This phase II trial tests how well vorinostat works in treating patients with prostate-specific membrane antigen (PSMA)-low castration-resistant prostate cancer that has spread from where it first started (primary site) to other places in the body (metastatic) (mCRPC). Prostate cancer that has not spread to other parts of the body (localized) is typically treated through surgery or radiotherapy, which for many men is curable. Despite definitive local therapy, cancer that has come back after a period of improvement (recurrent) disease develops in 27-53% of men. Often this is detected by measurement of prostate-specific antigen (PSA) without visible evidence of metastatic disease. Lutetium Lu 177 vipivotide tetraxetan (177Lu-prostate specific membrane antigen \[PSMA\]-617) is a new small molecule PSMA-targeted radioactive therapy that has been approved by the Food and Drug Administration for the treatment of adult patients with PSMA-positive mCRPC who have been treated with androgen receptor inhibitors and taxane-based chemotherapy. Vorinostat is used to treat various types of cancer that does not get better, gets worse, or comes back during or after treatment with other drugs. Vorinostat is a drug which inhibits the enzyme histone deacetylase and may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving vorinostat and 177Lu-PSMA-617 may kill more tumor cells in in patients with PSMA-low mCRPC.
Documented histologically confirmed adenocarcinoma of the prostate.
Patient must have evidence of castration resistant prostate cancer as evidenced by PSA progression (per Prostate Cancer Working Group 3 [PCWG3] criteria) and a castrate serum testosterone level (i.e., ≤ 50 mg/dL).
PSMA SUVmean < 10 as determined by 68Ga-PSMA-11 PET.
Patients must have received a next-generation androgen receptor-signaling inhibitor (e.g. abiraterone, enzalutamide, apalutamide, darolutamide). There must be at least a 2-week washout period after stopping these agents. Patients should be weaned off steroids at least 1 week prior to starting treatment.
Evidence of serious and/or unstable pre-existing medical, psychiatric or other condition that could interfere with patient safety or provision of informed consent to participate in this study.
Evidence of metastatic neuroendocrine/small cell prostate cancer (NEPC). Note: baseline biopsy is not required but is strongly encouraged if a patient is found to have an FDG-positive/PSMA-negative lesion on baseline imaging.
Patients receiving any systemic therapy (aside from an luteinizing hormone-releasing hormone [LHRH] analogue) or radiotherapy within 2 weeks prior to study treatment.
Any previous treatment with an HDAC inhibitor (including valproic acid) or 177Lu-PSMA-617.
Single group
Biopsy Procedure
Procedure/SurgeryUndergo biopsy
Biospecimen Collection
Procedure/SurgeryUndergo blood sample collection
Bone Scan
Procedure/SurgeryUndergo bone scan
Computed Tomography
Procedure/SurgeryUndergo CT, PET/CT, SPECT/CT
Fludeoxyglucose F-18
Other interventionUndergo FDG PET/CT
Gallium Ga 68 Gozetotide
Other interventionGiven IV
Lutetium Lu 177 Vipivotide Tetraxetan
DrugGiven 177Lu-PSMA-617
Positron Emission Tomography
Procedure/SurgeryUndergo 68Ga-PSMA-11 PET
Single Photon Emission Computed Tomography
Procedure/SurgeryUndergo SPECT/CT
Vorinostat
DrugGiven IV
Proportion of patients who convert from prostate-specific membrane antigen (PSMA) low to PSMA high
Will be calculated as the percentage with 95% confidence interval (CI) of the total number of patients who had PSMA-high expression on re-assessment gallium Ga 68 gozetotide (68Ga)-PSMA-11 positron emission tomography (PET).
Objective radiographic response rate
Will be determined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria.
Prostate specific antigen (PSA)50 response rate
The percent decline in PSA compared to baseline (the PSA level prior to initiation of lutetium Lu 177 vipivotide tetraxetan will be calculated for each patient for every on-study PSA value obtained. PSA50 response will be defined as a decline in PSA ≥ 50% compared to baseline. Will be reported as a percentage with 95% CI.
Progression free survival (PFS)
Disease progression measured by modified RECIST criteria or Prostate Cancer Working Group 3 criteria for bone lesions and clinical progression as determined by the treating physician. Will be estimated using Kaplan-Meier method.
PSA PFS
For patients showing an initial decline in PSA from baseline, PSA progression will be defined as an increase in PSA ≥ 25% and ≥ 2 ng/mL above the nadir, and which is confirmed by a second value 3 or more weeks later. For those with no decline in PSA from baseline, PSA progression will be defined as an increase in PSA that is ≥ 25% and ≥ 2ng/mL after 12 weeks. Will be estimated using Kaplan-Meier method.
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Fred Hutchinson Cancer Center
Lead sponsor
Novartis
Collaborator
Institute for Prostate Cancer Research (IPCR)
Collaborator
National Cancer Institute (NCI)
Collaborator
