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

Sponsor

European Organisation for Research and Treatment of Cancer - EORTC (Other)

Overall Status

Withdrawn

CT.gov ID

NCT03488810

Collaborator

(none)

Enrollment

Arms

75.2

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Prostate Cancer	Other: Radiation Therapy Drug: Apalutamide Drug: Luteinising Hormone Releasing Hormone analog agonist (LHRHa) Drug: Non-steroidal anti-androgen	Phase 3

Study Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Mar 10, 2020

Anticipated Primary Completion Date :

Jun 15, 2026

Anticipated Study Completion Date :

Jun 15, 2026

Arms and Interventions

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: Apalutamide 240 mg PO daily, started the same day as the first LHRHa injection, for 6 months Drug: Luteinising Hormone Releasing Hormone analog agonist (LHRHa) 2 injections of a three-monthly LHRH agonist depot

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: Apalutamide

240 mg PO daily, started the same day as the first LHRHa injection, for 6 months

Drug: Luteinising Hormone Releasing Hormone analog agonist (LHRHa)

2 injections of a three-monthly LHRH agonist depot

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

European Organisation for Research and Treatment of Cancer - EORTC

Investigators

Principal Investigator: Gilles Crehange, Centre Georges Francois Leclerc
Principal Investigator: Michel Bolla, CHU de Grenoble - La Tronche - Hôpital A. Michallon, France