Clinical trial NCT04925063: The Effect of Metformin in Patients With Newly Diagnosed mHSPC
Official title: A Prospective, Randomized Trial Comparing Metformin Plus Androgen Deprivation Therapy (ADT) and Abiraterone With ADT Plus Abiraterone in Newly Diagnosed Metastatic Hormone-Sensitive Prostate Cancer
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Metastatic Prostate Cancer
Keywords: metastatic hormone sensitive prostate cancer; abiraterone; metformin
Lead sponsor: Sun Yat-sen University
Sponsor class: OTHER
First posted: 2021-06-14
Enrollment: 266
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to assess the effect of the addition of metformin to abiraterone on survival in patients with newly diagnosed metastatic hormone-sensitive prostate cancer. The half the patients will receive metformin in combination with androgen deprivation therapy (ADT) and abiraterone, and the other half will receive ADT and abiraterone only.

Detailed description: Metastatic hormone-sensitive prostate cancer (mHSPC) can be treated with androgen-deprivation therapy (ADT) alone, ADT plus abiraterone, ADT plus enzalutamide, ADT plus apalutamide, ADT plus docetaxel. However, most patients eventually progress to castration-resistant prostate cancer (CRPC) and die of the disease. Therefore, there is still a need to improve the therapeutic effect for mHSPC.

Many studies have shown that metabolic syndrome and its components are associated with increased development and progression of aggressive prostate cancer. Metformin, a common well-tolerated oral biguanide prescribed for type II diabetes, could be used to decrease the risk of prostate cancer development and improve the efficacy of treatment. Some studies reported that metformin could enhance the effectiveness of ADT, and improve recurrence-free survival, overall survival and cancer-specific survival. A prospective randomized study reported that metformin potentially lengthen time to CRPC in advanced prostate cancer patients when combined with ADT especially in those with high risk localized prostate cancer, clinically node positive and in those with low tumor volume metastatic hormone-sensitive patients.

After extensive research, there is no published results from prospective randomized trials evaluating the effect of metformin in combination with ADT and abiraterone among patients with newly diagnosed mHSPC.

Eligibility criteria: Inclusion Criteria:

* Histologically confirmed and newly diagnosed metastatic hormone-sensitive adenocarcinoma of the prostate without small cell carcinoma or small cell components.
* Metastatic adenocarcinoma of the prostate proved by imaging (CT/MRI and/or bone scan).
* Patient must give written informed consent before registration and prior to any trial related investigations.
* Age ≥18 years.
* Serum potassium ≥3.5mmol/ L.
* ECOG performance status 0-2
* Ongoing androgen deprivation therapy with drugs or bilateral orchiectomy, and continuous abiraterone plus prednisone.
* Patient agrees not to father a child during participation in the trial and during 3 months thereafter.
* Patient agrees not to participate other interventional trials.
* Patients are able to swallow study drug as whole tablet.

Exclusion Criteria:

* Diagnosed diabetes or fasting blood-glucose ≥ 6.1mmol/L, or glycosylated hemoglobin ≥ 5.6%.
* Previous malignancy within 2 years prior to randomization, with the exception of localized non-melanoma skin cancer and Ta bladder cancer.
* Prior treatment for prostate cancer with drugs, radiotherapy and surgery, with the exception below:

  * ADT within 3 months before randomization, and no evidence of progression.
  * Palliative radiotherapy or surgery for metastases due to symptoms, at least 4 weeks before randomization.
* Major surgery within 4 weeks prior to randomization.
* Treatments with 5a-reductase inhibitors, estrogen, cyproterone acetate, and androgen within 4 weeks prior to randomization.
* Known or suspected Central nervous system CNS metastases or active leptomeningeal disease.
* Equivalent dosage of \>5mg/day prednisone of glucocorticoids for the treatment of prostate cancer within 4 weeks prior to randomization, or treatment with glucocorticoids for other reasons.
* Prior treatment for prostate cancer with flutamide, bicalutamide, ketoconazole, abiraterone, enzalutamide, apalutamide, docetaxel chemotherapy, or other interventional drugs for prostate cancer.
* Neutrophils \< 1.5 x 109/L, platelets \< 75 x 109/L, hemoglobin \< 100 g/L.
* ALT and AST ≥ 2.5 x ULN, bilirubin ≥ 1.5 x ULN.
* eGFR\<45 ml/min/1.73m2.
* Allergic to metformin or any ingredients of this tablet.
* Acute or chronic metabolic acidosis, including diabetic ketoacidosis.
* Albumin\< 30 g/L.
* Clinically significant cardiovascular disease including:

  * Myocardial infarction within 6 months prior to randomization.
  * Uncontrolled angina within 3 months prior to registration.
  * Congestive heart failure NYHA class III or IV.
  * History of clinically significant ventricular arrhythmias (e.g. ventricular tachycardia, ventricular fibrillation, torsades de pointes).
  * History of Mobitz II second or third degree heart block without a permanent pacemaker in place.
  * Systolic pressure\< 86 mmHg.
  * Bradycardia, heart rate\<45/min.
  * Uncontrolled hypertension as indicated by systolic blood pressure \> 170 mmHg OR diastolic blood pressure \> 105 mmHg.
* ADT with or without anti-androgens more than 3 months prior to randomization.
* Prior treatment with metformin after diagnosis of prostate cancer.
* Allergic to metformin or any drugs used in this trial.
* Serious underlying medical condition (at the judgment of the investigator) which could impair the ability of the patient to participate in the trial (e.g. uncontrolled or acute severe infection, uncontrolled diabetes).
* Active or symptomatic viral hepatitis or chronic liver disease.
* History of pituitary or adrenal dysfunction.
* Gastrointestinal disorder affecting absorption.

Primary outcomes:
measure: Castration-resistant prostate cancer free survival
timeFrame: 5 years
Secondary outcomes:
measure: Overall Survival
timeFrame: 5 years
measure: Radiographic progression-free survival
timeFrame: 5 years
measure: Safety
timeFrame: 5 years
Other outcomes:
Locations:
city: Guangzhou
country: China
facility: Sun Yat-Sen University Cancer Center
state: Guangdong
Study officials:
References: