ProBio: A Biomarker Driven Study in Patients With Metastatic Prostate Cancer
NCT ID: NCT03903835
Last Updated: 2025-04-09
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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RECRUITING
PHASE3
750 participants
INTERVENTIONAL
2019-02-01
2026-12-31
Brief Summary
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Detailed Description
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Patients will be randomised to control or experimental treatment class arms. Patients in the control arm will receive standard of care following national guidelines and will remain within the control arm throughout the course of the trial. Patients in the experimental arm will be randomised to a treatment class (consisting of one or multiple drugs) based on a biomarker signature. The biomarker signatures are defined as tumour properties or mutations in certain genes/pathways identified in the scientific literature as important in prostate cancer treatment response. The biomarker signatures are identified using a gene panel specifically designed for advanced prostate cancer.
Alterations in the following genes/pathways or combinations thereof constitute the biomarker signatures:
* Androgen receptor
* DNA-repair deficiency
* TP53
* TMPRSS2-ERG gene fusion
* PI3K pathway alterations
Patients in the experimental arm can be randomized to the following treatments classes:
for mHSPC
* AR signalling inhibitors (Abiraterone acetate, Enzalutamide, Apalutamide)
* Taxane-based chemotherapy in combination with ARSi (Docetaxel plus Abiraterone acetate, or Darolutamide)
* PolyADP Ribose Polymerase Inhibitors (Niraparib plus Abiraterone Acetate)
for mCRPC
* AR signalling inhibitors (Enzalutamide, Abiraterone acetate)
* Poly ADP Ribose Polymerase Inhibitors (Niraparib plus Abiraterone acetate)
* Selective AKT Inhibitor (Capivasertib plus Docetaxel)
ProBio will use outcome-adaptive randomization, adapting the randomization based on the observed progression free survival (PFS) within biomarker signatures. Treatments will initially be assigned to patients based on the biomarker signatures for which that treatment is most likely to be effective. The trial will be analyzed within a Bayesian framework, which allows for calculations of the probability for each treatment that it is superior to standard of care within a given signature. Each experimental arm will be evaluated for efficacy relative to the control arm with the same biomarker signatures.
Participants and treating physicians will be blinded to ctDNA profile of each patient. The biomarker signatures will thus not influence treatment choice among controls (reflecting today's standard of care).
Further, ProBio will use the sequential multiple assignments trial (SMART) concept, where each patient who progresses within the trial will re-enter the trial and be re-assigned to another treatment based on the patient's current ctDNA profile. Patients will be withdrawn after in total maximal three randomized consecutive treatments after inclusion into the study.
The randomization probabilities within the experimental arm are defined in proportion to the probability that each treatment is superior to standard of care within a given biomarker signature, and therefore change as data accumulates in the trial and knowledge accumulates for what biomarker signatures and specific treatments that are more probable to be effective.
Trial results will be evaluated regularly by an independent data and safety monitoring board (DSMB). The DSMB will evaluate treatment-signature combinations with respect to:
* Graduation for superiority: A treatment-biomarker signature combination will be graduated from the trial if it has a Bayesian predictive probability of success in a future confirmatory phase III trial exceeding a pre-specified threshold (85%).
* Termination for futility: Treatment-biomarker signature combinations will be dropped from the trial for futility when success probabilities drop sufficiently low (less than 10% using a minimum of 20 patients assigned to the specific treatment-biomarker signature combination).
* Alternatively, if the maximum sample size of 300 and 150 patients (for mHSPC and mCRPC, respectively) assigned to a treatment biomarker signature is reached without graduation for superiority, assignments to that combination will end.
ProBio is a platform study. This means that new treatments and biomarker signatures can be added to the experimental arm in the future. This will be done after protocol amendments.
Conditions
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Study Design
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RANDOMIZED
SEQUENTIAL
TREATMENT
NONE
Study Groups
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Control: Standard Care
Randomization between assignment to the control arm or the biomarker driven arm will be stratified on biomarker signatures, previous treatment, and fraction of ctDNA and will therefore occur after the results from the ctDNA profiling is obtained. Patients in the control arm will receive standard of care following national guidelines.
Enzalutamide Oral Capsule
Detailed conditions for the use of the study treatments including dose and dosages are described in accordance with the marketing authorization in the SmPC (Summary of Product Characteristics).
Abiraterone Oral Tablet
Detailed conditions for the use of the study treatment including dose and dosages are described in accordance with the marketing authorisation in the SmPC.
Cabazitaxel 60 mg Solution for Injection
Detailed conditions for the use of the study treatment including dose and dosages are described in accordance with the marketing authorisation in the SmPC.
Docetaxel Injectable Solution
Detailed conditions for the use of the study treatment including dose and dosages are described in accordance with the marketing authorisation in the SmPC.
Radium Chloride Ra-223
Detailed conditions for the use of the study treatment including dose and dosages are described in accordance with the marketing authorisation in the SmPC.
Apalutamide
Detailed conditions for the use of the study treatments including dose and dosages are described in accordance with the marketing authorization in the SmPC (Summary of Product Characteristics).
Treatment 1 in mHSPC: AR signalling inhibitors (ARSi)
Assignments to therapy in the biomarker driven arms will be done on the basis of the biomarker signature using the current information about the efficacy of the various regimens for that signature. Information from previous studies may be incorporated in the randomization at study onset if such reliable data exists. Specifically, patients with an intact androgen receptor (AR) and without TP53 mutations will have increased chance of being randomized to treatment with ARSi.
Enzalutamide Oral Capsule
Detailed conditions for the use of the study treatments including dose and dosages are described in accordance with the marketing authorization in the SmPC (Summary of Product Characteristics).
Abiraterone Oral Tablet
Detailed conditions for the use of the study treatment including dose and dosages are described in accordance with the marketing authorisation in the SmPC.
Apalutamide
Detailed conditions for the use of the study treatments including dose and dosages are described in accordance with the marketing authorization in the SmPC (Summary of Product Characteristics).
Treatment 2 in mHSPC: taxane-based chemotherapy in combination with ARSi
Patients with TP53 mutations and TMPRSS2-ERG gene fusions will have an increased chance of being randomised to treatment with chemotherapy plus an ARSi.
Abiraterone Oral Tablet
Detailed conditions for the use of the study treatment including dose and dosages are described in accordance with the marketing authorisation in the SmPC.
Docetaxel Injectable Solution
Detailed conditions for the use of the study treatment including dose and dosages are described in accordance with the marketing authorisation in the SmPC.
Darolutamide
Detailed conditions for the use of the study treatments including dose and dosages are described in accordance with the marketing authorization in the SmPC (Summary of Product Characteristics).
Treatment 3 in mHSPC: Poly ADP Ribose Polymerase (PARP) inhibitor
DNA-repair deficient patients will have an increased chance of receiving PARP inhibitors at study onset.
Niraparib plus Abiraterone acetate plus Prednisone
Niraparib and Abiraterone acetate will be provided by Janssen and will be provided either as a fixed dose combination or as single agents. Detailed use of the study treatment including dose and dosages are described in the Investigator's brochures and SmPC.
Treatment 1 in mCRPC: AR signalling inhibitors (ARSi)
Specifically, patients with an intact androgen receptor (AR) and without TP53 mutations will have increased chance of being randomized to treatment with ARSi.
Enzalutamide Oral Capsule
Detailed conditions for the use of the study treatments including dose and dosages are described in accordance with the marketing authorization in the SmPC (Summary of Product Characteristics).
Abiraterone Oral Tablet
Detailed conditions for the use of the study treatment including dose and dosages are described in accordance with the marketing authorisation in the SmPC.
Treatment 2 in mCRPC: Poly ADP Ribose Polymerase (PARP) inhibitor
DNA-repair deficient patients will have an increased chance of receiving PARP inhibitors at study onset.
Niraparib plus Abiraterone acetate plus Prednisone
Niraparib and Abiraterone acetate will be provided by Janssen and will be provided either as a fixed dose combination or as single agents. Detailed use of the study treatment including dose and dosages are described in the Investigator's brochures and SmPC.
Treatment 3 in mCRPC: selective AKT Inhibitor
Patients with alterations in the PI3K pathway will have an increased chance of receiving the combination treatment with Capivasertib plus Docetaxel.
Capivasertib plus Docetaxel
Capivasertib is provided by AstraZeneca and will be given in combination with Docetaxel. All subjects will be given up to ten 21-day docetaxel cycles. All subjects will receive Capivasertib, which will be administered as tablets taken twice a day orally, on a 4 days on/3 days off continuous schedule, commencing cycle one, day 2, until disease progression.
Treatment 4 in mCRPC: Carboplatin
Only patients with DNA-repair deficiency will be treated with Carboplatin as second line treatment in the castration-resistant phase of ProBio.
Carboplatin
Carboplatin will be administered every 3rd week with an AUC (area under curve) = 5 with a dose calculated according to the Carboplatin AUC Dose calculation (Calvert formula):Dose (mg) = TargetAUC (mg/ml x min) x \[GFR ml/min + 25\].
Interventions
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Enzalutamide Oral Capsule
Detailed conditions for the use of the study treatments including dose and dosages are described in accordance with the marketing authorization in the SmPC (Summary of Product Characteristics).
Abiraterone Oral Tablet
Detailed conditions for the use of the study treatment including dose and dosages are described in accordance with the marketing authorisation in the SmPC.
Carboplatin
Carboplatin will be administered every 3rd week with an AUC (area under curve) = 5 with a dose calculated according to the Carboplatin AUC Dose calculation (Calvert formula):Dose (mg) = TargetAUC (mg/ml x min) x \[GFR ml/min + 25\].
Cabazitaxel 60 mg Solution for Injection
Detailed conditions for the use of the study treatment including dose and dosages are described in accordance with the marketing authorisation in the SmPC.
Docetaxel Injectable Solution
Detailed conditions for the use of the study treatment including dose and dosages are described in accordance with the marketing authorisation in the SmPC.
Radium Chloride Ra-223
Detailed conditions for the use of the study treatment including dose and dosages are described in accordance with the marketing authorisation in the SmPC.
Niraparib plus Abiraterone acetate plus Prednisone
Niraparib and Abiraterone acetate will be provided by Janssen and will be provided either as a fixed dose combination or as single agents. Detailed use of the study treatment including dose and dosages are described in the Investigator's brochures and SmPC.
Capivasertib plus Docetaxel
Capivasertib is provided by AstraZeneca and will be given in combination with Docetaxel. All subjects will be given up to ten 21-day docetaxel cycles. All subjects will receive Capivasertib, which will be administered as tablets taken twice a day orally, on a 4 days on/3 days off continuous schedule, commencing cycle one, day 2, until disease progression.
Apalutamide
Detailed conditions for the use of the study treatments including dose and dosages are described in accordance with the marketing authorization in the SmPC (Summary of Product Characteristics).
Darolutamide
Detailed conditions for the use of the study treatments including dose and dosages are described in accordance with the marketing authorization in the SmPC (Summary of Product Characteristics).
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Distant metastatic disease documented by positive bone scan or metastatic lesions on CT or MRI
* Adequate health as assessed by the investigator to receive all available treatments in the trial
* ECOG/WHO (Eastern Cooperative Oncology Group/ World Health Organization) performance score 0-2
* Adequate organ and bone marrow function
* Albumin greater than or equal to 28 g/L
* Able to understand the patient information and sign written informed consent
Exclusion Criteria
* Within 6 months of randomization: myocardial infarction, unstable angina, angioplasty, bypass surgery, stroke, TIA (transient ischemic attack), or congestive heart failure NYHA (New York Heart Association) class III or IV
* Uncontrolled hypertension
* Uncontrolled hypotension
* Received systemic therapy (with the exception of standard ADT) prior to study inclusion, for the CRPC indication
* Any severe acute or chronic medical condition that places the patient at increased risk of serious toxicity or interferes with the interpretation of study results
* Unable to comply with study procedures
* Current participation in another clinical trial that will be in conflict with the present study, administration of an investigational therapeutic or invasive surgical procedure within 28 days prior to study enrolment
* Patients who are unlikely to comply with the protocol
* Any condition or situation which, in the opinion of the investigator, would put the subject at risk, may confound study results, or interfere with the subjects participation in this study.
* Any medical condition that would make use of the study treatments contraindicated, according to the SmPC, e.g. significant heart or liver disease.
18 Years
MALE
No
Sponsors
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The Swedish Research Council
OTHER_GOV
Kom Op Tegen Kanker
OTHER
Janssen Pharmaceutica N.V., Belgium
INDUSTRY
AstraZeneca
INDUSTRY
Cancerfonden
UNKNOWN
Karolinska Institutet
OTHER
Responsible Party
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Henrik Grönberg
Professor of Cancer Epidemiology
Principal Investigators
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Henrik Grönberg, Professor
Role: PRINCIPAL_INVESTIGATOR
Karolinska Institutet
Martin Eklund, Professor
Role: STUDY_DIRECTOR
Karolinska Institutet
Johan Lindberg, PhD
Role: STUDY_DIRECTOR
Karolinska Institutet
Piet Ost, Professor
Role: PRINCIPAL_INVESTIGATOR
University Hospital Ghent, Belgium
Jan Oldenburg, Professor
Role: PRINCIPAL_INVESTIGATOR
University Hospital, Akershus
Ashkan Mortezavi, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
University Hospital, Basel, Switzerland
Locations
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OLV Ziekenhuis Aalst
Aalst, , Belgium
GZA Sint-Augustinus
Antwerp, , Belgium
AZ Sint-Jan AV
Bruges, , Belgium
AZ Sint-Lucas
Bruges, , Belgium
Ziekenhuis Oost-Limburg
Genk, , Belgium
University Hospital Ghent
Ghent, , Belgium
AZ Jan Palfijn Ziekenhuis
Ghent, , Belgium
Jessa ziekenhuis
Hasselt, , Belgium
AZ Groeninge
Kortrijk, , Belgium
University Hospital Luik
Liège, , Belgium
AZ Damiaan
Ostend, , Belgium
VITAZ
Sint-Niklaas, , Belgium
Ålesund Sjukehus
Ålesund, , Norway
Kreftsenter Kristiansand
Kristiansand, , Norway
Akershus Universitetssykehus
Lørenskog, , Norway
Stavanger Universitetssjukehus
Stavanger, , Norway
Universitetssykehuset Nord-Norge Tromsö
Tromsø, , Norway
Falu lasarett
Falun, Region Dalarna, Sweden
Södra Alvsborgs sjukhus
Borås, , Sweden
Länssjukhuset Ryhov - Onkologiska kliniken
Jönköping, , Sweden
Länssjukhuset
Kalmar, , Sweden
Centralsjukhuset Region Värmland
Karlstad, , Sweden
Universitetssjukhuset Örebro
Örebro, , Sweden
Karolinska University Hospital
Stockholm, , Sweden
Capio St.Görans Hospital
Stockholm, , Sweden
Länssjukhuset Sundsvall Härnösand
Sundsvall, , Sweden
Norrlands Universitetssjukhus
Umeå, , Sweden
Akademiska sjukhuset
Uppsala, , Sweden
Hallands sjukhus Varberg
Varberg, , Sweden
Centrallasarettet Onkologkliniken
Vaxjo, , Sweden
St. Claraspital
Basel, , Switzerland
Universitätsspital Basel
Basel, , Switzerland
Countries
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Central Contacts
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Facility Contacts
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Berit Larsson, MSc
Role: primary
Berit Larsson, MSc
Role: primary
Berit Larsson, MSc
Role: primary
Role: backup
References
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Crippa A, Laere B, Discacciati A, Larsson B, Persson M, Johansson S, D'hondt S, Hjalm-Eriksson M, Pettersson L, Enblad G, Ullen A, Lumen N, Karlsson CT, Sandzen J, Janes E, Ghysel C, Olsson M, Sautois B, Schatteman P, Roock W, Bruwaene SV, Verbiene I, Darras J, Everaert E, Maeseneer D, Anden M, Strijbos M, Luyten D, Mortezavi A, Oldenburg J, Ost P, Lindberg J, Gronberg H, Eklund M; ProBio Investigators. Prognostic Value of the Circulating Tumor DNA Fraction in Metastatic Castration-resistant Prostate Cancer: Results from the ProBio Platform Trial. Eur Urol Oncol. 2025 Apr 21:S2588-9311(25)00037-9. doi: 10.1016/j.euo.2025.02.002. Online ahead of print.
De Laere B, Crippa A, Discacciati A, Larsson B, Persson M, Johansson S, D'hondt S, Bergstrom R, Chellappa V, Mayrhofer M, Banijamali M, Kotsalaynen A, Schelstraete C, Vanwelkenhuyzen JP, Hjalm-Eriksson M, Pettersson L, Ullen A, Lumen N, Enblad G, Thellenberg Karlsson C, Janes E, Sandzen J, Schatteman P, Nyre Vigmostad M, Olsson M, Ghysel C, Sautois B, De Roock W, Van Bruwaene S, Anden M, Verbiene I, De Maeseneer D, Everaert E, Darras J, Aksnessether BY, Luyten D, Strijbos M, Mortezavi A, Oldenburg J, Ost P, Eklund M, Gronberg H, Lindberg J. Androgen receptor pathway inhibitors and taxanes in metastatic prostate cancer: an outcome-adaptive randomized platform trial. Nat Med. 2024 Nov;30(11):3291-3302. doi: 10.1038/s41591-024-03204-2. Epub 2024 Aug 20.
De Laere B, Crippa A, Discacciati A, Larsson B, Oldenburg J, Mortezavi A, Ost P, Eklund M, Lindberg J, Gronberg H; ProBio Investigators. Clinical Trial Protocol for ProBio: An Outcome-adaptive and Randomised Multiarm Biomarker-driven Study in Patients with Metastatic Prostate Cancer. Eur Urol Focus. 2022 Nov;8(6):1617-1621. doi: 10.1016/j.euf.2022.03.005. Epub 2022 Mar 19.
Crippa A, De Laere B, Discacciati A, Larsson B, Connor JT, Gabriel EE, Thellenberg C, Janes E, Enblad G, Ullen A, Hjalm-Eriksson M, Oldenburg J, Ost P, Lindberg J, Eklund M, Gronberg H. The ProBio trial: molecular biomarkers for advancing personalized treatment decision in patients with metastatic castration-resistant prostate cancer. Trials. 2020 Jun 26;21(1):579. doi: 10.1186/s13063-020-04515-8.
Other Identifiers
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EudraCT No 2018-002350-78
Identifier Type: -
Identifier Source: org_study_id
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