ProBio Automatic Report

Accessibility level: Public. Report issued: 2025 January, 03. Data cut-off date: 2025 January, 02

This report contains summary information of the enrollment and follow-up of patients in ProBio. All the data are anonymized and blinded on both the subjects’ biomarker profile and randomized therapy

This is a computer-generated document. Contact the author Alessio Crippa for any question.

Overall information on study design, enrollment, and follow-up is reported in the Home. Separate information for metastatic Hormone-Sensitive Prostate Cancer (mHSPC) and metastatic Castration-Resistant Prostate Cancer (mCRPC) patients are reported in dedicated tabs.

The results are presented in separated tabs:

  • Study information:
    • Report summary;
    • Protocol synopsis;
    • Protocol amendment history;
    • Stopping rules.
  • Enrollment information:
    • indicators of enrolled and randomized patients, and enrolling centers;
    • maps of recruiting centers;
    • enrolled patients over time (by center);
    • info centers.
  • Follow-up variable:
    • flowchart;
    • classification patients (randomized, incomplete, excluded);
  • Data Manager:
    • info on incomplete patients;
    • info on excluded patients;
    • info on randomized patients.

Report summary

PROTOCOL TITLE: An outcome-adaptive and randomised multi-arm biomarker driven study in patients with metastatic prostate cancer
EUDRACT NUMBER: 2018-002350-78
CLINICALTRIALS.GOV NUMBER: NCT03903835
PROTOCOL VERSION: v5.1
PRINCIPAL INVESTIGATOR: Henrik Grönberg,
Professor, Department of Medical Epidemiology and Biostatistics,
Karolinska Institutet, Sweden
DATE REPORT ISSUED: 2025 January, 03
DATA CUTOFF DATE: 2025 January, 02
PREPARED BY: Alessio Crippa, PhD


Protocol synopsis

Protocol Title: ProBio is an outcome-adaptive and randomised multi-arm biomarker driven study in patients with metastatic prostate cancer
Principal Investigator: Henrik Grönberg, Professor
Study activation date: January 29th, 2019
Planned Accrual Period: Patients will be followed from time of consent through the study duration
Study design: ProBio is an outcome-adaptive, multi-arm, open-label, multiple assignment randomized biomarker driven platform trial in patients with metastatic prostate cancer
Study objectives: To determine whether therapy class choice based on a biomarker signature can improve Progression Free Survival (PFS) compared to standard of care in patients with metastatic prostate cancer
Treatment Description: Patients can be randomized to either the control group (i.e. standard-of-care) or to the experimental arm consisting of one of the following therapy classes: AR signalling inhibitors (ARSi), Taxane-based chemotherapy, Platinum-based chemotherapy, and PARP Inhibitor (PARPi)
Inclusion criteria: Male patients, aged above 18 years, with histologically confirmed prostate adenocarcinoma, initiating systemic therapy for metastatic disease, encompassing
- Newly diagnosed (i.e. de novo) metastatic hormone-sensitive prostate cancer (mHSPC) or
- First-line mCRPC, i.e. first evidence of progressive metastatic prostate cancer under castrate levels (<50 ng/dL) of serum testosterone, as defined by the EAU guidelines, encompassing biochemical and/or radiologic progression criteria
Exclusion criteria: Upon entering the mHSPC phase of the trial, prior systemic therapy (including ADT) is not allowed. Patients with mCRPC may not enter the trial when they have already received prior systemic therapy (with the exception of standard ADT) for mCRPC. Patients with mCRPC can enter the mCRPC phase of the trial regardless which prior therapy they received in the hormone-sensitive or non-metastatic CRPC phase
Study outcomes (mHSPC): PFS is defined as the time to development of castration-resistance, as defined by EAU guidelines (Cornford et al. 2017), i.e. whilst having castration levels of serum testosterone (<50ng/dL or 1.7 nmol/L) the time from randomisation to biochemical and/or radiologic progression
Study outcomes (mCRPC): PFS is defined as the time to no longer clinical benefit (NLCB), as defined by Prostate Cancer Working Group (PCWG) 3, i.e. the date and the specific reason(s) a therapy was ultimately discontinued, by evaluating biochemical, radiologic, and clinical progression criteria


Protocol amendment history

Major changes going from v4.1 to v5.1:

Major changes going from v3.0 to v4.1:

  1. Introduction of a structured clinical protocol, according to the guidelines of the Clinical Trials Facilitation and Coordination Group (CTFG), a working group of the Heads of Medicines Agencies (HMA) on clinical studies
  2. Expansion of the patient population into the disease stage before metastatic castration-resistant prostate cancer (i.e. current study), i.e. de novo metastatic hormone-sensitive prostate cancer (mHSPC)
  3. Addition of a new treatment arm with a PARP inhibitor: Niraparib + Abiraterone acetate. This can be done as single agents or as a fixed dose combination
  4. Addition of a new IMP Apalutamide (Erleada)
  5. Addition of new centers in Belgium, Sweden and Norway
  6. Addition of an extra PROM: BPI-SF


Stopping rules

Graduation: \(n \ge 25\) for the evaluated treatment-signature combination
\(\pi_s \ge 85\%\), \(\pi_s\) being the probability of superiority for the evaluated treatment vs the control within the biomarker signature
\(\pi_j \ge 70\%\), \(\pi_j\) being the probability of superiority for the evaluated treatment vs the control within all the biomarker subgroup combinations belonging to the evaluated signature
Futility: \(n \ge 25\) for the evaluated treatment-signature combination
\(\pi_s \le 30\%\), \(\pi_s\) being the probability of superiority for the evaluated treatment vs the control within the biomarker signature
\(\pi_j \le 50\%\), \(\pi_j\) being the probability of superiority for the evaluated treatment vs the control within all the biomarker subgroup combinations belonging to the evaluated signature
Max patients: \(n \ge 150\)

More information on the aims, study design and statistical aspects are available at http://rpubs.com/alecri/useR2019.

NB At least 5 patients are required in each biomarker subgroup combination.
Have a look at slide 20 for an intuition of the definition of a probability of superiority.

Visual indicators for progressive number of enrolling centers, enrolled patients (who signed the informed consent form), randomized patients.

Center maps


Interactive map with summary numbers of enrollment, randomization status, and progression for the recruiting centers.


Accrual plot


Cumulative number of enrolled patients over time (consent date). Solid line includes men enrolled in the study (also not randomized), dashed line includes only randomized patients.


Info centers

Summary numbers of enrollment for the recruiting centers.
Center City Total
Enrolled Randomized Excluded Incomplete Days from last enrollment
Sweden
Capio S:t Görans Sjukhus Stockholm 93 62 30 1 22
Karolinska Universitetssjukhuset Stockholm 47 30 16 1 4
Akademiska Sjukhuset Uppsala 44 27 17 0 260
Länssjukhuset I Sundsvall Sundsvall 44 30 13 1 21
Länssjukhuset I Ryhov Jönköping 41 27 14 0 43
Norrlands Universitetssjukhus Umeå 27 17 10 0 42
Norrlands Universitetssjukhus Sweden 27 17 10 0 42
Centralsjukhuset Karlstad Karlstad 23 13 10 0 199
Centralsjukhuset Karlstad Sweden 23 13 10 0 199
Växjö Lasarett Sweden 21 13 8 0 31
Länssjukhuset I Kalmar Kalmar 17 9 8 0 98
Falu Lasarett Falun 11 6 5 0 73
Södra Älvsborgs Sjukhus Borås 7 5 2 0 130
Universitetssjukhuset Örebro Örebro 3 2 1 0 84
Norway
Stavanger Universitetssjukehus Stavanger 67 34 27 6 16
Stavanger Universitetssjukehus Norway 67 34 27 6 16
Akershus Universitetssykehus Akershus University Hospital 44 21 22 1 4
Akershus Universitetssykehus Oslo 44 21 22 1 4
Sörlandet Sykehus Kristiansand Kristiansand 16 12 3 1 51
Ålesund Sjukehus Ålesund 13 4 9 0 46
Universitetssykehuset Nord-Norge Tromsö Tromsø 12 7 4 1 1
Sykehuset Östfold Kalnes Norway 11 6 4 1 24
Belgium
Gza Sint-Augustinus Antwerp 61 39 21 1 36
Uz Gent Ghent 47 25 21 1 8
Az St-Jan Brugge Bruges 38 21 17 0 79
Chu Liège Liège 34 24 8 2 22
Az Groeninge Kortrijk 32 19 12 1 31
Az Nikolaas Sint-Niklaas 28 16 10 2 23
Olv Aalst Aalst 27 8 18 1 15
Ziekenhuis Oost-Limburg Ziekenhuis Oost-Limburg 20 15 4 1 15
Az Damiaan Ostend 12 7 5 0 254
Az St-Lucas Brugge AZ Sint-Lucas 9 3 6 0 386
Az St-Lucas Brugge Bruges 9 3 6 0 386
Helora Hospital La Louviere Site Jolimont La Louvière 5 1 2 2 16
Jessa Ziekenhuis Hasselt 2 2 0 0 715
Switzerland
University Hospital Basel Basel 31 21 9 1 24
St. Claraspital Basel 8 4 3 1 122

Flowchart


Patient enrolled flowchart. Patients may enter ProBio a metastatic hormone-sensitive (mHS) or first line metastatic castration-resistant (mCR). Patients having progressive disease may be re-randomized up to two treatment lines for mCR prostate cancer. Patients in the control arm remain as control. Patients signing consent may not be randomized because of low circulated tumour DNA or techincal failure in liquid biospy test, MSI+ dection, or becaue of exclusion criteria.

Pie chart

Pie chart for randomization status of enrolled patients. Incomplete patients has not yet been randomized because of pending ctDNA analysis.

This panel is available only for data manager.



The results are presented in separated tabs:

  • Enrollment information:
    • indicators of enrolled and randomized patients, and enrolling centers;
    • maps of recruiting centers;
    • enrolled patients over time (by center);
    • inclusion rate;
    • info centers.
  • Follow-up variable:
    • classification patients (randomized, incomplete, excluded);
    • flowchart;
    • swimmer plot.
  • Baseline variables (tables 1 for):
    • clinical characteristics;
    • metastatic burden profile;
    • routine blood diagnostics.
  • Biomarkers:
    • prevalence of signatures and subgroup combinations (by treatment).
  • Therapies:
    • prevalence of therapies in the control group;
    • overlap of biomarker signatures by therapies.
  • Number of Progressions:
    • flowchart;
    • type of progressions (upset and alluvial plot);
    • response evaluation.
  • Evaluation of therapies:
    • results by therapy classes;
    • posterior STR/HR distributions;
    • PFS curves (Kaplan Meier and posterior).
  • Serious adverse events.

Visual indicators for progressive number of enrolling centers, enrolled patients (who signed the informed consent form), randomized and re-randomized (2nd randomization) patients.

Center maps


Interactive map with summary numbers of enrollment, randomization status, and progression for the recruiting centers.


Accrual plot


Cumulative number of enrolled patients over time (consent date). Solid line includes men enrolled in the study (also not randomized), dashed line includes only randomized patients.


Inclusion rate


Randomization rate by quarters of year (randomized/signed ICF) over time overall (dashed lines) and by country (solid coloured lines).


Info centers

Summary numbers of enrollment for the recruiting centers.
Center City Enrolled Randomized Excluded Incomplete days from last enrollment
Belgium
Az St-Jan Brugge Bruges 18 10 8 0 79
Uz Gent Ghent 7 4 3 0 36
Az Groeninge Kortrijk 21 13 7 1 31
Olv Aalst Aalst 4 0 3 1 15
Az Damiaan Ostend 9 6 3 0 254
Ziekenhuis Oost-Limburg Ziekenhuis Oost-Limburg 12 9 2 1 15
Az St-Lucas Brugge Bruges 3 0 3 0 386
Chu Liège Liège 23 17 4 2 22
Az Nikolaas Sint-Niklaas 16 10 4 2 23
Gza Sint-Augustinus Antwerp 33 23 10 0 43
Helora Hospital La Louviere Site Jolimont La Louvière 3 0 1 2 16
Norway
Akershus Universitetssykehus Oslo 17 11 5 1 4
Stavanger Universitetssjukehus Norway 22 13 6 3 16
Universitetssykehuset Nord-Norge Tromsö Tromsø 1 0 0 1 1
Ålesund Sjukehus Ålesund 3 1 2 0 46
Sörlandet Sykehus Kristiansand Kristiansand 11 8 2 1 51
Sykehuset Östfold Kalnes Norway 9 4 4 1 24
Sweden
Capio S:t Görans Sjukhus Stockholm 35 25 9 1 22
Karolinska Universitetssjukhuset Stockholm 8 5 2 1 4
Akademiska Sjukhuset Uppsala 11 6 5 0 260
Norrlands Universitetssjukhus Sweden 4 1 3 0 42
Länssjukhuset I Sundsvall Sundsvall 18 14 3 1 21
Länssjukhuset I Ryhov Jönköping 1 1 0 0 43
Växjö Lasarett Sweden 3 1 2 0 93
Länssjukhuset I Kalmar Kalmar 8 4 4 0 98
Switzerland
University Hospital Basel Basel 26 18 7 1 24
St. Claraspital Basel 4 4 0 0 127

Flowchart


Patient enrolled flowchart. Patients signing consent may not be randomized because of low circulated tumour DNA or techincal failure in liquid biospy test, MSI+ dection, or becaue of exclusion criteria. After first progression, patients in the experimental arms can be re-randomized to a second experimental treatment, while progressive patients in the control arm remain as control.

Pie chart

Pie chart for randomization status of enrolled patients. Incomplete patients has not yet been randomized because of pending ctDNA analysis.

Swimmer plot



This panel is available only for ProBio investigators or members in the DMSB.

Clinical characteristics by study arm of randomized participants

Metastatic burden profile by study arm of randomized participants

Routine blood diagnostics by study arm of randomized participants

This panel is available only for ProBio investigators or members in the DMSB.

Prevalence of biomarker signatures

Prevalence of biomarker subgroup combinations

Pie chart subgroup combinations

 

Prevalence of biomarker signatures across therapy classes

This panel is available only for ProBio investigators or members in the DMSB.

Prevalence of therapies in the control group

Overlap of biomarker signatures by therapies.

This panel is available only for ProBio investigators or members in the DMSB.

This panel is available only for members in the DMSB.

This panel is available only for ProBio investigators or members in the DMSB.

The results are presented in separated tabs:

  • Enrollment information:
    • indicators of enrolled and randomized patients, and enrolling centers;
    • maps of recruiting centers;
    • enrolled patients over time (by center);
    • inclusion rate;
    • info centers.
  • Follow-up variable:
    • therapies timeline;
    • classification patients (randomized, incomplete, excluded);
    • flowchart;
    • swimmer plot.
  • Baseline variables (tables 1 for):
    • clinical characteristics;
    • metastatic burden profile;
    • routine blood diagnostics;
    • baseline variables by randomization status.
  • Biomarkers (first randomization):
    • prevalence of signatures and subgroup combinations (by treatment);
    • changes after progression.
  • Therapies:
    • prevalence of therapies in the control group;
    • overlap of biomarker signatures by therapies.
  • Number of Progressions:
    • flowchart;
    • type of progressions (upset and alluvial plot);
    • response evaluation.
  • Evaluation of therapies:
    • results by therapy classes;
    • posterior STR/HR distributions;
    • PFS curves (Kaplan Meier and posterior).
  • Serious adverse events.

Visual indicators for progressive number of enrolling centers, enrolled patients (who signed the informed consent form), randomized and re-randomized (2nd randomization) patients.

Center maps


Interactive map with summary numbers of enrollment, randomization status, and progression for the recruiting centers.


Accrual plot


Cumulative number of enrolled patients over time (consent date). Solid line includes men enrolled in the study (also not randomized), dashed line includes only randomized patients.


Inclusion rate


Randomization rate by quarters of year (randomized/signed ICF) over time overall (dashed lines) and by country (solid coloured lines).


Info centers

Summary numbers of enrollment for the recruiting centers.
Center City Enrolled Randomized Re-randomized Excluded Incomplete days from last enrollment
Belgium
Az St-Jan Brugge Bruges 20 11 4 9 0 126
Uz Gent Ghent 40 21 10 18 1 8
Az Groeninge Kortrijk 12 7 4 5 0 32
Olv Aalst Aalst 23 8 1 15 0 57
Az Damiaan Ostend 3 1 0 2 0 745
Ziekenhuis Oost-Limburg Ziekenhuis Oost-Limburg 9 7 4 2 0 462
Az St-Lucas Brugge AZ Sint-Lucas 6 3 0 3 0 641
Chu Liège Liège 17 13 6 4 0 232
Jessa Ziekenhuis Hasselt 2 2 1 0 0 715
Az Nikolaas Sint-Niklaas 13 7 1 6 0 44
Gza Sint-Augustinus Antwerp 29 17 2 11 1 36
Helora Hospital La Louviere Site Jolimont La Louvière 2 1 0 1 0 36
Norway
Akershus Universitetssykehus Akershus University Hospital 27 10 6 17 0 77
Stavanger Universitetssjukehus Stavanger 45 21 9 21 3 17
Universitetssykehuset Nord-Norge Tromsö Tromsø 11 7 0 4 0 141
Ålesund Sjukehus Ålesund 10 3 1 7 0 137
Sörlandet Sykehus Kristiansand Kristiansand 6 5 1 1 0 101
Sykehuset Östfold Kalnes Norway 2 2 0 0 0 99
Sweden
Capio S:t Görans Sjukhus Stockholm 59 38 13 21 0 85
Karolinska Universitetssjukhuset Stockholm 39 25 12 14 0 105
Akademiska Sjukhuset Uppsala 34 22 9 12 0 282
Norrlands Universitetssjukhus Umeå 23 16 7 7 0 44
Länssjukhuset I Sundsvall Sundsvall 29 18 7 10 1 191
Länssjukhuset I Ryhov Jönköping 40 26 14 14 0 101
Växjö Lasarett Sweden 18 12 5 6 0 31
Centralsjukhuset Karlstad Karlstad 23 13 8 10 0 199
Länssjukhuset I Kalmar Kalmar 9 5 2 4 0 325
Falu Lasarett Falun 11 6 1 5 0 73
Södra Älvsborgs Sjukhus Borås 7 5 1 2 0 130
Universitetssjukhuset Örebro Örebro 3 2 0 1 0 84
Switzerland
University Hospital Basel Basel 8 6 1 2 0 134
St. Claraspital Basel 5 1 1 3 1 122

Flowchart


Patient enrolled flowchart. Patients signing consent may not be randomized because of low circulated tumour DNA or techincal failure in liquid biospy test, MSI+ dection, or becaue of exclusion criteria. After first progression, patients in the experimental arms can be re-randomized to a second experimental treatment, while progressive patients in the control arm remain as control.

Pie chart

Pie chart for randomization status of enrolled patients. Incomplete patients has not yet been randomized because of pending ctDNA analysis.

Swimmer plot


This panel is available only for ProBio investigators or members in the DMSB.

Clinical characteristics by study arm of randomized participants

Metastatic burden profile by study arm of randomized participants

Routine blood diagnostics by study arm of randomized participants

Treatment history by study arm of randomized participants

     

Baseline variables by randomization status

This panel is available only for ProBio investigators or members in the DMSB.

Prevalence of biomarker signatures

Prevalence of biomarker subgroup combinations

Pie chart subgroup combinations

Prevalence of biomarker signatures across therapy classes. Only first randomizations are included.

Change in subgroup combination

This panel is available only for ProBio investigators or members in the DMSB.

Prevalence of therapies in the control group

Overlap of biomarker signatures by therapies.

This panel is available only for ProBio investigators or members in the DMSB.

Flowchart

Type of progressions

Alluvial plot

 

Swimmer plot for response evaluation

This panel is available only for members in the DMSB.

This panel is available only for ProBio investigators or members in the DMSB.