Neoadjuvant And Adjuvant Abiraterone Acetate + Apalutamide Prostate Cancer Undergoing Prostatectomy

Study Overview
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Brief Summary
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This multicenter randomized phase II trial investigates the impact of intense androgen deprivation on radical prostatectomy (RP) pathologic response and radiographic and tissue biomarkers in localized prostate cancer (NCT02903368).

Detailed Description
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This is a multicenter, phase II, prospective, randomized trial designed to investigate the efficacy of neoadjuvant and adjuvant abiraterone acetate + apalutamide for men with intermediate-high risk prostate cancer who are candidates for RP. The study includes two parts. In part 1, patients will be randomized in 1:1 ratio to receive 6 months of abiraterone acetate, apalutamide, leuprolide and prednisone (Arm 1A) versus 6 months of abiraterone acetate, leuprolide and prednisone (Arm 1B) followed by RP, stratified by risk factor (intermediate versus high-risk). High-risk factors will be defined as a Gleason score ≥ 8, PSA > 20 ng/dL, or T3 disease on MRI. In part 2 (post-RP), patients will be randomized in 1:1 ratio to receive an additional 12 months of abiraterone acetate, apalutamide, leuprolide and prednisone (Arm 2A) or observation (Arm 2B) stratified by type of neoadjuvant therapy and pathological T-stage (< pT3 versus ≥ pT3) after RP but before cycle 7 day 1 following neoadjuvant therapy. There will be an early stopping rule for Part 2 should a high rate of patients refuse to participate or drop out early while receiving adjuvant therapy (<6 months).

Official Title
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Phase II Randomized Study Of Neoadjuvant And Adjuvant Abiraterone Acetate + Apalutamide For Intermediate-High Risk Prostate Cancer Undergoing Prostatectomy

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Apalutamide
* Drug: Leuprolide
* Drug: Prednisone
* Drug: Abiraterone Acetate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male ≥ 18 years of age. Histologically confirmed adenocarcinoma of the prostate without histological variants comprising >50% of the sample as determined by academic center central review (including neuroendocrine differentiation, small cell, sarcomatoid, ductal adenocarcinoma, squamous or transitional cell carcinoma). Must have 3 core biopsies involved with cancer (a minimum of 6 core biopsies must be obtained). Prostate biopsy must be within seven months from screening. Less than 3 core biopsies are allowed if the patient has >1 cm or T3 disease on MRI. Patients must have the following features: Gleason ≥ 4+3=7 OR Gleason 3+4=7 AND at least one of the following: PSA >20 ng/dL or T3 disease (as determined by MRI). No evidence of metastatic disease as determined by radionuclide bone scans and CT/MRI. Lymph nodes must be less than 20 mm in the short (transverse) axis. Participants must be candidates for RP and considered surgically resectable by urologic evaluation. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Participants must have normal organ and marrow function as defined below: Hemoglobin ≥ 9.0 g/dL Absolute neutrophil count (ANC) ≥ 1,500/mcL Platelets ≥ 100,000/mcL, independent of transfusions/growth factors within 3 months of treatment start Serum potassium ≥ 3.5 mmol/L Serum total bilirubin ≤ 2.0 x upper limit of normal (ULN) (except in subjects with Gilbert's syndrome who have a total bilirubin > 1.5 x ULN, measure direct and indirect bilirubin and if direct bilirubin is ≤ 1.5 x ULN, subject may be eligible) Aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤ 2.5 x ULN Serum albumin ≥ 3.0 g/dL Serum creatinine < 2.0 x ULN PTT≤60 Participant must agree to use a condom (even men with vasectomies) and another effective method of birth control if having sex with a woman of childbearing potential or must agree to use a condom if he is having sex with a woman who is pregnant while on study drug and for 3 months following the last dose of study drug. Participant must also agree not to donate sperm during the study and for 3 months after receiving the last dose of study drug. Medications known to lower the seizure threshold (see list under APPENDIX D: Representative Medications that May Predispose to Seizure) must be discontinued or substituted at least 1 week prior to study treatment. Exclusion Criteria: Prior hormone therapy for prostate cancer including orchiectomy, antiandrogens (including first-generation antiandrogens, enzalutamide, Apalutamide and others), CYP17 inhibitors (including abiraterone acetate, TAK-700, galeterone, ketoconazole, and others), estrogens, Luteinizing Hormone Releasing Hormone (LHRH) agonist/antagonists. Prior therapy with 5α-reductase inhibitors is allowed. LHRH therapy allowed if begun within 4 weeks of day 1. Prior chemotherapy, radiation therapy, or immunotherapy for prostate cancer. Prior systemic treatment with an azole drug within two weeks of start of treatment. Hypogonadism or severe androgen deficiency as defined by screening serum testosterone < 200 ng/dL. Clinically significant cardiovascular disease within 6 months of study treatment including: Severe or unstable angina; Myocardial infarction; Symptomatic congestive heart failure; New York Heart Association (NYHA) class II-IV heart disease; Arterial or venous thromboembolic events (such as pulmonary embolism cerebrovascular accident including transient ischemic attacks); History of clinically significant ventricular arrhythmias (e.g. ventricular tachycardia, ventricular fibrillation, torsades de pointes); Prolonged corrected QT interval by the Fridericia correction formula (QTcF) on screening EKG > 470 msec; History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place; Uncontrolled hypertension (systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg). Participants with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive therapy. History of seizure or any condition or concurrent medication that may predispose to seizure (including but not limited to prior stroke, transient ischemic attack, loss of consciousness within 1 year prior to randomization, brain arteriovenous malformation; or intracranial masses such as schwannomas and meningiomas that are causing edema or mass effect). History of allergic reactions attributed to compounds of similar chemical or biologic composition to Apalutamide, abiraterone acetate, or other study drugs. Severe hepatic impairment (Child-Pugh Class C). Active infection (such as human immunodeficiency virus (HIV) or viral hepatitis) or other medical condition that would make prednisone / prednisolone corticosteroid use contraindicated. History of pituitary or adrenal dysfunction. Gastrointestinal disorders (medical disorders or extensive surgery) which may interfere with the absorption of the study drug. Pre-existing condition that warrants long-term corticosteroid use greater than the equivalent of 10 mg prednisone daily. Physiologic replacement is permitted. Topical, intra-articular, or inhaled corticosteroids are permitted. Concomitant use of medications that may alter pharmacokinetics of abiraterone acetate or Apalutamide. Individuals with a history of a different malignancy are ineligible except for the following circumstances: 1) individuals with a history of other malignancies are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy, or 2) individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: non-muscle invasive bladder cancer, basal cell or squamous cell carcinoma of the skin. Major surgery or radiation therapy within 30 days of screening visit. Participants who have had a major surgery within 30 days of screening visit may be eligible provided the treating investigator deems that the participant is at low risk for complications. Any condition that in the opinion of the investigator would preclude participation in this study.

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1A: AAPL Neoadjuvant Therapy [Part 1]<br>Eligible Participants will be randomized to receive: AAPL: Abiraterone acetate (240 mg/day orally), Apalutamide (1000 mg/day orally), Leuprolide (22.5 mg every 12 weeks intramuscularly), Prednisone (5 mg/twice daily orally) for 6 months Pts x weeks to RP | Drug: Apalutamide<br> <br> * Other names: ARN-509;Drug: Leuprolide<br> <br> * Other names: Eligard;Drug: Prednisone<br> <br> * Other names: Deltasone;Drug: Abiraterone Acetate<br> <br> * Other names: Zytiga;|
| Experimental: Arm 1B: APL Neoadjuvant Therapy [Part 1]<br>Eligible Participants will be randomized to receive: APL: Abiraterone acetate (1000 mg/day orally), Leuprolide (22.5 mg every 12 weeks intramuscularly), Prednisone (5 mg/day orally) for 6 months | Drug: Leuprolide<br> <br> * Other names: Eligard;Drug: Prednisone<br> <br> * Other names: Deltasone;Drug: Abiraterone Acetate<br> <br> * Other names: Zytiga;|
| Experimental: Arm 2A: AAPL Adjuvant Therapy [Part 2]<br>Eligible Participants will be randomized to receive: AAPL: Abiraterone acetate (240 mg/day orally), Apalutamide (1000 mg/day orally), Leuprolide (22.5 mg every 12 weeks intramuscularly), Prednisone (5 mg/twice daily orally) for 12 months | Drug: Apalutamide<br> <br> * Other names: ARN-509;Drug: Leuprolide<br> <br> * Other names: Eligard;Drug: Prednisone<br> <br> * Other names: Deltasone;Drug: Abiraterone Acetate<br> <br> * Other names: Zytiga;|
| No Intervention: Arm 2B: Observation [Part 2]<br> | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Combined pCR or MRD Rate [Part 1] | Pathological response, defined as achieving either pCR or MRD at radical prostatectomy (RP). Pathological Complete Response (pCR) is defined as the absence of morphologically identifiable carcinoma in the RP specimen. MRD will be defined as residual tumor in the RP specimen measuring ≤ 5 mm. | Assessed from RP specimens, at 6 months from the initiation of neoadjuvant therapy. | 
| Biochemical Progression Free Survival (bPFS) Rate at 3 Years Post RP [Part 2] | 3-year bPFS rate is defined as the probability of biochemical progression free and survival at 3 years from the date of Part 2 randomization, which is estimated using Kaplan Meier methods. The event is considered to be biochemical progression (defined as a confirmed PSA ≥ 0.2 ng/mL), local, regional, or distant metastatic disease on CT/MRI or bone scan, or receipt of post-operative systemic therapy or radiotherapy for rising PSA, or death from any cause. Participants who are lost to follow-up before the 3-year mark are censored at date last disease evaluation. | At 3 years post RP | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of pCR at RP (Part 1) | Pathological Complete Response (pCR) is defined as the absence of morphologically identifiable carcinoma in the RP specimen at radical prostatectomy (RP). | Assessed from RP specimens, at 6 months from the initiation of neoadjuvant therapy. | 
| Median of Residual Cancer Burden (RCB) at RP (Part 1) | RCB was calculated as tumor volume (cm^3) X % cellularity. RCB was analyzed as a continuous score (with median and range) instead of a categorical variable based on the percentile cutoff point, at the time of radical prostatectomy (RP). | Assessed from RP specimens, at 6 months from the initiation of neoadjuvant therapy. | 
| Frequency of Presenting Cribriform at RP (Part 1) | Presence or cribriform was evaluated by central pathology review of specimens at radical prostatectomy (RP). | Assessed from RP specimens, at 6 months from the initiation of neoadjuvant therapy. | 
| Frequency of Presenting Intraductal Carcinoma at RP (Part 1) | Intraductal carcinoma was evaluated by central pathology review of specimens at Radical Prostatectomy (RP). | Assessed from RP specimens, at 6 months from the initiation of neoadjuvant therapy. | 
| Frequency of Positive Surgical Margins at RP (Part 1) | Pathologic specimens were centrally reviewed and counted for positive surgical margins at the time of Radical Prostatectomy (RP). | Assessed from RP specimens, at 6 months from the initiation of neoadjuvant therapy. | 
| Percent of Participants With Nadir PSA < 0.2 ng/mL Prior to RP (Part 1) | Prostate specific antigen (PSA) was measured on day 1 of each cycle during the neoadjuvant therapy. PSA nadir was defined as the lowest PSA value prior to Radical Prostatectomy (RP). Number and percent of participants with nadir PSA < 0.2 ng/mL were reported. | Assessed on day 1 of each cycle (1 cycle=28 +/- 2 days), up to 6 months from the initiation of neoadjuvant therapy. | 
| Frequency of Presenting Intra-operative Complications Following RP (Part 1) | Intra-operative complications were collected via questionnaire following Radical Prostatectomy. | Assessed post-RP, at 6 months from the initiation of neoadjuvant therapy. | 
| Biochemical Progression Free Survival (bPFS) Rate at 2 Years Post RP [Part 2] | 2-year bPFS rate is defined as the probability of biochemical progression free and survival at 2 years from the date of Part 2 randomization, which is estimated using Kaplan Meier methods. The event is considered to be biochemical progression (defined as a confirmed PSA ≥ 0.2 ng/mL), local, regional, or distant metastatic disease on CT/MRI or bone scan, or receipt of post-operative systemic therapy or radiotherapy for rising PSA, or death from any cause. Participants who are lost to follow-up before the 2-year mark are censored at date of last disease evaluation. | At 2 years post RP | 
| Biochemical Progression Free Survival (bPFS) Rate at 4 Years Post RP [Part 2] | 4-year bPFS rate is defined as the probability of biochemical progression free and survival at 4 years from the date of Part 2 randomization, which is estimated using Kaplan Meier methods. The event is considered to be biochemical progression (defined as a confirmed PSA ≥ 0.2 ng/mL), local, regional, or distant metastatic disease on CT/MRI or bone scan, or receipt of post-operative systemic therapy or radiotherapy for rising PSA, or death from any cause. Participants who are lost to follow-up before the 4-year mark are censored at date of last disease evaluation. | At 4 years post RP | 
| Rate of Freedom From Further Anti-cancer Therapy at 2-years Post RP (Part 2) | Defined as the probability of freedom from further anti-cancer therapy at 2-years from the date of Part 2 randomization, which is estimated using Kaplan Meier methods. The event includes initiation of anti-cancer therapy (radiation therapy, ADT, or other therapies) for rising PSAs and/or clinical progression. Participants who are lost to follow-up before the 2-year mark are censored at date of last follow-up. | At 2-years post RP | 
| Rate of Freedom From Further Anti-cancer Therapy at 3-years Post RP (Part 2) | Defined as the probability of freedom from further anti-cancer therapy at 3-years from the date of Part 2 randomization, which is estimated using Kaplan Meier methods. The event includes initiation of anti-cancer therapy (radiation therapy, ADT, or other therapies) for rising PSAs and/or clinical progression. Participants who are lost to follow-up before the 3-year mark are censored at date of last follow-up. | At 3 years post RP | 
| Rate of Freedom From Further Anti-cancer Therapy at 4-years Post RP (Part 2) | Defined as the probability of freedom from further anti-cancer therapy at 4-years from the date of Part 2 randomization, which is estimated using Kaplan Meier methods. The event includes initiation of anti-cancer therapy (radiation therapy, ADT, or other therapies) for rising PSAs and/or clinical progression. Participants who are lost to follow-up before the 4-year mark are censored at date of last follow-up. | At 4-years post RP | 
| Mean Scores for Quality of Life (QOL) Questionnaires EPIC-26 at 6-months Post-RP (Part 2) | The QOL will be measured using the Expanded Prostate Cancer Index Composite 26 (EPIC-26). For part 2, the questionnaires will be administered at 6 months, 12 months, and 24 months post RP. Resulting domain scores for EPIC-26 (urinary incontinence, urinary obstruction, sexual, bowel, hormonal/vitality) is on a 0-100 scale, with higher values representing a more favorable health-related QOL. | At 6-months post-RP | 
| Mean Scores for Quality of Life (QOL) Questionnaires EPIC-26 at 12-months Post-RP (Part 2) | The QOL will be measured using the Expanded Prostate Cancer Index Composite 26 (EPIC-26). For part 2, the questionnaires will be administered at 6 months, 12 months, and 24 months post RP. Resulting domain scores for EPIC-26 (urinary incontinence, urinary obstruction, sexual, bowel, hormonal/vitality) is on a 0-100 scale, with higher values representing a more favorable health-related QOL. | At 12-months post-RP | 
| Mean Scores for Quality of Life (QOL) Questionnaires EPIC-26 at 24-months Post-RP (Part 2) | The QOL will be measured using the Expanded Prostate Cancer Index Composite 26 (EPIC-26). For part 2, the questionnaires will be administered at 6 months, 12 months, and 24 months post RP. Resulting domain scores for EPIC-26 (urinary incontinence, urinary obstruction, sexual, bowel, hormonal/vitality) is on a 0-100 scale, with higher values representing a more favorable health-related QOL. | At 24-months post-RP | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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abiraterone acetate, apalutamide, leuprolide, prednisone, neoadjuvant therapy