This randomized phase III trial examines whether lengthening the dosage interval in an adaptive manner for the prostate cancer drug lutetium 177 Lu PSMA RLT improves quality of life without decreasing lifespan when compared to the standard way this medication is given. This study is for patients with hormone resistant prostate cancer that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body. Hormone resistant prostate cancer often has many cells containing a protein called prostate-specific membrane antigen (PSMA) on their surface. The normal cells in the prostate do not normally express as much PSMA protein on their surface as cancer cells. Lutetium 177 Lu PSMA RLT binds to the PSMA protein on the tumor cells. It builds up in these cells and gives off radiation that may kill them. Typically, this medication is given at the same dose every 6 weeks for up to 6 doses. In this trial, researchers want to see if treatment following the first two doses of lutetium 177 Lu PSMA RLT can be delayed until there is evidence of disease activity. This may be an effective way to improve quality of life without decreasing lifespan in patients with advanced prostate cancer.
PRE-REGISTRATION (STEP 0): Patients must have histological, pathological, and/or cytological confirmation of prostate adenocarcinoma
PRE-REGISTRATION (STEP 0): Patients must have a positive PSMA PET/CT scan (either gallium Ga 68 gozetotide [68Ga-PSMA-11], fluorine F 18 piflufolastat [18F- DCFPyl], or fluorine F 18 flotufolastat gallium [18F-rhPSMA-7.3]), as defined as uptake greater than liver with no PSMA negative measurable soft tissue disease
PRE-REGISTRATION (STEP 0): PSA greater than 2.0 ng/mL
Serum PSA progression defined as 2 consecutive increases in PSA over a previous reference value measured at least 1 week prior. The minimal start value is 2.0 ng/mL
None
Parallel
Lutetium Lu 177 Vipivotide Tetraxetan
DrugGiven IV
Biospecimen Collection
Procedure/SurgeryUndergo blood sample collection
Patient Monitoring
Procedure/SurgeryUndergo PSA monitoring
Computed Tomography
Procedure/SurgeryUndergo CT
Bone Scan
Procedure/SurgeryUndergo Bone Scan
PSMA PET Scan
Procedure/SurgeryUndergo PSMA PET Scan
MRI
Procedure/SurgeryUndergo MRI
Questionnaire Administration
Other interventionAncillary studies
Overall survival (OS)
Will be calculated as time from randomization until death due to any cause, censoring patients not known to have died at the time of their last follow-up. OS will be compared between the treatment arms using a stratified log rank test
Quality of life
Will be measured using the Functional Assessment of Cancer Therapy- Prostate (FACT-P) total scores. A repeated measures mixed model will be used to evaluate the between-arm mean difference in FACT-P Total scores across the first 30 months from treatment start. A point estimate of the difference and 95% confidence interval will be reported. Results of formal hypothesis testing will only be reported if adaptive dosing is deemed noninferior to standard dosing with regards to overall survival.
Duration of treatment
Calculated from the first administration of 177Lu PSMA RLT to the last administration of 177Lu PSMA RLT among randomized patients. Summary measures for the duration of treatment will be recorded by arm and the stratified Wilcoxon rank sum statistic will be used to test whether the treatment duration distribution differs between the standard and adaptive dose treatments.
Radiographic progression-free survival (rPFS)
Will be defined as time from randomization to the to the date of radiographic disease progression per the Prostate Cancer Clinical Trials Working Group 3 criteria or death from any cause, whichever occurs first. Patients who are alive without a disease progression will be censored at the time of their last disease evaluation. rPFS will be compared between the two treatment arms using a stratified logrank test.
Rate of Grade 3+ AEs
Will be assessed using Common Terminology Criteria for Adverse Events version 5.0. The proportion of patients that experience a grade 3+ AE regardless of attribution will be summarized as the number and percent of patients by treatment arm.
Prostate-specific antigen (PSA) response
There will be different thresholds used for PSA response, all measured as change from baseline and confirmed at least 3 weeks later by a second PSA test: PSA50 (a ≥ 50% decline), PSA75 (a ≥ 75% decline), and PSA90 (a ≥ 90% decline).
Frequency of tumor genomic aberrations
: Investigated tumor genomic aberrations include androgen receptor mutation/amplification, deoxyribonucleic acid repair, retinoblastoma 1, phosphatase and tensin homolog, and TP53. The frequency will be compared between treatment arms using a two-sample t-test (or a Fisher's exact test if more appropriate) among patients with ≥ 50% PSA decline and \< 50% PSA decline after 2 cycles of 177Lu PSMA RLT.
Association between initial PSA response and OS
The median survival time will be computed by the Kaplan-Meier estimator for patients with a pre-randomization PSA response between ≥ 50% and \< 75%, ≥ 75% and less than 90%, and ≥ 90%. A log rank test will be used to compare OS between the three groups.
Estimate of treatment effect by race
Estimates of the OS HR and the corresponding 95% CIs by race
Estimate of treatment effect by ethnicity
Estimates of the OS HR and the corresponding 95% CIs by ethnicity
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Alliance for Clinical Trials in Oncology
Lead sponsor
National Cancer Institute (NCI)
Collaborator
