A Phase Ib/IIa Study of the Pan-BET Inhibitor ZEN-3694 in Combination with Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer

Abstract

Purpose: ZEN-3694 is a bromodomain extraterminal inhibitor (BETi) with activity in androgen-signaling inhibitor (ASI)-resistant models. The safety and efficacy of ZEN-3694 plus enzalutamide was evaluated in a phase Ib/IIa study in metastatic castration-resistant prostate cancer (mCRPC).

Patients and methods: Patients had progressive mCRPC with prior resistance to abiraterone and/or enzalutamide. 3+3 dose escalation was followed by dose expansion in parallel cohorts (ZEN-3694 at 48 and 96 mg orally once daily, respectively).

Results: Seventy-five patients were enrolled (N = 26 and 14 in dose expansion at low- and high-dose ZEN-3694, respectively). Thirty (40.0%) patients were resistant to abiraterone, 34 (45.3%) to enzalutamide, and 11 (14.7%) to both. ZEN-3694 dosing ranged from 36 to 144 mg daily without reaching an MTD. Fourteen patients (18.7%) experienced grade ≥3 toxicities, including three patients with grade 3 thrombocytopenia (4%). An exposure-dependent decrease in whole-blood RNA expression of BETi targets was observed (up to fourfold mean difference at 4 hours post-ZEN-3694 dose; P ≤ 0.0001). The median radiographic progression-free survival (rPFS) was 9.0 months [95% confidence interval (CI), 4.6-12.9] and composite median radiographic or clinical progression-free survival (PFS) was 5.5 months (95% CI, 4.0-7.8). Median duration of treatment was 3.5 months (range, 0-34.7+). Lower androgen receptor (AR) transcriptional activity in baseline tumor biopsies was associated with longer rPFS (median rPFS 10.4 vs. 4.3 months).

Conclusions: ZEN-3694 plus enzalutamide demonstrated acceptable tolerability and potential efficacy in patients with ASI-resistant mCRPC. Further prospective study is warranted including in mCRPC harboring low AR transcriptional activity.

Figure 1.. Pharmacokinetic analyses.

A and B. Area-under-the-curve (AUC) from 0 to 24 hours (AUC_0–24) and maximum serum concentration, respectively, of ZEN-3694 + ZEN-3791 (first generation active metabolite) serum concentration on day 1 and day 15 of cycle 1 (red triangles). Overlaid AUC_0–24 data from the monotherapy trial of ZEN-3694 are shown for dose levels 48 and 72 mg daily (black circles). C. Ratio of ZEN-3791 (first generation active metabolite) vs. ZEN-3694 (parent compound) from the prior monotherapy trial and in combination with enzalutamide on day 1 and day 15 of cycle 1. D. Steady-state serum concentration of enzalutamide and desmethylenzalutamide following 14 day lead-in of enzalutamide (day −14 to day −1), by ZEN-3694 dose level.

Figure 2.. Pharmacodynamic assessments.

A. Fold-change from baseline in whole blood RNA expression of BET inhibitor target genes CCR1, IL1RN, IL-8, MYC, and GPR183 by ZEN-3694 dose level. B. Correlation between fold change from baseline in whole blood RNA expression of BET inhibitor target genes with AUC_0–24 of ZEN-3694 + ZEN-3791 indicates strong PK-PD relationship. C. Gene set enrichment analysis of change from baseline in gene expression by RNA-Seq in paired metastatic tumor biopsies. Down-regulation of MYC signaling pathway is observed in on-treatment versus baseline tumor biopsy.

Figure 3.. Radiographic progression-free survival and duration of treatment.

A. Kaplan-Meier curve demonstrating radiographic progression-free survival by PCWG2 criteria in all evaluable study participants (black curve), patients with prior enzalutamide progression (blue curve), or prior abiraterone progression (green curve). B. Kaplan-Meier curve demonstrating composite progression-free survival (time to first clinical or radiographic progression) in C. Swimmer’s plot showing duration of treatment, with color labels by ZEN-3694 dose level (hashed line = treatment ongoing). D and E. Kaplan-Meier curves showing radiographic progression-free survival in subsets of patients with radiographic progression or primary resistance to prior androgen signaling inhibitor, respectively.

Figure 4. AR signaling score and clinical outcomes

A. Lower AR activity level in baseline tumor biopsies is correlated with longer time on study (R²=0.38) using either the 5-gene AR score (left) or the HALLMARK_ANDROGEN_RESPONSE (right) signatures. For the hallmark signature, baseline gene expression of biopsies from patients with radiographic progression prior to 24 weeks vs. greater than 24 weeks were compared (FDR = 0.04). B. Kaplan-Meier curve showing significant increase in time to median radiographic progression free survival in patients with lower AR signaling compared to patients with higher AR signaling score (median rPFS 10.4 months in tumors with low AR score vs. 4.3 months in tumors with high AR activity). C. Patients with high tumor burden and lower baseline PSA levels (< 10 ng/mL) (blue curve) demonstrate longer PFS than patients with higher baseline PSA (> 10 ng/mL) levels.