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

This phase 2 randomized comparative study investigates the de-escalation of systemic therapy for patients with metastatic hormone-sensitive prostate cancer (mHSPC) (STEPDOWNmHSPC i.e. Strategy for Therapy Escalation Pruning in metastatic Hormone Sensitive Prostate Cancer)who have achieved an optimal response to initial treatment.

A. Background and Rationale:

In India, 40-60% of patients diagnosed with prostate cancer present with metastatic disease, a significantly higher rate than the 5-10% observed in Western cohorts. While indefinite doublet or triplet therapies (combining androgen deprivation therapy [ADT], androgen receptor pathway inhibitors [ARPI], and sometimes docetaxel) are the standard of care, they cause substantial cumulative physical, metabolic, and financial toxicities. Because a significant sub-population of patients achieves a deep response to these therapies, this trial evaluates whether carefully selected patients can safely de-escalate to ADT monotherapy without compromising oncological outcomes.

B. Study Objectives:

• Primary Objective: To determine if de-escalation to ADT monotherapy is non-inferior to continuing doublet or triplet therapy regarding 18-month radiographic progression-free survival (rPFS) and PSA Progression-Free Survival (PSA-PFS).
• Secondary Objectives: To compare overall survival, time to castration-resistant prostate cancer (CRPC), sustained complete PSMA PET responses at 12 and 24 months, quality of life (using EORTC QLQ-C30 i.e. European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30), incidence of severe adverse events, and economic burden between the two arms.

C. Study Design and Methodology:

• Target Population: Adult men with histologically confirmed prostate adenocarcinoma, an ECOG (Eastern Co-operative Oncology Group) performance status of 0-2, and documented metastatic disease on PSMA PET/CT.
• Run-In Phase: The study will initially enrol approximately 265 patients, who will undergo 6 to 7 months of standard doublet or triplet therapy.
• Randomization: Following the run-in phase, patients who achieve an "optimal response"-defined as a serum PSA < 0.2 ng/mL, castrate testosterone levels (< 50 ng/dL), and a partial or complete response on PSMA PET/CT with no new lesions-will be randomized 1:1 into two arms. The trial targets 170 randomized patients (85 per arm) to account for an estimated 10% attrition rate.

Arm A (Continuation): Patients will continue their initial ADT and ARPI regimen at the same doses.

Arm B (De-escalation): Patients will discontinue the ARPI and continue with ADT monotherapy.

D. Statistical Analysis:

To establish non-inferiority, the study utilizes a 15% margin with 80% power and a one-sided alpha of 0.10. Radiographic progression-free survival will be estimated using the Kaplan-Meier method, and treatments will be compared using a stratified log-rank test and Cox proportional hazards regression based on randomization stratification factors. The primary analysis will be performed on both the Intention-To-Treat (ITT) and Per-Protocol (PP) populations, requiring consistent findings in both to declare non-inferiority.

Inclusion criteria

Inclusion criteria

for enrolment:

• All patients of age group 18 to 80 years will be included
• Patients who would voluntarily agree to sign informed consent form
• Histologically confirmed adenocarcinoma of the prostate
• Evidence of metastatic disease at diagnosis (de novo) or after definitive local therapy, documented on PSMA PET/CT
• 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
• ECOG performance status 0-2
• 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
• Life expectancy ≥ 12 months

Criteria for randomization ("optimal responder"):

• Completion of 6-7 months of protocol-defined doublet or triplet therapy without unplanned interruption > 30 days
• Serum PSA < 0.2 ng/mL at re-staging
• Serum testosterone at castrate level (< 50 ng/dL)
• 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
• ECOG 0-2 at re-staging
• Adequate organ function (as at baseline)
• Ongoing willingness to participate and to comply with randomized treatment

Exclusion criteria

Exclusion criteria

for enrolment:

• Known small-cell, neuroendocrine or predominantly sarcomatoid histology
• 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
• Prior treatment with any ARPI, docetaxel, cabazitaxel, Ra-223 or 177Lu-PSMA
• 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
• Known active second malignancy requiring systemic therapy (except adequately treated non-melanoma skin cancer)
• Active uncontrolled infection including HIV, hepatitis B or C with detectable viral load, or tuberculosis on active treatment
• Any contraindication to the chosen ARPI, docetaxel or ADT per respective product labels
• Psychiatric or cognitive disorder limiting capacity to consent or comply with protocol

Exclusion criteria

at randomization:

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