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    Clinical Trial Results:
    PROMET - Multicenter, Randomized Phase II Trial of Salvage Radiotherapy +/- Metformin for Patients with Prostate Cancer after Prostatectomy

    Summary
    EudraCT number
    		 2016-003599-39
    Trial protocol
    		 DE   FR  
    Global end of trial date
    28 Feb 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Jul 2023
    First version publication date
    12 Jul 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SAKK08/15
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02945813
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Swiss Group for Clinical Cancer Research (SAKK)
    Sponsor organisation address
    Effingerstrasse 33, Bern, Switzerland, 3008
    Public contact
    Head Regulatory Affairs, Swiss Group for Clinical Cancer Research (SAKK), +41 31389 91 91, sakkcc@sak.ch
    Scientific contact
    Head Regulatory Affairs, Swiss Group for Clinical Cancer Research (SAKK), +41 31389 91 91, sakkcc@sak.ch
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    27 Feb 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Feb 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective of the trial is to determine if SRT plus metformin is superior to SRT alone in the endpoint of time to progression after prostatectomy failure.
    Protection of trial subjects
    Protection of trial subjects was ensured by Safety Monitoring, i.e. assessment of adverse events, serious adverse events, adverse drug reactions, and the continous assessment of laboratory values and vital signs.
    Background therapy
    		 Salvage radiotherapy (SRT): 70 Gy SRT* | SRT is started 4 weeks after the first dose of metformin (Arm A) / 4-6 weeks after randomization (Arm B) | Duration of SRT: 7 weeks *The total radiotherapy dose (including boost dose) can be 72-74Gy in case of evidence of macroscopic local recurrence.
    Evidence for comparator
    		 not applicable.
    Actual start date of recruitment
    24 Oct 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 10 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 46
    Country: Number of subjects enrolled
    Germany: 9
    Country: Number of subjects enrolled
    Switzerland: 54
    Worldwide total number of subjects
    109
    EEA total number of subjects
    55
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    50
    From 65 to 84 years
    59
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 111 of planned 170 patients at 17 sites in Switzerland (10 sites, 54 patients), Germany (3 sites, 9 patient), and France (4 sites, 48 patients) have been enrolled from October 2017 to November 2020. Note: Two patients enrolled in France, did not receive RT after randomization and were not included in the analysis.

    Pre-assignment
    Screening details
    		 Eligibility criteria of a patient were checked by the investigator. Once a patient fullfils all inclusion criteria and not any of the exclusion criteria, he/she was enrolled.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 SRT + Metformin
    Arm type
    		 Experimental

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    1,1-dimethylbiguanide hydrochloride
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    850 mg metformin p.o. (0-0-1) for 4 weeks, followed by 850 mg metformin p.o. b.i.d (1-0-1) for 48 weeks.

    Arm title
    		 Arm B
    Arm description
    		 SRT
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Arm A Arm B
    Started
    55
    54
    Completed
    55
    54
    Period 2
    Period 2 title
    Treatment phase
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 SRT + Metformin
    Arm type
    		 Experimental

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    1,1-dimethylbiguanide hydrochloride
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    850 mg metformin p.o. (0-0-1) for 4 weeks, followed by 850 mg metformin p.o. b.i.d (1-0-1) for 48 weeks.

    Arm title
    		 Arm B
    Arm description
    		 SRT
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		Arm A Arm B
    Started
    55
    54
    Completed
    55
    51
    Not completed
    0
    3
         Major eligibility violations
    -
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 SRT + Metformin

    Reporting group title
    Arm B
    Reporting group description
    		 SRT

    Reporting group values
    		 Arm A Arm B Total
    Number of subjects
    		 55 54 109
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 26 24 50
        From 65-84 years
    		 29 30 59
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0
        Male
    		 55 54 109

    End points

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    End points reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 SRT + Metformin

    Reporting group title
    Arm B
    Reporting group description
    		 SRT
    Reporting group title
    Arm A
    Reporting group description
    		 SRT + Metformin

    Reporting group title
    Arm B
    Reporting group description
    		 SRT

    Subject analysis set title
    Arm A - FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full analysis set of Arm A

    Subject analysis set title
    Arm B - FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full analysis set of Arm B (excluding three patients with major eligibility violations)

    Subject analysis set title
    Arm A - PPS
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per protocol set of Arm A (excluding 13 patients from the FAS due to RT interruption of >5 days [6 pts.] or MET interruption/discontinuation for >30 days [7 pts.])

    Subject analysis set title
    Arm B - PPS
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per protocol set of Arm B (excluding four patients from the FAS due to RT interruption of >5 days)

    Primary: PE | Time to progression (FAS)

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    End point title
    		 PE | Time to progression (FAS)
    End point description
    Biochemical progression [BP] defined as (1) Serum PSA value of 0.2 ng/mL or more above the post-radiotherapy nadir, (2) In case there is no PSA decline during trial treatment: Serum PSA value of 0.2 ng/mL or more above the PSA value at randomization. | The biochemical progression has to be confirmed by a second higher serum PSA value (at least 1 week apart, but no later than 4 weeks). The date of biochemical progression is the date of the first PSA rise of 0.2 ng/mL or more. Clinical progression [CP] defined as either local or regional recurrence of the disease or the appearance of distant metastases. Secondary cancers are not considered as being a clinical progression. No of events: Arm A = 9 [BP: 7 | CP: 2 | Death: 0] || Arm B = 7 [BP: 4 | CP: 3 | Death: 0] Note: Dummy data ("999") entered for median TTP due to database restrictions. Median TTP was not reached.
    End point type
    Primary
    End point timeframe
    From randomization until one of the following events, whichever comes first: (1) Biochemical progression [BP], (2) Clinical progression [CP] or (3) Death due to clinical progression [Death]
    End point values
    		 Arm A - FAS Arm B - FAS
    Number of subjects analysed
    55
    51
    Units: Time To Progression (months)
        median (confidence interval 95%)
    999 (999 to 999)
    999 (999 to 999)
    Statistical analysis title
    		 Log-rank test
    Comparison groups
    Arm B - FAS v Arm A - FAS
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.617
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 HR without stratification factors (95% CI)
    Statistical analysis description
    Stratification factors (Gleason score [<8/≥8], resection margins [R0/R1], PSA at randomization [≤0.5 ng/ml/>0.5 ng/ml], ADT use [yes/no], Macroscopic local recurrence [yes/no/missing]) Macroscopic local recurrence is not used as stratification factor as it is often missing and very unbalanced.
    Comparison groups
    Arm A - FAS v Arm B - FAS
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 3.46
    Statistical analysis title
    		 HR with stratification factors (95% CI)
    Statistical analysis description
    Stratification factors (Gleason score [<8/≥8], resection margins [R0/R1], PSA at randomization [≤0.5 ng/ml/>0.5 ng/ml], ADT use [yes/no], Macroscopic local recurrence [yes/no/missing]) Macroscopic local recurrence is not used as stratification factor as it is often missing and very unbalanced.
    Comparison groups
    Arm A - FAS v Arm B - FAS
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 3.94
    Statistical analysis title
    		 HR without stratification factors (1-sided 80% CI)
    Statistical analysis description
    Stratification factors (Gleason score [<8/≥8], resection margins [R0/R1], PSA at randomization [≤0.5 ng/ml/>0.5 ng/ml], ADT use [yes/no], Macroscopic local recurrence [yes/no/missing]) Macroscopic local recurrence is not used as stratification factor as it is often missing and very unbalanced.
    Comparison groups
    Arm A - FAS v Arm B - FAS
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.29
    Confidence interval
         level
    		 80%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 1.97
    Statistical analysis title
    		 HR with stratification factors (1-sided 80% CI)
    Statistical analysis description
    Stratification factors (Gleason score [<8/≥8], resection margins [R0/R1], PSA at randomization [≤0.5 ng/ml/>0.5 ng/ml], ADT use [yes/no], Macroscopic local recurrence [yes/no/missing]) Macroscopic local recurrence is not used as stratification factor as it is often missing and very unbalanced.
    Comparison groups
    Arm A - FAS v Arm B - FAS
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.25
    Confidence interval
         level
    		 80%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 2.05

    Primary: PE | Time to progression (PPS)

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    End point title
    		 PE | Time to progression (PPS)
    End point description
    Biochemical progression [BP] defined as (1) Serum PSA value of 0.2 ng/mL or more above the postradiotherapy nadir, (2) In case there is no PSA decline during trial treatment: Serum PSA value of 0.2 ng/mL or more above the PSA value at randomization. | The biochemical progression has to be confirmed by a second higher serum PSA value (at least 1 week apart, but no later than 4 weeks). The date of biochemical progression is the date of the first PSA rise of 0.2 ng/mL or more. Clinical progression [CP] defined as either local or regional recurrence of the disease or the appearance of distant metastases. Secondary cancers are not considered as being a clinical progression. No of events: Arm A = 7 [BP: 5 | CP: 2 | Death: 0] || Arm B = 6 [BP: 3 | CP: 3 | Death: 0] Note: Dummy data ("999") entered for median TTP due to database restrictions. Median TTP was not reached.
    End point type
    Primary
    End point timeframe
    From randomization until one of the following events, whichever comes first: (1) Biochemical progression [BP], (2) Clinical progression [CP] or (3) Death due to clinical progression [Death]
    End point values
    		 Arm A - PPS Arm B - PPS
    Number of subjects analysed
    42
    47
    Units: Time to progression (months)
        median (confidence interval 95%)
    999 (999 to 999)
    999 (999 to 999)
    Statistical analysis title
    		 Log-rank test
    Comparison groups
    Arm A - PPS v Arm B - PPS
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.519
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 HR without stratification factors (95% CI)
    Statistical analysis description
    Stratification factors (Gleason score [<8/≥8], resection margins [R0/R1], PSA at randomization [≤0.5 ng/ml/>0.5 ng/ml], ADT use [yes/no], Macroscopic local recurrence [yes/no/missing]) Macroscopic local recurrence is not used as stratification factor as it is often missing and very unbalanced.
    Comparison groups
    Arm A - PPS v Arm B - PPS
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 4.26
    Statistical analysis title
    		 HR with stratification factors (95% CI)
    Statistical analysis description
    Stratification factors (Gleason score [<8/≥8], resection margins [R0/R1], PSA at randomization [≤0.5 ng/ml/>0.5 ng/ml], ADT use [yes/no], Macroscopic local recurrence [yes/no/missing]) Macroscopic local recurrence is not used as stratification factor as it is often missing and very unbalanced.
    Comparison groups
    Arm B - PPS v Arm A - PPS
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 5.58
    Statistical analysis title
    		 HR without stratification factors (1-sided 80% CI)
    Statistical analysis description
    Stratification factors (Gleason score [<8/≥8], resection margins [R0/R1], PSA at randomization [≤0.5 ng/ml/>0.5 ng/ml], ADT use [yes/no], Macroscopic local recurrence [yes/no/missing]) Macroscopic local recurrence is not used as stratification factor as it is often missing and very unbalanced.
    Comparison groups
    Arm A - PPS v Arm B - PPS
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.43
    Confidence interval
         level
    		 80%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 2.29
    Statistical analysis title
    		 HR with stratification factors (1-sided 80% CI)
    Statistical analysis description
    Stratification factors (Gleason score [<8/≥8], resection margins [R0/R1], PSA at randomization [≤0.5 ng/ml/>0.5 ng/ml], ADT use [yes/no], Macroscopic local recurrence [yes/no/missing]) Macroscopic local recurrence is not used as stratification factor as it is often missing and very unbalanced.
    Comparison groups
    Arm A - PPS v Arm B - PPS
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.63
    Confidence interval
         level
    		 80%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 2.77

    Secondary: SE | Progression-free survival

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    End point title
    		 SE | Progression-free survival
    End point description
    Biochemical progression [BP] and Clinical progression [CP] as defined for the primary endpoint. No of events: Arm A = 10 [BP: 7 | CP: 2 | Death: 1] | Arm B = 7 [BP: 4 | CP: 3] Note: Dummy data ("999") entered for median TTP due to database restrictions. Median TTP was not reached.
    End point type
    Secondary
    End point timeframe
    From randomization until one of the following events, whichever comes first: (1) Biochemical progression [BP], (2) Clinical progression [CP] or (3) Death due to clinical progression [Death]
    End point values
    		 Arm A - FAS Arm B - FAS
    Number of subjects analysed
    55
    51
    Units: Progression-free survival (months)
        median (confidence interval 95%)
    999 (999 to 999)
    999 (999 to 999)
    Statistical analysis title
    		 Log-rank test
    Comparison groups
    Arm A - FAS v Arm B - FAS
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.475
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 HR without stratification factors (95% CI)
    Statistical analysis description
    Stratification factors: see information provided for the primary analysis.
    Comparison groups
    Arm A - FAS v Arm B - FAS
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 3.73
    Statistical analysis title
    		 HR with stratification factors (95% CI)
    Statistical analysis description
    Stratification factors: see information provided for the primary analysis.
    Comparison groups
    Arm A - FAS v Arm B - FAS
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 4.45

    Secondary: SE | Undetectable PSA under normal testosterone levels

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    End point title
    		 SE | Undetectable PSA under normal testosterone levels
    End point description
    Undetectable PSA is defined as a serum PSA value of ≤ 0.05 ng/mL for at least two consecutive measurements after the last radiotherapy fraction and up to 18 months thereafter. To count as undetectable PSA under normal testosterone levels, the testosterone level has to be ≥ 50 ng/dL (i.e. a non-castrate testosterone level).
    End point type
    Secondary
    End point timeframe
    At at least two consecutive measurements after the last radiotherapy fraction and up to 18 months thereafter.
    End point values
    		 Arm A - FAS Arm B - FAS
    Number of subjects analysed
    55
    51
    Units: Patients (%)
        number (confidence interval 95%)
    58.2 (44.1 to 71.3)
    70.6 (56.2 to 82.5)
    Statistical analysis title
    		 Fisher's Exact Test
    Comparison groups
    Arm A - FAS v Arm B - FAS
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.226
    Method
    		 Fisher exact
    Confidence interval

    Secondary: SE | 50% PSA response

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    End point title
    		 SE | 50% PSA response
    End point description
    50% PSA response is defined as a ≥ 50% PSA decline after radiotherapy compared to the serum PSA level at randomization up to 12 months after last radiotherapy fraction.
    End point type
    Secondary
    End point timeframe
    Up to 12 months after last radiotherapy fraction.
    End point values
    		 Arm A - FAS Arm B - FAS
    Number of subjects analysed
    55
    51
    Units: Patients (%)
        number (confidence interval 95%)
    81.8 (69.1 to 90.9)
    88.2 (76.1 to 95.6)
    Statistical analysis title
    		 Fisher's Exact Test
    Comparison groups
    Arm A - FAS v Arm B - FAS
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.423
    Method
    		 Fisher exact
    Confidence interval

    Secondary: SE | Best response

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    End point title
    		 SE | Best response
    End point description
    Best response is defined as the percentage of change in PSA from randomization to the maximum decline in PSA at any point after radiotherapy and up to 12 months after last radiotherapy fraction. If PSA after radiotherapy and up to 12 months after last radiotherapy fraction was always higher than PSA at randomization, the best response is defined as the percentage of change in PSA at randomization to the minimal PSA value after radiotherapy and up to 12 months after last radiotherapy fraction.
    End point type
    Secondary
    End point timeframe
    Up to 12 months after last radiotherapy fraction.
    End point values
    		 Arm A - FAS Arm B - FAS
    Number of subjects analysed
    55
    51
    Units: Best response (%)
        median (full range (min-max))
    -91.3 (-100 to 120.4)
    -91.7 (-100 to 56.8)
    Statistical analysis title
    		 Wilcoxon rank-sum test
    Comparison groups
    Arm A - FAS v Arm B - FAS
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.64
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: SE | Clinical progression-free survival

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    End point title
    		 SE | Clinical progression-free survival
    End point description
    Clinical progression (as defined for the primary endpoint). No of events: Arm A = 8 | Arm B = 4 Note: Dummy data ("999") entered for median clincial PFS due to database restrictions. Median clinical PFS was not reached.
    End point type
    Secondary
    End point timeframe
    From randomization until clinical progression [CP] or death due to any cause.
    End point values
    		 Arm A - FAS Arm B - FAS
    Number of subjects analysed
    55
    51
    Units: Time to clinical PFS (months)
        median (confidence interval 95%)
    999 (999 to 999)
    999 (999 to 999)
    Statistical analysis title
    		 Log-rank test
    Comparison groups
    Arm A - FAS v Arm B - FAS
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.243
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 HR without stratification factors (95% CI)
    Statistical analysis description
    Stratification factors: see information provided for the primary analysis.
    Comparison groups
    Arm A - FAS v Arm B - FAS
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    2.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 6.71
    Statistical analysis title
    		 HR with stratification factors (95% CI)
    Statistical analysis description
    Stratification factors: see information provided for the primary analysis.
    Comparison groups
    Arm A - FAS v Arm B - FAS
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    3.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 17.4

    Secondary: SE | Time to further anti-cancer systemic therapy (TTFT)

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    End point title
    		 SE | Time to further anti-cancer systemic therapy (TTFT)
    End point description
    No of events: Arm A = 6 | Arm B = 2 Note: Dummy data ("999") entered for median TTFT due to database restrictions. Median TTFT was not reached.
    End point type
    Secondary
    End point timeframe
    From randomization until the start of any type of salvage systemic treatment.
    End point values
    		 Arm A - FAS Arm B - FAS
    Number of subjects analysed
    55
    51
    Units: TTFT (months)
        median (confidence interval 95%)
    999 (999 to 999)
    999 (999 to 999)
    Statistical analysis title
    		 Log-rank test
    Comparison groups
    Arm A - FAS v Arm B - FAS
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.175
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 HR without stratification factors (95% CI)
    Statistical analysis description
    Stratification factors: see information provided for the primary endpoint.
    Comparison groups
    Arm A - FAS v Arm B - FAS
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    2.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 14.29
    Statistical analysis title
    		 HR with stratification factors (95% CI)
    Statistical analysis description
    Stratification factors: see information provided for the primary endpoint.
    Comparison groups
    Arm A - FAS v Arm B - FAS
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    2.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 12.85

    Secondary: SE | Prostate cancer-specific survival (PCSS)

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    End point title
    		 SE | Prostate cancer-specific survival (PCSS)
    End point description
    End point type
    Secondary
    End point timeframe
    From randomization to the date of death due to prostate cancer.
    End point values
    		 Arm A - FAS Arm B - FAS
    Number of subjects analysed
    55
    51
    Units: Death due to prostate cancer
    0
    0
    No statistical analyses for this end point

    Secondary: SE | Overall survival (OS)

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    End point title
    		 SE | Overall survival (OS)
    End point description
    Until the time of this analysis one patient (0.9%) died. Therefore, only survival status is summarized.
    End point type
    Secondary
    End point timeframe
    From randomization to the date of death from any cause.
    End point values
    		 Arm A - FAS Arm B - FAS
    Number of subjects analysed
    55
    51
    Units: Patients (%)
    number (not applicable)
        Alive
    90.9
    96.1
        Dead
    1.8
    0.0
        Lost to follow-up
    7.3
    3.9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From registration and up to 28 days after end of treatment phase (week 52).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 SRT + Metformin

    Reporting group title
    Arm B
    Reporting group description
    		 SRT

    Serious adverse events
    		 Arm A Arm B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 55 (3.64%)
    3 / 54 (5.56%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Alanine aminotransferase increased
    Additional description: AST and ALT increased.
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Hip arthroplasty
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A Arm B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    48 / 55 (87.27%)
    44 / 54 (81.48%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    6 / 55 (10.91%)
    7 / 54 (12.96%)
         occurrences all number
    7
    8
    Hypertension
         subjects affected / exposed
    5 / 55 (9.09%)
    3 / 54 (5.56%)
         occurrences all number
    5
    5
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    14 / 55 (25.45%)
    13 / 54 (24.07%)
         occurrences all number
    17
    14
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    7 / 55 (12.73%)
    1 / 54 (1.85%)
         occurrences all number
    9
    1
    Anal haemorrhage
         subjects affected / exposed
    3 / 55 (5.45%)
    1 / 54 (1.85%)
         occurrences all number
    4
    1
    Proctalgia
         subjects affected / exposed
    3 / 55 (5.45%)
    1 / 54 (1.85%)
         occurrences all number
    3
    1
    Constipation
         subjects affected / exposed
    4 / 55 (7.27%)
    6 / 54 (11.11%)
         occurrences all number
    4
    8
    Diarrhoea
         subjects affected / exposed
    29 / 55 (52.73%)
    13 / 54 (24.07%)
         occurrences all number
    43
    15
    Flatulence
         subjects affected / exposed
    4 / 55 (7.27%)
    3 / 54 (5.56%)
         occurrences all number
    4
    4
    Nausea
         subjects affected / exposed
    5 / 55 (9.09%)
    0 / 54 (0.00%)
         occurrences all number
    6
    0
    Proctitis
         subjects affected / exposed
    1 / 55 (1.82%)
    3 / 54 (5.56%)
         occurrences all number
    1
    3
    Rectal haemorrhage
         subjects affected / exposed
    4 / 55 (7.27%)
    3 / 54 (5.56%)
         occurrences all number
    4
    3
    Reproductive system and breast disorders
    Erectile dysfunction
         subjects affected / exposed
    5 / 55 (9.09%)
    7 / 54 (12.96%)
         occurrences all number
    5
    8
    Renal and urinary disorders
    Cystitis noninfective
         subjects affected / exposed
    8 / 55 (14.55%)
    5 / 54 (9.26%)
         occurrences all number
    8
    5
    Dysuria
         subjects affected / exposed
    5 / 55 (9.09%)
    0 / 54 (0.00%)
         occurrences all number
    6
    0
    Pollakiuria
         subjects affected / exposed
    18 / 55 (32.73%)
    17 / 54 (31.48%)
         occurrences all number
    21
    20
    Urinary incontinence
         subjects affected / exposed
    15 / 55 (27.27%)
    11 / 54 (20.37%)
         occurrences all number
    16
    13
    Micturition urgency
         subjects affected / exposed
    7 / 55 (12.73%)
    3 / 54 (5.56%)
         occurrences all number
    10
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Nov 2017
    Clarifications and administrative changes requested by German authorities. Please note that version 2.0 has been submitted and approved exclusively in Germany.
    17 Jan 2018
    Clarifications and administrative changes requested during the initial submission of the protocol by the Swiss, French and German authorities.
    02 Sep 2019
    Allow inclusion of local recurrences detected on PET or MRI, adaption of definition of clinical progression for the primary endpoint, adaption of trial timelines.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to early closure of the trial, a time window of up to 12 months after radiotherapy instead of 18 months was considered. This has been adapted in the definition of the secondary endpoints undetectable PSA and 50% PSA response.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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