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

NCT ID: NCT05393791

Last Updated: 2024-11-26

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

PHASE2

Total Enrollment

168 participants

Study Classification

INTERVENTIONAL

Study Start Date

2022-11-10

Study Completion Date

2027-11-10

Brief Summary

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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.

Detailed Description

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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.

Conditions

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Prostatic Neoplasms, Castration-Resistant

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Control group and experimental group
Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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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.

Group Type EXPERIMENTAL

Patient-specific adaptive therapy

Intervention Type OTHER

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).

Abiraterone acetate

Intervention Type DRUG

Use of abiraterone or enzalutamide

Enzalutamide

Intervention Type DRUG

Use of abiraterone or enzalutamide

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.

Group Type ACTIVE_COMPARATOR

Abiraterone acetate

Intervention Type DRUG

Use of abiraterone or enzalutamide

Enzalutamide

Intervention Type DRUG

Use of abiraterone or enzalutamide

Interventions

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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).

Intervention Type OTHER

Abiraterone acetate

Use of abiraterone or enzalutamide

Intervention Type DRUG

Enzalutamide

Use of abiraterone or enzalutamide

Intervention Type DRUG

Other Intervention Names

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Zytiga Xtandi

Eligibility Criteria

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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.
Minimum Eligible Age

18 Years

Eligible Sex

MALE

Accepts Healthy Volunteers

No

Sponsors

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Australian and New Zealand Urogenital and Prostate Cancer Trials Group

OTHER

Sponsor Role collaborator

Anticancer Fund, Belgium

OTHER

Sponsor Role collaborator

Leiden University Medical Center

OTHER

Sponsor Role lead

Responsible Party

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dr. Tom van der Hulle

Principal Investigator

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Tom van der Hulle, MD

Role: PRINCIPAL_INVESTIGATOR

Leiden University Medical Center

A/Prof. Craig Gedye, MBChB,FRACP

Role: STUDY_CHAIR

Australian and New Zealand Urogenital and Prostate Cancer Trials Group

Dr. Laurence Krieger, MBChB,FRACP

Role: PRINCIPAL_INVESTIGATOR

Australian and New Zealand Urogenital and Prostate Cancer Trials Group

Dr. Amy Rieborn

Role: PRINCIPAL_INVESTIGATOR

Leiden University Medical Center

Locations

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Border Medical Oncology Research Unit / The Border Cancer Hospital

Albury, New South Wales, Australia

Site Status RECRUITING

Chris O'Brien Lifehouse

Camperdown, New South Wales, Australia

Site Status RECRUITING

St George Hospital

Kogarah, New South Wales, Australia

Site Status RECRUITING

Calvary Mater Newcastle

Newcastle, New South Wales, Australia

Site Status RECRUITING

Genesis Care North Shore

St Leonards, New South Wales, Australia

Site Status RECRUITING

Sydney Adventist Hospital

Wahroonga, New South Wales, Australia

Site Status RECRUITING

Sunshine Coast University Hospital

Birtinya, Queensland, Australia

Site Status RECRUITING

Mater Hospital Brisbane

South Brisbane, Queensland, Australia

Site Status RECRUITING

Royal Adelaide Hospital

Adelaide, South Australia, Australia

Site Status RECRUITING

ICON Cancer Centre

Adelaide, South Australia, Australia

Site Status RECRUITING

Eastern Health Box Hill

Box Hill, Victoria, Australia

Site Status RECRUITING

Fiona Stanly Hospital

Murdoch, Western Australia, Australia

Site Status RECRUITING

Radboud Univeristy Medical Centre

Nijmegen, Gelderland, Netherlands

Site Status RECRUITING

Spaarne Gasthuis

Hoofddorp, North Holland, Netherlands

Site Status RECRUITING

Isala Ziekenhuis

Zwolle, Overijssel, Netherlands

Site Status RECRUITING

Groene Hart Ziekenhuis

Gouda, South Holland, Netherlands

Site Status RECRUITING

Leids Universitair Medisch Centrum

Leiden, South Holland, Netherlands

Site Status RECRUITING

Meander Medical Centre

Amersfoort, Utrecht, Netherlands

Site Status RECRUITING

University Medical Center Groningen

Groningen, , Netherlands

Site Status RECRUITING

Countries

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Australia Netherlands

Central Contacts

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Tom van der Hulle, MD PhD

Role: CONTACT

0031715263464

Samantha Oakes, Prof.

Role: CONTACT

+61 2 90543600

Facility Contacts

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Craig Underhill

Role: primary

Jacqui McBurnie

Role: backup

+61260641508

Jacquie Harvey, MBBS FRACP

Role: primary

+61 2 8514 0194

Raymund Austria

Role: primary

+61 2 9113 1111

Kim Adler

Role: primary

+612 40143282

Grace Till

Role: primary

+61 474 164 541

Nina Singh

Role: primary

+61 2 9480 6280

Christine Cook

Role: primary

+61752020651

Donna Harvey

Role: primary

Hsiang Tan

Role: primary

+6170742336

Sue Yeend

Role: primary

+61884740220

Kiko Liu

Role: primary

+61390952465

Caroline Stone

Role: primary

+61 8 6152 6530

Inge van Oort, MD PhD

Role: primary

0031243613735

Aart Beeker, MD PhD

Role: primary

0031232245802

Metin Tascilar, MD PhD

Role: primary

Wendy van der Deure, MD PhD

Role: primary

0031182505005

Tom van der Hulle, MD PhD

Role: primary

0031715263464

Amy Rieborn, MD

Role: backup

0031652887817

Joyce van Dodewaard - de Jong, MD PhD

Role: primary

0031338507278

Michel van Kruchten, MD PhD

Role: primary

Other Identifiers

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ANZUP 2101

Identifier Type: OTHER

Identifier Source: secondary_id

79835

Identifier Type: -

Identifier Source: org_study_id

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