GUARD-QUANTUM is a prospective, phase II, single-arm, non-randomized, non-blinded, investigator-initiated study. The rationale behind studying this combination lies in the potential additive or synergistic benefits that may arise from concurrently targeting androgen receptor signaling pathways and bone metastases.
Patients must be fully informed about the study and sign the informed consent form (ICF) before any study specific assessment.
Patients ≥18 years old.
ECOG performance status of 0 to 2 and Charlson score ≤ 3 prior to study entry, after docetaxel.
Patients with histologically or cytologically confirmed diagnosis of prostate adenocarcinoma.
Presence of tumor lesion in central nervous system through radiologically confirmed diagnosis.
Prior history of malignancies other than prostate adenocarcinoma (except patients with basal cell, squamous cell carcinoma of the skin, in-situ carcinoma or low-grade superficial bladder cancer, or the patient has been free of malignancy for a period of 3 years prior to inclusion).
Patients experiencing progression during previous ADT or meeting criteria for castration resistant prostate cancer (CRPC).
External irradiation, brachytherapy, or local treatment (including radiofrequency ablation, cryotherapy, high intensity focused ultrasound, etc.) within 4 weeks prior to the first dose of study treatment.
Single group
Ra223
DrugSix intravenous administrations of Radium-223 chloride, in a dose of 55 kBq/kg body weight standard dose with a treatment interval between administrations of 4 weeks. Treatment with Ra223 could be prematurely discontinued in case of progression, unacceptable toxicity, withdrawal or death.
Darolutamide Oral Tablet
DrugDarolutamide at 600 mg twice daily. Darolutamide administration will continue until progression, unacceptable toxicity, withdrawal or death, whichever comes first.
Androgen Deprivation Therapy (ADT)
Other interventionStandard of care ADT (surgical or drug). Administration will continue until progression, unacceptable toxicity, withdrawal or death, whichever comes first.
Treatment compliance
Measured as the total number of cycles administered to each patient. Patients will be categorized in two groups, complete treatment compliance (complete ≥5 cycles of Ra223) and incomplete treatment compliance (complete \<5 cycles of Ra223). The proportion of patients in each category and their 95% confidence interval (CI) calculated by Clopper-Pearson will be given.
Prostate-specific antigen (PSA) response rates
Response is defined as PSA \<0.02 ng/mL at Ra223 completion. Rate of PSA response is defined as the number of subjects with absolute PSA response, divided by the total number of subjects evaluable for absolute PSA response (with high PSA levels at baseline).
Total alkaline phosphatase response rates
Defined as a reduction of ≥30% from the baseline value, before the first dose of study treatment (Ra223). The ALP response will be assessed only in patients with ALP increased levels at baseline. Percentage of patients who experience these reductions throughout the study period.
Radiographic progression-free survival (rPFS)
Defined from the day of first dose of Ra223 to the day the first event of radiological progression or death (due to any cause) is recorded. Assessed by investigator and defined as motivated by the recommendations of the Prostate Cancer Clinical Trials Working Group 3for the "delay/prevent" objective. rPFS will be estimated by Kaplan-Meier method. Patients who are alive without evidence of radiological progression at their last imaging assessment will be censored at that date.
Time to pain progression
Measured according to Brief Pain Inventory (BPI). Pain progression is defined in patients in the 'pain evaluable' population as: an increase of 2 or more points in the BPI's "worst pain in 24 hours"-score from baseline observed at 2 consecutive evaluations ≥4 weeks apart, or initiation of short or long-acting opioid use for pain. Time-to-pain progression is defined as the time (days) from the first dose of study treatment (Ra223) date, to the date of pain progression
Assessment of disease volume by novel imaging modalities (Prostate-Specific Membrane Antigen Positron Emission Tomography [PET-PSMA])
Patients will be assessed through PT-PSMA. The volume of disease will be reported trhough time. Best tumor size reduction will be reported
Biomarkers
Transcriptome and whole genome sequencing to identify biomarkers that correlate with prognosis. Here we will report the most frequent genetic alterations and their prevalence in the study population. The analysis will be done in tumor and blood samples.
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Alianza multidisciplinar para la investigación de los tumores genitourinarios -GUARD
Lead sponsor
Bayer
Collaborator
MFAR
Collaborator
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