Randomized Phase 2 Assessment of De-escalation to Androgen Deprivation Therapy Alone Versus Continuation of Doublet or Triplet Therapy in Responders With Metastatic Hormone-Sensitive Prostate Cancer
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 170
- 试验地点
- 1
- 主要终点
- 18-month radiographic progression-free survival (rPFS)
研究概览
简要总结
The goal of this randomized comparative study (a study where participants are placed into groups by chance) is to find out if reducing treatment to androgen deprivation therapy (ADT)-a treatment that lowers testosterone-by itself works just as well as continuing the original combination of drugs. This study involves adult men with metastatic hormone-sensitive prostate cancer (prostate cancer that has spread to other parts of the body but still responds to hormone treatments) who have responded very well after 6 to 7 months of their initial two-drug or three-drug treatment.
The main questions it aims to answer are:
- Does reducing treatment to ADT alone work as well as the combination treatment at keeping the cancer from growing on imaging scans after 18 months, also known as radiographic progression-free survival (rPFS)?
- Does reducing treatment to ADT alone work as well as the combination treatment at preventing a rise in prostate-specific antigen (PSA), known as PSA progression-free survival (PSA-PFS)?
Researchers will compare a continuation group, which continues their initial two-drug or three-drug treatment, to a reduced-treatment group, which stops taking the androgen receptor pathway inhibitor (ARPI)-a drug that blocks the effects of hormones on cancer cells. Researchers want to see if reducing the treatment safely controls the cancer while lowering drug side effects and financial costs.
Participants will:
- Complete a 6- to 7-month initial period receiving a two-drug or three-drug treatment chosen by their doctor.
- Have blood tests for PSA and testosterone, and undergo a specialized imaging scan called a prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) scan, to confirm the treatment is working very well before being assigned to a study group.
- Stop taking the ARPI drug if assigned to the reduced-treatment group, or continue their current medications if assigned to the continuation group.
- Go to check-up visits every 3 months for the first 24 months to complete physical exams, blood tests, and quality-of-life surveys.
- Have a PSMA PET/CT scan every 6 months after being put into a group to check if the cancer has grown.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Arm A - Continuation
Patients continue the same ADT and ARPI that were administered during the run-in phase, at the same doses, until radiographic progression, unacceptable toxicity, death, withdrawal of consent, or end of assessment. Docetaxel will have been completed by month 6 and is therefore not continued.
干预措施: Continuation of initial Androgen Deprivation Therapy (ADT) and Androgen Receptor Pathway Inhibitor (ARPI) combination therapy at standard doses (Drug)
Arm B - De-escalation
Patients discontinue the ARPI (and any corticosteroid associated with abiraterone) at the randomization visit. ADT is continued uninterrupted at the same schedule as during the run-in phase. No other systemic anti-cancer therapy is administered unless progression is documented.
干预措施: De-escalation strategy (Other)
结局指标
主要结局
18-month radiographic progression-free survival (rPFS)
时间窗: 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
时间窗: 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
次要结局
- PSMA PET complete response(From randomization, 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)
- Time to CRPC(Through study completion, an average of 5 years)
- 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))
- 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))
研究者
Dr. TB Yuvaraja
Director (Group) - Uro-Oncology and Robotic Surgery
Kokilaben Dheerubhai Ambani Hospital and Research