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

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

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 Patients in the experimental arm can be randomized to the following treatments: Enzalutamide Abiraterone Apalutamide Docetaxel Cabazitaxel Carboplatin Niraparib plus Abiraterone acetate plus Prednisone 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.

Metastatic Castration-resistant Prostate Cancer, Metastatic Hormone-Sensitive Prostate Cancer (mHSPC)

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.

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 of Abiraterone or Enzalutamide.

Patients with an intact androgen receptor (AR) and without TP53 mutations will have an increased chance of being randomised to treatment of Abiraterone or Enzalutamide.

Patients with the TMPRSS2-ERG gene fusion will have increased chance of receiving chemotherapy at study onset.

Patients with the TMPRSS2-ERG gene fusion will have increased chance of receiving chemotherapy at study onset.

DNA-repair deficient patients will have an increased chance of receiving the combination treatment with Niraparib plus Abiraterone acetate plus Prednisone.

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).

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 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].

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

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

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 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.

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).

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

Inclusion Criteria: Man with metastatic castrate resistant prostate cancer (histologically confirmed prostate adenocarcinoma) and castrate levels < 50 ng/dl of serum 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 umol/L Able to understand the patient information and sign written informed consent Exclusion Criteria: 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 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.

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.