Multimodal Approach in Patients With mHSPC. Randomized Trial of APA+ADT vs APA-ADT and Local Treatment

Study Overview
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Brief Summary
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Italian multicenter study, will enroll  566 pts with oligometastatic hormone sensitive prostate cancer who are candidates to receive treatment with apalutamide. After 6 months from the start of treatment, patients will be randomized to receive local treatment based on the investigator's choice ( either one between primary radiotherapy or cytoreductive prostatectomy), in addition to apalutamide, or to continue just with medical therapy.

Detailed Description
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Primary end point: To determine whether treatment with apalutamide in combination with androgen-deprivative therapy for 6 months followed by locoregional treatment with radiotherapy or radical prostatectomy has better efficacy than medical treatment with apalutamide + ADT alone in terms of radiographic progression-free survival (rPFS), specifically time to radiographic progression in soft tissue per RECIST 1.1 or in bone per PCWG3 criteria by investigator, or death. Secondary end points: To evaluate tumor shrinkage after locoregional approach and to evaluate short and long term side effects after locoregional surgery or RT, time to PSA progression, time to castration resistance, cancer specific survival, overall survival and quality of life according to EPIC-26 and EQ-5D-5L questionnaires.

Official Title
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APPROACH : Multimodal Approach in Patients With mHSPC. A Pragmatic Randomized Trial of Apalutamide Plus Androgen Deprivation Therapy (APA-ADT) Versus APA-ADT Plus Local Treatment. A Meet-URO 29 Study

Conditions
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Metastatic Hormone-Sensitive Prostate Cancer (mHSPC)

Intervention / Treatment
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* Drug: APA + ADT
* Procedure: Local Treatmetn RT or RP


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 18 Histologically confirmed diagnosis of prostate adenocarcinoma Metastatic disease documented by ≥1 bone lesion with Technetium 99m (99mTc) bone scan. Individuals with only one bone lesion should have confirmation of that lesion on CT or MRI. Eastern Cooperative Oncology Group Performance Status (ECOG PS) Grade ≤ 2 No previous treatment with antiandrogens or GnRH analogues, or a treatment ≤ 3 months. No previous systemic or local treatment for prostate adenocarcinoma, including pelvic radiotherapy. Laboratory values at the time of screening: a. Neutrophils ≥ 1500/μL b. Hemoglobin ≥ 9.0 mg/μL (no transfusions in the past 28 days) c. Platelets ≥ 100,000/μL d. Creatinine ≤ 2 x upper limit of normal and serum albumin ≥ 3.0 g/dL f. Total bilirubin ≤ 1.5 x upper limit of normal [NOTE: In subjects with Gilbert syndrome, if total bilirubin is >1.5 x ULN, measure direct and indirect bilirubin, and if direct bilirubin is ≤ 1.5 x ULN subjects may be eligible]; g. AST and ALT ≤ 2.5 x upper limit of normal Able to swallow Apalutamide tablets whole. All subjects must sign an Informed Consent Form indicating that they understand the purpose of the study and its procedures and intend to participate. The subject must be willing and must be able to comply with the restrictions specified in this protocol. Inclusion criteria for cytoreductive surgery: Age >18 years Clinical stage cT3 Robot-assisted radical prostatectomy with iliac obturator lymphadenectomy Surgical piece management criteria similar to Proteus criteria. Exclusion Criteria: Pathologic findings consistent with small cell, ductal, or neuroendocrine prostate cancer. Known brain metastases. Lymph node metastases only. Visceral metastases. Patients not eligible for surgery or radiotherapy. Unacceptable increase in cardiovascular risk, defined as the occurrence of at least one of the following episodes in the 6 months prior to randomization: unstable angina, myocardial infarction, symptomatic congestive heart failure, clinically significant thromboembolic events (e.g., pulmonary embolism), or clinically significant ventricular arrhythmias . Uncontrolled high blood pressure (systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg). Previous treatment with antiandrogens, GnRH analogues, or other systemic treatments for adenocarcinoma of the prostate. Previous local treatment with surgery and/or radiotherapy. Any prior malignancy (except adequately treated basal cell carcinoma or a squamous cell skin carcinoma, superficial bladder carcinoma, or any other in situ carcinoma currently in complete remission) within 5 years of randomization. Known allergies, hypersensitivity or intolerance to the excipients of Apalutamide. Patients who, within 28 days prior to randomisation, have received: transfusions (red blood cells and/or platelets); hematopoietic growth factors; major surgery. Symptomatic and/or chronic viral hepatitis; chronic liver disease; moderate or severe liver failure (class B and C according to the Child-Pugh scale); encephalopathy, ascites or thrombo-haemorrhagic disorders secondary to liver failure. Gastrointestinal disorders affecting drug absorption Active infections requiring systemic therapy such as human immunodeficiency virus (HIV); Any condition or situation which, in the judgment of the investigator, precludes participation in this trial. Exclusion criteria for cytoreductive surgery: Contraindication for surgery

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: APA + ADT + RP/RT<br>Apalutamide 240 mg, four 60 mg tablets as an oral single daily dose, according to clinical practice, plus Androgen Deprivation Therapy (ADT) plus clinician-driven choice local treatment with Radiotherapy or Radical Prostatectomy, six months after starting treatment with apalutamide | Drug: APA + ADT<br>* All participants will receive apalutamide 240 mg (4 x 60 mg) tablets orally once daily. Apalutamide is distributed in Italy under the trade name of Erleada® 60 mg. All patients not undergoing surgical castration should also continue medical castration by taking a gonadotropin-releasing hormone (GnRHa) analogue during treatment.<br>* Other names: Apalutamide 240 mg + Androgen Deprivation Therapy;Procedure: Local Treatmetn RT or RP<br>* Patients who will undergo radiotherapy as a local treatment must be treated according to the following scheme: External beam radiotherapy administered at 36 Gy in six consecutive weekly fractions of 6 Gy, or 55 Gy in 20 daily fractions of 2・75 Gy over 4 weeks. Radiation therapy will be given with the patient supine and with a full bladder and an empty rectum. The planned target volume is prostate only, with an 8 mm margin posteriorly and a 10 mm margin elsewhere. No RT on lymph nodes is foreseen. RT should begin 6 months after the first dose of apalutamide (+/- 2 weeks). Radical prostatectomy should be performed 6 months after the first dose of apalutamide (+/- 2 weeks).<br>* Other names: Local treatment with radiotherapy or radical prostatectomy, clinician-driven choice;|
| Other: APA + ADT<br>Apalutamide 240 mg, four 60 mg tablets as an oral single daily dose, according to clinical practice, plus Androgen Deprivation Therapy (ADT) | Drug: APA + ADT<br>* All participants will receive apalutamide 240 mg (4 x 60 mg) tablets orally once daily. Apalutamide is distributed in Italy under the trade name of Erleada® 60 mg. All patients not undergoing surgical castration should also continue medical castration by taking a gonadotropin-releasing hormone (GnRHa) analogue during treatment.<br>* Other names: Apalutamide 240 mg + Androgen Deprivation Therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiographic Progression-Free Survival (rPFS) | Evaluation of the efficacy of treatment with APA+ADT for 6 months followed by locoregional treatment with radiotherapy or radical prostatectomy compared to treatment with APA+ ADT alone in terms of Radiographic Progression-Free Survival (rPFS) in patients with hormone prostate adenocarcinoma -susceptible with low-volume metastatic disease. | Up to 48 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local event - free survival | Defined as the absence of one of the following conditions in the follow up: urinary retention, hydronephrosis, acute or chronic renal failure exacerbation, intestinal obstruction | Up to 48 months | 
| Local treatment - free survival | Defined as the absence of the need for one of the following interventions: trans-urethral resection of the prostate, placement of a ureteral stent or nephrostomy for hydronephrosis, bladder catheterization, surgery for intestinal obstruction/colostomy | Up to 48 months |