A Phase 3 Study of Androgen Annihilation in High-Risk Biochemically Relapsed Prostate Cancer
Overview
- Phase
- Phase 3
- Intervention
- LHRH Analogue
- Conditions
- Prostate Cancer
- Sponsor
- Alliance Foundation Trials, LLC.
- Enrollment
- 504
- Locations
- 55
- Primary Endpoint
- PSA progression-free survival in the intent-to-treat population
- Status
- Completed
- Last Updated
- 4 months ago
Overview
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.
Investigators
Eligibility Criteria
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
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
Arms & Interventions
Arm A: Degarelix Monotherapy OR Leuprolide/Bicalutamide
Patients will receive degarelix OR leuprolide with bicalutamide.
Intervention: LHRH Analogue
Arm B: Degarelix/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.
Intervention: Apalutamide
Arm B: Degarelix/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.
Intervention: LHRH Analogue
Arm C: Degarelix/Apalutamide/Abiraterone/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.
Intervention: Apalutamide
Arm C: Degarelix/Apalutamide/Abiraterone/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.
Intervention: LHRH Analogue
Arm C: Degarelix/Apalutamide/Abiraterone/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.
Intervention: Abiraterone Acetate
Arm C: Degarelix/Apalutamide/Abiraterone/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.
Intervention: Prednisone
Outcomes
Primary Outcomes
PSA progression-free survival in the intent-to-treat population
Time Frame: 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 Outcomes
- Serum testosterone(12 months)
- Metastasis-Free Survival(6 years)
- Overall Survival(6 years)
- Quality of life Expanded Prostate Cancer Index Composite (EPIC)(72 months)
- Quality of life Hot Flash Daily Interference Scale (HFRDIS)(72 months)
- Time to castration resistance(6 years)
- Number of participants with treatment-related adverse events as assessed by CTCAE v4.0(6 years)
- Quality of life PROMIS Fatigue(72 months)
- PSA progression-free survival in the testosterone-evaluable population(36 months)
- PSA progression-free survival in both the intent-to-treat and testosterone-evaluable populations(36 months)
- Quality of life EQ-5D-5L(72 months)
- Quality-adjusted survival(72 months)