Clinical trial NCT05393791: Phase II Randomised Controlled Trial of Patient-specific Adaptive vs. Continuous Abiraterone or eNZalutamide in mCRPC
Official title: ANZadapt: Phase II Randomised Controlled Trial of Patient-specific Adaptive Versus Continuous Abiraterone or eNZalutamide in Metastatic Castration-resistant Prostate Cancer
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Prostatic Neoplasms, Castration-Resistant
Keywords: Antineoplastic Agents, Hormonal
Evolution
Quality of Life
Prostatic Neoplasms, Castration-Resistant / drug therapy
Lead sponsor: Leiden University Medical Center
Sponsor class: OTHER
Collaborators: name: Australian and New Zealand Urogenital and Prostate Cancer Trials Group
name: Anticancer Fund, Belgium
First posted: 2022-05-26
Enrollment: 168
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Control group and experimental group
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Time to treatment failure
timeFrame: 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 outcomes:
measure: Time to PSA progression while on treatment
timeFrame: 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.
measure: Radiographic progression-free survival while on study treatment
timeFrame: 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.
measure: Overall survival
timeFrame: 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.
measure: Time to first skeletal-related event
timeFrame: 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.
measure: Health Related Quality of Life - FACT-P
timeFrame: FACT-P questionnaire will be obtained every 12 weeks up to 3 years after randomization
measure: Health Related Quality of Life - EQ-5D-5L
timeFrame: EQ-5D-5L questionnaire will be obtained every 12 weeks up to 3 years after randomization
measure: Health Related Quality of Life - Pain
timeFrame: Brief Pain Inventory questionnaire will be obtained every 12 weeks up to 3 years after randomization
measure: Adverse events
timeFrame: Adverse events will be measured every 12 weeks, up to 3 years after randomization.
Other outcomes:
measure: Cost-effectiveness analysis
timeFrame: 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.
measure: Cumulative duration on treatment
timeFrame: Every 4 weeks up to 3 years after randomization
measure: Translational Biospecimens
timeFrame: Baseline and every 12 weeks
Locations:
city: Albury
country: Australia
facility: Border Medical Oncology Research Unit / The Border Cancer Hospital
state: New South Wales
city: Camperdown
country: Australia
facility: Chris O'Brien Lifehouse
state: New South Wales
city: Kogarah
country: Australia
facility: St George Hospital
state: New South Wales
city: Newcastle
country: Australia
facility: Calvary Mater Newcastle
state: New South Wales
city: St Leonards
country: Australia
facility: Genesis Care North Shore
state: New South Wales
city: Wahroonga
country: Australia
facility: Sydney Adventist Hospital
state: New South Wales
city: Birtinya
country: Australia
facility: Sunshine Coast University Hospital
state: Queensland
city: South Brisbane
country: Australia
facility: Mater Hospital Brisbane
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Adelaide
country: Australia
facility: ICON Cancer Centre
state: South Australia
city: Box Hill
country: Australia
facility: Eastern Health Box Hill
state: Victoria
city: Murdoch
country: Australia
facility: Fiona Stanly Hospital
state: Western Australia
city: Nijmegen
country: Netherlands
facility: Radboud Univeristy Medical Centre
state: Gelderland
city: Hoofddorp
country: Netherlands
facility: Spaarne Gasthuis
state: Noord-Holland
city: Zwolle
country: Netherlands
facility: Isala Ziekenhuis
state: Overijssel
city: Amersfoort
country: Netherlands
facility: Meander Medical Centre
state: Utrecht
city: Gouda
country: Netherlands
facility: Groene Hart Ziekenhuis
state: Zuid-Holland
city: Leiden
country: Netherlands
facility: Leids Universitair Medisch Centrum
state: Zuid-Holland
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
Study officials:
affiliation: Leiden University Medical Center
name: Tom van der Hulle, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Australian and New Zealand Urogenital and Prostate Cancer Trials Group
name: A/Prof. Craig Gedye, MBChB,FRACP
role: STUDY_CHAIR
affiliation: Australian and New Zealand Urogenital and Prostate Cancer Trials Group
name: Dr. Laurence Krieger, MBChB,FRACP
role: PRINCIPAL_INVESTIGATOR
affiliation: Leiden University Medical Center
name: Dr. Amy Rieborn
role: PRINCIPAL_INVESTIGATOR
References: