Randomized Study Comparing Docetaxel Plus Dasatinib to Docetaxel Plus Placebo in Castration-resistant Prostate Cancer

Overall survival is defined as time in months from the randomization date to the date of death due to any cause (in the randomized population). If the patient did not die, survival was censored on the last date he or she was known to be alive.

Time frame: From randomization to death or date of last contact (maximum reached: 45 months)

Population: All participants who were randomized to receive any treatment

Objective tumor response rate=the percentage of randomized participants with a best tumor response of partial (PR) or complete response (CR), within 42 days of end of dosing, divided by total number of patients who were evaluable (with at least 1 target lesion at baseline). By RECIST: CR=disappearance of clinical and radiologic evidence of target and nontarget lesions confirmed by another evaluation at least 6 weeks later. PR=a \>30% or greater decrease in the sum of longest diameter (LD) of target lesions in reference to the baseline sum LD confirmed by another evaluation at least 6 weeks later. Stable disease=neither sufficient increase to qualify for PD nor shrinkage to qualify for PR, and at least 8 weeks since start of study therapy. Progressive disease=a 20% or greater increase in sum of LD of all target lesions, taking as reference the smallest sum of LD at or following baseline, or unequivocal progression on existing nontarget lesions, or new lesions are present.

Time frame: At baseline and every 12 weeks thereafter to end of treatment, at end of treatment, and at follow-up (within 42 days of end of dosing)

Population: Participants with at least 1 target lesion at baseline

The percentage of participants with a reduction in pain intensity from baseline was defined as the number of participants who achieved a 30% or more decrease in pain intensity from baseline for at least 2 consecutive pain assessments (at least 14 days apart) within 14 days of end of dosing divided by the number of randomized participants who had a baseline pain intensity of at least 2. Pain intensity was assessed based on question 3 of the brief pain inventory questionnaire.

Time frame: At baseline, prior to each docetaxel infusion (every 3 weeks), at end of treatment, and at follow-up (within 14 days of end of dosing)

Population: Participants with a baseline pain intensity of 2 or greater

The percentage of participants who had an on-study uNTx value confirmed (at least 3 weeks later) within normal limits (or ≥3 and \<60 nmol/mmol creatinine, if normal limits were missing) or an on-study uNTx level reduction from baseline of ≥35%, even when on-study uNTx value remained abnormal.

Time frame: At baseline, prior to each docetaxel infusion (every 3 weeks) to end of treatment, at end of treatment, and at follow-up (within 14 days of end of dosing)

Population: Participants who entered the study with baseline urinary N-telopeptide values higher than the upper limit of normal (ULN), or ≥60 nmol/mmol creatinine, if ULN was missing

PFS is defined as the time from the randomization date until the date of earliest evidence of disease progression or death, for participants who progressed or died before subsequent cancer therapy. Those who progressed or died while on subsequent cancer therapy and those who did not die or progress were censored at their last radiologic bone scan/imaging, skeletal related-event, or tumor assessment or at measurement of prostate specific antigen levels, whichever occurred last prior to start of subsequent cancer therapy ,if any. Participants with no assessments were censored on the day of randomization.

Time frame: From day of randomization to disease progression or death (or to last clinical assessment, if subsequent cancer therapy started or no progression or death) (maximum reached: approximately 43 months)

Population: All participants who were randomized to receive any treatment

Time to first SRE is defined as the time in months from the date of randomization to the date of first SRE (unless SRE occurred while the patient was undergoing subsequent cancer therapy). Participants with a first SRE while on subsequent cancer therapy, those who died without a reported SRE, and those who did not have an SRE were censored on the date of their last SRE assessment prior to start of subsequent cancer therapy, if any. Participants who had no SRE assessments were censored on the day they were randomized.

Time frame: From day of randomization to date of first SRE or to last SRE assessment, if subsequent cancer therapy begun or no SRE (maximum reached: 42 months)

Population: All participants who were randomized to receive any treatment

PSA progression is defined as the time from randomization to the date of the first PSA level measurement that led to confirmed PSA progression, for participants who had not started subsequent cancer therapy. For participants who did not progress or who progressed on cancer therapy, PSA progression is defined as the time from randomization to the date of the last PSA level measurement before the start of cancer therapy, if any. Participants who had no on-study PSA level measurements were censored on the day they were randomized.

Time frame: From randomization to date of first PSA measurement leading to confirmed PSA progression (or to last bone scan assessment, if no progression or if cancer therapy started) (maximum reached: 30 months)

Population: All participants who were randomized to receive any treatment

QTc interval measured by electrocardiogram (ECG). Although a participant may have had several ECGs, only the longest QTc interval was included.

Time frame: At baseline, approximately 12 weeks after starting treatment, and then whenever clinically indicated up to within 30 days of end of dosing

Population: All participants who received treatment. n=number evaluable

ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of normal. Abnormalities were graded according to the Common Toxicity Criteria (CTC), version 3.0, of the National Cancer Institute. CTC are graded from 1 (least severe) to 4 (life threatening). ALP, ALT, and AST, Grade 3, \>5.0-20.0\*ULN; Grade 4, \>20.0\*ULN. Total bilirubin, Grade 3, \>3.0-10.0\*ULN; Grade 4, \>10.0\*ULN. Creatinine, Grade 3, \>3.0-6.0\*ULN; Grade 4, \>6.0\*ULN. Hypercalcemia(serum calcium, mmol/L), Grade 3, \>3.1-3.4; Grade 4, \>3.4. Hypocalcemia (serum calcium, mmol/L), Grade 3, \<1.75-1.5; Grade 4, \<1.5. Hyperkalemia(serum calcium, mmol/L), Grade 3, \>6.0-7.0; Grade 4, \>7.0. Hypokalemia(serum calcium, mmol/L), Grade 3, \<3.0-2.5; Grade 4, \<2.5. Hypernatremia (serum calcium, mmol/L), Grade 3, \>155-160; Grade 4, \>160. Hyponatremia (serum sodium, mmol/L), Grade 3, \<130-120; Grade 4, \<120. Phosphorus (serum sodium, mmol/L), Grade 3, \<0.6-0.3; Grade 4, \<0.3.

Time frame: At baseline, within 3 days prior to each infusion of docetaxel (each cycle), to end of treatment. If docetaxel is discontinued, every other cycle.

Population: All participants who received treatment

Abnormalities were graded according to the Common Toxicity Criteria (CTC), version 3.0, of the National Cancer Institute. CTC are graded from 1 (least severe) to 4 (life threatening ). Grade 3 and 4 criteria are defined as follows: Absolute neutrophil count, Grade 3, neutrophils \<1.0-0.5\*10\^9/L; Grade 4, \<0.5\*10\^9/L. Hemoglobin, Grade 3, \<4.9-4.0 mmol/L; Grade 4, \<4.0 mmol/L. Platelets, Grade 3, \<50.0-25.0\*10\^9/L; Grade 4, \<25.0\*10\^9/L. Leukocytes, Grade 3, \<2.0-1.0\*10\^9/L; Grade 4, \<1.0\*10\^9/L.

Time frame: At baseline, within 3 days prior to each infusion of docetaxel (each cycle) and at end of treatment. If docetaxel is discontinued, every other cycle.

Population: All participants who received treatment

Abnormal=positive, defined as the presence of \>=30 mg/dL of protein; a small, moderate, or large amount of blood; or \>0 g/dL glucose in urine. BL=baseline; neg=negative

Time frame: At baseline, within 3 days prior to each infusion of docetaxel (each cycle), to end of treatment. If docetaxel is discontinued, every other cycle.

Population: All participants who received treatment.

BL=baseline; OS=on-study

Time frame: At baseline, approximately 12 weeks after start of treatment, and thereafter whenever clinically indicated

Population: All participants who were randomized to receive any treatment

QTc interval measured by electrocardiogram (ECG). Although a participant may have had several ECGs, only the longest QTc interval was included.

Time frame: At baseline, approximately 12 weeks after starting treatment, and then whenever clinically indicated up to within 30 days of end of dosing

Population: All participants who received treatment. n=number evaluable

AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. AEs of Special Interest=recognized events in other agents within this drug class or events for which safety data from nonclinical and clinical studies with dasatinib indicate that careful evaluation is warranted. Drug-related=having certain, probable, possible, or missing relationship to study drug. Drug-related AEs of Special Interest are identified by the medical and safety representatives of the sponsor based on MedDRA preferred terms or laboratory data. ANC=absolute neutrophil count.

Time frame: Continuously throughout study to <=30 days after last dose of study drug; included AEs with an onset date >= day 1 and <= last dose date + 30 days

Population: All participants who received treatment

AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Drug-related=having certain, probable, possible, or missing relationship to study drug

Time frame: Continuously throughout study to <=30 days after last dose of study drug; included AEs with an onset date >= day 1 and <= last dose date + 30 days

Population: All participants who received treatment