Novel regimen shows potential in mCRPC with androgen signaling inhibitor resistance

The combination of the investigational pan-BET bromodomain inhibitor ZEN-3694 and enzalutamide (Xtandi) showed potential in patients with metastatic castration-resistant prostate cancer (mCRPC) resistant to androgen receptor pathway inhibitors.¹

In a phase 1b/2a study published in Clinical Cancer Research, the exploratory regimen led to an exposure-dependent decrease in whole blood RNA expression of bromodomain extra-terminal inhibitor targets (up to 4-fold mean difference at 4 hours post-ZEN-3694 dose; P ≤.0001) in patients with mCRPC and prior resistance to abiraterone acetate (Zytiga) and or enzalutamide.

The median radiographic progression-free survival (rPFS) was 9.0 months (95% CI, 4.6-12.9) and composite median radiographic or clinical PFS was 5.5 months (95% CI, 4.0-7.8). Of note, lower androgen receptor transcriptional activity in baseline tumor biopsies was associated with longer rPFS (median rPFS, 10.4 vs 4.3 months).

“Resistance to androgen receptor-targeting agents is inevitable in metastatic, castration-resistant prostate cancer,” co-senior study author Joshi Alumkal, MD, who leads the Prostate and Genitourinary Medical Oncology Section at the U-M Rogel Cancer Center, stated in a press release.² “This study provides evidence that inhibition of BET bromodomain proteins that facilitate gene activation may be able to overcome resistance mechanisms and re-sensitize patients to androgen receptor-targeting agents.”

The study enrolled patients with progressive mCRPC with prior resistance to abiraterone 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.

Overall, 30 (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. Median duration of treatment was 3.5 months (range 0 ­- 34.7+).

“We saw particular benefit in patients who were in high-risk subgroups, including those with more aggressive disease with lower androgen receptor activity in their tumors,” Alumkal stated in the press release.

Regarding safety, 14 patients (18.7%) experienced toxicities of grade 3 or less, including 3 patients with grade 3 thrombocytopenia (4%).

In the study conclusion, the researchers noted that further prospective study is warranted, including in patients with mCRPC harboring low androgen receptor transcriptional activity.

Alumkal recently led a separate trial, published in the Proceedings of the National Academy of Sciences, that found that a gene program associated with lower androgen receptor activity contributes to upfront resistance in the one-third of cancers that do not respond at all to enzalutamide treatment.³

“That subset of patients with frontline resistance to enzalutamide or abiraterone and low androgen receptor activity are the ones who appeared to respond best to ZEN-3694 — suggesting a promising treatment approach for this group of patients whose cancers behave quite poorly with currently approved treatments,” Alumkal concluded.

References:

1. 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. doi: 10.1158/1078-0432.CCR-20-1707

2. Researchers Optimistic After Dose-Determining Trial of Compound Against Metastatic Castration-Resistant Prostate Cancer [news release]. Michigan Medicine – University of Michigan. Published July 29, 2020. https://bit.ly/32DV1eE. Accessed August 17, 2020.

3. Clinical Trial Offers Clues About Why Some Metastatic Prostate Cancers Don’t Respond to Anti-Androgen Therapy [news release]. Michigan Medicine – University of Michigan. Published April 27, 2020. https://bit.ly/3lrQvsn. Accessed August 17, 2020.