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

Study Type:	Interventional
Study Design:	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
Condition:	Prostatic Neoplasms
Interventions:	Drug: Placebo; Drug: Dasatinib; Drug: Docetaxel; Drug: Prednisone

  Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
1930 participants enrolled, 1522 randomized to a treatment group (762 dasatinib, 760 placebo). 408 not randomized. Reasons for non-randomization include 7 adverse events, 42 withdrew consent, 6 deaths, 2 lost to follow up, 3 poor/non compliance, 332 no longer met study criteria, 1 administrative reason by sponsor, and 15 non-specified reasons.

Reporting Groups

	Description
Placebo	Participants received placebo, given orally once daily, plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily
Dasatinib	Participants received dasatinib, 100 mg, orally once daily plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily

Participant Flow:   Overall Study

	Placebo	Dasatinib
STARTED	760 [1]	762 [1]
Received Treatment	757	761
COMPLETED	0	0
NOT COMPLETED	760	762
Withdrawal by Subject	21	18
Death	11	9
Lost to Follow-up	4	2
Poor compliance/noncompliance	9	5
No longer meets study criteria	7	3
Administrative Reason By Sponsor	25	8
Disease progression	312	219
Study drug toxicity	68	141
Adverse event unrelated to study drug	78	122
Patient requested to stop study drug	65	80
Maximum clinical benefit	141	142
Not defined	19	13

[1]	Randomized

  Baseline Characteristics

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Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All participants who were randomized to receive any treatment

Reporting Groups

	Description
Placebo	Participants received placebo, given orally once daily, plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily
Dasatinib	Participants received dasatinib, 100 mg, orally once daily plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily
Total	Total of all reporting groups

Baseline Measures

	Placebo	Dasatinib	Total
Overall Participants Analyzed; [Units: Participants]	760	762	1522
Age, Customized; [Units: Participants]
Younger than 65 years	263	251	514
65 to younger than 75 years	323	333	656
75 years or older	174	178	352
Gender; [Units: Participants]
Female	0	0	0
Male	760	762	1522
Race/Ethnicity, Customized; [Units: Participants]
Asian	56	55	111
Native Hawaiian or Other Pacific Islander	1	1	2
Black or African American	34	23	57
White	645	656	1301
Other	24	27	51
Type of metastatic disease; [Units: Participants]
Bone disease only	286	307	593
Visceral/nodal disease only	73	80	153
Both bone and visceral/nodal disease	399	373	772
No evidence of metastatic disease	2	2	4

  Outcome Measures

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1. Primary:

Overall Survival: Time From Randomization to Date of Death [ Time Frame: From randomization to death or date of last contact (maximum reached: 45 months) ]

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Measure Type	Primary
Measure Title	Overall Survival: Time From Randomization to Date of Death
Measure Description	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 Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All participants who were randomized to receive any treatment

Reporting Groups

	Description
Placebo	Participants received placebo, given orally once daily, plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily
Dasatinib	Participants received dasatinib, 100 mg, orally once daily plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily

Measured Values

	Placebo	Dasatinib
Participants Analyzed; [Units: Participants]	760	762
Overall Survival: Time From Randomization to Date of Death; [Units: Months]; Median (95% Confidence Interval)	21.2; (20.0 to 23.4)	21.5; (20.3 to 22.8)

Statistical Analysis 1 for Overall Survival: Time From Randomization to Date of Death

Groups [1]	All groups
Statistical Test Type [2]	Superiority or Other
Statistical Method [3]	Log Rank
P Value [4]	0.9009
Hazard Ratio (HR) [5]	0.99
95.53% Confidence Interval	0.87 to 1.13

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Confidence intervals for median overall survival calculated using Brookmeyer and Crowley method. Compared survival in arms by 2-sided, alpha=0.0447 level, log-rank test, stratified by bisphosphonate intake (yes/no) and urinary N-telopeptide category (<60 vs ≥60 nmol/mmol creatinine) defined at randomization. Null hypothesis was survival equal in both arms. Power calculations were that ≥858 deaths would lead to ≥90% power at 5% level for rejecting null hypothesis, given true hazard ratio of 0.8.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	An interim analysis on survival was performed and the final test was corrected for multiplicity.
[5]	Other relevant estimation information:
	No text entered.

2. Secondary:

Percentage of Participants With an Objective Tumor Response by Modified Response Evaluation Criteria in Solid Tumors (RECIST) [ 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) ]

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3. Secondary:

Time to First Skeletal-related Event (SRE) [ 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) ]

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4. Secondary:

Percentage of Participants With A Reduction in Urinary N-telopeptide (uNTx) Level From Baseline [ 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) ]

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5. Secondary:

Progression-free Survival (PFS) [ 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) ]

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Measure Type	Secondary
Measure Title	Progression-free Survival (PFS)
Measure Description	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 Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All participants who were randomized to receive any treatment

Reporting Groups

	Description
Placebo	Participants received placebo, given orally once daily, plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily
Dasatinib	Participants received dasatinib, 100 mg, orally once daily plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily

Measured Values

	Placebo	Dasatinib
Participants Analyzed; [Units: Participants]	760	762
Progression-free Survival (PFS); [Units: Months]; Median (95% Confidence Interval)	11.1; (10.8 to 11.7)	11.8; (11.1 to 13.4)

Statistical Analysis 1 for Progression-free Survival (PFS)

Groups [1]	All groups
Statistical Test Type [2]	Superiority or Other
Hazard Ratio (HR) [3]	0.92
95% Confidence Interval	0.82 to 1.05

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Since superiority of the dasatinib treatment group was not demonstrated for Overall Survival, secondary endpoints were not tested. The hazard ratio is presented for experimental to control group.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant estimation information:
	No text entered.

6. Secondary:

Time to Prostate Specific Antigen (PSA) Progression [ 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) ]

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7. Secondary:

Percentage of Participants With a Reduction in Pain Intensity From Baseline [ 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) ]

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8. Other Pre-specified:

Number of Participants With Serious Adverse Event (SAEs), Drug-related SAEs, Drug-related AEs, Drug-related AEs Leading to Discontinuation, and All Deaths [ 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 ]

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9. Other Pre-specified:

Number of Participants With Drug-Related Adverse Events (AEs) of Special Interest [ 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 ]

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10. Other Pre-specified:

Number of Participants With Abnormalities in Results of Clinical Laboratory Tests in Hematology [ 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. ]

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11. Other Pre-specified:

Number of Participants With Abnormalities in Results of Clinical Laboratory Tests Assessing Liver Function, Renal Function, and Electrolytes [ 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. ]

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12. Other Pre-specified:

Number of Participants With Abnormal Results in Urinalysis [ 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. ]

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13. Other Pre-specified:

Number of Participants by Maximal On-study Fridericia-corrected QTc Interval [ Time Frame: At baseline, approximately 12 weeks after starting treatment, and then whenever clinically indicated up to within 30 days of end of dosing ]

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14. Other Pre-specified:

Number of Participants With Changes From Baseline in Fridericia-corrected QTc Interval [ Time Frame: At baseline, approximately 12 weeks after starting treatment, and then whenever clinically indicated up to within 30 days of end of dosing ]

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15. Other Pre-specified:

Number of Participants With and Without Pericardial Effusion at Baseline and On-study and With Left Ventricular Ejection Fraction (LVEF) <40% and >=40% On-study [ Time Frame: At baseline, approximately 12 weeks after start of treatment, and thereafter whenever clinically indicated ]

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  Serious Adverse Events

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  Other Adverse Events

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  Limitations and Caveats

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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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  More Information

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