Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Immune System Diseases

Prostatic Neoplasms

Hypersensitivity

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

All Drugs and Chemicals

Antineoplastic Agents

Pharmaceutical Solutions

Anti-Inflammatory Agents

Androgens

Carboplatin

Niraparib

Docetaxel

Abiraterone Acetate

Prednisone

Taxane

Poly(ADP-ribose) Polymerase Inhibitors

Radium Ra 223 dichloride

Tubulin Modulators

Antimitotic Agents

Glucocorticoids

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

Enzyme Inhibitors

Cytochrome P-450 Enzyme Inhibitors

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.

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.

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

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

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

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

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

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).

Enzalutamide Oral Capsule

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

Abiraterone Oral Tablet

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

Docetaxel Injectable Solution

Radium Chloride Ra-223

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.

Niraparib plus Abiraterone acetate plus Prednisone

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.

Capivasertib plus Docetaxel

Apalutamide

Darolutamide

Berit Larsson, MSc

Henrik Grönberg, Professor

Bram De Laere, PhD

Peter Schatterman, MD

Michiel Strijbos, MD, PhD

Christophe Ghysel, MD

Daan De Maeseneer

Wendy De Roock, MD

Caroline Verbaeys, MD, PhD

Piet Ost, Prof. dr.

Daisy Luyten, MD

Siska Van Bruwaene

Brieuc Sautois, MD

Jochen Darras, MD

Els Everaert, MD, PhD

Maria Persson, RN

Christoph Müller, MD, PhD

Jan Oldenburg, Prof. dr

Maria N Vigmostad, MD, PhD

Hege S Haugnes, Prof, dr

Bjorg Y Aksnessaether, MD PhD

Ingrida Verbiéne, MD, PhD

Susanne Johansson, B.Sc.

Christine Jaredsson, MD, PhD

Linn Pettersson, MD, PhD

Mats Andén, MD, PhD

Johan Sandzen, MD, PhD

Anders Ullén, MD, PhD

Marie Hjälm Eriksson, MD PhD

Elin Jänes, MD PhD

Camilla Thellenberg Karlsson, MD PhD

Gunilla Enblad, Professor

Ingela Franck Lissbrant, MD, PhD

Martha Olsson, MD, PhD

Jenny Kahlmeter Brandell, MD, PhD

Arnoud Templeton, MD

Ashkan Mortezavi, MD PhD

Martin Eklund, Professor

Johan Lindberg, PhD

Piet Ost, Professor

Jan Oldenburg, Professor

Ashkan Mortezavi, MD, PhD

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.

ProBio is an outcome-adaptive, multi-arm, open-label, multiple assignment randomised biomarker driven platform trial in patients with metastatic hormone-sensitive and castration-resistant prostate cancer.

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.

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.

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

ProBio: An Outcome-adaptive and Randomized Multi-arm Biomarker Driven Study in Patients With Metastatic Prostate Cancer

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).

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

Treatment response is evaluated according to PCWG3 and RECIST 1.1

OS is defined as time to death from any cause (overall and prostate cancer specific)

QoL will be assessed using the EORTC QLQ-C30 instrument

Cost effectiveness will be assessed by using the EQ-5D-5L instrument to estimate health utilities. Treatment costs will be based on drug costs and reimbursement data.

Common Terminology Criteria for Adverse Events (CTCAE) developed and maintained by the US National Cancer Institute will be used to record adverse events

Response rates at 6 months on therapy will be evaluated by the established standards of EAU Guidelines

Spots Global Cancer Trial Database for docetaxel injectable solution