BET Bromodomain Inhibitor Plus Enzalutamide in Metastatic Prostate Cancer
Posted: Thursday, August 27, 2020
The BET bromodomain inhibitor ZEN-3694 in combination with enzalutamide demonstrated potential efficacy in patients with androgen signaling inhibitor–resistant metastatic castration-resistant prostate cancer, according to a phase Ib/IIa study published in Clinical Cancer Research. Joshi J. Alumkal, MD, of the University of Michigan Rogel Cancer Center, Ann Arbor, and colleagues noted this combination also had an acceptable tolerability profile.
“Resistance to androgen receptor–targeting agents is inevitable in metastatic castration-resistant prostate cancer,” Dr. Alumkal commented in an institutional press release. “This study provides evidence that inhibition of BET bromodomain proteins that facilitate gene activation may be able to overcome resistance mechanisms and resensitize patients to androgen receptor–targeting agents.”
A total of 75 patients with progressive metastatic castration-resistant prostate cancer were enrolled; all patients had experienced disease progression after treatment with abiraterone or enzalutamide. Using a 3+3 dose-escalation scheme, ZEN‐3694 was administered orally in doses ranging from 36 to 144 mg daily. Subsequently, dose expansion was performed in two cohorts in parallel: a low-dose cohort of 48 mg daily (n = 14) and a high-dose cohort of 96 mg daily (n = 26). All patients received a standard dose of enzalutamide at 160 mg daily.
A maximum tolerated dose was not reached. Severe adverse reactions were reported in 18.7% of patients, including 4% of those who experienced grade 3 thrombocytopenia. There seemed to be a significant exposure-dependent decrease in whole blood RNA expression of BET bromodomain inhibitor targets (P ≤ .0001). The median durations of radiographic progression-free survival and composite median radiographic or clinical progression-free survival were 9.0 and 5.5 months, respectively. According to the investigators, patients with low levels of androgen receptor transcriptional activity detected in baseline tumor biopsies seemed to experience a longer radiographic progression-free survival (median: 10.4 vs. 4.3 months).
Disclosure: For full disclosures of the study authors, visit clincancerres.aacrjournals.org.