Background: Enzalutamide is a second-generation androgen receptor inhibitor that showed to prolong survival in different setting of prostate cancer. Visceral metastases, occurring in 10–30% of mCRPC pts, have been associated with poor outcomes. Given the poor prognosis, trial investigating hormone therapies often excluded men with visceral disease, especially in the pre-docetaxel setting. To date, there are no prospective studies designed ad hoc to test hormone therapies in this subgroup of pts. Methods: In this open label phase II multicentre study mCRPC pts with visceral metastases were treated with enzalutamide 160 mg orally once daily as first or second line after docetaxel until progressive disease or unacceptable toxicity. Pts were eligible if they had documented measurable metastatic visceral disease (according to RECIST 1.1 criteria), including lesions in lung or liver or extraregional lymphnodes. Pts must have PSA progression or radiographic progression (according to PCWG2). Primary endpoint was to determine the clinical benefit, as measured by 3-months (mo) disease control rate (DCR) defined as the proportion of pts with best overall response of confirmed complete (CR) or partial responses (PR) or stable disease as per RECIST 1.1 at mo 3. Secondary endpoints were safety, quality of life (assessed by EQ-5D-5L e FACT-P questionnaire), pain assessment (by BPI-SF questionnaire). Exploratory objectives were to assess the association between ARv7 splicing variants (in CTCs samples) and treatment response/resistance. For CTC and ARv7 detection, we used the Adna test Prostate Cancer Panel. Results: From March 2017 through January 2021, 68 pts were enrolled at 6 Italian centres. One pt never started treatment because of withdrawal of consent. Median age was 70 years (IQR 65- 78). All pts presented with visceral disease at baseline: 27, 6, 55 pts presented with lung, liver and lymphnodes lesions, respectively. 26 pts presented with only one metastatic site, 22 pts with two, while the remaining part with multiple sites. 15 pts received a previous treatment with docetaxel in the mCRPC phase. The median follow-up was 10 mo. The median time on treatment was 8 mo. At mo 3, 24 pts presented a stable disease, 1 pt achieved a confirmed CR and 20 pts a PR for a 3 mo-DCR of 67% (45/67). Discontinuations due to adverse-events, disease-related death, or disease progression occurred in 6%, 7%, and 40% of pts, respectively. So far, only 26 patients were evaluated for baseline CTC and ARv7. Interestingly, 75% of patients experiencing a progression at month 3 were classified as ARv7 positive at baseline. Conclusions: The study met its primary endpoint showing enzalutamide is an active treatment option for men with mCRPC and visceral disease in both pre or post-docetaxel setting. CTCs status combined with ARv7 detection could be useful to personalize treatments. Clinical trial information: NCT03103724