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:

1. 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).
2. 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:

1. 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.
2. Run-In Phase: The study will initially enrol approximately 265 patients, who will undergo 6 to 7 months of standard doublet or triplet therapy.
3. 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.

• De-escalation strategy (Other): The experimental intervention is a response-adapted de-escalation to Androgen Deprivation Therapy (ADT) monotherapy, achieved by completely discontinuing Androgen Receptor Pathway Inhibitor (ARPI) treatment (and associated corticosteroids). This de-escalation is initiated only after patients complete a 6-to-7-month run-in phase of standard doublet or triplet therapy.
• Continuation of initial Androgen Deprivation Therapy (ADT) and Androgen Receptor Pathway Inhibitor (ARPI) combination therapy at standard doses (Drug): Arm-A serves as the standard-of-care control arm, in which patients continue their intensified combination therapy despite having achieved a deep clinical and molecular response. The intervention strictly involves continuing the identical Androgen Deprivation Therapy (ADT) and Androgen Receptor Pathway Inhibitor (ARPI) regimen-such as abiraterone, enzalutamide, apalutamide, or darolutamide-administered during the 6-to-7-month run-in phase, maintained at original doses.

Primary outcomes

• 18-month radiographic progression-free survival (rPFS) [Assessed from the date of randomization up to 18 months, with routine PSMA PET/CT imaging conducted every 6 months (patients without an event at 18 months are censored at their last assessment)]: Time from randomization to the earliest of: radiographic progression per PCWG4 on PSMA PET; unequivocal progression on PSMA PET (≥ 2 new lesions or PPP progression); or death from any cause. Patients without an event at 18 months are censored at last assessment.
• PSA progression-free survival [Assessed from the time of randomization until confirmed PSA progression or death, evaluated every 3 months for the first 24 months and every 6 months thereafter, through the total follow-up period (minimum 24 months post-randomization; up to 60 months)]: Time from randomization to confirmed PSA progression per PCWG4 (≥ 25 % rise and ≥ 2 ng/mL above nadir, confirmed ≥ 3 weeks later), or death

Secondary outcomes

• Time to CRPC [Through study completion, an average of 5 years]: Time from randomization to castration resistance per EAU/PCWG4 definition
• Overall survival [Assessed continuously from the date of randomization until death from any cause, with survival follow-up conducted every 6 months until study conclusion (up to approximately 60 months total duration)]: Time from randomization to death from any cause
• PSMA PET complete response [From randomization, at 12 and 24 months]: Proportion with sustained PSMA PET complete response per modified PPP/RECIP at 12 and 24 months
• Change in Quality of Life Measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) [Assessed via changes from baseline, measured at screening, at the 6-7 month re-staging/randomization visit, and every 3 months post-randomization for the first 24 months]: Change from baseline in health-related quality of life assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). The EORTC QLQ-C30 includes a Global Health Status/Quality of Life (GHS/QoL) scale, functional scales, and symptom scales/items. All scales and single items range from 0 to 100. For the Global Health Status and functional scales, a higher score represents a higher/better level of functioning and quality of life. For symptom scales and items, a higher score represents a higher/worse level of symptoms or problems.
• Incidence of Toxicity [Monitored continuously and evaluated at every scheduled visit (every 3 months during the 6-7 month run-in phase, every 3 months for the first 24 months post-randomization, and every 6 months (up to 60 months)]: Incidence of grade ≥3 AEs per CTCAE (Common Terminology Criteria for Adverse Events) v5.0

Other outcomes

• Biomarker-outcome associations [PSMA PET metrics, are assessed at baseline, at the 6-to-7-month re-staging visit, every 6 months post-randomization up to 60 months]: Baseline and on-treatment PSMA PET metrics

Sex: Male, ages: 18 Years to 80 Years

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