A Study of Androgen Annihilation in High-Risk Biochemically Relapsed Prostate Cancer
- Conditions
- Prostate Cancer
- Interventions
- Registration Number
- NCT03009981
- Lead Sponsor
- Alliance Foundation Trials, LLC.
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- Male
- Target Recruitment
- 504
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Histologically confirmed prostate adenocarcinoma
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Prior radical prostatectomy
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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)
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Prior adjuvant or salvage radiation or not a candidate for radiation based upon clinical assessment of disease characteristics and patient co-morbidities.
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Screening PSA > 0.5 ng/mL
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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.
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Screening serum testosterone > 150 ng/dL
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Eastern Cooperative Oncology Group (ECOG) Performance Status grade 0 or 1
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Age ≥ 18 years
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Medications known to lower the seizure threshold must be discontinued or substituted at least 4 weeks prior to cycle 1 day 1
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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.
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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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm B: Degarelix/Apalutamide LHRH Analogue Patients will receive apalutamide and either degarelix OR leuprolide. Patients on this arm will NOT take bicalutamide at any point in the treatment course. Arm A: Degarelix Monotherapy OR Leuprolide/Bicalutamide LHRH Analogue Patients will receive degarelix OR leuprolide with bicalutamide. Arm C: Degarelix/Apalutamide/Abiraterone/Prednisone LHRH Analogue 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. Arm B: Degarelix/Apalutamide Apalutamide Patients will receive apalutamide and either degarelix OR leuprolide. Patients on this arm will NOT take bicalutamide at any point in the treatment course. Arm C: Degarelix/Apalutamide/Abiraterone/Prednisone Apalutamide 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. Arm C: Degarelix/Apalutamide/Abiraterone/Prednisone Abiraterone Acetate 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. Arm C: Degarelix/Apalutamide/Abiraterone/Prednisone Prednisone 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.
- Primary Outcome Measures
Name Time Method PSA progression-free survival in the intent-to-treat population 36 months 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).
- Secondary Outcome Measures
Name Time Method Overall Survival 6 years To compare overall survival in each experimental arm versus the control arm.
Serum testosterone 12 months To compare the time to recovery of serum testosterone to greater than 50 ng/dL in each experimental arm versus the control arm.
Metastasis-Free Survival 6 years To compare metastasis-free survival in each experimental arm versus the control arm.
Quality of life Expanded Prostate Cancer Index Composite (EPIC) 72 months Expanded Prostate Cancer Index Composite (EPIC)
Quality of life Hot Flash Daily Interference Scale (HFRDIS) 72 months Hot Flash Daily Interference Scale (HFRDIS)
Time to castration resistance 6 years To compare the time to castration resistance in each experimental arm versus the control arm.
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 6 years To characterize the safety profile in each treatment arm
Quality of life PROMIS Fatigue 72 months PROMIS Fatigue
PSA progression-free survival in the testosterone-evaluable population 36 months 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
PSA progression-free survival in both the intent-to-treat and testosterone-evaluable populations 36 months 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.
Quality of life EQ-5D-5L 72 months EQ-5D-5L
Quality-adjusted survival 72 months To compare the quality-adjusted survival (overall survival multiplied by utility score) of patients in each experimental arm versus the control arm.
Trial Locations
- Locations (55)
Memorial Sloan Kettering Basking Ridge
🇺🇸Basking Ridge, New Jersey, United States
Atlantic Health System/Morristown Medical Center
🇺🇸Morristown, New Jersey, United States
The Toledo Clinic
🇺🇸Toledo, Ohio, United States
Spartanburg Medical Center/Gibbs Cancer Center
🇺🇸Spartanburg, South Carolina, United States
MedStar Washington Hospital Center
🇺🇸Washington, District of Columbia, United States
Pali Momi Medical Center
🇺🇸'Aiea, Hawaii, United States
Nevada Cancer Research Foundation
🇺🇸Las Vegas, Nevada, United States
Sharp Memorial Hospital
🇺🇸San Diego, California, United States
The Mayo Clinic - Phoenix
🇺🇸Phoenix, Arizona, United States
University of California San Francisco
🇺🇸San Francisco, California, United States
Metro Minnesota Community Oncology Research Consortium
🇺🇸Saint Louis Park, Minnesota, United States
Cancer Center of Kansas
🇺🇸Wichita, Kansas, United States
University of Minnesota
🇺🇸Minneapolis, Minnesota, United States
City of Hope National Medical Center
🇺🇸Duarte, California, United States
University of California San Diego - Moores Cancer Center
🇺🇸San Diego, California, United States
Adventist Health St. Helena/St. Helena Hospital/Martin O'Neil Cancer Center
🇺🇸Saint Helena, California, United States
VA Central California Health Care System
🇺🇸Fresno, California, United States
Rush University Medical Center
🇺🇸Chicago, Illinois, United States
University of Chicago Comprehensive Cancer Center
🇺🇸Chicago, Illinois, United States
Quincy Medical Group
🇺🇸Quincy, Illinois, United States
Loyola University
🇺🇸Maywood, Illinois, United States
Northshore University Health System
🇺🇸Evanston, Illinois, United States
New Mexico Oncology Hematology Consultants
🇺🇸Albuquerque, New Mexico, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
Carle Cancer Center
🇺🇸Urbana, Illinois, United States
University of New Mexico Comprehensive Cancer Center
🇺🇸Albuquerque, New Mexico, United States
Memorial Medical Center- Cancer Center
🇺🇸Las Cruces, New Mexico, United States
Christus St. Vincent's Regional Cancer Center
🇺🇸Santa Fe, New Mexico, United States
VA Western New York
🇺🇸Buffalo, New York, United States
Weill Cornell Medical Ctr - New York Presbyterian Hospital
🇺🇸New York, New York, United States
Novant Health Presbyterian Medical Center
🇺🇸Charlotte, North Carolina, United States
Roswell Park Cancer Institute
🇺🇸Buffalo, New York, United States
SUNY Upstate Medical University
🇺🇸Syracuse, New York, United States
VA Salisbury
🇺🇸Salisbury, North Carolina, United States
The Ohio State University Comprehensive Cancer Center
🇺🇸Columbus, Ohio, United States
University of Pittsburgh Medical Center
🇺🇸Pittsburgh, Pennsylvania, United States
University of Texas MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
Dayton Physicians Miami Valley South
🇺🇸Centerville, Ohio, United States
Oklahoma Cancer Specialists and Research Institute
🇺🇸Tulsa, Oklahoma, United States
Palo Alto Medical Foundation
🇺🇸Sunnyvale, California, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Nebraska Methodist Hospital
🇺🇸Omaha, Nebraska, United States
Providence Portland Medical Center
🇺🇸Portland, Oregon, United States
Oregon Health & Science University
🇺🇸Portland, Oregon, United States
Wake Forest University Health Sciences
🇺🇸Winston-Salem, North Carolina, United States
Dana Farber Cancer Institute
🇺🇸South Weymouth, Massachusetts, United States
Eastern Maine Medical Center
🇺🇸Brewer, Maine, United States
Marshfield Clinic Cancer Center
🇺🇸Marshfield, Wisconsin, United States
Froedtert Hospital/Medical College of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
New England Cancer Specialists
🇺🇸Topsham, Maine, United States
New Hampshire Oncology & Hematology
🇺🇸Hooksett, New Hampshire, United States
University of North Carolina Hospital
🇺🇸Chapel Hill, North Carolina, United States
University of Hawaii Cancer Center
🇺🇸Honolulu, Hawaii, United States
Georgetown University Medical Center
🇺🇸Washington, District of Columbia, United States
Montefiore Medical Center
🇺🇸New York, New York, United States