This is a phase III, randomized, open-label, multi-center study to assess the efficacy of treatment intensification with docetaxel plus apalutamide and ADT, assessed by event-free survival, in patients with mHSPC who do not achieve deep PSA response (≤0,2 ng/ml or PSA90 response in combination with a PSA ≤ 4 ng/ml) after initial treatment with apalutamide and ADT. A non-deep PSA response is defined as PSA \> 0.2 ng/ml in combination with a PSA response \< 90%, or a PSA response ≥90% in combination with a PSA \> 4 ng/ml.
Approximately 320 patients will be randomized in a 1:1 ratio to the treatments as specified below: * Arm A (experimental arm): docetaxel (75 mg/m2 every three weeks), for 6 planned cycles, plus apalutamide and ADT (240 mg, oral single daily dose). * Arm B (control arm): continuation of SOC treatment with apalutamide and ADT (240 mg, oral single daily dose). Randomization will be stratified by 3 factors: * Metastasis timing (synchronous vs metachronous) * Visceral metastasis at diagnosis (yes vs no) * PSA at study inclusion (≤ 4 ng/ml vs \>4 ng/ml) An IDMC will be established for regular safety monitoring, for the pre-planned interim analysis and the PK sub-study when available. The composition, role, responsibilities and procedures of the IDMC will be detailed in the IDMC Charter.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
320
The dose of 240 mg (four 60 mg tablets or one single 240 mg tablet) daily of apalutamide is the recommended dose in the SmPC. ADT will be chosen and administered according to standard clinical practice at each participating site and has not been included in the table below.
The recommended dose of docetaxel is 75 mg/m2 day 1 every 21 days. Six cycles of docetaxel will be administered.
CH Bayonne
Bayonne, France
Institut Bergonié
Bordeaux, France
CHP Brest - Pasteur
Brest, France
Hôpital Henri-Mondor
Créteil, France
GHM Cancérologie - Institut Daniel Hollard
Grenoble, France
Hôpital Franco-Britannique
Levallois-Perret, France
Event-free Survival (EFS)
Event-free survival is defined as the time from randomization to occurrence of the following events, whichever occurs first in each treatment arm: PSA progression or radiographic progression of soft-tissue, visceral, or bone lesions or death from any cause.
Time frame: 48 months
Time to castration resistance
Time to castration resistance is defined as time from randomization to radiographic disease progression, PSA progression per PCWG3 criteria, or symptomatic skeletal event (defined as radiation to bone, pathologic fracture, spinal cord compression, or surgery to bone due to symptoms), whichever occurred first in each treatment arm.
Time frame: 48 months
Radiographic progression-free survival (rPFS)
Radiographic Progression-Free Survival is defined as the time from randomization to the first documented evidence of radiographic disease progression, as assessed by the investigator per Prostate Cancer Working Group 3 (PCWG3) criteria for bone lesions and RECIST v1.1 for soft tissue lesions, or death from any cause, whichever occurs first in each treatment arm.
Time frame: 48 months
PSA progression-free survival
PSA progression-free survival (PSA-PFS) is defined according to PCWG3 criteria as the time from randomization to the date of PSA progression (a ≥25% increase and an absolute increase of ≥2 ng/mL from nadir, confirmed by a second value ≥3 weeks later) or death from any cause, whichever occurs first in each treatment arm.
Time frame: 48 months
Overall survival
Overall survival is defined as time from randomization to date of death from any cause in each treatment arm.
Time frame: 48 months
Time to subsequent treatment
Time to subsequent treatment is defined as the time from randomization to the initiation of the first subsequent systemic anticancer therapy after study drugs discontinuation, or death, whichever occurs first in each treatment arm.
Time frame: 48 months
Deep PSA response rate at 6 months in each treatment arm.
Deep PSA response is defined as achieving a prostate-specific antigen (PSA) level ≤0.2 ng/mL or PSA Response ≥90% in combination with a PSA ≤ 4 ng/ml.
Time frame: 6 months
Ultradeep PSA response rate at 6 months in each treatment arm.
Ultradeep PSA response 1 is defined as achieving a prostate-specific antigen (PSA) level between 0.2 and 0.02 ng/mL. Ultradeep PSA response 2 is defined as achieving a prostate-specific antigen (PSA) level ≤ 0.02 ng/mL.
Time frame: 6 months
Symptomatic skeletal event-free survival
Symptomatic skeletal event-free survival (SSE-FS) is defined as the time from randomization to the first occurrence of a symptomatic skeletal event (defined as radiation to bone, pathologic fracture, spinal cord compression, or surgery to bone due to symptoms) or death from any cause, whichever occurred first in each treatment arm.
Time frame: 48 months
To evaluate the safety profile of treatment intensification with docetaxel plus apalutamide and ADT (Adverse events)
Percentage of patients with at least one adverse event. Toxicity profile will be assessed using the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE), version 5.0. Patients with each adverse event will be calculated over the total number of patients exposed in each treatment arm.
Time frame: 25 months
Time to initiate opioid use (≥ 7 days)
Time to initiate opioid use (≥ 7 days) is defined as the time from randomization to the first initiation of opioid analgesic use lasting for 7 or more consecutive days, regardless of the reason, or until death, whichever occurs first in each treatment arm.
Time frame: 48 months
To evaluate the safety profile of treatment intensification with docetaxel plus apalutamide and ADT (Serious adverse events).
Patients with at least a serious adverse event will be calculated over the total number of patients exposed in each treatment arm.
Time frame: 25 months
To evaluate the safety profile of treatment intensification with docetaxel plus apalutamide and ADT (Adverse events leading to treatment discontinuation ).
Patients with at least an adverse event leading to treatment discontinuation and adverse events leading to death will be calculated over the total number of patients exposed in each treatment arm.
Time frame: 25 months
To evaluate the safety profile of treatment intensification with docetaxel plus apalutamide and ADT (Death)
Dead patients calculated over the total number of patients exposed in each treatment arm.
Time frame: 25 months
To assess the quality of life of patients with FACT-P subscale
Change from baseline over time in FACT-P subscale in each treatment arm.
Time frame: 24 months
To assess the quality of life of patients with BPI-SF interference subscale
Change from baseline over time in BPI-SF interference subscale in each treatment arm.
Time frame: 24 months
To assess the quality of life of patients with BPI-SF interference subscale.
Change from baseline over time in BFI subscale in each treatment arm.
Time frame: 24 months
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GHBS - Hôpital du Scorff
Lorient, France
Centre De Cancérologie Du Grand Montpellier
Montpellier, France
Institut du Cancer de Montpellier - Val d'Aurelle (ICM)
Montpellier, France
CHU Nîmes
Nîmes, France
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