Phase II trial of multi-kinase inhibitor ESK981 in patients with metastatic castration-resistant prostate cancer.

ESK981 is a potent tyrosine kinase and PIKfyve lipid kinase inhibitor. This phase II trial evaluated the efficacy of ESK981 as a single agent in patients with androgen receptor-positive (AR +) metastatic castration-resistant prostate cancer (mCRPC). Eligible patients had mCRPC with progression on AR-targeted agents and without prior chemotherapy treatment. Each patient received 160 mg ESK981 once daily for 5 days per week for 4 weeks per cycle (except for an adverse event (AE) occurrence). The primary endpoints were a 50% reduction in prostate-specific antigen (PSA50), and safety. Secondary endpoints included the time and the duration of PSA response, PSA progression rates, PSA progression free survival (PFS) and overall survival (OS). Exploratory investigations included whole exome sequencing in patients before treatment, and morphological evaluation of biopsy samples pre- and post-treatment. PSA was evaluated in 13 patients. Only one patient (7.7% two-sided 95% Wilson CI (0.4%, 33.3%)) experienced a reduction in their PSA levels by 50% or more. The most common grade 3 treatment-related AEs were cardiac disorders, diarrhea, hypertension, alanine transaminase and aspartate transaminase elevations. No grade 4-5 events occurred. Median PFS was 1.8 months, and median OS was 12.1 months. Peripheral immune cells showed increased T cell activation and cytokine production in two patients who received 12-weeks of ESK981. Although relatively well tolerated, ESK981 alone showed no anti-tumor activity in patients with AR + mCRPC and its further evaluation as a single agent in AR + mCRPC is not warranted. (Trial registration: ClinicalTrials.gov, NCT03456804. Registration date: March 7, 2018).