Phase II Randomised Controlled Trial of Patient-specific Adaptive vs. Continuous Abiraterone or eNZalutamide in mCRPC (ANZadapt)

November 25, 2024 updated by: dr. Tom van der Hulle, Leiden University Medical Center

ANZadapt: Phase II Randomised Controlled Trial of Patient-specific Adaptive Versus Continuous Abiraterone or eNZalutamide in Metastatic Castration-resistant Prostate Cancer

Hormone tablets, abiraterone (Zytiga®) and enzalutamide (Xtandi®) are approved to treat advanced prostate cancer. However, even if these drugs are helpful, their effectiveness usually diminishes over time. Small pilot studies have indicated that using hormone tablets sparingly, for just long enough to control the cancer, followed by a break in treatment and restarting them later, seems to improve how long hormone tablets can control the cancer. This study aims to find out if this pause/restart strategy is better than taking hormone tablets every day continuously. The study will include 168 people with metastatic castrate resistant prostate cancer in the Netherlands and Australia. Patients will be randomly 1:1 assigned between the control group and the experimental group. In the control group, patients will take the treatment with AA/ENZ every day until the prostate cancer doesn't respond anymore to the treatment. In the experimental group, patients will start with daily AA/ENZ until the PSA has declined for >50%. The treatment will then be paused and monthly PSA measurements will be performed. The treatment will be re-initiated when the PSA has increased to the level of before starting treatment. The treatment will be continued daily until the PSA has again dropped for >50%. This pause/restart cycle will be repeated until the prostate cancer doesn't respond anymore to the treatment.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Abiraterone and enzalutamide (AA/ENZ) are drugs which are being used to treat metastatic prostate cancer. These drugs are a form of additional hormonal therapy and have been used for many years. For most patients, these drugs work well and the prostate cancer stays under control for several months to years. In all patients, there will be a moment when the prostate cancer doesn't respond anymore to the treatment. This is called resistance. This leads to increasement of PSA, tumor growth on the CT-scan and/or bone scan or decline of condition. The investigators want to establish if it is possible to delay the development of resistance by using the drugs differently. It is now recommended to use AA/ENZ daily until the prostate cancer doesn't respond anymore to the treatment. During treatment, all cancer cells sensitive to treatment will die and all cells resistant for treatment will survive. Based on evolutionary principles, this might not be a wise strategy. The groups of resistant cancer cells will prevail and will grow faster and faster. This will lead to increasement of PSA, tumor growth on the CT-scan and/or bone scan or decline of condition. The investigators want to establish if it is better to not take the treatment drugs daily, but to pause the treatment on regular basis. The theory of the investigators is that, due to just in time pausing the treatment, a part of the treatment sensitive cells will remain alive. These treatment sensitive cancer cells will compete with the treatment resistant cells for limited space and nutrients. In this way, the treatment sensitive cancer cells prevent the accelerating growth of the treatment resistant cancer cells. Due to this phenomenon, the investigator hypothesis is the prostate cancer will respond longer to treatment. It will take longer until a new treatment is necessary or until a patients develops complaints. When the treatment is paused, patients might experience less side effects. It is easy to establish whether the prostate cancer responds to treatment by measuring PSA.

Study Type

Interventional

Enrollment (Estimated)

168

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Australia
    • New South Wales
      • Albury, New South Wales, Australia, 2460
      • Camperdown, New South Wales, Australia, 2050
        • Recruiting
        • Chris O'Brien Lifehouse
        • Contact:
        • Principal Investigator:
          • Prof. Lisa Horvath, Horvath
      • Kogarah, New South Wales, Australia
      • Newcastle, New South Wales, Australia, 2298
        • Recruiting
        • Calvary Mater Newcastle
        • Contact:
        • Principal Investigator:
          • Howard Chan, Dr.
      • St Leonards, New South Wales, Australia, 2065
        • Recruiting
        • Genesis Care North Shore
        • Contact:
        • Principal Investigator:
          • Dr. Laurence Krieger, MBChB, FRACP
      • Wahroonga, New South Wales, Australia, 2076
        • Recruiting
        • Sydney Adventist Hospital
        • Contact:
        • Principal Investigator:
          • Prof. Gavin Marx
    • Queensland
      • Birtinya, Queensland, Australia
        • Recruiting
        • Sunshine Coast University Hospital
        • Contact:
        • Principal Investigator:
          • Andrew Schmidt, Dr.
      • South Brisbane, Queensland, Australia, 4101
        • Recruiting
        • Mater Hospital Brisbane
        • Contact:
        • Principal Investigator:
          • Dr. Niara Oliveira
    • South Australia
      • Adelaide, South Australia, Australia, 5000
        • Recruiting
        • Royal Adelaide Hospital
        • Contact:
      • Adelaide, South Australia, Australia
        • Recruiting
        • Icon Cancer Centre
        • Contact:
        • Principal Investigator:
          • Craig Gedye, A/Prof
    • Victoria
      • Box Hill, Victoria, Australia
        • Recruiting
        • Eastern Health Box Hill
        • Contact:
        • Principal Investigator:
          • Iris Tung, dr.
    • Western Australia
      • Murdoch, Western Australia, Australia, 6150
        • Recruiting
        • Fiona Stanly Hospital
        • Contact:
        • Principal Investigator:
          • Dr Thomas Ferguson
  • Netherlands
      • Groningen, Netherlands, 9713 GZ
        • Recruiting
        • University Medical Center Groningen
        • Contact:
        • Principal Investigator:
          • Michel van Kruchten, MD PhD
    • Gelderland
      • Nijmegen, Gelderland, Netherlands, 6525 GA
        • Recruiting
        • Radboud Univeristy Medical Centre
        • Contact:
        • Principal Investigator:
          • Inge van Oort, MD PhD
    • Noord-Holland
      • Hoofddorp, Noord-Holland, Netherlands, 2134 TM
        • Recruiting
        • Spaarne Gasthuis
        • Contact:
        • Principal Investigator:
          • Aart Beeker, MD PhD
    • Overijssel
      • Zwolle, Overijssel, Netherlands, 8025 AB
        • Recruiting
        • Isala Ziekenhuis
        • Contact:
        • Principal Investigator:
          • Metin Tascilar, MD PhD
    • Utrecht
      • Amersfoort, Utrecht, Netherlands, 3813 TZ
        • Recruiting
        • Meander Medical Centre
        • Contact:
        • Principal Investigator:
          • Joyce van Dodewaard - de Jong, MD PhD
    • Zuid-Holland
      • Gouda, Zuid-Holland, Netherlands, 2803 HH
        • Recruiting
        • Groene Hart Ziekenhuis
        • Contact:
        • Principal Investigator:
          • Wendy van der Deure, MD PhD
      • Leiden, Zuid-Holland, Netherlands, 2333 ZA
        • Recruiting
        • Leids Universitair Medisch Centrum
        • Contact:
        • Contact:
        • Principal Investigator:
          • Tom van der Hulle, MD PhD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Willing and able to provide informed consent;
  2. Aged 18 or older;
  3. Histologically or cytologically confirmed adenocarcinoma of the prostate;
  4. Ongoing androgen deprivation therapy with a GnRH analogue or bilateral orchiectomy (i.e. surgical or medical castration with testosterone at screening ≤1.7 nmol/L (<0.5 ng/mL)); patients who have not had a bilateral orchiectomy, must have a plan to maintain effective GnRH-analogue therapy for the duration of the trial;
  5. Presence of metastatic disease on WBBS and/or CT-scan;

  6. Progressive disease at study entry defined as per PCWG3 as one or more of the following criteria that occurred while the patient was on ADT:

    1. PSA progression defined by a minimum of 2 rising PSA levels with an interval of ≥1 week between each determination. Patients who received an anti-androgen must have progression after withdrawal (≥4 weeks since last flutamide or ≥6 weeks since last bicalutamide or nilutamide); OR
    2. Radiographic PD on bone scintigraphy and/or CT-scan;
  7. A PSA concentration of ≥2 ng/mL.
  8. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2;
  9. Controlled symptoms (opioids for cancer related pain stable for >4 weeks, no need for urgent radiotherapy for symptomatic lesions);
  10. Estimated life expectancy of ≥12 months;
  11. Patient has archival prostate cancer tissue available and which he consents to share or is willing to undergo a new tumour biopsy;
  12. Adequate organ function: absolute neutrophil count > 1,500/μL (> 1.5*109/L); platelet count > 100,000/μL (> 100*109/L), haemoglobin > 90 g/L; total bilirubin < 1.5 times ULN, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) < 3 times ULN; creatinine < 175 μmol/L; albumin > 30 g/L;
  13. Any other therapies for CRPC (excluding denosumab and bisphosphonates) have to be discontinued 3 weeks prior to study randomisation;
  14. Able to swallow the study drug and comply with study requirements.

Exclusion Criteria:

  1. Life-threatening or serious medical or psychiatric illness that could, in investigator's opinion, potentially interfere with participation in this study;
  2. Diagnosis or treatment for another systemic malignancy within 2 years before the first dose of study drugs. Potential participants with non-melanoma skin cancer, non-muscle invasive bladder cancer, or carcinoma in situ of any type are allowed if they have undergone complete resection;
  3. Known or suspected brain metastasis or leptomeningeal disease;
  4. Small-cell or neuroendocrine differentiation of prostate cancer;
  5. Radiation therapy for treatment of the primary tumour within 3 weeks of screening visit;
  6. Radiation or radionuclide therapy for treatment of metastasis within 3 weeks of screening visit, excluding radiation to reduce pain symptoms;
  7. History of uncontrolled seizures (if patient and investigator wish to choose treatment with enzalutamide)
  8. Unstable symptomatic ischemic heart disease, ongoing arrhythmias or New York Heart Association (NYHA) Class III or IV heart failure;
  9. Known HIV infection, active chronic hepatitis B or C;
  10. Known gastrointestinal (GI) disease that could interfere with GI absorption/tolerance of study drugs;
  11. Prior treatments with CYP17 inhibitors (e.g. ketoconazole) or novel androgen receptor inhibitors (e.g. abiraterone, apalutamide, darolutamide or enzalutamide). Bicalutamide and nilutamide should be stopped >6 weeks before screening visit. Prior treatment with docetaxel in the mHSPC setting is allowed.
  12. Any condition or reason that, in the opinion of the Investigator, interferes with the ability of the patient to participate in the trial, which places the patient at undue risk, or complicates the interpretation of safety data.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Control group
In the control group, patients will receive the standard continuous treatment with abiraterone or enzalutamide (AA/ENZ) until criteria for treatment failure are met.
Drug: Abiraterone acetate
Use of abiraterone or enzalutamide
Other Names:
  • Zytiga
Drug: Enzalutamide
Use of abiraterone or enzalutamide
Other Names:
  • Xtandi
Experimental: Experimental group
In the experimental group, treatment will be paused if there is a >50% decline in baseline PSA. AA/ENZ will be restarted if the PSA rises to the same level or higher than the pre-treatment PSA. AA/ENZ treatment will be paused again after the PSA declines >50% from the baseline. This pause/restart cycle of adaptive therapy will be repeated presuming consent, tolerance and safety. Patients who do not have a >50% decline of their baseline PSA level after restarting AA/ENZ remain on treatment until the criteria for treatment failure are met.
Drug: Abiraterone acetate
Use of abiraterone or enzalutamide
Other Names:
  • Zytiga
Drug: Enzalutamide
Use of abiraterone or enzalutamide
Other Names:
  • Xtandi
Other: Patient-specific adaptive therapy
Patients will start taking abiraterone or enzalutamide (AA/ENZ) daily. PSA will be measured every month as well as radiological evaluation by CT-scan and bone scan. Treatment will be continued until PSA has dropped >50%. The treatment will then be paused. Once the PSA has risen again above the pretreatment baseline, treatment will be re-initiated. AA/ENZ will be stopped again after the PSA declines >50% from the baseline. This will be continued until criteria for treatment failure are met (death by any cause or at least 2 out of 3 of the following events while on treatment: radiographic progression on CT-scan and/or bone scan, PSA progression or clinical progression).

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Time to treatment failure
Time Frame: Time from randomization until death by any cause, or until criteria for treatment failure are met. PSA progression and clinical progression will be measured every 4 weeks, radiographic progression every 12 weeks, both up to 3 years after randomization.

Defined as the time from randomization until death by any cause, or the occurrence of ≥2 of the following events:

  • Radiographic progression according to RECIST 1.1 and/or PWCG3 criteria on the CT-scan and/or WBBS while a subject received treatment with AA/ENZ during the whole period between the imaging tests. NB: Radiologic progression while a subject is off treatment in the experimental arm will trigger the endpoint, but may be an indication to restart treatment and continue with the adaptive dosing strategy
  • PSA progression, defined as an increase of PSA of >25% and >2 ng/mL occurring while a patient is on consecutive treatment with AA/ENZ for at least 8 weeks.
  • Clinical progression in the judgment of the treating clinician occurring while a patient is on consecutive treatment with AA/ENZ for at least 8 weeks.
Time from randomization until death by any cause, or until criteria for treatment failure are met. PSA progression and clinical progression will be measured every 4 weeks, radiographic progression every 12 weeks, both up to 3 years after randomization.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall survival
Time Frame: Time from randomization to the date of death due to any cause. Measured every 4 weeks up to 3 years after randomizaton and after end of treatment visit every 6 months until 2 years after end of treatment visit.
defined as the time from randomization to the date of death due to any cause. For patients with no documented death by the end of the study, OS will be censored on the last date the patient was known to be alive. Patients who are lost to follow up will be censored at their last assessment time. Patients who begin a new anticancer treatment and have not had a documented treatment failure event will be censored at their last assessment point prior to beginning their new treatment.
Time from randomization to the date of death due to any cause. Measured every 4 weeks up to 3 years after randomizaton and after end of treatment visit every 6 months until 2 years after end of treatment visit.
Time to first skeletal-related event
Time Frame: Time from randomization to first skeletal-related event or death. Bone scan and CT-scan will be measured every 12 weeks up to 3 years after randomization.
Time from randomization to first skeletal-related event or death will be assessed. A skeletal-related event is defined as radiation therapy or surgery to bone, pathologic bone fracture, spinal cord compression, or change of anti-neoplastic therapy to treat bone pain. Patients without documented skeletal-related event or have not died will be censored at the last known time that the patient was progression-free. Patients who are lost to follow up will be censored at their last assessment time. Patients who begin a new anticancer treatment and have not had a documented treatment failure event will be censored at their last assessment point prior to beginning their new treatment.
Time from randomization to first skeletal-related event or death. Bone scan and CT-scan will be measured every 12 weeks up to 3 years after randomization.
Health Related Quality of Life - FACT-P
Time Frame: FACT-P questionnaire will be obtained every 12 weeks up to 3 years after randomization
FACT-P Quality of Life questionnaire
FACT-P questionnaire will be obtained every 12 weeks up to 3 years after randomization
Health Related Quality of Life - EQ-5D-5L
Time Frame: EQ-5D-5L questionnaire will be obtained every 12 weeks up to 3 years after randomization
EQ-5D-5L questionnaire.
EQ-5D-5L questionnaire will be obtained every 12 weeks up to 3 years after randomization
Health Related Quality of Life - Pain
Time Frame: Brief Pain Inventory questionnaire will be obtained every 12 weeks up to 3 years after randomization
Pain score per Brief Pain Inventory.
Brief Pain Inventory questionnaire will be obtained every 12 weeks up to 3 years after randomization
Adverse events
Time Frame: Adverse events will be measured every 12 weeks, up to 3 years after randomization.
An adverse event is defined as any symptom, sign, illness, or untoward experience (including a clinically significant laboratory finding classified as Grade 3 or higher by the National Cancer Institute's Common Terminology Criteria for Adverse Events v5.0) that develops or worsens during the course of the study, whether or not the event is considered related to study drug. Such an event should be recorded as an adverse event only after the first dose of study drug is taken. Adverse events will be assessed every 12 weeks.
Adverse events will be measured every 12 weeks, up to 3 years after randomization.
Time to PSA progression while on treatment
Time Frame: Time from randomization until an increase of PSA of >25% and >2 ng/mL persisting while a patient is on consecutive treatment for at least 8 weeks or death. PSA will be measured every 4 weeks until 3 years after randomization.
defined as the time from randomization until an increase of PSA of >25% and >2 ng/mL persisting while a patient is on consecutive treatment for at least 8 weeks (according to PCWG3 criteria) or death. Patients without documented PSA progression or have not died will be censored at the last known time that the patient was progression-free. Patients who are lost to follow up will be censored at their last assessment time. Patients who begin a new anticancer treatment and have not had documented PSA progression will be censored at their last assessment point prior to beginning their new treatment.
Time from randomization until an increase of PSA of >25% and >2 ng/mL persisting while a patient is on consecutive treatment for at least 8 weeks or death. PSA will be measured every 4 weeks until 3 years after randomization.
Radiographic progression-free survival while on study treatment
Time Frame: Time from randomization to death or the first occurrence of radiographic progression while a subject received treatment between the imaging tests. Bone scan and CT-scan will be measured every 12 weeks until 3 years after randomization.
Defined as the time from randomisation to first occurrence of radiographic progression by PCWG3 criteria and/or RECIST 1.1 on the CT-scan and/or WBBS while a subject received treatment with AA/ENZ during the whole period between the imaging tests or death. Patients without documented disease progression or have not died will be censored at the last known time that the patient was progression-free. Patients who are lost to follow up will be censored at their last assessment time. Patients who begin a new anticancer treatment and have not had a documented treatment failure event will be censored at their last assessment point prior to beginning their new treatment.
Time from randomization to death or the first occurrence of radiographic progression while a subject received treatment between the imaging tests. Bone scan and CT-scan will be measured every 12 weeks until 3 years after randomization.

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Cost-effectiveness analysis
Time Frame: QoL and adverse events will be measured every 12 weeks up to 3 years after randomization. Treatment duration will be evaluated every 4 weeks up to 3 years after randomization.
A cost-utility analysis will be performed from a healthcare perspective. Medication and other hospital costs will be assessed from hospital registrations. Quality-adjusted life years (QALYs) will be estimated using the Dutch tariff for the EQ-5D-5L (and the EQ-VAS as secondary analysis). Costs and QALYs will be extrapolated to a life-long horizon.
QoL and adverse events will be measured every 12 weeks up to 3 years after randomization. Treatment duration will be evaluated every 4 weeks up to 3 years after randomization.
Cumulative duration on treatment
Time Frame: Every 4 weeks up to 3 years after randomization
defined as the number of weeks on active treatment from randomization to the occurrence of treatment failure while on treatment.
Every 4 weeks up to 3 years after randomization
Translational Biospecimens
Time Frame: Baseline and every 12 weeks
Plasma samples suitable for circulating tumour DNA (ctDNA) analyses will be collected. The aim would be to perform explorative analyses on ctDNA to understand mechanisms of resistance, predictors of occurrence of progressive disease, and whether these results support the eco-evolutionary dynamics theory.
Baseline and every 12 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Leiden University Medical Center

Collaborators

Australian and New Zealand Urogenital and Prostate Cancer Trials Group
Anticancer Fund, Belgium

Investigators

  • Principal Investigator: Tom van der Hulle, MD, Leiden University Medical Center
  • Study Chair: A/Prof. Craig Gedye, MBChB,FRACP, Australian and New Zealand Urogenital and Prostate Cancer Trials Group
  • Principal Investigator: Dr. Laurence Krieger, MBChB,FRACP, Australian and New Zealand Urogenital and Prostate Cancer Trials Group
  • Principal Investigator: Dr. Amy Rieborn, Leiden University Medical Center

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 10, 2022

Primary Completion (Estimated)

November 10, 2027

Study Completion (Estimated)

November 10, 2027

Study Registration Dates

First Submitted

May 18, 2022

First Submitted That Met QC Criteria

May 23, 2022

First Posted (Actual)

May 26, 2022

Study Record Updates

Last Update Posted (Estimated)

November 26, 2024

Last Update Submitted That Met QC Criteria

November 25, 2024

Last Verified

November 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 79835
  • ANZUP 2101 (Other Identifier: ANZUP)

Plan for Individual participant data (IPD)

IPD Plan Description

To be determined in detail

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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