A new trial will investigate the combination of ZEN-3694 and talazoparib in patients who previous received a TROP2 antibody-drug conjugate.
A new trial of the investigational agent ZEN-3694 plus talazoparib (Talzenna) has been initiated to further evaluate the combination’s efficacy and safety in patients with locally advanced or metastatic triple-negative breast cancer (TNBC), according to a press release from Zenith Epigenetics.1
The phase 2b trial is an extension of the phase 1b/2 ZEN003694-004 trial (NCT03901469) of ZEN-3694/talazoparib, whose results will be presented in an oral poster session at the 2022 American Society for Medical Oncology (ASCO) annual meeting on June 6. The new trial will enroll patients with TNBC without BRCA1/2 mutations who have been previously treated with a TROP2 antibody-drug conjugate.
“The data from the phase 1b/2 trial has shown that the ZEN-3694 plus talazoparib combination regimen induced durable responses in tumors of TNBC patients which do not harbor mutations in BRCA1/2,” Mark E. Robson, MD, a principal investigator and medical oncologist at The Memorial Sloan Kettering Cancer Center, said in a statement. “These clinical results confirm the rationale and data from preclinical experiments which have shown that BET inhibition can sensitize wild type BRCA1/2 TNBC tumors to PARP inhibition. This interesting data warrants the continued clinical evaluation of this combination.”
Talazoparib is a PARP inhibitor currently approved for treatment of patients with locally advanced or metastatic BRCA-mutated HER2-negative breast cancer.2 ZEN-3694 is a BET inhibitor that can reduce DNA repair activity from proteins such as BRCA1/2 and RAD51 in order to increase sensitization to PARP inhibition in tumor cells.1
The phase 1b/2 trial consisted of a dose-escalation part with 15 patients followed by a Simon 2-stage phase 2a part with 17 patients in the first stage and 20 in the second stage. The primary end point was the incidence of treatment-related adverse events (AEs) and serious treatment-related AEs. Part 1 also had a primary end point of dose-limiting toxicity (DLT), while part 2 had a primary end point of overall response rate (ORR).
In the dose escalation part, the first cohort received 1 mg of talazoparib daily plus 48 mg of ZEN-3694, resulting in 2 out of 6 patients exhibiting DLTs.3 The second cohort of 3 patients received 1 mg of talazoparib and 36 mg of ZEN-3694 with no DLTs, while the third received 0.75 mg of talazoparib and 48 mg of ZEN-3694, resulting in 1 DLT. The recommended phase 2 dose was selected to be 0.75 mg talazoparib plus 48 mg ZEN-3694.
As of December 2020, 32 total patients were evaluated in the dose escalation and stage 1. There was an ORR of 29% and a clinical benefit rate of 44%, which included patients with stable disease for at least 4 months. One patient was found to have a somatic BRCA1 mutation, and they did not respond to treatment. Results of the second stage will be presented at the ASCO oral presentation.
In terms of safety, the most common AEs observed were thrombocytopenia, nausea, and neutropenia. There were 17 patients (53.1%) with thrombocytopenia events across dose escalation and Simon stage 1 of the trial, 12 of which were grade 3, and 4 were grade 4. Thrombocytopenia was reversible with dose interruption and reduction.
TROP2 antibody-drug conjugates such as sacituzumab govitecan (Trodelvy) have shown efficacy in treating metastatic TNBC.4 The phase 2b trial will investigate if PARP inhibition plus BET inhibition will improve outcomes in patients who have received a TROP2 antibody-drug conjugate previously.
“We are very pleased to advance our TNBC program to phase 2b and closer to possible registration,” Donald J. McCaffery, president and CEO of Zenith Epigenetics, said in a statement.1 “There is a significant unmet need in this aggressive cancer with few non-cytotoxic therapy options available for the patient.”
References:
1. Zenith Epigenetics announces initiation of a phase 2b triple negative breast cancer (TNBC) clinical trial. Zenith Epigenetics. Published May 10, 2022. Accessed May 13, 2022. https://bit.ly/3a3W3s1
2. FDA approves talazoparib for gBRCAm HER2-negative locally advanced or metastatic breast cancer. FDA. Published October 16, 2018. Accessed May 13, 2022. https://bit.ly/3lbyob8
3. Aftimos P, Boni V, Domchek S, et al. Phase 1b/2 combination study of the BET inhibitor ZEN-3694 with the PARP inhibitor talazoparib for the treatment of TNBC patients without germline BRCA1/2 mutations. Presented at: TNBC Drug Development Summit; April 29, 2021; virtual. Accessed May 13, 2022. https://bit.ly/3NcJoRz
4. Bardia A, Hurvitz SA, Tolaney SM, et al. Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med. 2021;384(16):1529-1541. doi:10.1056/NEJMoa2028485
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