Background: The optimal timing for initiating androgen deprivation therapy (ADT) in biochemical recurrent (BCR) prostate cancer (PC) patients, specifically those with PSA doubling time > 10 months, remains uncertain. Therefore, there is a compelling need for clinical trials exploring alternatives to ADT. Artesunate, derived from Artemisinin which is extracted from Artemisia annua (Aa), shows anti-cancer effects. Aa comprises several active constituents including dihydroartemisinic acid, artemisinic acid, and artemisinin. Our research group assessed the sensitivity of prostate cancer cells to Artesunate using established PC cell lines such as LNCaP, C4-2, CWR-22Rv1 and PC-3. Two cell lines, LNCaP (PSA and AR positive, hormone naïve) with an IC50 of 3.30 µM (95% CI 2.28-4.79) and C4-2 (PSA and AR positive, castration resistant) with an IC50 of 3.99 µM (3.13-5.10 µM) demonstrated sensitivity to Artesunate. Wang et. al (2017) reported that Artesunate, administered at varying doses, effectively suppressed tumor growth, inhibited cell viability and enhanced apoptosis in a mouse xenograft model using the 22rv1 PC cell line. Based on these promising preclinical findings, we hypothesize that Aa decaf coffee has the potential to decrease rising PSA levels in patients with BCR PC. Our research group previously conducted a phase I dose escalation of ArtemiCoffee in ovarian cancer (NCT04805333) and preliminary results indicated no grade ≥3 toxicities at the proposed dose (unpublished data). In this study, we aim to conduct a phase II study of Aa decaf coffee in men with BCR PC. Methods: An open-label, single center, phase II study targets men with BCR PC following primary definitive local therapy and a PSA doubling time > 10 months. Commercially available Aa decaf coffee pods supplied by ArtemiLife Inc. will be utilized. These decaf coffee pods adhere to FDA food-grade quality standards and Aa plants used for ArtemiLife coffee are cultivated in Kentucky, USA. Aa decaf coffee will be self-administered three times daily (total of 1,350mg Aa) on an outpatient basis for 24 weeks. The primary endpoint is to determine the proportion of patients achieving a ≥50% decline in PSA levels within 24 weeks of Aa decaf coffee treatment in BCR population. A total of 30 patients will be enrolled in this study, ensuring a maximum margin of error of approximately 16% in the 95% confidence interval for the primary endpoint. Secondary endpoints include safety and tolerability. Correlative endpoints include 1) changes in downstream biomarkers of the NRF2/KEAP1 signaling pathway and 2) changes in plasma concentrations of artemisinin and dihydroartemisinin by comparing pre- and post-treatment with Aa decaf coffee using non-parametric paired test. The study commenced accrual in August 2023. Clinical trial information: NCT05478239.