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    Clinical Trial Results:
    Randomised phase 2 trial of stereotactic body radiation therapy, SBRT, in combination with checkpoint inhibitors in metastatic castration-resistant prostate cancer

    Summary
    EudraCT number
    		 2018-003461-34
    Trial protocol
    		 DK  
    Global end of trial date
    30 Aug 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Aug 2025
    First version publication date
    06 Aug 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    UR1840
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05655715
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 BMS study number: CA209-8TY
    Sponsors
    Sponsor organisation name
    Department of Oncology, Herlev & Gentofte Hospital
    Sponsor organisation address
    Borgmester Ib Juuls Vej 1, Herlev, Denmark, 2730
    Public contact
    PI Rikke Løvendahl Eefsen, Department of Oncology, Herlev & Gentofte Hospital, +45 3868 9381, rikke.helene.loevendahl.eefsen@regionh.dk
    Scientific contact
    PI Rikke Løvendahl Eefsen, Department of Oncology, Herlev & Gentofte Hospital, +45 3868 9381, rikke.helene.loevendahl.eefsen@regionh.dk
    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
    19 Nov 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Aug 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Aug 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the response rate of immune checkpoint inhibition, ipilimumab and nivolumab in combination with SBRT and compare to combination immunotherapy with ipilimumab and nivolumab.
    Protection of trial subjects
    Patients that signed informed consent and fulfilling eligibility criteria were included. Continued monitoring of standard safety parameters during treatment.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Nov 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 91
    Worldwide total number of subjects
    91
    EEA total number of subjects
    91
    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)
    19
    From 65 to 84 years
    72
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was open for recruitment of patients from November 2019 to Jan 2024. All patients are recruited at a single site: Copenhagen University Hospital - Herlev and Gentofte in Denmark.

    Pre-assignment
    Screening details
    		 Eligible patients were ≥ 18 years with metastatic castration-resistant prostate cancer Evidence of disease progression after prior therapy for mCRPC, ECOG PS 0-1, adequate organ and hematologic function. (Pre-assignment section used to depicture patients initially included and randomised, but not started intervention)

    Pre-assignment period milestones
    Number of subjects started
    		 91
    Number of subjects completed
    		 81

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Clinical deterioration: 10
    Period 1
    Period 1 title
    CheckPRO treatment (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A - SBRT + nivolumab and ipilimumab
    Arm description
    		 Stereotactic body radiotherapy of 8 Gray (Gy) x 3 on one soft tissue or bone metastasis and immunotherapy
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab 3 mg/kg every 3 weeks (q3w) for 4 cycles and in absence of disease progression continued with flat dosing 480 mg every 4 weeks (q4w). Treatment in the trial continued until disease progression, unacceptable toxicity, withdrawal of consent or completion of 12 months of treatment, whichever occured first.

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ipilimumab (1mg/kg) was given every 3 weeks for a maximum of four cycles.

    Arm title
    		 Arm B - nivolumab and ipilimumab
    Arm description
    		 Immunotherapy
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab 3 mg/kg every 3 weeks (q3w) for 4 cycles and in absence of disease progression continued with flat dosing 480 mg every 4 weeks (q4w). Treatment in the trial continued until disease progression, unacceptable toxicity, withdrawal of consent or completion of 12 months of treatment, whichever occured first.

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ipilimumab (1mg/kg) was given every 3 weeks for a maximum of four cycles.

    Number of subjects in period 1 [1]
    		Arm A - SBRT + nivolumab and ipilimumab Arm B - nivolumab and ipilimumab
    Started
    37
    44
    Completed
    30
    41
    Not completed
    7
    3
         Adverse event, non-fatal
    7
    3
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The difference in subjects is due to the fact that 10 subjects , that had been randomised (8 in arm A, 2 in arm B), did not start treatment - those are listed as non-completion in the pre-assignment period section.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A - SBRT + nivolumab and ipilimumab
    Reporting group description
    		 Stereotactic body radiotherapy of 8 Gray (Gy) x 3 on one soft tissue or bone metastasis and immunotherapy

    Reporting group title
    Arm B - nivolumab and ipilimumab
    Reporting group description
    		 Immunotherapy

    Reporting group values
    		 Arm A - SBRT + nivolumab and ipilimumab Arm B - nivolumab and ipilimumab Total
    Number of subjects
    		 37 44 81
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 8 8 16
        From 65-84 years
    		 29 36 65
    Age continuous
    Units: years
        median (full range (min-max))
    		 72 (58 to 81) 73 (46 to 82) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0
        Male
    		 37 44 81
    ECOG Performance status
    Units: Subjects
        PS 0
    		 18 21 39
        PS 1
    		 19 23 42
    Bone lesions at baseline
    Units: Subjects
        None
    		 1 6 7
        Less than 5
    		 2 2 4
        At least 5
    		 34 36 70
    Mesurable disease at baseline
    Measurable disease as defined by RECIST version 1.1
    Units: Subjects
        Yes
    		 24 36 60
        No
    		 13 8 21
    Number of prior lines of systemic therapy for metastatic disease
    Units: Subjects
        < 3 lines
    		 0 3 3
        ≥ 3 lines
    		 37 41 78

    End points

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    End points reporting groups
    Reporting group title
    Arm A - SBRT + nivolumab and ipilimumab
    Reporting group description
    		 Stereotactic body radiotherapy of 8 Gray (Gy) x 3 on one soft tissue or bone metastasis and immunotherapy

    Reporting group title
    Arm B - nivolumab and ipilimumab
    Reporting group description
    		 Immunotherapy

    Primary: PSA response

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    End point title
    		 PSA response [1]
    End point description
    Percentage of subjects achieving a ≥ 50% decline in PSA from baseline at any time from treatment start (confirmed bey another measurement after ≥ 3 weeks)
    End point type
    Primary
    End point timeframe
    at any time from treatment start to end of treatment wihtin study or prior to any further anti cancer treatment.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: See co-primary endpoint ORR . With PSA response achieved for n ≥ 8 subjects in each of the treatment arms and a difference between arms is < 5, both treatments pass the testing procedure. Both treatments have at least a certain number of responses, and the difference in response is small. Therefore, no claim can be made that one treatment is more efficacious than the other.
    End point values
    		 Arm A - SBRT + nivolumab and ipilimumab Arm B - nivolumab and ipilimumab
    Number of subjects analysed
    37
    44 [2]
    Units: percent
        number (confidence interval 95%)
    21.6 (9.8 to 38.2)
    20.5 (9.8 to 35.3)
    Notes
    [2] - 2 subjects with baseline PSA <1
    No statistical analyses for this end point

    Primary: ORR

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    End point title
    		 ORR [3]
    End point description
    Objective response-rate per modified RECIST1.1/PCWG3 for patients with measurable disease
    End point type
    Primary
    End point timeframe
    Assessments were done every 8 weeks from treatment start to confirmation of progression of disease
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The study is not designed to directly compare arms, but based on a two-stage design for randomized phase II trials with two experimental treatment arms, with the following features: (1) the type I error rate and power within each arm are controlled in a fashion similar to that of a typical single-arm phase II anticancer trial; and (2) the probability of mistakenly selecting an inferior arm and the probability of correctly selecting a superior arm are controlled at prespecified levels.
    End point values
    		 Arm A - SBRT + nivolumab and ipilimumab Arm B - nivolumab and ipilimumab
    Number of subjects analysed
    24 [4]
    36 [5]
    Units: percent
        number (confidence interval 95%)
    16.7 (4.7 to 37.4)
    22.2 (10.1 to 39.2)
    Notes
    [4] - subjects with measurable disease only
    [5] - subjects with measurable disease only
    No statistical analyses for this end point

    Secondary: Time to PSA progression

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    End point title
    		 Time to PSA progression
    End point description
    Time to PSA progression is the time from treatment initiation until PSA progression defined as ≥25% increase and ≥2ng/ml above the nadir 12 weeks after initiation of study treatment, confirmed ≥3 weeks later if there is a PSA decline from baseline
    End point type
    Secondary
    End point timeframe
    PSA measurements were done every cycle (q3w or q4w) until end of study
    End point values
    		 Arm A - SBRT + nivolumab and ipilimumab Arm B - nivolumab and ipilimumab
    Number of subjects analysed
    37
    42 [6]
    Units: months
        median (confidence interval 95%)
    2.63 (1.94 to 3.81)
    2.5 (1.97 to 2.99)
    Notes
    [6] - 2 patients not evaluable for PSA
    No statistical analyses for this end point

    Secondary: rPFS

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    End point title
    		 rPFS
    End point description
    Time from treatment initiation to radiographic progression according to PCWG3 modified RECIST 1.1 or death.
    End point type
    Secondary
    End point timeframe
    Tumor assessments will be performed by CT scans/18F–NaF PET/CT scans every 8 weeks from treatment start to progression of disease
    End point values
    		 Arm A - SBRT + nivolumab and ipilimumab Arm B - nivolumab and ipilimumab
    Number of subjects analysed
    37
    44
    Units: month
        median (confidence interval 95%)
    2.10 (1.91 to 3.81)
    1.87 (1.84 to 2.53)
    No statistical analyses for this end point

    Secondary: OS

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    End point title
    		 OS
    End point description
    End point type
    Secondary
    End point timeframe
    from treatment initiation to death (includes at least 1 year of follow up for each subject without event)
    End point values
    		 Arm A - SBRT + nivolumab and ipilimumab Arm B - nivolumab and ipilimumab
    Number of subjects analysed
    37
    44
    Units: month
        median (confidence interval 95%)
    10.2 (7.13 to 14.1)
    9.2 (7.06 to 14.1)
    No statistical analyses for this end point

    Secondary: CBR

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    End point title
    		 CBR
    End point description
    For patients with measurable disease, Clinical Benefit rate (CBR) is defined as CR, PR, stable disease (SD) for more than 6 months. For patients with evaluable disease based on bone lesions (non-measurable disease), CBR includes those patients that had non-progressive disease documented in 3 or more assessments.
    End point type
    Secondary
    End point timeframe
    Assessments were done every 8 weeks from treatment start to confirmation of progression of disease.
    End point values
    		 Arm A - SBRT + nivolumab and ipilimumab Arm B - nivolumab and ipilimumab
    Number of subjects analysed
    37
    44
    Units: percent
        number (confidence interval 95%)
    21.6 (9.8 to 38.2)
    22.7 (11.5 to 37.8)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AE were collected from initiation of study treatment until 100 days after discontinuation of dosing or until starting a new anti-neoplastic therapy (whichever occured first)
    Adverse event reporting additional description
    All serious AE are reported. Non serious adverse event are reported if events were assessed with causal relationship to study treatment only.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NCI-CTCAE
    Dictionary version
    5
    Reporting groups
    Reporting group title
    Arm A - SBRT + nivolumab and ipilimumab
    Reporting group description
    		 Stereotactic body radiotherapy of 8 Gray (Gy) x 3 on one soft tissue or bone metastasis and immunotherapy

    Reporting group title
    Arm B - nivolumab and ipilimumab
    Reporting group description
    		 Immunotherapy

    Serious adverse events
    		 Arm A - SBRT + nivolumab and ipilimumab Arm B - nivolumab and ipilimumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 37 (56.76%)
    29 / 44 (65.91%)
         number of deaths (all causes)
    30
    37
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Thromboembolic event
    Additional description: Includes terms: Pulmonary embolism and Deep vein thrombosis
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
    Additional description: includes terms: pain in groin, back pain
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Phimosis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Stroke
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischemia cerebrovascular
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhea
         subjects affected / exposed
    1 / 37 (2.70%)
    3 / 44 (6.82%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    6 / 37 (16.22%)
    3 / 44 (6.82%)
         occurrences causally related to treatment / all
    8 / 9
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraperitoneal hemmorrhage
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis
         subjects affected / exposed
    2 / 37 (5.41%)
    3 / 44 (6.82%)
         occurrences causally related to treatment / all
    3 / 3
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Urticaria acuta
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erythema multiforme
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephritis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 44 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hematuria
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 44 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adrenal insufficiency
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 44 (4.55%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophysitis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Myositis
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Covid-19
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 37 (2.70%)
    6 / 44 (13.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection - unknown focus
         subjects affected / exposed
    2 / 37 (5.41%)
    7 / 44 (15.91%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 44 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycemia
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 44 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic Ketoacidosis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         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 - SBRT + nivolumab and ipilimumab Arm B - nivolumab and ipilimumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    37 / 37 (100.00%)
    44 / 44 (100.00%)
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    10 / 37 (27.03%)
    8 / 44 (18.18%)
         occurrences all number
    15
    8
    Alanine aminotransferase increased
         subjects affected / exposed
    8 / 37 (21.62%)
    6 / 44 (13.64%)
         occurrences all number
    10
    8
    Nervous system disorders
    Myasthenia gravis
         subjects affected / exposed
    2 / 37 (5.41%)
    9 / 44 (20.45%)
         occurrences all number
    2
    11
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 37 (5.41%)
    8 / 44 (18.18%)
         occurrences all number
    2
    15
    Eye disorders
    Dry Eyes
         subjects affected / exposed
    7 / 37 (18.92%)
    2 / 44 (4.55%)
         occurrences all number
    7
    2
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    9 / 37 (24.32%)
    6 / 44 (13.64%)
         occurrences all number
    15
    10
    Diarrhea
         subjects affected / exposed
    9 / 37 (24.32%)
    7 / 44 (15.91%)
         occurrences all number
    13
    13
    Nausea
         subjects affected / exposed
    3 / 37 (8.11%)
    5 / 44 (11.36%)
         occurrences all number
    3
    8
    Vomiting
         subjects affected / exposed
    0 / 37 (0.00%)
    5 / 44 (11.36%)
         occurrences all number
    0
    6
    Mucositis oral
         subjects affected / exposed
    6 / 37 (16.22%)
    6 / 44 (13.64%)
         occurrences all number
    6
    6
    Abdominal pain
         subjects affected / exposed
    4 / 37 (10.81%)
    2 / 44 (4.55%)
         occurrences all number
    4
    3
    Hepatobiliary disorders
    Hepatitis
         subjects affected / exposed
    3 / 37 (8.11%)
    3 / 44 (6.82%)
         occurrences all number
    3
    3
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    4 / 37 (10.81%)
    3 / 44 (6.82%)
         occurrences all number
    8
    3
    Dyspnea
         subjects affected / exposed
    5 / 37 (13.51%)
    5 / 44 (11.36%)
         occurrences all number
    8
    5
    Cough
         subjects affected / exposed
    5 / 37 (13.51%)
    5 / 44 (11.36%)
         occurrences all number
    8
    5
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    13 / 37 (35.14%)
    19 / 44 (43.18%)
         occurrences all number
    18
    30
    Rash maculo-papular
         subjects affected / exposed
    11 / 37 (29.73%)
    18 / 44 (40.91%)
         occurrences all number
    25
    25
    Dry skin
         subjects affected / exposed
    8 / 37 (21.62%)
    15 / 44 (34.09%)
         occurrences all number
    9
    17
    Endocrine disorders
    Hypothroidism
         subjects affected / exposed
    5 / 37 (13.51%)
    11 / 44 (25.00%)
         occurrences all number
    5
    14
    Hyperthroidism
         subjects affected / exposed
    3 / 37 (8.11%)
    10 / 44 (22.73%)
         occurrences all number
    3
    10
    Adrenal Insufficiency
         subjects affected / exposed
    2 / 37 (5.41%)
    5 / 44 (11.36%)
         occurrences all number
    3
    7
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    7 / 37 (18.92%)
    8 / 44 (18.18%)
         occurrences all number
    11
    12
    Athralgia
         subjects affected / exposed
    5 / 37 (13.51%)
    7 / 44 (15.91%)
         occurrences all number
    6
    7
    Myositis
         subjects affected / exposed
    1 / 37 (2.70%)
    4 / 44 (9.09%)
         occurrences all number
    2
    4
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    4 / 37 (10.81%)
    9 / 44 (20.45%)
         occurrences all number
    4
    13
    Hyperglycemia
         subjects affected / exposed
    4 / 37 (10.81%)
    4 / 44 (9.09%)
         occurrences all number
    6
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Jan 2020
    - Scanning modality for tumor assessments amended from CT-scan to 18F–NaF PET/CT scan. - Clarification of timing of SBRT - Added cortisol, creatine kinase, troponin to safety laboratory assessments
    01 Dec 2021
    - removal of inclusion criteria that requires presence of at least two soft tissue metastases, hence patients with both predominant bone metastases AND/OR soft tissue metastases were subsequnetly allowed to be recruited to the trial - primary endpoint has been changed to co-primary endpoints where clinical beneficial rate (CBR) has been replaced by: - Objective response rate (complete and partial response, ORR) per RECIST 1.1 (for patients with measurable disease) - Prostate-specific antigen (PSA) response-rate of ≥ 50% decline from baseline at any time from treatment start (confirmed after ≥ 4 weeks, all patients with measurable and non-measurable disease) - added the secondary endpoints of radiographic progression-free survival (rPFS), PSA progression-free survival (PSA-PFS) and transferred the initial primary endpoint (CBR) to the secondary - added PSA assessment q4w (instead of simultanously with scans) - translational analyses extended with single-cell sequencing on T cells. - adjustment of study time lines

    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.
    None reported
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