A Study Testing if Patients With Advanced Prostate Cancer Who Are Responding Well to Combination Treatment Can Safely Reduce Their Medication to a Single Hormone Therapy, Compared to Continuing Their Current Drugs

Inclusion Criteria:

Inclusion criteria for enrolment:

1. All patients of age group 18 to 80 years will be included
2. Patients who would voluntarily agree to sign informed consent form
3. Histologically confirmed adenocarcinoma of the prostate
4. Evidence of metastatic disease at diagnosis (de novo) or after definitive local therapy, documented on PSMA PET/CT
5. Intended to receive ADT plus an ARPI (abiraterone, enzalutamide, apalutamide or darolutamide) OR ADT plus ARPI plus docetaxel, as determined by the treating physician prior to enrolment
6. ECOG performance status 0-2
7. Adequate organ function: haemoglobin ≥ 9 g/dL; absolute neutrophil count ≥ 1.5 × 10⁹/L; platelets ≥ 100 × 10⁹/L; serum creatinine ≤ 1.5 × ULN or estimated GFR ≥ 45 mL/min; total bilirubin ≤ 1.5 × ULN; AST/ALT ≤ 2.5 × ULN
8. Life expectancy ≥ 12 months

Criteria for randomization ("optimal responder"):

1. Completion of 6-7 months of protocol-defined doublet or triplet therapy without unplanned interruption \> 30 days
2. Serum PSA \< 0.2 ng/mL at re-staging
3. Serum testosterone at castrate level (\< 50 ng/dL)
4. PSMA PET/CT demonstrating partial or complete response as per PPP criteria: (i) no new PSMA-avid lesions; (ii) \> 30 % decrease in total PSMA tumour volume compared with baseline; and (iii) no progression at existing sites
5. ECOG 0-2 at re-staging
6. Adequate organ function (as at baseline)
7. Ongoing willingness to participate and to comply with randomized treatment

Exclusion Criteria:

Exclusion criteria for enrolment:

1. Known small-cell, neuroendocrine or predominantly sarcomatoid histology
2. Prior systemic therapy for prostate cancer other than ≤ 90 days of ADT (± a short course of first-generation anti-androgen for flare prevention) at enrolment
3. Prior treatment with any ARPI, docetaxel, cabazitaxel, Ra-223 or 177Lu-PSMA
4. Uncontrolled hypertension (systolic ≥ 160 mm Hg or diastolic ≥ 100 mm Hg despite therapy), history of seizures or predisposing conditions (for enzalutamide candidates), unstable cardiac disease, recent myocardial infarction or stroke within 6 months
5. Known active second malignancy requiring systemic therapy (except adequately treated non-melanoma skin cancer)
6. Active uncontrolled infection including HIV, hepatitis B or C with detectable viral load, or tuberculosis on active treatment
7. Any contraindication to the chosen ARPI, docetaxel or ADT per respective product labels
8. Psychiatric or cognitive disorder limiting capacity to consent or comply with protocol

Exclusion criteria at randomization:

1. Serum PSA ≥ 0.2 ng/mL or any PSA rise above nadir of ≥ 25 %
2. Any new lesion on PSMA PET or conventional imaging
3. Progression at existing sites per PCWG4 or PPP
4. Testosterone ≥ 50 ng/dL (non-castrate)
5. Development of symptomatic disease (e.g. new bone pain requiring opioid therapy, cord compression, pathological fracture)
6. Grade ≥ 3 ongoing toxicities attributable to current therapy that precludes continuation
7. Withdrawal of consent