ADT +/- Darolutamide in de Novo Metastatic Prostate Cancer Patients With Vulnerable Functional Ability (PEACE6-Vulnerable)
- Conditions
- Prostate Cancer Metastatic
- Interventions
- Registration Number
- NCT04916613
- Lead Sponsor
- UNICANCER
- Brief Summary
This is a Phase III, international, multicentre, randomised, double-blinded placebo controlled trial, evaluating the efficacy and safety of ADT +/- darolutamide in castration-naïve de novo metastatic prostate cancer patients with vulnerable functional ability who have not elected for docetaxel or other androgen receptor pathway inhibitors.
- Detailed Description
This is a Phase III, international, multicentre, randomised, double-blinded placebo controlled trial, evaluating the efficacy and safety of ADT +/- darolutamide in castration-naïve de novo metastatic prostate cancer patients with vulnerable functional ability who have not elected for docetaxel or other androgen receptor pathway inhibitors. The study plans to enroll 300 patients who will be randomized (1:1) to receive either: (i) Experimental arm: ADT + darolutamide 600 mg po bid, or (ii) Control arm: ADT + placebo po bid. Response to treatment will be assessed according to the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria (Scher, 2016). Treatment will be continued until radiographic disease progression. Treatment may also be terminated at the initiative of either the patient or the investigator for any reason that would be beneficial to the patient, including: unacceptable toxicity, intercurrent conditions that preclude continuation of treatment, or patient request. Following treatment discontinuation patients will enter the follow-up period and will be monitored for up to 10 years with regards to survival status, subsequent antineoplastic treatments and the status of ongoing adverse events (AEs) and/or new investigational product related AEs.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- Male
- Target Recruitment
- 300
-
Signed a written informed consent form prior to any trial specific procedures.
-
Men with histologically or cytologically confirmed adenocarcinoma of the prostate.
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Aged ≥18 years old at the time of signing informed consent.
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De novo metastatic disease defined by clinical or radiological evidence of metastases.
Note: For patients with nodal metastases only, only patients with extra-pelvic enlarged lymph nodes (lymph nodes located above the iliac bifurcation) can be included if they have either:
- At least one extra-pelvic lymph node ≥2 cm
- At least one extra-pelvic lymph node ≥1 cm if the patients also have at least one pelvic lymph node ≥2 cm
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Measurable disease or bone lesions that are evaluable according to PCWG3 criteria.
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Ineligible for treatment with all of the following drugs: docetaxel, abiraterone, enzalutamide, apalutamide; AND meets at least one of the following frailty criteria:
- Activities of daily living (ADL) assessment (excluding urinary incontinence question) score 3 or 4/5;
- 4-Instrumental activities of daily living (4-IADL) assessment score 2 or 3/4;
- A Grade 3 event on the Cumulative Illness Score Rating-Geriatrics (CISR-G) questionnaire;
- Body mass index (BMI) ≤21 kg/m² and/or >10% weight loss in the last 6 months;
- Timed up and go test (TUG) >14 sec.
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Adequate bone marrow function: haemoglobin ≥80 g/L, white blood cells ≥3.0 x10⁹/L and platelets ≥80 x10⁹/L.
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Adequate liver function: alanine aminotransferase (ALT) <2 x upper limit of normal (ULN) and bilirubin <1.5 x ULN, (or if bilirubin is between 1.5-2 x ULN, they must have a normal conjugated bilirubin). For patients with documented liver metastasis, ALT <5 x ULN is acceptable.
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Adequate renal function: calculated creatinine clearance >30 ml/min (using the Modification of Diet in Renal Disease [MDRD] or Chronic Kidney Disease Epidemiology Collaboration [CKD EPI) method).
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For sexually active men, agreement to use adequate contraception for the duration of trial participation and up to 2 weeks after completing study treatment.
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Affiliated to the social security system or in possession of equivalent private health insurance (according to local regulations for participation in clinical trials).
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Willing and able to comply with the protocol for the duration of the trial including undergoing treatment and scheduled visits, and examinations including follow-up.
- Three or more Grade 3, or any Grade 4 events on the CISR-G questionnaire.
- Eastern Cooperative Oncology Group (ECOG) performance status score ≥3.
- Hypertension not controlled by an anti-hypertensive treatment (systolic blood pressure [BP] ≥160 mmHg or diastolic BP ≥95 mmHg; 3 consecutive measures taken 5 minutes apart).
- Acute toxicities of prior treatments and procedures not resolved to grade ≤1 or baseline before randomisation, with the exception of hot flushes and erectile dysfunction.
- Previous systemic treatment for prostate cancer, except less than 12 weeks of ADT and/or an old-generation AR inhibitor.
- Severe or uncontrolled concurrent disease, infection or co-morbidity.
- Known hypersensitivity to the study treatment or any of its ingredients.
- Major surgery within 28 days before randomisation.
- Any of the following within 6 months before randomisation: stroke, myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft; congestive heart failure New York Heart Association (NYHA) Class III or IV.
- Prior malignancy ≤3 years before study enrolment. Adequately treated basal cell or squamous cell carcinoma of skin or superficial bladder cancer that has not spread behind the connective tissue layer (i.e., pTis, pTa, and pT1) is allowed, as well as any localized cancer for which treatment has been completed ≥6 months before randomisation and from which the subject has been disease-free, or for which the risk of relapse is less than 30%, as well as early stage chronic lymphocytic leukaemia that does not require any specific treatment.
- Inability to swallow oral medications.
- Gastrointestinal disorder or procedure that can be expected to interfere significantly with the absorption of study treatment.
- Known to have active viral hepatitis, active human immunodeficiency virus (HIV) or chronic liver disease at screening.
- Treatment with any investigational product within 28 days before randomisation.
- Concurrent participation in another clinical trial involving an investigational product (patients enrolled in non-experimental trials with no modification of the standard of care can be included).
- Individual deprived of liberty or placed under the authority of a tutor.
- Significantly altered mental status prohibiting the understanding of the study or with psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule or any condition that, in the opinion of the investigator, would preclude participation in this trial.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description ADT + darolutamide Androgen deprivation therapy ADT + darolutamide 600 mg po bid ADT + placebo Placebo ADT + placebo po bid ADT + darolutamide Darolutamide 300 mg ADT + darolutamide 600 mg po bid ADT + placebo Androgen deprivation therapy ADT + placebo po bid
- Primary Outcome Measures
Name Time Method Radiographic progression-free survival From randomisation to radiographic progression or death, up to 18 months Time from randomisation to radiographic progression according to the Prostate Cancer Working Group 3 (PCWG3) criteria or death, whichever occurs first
- Secondary Outcome Measures
Name Time Method Castration-resistant prostate cancer-free survival From randomisation to onset of CRPC or death, up to 18 months Time from randomisation to onset of castrate resistant prostate cancer (CRPC) according to PCWG3 criteria, or death, whichever occurs first
Clinical progression-free survival From randomisation to clinical progression or death, up to 18 months Time from randomisation to first occurrence of any one of the following:
(i) Cancer pain deterioration (2-point deterioration from baseline according to the Brief Pain Inventory - Short Form \[BPI-SF\] questionnaire; initiation of opioid therapy, or a ≥30% increase in opiate use) (ii) Any deterioration of physical function measured using the 4-IADL assessment tools (Lawton, 1969) (iii) A deterioration in ECOG performance status of at least 2 points from baseline (iv) Death from any cause.Frequency and severity of adverse events From inclusion until 100 days after last dose of investigational product The National Cancer Institute-Common Terminology Criteria for Adverse Events version 5 (NCI-CTCAE v5) is widely accepted in the community of oncology research as the leading rating scale for adverse events. This scale, divided into 5 grades (1 = "mild", 2 = "moderate", 3 = "severe", 4 = "life-threatening", and 5 = "death") determined by the investigator, will make it possible to assess the severity of the disorders
Time to next symptomatic skeletal event From randomisation to occurence of a skeletal event, up to 18 months Time from randomisation until first occurrence of one of the following: a symptomatic fracture, radiation or surgery to bone or a spinal cord compression
Second line radiographic progression-free survival From randomization up to 10 years. Time from the date of initiation of a second SACT for CRPC to radiographic progression or death, whichever occurs first.
Progression-free survival after next line of treatment (PFS2) From randomization up to 10 years. Time from randomisation to second objective disease progression, or death from any cause, whichever first
Geriatric status At baseline and every 120 days during first years of treatment and every 180 days thereafter if treatment is continued for more than 1 year Evaluated using the G-CODE (Paillaud, 2018), a core set of commonly used tools/items for geriatric assessment which has been validated for the collection of geriatric data in clinical cancer trials of older adults, enabling comparison across trials. The tools/items proposed in G-CODE are:
(i) Social assessment: living alone or support requested to stay at home; (ii) Functional autonomy: Activities of Daily Living (ADL) questionnaire and short instrumental ADL questionnaire (4-IADL); (iii) Mobility: Timed Up and Go test; (iv) Nutrition: weight loss during the past 6 months and body mass index; (v) Cognition: Mini-Cog test; (vi) Mood: mini-Geriatric Depression Scale; (vii) Comorbidity: updated Charlson Comorbidity Index.Overall survival From randomization to death from any cause, up to 10 years. Time from randomisation to the time of death from any cause
Prostate cancer-specific survival From randomization to death from prostate cancer, up to 10 years. Time from randomisation to the date of death due to prostate cancer (deaths due to other causes will be censored)
Health related quality of life questionnaire Brief Pain Inventory - Short Form (BPI-SF) On treatment day 1 and every 120 days during first years of treatment and every 180 days thereafter if treatment is continued for more than 1 year The Brief Pain Inventory is a self reporting tool to assess the severity of pain and the impact of pain on daily functions in patients with chronically painful diseases or conditions such as cancer, osteoarthritis and low back pain, or with pain from acute conditions such as postoperative pain. The Short Form of the questionnaire (BPI-SF) has been specifically developed for clinical trials.
Time to worsening in prostate cancer-related urinary symptoms On treatment day 1 and every 120 days during first years of treatment and every 180 days thereafter if treatment is continued for more than 1 year Time from randomisation to first increase from baseline of greater or equal to 8 points in the urinary symptom scale/score (PRURI) measured using the prostate cancer module of the EORTC quality of life questionnaire (EORTC-QLQ-PR25).
This EORTC prostate cancer specific questionnaire is intended to supplement the QLQ-C30. The prostate cancer module is a 25-item questionnaire designed for use among patients with localized and metastatic prostate cancer. It includes subscales assessing urinary symptoms (9 items), bowel symptoms (4 items), treatment-related symptoms (6 items) and sexual functioning (6 items). Using a 4-point Likert scale (1 = "not at all", 2 = "a little", 3 = "quite a bit", and 4 = "very much"), patients indicate the degree to which they have experienced symptoms.Complete prostate specific antigen (PSA) response At 6 months Defined according to PCWG3 criteria as PSA ≤ 0.2 ng/ml
Time to first subsequent systemic anti-cancer therapy (SACT) From randomization up to 10 years. Time from randomisation to the date of initiation of any SACT for CRPC, following initiation of the study treatment
Second line overall survival From randomization up to 10 years. Time from the date of initiation of a second SACT for CRPC to death
Time to deterioration for EORTC QLQ-PR25 symptom subscales On treatment day 1 and every 120 days during first years of treatment and every 180 days thereafter if treatment is continued for more than 1 year Defined as the first decline in the HRQoL score from baseline equal to or greater than the minimally important difference (MID; a measure of clinical significance) defined as half the standard deviation of the baseline value for each subscale. The prostate cancer module QLQ-PR25 is a 25-item questionnaire designed for use among patients with localized and metastatic prostate cancer. It includes subscales assessing urinary symptoms (9 items), bowel symptoms (4 items), treatment-related symptoms (6 items) and sexual functioning (6 items). Using a 4-point Likert scale (1 = "not at all", 2 = "a little", 3 = "quite a bit", and 4 = "very much"), patients indicate the degree to which they have experienced symptoms.
Health related quality of life questionnaire EORTC-QLQ-PR25 On treatment day 1 and every 120 days during first years of treatment and every 180 days thereafter if treatment is continued for more than 1 year This EORTC prostate cancer specific questionnaire is intended to supplement the QLQ-C30.
The prostate cancer module is a 25-item questionnaire designed for use among patients with localized and metastatic prostate cancer. It includes subscales assessing urinary symptoms (9 items), bowel symptoms (4 items), treatment-related symptoms (6 items) and sexual functioning (6 items). Using a 4-point Likert scale (1 = "not at all", 2 = "a little", 3 = "quite a bit", and 4 = "very much"), patients indicate the degree to which they have experienced symptoms.Health related quality of life questionnaire EORTC-QLQ-C30 On treatment day 1 and every 120 days during first years of treatment and every 180 days thereafter if treatment is continued for more than 1 year Developed by the EORTC, this self-reported questionnaire assesses the health-related quality of life of cancer patients in clinical trials.
The questionnaire includes five functional scales (physical, everyday activity, cognitive, emotional, and social), three symptom scales (fatigue, pain, nausea and vomiting), a health/quality of life overall scale, and a number of additional elements assessing common symptoms (including dyspnea, loss of appetite, insomnia, constipation, and diarrhea), as well as, the perceived financial impact of the disease.
All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level.
Trial Locations
- Locations (90)
CHU de la Martinique - Hôpital Albert Clarac
🇫🇷Fort-de-France, France
Universitätsmedizin Essen Hufelandstraße
🇩🇪Essen, Germany
University cancer center Hamburg-Eppendorf Martinistraße
🇩🇪Hamburg, Germany
Universitätsklinikum Münster Klinik für Urologie und Kinderurologie Albert-Schweitzer-Campus 1 Gebäude A1
🇩🇪Münster, Germany
University of Bari, Policlinico
🇮🇹Bari, Italy
FPO IRCCS Candiolo Turin
🇮🇹Candiolo, Italy
Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.)
🇮🇹Meldola, Italy
Fondazione IRCSS Istituto Nazionale Tumori
🇮🇹Milano, Italy
istituto tumori Fondazione "G.Pascale"
🇮🇹Napoli, Italy
Azienda Ospedaliera S. Camillo-Forlanini
🇮🇹Roma, Italy
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
🇮🇹Roma, Italy
Istituto Clinico Humanitas - IRCCS
🇮🇹Rozzano, Italy
UOC Oncologia Medica
🇮🇹Siracusa, Italy
Santa Chiara Hospital
🇮🇹Trento, Italy
Albert Schweizer Hospital
🇳🇱Dordrecht, Netherlands
Radboudumc - Dutch Uro-Oncology Study Group (DUOS)
🇳🇱Nijmegen, Netherlands
Institutul Oncologic Prof Dr Al Trestioreanu Bucuresti
🇷🇴Bucharest, Romania
Amethyst Radiotherapy Center Cluj SRL
🇷🇴Cluj, Romania
Institul Oncologic Cluj-Napoca
🇷🇴Cluj, Romania
OncoHelp Hospital
🇷🇴Timişoara, Romania
Narodny Onkologicky Institut
🇸🇰Bratislava, Slovakia
Sahlgrenska University Hospital
🇸🇪Gothenburg, Sweden
Skane University Hospital
🇸🇪Malmö, Sweden
Istituto Oncologico della Svizzera Italiana (IOSI) - Ospedale S.Giovanni
🇨🇭Bellinzona, Switzerland
Kantonsspital Graubünden, Onkologie/ Hämatologie
🇨🇭Chur, Switzerland
Cantonal Hospital St.Gallen
🇨🇭Saint Gallen, Switzerland
Istituto Oncologico della Svizzera Italiana (IOSI) - Ospedale Italiano di Lugano
🇨🇭Viganello, Switzerland
Universitätsspital Zürich - Onkologie
🇨🇭Zürich, Switzerland
Grand Hopital de Charleroi - site Notre Dame
🇧🇪Charleroi, Belgium
Groupe Jolimont - Hôpital De Jolimont
🇧🇪Haine-Saint-Paul, Belgium
CHU UCL NAMUR - Site STE. ELISABETH
🇧🇪Namur, Belgium
Clinique Saint Pierre
🇧🇪Ottignies, Belgium
Institut Sainte Catherine
🇫🇷Avignon, France
Centre Hospitalier Cote basque
🇫🇷Bayonne, France
CHU Besançon - Hopital Jean Mijoz
🇫🇷Besançon, France
Centre Institut Bergonié
🇫🇷Bordeaux, France
Clinique Pasteur
🇫🇷Brest, France
Centre François Baclesse
🇫🇷Caen, France
Centre Hospitalier Métropole Savoie
🇫🇷Chambéry, France
Centre Jean Perrin
🇫🇷Clermont-Ferrand, France
APHP - Hôpital Henri Mondor
🇫🇷Créteil, France
Centre Georges François Leclerc
🇫🇷Dijon, France
CHU Grenoble
🇫🇷Grenoble, France
Centre CHV Vendée
🇫🇷La Roche-sur-Yon, France
CHU le MANS
🇫🇷Le Mans, France
Centre Oscar Lambret
🇫🇷Lille, France
Polyclinique de Limoges
🇫🇷Limoges, France
Groupe Hospitalier Bretagne Sud
🇫🇷Lorient, France
Centre Léon Bérard
🇫🇷Lyon, France
Institut Paoli-Calmettes
🇫🇷Marseille, France
Centre Azuréen de Cancérologie
🇫🇷Mougins, France
Centre Antoine Lacassagne
🇫🇷Nice, France
CHU Nîmes
🇫🇷Nîmes, France
Centre Groupe Hospitalier Diaconesses Croix Saint-Simon
🇫🇷Paris, France
Hôpital Saint Louis
🇫🇷Paris, France
Hôpital Européen Georges Pompidou
🇫🇷Paris, France
Hospices Civils de Lyon -Lyon Sud
🇫🇷Pierre-Bénite, France
Hôpital Tenon
🇫🇷Paris, France
CHU de Poitiers - Pôle Régional de Cancérologie
🇫🇷Poitiers, France
CH Annecy Genevois
🇫🇷Pringy, France
CHIC Quimper
🇫🇷Quimper, France
Institut Jean Godinot
🇫🇷Reims, France
Centre Eugène Marquis
🇫🇷Rennes, France
Centre Hospitalier Rodez
🇫🇷Rodez, France
CHP Centre Saint Grégoire
🇫🇷Saint Grégoire, France
Hôpital Instruction des Armées - BEGIN
🇫🇷Saint Mandé, France
CHU Saint-Etienne
🇫🇷Saint-Étienne, France
Hôpital Privé de la Loire
🇫🇷Saint-Étienne, France
Clinique Sainte Anne - Strasbourg Oncologie Libérale
🇫🇷Strasbourg, France
Institut de cancérologie Strasbourg Europe
🇫🇷Strasbourg, France
Hôpital FOCH
🇫🇷Suresnes, France
Centre Hospitalier Intercommunal de Toulon-La Seyne - Hôpital Ste Musse
🇫🇷Toulon, France
IUCT Oncopole
🇫🇷Toulouse, France
Clinique Pasteur ONCORAD
🇫🇷Toulouse, France
CHRU de Tours -Hôpital Bretonneau
🇫🇷Tours, France
Institut de Cancérologie de Lorraine
🇫🇷Vandœuvre-lès-Nancy, France
Gustave Roussy Center
🇫🇷Villejuif, France
St Vincent's University Hospital
🇮🇪Dublin, Ireland
Tallaght university Hospital
🇮🇪Dublin, Ireland
Mater Misericordiae University Hospital
🇮🇪Dublin, Ireland
Mater Private Hospital
🇮🇪Dublin, Ireland
Institut Catala d'Oncologia, Badalona-Hospital Germans Trias i Pujol
🇪🇸Badalona, Spain
Hospital Clinic
🇪🇸Barcelona, Spain
Hospital del Mar
🇪🇸Barcelona, Spain
Vall d'Hebron Institute of Oncology. Vall d'Hebron University Hospital
🇪🇸Barcelona, Spain
Institut Català d'Oncologia de Girona
🇪🇸Girona, Spain
Centro Integral Oncologico HM Clara Campal
🇪🇸Madrid, Spain
Hospital Universitario 12 de Octubre
🇪🇸Madrid, Spain
Althaia, Xara Assistencial Universitaria Mansera
🇪🇸Manresa, Spain
Fundacion Instituto Valenciano De Oncologia
🇪🇸Valencia, Spain