A Study of Androgen Annihilation in High-Risk Biochemically Relapsed Prostate Cancer

Study Overview
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Brief Summary
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This is a randomized, open-label, three-arm, phase 3 study in men with biochemically recurrent prostate cancer and PSA doubling time ≤ 9 months at the time of study entry.

Detailed Description
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Patients will be stratified by PSA doubling time (< 3 months vs. 3-9 months) and randomized in 1:1:1 fashion to one of three treatment arms: (1) Control arm consisting of LHRH analogue monotherapy (degarelix or leuprolide), (2) Experimental arm consisting of apalutamide in combination with LHRH analogue, and (3) Experimental arm consisting of apalutamide, abiraterone acetate + prednisone, and LHRH analogue. Patients will be treated for a maximum duration of 52 weeks and then enter follow up phase until the time of PSA progression, development of metastasis, or patient withdrawal from study, whichever occurs first. Patients with PSA progression will be followed long term until the development of castration resistance, first metastasis, and death. The primary endpoint of the study is PSA progression-free survival in the intent-to-treat patient population. PSA progression during the 52-week treatment period is defined as a rising PSA confirmed on repeat measurement, and at least 25% and 2 ng/mL above nadir or baseline, whichever is lower. PSA progression during follow up defined as PSA > 0.2 ng/mL confirmed by repeat measurement at least 2 weeks later. Secondary study endpoints include PSA progression-free survival in testosterone-evaluable population, 36-month PSA progression-free survival rate in both intent-to-treat and testosterone-evaluable populations, time to testosterone recovery, time to castration resistance, metastasis-free survival, quality of life, and safety. Each experimental arm will be compared against the control arm in pair-wise fashion. The study is not powered to detect differences in primary or secondary endpoints between the two experimental arms.

Official Title
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A Phase 3 Study of Androgen Annihilation in High-Risk Biochemically Relapsed Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Apalutamide
* Drug: LHRH Analogue
* Drug: Abiraterone Acetate
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed prostate adenocarcinoma Prior radical prostatectomy Biochemically recurrent prostate cancer with PSA doubling time ≤ 9 months at the time of study entry. Calculation of PSA doubling time should include the use of all available PSA values obtained within past 6-12 months prior to randomization, with a minimum of 3 values separated by at least 2 weeks apart. PSA values obtained prior to therapeutic interventions (e.g. salvage radiation) will be excluded. PSA doubling time to be estimated using Memorial Sloan Kettering Cancer Center online calculator (https://www.mskcc.org/nomograms/prostate/psa-doubling-time) Prior adjuvant or salvage radiation or not a candidate for radiation based upon clinical assessment of disease characteristics and patient co-morbidities. Screening PSA > 0.5 ng/mL No definitive evidence of metastases on screening CT or MRI of abdomen/pelvis and radionuclide whole body bone scan per the judgment of the investigator. Abdominal and/or pelvic lymph nodes measuring 2 cm or less in short axis diameter are allowed. Lesions identified on other imaging modalities (e.g. PSMA or choline PET) that are not visualized on CT and/or MRI or radionuclide bone scan are allowed. Equivocal lesions on bone scan should be followed up with additional imaging as clinically indicated. Screening serum testosterone > 150 ng/dL Eastern Cooperative Oncology Group (ECOG) Performance Status grade 0 or 1 Age ≥ 18 years Medications known to lower the seizure threshold must be discontinued or substituted at least 4 weeks prior to cycle 1 day 1 Agrees to use a condom (even men with vasectomies) and another effective method of birth control if he is having sex with a woman of childbearing potential or agrees 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. Must also agree not to donate sperm during the study and for 3 months after receiving the last dose of study drug. Adequate organ function as defined by the following laboratory values at screening: Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase [SGOT]) and serum alanine transaminase (ALT; serum glutamic pyruvic transaminase [SGPT]) < 2.5 x upper limit of normal (ULN) Total serum bilirubin ≤1.5 x ULN. In subjects with Gilbert's syndrome, if total bilirubin is >1.5 × ULN, measure direct and indirect bilirubin and if direct bilirubin is ≤1.5 × ULN, subject may be eligible) Serum potassium ≥ 3.5 mmol/L. Supplementation and re-screening is allowed. Estimated creatinine clearance > 45 ml/min using Cockroft-Gault equation Platelets ≥ 100,000/microliter independent of transfusion and/or growth factors within 3 months prior to randomization Hemoglobin ≥ 9.0 g/dL independent of transfusion and/or growth factors within 3 months prior to randomization Serum albumin ≥ 3.0 g/dL Exclusion Criteria: Prior androgen deprivation therapy and/or first generation anti-androgen (e.g. bicalutamide, nilutamide, flutamide) for biochemically recurrent prostate cancer. Prior ADT and/or first generation anti-androgen in the (neo)adjuvant and/or salvage setting before, during, and/or following radiation or surgery is allowed provided last effective dose of ADT and/or first-generation anti-androgen is > 9 months prior to date of randomization and total duration of prior therapy is ≤ 36 months. Prior treatment with CYP17 inhibitor (e.g. ketoconazole, abiraterone acetate, galeterone) or second generation androgen receptor antagonist including apalutamide or enzalutamide Prior chemotherapy for prostate cancer except if administered in neoadjuvant or adjuvant setting Use of 5-alpha reductase inhibitor within 42 days prior to cycle 1 day 1 Use of investigational agent within 28 days prior to randomization Use of other prohibited medications within 7 days prior to cycle 1 day 1 on study (Arms B and C only) Prior bilateral orchiectomy Seizure or known condition that may pre-dispose to seizure (e.g. prior stroke within 1year to randomization, brain arteriovenous malformation, Schwannoma, meningioma, or other benign CNS or meningeal disease which may require treatment with surgery or radiation therapy) Uncontrolled hypertension Gastrointestinal disorder affecting absorption or the ability to swallow tablets Baseline severe hepatic impairment (Child-Pugh Class B & C) Intercurrent illness that is not controlled such as active infection, psychiatric illness/social situations that would limit compliance with study requirements Any chronic medical condition requiring a higher dose of corticosteroid than equivalent of 5 mg prednisone/prednisolone once daily

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 |
| --- | --- |
| Active Comparator: Arm A: Degarelix Monotherapy OR Leuprolide/Bicalutamide<br>Patients will receive degarelix OR leuprolide with bicalutamide. | Drug: LHRH Analogue<br>* Patients will receive a LHRH analogue therapy of either Degarelix OR Leuprolide with bicalutamide. Degarelix: Patients will receive subcutaneous injections every 28 days (+/- 3 days). Patients will receive a loading dose of 240 mg (two 120 mg injections) on C1D1, followed by maintenance dose of 80 mg on Day 1 of subsequent cycles. Leuprolide: Patients treated with leuprolide will receive a 7.5 mg IM injection on C1D1. Patients in arm A ONLY will take this in combination with bicalutamide 50 mg orally once daily starting on C1D1 and continuing for 28 days through completion of cycle 1. Starting on C2D1, patients will continue on one of the following two treatments at investigator discretion: Leuprolide 7.5 mg IM injection on Day 1 of subsequent cycles without concurrent bicalutamide. OR: Leuprolide 22.5 mg IM injection at the following visits without concurrent bicalutamide: C2D1, C5D1, C8D1, and C11D1.<br>* Other names: Leuprolide (Lupron) and Bicalutamide;|
| Experimental: Arm B: Degarelix/Apalutamide<br>Patients will receive apalutamide and either degarelix OR leuprolide. Patients on this arm will NOT take bicalutamide at any point in the treatment course. | Drug: Apalutamide<br>* Take apalutamide 240 mg (four 60 mg tablets) orally once daily, starting on C1D1 and continuing throughout 52-week treatment period.<br>* Other names: Erleada;Drug: LHRH Analogue<br>* Patients will receive a LHRH analogue therapy of either Degarelix OR Leuprolide with bicalutamide. Degarelix: Patients will receive subcutaneous injections every 28 days (+/- 3 days). Patients will receive a loading dose of 240 mg (two 120 mg injections) on C1D1, followed by maintenance dose of 80 mg on Day 1 of subsequent cycles. Leuprolide: Patients treated with leuprolide will receive a 7.5 mg IM injection on C1D1. Patients in arm A ONLY will take this in combination with bicalutamide 50 mg orally once daily starting on C1D1 and continuing for 28 days through completion of cycle 1. Starting on C2D1, patients will continue on one of the following two treatments at investigator discretion: Leuprolide 7.5 mg IM injection on Day 1 of subsequent cycles without concurrent bicalutamide. OR: Leuprolide 22.5 mg IM injection at the following visits without concurrent bicalutamide: C2D1, C5D1, C8D1, and C11D1.<br>* Other names: Leuprolide (Lupron) and Bicalutamide;|
| Experimental: Arm C: Degarelix/Apalutamide/Abiraterone/Prednisone<br>Patients will receive apalutamide and abiraterone acetate, in addition to either degarelix OR leuprolide. Patients on this arm will NOT take bicalutamide at any point in the treatment course. | Drug: Apalutamide<br>* Take apalutamide 240 mg (four 60 mg tablets) orally once daily, starting on C1D1 and continuing throughout 52-week treatment period.<br>* Other names: Erleada;Drug: LHRH Analogue<br>* Patients will receive a LHRH analogue therapy of either Degarelix OR Leuprolide with bicalutamide. Degarelix: Patients will receive subcutaneous injections every 28 days (+/- 3 days). Patients will receive a loading dose of 240 mg (two 120 mg injections) on C1D1, followed by maintenance dose of 80 mg on Day 1 of subsequent cycles. Leuprolide: Patients treated with leuprolide will receive a 7.5 mg IM injection on C1D1. Patients in arm A ONLY will take this in combination with bicalutamide 50 mg orally once daily starting on C1D1 and continuing for 28 days through completion of cycle 1. Starting on C2D1, patients will continue on one of the following two treatments at investigator discretion: Leuprolide 7.5 mg IM injection on Day 1 of subsequent cycles without concurrent bicalutamide. OR: Leuprolide 22.5 mg IM injection at the following visits without concurrent bicalutamide: C2D1, C5D1, C8D1, and C11D1.<br>* Other names: Leuprolide (Lupron) and Bicalutamide;Drug: Abiraterone Acetate<br>* Take abiraterone acetate 1000 mg (four 250 mg tablets) orally once daily, starting on C1D1 and continuing throughout 52-week treatment period.<br>* Other names: Zytiga;Drug: Prednisone<br>* Take two prednisone 5 mg tablets daily, starting on C1D1 and continuing throughout the 52-week treatment period. Following completion of treatment period, patients will taper off prednisone per institutional guidelines. Suggested tapering plan: prednisone 5 mg daily for 7 days, then 2.5 mg daily for 7 days before discontinuing.<br>* Other names: Deltasone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PSA progression-free survival in the intent-to-treat population | To compare PSA progression-free survival in each of the experimental arms (LHRH analogue + apalutamide; LHRH analogue + apalutamide +abiraterone acetate) versus the control arm (LHRH analogue) among all randomized patients (intent-to-treat population). | 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PSA progression-free survival in the testosterone-evaluable population | Compare PSA progression-free survival in testosterone-evaluable population in each experimental arm versus the control arm. Testosterone-evaluable population includes all patients who achieve serum testosterone recovery to > 50 ng/dL with subsequent PSA measurements sufficient for evaluation | 36 months | 
| PSA progression-free survival in both the intent-to-treat and testosterone-evaluable populations | To compare the 36-month PSA progression-free survival rate in each experimental arm versus the control arm in both the intent-to-treat and testosterone-evaluable populations. | 36 months | 
| Serum testosterone | To compare the time to recovery of serum testosterone to greater than 50 ng/dL in each experimental arm versus the control arm. | 12 months | 
| Time to castration resistance | To compare the time to castration resistance in each experimental arm versus the control arm. | 6 years | 
| Metastasis-Free Survival | To compare metastasis-free survival in each experimental arm versus the control arm. | 6 years | 
| Overall Survival | To compare overall survival in each experimental arm versus the control arm. | 6 years | 
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | To characterize the safety profile in each treatment arm | 6 years | 
| Quality of life Expanded Prostate Cancer Index Composite (EPIC) | Expanded Prostate Cancer Index Composite (EPIC) | 72 months | 
| Quality of life Hot Flash Daily Interference Scale (HFRDIS) | Hot Flash Daily Interference Scale (HFRDIS) | 72 months | 
| Quality of life EQ-5D-5L | EQ-5D-5L | 72 months | 
| Quality of life PROMIS Fatigue | PROMIS Fatigue | 72 months | 
| Quality-adjusted survival | To compare the quality-adjusted survival (overall survival multiplied by utility score) of patients in each experimental arm versus the control arm. | 72 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PSA, Degarelix, Apalutamide, Abiraterone Acetate, Radical Prostatectomy, Bicalutamide, Leuprolide, Lupron