Prostate Cancer, Metastatic Prostate Cancer
Conditions
Keywords
prostate cancer, sglt2
Brief summary
Dapagliflozin is a well-established medication being marketed and used for treatment Type 2 diabetes mellitus (T2DM). In retrospective cohort studies done by our team, we found that metastatic prostate cancer patients who received Dapagliflozin together with standard anti-cancer treatment, androgen deprivation therapy (ADT) combined with novel hormonal agent (NHA), had better tumor control than those having ADT and NHA.
Detailed description
Androgen deprivation therapy (ADT) combined with novel hormonal agent (NHA) is a standard treatment for metastatic castrate-resistant prostate cancer (mCRPC) but treatment failure and side effects remain significant concerns. Researchers are identifying non-castrating therapies to improve treatment tolerance and quality of life. Recently, the anti-tumor effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors has been revealed in vitro, vivo, and population-based observational studies. However, only one phase I trial has assessed their safety in PCa, and no randomized controlled trial (RCT) has evaluated their efficacy. A phase 2 multicenter, open-label RCT will be performed in Queen Mary Hospital, Ruijin Hospital and Huashan Hospital (subject to Ethics Committee approval at each center) with 60 mCRPC patients proposed to be recruited. Data will be collected through radiological scan, laboratory test and case report form. Eligible patients will be randomized into two treatment groups with a 1:1 ratio. Patients in the test group will receive dapagliflozin on top of NHA plus ADT while those in the control group will receive standard of care NHA plus ADT. The primary outcome is radiographic progression-free survival. Secondary outcomes include overall survival, biomedical recurrence-free survival, time to first subsequent anti-cancer therapy, time to treatment failure, objective response rate and duration of response. Exploratory outcomes include treatment-related adverse events, quality of life, fear of cancer recurrence, and severity of pain. The primary analysis is efficacy analysis based on the intention-to-treat population. Hazard ratios will be calculated using Cox regression. Interim and finial analyses will be performed upon different study stages. This study will be the first RCT to evaluate the efficacy and safety of SGLT2 inhibitors combined with the first-line next-generation hormonal agent (NHA) for mCRPC treatment. Given their general tolerability and clinical use, repurposing SGLT2 inhibitors as a non-castrating therapy may lead to better outcomes for PCa patients. Findings of this study will inform a novel combination therapy for advanced PCa, potentially enhancing clinical practice guidelines for its treatment and management in Hong Kong and mainland China
Interventions
Dapagliflozin (10mg Tab)
DRUGstandard medical care (ADT + NHA)
standard medical care for metastatic prostate cancer (ADT + NHA), the choice of NHA and ADT to be agreed among participant and treating physician with dosage and frequency according to local guideline. Surgical castration is also acceptable as ADT.
Sponsors
Yung NA
Ruijin Hospital
Huashan Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age of 18 years and above * Histologically or cytologically confirmed diagnosis of prostatic adenocarcinoma without neuroendocrine/ small cell histology; * PCa progression while receiving ADT (or post bilateral orchiectomy) within 6 months before screening: two consecutive rising PSA levels, radiographic soft tissue or bone progression; * Current evidence of metastatic disease by radiological scan; * Decided to receive any of the NHA (including Abiraterone Acetate, Enzalutamide, Apalutamide or Darolutamide) under standard of care setting, or started NHA for no more than 28 days at the time of treatment period start; * Ongoing androgen deprivation with serum testosterone \<50 ng/dL (\<1.7 nM); * Naïve of taxane-based chemotherapy regimens; * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1; * Normal hematologic and organ function as defined below: (a) leukocytes ≥ 3,000/mcL; (b) absolute neutrophil count ≥ 1,500/mcL; (c) platelets ≥ 100,000/mcL; (d) total bilirubin ≤ 1.5 x institutional upper limit of normal (IULN); (e) AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN; (f) estimated glomerular filtration rate eGFR ≥ 30 mL/min/1.73m2; * Ability to understand and willingness to sign an IRB-approved written informed consent document.
Exclusion criteria
* Current or previous treatment with SGLT2 inhibitors or thiazolidinedione; * Presence of type 1 diabetes mellitus, insulin-requiring diabetes mellitus or poorly controlled diabetes mellitus (i.e., HbA1c \> 10%, unless approved by endocrinologist); * Presence of malignancies other than prostate cancer within two years prior to study enrollment; * Disease progressed during or after treatment with one NHA; * A history of allergic reactions attributed to compounds of similar chemical or biologic composition to dapagliflozin; * Clinically significant abnormal serum potassium or sodium level; * Presence of uncontrolled comorbidities including but not limited to ongoing or active infection (e.g., HIV, HBV, HCV and tuberculosis), symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, peripheral arterial disease, ketoacidosis, severe kidney disease, symptomatic hypotension, and chronic/frequent urinary tract infections or yeast infections; * Participation in another clinical trial with therapeutic intent within 28 days prior to enrollment; * Inability to swallow capsules/tablets * Any medical conditions that might deem unsafe or contraindicated for inclusion in the clinical trial, per investigator's discretion
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Radiographic Progression-Free Survival (rPFS) | From randomization to radiographic disease progression or death from any cause, whichever occurs first, assessed up to 60 months. | Radiographic progression-free survival is defined as the time from randomization to radiographic disease progression or death from any cause, whichever occurs first. Radiographic progression is assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for soft-tissue lesions and standard criteria for bone metastases. Participants without documented radiographic progression or death will be censored at the date of their last radiographic assessment showing no progression. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From randomization to death from any cause, assessed up to 60 months. | Overall survival is defined as the time from randomization to death from any cause. |
| Biochemical Recurrence-Free Survival (bRFS) | From randomization to biochemical recurrence, assessed up to 60 months. | Biochemical recurrence-free survival is defined as the time from randomization to biochemical recurrence. Biochemical recurrence is defined as an increase in prostate-specific antigen (PSA) of at least 25% and an absolute increase of at least 2 ng/mL above the nadir, confirmed by a repeat PSA measurement obtained at least 3 weeks later. PSA is assessed every 12 weeks (±2 weeks), with an additional measurement to confirm suspected biochemical recurrence. |
| Time to First Subsequent Anticancer Therapy (TFST) | From randomization to initiation of the first subsequent anticancer therapy or death from any cause, whichever occurs first, assessed up to 60 months. | Time to first subsequent anticancer therapy is defined as the time from randomization to initiation of the first subsequent anticancer therapy or death from any cause, whichever occurs first. |
| Time to Treatment Failure (TTF) | From randomization to treatment failure, assessed up to 60 months. | Time to treatment failure is defined as the time from randomization to permanent discontinuation of the next-generation hormonal agent (NHA) and/or dapagliflozin due to disease progression, toxicity, or death. |
| Objective Response Rate (ORR) | From randomization to radiographic disease progression, assessed up to 60 months. | Objective response rate is defined as the percentage of participants with measurable disease who achieve a complete response or partial response according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. |
| Duration of Response (DOR) | From the date of first documented complete or partial response to radiographic disease progression or death from any cause, whichever occurs first, assessed up to 60 months. | Duration of response is evaluated in participants who achieve a complete response or partial response according to RECIST version 1.1. |
Countries
China
Contacts
CONTACTStudy Coordinator
PRINCIPAL_INVESTIGATORYung Na, BM, MD, MPH
The University of Hong Kong
Outcome results
None listed