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Combo of Novel BET inhibitor and enzalutamide advances in mCRPC pipeline


A phase 2b randomized trial is launching exploring the combination of the investigational BET inhibitor ZEN-3694 and enzalutamide (Xtandi) in patients with metastatic castration-resistant prostate cancer (mCRPC) who have progressed on a prior androgen receptor signaling inhibitor (ARSi).1

Patients will be randomized to the combination or the ARSi enzalutamide alone. Previously, phase 1b/2a data published in Clinical Cancer Research showed promising early activity with the combination.2 Zenith Epigenetics and Astellas Pharma, the developers of ZEN-3694 and enzalutamide, respectively, anticipate that the phase 2b study will officially launch in the second quarter of this year.

“We are delighted to collaborate with Astellas to continue the development of ZEN-3694 in combination with enzalutamide in mCRPC patients, who are resistant to an ARSi,” said Donald McCaffrey, President and Chief Executive Officer of Zenith.

“Data from our recently executed single arm phase 1b/2a study has shown that the aforementioned combination may prolong radiographic progression-free survival (rPFS) in mCRPC patients and particularly in a subset of patients who had a poor response to prior ARSi and whose tumors had low androgen receptor signaling activity. There is a significant unmet need in mCRPC patients who are ARSi resistant and their current treatment options only include chemotherapy with considerable side effects. We are looking forward to validating our initial clinical findings with this well-designed randomized study.”

Phase 1b/2a trial

ZEN-3694 works by inhibiting expression of the MYC gene, which blocks cellular growth in prostate cancer tumors. The phase 1b/2a study of ZEN-3694/enzalutamide enrolled patients with progressive mCRPC with prior resistance to the ARSi abiraterone acetate (Zytiga) and/or enzalutamide. Dose escalation was followed by dose expansion in parallel cohorts, which were administered ZEN‑3694 at 48 and 96 mg orally once daily, respectively. Overall, 75 patients were enrolled, including 26 and 14 in dose expansion at low- and high-dose ZEN-3694.

Thirty (40%) patients were resistant to abiraterone, 34 (45.3%) to enzalutamide, and 11 (14.7%) to both. ZEN-3694 dosing ranged from 36 mg to 144 mg daily without reaching a maximum-tolerated dose. Patients were treated for a median duration of 3.5 months (range, 0-34.7+).

The median rPFS was 9 months. Additionally, the composite median radiographic or clinical PFS was 5.5 months. The investigators also reported a link between lower androgen receptor transcriptional activity in baseline tumor biopsies and longer rPFS (10.4 vs 4.3 months).

Regarding safety, grade ≥3 toxicities occurred in 14 patients (18.7%). Of note, there were 3 patients with grade 3 thrombocytopenia.

A separate ongoing phase 2 trial (NCT04471974) is examining a triplet regimen combining ZEN-3694 with the PD-1 inhibitor pembrolizumab (Keytruda) and enzalutamide in patients with mCRPC who have become resistant to first-line treatment with an ARSi.3

The open-label, nonrandomized phase 2 trial is accruing patients with prostate adenocarcinoma that is histologically confirmed at diagnosis, with ensuing development of mCRPC. At the time of enrollment, there must be evidence of progressive disease as shown by PSA and/or radiographic progression (PCWG3 criteria).


1. Zenith Epigenetics Announces Clinical Collaboration with Astellas. Published online April 22, 2021. Accessed April 22, 2021. https://yhoo.it/3vdoCZe.

2. Aggarwal RR, Schweizer MT, Nanus DM, et al. A phase 1b/2a study of the pan-BET bromodomain inhibitor ZEN-3694 in Combination with enzalutamide in patients with metastatic castration resistant prostate cancer. Clinical Cancer Research. 2020;26(20):5338-5347. doi: 10.1158/1078-0432.CCR-20-1707

3. NIH US National Library of Medicine Clinical Trials.gov. ZEN-3694, Enzalutamide, and Pembrolizumab for the Treatment of Metastatic Castration-Resistant Prostate Cancer. Last updated December 22, 2020. Accessed March 17, 2021. https://clinicaltrials.gov/ct2/show/NCT04471974.

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