Apalutamide With Radiotherapy and Androgen Deprivation Therapy in Prostate Cancer (ARN-509)

Radiotherapy and 6-month Androgen Deprivation Therapy With or Without Apalutamide in Intermediate and Limited High Risk Localized Prostate Cancer: a Phase III Study

The main objective of the trial to determine if the combination of apalutamide with 6 months of androgen deprivation therapy by LHRH agonists in patients with intermediate and limited high-risk, localized prostate cancer receiving primary radiation therapy (RT) results in an improvement of disease-free survival (DFS) evaluated by the treating physician, in comparison to the combination of radiation and androgen deprivation therapy without the addition of apalutamide.

Study Overview

• Status: Withdrawn
• Conditions: Prostate Cancer
• Intervention / Treatment: Other: Radiation Therapy; Drug: Luteinising Hormone Releasing Hormone analog agonist (LHRHa); Drug: Non-steroidal anti-androgen; Drug: Apalutamide

• Study Type: Interventional
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Histologically confirmed diagnosis of prostate adenocarcinoma diagnosed by ultrasound guided biopsy of the prostate containing 10-12 cores showing no neuroendocrine component
• Either of: Favorable intermediate risk (according to EAU risk groups): PSA 10-20 ng/mL, -or Gleason score 7 (3 +4) (ISUP Grade 2), or cT2b. Infavorable intermediate risk (according to EAU risk groups): PSA 10-20 ng/mL, -or Gleason score 7 (4+3) (ISUP Grade 3), or cT2b. Limited high risk : PSA > 20 ng/mL or Gleason score >7 (ISUP Grade 4/5)
• M0 by standard imaging work-up
• Scheduled to be treated with primary prostate RT
• WHO Performance Status ≤ 2
• No risk of urinary retention based on the International Prostate Symptom Score (IPSS) : IPSS < 20
• Adequate liver function determined by the following: aspartate aminotransferase (AST), alanine aminotransferase (ALT), < 2.5 x upper limit of normal (ULN). Total bilirubin <1.5 x upper limit of normal (ULN)
• Adequate renal function: creatinine level < 2 x ULN
• Serum albumin ≥ 3.0 g/dL
• Serum potassium ≥ 3.5 mmol/L
• Hemoglobin ≥ 10.0 g/dL, independent of transfusion and/or growth factors within 3 months prior to randomization
• Platelet count ≥ 100,000 x 109/L independent of transfusion and/or growth factors within 3 months prior to randomization
• Be able to swallow whole study drug tablets

Exclusion Criteria:

• cT2c, T3, T4 or pelvic lymph nodes involvement, as assessed by CT scan or MRI (cN1) or pelvic lymph node dissection (pN1)
• Previous pelvic irradiation or radical prostatectomy.
• Bilateral orchiectomy
• Prior systemic (e.g., chemotherapy) or procedural (e.g., prostatectomy, cryotherapy) treatment for prostate cancer
• Prior treatment with 5-alpha reductase inhibitors for benign prostatic hypertrophy not discontinued 4 weeks prior to randomization
• Prior treatment with any LHRH agonist or antagonist, bicalutamide, flutamide or nilutamide, enzalutamide, abiraterone acetate, orteronel, galeterone, ketoconazole, aminoglutethimide, estrogens, megestrol acetate, and progestational agents for prostate cancer
• Prior treatment with radiopharmaceutical agents (e.g., strontium-89) or immunotherapy for prostate cancer
• Other malignancy except adequately treated basal cell carcinoma of the skin or other malignancy from which the patient has been cured for at least 5 years.
• History of Ulcerative Colitis, Crohn's Disease, Ataxia Telangiectasia, systemic lupus erythematosus or Fanconi anemia
• History of seizure or condition that may predispose to seizure (including, but not limited to prior stroke, transient ischemic attack or loss of consciousness ≤ 1 year prior to randomization; brain arteriovenous malformation; or intracranial masses such as schwannomas and meningiomas that are causing edema or mass effect).
• Medications known to lower the seizure thresholdmust be discontinued or substituted at least 4 weeks prior to study entry
• Certain risk factors for abnormal heart rhythms/QT prolongation: torsade de pointes ventricular arrhythmias (e.g., heart failure, hypokalemia, or a family history of a long QT syndrome), a QT or corrected QT (QTc) interval > 450 ms at baseline
• Uncontrolled hypertension (systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg); patients with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment
• Bilateral hip prostheses
• Prior treatment with systemic glucocorticoids ≤ 4 weeks prior to randomization or is expected to require long-term use of corticosteroids during the study
• Use of any investigational agent ≤ 4 weeks prior to randomization
• Current chronic use of opioid analgesics for ≥3 weeks for oral or ≥ 7 days for non-oral formulations
• Major surgery ≤ 4 weeks prior to randomization
• Known or suspected contraindications or hypersensitivity to apalutamide, bicalutamide or LHRHa agonists or any of the components of the formulations
• Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm A: ADT + radiation therapy; Patient will receive 2 injections of a three-monthly LHRH agonist depot plus non-steroidal anti-androgen (rescue treatment) (e. g. flutamide, bicalutamide) PO daily for 4 weeks, started 2 weeks before the first LHRH agonist injection. All patients will receive standard fractionation radiation therapy (RT) between 0 and 12 weeks after first injection of LHRH agonist.	Other: Radiation Therapy; Dose escalated Intensity-Modulated Radiation therapy (IMRT) with conventional fractionation, hypofractionation and prostate brachytherapy are allowed.; Drug: Luteinising Hormone Releasing Hormone analog agonist (LHRHa); 2 injections of a three-monthly LHRH agonist depot; Drug: Non-steroidal anti-androgen; Non-steroidal anti-androgen (e. g. flutamide, bicalutamide) PO daily for 4 weeks, started 2 weeks before the first LHRH agonist injection
Experimental: Arm B: ADT + radiation therapy + Apalutamide; Patients will receive 2 injections of a three-monthly LHRH agonist depot. Apalutamide treatment: 240 mg PO daily, started the same day as the first LHRHa injection, for 6 months. All patients will receive standard fractionation radiation therapy (RT) between 0 and 12 weeks after first injection of LHRH agonist.	Other: Radiation Therapy; Dose escalated Intensity-Modulated Radiation therapy (IMRT) with conventional fractionation, hypofractionation and prostate brachytherapy are allowed.; Drug: Luteinising Hormone Releasing Hormone analog agonist (LHRHa); 2 injections of a three-monthly LHRH agonist depot; Drug: Apalutamide; 240 mg PO daily, started the same day as the first LHRHa injection, for 6 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease-free survival	Events for this endpoint include loco-regional recurrence, distant metastases (radiologically or pathologically confirmed), death from any cause, whichever occurs first	7.8 years from First Patient In (FPI)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival	includes first events of biochemical failure by Phoenix criteria in addition to the events listed in the primary endpoint DFS	7.8 years from First Patient In (FPI)
Distant Metastasis-free survival		7.8 years from First Patient In (FPI)
Overall survival		7.8 years from First Patient In (FPI)
Prostate cancer specific survival		7.8 years from First Patient In (FPI)
Prostate-Specific Antigen (PSA) value	Prostate-Specific Antigen (PSA) value will be assessed at the end of the treatment of each patient	5.5 years from First Patient In (FPI)
Adverse events graded according to the National Cancer Institute Common Occurrence of Adverse Events	Adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for adverse events (NCI-CTCAE) version 4.0	7.8 years from First Patient In (FPI)
Health-related quality of life	Health-related quality of life will be evaluated using self-administered EORTC QLQ-C30 questionnaire	7.8 years from First Patient In (FPI)
Health-related quality of life	Health-related quality of life will be evaluated using EORTC QLQ-PR25 instruments	7.8 years from First Patient In (FPI)
Prostate-Specific Antigen (PSA) nadir	Prostate-Specific Antigen (PSA) nadir will be assessed as the lowest value achievement on treatment	5.5 years from First Patient In (FPI)

Collaborators and Investigators

• Sponsor: European Organisation for Research and Treatment of Cancer - EORTC
• Investigators: Principal Investigator: Gilles Crehange, Centre Georges François Leclerc; Principal Investigator: Michel Bolla, CHU de Grenoble - La Tronche - Hôpital A. Michallon, France

Study record dates

Study Major Dates

• Study Start (Anticipated): March 10, 2020
• Primary Completion (Anticipated): June 15, 2026
• Study Completion (Anticipated): June 15, 2026

Study Registration Dates

• First Submitted: March 27, 2018
• First Submitted That Met QC Criteria: April 4, 2018
• First Posted (Actual): April 5, 2018

Study Record Updates

• Last Update Posted (Actual): August 17, 2020
• Last Update Submitted That Met QC Criteria: August 13, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Keywords: Apalutamide Prostate Cancer Radiotherapy
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Hormones; Androgens; Androgen Antagonists; Nonsteroidal Anti-Androgens
• Other Study ID Numbers: EORTC-1531-ROG

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No