Darolutamide + Androgen Deprivation Therapy (ADT) compared with ADT alone, for Chinese men with high risk, nonmetastatic prostate cancer
Researchers are looking for a better way to treat men who have non-metastatic castration resistant prostate cancer (nmCRPC). This is a type of cancer in the prostate that has not yet spread to other parts of the body and keeps progressing even when the amount of testosterone (androgen) is reduced to very low levels. Men with nmCRPC usually have higher levels of prostate-specific antigen (PSA) than normal. It is a protein that is made by both normal cells and by cancerous cells in the body. Androgen deprivation therapy (ADT) is a treatment that commonly used to lower the amount of hormones called androgens in the body.
The study drug, darolutamide, is already available for doctors to prescribe to patients with prostate cancer that has not yet spread to other parts of the body. It works by blocking hormones, called androgens, from attaching to proteins in cancer cells in the prostate. These hormones are thought to play a role in prostate cancer.
There has been a study to research how patients with nmCRPC benefit with darolutamide plus Androgen deprivation therapy (ADT) as compared to placebo plus ADT therapy.
In this focused study of Chinese participants, researchers will be using a "marker" of cancer- PSA- to detect when that marker increases as a sign that the cancer appears to be progressing. The researchers want to learn how much longer it will take for participants who are treated with darolutamide added to ADT to have a rise in their PSA levels, compared with the time for PSA to rise in men who are treated with ADT alone. In this study, time to "progress" will be defined by a documented and confirmed rise in PSA by> 25% from the baseline value ( and > 2 ng/mL above the lowest value measured). In previous studies, PSA was observed to rise approximately 8 mo.-1 year prior to the development of "metastasis" (tumor spread to other organs). By using the tumor marker PSA , researchers can more quickly identify how study participants are responding to their study treatment.
The participants in this study will take either darolutamide or a placebo. A placebo looks like a treatment but does not have any medicine in it. All the participants will also take ADT. Doctors are able to prescribe ADT to patients with prostate cancer.
During the study, the participants will take darolutamide or the placebo until:
• their cancer spreads
• they start another type of cancer treatment
• they have adverse events. An adverse event is any medical problem that a participant has during a study. Doctors keep track of all adverse events that happen in studies, even if they do not think the adverse events might be related to the study treatments.
• they take another type of medication that is not able to be taken during this study
• they decide to leave the trial
• the participant dies
The participants will visit the study site every 12 weeks during treatment and after stopping treatment. The whole study will last about 35 months. During the study, the doctors will:
• check the participants’ overall health and heart health
• take blood samples
• take pictures of the participants’ tumors and bones using CT, MRI, and bone scans
• ask the participants questions about how they are feeling, what medications they are taking, and what adverse events they are having.
- Participant must be ≥18 years of age inclusive, at the time of signing the informed consent. - Histologically or cytologically confirmed adenocarcinoma of prostate without neuroendocrine differentiation or small cell features. - Castration resistance, demonstrated by: -- a minimum of 3 rising PSA values while the participant is on continuous ADT (started at least 4 weeks prior to the PSA measurement or, PSA measured at least 4 weeks after bilateral orchiectomy) and -- the interval between each PSA measurement must be ≥1 week, and -- the PSA value at screening must be ≥1 ng/mL (1 μg/L). (To confirm this eligibility criterion, it is acceptable for 2 out of the 3 PSA measurements to be taken during the 28-day screening period (after participant has signed consent), provided the measurements are ≥1 week apart. In this case, the last PSA value should be recorded as the screening value.) - Castrate level of serum testosterone (< 1.7 nmol/l [50 ng/dl]) on GnRH agonist or antagonist therapy or after bilateral orchiectomy. Participants who have not undergone bilateral orchiectomy must continue GnRH therapy during the study. - Prostate-specific antigen doubling time (PSADT) of ≤ 10 months. - Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. - Blood counts at screening: hemoglobin ≥ 9.0 g/dl, absolute neutrophil count ≥ 1500/μl (1.5x109/l), platelet count ≥ 100,000/μl (100x109/l ) (participant must not have received any growth factor or blood transfusion within 7 days of the hematology laboratory obtained at screening). - Screening values of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x upper limit of normal (ULN), total bilirubin (TBL) ≤1.5 x ULN (except participants with a diagnosis of Gilbert’s disease), creatinine ≤2.0 x ULN. - Male: Sexually active participants, unless surgically sterile, must agree to use condoms as an effective barrier method and refrain from sperm donation during the study treatment and for 1 week after the end of the study treatment. Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
- History of metastatic disease at any time or presence of detectable metastases assessed by the investigator within 42 days prior to start of study treatment. Presence of pelvic lymph nodes < 1.5 cm in short axis below the aortic bifurcation is allowed. - Symptomatic local-regional disease that requires medical intervention including moderate/severe urinary obstruction or hydronephrosis due to prostate cancer. - Acute toxicities of prior treatments and procedures not resolved to ≤ CTCAE v5.0 grade 1 or baseline before randomization. - Severe or uncontrolled concurrent disease, infection or co-morbidity that, in the opinion of the investigator, would make the participant inappropriate for enrollment. - Known hypersensitivity to the study treatment or any of its ingredients. - Major surgery within 28 days before randomization. - Any of the following within 6 months before randomization: stroke, myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft; congestive heart failure New York Heart Association (NYHA) Class III or IV. - Uncontrolled hypertension as indicated by a systolic blood pressure (BP) ≥ 160 mmHg or diastolic BP ≥ 100 mmHg despite medical management at screening. - Prior malignancy. Adequately treated basal cell or squamous cell carcinoma of skin or superficial bladder cancer that has not spread behind the connective tissue layer (i.e. pTis, pTa, and pT1) is allowed, as well as any other cancer for which treatment has been completed ≥ 5 years ago and from which the participant has been disease-free. - Gastrointestinal disorder or procedure which expects to interfere significantly with absorption of study treatment. - Active viral hepatitis, known human immunodeficiency virus (HIV) infection with detectable viral load, or chronic liver disease with a need of treatment. - Any condition that in the opinion of the investigator would impair the participants’ ability to comply with the study procedures. - Unable to swallow study medications and/or comply with study requirements. - Prior treatment with: -- second generation AR inhibitors such as enzalutamide, apalutamide, darolutamide, other investigational AR inhibitors -- CYP17 enzyme inhibitor such as abiraterone acetate, TAK-700 or -- oral ketoconazole longer than for 28 days (continuous use). - Use of estrogens or 5-α reductase inhibitors (finasteride, dutasteride) within 28 days before randomization and AR inhibitors (bicalutamide, flutamide, nilutamide, cyproterone acetate) at least 28 days before screening. - Prior chemotherapy or immunotherapy for prostate cancer, except adjuvant/neoadjuvant treatment completed > 2 years before randomization. - Use of systemic corticosteroid with dose greater than the equivalent 10 mg of prednisone/day within 28 days before randomization. - Radiation therapy (external beam radiation therapy [EBRT], brachytherapy, or radiopharmaceuticals) within 12 weeks before randomization. - Treatment with an osteoclast-targeted therapy (bisphosphonate or denosumab) to prevent skeletal-related events within 12 weeks before randomization. Participants receiving osteoclast-targeted therapy to prevent bone loss at a dose and schedule indicated for osteoporosis may continue treatment at the same dose and schedule. - Treatment with any investigational drug within 28 days before randomization. - Treatment with any investigational drug, or Traditional Chinese Medication (TCM) that is approved as a cancer treatment, within 28 days before randomization.
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A randomized, double-blind, placebo-controlled Phase 2 study of darolutamide versus placebo in addition to standard androgen deprivation therapy for participants with high-risk non-metastatic castration resistant prostate cancer (nmCRPC)