Phase II randomised controlled trial of patient-specific adaptive versus continuous Abiraterone or eNZalutamide in metastatic castration-resistant prostate cancer.
According to physicians’ choice and in conjunction with the participant, participants will be nominated to commence AA or ENZ for treatment of metastatic PC. Participants will be randomly 1:1 assigned between the control group and the experimental group. In the control group, patients will receive the standard continuous treatment with AA/ENZ until progressive disease (PD). In the experimental group patients will start with AA/ENZ until achieving a >50% decline in baseline PSA concentration. Upon achieving this decline, treatment will be suspended. Patients will be monitored every month including PSA concentration measurement. AA/ENZ will be reinitiated when the PSA increases to or above the pre-treatment PSA baseline concentration. AA/ENZ treatment will be paused again after the PSA declines >50% from the baseline. This pause/restart cycle of patient-individualised precision adaptive therapy will be repeated presuming consent, tolerance and safety. Patients who do not achieve a >50% decline of their baseline PSA concentration after restarting AA/ENZ remain on treatment until the development of PD.
- Histologically or cytologically confirmed adenocarcinoma of the prostate;
- 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/L)); patients who have not had a bilateral orchiectomy, must have a plan to maintain effective GnRH-analogue therapy for the duration of the trial;
- Presence of metastatic disease on WBBS and/or CT-scan;
- 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:
- 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
- Radiographic PD on bone scintigraphy and/or CT-scan;
- A PSA concentration of ≥10 ng/mL.
- Controlled symptoms (opioids for cancer related pain stable for >4 weeks, no need for urgent radiotherapy for symptomatic lesions);
- Patient has archival prostate cancer tissue available and which he consents to share or is willing to undergo a new tumour biopsy;
- Known or suspected brain metastasis or leptomeningeal disease;
- Small-cell or neuroendocrine differentiation of prostate cancer;
- History of uncontrolled seizures (if patient and investigator wish to choose treatment with enzalutamide)
- Unstable symptomatic ischemic heart disease, ongoing arrhythmias or New York Heart Association (NYHA) Class III or IV heart failure;
- Known gastrointestinal (GI) disease that could interfere with GI absorption/tolerance of study drugs;
- 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
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