Study of JAK inhibition in stem-like prostate cancer (JASPER): A phase 1/2 multicenter study of ruxolitinib and enzalutamide in castration resistant prostate cancer undergoing lineage plasticity.
Authors: Thomas Christopher Westbrook, Frank Cameron Cackowski, Joshi J. Alumkal, Anbarasu Kumaraswamy, Megan Veresh Caram, Sarah Elizabeth Yentz, Ulka N. Vaishampayan, Manjunath Pai, Thomas Braun, Zachery R Reichert
Journal: Journal of Clinical Oncology (2025)

TPS297 Background: Lineage plasticity (LP) is an increasingly recognized route of resistance in advanced metastatic prostate cancer, and present in approximately 35% of patients at time of death. LP is a continuum of disease states from adenocarcinoma driven by androgen receptor (AR) to AR-independent double negative prostate cancer (DNPC) and neuroendocrine prostate cancer (NEPC). LP has been associated with significantly decreased overall survival compared to other modes of resistance in castration resistant prostate cancer (CRPC). LP can be defined using a combination of molecular and clinical features, but treatment remains imprecise with doublet chemotherapy. Preclinical studies of LP evolution point toward JAK/STAT signaling as important to the process of early lineage plasticity. Furthermore, JAK inhibition combined with AR pathway inhibitor, enzalutamide (enza), was shown to sensitize enza resistant LP models to enza. Genomic studies of patient samples have similarly found JAK/STAT pathway upregulation in tumors which undergo lineage plasticity to DNPC. JAK inhibition in combination with enza may be a promising therapy for prostate cancer at risk or undergoing LP. Methods: JASPER is a phase1/2, multi-center study to evaluate the safety, tolerability, antitumor activity, and pharmacology of ruxolitinib (rux, a JAK inhibitor) combined with enza (160 mg per day) in patients with metastatic CRPC with poor response to prior abiraterone treatment. Poor response is defined as progression within 12 months of starting therapy within hormone-naïve prostate cancer or within 6 months of starting it within CRPC. In the dose escalation phase, a unique pharmacology approach is employed to understand enza’s CYP3A4 induction. A single dose of rux determines intrapatient pharmacokinetics. One week later, the combination starts and the plasma rux values correlated. The pharmacodynamic biomarker phospho-STAT3 in leukocytes will be measured by ELISA. A Bayesian Optimal Interval (BOIN) design determines the maximum tolerated dose (MTD) of rux with enza for the expansion cohort. The expansion cohort has a Simon’s 2 phase design with a 40% response rate goal (3 responses required out of first 13 patients at MTD, total of 39 maximum). The primary endpoint is the MTD of the combination based on rate of drug-related grade 3-5 adverse events experienced within the first 4 weeks of study treatment. Secondary endpoints are a) disease response rate within 6 months of combination therapy start defined by PSA50 decline and/or RECIST 1.1 criteria of partial response or complete response and b) progression free survival defined by Prostate Cancer Working Group 3 criteria. Enrollment is open. Clinical trial information: NCT06616155 .