Abstract PS11-10: A Phase 1b/2 Study of the BET inhibitor ZEN003694 in combination with talazoparib for treatment of patients with TNBC without gBRCA1/2 mutations

• Published in: Cancer research (Chicago, Ill.) Vol. 81; no. 4_Supplement; p. PS11-10
• Main Authors: Aftimos, Philippe, Oliveira, Mafalda, Punie, Kevin, Boni, Valentina, Hamilton, Erika, Gucalp, Ayca, Shah, Payal, Mina, Lida, Sharma, Priyanka, Bauman, Lisa, Campeau, Eric, Attwell, Sarah, Snyder, Margo, Norek, Karen, Czibere, Akos, Yu, Yanke, Silverman, Michael H, Lakhotia, Sanjay, Domchek, Susan, Litton, Jennifer, Robson, Mark
• Format: Journal Article
• Language: English
• Published: 15-02-2021
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.SABCS20-PS11-10

Background: Metastatic triple-negative breast cancer (TNBC) is an aggressive and heterogeneous cancer with limited therapeutic options. PARP inhibitors (PARPi) are approved to treat breast cancer harboring germline BRCA1/2 (gBRCA1/2) mutations and have not shown efficacy in homologous recombination DNA repair (HRR) proficient tumors. In pre-clinical models, the BET inhibitor (BETi) ZEN003694 sensitizes wild-type BRCA1/2 tumors to PARPi through downregulation of HRR gene expression, providing a rationale for combination therapy. We report initial results from a Ph 1b/2 trial evaluating the combination of ZEN003694 and the PARPi, talazoparib, in TNBC patients without gBRCA1/2 mutations.
Methods: A Ph 1b dose-finding segment will be followed by a single-arm Ph 2 Simon 2-stage segment. Ph 1b evaluated several dose combinations of ZEN003694 and talazoparib, with safety and recommended Ph 2 dose (RP2D) as primary endpoints and pharmacokinetics (PK), pharmacodynamics (PD), and clinical benefit rate (CBR = Objective response rate (ORR) + stable disease > 4 months) as secondary endpoints. The Ph 2 segment has CBR as the primary endpoint and progression free survival (PFS) and duration of response as secondary endpoints. Eligibility criteria included TNBC (ER/PR < 10% and not a candidate for endocrine therapy), HER2-, wild-type gBRCA1/2, and > 1 prior chemotherapy regimen for metastatic disease. Patients were dosed daily in continuous 28-day cycles until disease progression or unacceptable toxicity. Dose limiting toxicity (DLT) period was one cycle. Adverse events (AE), PK, and PD in whole blood and tissue biopsies were assessed. Response endpoints were assessed per RECIST 1.1 every 2 cycles.
Results: Findings of the Ph 1b are reported. 15 patients with a median 3 lines of prior therapy in the metastatic setting were enrolled in 3 dose-finding cohorts. RP2D was determined to be 48mg ZEN003694 plus 0.75mg talazoparib. Across the cohorts, the most common AE was thrombocytopenia (TCP) (73%) with 53% G3/4 (Table 1). G4 TCP was the DLT and 1 DLT patient required a platelet transfusion. TCP could be managed to G1/2 levels with intermittent dose holds and reductions. Other G1/2 AEs included fatigue, anorexia, neutropenia, nausea, dysgeusia, and photophobia. Dose intensity analysis showed average daily doses of ZEN003694 and talazoparib could be maintained above 40mg and 0.5mg, respectively, over 4 cycles. Exposures of ZEN003694 and talazoparib were dose proportional with no drug-drug PK interactions. At RP2D, PD assessment by a whole blood mRNA assay for BET-dependent genes demonstrated robust down-regulation of CCR1, IL1RN, and IL8 to < 50% of baseline for > 8 h. Expression of HRR genes, RAD51 and BRCA1, in whole blood also decreased for > 8 h. Analysis of an on-treatment biopsy showed robust and durable BET target modulation assessed by comparing RNA sequence data with a reference BET dependent signature. Across the 3 cohorts, ORR by Investigator was 38% (5/13), including 1 CR and 4 PRs, and CBR was 57% (8/14). 6 of the 15 patients are ongoing as of data analysis date (2-9 cycles), with 1 patient responding for > 6 months.
Conclusions: Combination of ZEN003694 and talazoparib demonstrated anti-cancer activity in pretreated metastatic TNBC patients without gBRCA1/2 mutations. TCP is frequent but manageable with dose adjustments. PK is predictable, and PD data show meaningful target engagement. The Ph 2 part of the trial is currently ongoing.
Grade 3/4 Adverse EventsCohort 1(1mg talazoparib + 48mg ZEN003694)N=6Cohort 2(0.75 mg talazoparib + 48mg ZEN003694)N=6Cohort 3(1mg talazoparib + 36mg ZEN003694)N=3Thrombocytopenia3 (G3), 2 (G4, DLT)1 (G3), 1 (G4, DLT)1 (G3)Diarrhea1 (G3)00Neutropenia01 (G3)0
Citation Format: Philippe Aftimos, Mafalda Oliveira, Kevin Punie, Valentina Boni, Erika Hamilton, Ayca Gucalp, Payal Shah, Lida Mina, Priyanka Sharma, Lisa Bauman, Eric Campeau, Sarah Attwell, Margo Snyder, Karen Norek, Akos Czibere, Yanke Yu, Michael H Silverman, Sanjay Lakhotia, Susan Domchek, Jennifer Litton, Mark Robson. A Phase 1b/2 Study of the BET inhibitor ZEN003694 in combination with talazoparib for treatment of patients with TNBC without gBRCA1/2 mutations [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-10.