A Phase II trial investigating the combination of ESK981, a multi-tyrosine kinase inhibitor, and nivolumab, a PD-1 inhibitor, has been terminated early due to a lack of efficacy in patients with metastatic castration-resistant prostate cancer (mCRPC). The study, aimed at improving response rates to immune checkpoint inhibitors in this challenging patient population, failed to demonstrate meaningful antitumor activity.
The trial enrolled ten patients with mCRPC who had progressed on androgen receptor (AR)-targeted agents and chemotherapy. Patients received ESK981 orally once daily for five consecutive days, followed by a two-day break, in combination with intravenous nivolumab on Day 1 of each 28-day cycle. The primary endpoint was a 50% reduction in prostate-specific antigen (PSA50), along with safety. Secondary endpoints included radiographic progression-free survival (rPFS) and overall survival (OS).
Limited Efficacy and Tolerability
The results indicated minimal clinical benefit. The maximum PSA decline from baseline was only 14%, observed in a single patient. The median rPFS was 3.7 months (95% CI, 1.6-8.4), and the median OS was 9.6 months (95% CI, 1.8-22.4). Grade 3 treatment-related adverse events (AEs) included fatigue, anemia, and lymphopenia. There were no Grade 4 events reported.
Genomic Analysis
Whole exome sequencing identified AR amplification in 63% of patients (5/8). The study investigators concluded that ESK981 in combination with nivolumab showed no antitumor activity in patients with AR-positive mCRPC, suggesting that further evaluation of this combination in this patient population is not warranted.
The trial is registered at ClinicalTrials.gov under the identifier NCT04159896.
