Clinical trial NCT04916613: ADT +/- Darolutamide in de Novo Metastatic Prostate Cancer Patients With Vulnerable Functional Ability (PEACE6-Vulnerable)
Official title: A Double-blind Randomised Phase III Trial Evaluating the Efficacy of ADT +/- Darolutamide in de Novo Metastatic Prostate Cancer Patients With Vulnerable Functional Ability and Not Elected for Docetaxel or Androgen Receptor Targeted Agents
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Prostate Cancer Metastatic
Lead sponsor: UNICANCER
Sponsor class: OTHER
Collaborators: name: Bayer
First posted: 2021-06-07
Enrollment: 300
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Phase III, international, multicenter, randomized
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

1. Signed a written informed consent form prior to any trial specific procedures.
2. Men with histologically or cytologically confirmed adenocarcinoma of the prostate.
3. Aged ≥18 years old at the time of signing informed consent.
4. 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
5. Measurable disease or bone lesions that are evaluable according to PCWG3 criteria.
6. Ineligible for treatment with all of the following drugs: docetaxel, abiraterone, enzalutamide, apalutamide; AND meets at least one of the following frailty criteria:

   1. Activities of daily living (ADL) assessment (excluding urinary incontinence question) score 3 or 4/5, or;
   2. 4-Instrumental activities of daily living (4-IADL) assessment score 2 or 3/4, or;
   3. A Grade 3 event on the Cumulative Illness Score Rating-Geriatrics (CISR-G) questionnaire, or;
   4. Body mass index (BMI) ≤21 kg/m² and/or \>5% weight loss in the last 6 months, or;
   5. Timed up and go test (TUG) \>14 sec. Nota Bene: Regarding CISR-G assessment, more specifically genitourinary scoring, score N°4 is not applicable.
7. Adequate bone marrow function: haemoglobin ≥80 g/L, white blood cells ≥3.0 x10⁹/L and platelets ≥80 x10⁹/L.
8. 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.
9. 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).
10. For sexually active men, agreement to use adequate contraception for the duration of trial participation and up to 2 weeks after completing study treatment.
11. Affiliated to the social security system or in possession of equivalent private health insurance (according to local regulations for participation in clinical trials).
12. 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.

Exclusion Criteria:

1. Three or more Grade 3, or any Grade 4 events on the CISR-G questionnaire. Nota Bene: (Regarding CISR-G assessment, more specifically genitourinary scoring, score N°4 is not applicable).
2. Eastern Cooperative Oncology Group (ECOG) performance status score ≥3.
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).
4. 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.
5. Previous systemic treatment for prostate cancer, except less than 12 weeks of ADT and/or an old-generation AR inhibitor.
6. Severe or uncontrolled concurrent disease, infection or co-morbidity.
7. Known hypersensitivity to the study treatment or any of its ingredients.
8. Major surgery within 28 days before randomisation.
9. 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.
10. 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.
11. Inability to swallow oral medications.
12. Gastrointestinal disorder or procedure that can be expected to interfere significantly with the absorption of study treatment.
13. Known to have active viral hepatitis, active human immunodeficiency virus (HIV) or chronic liver disease at screening.
14. Treatment with any investigational product within 28 days before randomisation.
15. 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).
16. Individual deprived of liberty or placed under the authority of a tutor.
17. 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.

Primary outcomes:
measure: Radiographic progression-free survival
timeFrame: From randomisation to radiographic progression or death, up to 18 months
Secondary outcomes:
measure: Castration-resistant prostate cancer-free survival
timeFrame: From randomisation to onset of CRPC or death, up to 18 months
measure: Clinical progression-free survival
timeFrame: From randomisation to clinical progression or death, up to 18 months
measure: Overall survival
timeFrame: From randomization to death from any cause, up to 10 years.
measure: Frequency and severity of adverse events
timeFrame: From inclusion until 100 days after last dose of investigational product
measure: Time to worsening in prostate cancer-related urinary symptoms
timeFrame: 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
measure: Time to next symptomatic skeletal event
timeFrame: From randomisation to occurence of a skeletal event, up to 18 months
measure: Complete prostate specific antigen (PSA) response
timeFrame: At 6 months
measure: Prostate cancer-specific survival
timeFrame: From randomization to death from prostate cancer, up to 10 years.
measure: Time to first subsequent systemic anti-cancer therapy (SACT)
timeFrame: From randomization up to 10 years.
measure: Second line radiographic progression-free survival
timeFrame: From randomization up to 10 years.
measure: Second line overall survival
timeFrame: From randomization up to 10 years.
measure: Progression-free survival after next line of treatment (PFS2)
timeFrame: From randomization up to 10 years.
measure: Geriatric status
timeFrame: 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
measure: Time to deterioration for EORTC QLQ-PR25 symptom subscales
timeFrame: 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
measure: Health related quality of life questionnaire EORTC-QLQ-C30
timeFrame: 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
measure: Health related quality of life questionnaire EORTC-QLQ-PR25
timeFrame: 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
measure: Health related quality of life questionnaire Brief Pain Inventory - Short Form (BPI-SF)
timeFrame: 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
Other outcomes:
Locations:
city: Charleroi
country: Belgium
facility: Grand Hopital de Charleroi - site Notre Dame
city: Haine-Saint-Paul
country: Belgium
facility: Groupe Jolimont - Hôpital De Jolimont
city: Namur
country: Belgium
facility: CHU UCL NAMUR - Site STE. ELISABETH
city: Ottignies
country: Belgium
facility: Clinique Saint Pierre
city: Avignon
country: France
facility: Institut Sainte Catherine
city: Bayonne
country: France
facility: Centre Hospitalier Cote basque
city: Besançon
country: France
facility: CHU Besançon - Hopital Jean Mijoz
city: Bordeaux
country: France
facility: Centre Institut Bergonié
city: Brest
country: France
facility: Clinique Pasteur
city: Caen
country: France
facility: Centre François Baclesse
city: Chambéry
country: France
facility: Centre Hospitalier Métropole Savoie
city: Clermont-Ferrand
country: France
facility: Centre Jean Perrin
city: Créteil
country: France
facility: APHP - Hôpital Henri Mondor
city: Dijon
country: France
facility: Centre Georges François Leclerc
city: Fort-de-France
country: France
facility: CHU de la Martinique - Hôpital Albert Clarac
city: Grenoble
country: France
facility: CHU Grenoble
city: La Roche-sur-Yon
country: France
facility: Centre CHV Vendée
city: Le Mans
country: France
facility: CHU le MANS
city: Lille
country: France
facility: Centre Oscar Lambret
city: Limoges
country: France
facility: Polyclinique de Limoges
city: Lorient
country: France
facility: Groupe Hospitalier Bretagne Sud
city: Lyon
country: France
facility: Centre Léon Bérard
city: Marseille
country: France
facility: Institut Paoli-Calmettes
city: Mougins
country: France
facility: Centre Azuréen de Cancérologie
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Nîmes
country: France
facility: CHU Nîmes
city: Paris
country: France
facility: Centre Groupe Hospitalier Diaconesses Croix Saint-Simon
city: Paris
country: France
facility: Hôpital Saint Louis
city: Paris
country: France
facility: Hôpital Européen Georges Pompidou
city: Paris
country: France
facility: Hôpital Tenon
city: Pierre-Bénite
country: France
facility: Hospices Civils de Lyon -Lyon Sud
city: Poitiers
country: France
facility: CHU de Poitiers - Pôle Régional de Cancérologie
city: Pringy
country: France
facility: CH Annecy Genevois
city: Quimper
country: France
facility: CHIC Quimper
city: Reims
country: France
facility: Institut Jean Godinot
city: Rennes
country: France
facility: Centre Eugène Marquis
city: Rodez
country: France
facility: Centre Hospitalier Rodez
city: Saint Grégoire
country: France
facility: CHP Centre Saint Grégoire
city: Saint Mandé
country: France
facility: Hôpital Instruction des Armées - BEGIN
city: Saint-Étienne
country: France
facility: CHU Saint-Etienne
city: Saint-Étienne
country: France
facility: Hôpital Privé de la Loire
city: Strasbourg
country: France
facility: Clinique Sainte Anne - Strasbourg Oncologie Libérale
city: Strasbourg
country: France
facility: Institut de cancérologie Strasbourg Europe
city: Suresnes
country: France
facility: Hôpital FOCH
city: Toulon
country: France
facility: Centre Hospitalier Intercommunal de Toulon-La Seyne - Hôpital Ste Musse
city: Toulouse
country: France
facility: IUCT Oncopole
city: Toulouse
country: France
facility: Clinique Pasteur ONCORAD
city: Tours
country: France
facility: CHRU de Tours -Hôpital Bretonneau
city: Vandœuvre-lès-Nancy
country: France
facility: Institut de Cancérologie de Lorraine
city: Villejuif
country: France
facility: Gustave Roussy Center
city: Essen
country: Germany
facility: Universitätsmedizin Essen Hufelandstraße
city: Hamburg
country: Germany
facility: University cancer center Hamburg-Eppendorf Martinistraße
city: Münster
country: Germany
facility: Universitätsklinikum Münster Klinik für Urologie und Kinderurologie Albert-Schweitzer-Campus 1 Gebäude A1
city: Dublin
country: Ireland
facility: St Vincent's University Hospital
city: Dublin
country: Ireland
facility: Tallaght university Hospital
city: Dublin
country: Ireland
facility: Mater Misericordiae University Hospital
city: Dublin
country: Ireland
facility: Mater Private Hospital
city: Bari
country: Italy
facility: University of Bari, Policlinico
city: Candiolo
country: Italy
facility: FPO IRCCS Candiolo Turin
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.)
city: Milano
country: Italy
facility: Fondazione IRCSS Istituto Nazionale Tumori
city: Napoli
country: Italy
facility: istituto tumori Fondazione "G.Pascale"
city: Roma
country: Italy
facility: Azienda Ospedaliera S. Camillo-Forlanini
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas - IRCCS
city: Siracusa
country: Italy
facility: UOC Oncologia Medica
city: Trento
country: Italy
facility: Santa Chiara Hospital
city: Dordrecht
country: Netherlands
facility: Albert Schweizer Hospital
city: Nijmegen
country: Netherlands
facility: Radboudumc - Dutch Uro-Oncology Study Group (DUOS)
city: Bucharest
country: Romania
facility: Institutul Oncologic Prof Dr Al Trestioreanu Bucuresti
city: Cluj
country: Romania
facility: Amethyst Radiotherapy Center Cluj SRL
city: Cluj
country: Romania
facility: Institul Oncologic Cluj-Napoca
city: Timişoara
country: Romania
facility: OncoHelp Hospital
city: Bratislava
country: Slovakia
facility: Narodny Onkologicky Institut
city: Badalona
country: Spain
facility: Institut Catala d'Oncologia, Badalona-Hospital Germans Trias i Pujol
city: Barcelona
country: Spain
facility: Hospital Clinic
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Vall d'Hebron Institute of Oncology. Vall d'Hebron University Hospital
city: Girona
country: Spain
facility: Institut Català d'Oncologia de Girona
city: Madrid
country: Spain
facility: Centro Integral Oncologico HM Clara Campal
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Manresa
country: Spain
facility: Althaia, Xara Assistencial Universitaria Mansera
city: Valencia
country: Spain
facility: Fundacion Instituto Valenciano De Oncologia
city: Gothenburg
country: Sweden
facility: Sahlgrenska University Hospital
city: Malmö
country: Sweden
facility: Skane University Hospital
city: Bellinzona
country: Switzerland
facility: Istituto Oncologico della Svizzera Italiana (IOSI) - Ospedale S.Giovanni
city: Chur
country: Switzerland
facility: Kantonsspital Graubünden, Onkologie/ Hämatologie
city: Saint Gallen
country: Switzerland
facility: Cantonal Hospital St.Gallen
city: Viganello
country: Switzerland
facility: Istituto Oncologico della Svizzera Italiana (IOSI) - Ospedale Italiano di Lugano
city: Zürich
country: Switzerland
facility: Universitätsspital Zürich - Onkologie
Study officials:
affiliation: San Camillo-Forlanino hospital, Italy
name: Giulia Baciarello, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Gustave Roussy Cancer Campus, France
name: Karim Fizazi, MD
role: PRINCIPAL_INVESTIGATOR
References: