Background: Androgen deprivation therapy (ADT) achieved with gonadotropin releasing hormone (GnRH) agonist or antagonist is considered the standard of care for men with prostate cancer (PC) who develop biochemical recurrence (BCR) after definitive treatment. ADT is associated with significant adverse effects in this asymptomatic population, and hence there is an unmet need for alternate non-hormonal options. Androgen receptor (AR) and its variants (AR-V) are persistently expressed in the majority of the cells in recurrent PCs and drives PC growth. Jak2-Stat5 signaling has been shown to sustain PC cell viability and is critical for PC tumor growth. Stat5 activation in PC at the time of surgery predicts early PC recurrence. Our investigation of the molecular targets downstream of Jak2-Stat5 signaling have revealed the AR gene as a critical target, and the Jak2-Stat5 pathway represents a target to inhibit expression of diverse AR and AR-V species and thereby control of PC growth. Pacritinib (PAC) is a novel JAK2 inhibitor that suppresses wild-type Jak2 in cell-based assays and has demonstrated promising antitumor activity in myelofibrosis. We hypothesize that PAC inhibition of Jak2-Stat5 signaling will induce biochemical responses in men with recurrent PC by depleting AR and AR-V. Methods: BLAST (NCT04635059) is a single arm, open-label, phase 2 study of PAC (200mg BID) for patients with PC who underwent definitive treatment and developed BCR. Eligibility criteria include histologically confirmed PC, BCR with a PSA doubling time ≤ 9 months, PSA > 0.5 ng/mL, and serum testosterone > 150 ng/dL. 46 subjects will be enrolled with a primary objective to assess the effect of PAC on time to PSA progression. The primary endpoint is six-month PSA progression free survival per PCWG3 criteria. The null hypothesis that the median PSA-progression-free survival is six months will be tested against a one-sided alternative for the six-month PSA-progression-free survival probability exceeding 50%. Secondary endpoints include time to subsequent therapy, safety and toxicity. Exploratory endpoints include effect of PAC on geriatric domains. An interim analysis will be performed when 10 patients have been treated and followed for six months. Accrual began in July 2021. Clinical trial information: NCT04635059.