ProBio: A Biomarker Driven Study in Patients With Metastatic Prostate Cancer

NCT03903835 | Recruiting Phase 3 DMC

• 1 other identifier: EudraCT No 2018-002350-78
• Study Type: interventional
• Target: 750
• Locations: 4 countries
• Sites: 32

Brief Summary

ProBio is an international, outcome-adaptive, multi-arm, open-label, multiple assignment randomized biomarker driven platform trial in patients with metastatic prostate cancer. Patients will be randomized to control or experimental treatment arms. Patients in the control arm will receive standard of care following national guidelines. Patients in the experimental arm will be randomized to treatments based on a biomarker signature inferred from diagnostic tissue or liquid biopsy profiling. The predefined biomarker signatures are tumor properties or mutations in genes/pathways with previously demonstrated clinical validity (e.g. prognostic value or association with treatment response). The biomarker signatures are identified using a hybridisation capture gene panel specifically designed for prostate cancer.

Conditions

Metastatic Castration-resistant Prostate Cancer (mCRPC); Metastatic Hormone-Sensitive Prostate Cancer (mHSPC)

Keywords

mCRPC; mHSPC; cfDNA; Genomics; Liquid Biopsy

Outcome Measures

Primary Outcomes (2)

• Progression free survival (PFS) in mCRPC

  Progression will be evaluated by the established international standards of the Prostate Cancer Working Group version 3 (PCWG3) and for soft tissue metastases (e.g. lung, liver and lymph nodes) according to the Response Evaluation Criteria in Solid Tumors (RECIST v. 1.1).

  Until progressive disease or 60 months from start of treatment, whatever occurs first.

• Progression free survival (PFS) in mHSPC

  Time to development of castration-resistance, as defined by EAU guidelines (biochemical progression or radiologic progression)

  From date of treatment start until the date of first documentation of progression, assessed up to 60 months

Secondary Outcomes (6)

• Treatment response rate in mCRPC

  4 months after treatment start

• Overall survival (OS)

  From enrolment to completion of study (60 months)

• Patient Reported Outcome Measures (PROM)

  From enrolment to completion of study (60 months)

• Cost-effectiveness

  From enrolment to completion of study (60 months)

• Number of Participants With Adverse Events as a Measure of Safety and Tolerability

  From enrolment to completion of study (60 months)

Study Arms (8)

Control: Standard Care

ACTIVE COMPARATOR

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.

Drug: Enzalutamide Oral Capsule; Drug: Abiraterone Oral Tablet; Drug: Cabazitaxel 60 mg Solution for Injection; Drug: Docetaxel Injectable Solution; Drug: Radium Chloride Ra-223; Drug: Apalutamide

Treatment 1 in mHSPC: AR signalling inhibitors (ARSi)

EXPERIMENTAL

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.

Drug: Enzalutamide Oral Capsule; Drug: Abiraterone Oral Tablet; Drug: Apalutamide

Treatment 2 in mHSPC: taxane-based chemotherapy in combination with ARSi

EXPERIMENTAL

Patients with TP53 mutations and TMPRSS2-ERG gene fusions will have an increased chance of being randomised to treatment with chemotherapy plus an ARSi.

Drug: Abiraterone Oral Tablet; Drug: Docetaxel Injectable Solution; Drug: Darolutamide

Treatment 3 in mHSPC: Poly ADP Ribose Polymerase (PARP) inhibitor

EXPERIMENTAL

DNA-repair deficient patients will have an increased chance of receiving PARP inhibitors at study onset.

Drug: Niraparib plus Abiraterone acetate plus Prednisone

Treatment 1 in mCRPC: AR signalling inhibitors (ARSi)

EXPERIMENTAL

Specifically, patients with an intact androgen receptor (AR) and without TP53 mutations will have increased chance of being randomized to treatment with ARSi.

Drug: Enzalutamide Oral Capsule; Drug: Abiraterone Oral Tablet

Treatment 2 in mCRPC: Poly ADP Ribose Polymerase (PARP) inhibitor

EXPERIMENTAL

DNA-repair deficient patients will have an increased chance of receiving PARP inhibitors at study onset.

Drug: Niraparib plus Abiraterone acetate plus Prednisone

Treatment 3 in mCRPC: selective AKT Inhibitor

EXPERIMENTAL

Patients with alterations in the PI3K pathway will have an increased chance of receiving the combination treatment with Capivasertib plus Docetaxel.

Drug: Capivasertib plus Docetaxel

Treatment 4 in mCRPC: Carboplatin

EXPERIMENTAL

Only patients with DNA-repair deficiency will be treated with Carboplatin as second line treatment in the castration-resistant phase of ProBio.

Drug: Carboplatin

Interventions

Enzalutamide Oral Capsule DRUG

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).

Also known as: Xtandi

Control: Standard Care; Treatment 1 in mCRPC: AR signalling inhibitors (ARSi); Treatment 1 in mHSPC: AR signalling inhibitors (ARSi)

Abiraterone Oral Tablet DRUG

Detailed conditions for the use of the study treatment including dose and dosages are described in accordance with the marketing authorisation in the SmPC.

Also known as: Zytiga

Control: Standard Care; Treatment 1 in mCRPC: AR signalling inhibitors (ARSi); Treatment 1 in mHSPC: AR signalling inhibitors (ARSi); Treatment 2 in mHSPC: taxane-based chemotherapy in combination with ARSi

Carboplatin DRUG

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 \[GFR ml/min + 25\].

Treatment 4 in mCRPC: Carboplatin

Cabazitaxel 60 mg Solution for Injection DRUG

Detailed conditions for the use of the study treatment including dose and dosages are described in accordance with the marketing authorisation in the SmPC.

Control: Standard Care

Docetaxel Injectable Solution DRUG

Detailed conditions for the use of the study treatment including dose and dosages are described in accordance with the marketing authorisation in the SmPC.

Control: Standard Care; Treatment 2 in mHSPC: taxane-based chemotherapy in combination with ARSi

Radium Chloride Ra-223 DRUG

Detailed conditions for the use of the study treatment including dose and dosages are described in accordance with the marketing authorisation in the SmPC.

Also known as: Xofigo

Control: Standard Care

Niraparib plus Abiraterone acetate plus Prednisone DRUG

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.

Also known as: Akeega

Treatment 2 in mCRPC: Poly ADP Ribose Polymerase (PARP) inhibitor; Treatment 3 in mHSPC: Poly ADP Ribose Polymerase (PARP) inhibitor

Capivasertib plus Docetaxel DRUG

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 3 in mCRPC: selective AKT Inhibitor

Apalutamide DRUG

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).

Also known as: Erleada

Control: Standard Care; Treatment 1 in mHSPC: AR signalling inhibitors (ARSi)

Darolutamide DRUG

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).

Also known as: Nubeqa

Treatment 2 in mHSPC: taxane-based chemotherapy in combination with ARSi

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Man with histologically confirmed prostate adenocarcinoma, initiating systemic therapy for metastatic disease, encompassing newly diagnosed (i.e. de novo) hormone sensitive prostate cancer (mHSPC) or first-line castration resistant prostate cancer (mCRPC)
• 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

You may not qualify if:

• Other malignancies within 5 years except non-melanoma skin cancer
• 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
• 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.

Sponsors & Collaborators

• Karolinska Institutet: lead
• The Swedish Research Council: collaborator
• Kom Op Tegen Kanker: collaborator
• Janssen Pharmaceutica N.V., Belgium: collaborator
• AstraZeneca: collaborator
• Cancerfonden: collaborator

Study Sites (32)

OLV Ziekenhuis Aalst

Aalst, Belgium

RECRUITING

GZA Sint-Augustinus

Antwerp, Belgium

RECRUITING

AZ Sint-Jan AV

Bruges, B-8000, Belgium

RECRUITING

AZ Sint-Lucas

Bruges, Belgium

RECRUITING

Ziekenhuis Oost-Limburg

Genk, Belgium

RECRUITING

University Hospital Ghent

Ghent, B-9000, Belgium

RECRUITING

AZ Jan Palfijn Ziekenhuis

Ghent, Belgium

NOT YET RECRUITING

Jessa ziekenhuis

Hasselt, Belgium

RECRUITING

AZ Groeninge

Kortrijk, Belgium

RECRUITING

University Hospital Luik

Liège, Belgium

RECRUITING

AZ Damiaan

Ostend, Belgium

RECRUITING

VITAZ

Sint-Niklaas, Belgium

RECRUITING

Ålesund Sjukehus

Ålesund, Norway

NOT YET RECRUITING

Kreftsenter Kristiansand

Kristiansand, Norway

RECRUITING

Akershus Universitetssykehus

Lørenskog, Norway

RECRUITING

Stavanger Universitetssjukehus

Stavanger, Norway

RECRUITING

Universitetssykehuset Nord-Norge Tromsö

Tromsø, Norway

NOT YET RECRUITING

Falu lasarett

Falun, Region Dalarna, 79182, Sweden

RECRUITING

Södra Alvsborgs sjukhus

Borås, Sweden

RECRUITING

Länssjukhuset Ryhov - Onkologiska kliniken

Jönköping, 551 11, Sweden

RECRUITING

Länssjukhuset

Kalmar, 392 44, Sweden

RECRUITING

Centralsjukhuset Region Värmland

Karlstad, 651 85, Sweden

RECRUITING

Universitetssjukhuset Örebro

Örebro, Sweden

RECRUITING

Karolinska University Hospital

Stockholm, 17176, Sweden

RECRUITING

Capio St.Görans Hospital

Stockholm, Sweden

RECRUITING

Länssjukhuset Sundsvall Härnösand

Sundsvall, 851 86, Sweden

RECRUITING

Norrlands Universitetssjukhus

Umeå, 90185, Sweden

RECRUITING

Akademiska sjukhuset

Uppsala, 75185, Sweden

RECRUITING

Hallands sjukhus Varberg

Varberg, Sweden

RECRUITING

Centrallasarettet Onkologkliniken

Vaxjo, 351 85, Sweden

RECRUITING

St. Claraspital

Basel, Switzerland

RECRUITING

Universitätsspital Basel

Basel, Switzerland

RECRUITING

Related Publications (4)

• 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 Dec;8(6):1486-1495. doi: 10.1016/j.euo.2025.02.002. Epub 2025 Apr 21.

  PMID: 40263079 DERIVED

• 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.

  PMID: 39164518 DERIVED

• 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.

  PMID: 35317973 DERIVED

• 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.

  PMID: 32586393 DERIVED

MeSH Terms

Interventions

enzalutamide; abiraterone; Abiraterone Acetate; Carboplatin; cabazitaxel; Solutions; Injections; radium Ra 223 dichloride; niraparib; Prednisone; capivasertib; Docetaxel; apalutamide; darolutamide

Intervention Hierarchy (Ancestors)

Androstenes; Androstanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Coordination Complexes; Organic Chemicals; Pharmaceutical Preparations; Drug Administration Routes; Drug Therapy; Therapeutics; Pregnadienediols; Pregnadienes; Pregnanes; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Diterpenes; Terpenes

Study Officials

• Henrik Grönberg, Professor

  Karolinska Institutet

  PRINCIPAL INVESTIGATOR

• Martin Eklund, Professor

  Karolinska Institutet

  STUDY DIRECTOR

• Johan Lindberg, PhD

  Karolinska Institutet

  STUDY DIRECTOR

• Piet Ost, Professor

  University Hospital Ghent, Belgium

  PRINCIPAL INVESTIGATOR

• Jan Oldenburg, Professor

  University Hospital, Akershus

  PRINCIPAL INVESTIGATOR

• Ashkan Mortezavi, MD, PhD

  University Hospital, Basel, Switzerland

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Berit Larsson, MSc

CONTACT

+46 8 52482576; berit.larsson@ki.se

Henrik Grönberg, Professor

CONTACT

+46 70 3411356; Henrik.gronberg@ki.se

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Cancer Epidemiology

Model Details: ProBio will use outcome-adaptive randomization, adapting the randomization based on the observed 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 analysed within a Bayesian framework, which allows for calculations of the probability for each treatment that 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.

Study Record Dates

• First Submitted: March 29, 2019
• First Posted: April 4, 2019
• Study Start: February 1, 2019
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026
• Last Updated: April 9, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

NO (5); CH (2); SE (13); BE (12)