Abstract 1404P
Background
ZEN is a potent and selective BET bromodomain inhibitor (BETi) with encouraging clinical activity in combination with ENZ in patients (pts) with second generation androgen receptor signaling inhibitor (ARSI)-resistant mCRPC. ZEN has synergy with immune checkpoint inhibition in pre-clinical assays. The safety and efficacy of ZEN in combination with ENZ plus P was evaluated (NCT04471974).
Methods
Pts were required to have progressive mCRPC, prior resistance to ≥ 1 second generation ARSI, and no prior chemotherapy for mCRPC. A safety lead-in (N = 6) followed by dose expansion was utilized, with a starting dose of ZEN 72 mg/day, ENZ 160 mg/day, and P 200 mg IV every 3 weeks. The primary objective was to determine the recommended phase 2 dose (RP2D); key efficacy endpoints included PSA50 response.
Results
Twenty-two pts have been enrolled to date (n = 6 safety lead-in; n = 16 dose expansion). Median age and serum PSA at study entry was 71 (range 54 – 82) and 30.6 ng/mL (range 5.6 – 560.1), respectively. Ten pts (45%) had prior treatment with > 1 ARSI. Fourteen pts (64%) remain on treatment, 7 discontinued for progression, and one discontinued due to toxicity (Grade 3 LFTs). There were no dose-limiting toxicities during safety lead-in; ZEN 72 mg daily + ENZ 160 mg/day + P 200 mg IV q 3 weeks was the RP2D. Grade 3 treatment-related adverse events (AEs) for the study cohort included fatigue (n = 3), decreased appetite (n = 1), rash (n = 1), and elevated AST/ALT (n = 1). Immune-related AEs included: skin rash (Grade 1/2: n = 9; grade 3: n = 1), colitis (Grade 1/2: n = 6; grade 3: n = 0), pruritus (grade 1/2: n = 2; grade 3: n = 0), and autoimmune hepatitis (Grade 3, n = 1). The PSA50 response proportion was 27% (6/22 pts), including 2 pts who had previously progressed on ENZ. None of the responders were MSI-high by targeted next-gen sequencing. PSA responses were durable, including 2 pts who remain on treatment for 13.6+ and 12.7+ months, respectively.
Conclusions
The combination of ZEN, ENZ, and P had an acceptable safety profile. Preliminary clinical activity was observed, including responses in ENZ-resistant microsatellite-stable mCRPC. Further investigation of the combination is ongoing including in an AR-independent cohort.
Clinical trial identification
NCT04471974.
Editorial acknowledgement
Legal entity responsible for the study
University of California San Francisco.
Funding
Merck Pharmaceuticals.
Disclosure
J. Alumkal: Financial Interests, Institutional, Research Grant: Zenith Epigenetics, Beactica. R. Aggarwal: Financial Interests, Institutional, Research Grant: Zenith Epigenetics, Merck; Financial Interests, Personal, Advisory Board: Pfizer. All other authors have declared no conflicts of interest.