¹⁸F-PSMA-1007 PET-CT-Directed Focal Therapy for MRI-Invisible Prostate Cancer

Seeing the Unseen: ¹⁸F-PSMA-1007 PET-CT-Directed Focal Therapy for MRI-Invisible Prostate Cancer (The FOCUS-PSMA Study)

Multiparametric magnetic resonance imaging (mpMRI) is the standard imaging modality for prostate cancer diagnosis and focal therapy planning. However, 10-20% of clinically significant prostate cancers (csPCa) are not visible on mpMRI (PI-RADS 1-2). These MRI-invisible lesions, typically identified only on systematic biopsy, are currently not targetable by MRI-guided focal therapy, leaving patients with the choice between whole-gland radical treatment or active surveillance. This prospective, multi-centre, single-arm phase II trial investigates whether pelvis-only ¹⁸F-PSMA-1007 positron emission tomography-computed tomography (PET-CT) can identify MRI-invisible csPCa and serve as the therapeutic navigation tool for focal ablation. Men aged ≥50 years with localized, intermediate-risk prostate cancer (ISUP Grade Group 2-3) and at least one MRI-invisible csPCa focus undergo a PET-CT. If a PET-avid lesion corresponds anatomically to the MRI-invisible biopsy-positive site, the patient receives focal therapy using an energy modality (targeted microwave ablation, high-intensity focused ultrasound, or irreversible electroporation) selected based on tumour anatomy, guided by organ-based tracking. The primary endpoint is the absence of csPCa (Grade Group ≥2) on 6-month targeted biopsy of all treated zones. Secondary endpoints include out-of-field recurrence, functional outcomes, and safety. The study requires 45 treated patients (total enrolment ~60) across two Hong Kong centres and will be completed within 3 years.

This is a prospective, multi-centre, single-arm Phase II trial conducted at Queen Mary Hospital and Princess Margaret Hospital, Hong Kong. The study adheres to the Declaration of Helsinki and ICH-GCP guidelines, with ethics approval obtained prior to initiation. Eligible patients are men aged ≥50 years, life expectancy >10 years, with histologically confirmed localized prostate cancer (ISUP Grade Group 2 or 3), at least one csPCa focus identified on systematic biopsy that is MRI-invisible (PI-RADS v2.1 score 1-2 in the corresponding region), total of 1-2 discrete cancer foci, PSA <20 ng/mL, and organ-confined disease. Exclusion criteria include prior prostate cancer treatment, pelvic radiotherapy, contraindications to MRI or PSMA PET-CT, and uncorrectable coagulopathy.

Enrolled patients undergo a dedicated pelvis-only ¹⁸F-PSMA-1007 PET-CT within 4 weeks of enrolment. No fasting is required; activity is weight-based. After a 90-minute uptake period, low-dose non-contrast CT and PET imaging of the pelvis are acquired. Iterative reconstruction optimised for small lesion detection is applied. A PRIMARY-adapted five-point PET-score system (1 to 5) is used; focal uptake scoring 3, 4, or 5 defines a PET-positive lesion. Only patients with a PET-positive lesion anatomically correlated with the MRI-invisible biopsy-positive location proceed to focal therapy.

Focal therapy is performed under general or spinal anaesthesia. The ¹⁸F-PSMA-1007 PET-CT DICOM dataset is imported into the Koelis Trinity® platform and fused with real-time transrectal ultrasound using organ-based tracking (OBT). The urologist selects the ablative modality based on tumour location and constraints from the following: targeted microwave ablation (TMA) using the TATO3® needle; high-intensity focused ultrasound (HIFU) using the Sonablate® system; or irreversible electroporation (IRE) using the NanoKnife® or PoriNova® systems. Treatment is transperineal, with a 5-10 mm intraprostatic margin around the PET-avid and any concurrent MRI-visible lesions, while maintaining a ≥5 mm safety distance from sphincter, rectum, and neurovascular bundles.

Follow-up includes PSA, adverse events, and validated questionnaires (IPSS, IIEF-5, EPIC-26) at month 3 and month 6. At month 6, a repeat mpMRI and transperineal MRI/ultrasound fusion biopsy (3-4 cores per treated area plus a 12-core systematic template) are performed. Pathology is read by dedicated uropathologists with ISUP Grade Group reporting per core and per lesion. Primary outcome: per-patient absence of csPCa (≥ Grade Group 2) on targeted biopsy of all treated zones at 6 months. Secondary outcomes: any cancer in treated zones, out-of-field recurrence, PSA kinetics, functional score changes, adverse events (Clavien-Dindo), quality of life, PET positivity proportion among enrolled patients, and technical success of PET/US fusion.

Sample size uses A'Hern's single-stage phase II design. With an assumed true in-field success rate (p₁) of 0.88 and an unacceptable threshold (p₀) of 0.73, one-sided α=0.05, power=0.80, the critical value is 34 successes out of 40 treated patients. Accounting for a 10% loss to follow-up/biopsy, 45 treated patients are required. Estimating that 75% of enrolled MRI-invisible csPCa patients will have a PET-avid lesion, a total of 60 patients will be enrolled. Recruitment over 24 months is feasible across the two centres, each performing ~200 MRI-guided biopsies annually, with ~15% revealing MRI-invisible csPCa. The primary analysis will be performed on the protocol population; the proportion achieving the primary endpoint will be reported with an exact 95% confidence interval. Secondary endpoints will be analysed using paired t-tests or Wilcoxon signed-rank tests for continuous variables, and McNemar or chi-square tests for categorical variables, with p<0.05 considered significant. SPSS will be used.

Data will be handled in accordance with Hospital Authority policies. Personal data will be coded, stored in locked cabinets and password-protected servers with restricted access, and retained for 10 years post-completion before destruction. Patients who are PET-negative will be managed per institutional standard, with their data collected for secondary analyses. The study is funded by The University of Hong Kong, with consumables for IRE and TMA provided free of charge by Zhejiang CuraWay Medical Technology Co., Ltd. and Chindex Hong Kong Limited, respectively.

Inclusion Criteria:

1. Men aged ≥50 years

2. Life expectancy >10 years

3. Histologically confirmed localized prostate cancer, ISUP Grade Group 2 or 3

4. At least one clinically significant cancer focus (≥1 systematic biopsy core with Grade Group 2-3) that is MRI-invisible, defined as:

   - The corresponding sextant/region on mpMRI (performed within 6 months) shows PI-RADS v2.1 score 1 or 2, or no identifiable lesion that could account for the positive biopsy

5. Total of 1-2 discrete cancer foci (MRI-visible + PET-detected MRI-invisible) on study entry, with each MRI-visible focus having maximum diameter ≤15 mm on mpMRI

6. Organ-confined disease on mpMRI and no evidence of seminal vesicle invasion or lymph node/distant metastasis

7. Serum PSA <20 ng/mL

8. Able to provide informed consent

Exclusion Criteria:

1. Previous treatment for prostate cancer (radiotherapy, surgery, focal therapy, androgen deprivation)
2. Prior pelvic radiotherapy for any cause
3. Contraindication to MRI or gadolinium contrast
4. Contraindication to PSMA PET-CT (e.g. severe claustrophobia, inability to lie flat)
5. Contraindication to general or spinal anaesthesia
6. Uncorrectable coagulopathy (INR >1.5, platelet <50×10⁹/L) or anticoagulant/antiplatelet therapy that cannot be stopped (low-dose aspirin 80-100 mg is permitted)
7. Active urinary tract infection or acute prostatitis
8. MRI-invisible focus located in a region where focal therapy would likely cause sphincter or rectal injury, as determined by biopsy mapping and anatomical constraints
9. Bladder pathology (bladder stone, bladder cancer) or known urethral stricture