showed average daily doses of ZEN-3694 and talazoparib could be maintained above 40mg and 0.5mg, respectively, over 8 cycles. Robust target engagement was demonstrated using BET-dependent and HRR transcripts assessed in paired tumor biopsies. Ph 2 portion of the trial met its primary endpoint with a CBR of 30% (11/37). For the Ph 1b/2 trial, investgator assessed ORR was 22% (11/50), including 2 CR, CBR was 35% (18/51) and the median DOR was 24 weeks. For the subset of TNBC at diagnosis patients (no history of HR+ disease), ORR was 32% (11/34), and CBR was 44% (15/34). Conclusions: Combination of ZEN-3694 and talazoparib demonstrated anti-cancer activity in pretreated mTNBC WT gBRCA1/2 patients. All confirmed responses were observed in TNBC at diagnosis patients, whose tumors are expected to be more sensitive to the combination due to their basal-like properties. The trial is being expanded to Ph. 2b to accrue an additional 80 TNBC at diagnosis patients. Clinical trial information: NCT03901469.