Background: Recent studies have shown that targeting lipid synthesis is a novel therapeutic strategy to overcome androgen resistance in mCRPC. TVB-2640 is a first-in-class FASN inhibitor, a key enzyme in de novo lipogenesis that is overexpressed and androgen-regulated in CRPC. FASN promotes the synthesis of palmitate that can be elongated and desaturated to produce saturated fatty acids (SFAs) and monounsaturated FA (MUFAs) that can support membrane synthesis and energy production, protect against free radicals and chemotherapeutics, and regulate post-translational modifications of major oncogenic pathways. Our preliminary in vitro and in vivo data show that TVB-2640 co-administered with enza to CRPC cells significantly reduced cell growth, increased apoptosis, and promoted cell cycle arrest, as well as down-regulating full-length androgen receptor (AR) and its splice variant, AR-V7. Methods: This is an open-label, single-arm, Phase I dose-escalation study that enrolls pts with mCRPC who are candidates to receive enza. The primary objective is to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of TVB-2640 in combination with enza. Secondary objectives include safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity. Exploratory objectives include the effects of FASN inhibition on metabolites, genetics, and lipids in human blood and tumor tissue, to identify potential predictive and prognostic markers of response. Pts with a confirmed histological or cytological diagnosis of PC, evidence of metastatic PC on imaging (bone scan and/or CT/MRI scan), serum testosterone <50 ng/dl, who had progressed on androgen-depletion therapy (ADT), with documented progressive metastatic castration-resistant prostate cancer (mCRPC) based on Prostate Cancer Working Group 3 (PCWG3) criteria a are eligible. Enrolled pts will receive enza at a daily dose of 160 mg for 36 days to reach a steady state, followed by the addition of oral TVB-2640 starting at 100 mg/daily. The dose escalation will follow the Bayesian optimal interval (BOIN) design with additional dose levels of 150 mg, 200 mg, 250 mg, and 300 mg daily. The maximum sample size for this study is 30 pts, with a target dose-limiting toxicity (DLT) rate of 25% or less and a maximum of 15 pts at any given dose level. This is the first clinical trial to evaluate the targeting of the AR pathway through inhibition of lipid synthesis as a new approach to treating mCRPC. Enrollment of Cohort 1 began in August 2023. Clinical trial information: NCT05743621.