This study is a single-arm prospective cohort study designed to evaluate the efficacy and safety of triple therapy (ADT + darolutamide + docetaxel) combined with transrectal high-intensity focused ultrasound (HIFU) focal therapy in patients with high-tumor-burden metastatic hormone-sensitive prostate cancer (mHSPC).

A total of 116 high-tumor-burden mHSPC patients will be enrolled and are scheduled to receive the following treatment:

Darolutamide + Docetaxel + ADT + Transrectal HIFU Focal Therapy for the Prostate.

Prostate cancer ranked as the second most commonly diagnosed cancer and the fifth leading cause of cancer death among men worldwide in 2020, with approximately 1.4 million new cases and 375,000 deaths. In China, both the incidence and mortality rates of prostate cancer have shown a significant upward trend.

For prostate cancer treatment, effective management of high-tumor-burden metastatic hormone-sensitive prostate cancer (mHSPC) is crucial for delaying disease progression and improving long-term survival, representing one of the most critical clinical challenges. Although androgen deprivation therapy (ADT) combined with docetaxel or novel hormonal therapy has been established as standard treatment in both domestic and international guidelines, the clinical adoption of these novel ADT-based combination regimens remains limited due to the risk of adverse events (AEs) associated with chemotherapy and prolonged hormone exposure.

Recent advances in mHSPC treatment have brought new hope. The phase III PEACE-1 trial demonstrated that adding abiraterone to standard ADT plus docetaxel significantly reduced mortality risk (median overall survival not reached vs. 4.4 years; HR, 0.75; 95% CI, 0.59-0.96; P=0.021).

SonaCare Medical's Sonablate HIFU system is a global leader in high-intensity focused ultrasound technology, being the first prostate tissue ablation device to receive FDA 510(k) clearance. On July 8, 2020, the Sonablate device obtained approval from China's National Medical Products Administration (NMPA Approval No. 20203010342) for treating both prostate cancer and benign prostatic hyperplasia.

Therefore, this project proposes a single-arm clinical study. From 2022 to 2025, eligible high-tumor-burden mHSPC patients will be enrolled after providing informed consent and baseline data collection. Participants will receive either:

• Apalutamide + docetaxel + ADT, or
• Apalutamide + ADT combined with transrectal high-intensity focused ultrasound (HIFU) focal therapy The primary endpoint is 3-year radiographic progression-free survival (rPFS) rate. Follow-up assessments will be conducted per protocol to evaluate efficacy and safety outcomes. This study aims to provide new therapeutic possibilities for high-tumor-burden mHSPC through combination therapy, potentially improving patient prognosis and reducing disease burden.

Inclusion Criteria:

1. Patients who agree to participate in the study and sign the informed consent form.

2. Age ≥18 years, male.

3. Histologically or cytologically confirmed prostate adenocarcinoma.

4. Bone scan, CT, or MRI showing ≥4 bone metastases (with ≥1 outside the pelvis or spine) or visceral metastases.

5. Newly diagnosed or recurrent disease after local therapy, with sensitivity to androgen deprivation therapy (ADT).

6. Patients who have received ADT (medical or surgical castration) with or without first-generation antiandrogens for ≤3 months, without evidence of soft tissue disease progression (per RECIST 1.1) or clinically significant PSA progression (≥50% increase from nadir with serum testosterone at castrate levels).

7. Planned treatment with docetaxel plus apalutamide and ADT, or apalutamide plus ADT.

8. ECOG Performance Status (PS) score of 0-1.

9. Adequate hematologic and organ function:

   • **Bone marrow function (without transfusion or growth factor support):**
   • Absolute neutrophil count (ANC) ≥1.5 × 10⁹/L (1500/μL)
   • Hemoglobin ≥90 g/L (9.0 g/dL)
   • Platelet count ≥100 × 10⁹/L (100,000/μL)
   • **Liver function:**
   • Total bilirubin (TBIL) ≤1.5 × ULN
   • AST, ALT, and alkaline phosphatase (ALP) ≤2.5 × ULN
   • **Renal function:**
   • Serum creatinine ≤1.5 × ULN **or** calculated creatinine clearance ≥30 mL/min (Cockcroft-Gault formula)
   • **Coagulation function (without anticoagulation therapy):** INR ≤1.5

10. Patients of reproductive potential must use effective contraception during the study and for 6 months after the last dose.

Exclusion Criteria:

1. Lesions located at the prostate apex or in areas inaccessible for focal therapy.
2. Beaded prostatic calculi or cysts >1 cm in diameter within the treatment or ultrasound pathway.
3. Urethral stricture or presence of metal/other implants in the urethra.
4. Prior rectal surgery.
5. History of or existing rectal fistula.
6. Rectal stenosis preventing transrectal ultrasound.
7. Rectal invasion.
8. Active severe urinary tract infection.
9. Severe cardiovascular or cerebrovascular disease affecting anesthesia/surgery.
10. History of hypersensitivity or intolerance to any study drugs.
11. Planned concurrent anticancer therapy during the study.
12. Prior treatment with second-generation androgen receptor (AR) inhibitors (e.g., apalutamide, enzalutamide, darolutamide), CYP17 inhibitors (e.g., abiraterone acetate, ketoconazole), chemotherapy, immunotherapy, or adjuvant/neoadjuvant therapy.
13. Use of herbal products with anti-prostate cancer or PSA-lowering effects (e.g., saw palmetto) within 4 weeks before study treatment.
14. History of seizures, medications that lower seizure threshold, or conditions predisposing to seizures within 12 months (including TIA, stroke, or traumatic brain injury with hospitalization).
15. Active cardiac disease within 6 months before treatment: severe/unstable angina, myocardial infarction, congestive heart failure (NYHA Class III/IV), or arrhythmia requiring medication.
16. Conditions impairing drug absorption (e.g., dysphagia, chronic diarrhea, intestinal obstruction).
17. Immunodeficiency (e.g., HIV-positive, congenital/acquired immunodeficiency) or organ transplant history.
18. Known brain metastases.
19. Other malignancies within 5 years (except cured basal cell carcinoma or cervical carcinoma in situ).
20. Concurrent participation in another investigational drug/device trial.
21. Poor compliance likely to hinder treatment/follow-up.
22. Uncontrolled comorbidities (e.g., hypertension, diabetes, neuropsychiatric disorders) that may compromise safety or confound results, per investigator judgment.
23. Any other condition deemed unsuitable for inclusion by the investigator.