STATE OF THE ART

 

mCRPC and the evolving therapeutic landscape

 

Prostate cancer is the most commonly diagnosed cancer in European men. Every year more than 400,000 men are diagnosed and about 107,000 die of prostate cancer. In men with metastatic prostate cancer (mPC), hormonal treatment (surgical or medical castration) has been standard care the last 50 years. The latter demonstrated benificial effects from the combination with docetaxel or AR-signalling inhibitors when compared to men receiving only castration in the context of primary metastatic prostate cancer. However, eventually all men will progress and develop metastatic castrate resistant prostate cancer (mCRPC). It is estimated that around 2,500 men develop mCRPC in Sweden yearly. The last years, four new drugs have been approved for treatment of mCRPC. These drugs all lead to a moderate increase in overall survival. The drugs are enzalutamide (Xtandi), abiraterone (Zytiga), cabazitaxel (Jevtana) and Ra-223 (Xofigo). Although these new drugs are definitely beneficial for many patients they carry three serious disadvantages, which leads to ineffective trial-and-error in treatment decisions:

  • These drugs are all very expensive.

  • The response rates to these drugs are low

  • There are no predictive treatment markers available in clinical care today

 

Liquid biopsies

 

The lack of predictive biomarkers in mCRPC is partly due to the difficulty of obtaining metastatic tissue for molecular analysis as the majority metastasize to the bone. An option to metastatic tissue is a blood-based liquid biopsy. Multiple studies on circulating tumor DNA (ctDNA) have demonstrated its potential as a surrogate for tissue in mCRPC. Comparing the higher success-rate of ctDNA with what is achievable with metastatic tissue biopsy procedures, it has several additional advantages as it: 

  1. has faster turnover

  2. cost less

  3. has no side-effects

  4. allows for longitudinal monitoring

  5. provides information from multiple metastatic sites.

 

During Probio biomarker signatures will be identified using a circulating tumor DNA (ctDNA) panel specifically designed for mCRPC. Alterations in the following genes/pathways or combinations thereof constitute the initial biomarker signatures:

 

  • Androgen receptor 

  • DNA-repair deficiency 

  • TP53

  • TMPRSS2-ERG gene fusion 

 

Novel statistical trial designs

 

Probio will use outcome-adaptive randomization, adapting the randomization based on progression free survival within combinations of treatment and biomarker signatures. Treatments will initially be assigned to all biomarker signatures where they might 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 relative to patients in the control arm with the same biomarker signature. Participants and treating physicians will be blinded to the biomarker signature in the control arm. This information 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 biomarker signature. The randomization probabilities within the experimental arm are defined in proportion to the probability that each treatment is superior to standard of care for a given biomarker signature, and therefore change as data accumulates in the trial and knowledge accumulates for what biomarker signature specific treatments are more probable to be effective. Trial results will be evaluated bi-monthly 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 from the trial will be graduated 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 100 patients 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 profiles can be added to the experimental arm in the future. This will be done after protocol amendments.

STUDY DESIGN

General overview and hypothesis

 

The proposed hypothesis is that treatment decisions based on biomarker signatures identified by sequencing ctDNA significantly will increase the progression free survival (PFS) in patients with metastatic castrate resistant prostate cancer (mCRPC) compared to current clinical standard of care. This hypothesis will be tested in a large multicentre randomized controlled trial with an outcome-adaptive multi-arm biomarker driven design in male patients with mCRPC (i.e. males only). Specifically, in comparison to current standard of care we aim to investigate if treatment decisions based on a mCRPC biomarker signature identified by sequencing circulating tumor DNA:  
 

  • improves PFS (primary endpoint).

  • improves treatment response rate (RR) after 3-4 months of treatment

  • improves overall survival

  • improves quality of life

  • improves health economy

  • does not increase toxicity

ProBio trial design

 

Treatments

 

Patients in the experimental arm can be randomized to the following treatments:

  • Enzalutamide 

  • Abiraterone 

  • Cabazitaxel 

  • Docetaxel 

  • Carboplatin 

 

Primary and Secondary endpoints

 

Primary objective:

To determine whether treatment choice based on a biomarker signature can improve Progression Free Survival (PFS) compared to standard of care in patients with metastatic castrate resistant prostate cancer.

Secondary objective:

To determine whether treatment choices based on a biomarker signature can, compared to standard of care

  • improve treatment response rate (RR) after 4 months of treatment 

  • improve overall survival 

  • improve quality of life 

  • improve health economy 

  • does not increase toxicity

To identify additional predictive and prognostic biomarkers.

To determine whether a certain treatment is superior for a certain biomarker signature compared to other treatments.

IMPACT

 

Short and long-term effects on patient management

 

The molecular characteristics of a patient’s tumour will become an essential prerequisite of routine diagnostics to prognosticate the patient and to define the treatment management by predictive biomarker assessment.

 

In the short term our study will:

  • introduce a minimal invasive liquid biopsy in the daily practice of treating physicians 

  • allow for better patient monitoring and management

  • potentially provide longer benefit for those recruited patients that will be randomised to a biomarker signature-driven treatment arm 

 

Since we envision treatment will become patient-tailored, aiming towards a maximal response probability of the actual treatment that is being prescribed, our study will in the long term:

  • introduce the use of predictive blood-based molecular signatures in standard-of-care 

  • result in the identification of a subpopulation of patients who would not benefit from standard-of-care therapy and immediately direct these patients to more novel drugs or experimental trials 

  • introduce true precision urologic oncology in mCRPC, aiming to maximise quality-of-life and prognosis in this rapidly expanding patient population. 

 

Valorisation strategy and future vision

 

Probio aims to valorise its results and brings these as rapid as possible to the relevant patient group in daily practice. Our valorisation strategy encompasses:

  • Implementing a validation arm in our trial design to test graduated biomarker signature/therapy combinations in standard-of-care 

  • Actively involve the Ministries of Healthcare to discuss reimbursement strategies of the liquid biopsy test 

  • Development of a centralised liquid biopsy laboratory on a national level 

  • Organise knowledge diffusion symposia for clinicians, general practitioners and patient organisations

  • Publishing our results in both national and international journals 

  • Attend scientific conferences to discuss the results 

 

Probio’s future vision is a molecularly-driven selection of a (systemic) therapy that benefits the patient the most.

 

WHAT ARE OUR EXPLORATORY SUBSTUDIES?

  • Can ctDNA fraction dynamics be used for therapy response assessment and become a new trial endpoint?

  • Can ctDNA fraction bursts predict therapy response?

  • Retrospective analysis of the ctDNA profile to identify new biomarker signature - treatment associations

  • Analysis of cell-free RNA

  • RNA Analysis of thrombocytes

  • Prospective DNA analysis of CTCs

  • RNA analysis of CTCs

  • cfRNA and cfDNA analysis of urine

QUICK LINKS

CONTACT US

Probio Clinical Trial Team

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet
171 77 Stockholm | Nobels väg 12 A.

 

Probio on Twitter

EMAIL: info@probiotrial.org

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