A 67-year-old man was presented to his local hospital outpatient service with dysuria and weak urine stream for 3 months. Prostate ultrasound indicated benign prostatic hyperplasia (BPH) and no obvious nodule was detected. Besides, the level of serum prostate-specific antigen (PSA) was not elevated. So he was given oral treatment with tamsulosin and finasteride for 2 months, but he felt the dysuria symptoms gradually worsened. To further deal with dysuria, the patient was hospitalized in local hospital. Physical examination upon admission of the patient showed the prostate had increased volume with hard texture and the central groove disappeared, oppressed the rectum. No other apparently positive signs were found. He had no special medical, family, and psycho-social history except chronic B-viral hepatitis for over 30 years and denied any alcohol, drug or smoke consumption. So he underwent transurethral Holmium laser prostate surgery. Postoperative pathology result revealed small blue round cell malignant tumor. To further clarify the pathological types of tumor tissue, immunohistochemistry (IHC) was performed, suggesting high-grade prostate cancer with neuroendocrine and neuroectodermal differentiation. To further confirm the diagnosis, fluorescence in situ hybridization (FISH) examination was performed and found no SYT gene disruption and rearrangement, and no EWSR1/FLI1 fusion gene. The dysuria symptoms significantly relieved but aggravated again 1 month after operation, and the symptoms of dribbling at the end of urination appeared, accompanied with increased frequency of urination at night (1-h interval). For further treatment, the patient presented to our hospital. The patient underwent magnetic resonance (MR) examination and found prostate enlargement with irregular masses, unclear boundary between central lobe and peripheral lobe, uneven signal on T2WI image, obviously high signal on DWI image. Further PET–CT found that abnormal glucose metabolism of the prostate was increased and the posterior wall of the bladder was involved but no distant organ metastasis was found. Therefore, after multiple disciplinary team discussion, a da Vinci robotic prostatectomy was performed. Tumor resection specimens were subjected to further whole-genome sequencing. The results suggested that there were three somatic variations that may have clinical significance, including RAF1 (CCDC6-RAF1 fusion), ARID1A, and SMARCA4. Moreover, one germline variation that may have clinical significance is BCL2L11 (2903-bp deletion). Besides, it was found that the tumor mutation burden was 2.33 and microsatellite stable (MSS). What is more, there were no mutation on ALK, BRAF, BRCA1/2, PD-L1, EGFR, EGFR2/3, HER2, KIT, KRAS, MET, NRAS, NTRK1/2/3, PDGFRA, PIK3CA, RET, ROS1, which have potential Food and Drug Administration (FDA)-approved targeted drugs for choosing. The test results did not find specific targeted drugs that could be used clinically in this patient at present. Postoperative recovery was uneventful and the patient was discharged on the 11th postoperative day with smooth urination. Then the patient received four cycles of Ewing-type therapeutic regimens treatment (Vinorelbine Tartrate 30 mg on Day 1 + Epirubicin Hydrochloride 70 mg on Day 1–2 + cyclophosphamide 1 g on Day 1) every 3 weeks. He has been followed up to date and is currently undergoing stable follow-up for over 24 months.