VISION: Study of 177Lu-PSMA-617 In Metastatic Castrate-Resistant Prostate Cancer

• Sponsor: Endocyte (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT03511664
• Collaborator: (none)
• Enrollment: 831
• Locations: 88
• Arms: 2
• Anticipated Duration (Months): 66.1
• Patients Per Site: 9.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The primary objective of this study was to compare the two alternate primary endpoints of radiographic progression-free survival (rPFS) and overall survival (OS) in patients with progressive prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) who received 177Lu-PSMA-617 in addition to best supportive/best standard of care (BSC/BSoC) versus patients treated with best supportive/best standard of care alone.

Condition or Disease	Intervention/Treatment	Phase
Prostate Cancer	Drug: 177Lu-PSMA-617; Other: Best supportive/best standard of care	Phase 3

Detailed Description

The study for each participant consisted of a Screening period, a Treatment period and a Follow-up period

Screening and randomization During the screening period of up to 28 days before starting randomized treatment, each participant was assessed for PSMA positivity by gallium (68Ga) gozetotide imaging PET/scan per the pre-defined read rules, by the Sponsor's central reader. Only patients with PSMA-positive metastatic PC and meeting all other inclusion/exclusion criteria were randomized in a 2:1 ratio to receive either 177Lu-PSMA-617 plus BSC/BSoC or BSC/BSoC only. Randomized patients were stratified on the following factors: LDH level (=< or

260 UI/L), presence of liver metastases (Yes or No), eastern cooperative oncology group (ECOG) score (0-1 or 2) and inclusion of NAAD in the BSC/BSoC (at time of randomization (Yes or No)). Protocol-specified BSC/BSoC for each patients was initiated by the investigating physician prior to patient randomization and maintained throughout the study. On-study changes to BSC/BSoC were allowed and at the discretion of the investigating physician..

Randomized treatment "Randomized treatment" in this study referred to 177Lu-PSMA-617+BSC/BSoC (investigational arm) and BSC/BSoC only (control arm). Patients randomized to the investigational arm began 177Lu-PSMA-617 administration within 28 days after randomization (C1D1). These patients received 7.4 gigabequerel (GBq) (+/- 10%) 177Lu-PSMA-617 once every 6 weeks (+/- 1 week) for a maximum of 6 cycles while receiving BSC/BSoC. After Cycle 4 treatment and prior to Cycle 5 treatment, the investigator assessed the following criteria to determine whether:

• The patient showed evidence of response (i.e. radiological, PSA, clinical benefit)

• The patient had signs of residual disease on CT with contrast/MRI or bone scan

• The patient had shown good tolerance to the 177Lu-PSMA-617 treatment.

If the patient met all of the criteria above and agreed to continue with additional treatment of 177Lu-PSMA-617, the Investigator could administer 2 additional cycles. A maximum of 6 cycles of 177Lu-PSMA-617 as allowed.

If the patient did not meet any of the criteria or did not agree to additional 177Lu-PSMA-617 treatment, then no additional doses of 177Lu-PSMA-617 were administered after Cycle 4. After the last cycle of 177Lu-PSMA-617, patients continued to be treated with BSC/BSoC as long as the investigator felt they were clinically benefiting (regardless of radiographic progressive disease based on Investigator's assessment per PCWG3 criteria) or until they required a treatment regimen not allowed on this study.

For both treatment arms, the cycle duration for Cycle 1-6 was 6 weeks and for Cycle 7 and beyond, was 12 weeks. From Cycle 7 onwards, all patients from both treatment arms only received BSC/BSoC.

End of treatment The EOT visit was scheduled approximately 30 days after the last dose of 177Lu-PSMA-617 or the date of the BSC/BSoC EOT decision (whichever occurred later), but before the initiation of subsequent anti-cancer treatment, outside of what was allowed on study

Long-term follow-up Patients who consented to be followed for long-term status updates, entered the long-term follow-up period after the EOT visit. The long-term follow-up included the collection of radiographic images (if a patient discontinued for reasons other than radiographic progression), OS, information about new treatments along with the patient's response to these treatments, AE assessment, and results of hematology and chemistry testing. During the follow-up, patients are contacted every 3 months (+/-1 month) via phone, email, or letter until the end of long-term the follow-up period (24 months after the first patient enters long-term follow-up) or until 508 deaths had occurred.

Study Design

• Study Type: Interventional
• Actual Enrollment: 831 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: The study population included patients with progressive PSMA-positive mCRPC who received at least one novel androgen axis drug [NAAD] (such as enzalutamide or abiraterone) and were previously treated with 1 to 2 taxane containing regimens. Patients treated with only 1 prior taxane regimen were eligible if the patient was unwilling or the patient's physician deemed the patient unsuitable to receive a second regimen.The study population included patients with progressive PSMA-positive mCRPC who received at least one novel androgen axis drug [NAAD] (such as enzalutamide or abiraterone) and were previously treated with 1 to 2 taxane containing regimens. Patients treated with only 1 prior taxane regimen were eligible if the patient was unwilling or the patient's physician deemed the patient unsuitable to receive a second regimen.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: VISION: An International, Prospective, Open Label, Multicenter, Randomized Phase 3 Study of 177Lu-PSMA-617 in the Treatment of Patients With Progressive PSMA-positive Metastatic Castration-resistant Prostate Cancer (mCRPC)
• Actual Study Start Date: May 29, 2018
• Actual Primary Completion Date: Jan 27, 2021
• Anticipated Study Completion Date: Nov 30, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 177Lu-PSMA-617 plus best supportive/best standard of care (BS/BSOC) Patients randomized to receive the investigational product received 7.4 GBq (+/- 10%) 177Lu-PSMA-617 intravenously every 6 weeks (+/- 1 week) for a maximum of 6 cycles. Best supportive/best standard of care (BS/BSOC) might be used	Drug: 177Lu-PSMA-617; Administered intravenously once every 6 weeks (1 cycle) for a maximum of 6 cycles. After 4 cycles, patients were assessed for (1) evidence of response, (2) residual disease, and (3) tolerance to 177Lu-PSMA-617. If all 3 assessments were met the patient might received an additional 2 cycles of 177Lu-PSMA-617.; Other: Best supportive/best standard of care; Best supportive/best standard of care as defined by the local investigator
Other: Best supportive/best standard of care (BS/BSOC) alone Patients randomized to this arm received best supportive/best standard of care (BS/BSOC) as determined by the investigator	Other: Best supportive/best standard of care; Best supportive/best standard of care as defined by the local investigator

Outcome Measures

Primary Outcome Measures

1. Radiographic Progression-free Survival (rPFS) [From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)]

   Radiographic progression-free survival (rPFS) was defined as the time (in months) from the date of randomization to the date of radiographic disease progression based on the central review assessment per the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria or death due to any cause. Patients who were alive without radiographic progression at the analysis data cut-off were censored for rPFS at the time of their last evaluable radiographic assessment. Date of censoring for rPFS: 1) The censoring date was the date when the last evaluable radiographic assessment (CT/MRI/bone scan) determined a lack of progression; 2) If there were no evaluable assessments, censoring occurred at the date of randomization; 3) Patients who had 2 or more consecutive missed tumor assessments immediately prior to PD or death were censored at the date of the last evaluable tumor assessment prior to those missing tumor assessments.

2. Overall Survival (OS) [From date of randomization until date of death from any cause, assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)]

   Overall Survival (OS) was defined as the time (in months) from the date of randomization to the date of death due to any cause. If the patient was not known to have died, then OS was censored. The censoring date was date of the last study visit, or contact, until the cut-off date. The cut-off date was not used for last contact date, unless the patient was seen or contacted on that date.

Secondary Outcome Measures

1. Number of Participants With Treatment Emergent Adverse Events [From randomization till 30 days safety follow-up, assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)]

   The distribution of adverse events (AE) was done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs) and Serious Adverse Event (TESAEs), through the monitoring of relevant clinical and laboratory safety parameters.

2. Overall Response Rate (ORR) [From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)]

   Overall Response Rate (ORR) was defined as the proportion of participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR). ORR was based on RECIST 1.1 response for patients with measurable disease at baseline per central review assessment.

3. Disease Control Rate (DCR) [From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)]

   Disease control rate (DCR) was defined as the proportion of participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) or Stable Disease (SD) according to RECIST v1.1 per central review assessment.

4. Duration of Response (DOR) [From first documented evidence of CR or PR (the response prior to confirmation) until time of documented disease progression or death due to any cause, whichever comes first, assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)]

   Duration of Response (DOR) was defined as the duration between the date of first documented Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) and the date of first documented radiographic progression or death due to any cause as per central review assessment.

5. Time to First Symptomatic Skeletal Event (SSE) [From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)]

   Time to first Symptomatic Skeletal Event (SSE) was defined as the time (in months) from the date of randomization to the date of the SSE or death from any cause. The SSE date was the date of first new symptomatic pathological bone fracture, spinal cord compression, tumor-related orthopedic surgical intervention, requirement for radiation therapy to relieve bone pain, or death due to any cause, whichever occurred first. SSE data for this endpoint were collected up through EOT visit. The censoring date was date of the last study visit (on or before the EOT visit).

6. Progression-free Survival (PFS) [From date of randomization until date of progression or date of death from any cause, whichever come first, assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)]

   Progression-free survival (PFS) was defined as the time (in months) from the date of randomization to the date of first evidence of radiographic, clinical or PSA progression or death due to any cause, whichever occurred first.

7. Best Percentage Change From Baseline in Prostate-specific Antigen (PSA) Level [From date of randomization till 30 days safety fup, assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)]

   Best percentage change from baseline in PSA level was defined as the maximum percent decrease at any time post-baseline, including only patients with a baseline value and at least one non-missing post-baseline value (scheduled and unscheduled).

8. Percentage of Participants Achieving Prostate-specific Antigen (PSA) Response [From date of randomization till 30 days safety fup, assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)]

   PSA response was defined as the proportion of patients who had a >= 50% decrease in PSA from baseline confirmed by a PSA measurement >= 4 weeks later.

9. Prostate-specific Antigen 80 (PSA80) Response [From date of randomization till 30 days safety fup, assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)]

   PSA80 response was defined as the proportion of participants who had a >= 80% decrease in PSA from baseline confirmed by a PSA measurement >= 4 weeks later.

10. Duration of PSA Response [From date of first documented PSA response till 30 days safety fup, assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)]

    Duration of PSA response was defined as the duration between the date of first document PSA response (i.e. >= 50% decrease in PSA from Baseline) and the earliest date of PSA progression, where date of PSA progression was defined as: 1) Where a decline from baseline was documented, date that a >= 25% increase in PSA and an absolute increase of 2 ng/mL or more from the nadir was documented and confirmed by a second consecutive value obtained at least 3 weeks later. Rises in PSA within the first 12 weeks of the date of first dose of randomized treatment were ignored; 2) Where no decline from baseline was documented, PSA progression was defined as a >= 25% increase from the baseline value along with an increase in absolute value of 2 ng/mL or more after 12 weeks from the date of first dose of randomized treatment (without confirmation) as specified in the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) guidelines.

11. Best Percentage Change From Baseline in Alkaline Phosphatase (ALP) Level [From date of randomization till 30 days safety fup, assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)]

    Best percentage change from baseline in alkaline phosphatase (ALP) level was defined as the maximum percent decrease at any time post-baseline, including only patients with a baseline value and at least one non-missing post-baseline value (scheduled and unscheduled).

12. Best Percentage Change From Baseline in Lactate Dehydrogenase (LDH) Level [From date of randomization till 30 days safety fup, assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)]

    Best percentage change from baseline in lactate dehydrogenase (LDH) level was defined as the maximum percent decrease at any time post-baseline, including only patients with a baseline value and at least one non-missing post-baseline value (scheduled and unscheduled).

13. Time to Worsening in BPI-SF Pain Intensity Scale [From date of randomization until date of End of Treatment (EoT), assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)]

    Time to worsening in BPI-SF pain intensity scale was defined as the time from randomization to the first occurring of an increase of worsening threshold (>=30% of baseline or >=2-point increase) at any time up through EOT visit compared to baseline, clinical disease progression, or death.

14. Time to Improvement After Worsening in BPI-SF Pain Intensity Scale [From date of randomization until date of End of Treatment (EoT), assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)]

    Time to improvement after worsening in BPI-SF pain intensity scale was defined as the time from worsening of Pain Intensity score to a Pain Intensity score <= baseline.

15. Time to Worsening in BPI-SF Pain Interference Scale [From date of randomization until date of End of Treatment (EoT), assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)]

    Time to worsening in BPI-SF pain interference scale was defined as the time from randomization to the first occurring of 1) an increase of worsening threshold (>=30% of baseline or >=2-point increase) at any time up through EOT visit compared to baseline, 2) clinical disease progression, or 3) death.

16. Time to Improvement After Worsening in BPI-SF Pain Interference Scale [From date of randomization until date of End of Treatment (EoT), assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)]

    Time to improvement after worsening in BPI-SF pain interference scale was defined as the time from worsening of Pain Interference score to a Pain Interference score <= baseline.

17. Time to Worsening in BPI-SF Worst Pain Intensity Scale (Time to Disease Related Pain) [From date of randomization until date of End of Treatment (EoT), assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)]

    Time to worsening in BPI-SF worst pain intensity scale (time to disease related pain) was defined as the time from randomization to the first occurring of worsening exceeding the threshold threshold (>=30% of baseline or >=2 point increase) at any time up through EOT visit compared to baseline, clinical disease progression, or death.

18. Change From Baseline in BPI-SF (Brief-Pain Inventory - Short Form) Pain Intensity Scale [Baseline (BL), Cycle 2 to Cycle 13 (Week 1 Day 1), End of Treatment (EoT) (cycle duration for Cycle 1-6 = 6 weeks and for Cycle 7 and beyond = 12 weeks)]

    The BPI-SF is a generic pain assessment tool used in research and practice for pain assessment in musculoskeletal conditions. The higher the BPI-SF score, the worse the pain. The BPI-SF consists of 4 questions regarding pain intensity (worst pain intensity, least pain intensity, average pain intensity and pain right now), 2 questions on the use of analgesics, and 7 questions on how the level pain has interfered with the subject's life (General Activity, Mood, Walking Ability, Normal Work, Relations with other people, Sleep, Enjoyment of Life). Intensity items consist of an 11-response rating scale scored from 0 ("No Pain") to 10 ("Pain As Bad As You Can Imagine"). BPI-SF Pain intensity is the mean of non-missing items of the 4 individual scales, if there are 3 or more items not missing; otherwise this scale is set to missing.

19. Change From Baseline in BPI-SF (Brief-Pain Inventory - Short Form) Pain Interference Scale [Baseline (BL), Cycle 2 to Cycle 13 (Week 1 Day 1), End of Treatment (EoT) (cycle duration for Cycle 1-6 = 6 weeks and for Cycle 7 and beyond = 12 weeks)]

    "The BPI-SF is a generic pain assessment tool used in research and practice for pain assessment in musculoskeletal conditions. The higher the BPI-SF score, the worse the pain. The BPI-SF consists of 4 questions regarding pain intensity (worst pain intensity, least pain intensity, average pain intensity and pain right now), 2 questions on the use of analgesics, and 7 questions on how the level pain has interfered with the subject's life (General Activity, Mood, Walking Ability, Normal Work, Relations with other people, Sleep, Enjoyment of Life). Interference items consist of scores from 0 ("Does Not Interfere") to 10 ("Completely Interferes"). BPI-SF Interference scale is the mean of non-missing items of the 7 items on pain interference, if there are 4 or more items not missing; otherwise this scale is set to missing."

20. Time to Worsening in FACT-P Total Score [From date of randomization until date of End of Treatment (EoT), assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)]

    Time to worsening was defined as the time from randomization to the first occurring of a >=10 point decrease in FACT-P total score compared to baseline, clinical disease progression, or death.

21. Change From Baseline in FACT-P (Functional Assessment of Cancer Therapy - Prostate) Total Score [Baseline (BL), Cycle 2 to Cycle 13 (Week 1 Day 1), End of Treatment (EoT) (cycle duration for Cycle 1-6 = 6 weeks and for Cycle 7 and beyond = 12 weeks)]

    The FACT-P total score (range 0-156) consist of five subscales (Physical (0-28), Functional (0-28), Social (0-28), and Emotional Well-being (0-24)) and a functional well-being and prostate cancer subscale (range 0-48). Higher scores indicate higher degree of functioning and better quality of life.

22. Time to Worsening in EQ-5D-5L Utility Score [From date of randomization until date of End of Treatment (EoT), assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)]

    Time to worsening for utility score was defined as time from randomization to the first occurrence of worsening in utility score relative to baseline (no change or any decrease), clinical disease progression, or death.

23. Change From Baseline in the European Quality of Life (EuroQol) - 5 Domain 5 Level Scale (EQ-5D-5L) Utility Score [Baseline (BL), Cycle 2 to Cycle 13 (Week 1 Day 1), End of Treatment (EoT) (cycle duration for Cycle 1-6 = 6 weeks and for Cycle 7 and beyond = 12 weeks)]

    The EQ-5D-5L is a standardized participant completed questionnaire that measures health-related quality of life. EQ-5D-5L consists of two components: a health state profile and an optional visual analogue scale (VAS). EQ-5D health state profile is comprised of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: 1= no problems, 2= slight problems, 3=moderate problems, 4= severe problems, and 5= extreme problems. Higher scores indicated greater levels of problems across each of the five dimensions. A utility score was obtained by using a weighted combination of the levels of the five dimension-scales. The weights were based on value sets which were country-specific for the U.K. Utility scores ranges from the lowest possible score for a living patient of -0.594 (when all responses are '5') to 1 (when all responses are '1').If a patient died, he was assigned a score of 0 on the date of death.

24. Change From Baseline in the European Quality of Life (EuroQol) - 5 Domain 5 Level Scale (EQ-5D-5L) EQ-VAS [Baseline (BL), Cycle 2 to Cycle 13 (Week 1 Day 1), End of Treatment (EoT) (cycle duration for Cycle 1-6 = 6 weeks and for Cycle 7 and beyond = 12 weeks)]

    The EQ-5D-5L is a standardized participant completed questionnaire that measures health-related quality of life. EQ-5D-5L consists of two components: a health state profile and an optional visual analogue scale (VAS). EQ VAS records the patient's self-rated health on a vertical visual analogue 0-100 scale, where the endpoints are labelled 'The best health you can imagine' and 'The worst health you can imagine'. The higher the EQ-VAS score, the better the QoL.

25. Number of Participants Hospitalized as In-patient [From date of randomization till 30 days safety fup, assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)]

    The number of hospitalizations (yes/no) (admitted as in-patient) was collected as part of the hospital admission for health economic evaluations.

26. Duration of Time in Hospital Following 177Lu-PSMA-617 Administration [From date of randomization till 30 days safety fup, assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)]

    The duration of time in hospital following 177Lu-PSMA-617 administration (hours) was the time span of patient discharged as captured on the 177Lu-PSMA-617 administration Case Report Form (CRF).

27. Concomitant Drug Use for Health Economics Analysis [From date of randomization till 30 days safety fup, assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)]

    The list of concomitant drugs as captured on the concomitant medication/therapy CRF page to include in each category was pre-specified and flagged prior to the pre planned analyses. (1) Bisphosphonates (including but not limited to zoledronic acid, alendronic acid, etc.), denosumab, and other bone targeted therapies), (2) Corticosteroids for systemic use (3), Antifungals for systemic use (i.e. ketoconazole), (4) ESA (erythropoietin stimulating agents, i.e. epoetin alfa), (5) Granulocyte macrophage colony-stimulating factor (GM-CSF), (6) Novel androgen axis drugs (NAADs; i.e. enzalutamide, abiraterone, apalutamide), (7) Antiemetics and (8) Opioid analgesics use for cancer-related pain.

28. Therapeutic Interventions for Health Economics Analysis [From date of randomization till 30 days safety fup, assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)]

    The list of therapeutic interventions was pre-specified and flagged prior to the pre planned analyses as captured on: 1) the concurrent radiotherapy CRF page to include local external beam radiotherapy (inclusive of palliative external radiation), 2) on the concomitant medication/therapy CRF page to include blood transfusion (full blood or derivates).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Patients must have the ability to understand and sign an approved informed consent form (ICF).

2. Patients must have the ability to understand and comply with all protocol requirements.

3. Patients must be >= 18 years of age.

4. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

5. Patients must have a life expectancy >6 months.

6. Patients must have histological, pathological, and/or cytological confirmation of prostate cancer.

7. Patients must be 68Ga-PSMA-11 Positron Emission Tomography (PET)/Computed Tomography (CT) scan positive, and eligible as determined by the sponsor's central reader.

8. Patients must have a castrate level of serum/plasma testosterone (<50 ng/dL or <1.7 nmol/L).

9. Patients must have received at least one NAAD (such as enzalutamide and/or abiraterone).

10. Patients must have been previously treated with at least 1, but no more than 2 previous taxane regimens. A taxane regimen is defined as a minimum exposure of 2 cycles of a taxane. If a patient has received only 1 taxane regimen, the patient is eligible if: a. The patient's physician deems him unsuitable to receive a second taxane regimen (e.g. frailty assessed by geriatric or health status evaluation, intolerance, etc.).

11. Patients must have progressive mCRPC. Documented progressive mCRPC will be based on at least 1 of the following criteria:

12. Serum/plasma PSA progression defined as 2 consecutive increases in PSA over a previous reference value measured at least 1 week prior. The minimal start value is 2.0 ng/mL.

13. Soft-tissue progression defined as an increase >= 20% in the sum of the diameter (SOD) (short axis for nodal lesions and long axis for non-nodal lesions) of all target lesions based on the smallest SOD since treatment started or the appearance of one or more new lesions.

14. Progression of bone disease: evaluable disease or new bone lesions(s) by bone scan (2+2 PCWG3 criteria, Scher et al 2016).

15. Patients must have >= 1 metastatic lesion that is present on baseline CT, MRI, or bone scan imaging obtained =< 28 days prior to beginning study therapy.

16. Patients must have recovered to =< Grade 2 from all clinically significant toxicities related to prior therapies (i.e. prior chemotherapy, radiation, immunotherapy, etc.).

17. Patients must have adequate organ function:

1. Bone marrow reserve:

• White blood cell (WBC) count >= 2.5 x 10^{9/L (2.5 x 10}9/L is equivalent to 2.5 x 10^{3/μL and 2.5 x K/μL and 2.5 x 10}3/cumm and 2500/μL) OR absolute neutrophil count (ANC) >= 1.5 x 10^{9/L (1.5 x 10}9/L is equivalent to 1.5 x 10^{3/μL and 1.5 x K/μL and 1.5 x 10}3/cumm and 1500/μL)

• Platelets >= 100 x 10^{9/L (100 x 10}9/L is equivalent to 100 x 10^{3/μL and 100 x K/μL and 100 x 10}3/cumm and 100,000/μL)

• Hemoglobin >= 9 g/dL (9 g/dL is equivalent to 90 g/L and 5.59 mmol/L) b. Hepatic:

• Total bilirubin =< 1.5 x the institutional upper limit of normal (ULN). For patients with known Gilbert's Syndrome =< 3 x ULN is permitted

• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) =< 3.0 x ULN

OR =< 5.0 x ULN for patients with liver metastases c. Renal:

• Serum/plasma creatinine =< 1.5 x ULN or creatinine clearance >= 50 mL/min

1. Albumin >3.0 g/dL (3.0 g/dL is equivalent to 30 g/L) [Inclusion #16 has been removed]

2. HIV-infected patients who are healthy and have a low risk of AIDS-related outcomes are included in this trial.

3. For patients who have partners of childbearing potential: Partner and/or patient must use a method of birth control with adequate barrier protection, deemed acceptable by the principle investigator during the study and for 6 months after last study drug administration.

4. The best standard of care/ best supportive care options planned for this patient:

5. Are allowed by the protocol

6. Have been agreed to by the treating investigator and patient

7. Allow for the management of the patient without 177Lu-PSMA-617

Exclusion Criteria:

1. Previous treatment with any of the following within 6 months of randomization: Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223, hemi-body irradiation. Previous PSMA-targeted radioligand therapy is not allowed.

2. Any systemic anti-cancer therapy (e.g. chemotherapy, immunotherapy or biological therapy [including monoclonal antibodies]) within 28 days prior to day of randomization.

3. Any investigational agents within 28 days prior to day of randomization.

4. Known hypersensitivity to the components of the study therapy or its analogs.

5. Other concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, or investigational therapy.

6. Transfusion for the sole purpose of making a subject eligible for study inclusion.

7. Patients with a history of Central Nervous System (CNS) metastases must have received therapy (surgery, radiotherapy, gamma knife) and be neurologically stable, asymptomatic, and not receiving corticosteroids for the purposes of maintaining neurologic integrity. Patients with epidural disease, canal disease and prior cord involvement are eligible if those areas have been treated, are stable, and not neurologically impaired. For patients with parenchymal CNS metastasis (or a history of CNS metastasis), baseline and subsequent radiological imaging must include evaluation of the brain (MRI preferred or CT with contrast).

8. A superscan as seen in the baseline bone scan.

9. Symptomatic cord compression, or clinical or radiologic findings indicative of impending cord compression.

10. Concurrent serious (as determined by the Principal Investigator) medical conditions, including, but not limited to, New York Heart Association class III or IV congestive heart failure, history of congenital prolonged QT syndrome, uncontrolled infection, known active hepatitis B or C, or other significant co-morbid conditions that in the opinion of the investigator would impair study participation or cooperation.

11. Diagnosed with other malignancies that are expected to alter life expectancy or may interfere with disease assessment. However, patients with a prior history of malignancy that has been adequately treated and who have been disease free for more than 3 years are eligible, as are patients with adequately treated non-melanoma skin cancer, superficial bladder cancer.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	HonorHealth Institute	Scottsdale	Arizona	United States	85258
2	University of Arizona Cancer Center	Tucson	Arizona	United States	85719-1454
3	VA Greater Los Angeles Healthcare System	Los Angeles	California	United States	90073
4	UCLA	Los Angeles	California	United States	90095-7370
5	Stanford University	Palo Alto	California	United States	94304
6	UCSF Medical Center at Mission Bay	San Francisco	California	United States	94158
7	University of Colorado Denver	Aurora	Colorado	United States	80045
8	Yale Cancer Center, Clinical Trials Office	New Haven	Connecticut	United States	06519
9	Washington DC VA Medical Center, Nuclear Medicine Service	Washington	District of Columbia	United States	20422
10	H. Lee Moffitt Cancer Center & Research Institute	Tampa	Florida	United States	33612
11	Northwestern University	Chicago	Illinois	United States	60611
12	Parkview Cancer Institute	Fort Wayne	Indiana	United States	46845
13	IU Melvin and Bren Simon Cancer Center	Indianapolis	Indiana	United States	46202
14	University of Iowa Hospitals and Clinics Cancer Center Research	Iowa City	Iowa	United States	52242
15	Iowa VA Medical Center	Iowa City	Iowa	United States	52246
16	Norton Cancer Institute	Louisville	Kentucky	United States	40207
17	Tulane Cancer Center	New Orleans	Louisiana	United States	70112
18	University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center	Baltimore	Maryland	United States	21201
19	Chesapeake Urology Research Associates	Towson	Maryland	United States	21204
20	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
21	The Lank Center for Genitourinary Oncology	Boston	Massachusetts	United States	02215
22	VA Ann Arbor Healthcare System	Ann Arbor	Michigan	United States	48105
23	University of Michigan Medical Center, Division of Nuclear Medicine	Ann Arbor	Michigan	United States	48109
24	Karmanos Cancer Center	Detroit	Michigan	United States	48201
25	Mayo Clinic	Rochester	Minnesota	United States	55905
26	John Cochran St. Louis Veterans Medical Center	Saint Louis	Missouri	United States	63106
27	Washington University School of Medicine	Saint Louis	Missouri	United States	63110-1093
28	St. Louis University Hospital	Saint Louis	Missouri	United States	63110
29	GU Research Network/ Urology Cancer Center	Omaha	Nebraska	United States	68130
30	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada	United States	89148
31	Regional Cancer Care Associates	East Brunswick	New Jersey	United States	08816
32	New Mexico Oncology & Hematology Consultants	Albuquerque	New Mexico	United States	87109
33	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
34	New York Presbyterian Hospital/Weill Cornell Medical Center	New York	New York	United States	10065
35	Duke University School of Medicine, Duke Cancer Institute	Durham	North Carolina	United States	27710
36	Precision Cancer Research/ Dayton Physicians Network	Kettering	Ohio	United States	45409
37	Oregon Health and Science University Nuclear Medicine Department	Portland	Oregon	United States	97239-3098
38	Gettysburg Cancer Center	Gettysburg	Pennsylvania	United States	17325
39	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania	United States	19107
40	Carolina Urologic Research Center	Myrtle Beach	South Carolina	United States	29572
41	Dallas VA Research Organization	Dallas	Texas	United States	75216
42	UT Southwestern Medical Center	Dallas	Texas	United States	75390
43	Excel Diagnostics & Nuclear Oncology Center	Houston	Texas	United States	77042
44	UVA Cancer Care	Charlottesville	Virginia	United States	22903
45	Swedish Cancer Institute	Seattle	Washington	United States	98104
46	Cliniques Universitaires Saint Luc	Brussels		Belgium
47	Institut Jules Bordet	Brussels		Belgium
48	University Hospitals Leuven, Campus Gasthuisberg, Department of Nuclear Medicine	Leuven		Belgium
49	BC Cancer - Vancouver	Vancouver	British Columbia	Canada	V5Z 4E6
50	London Health Sciences Centre, Division of Nuclear Medicine	London	Ontario	Canada	N6A 5W9
51	The Ottawa Hospital Cancer Centre	Ottawa	Ontario	Canada	K1H8L6
52	Odette Cancer Centre	Toronto	Ontario	Canada	M4N 3M5
53	CHUM - Hotel Dieu Hospital	Montréal	Quebec	Canada	H2X OA9
54	Jewish General Hospital	Montréal	Quebec	Canada	H3T 1E2
55	Hotel Dieu Hospital in Quebec	Québec	Quebec	Canada	G1R2J6
56	Aalborg University Hospital Klinik Kirurgi-Kræft Clinical Research Unit Department of Oncology	Aalborg		Denmark
57	Aarhus Universitetshospital	Aarhus		Denmark
58	Rigshospitalet - University Hospital Copenhagen, Department of Oncology	Copenhagen		Denmark
59	Bergonie Institute	Bordeaux		France
60	Center Jean Perrin	Clermont-Ferrand		France
61	Leon Berard Center	Lyon		France
62	Centre d'Investigations et de Recherche Clinique en Oncologie Hospital SAINT-LOUIS	Paris		France
63	Tenon Hospital	Paris		France
64	Institute Claudius Regaud, Toulouse Cancer Research Center	Toulouse		France
65	Gustave Roussy Oncology Institute	Villejuif		France
66	University Hospital Essen, Clinic for Nuclear Medicine	Essen		Germany
67	University Hospital Muenster, Department of Nuclear Medicine	Muenster		Germany
68	Hospital rechts der Isar, Department of Nuclear Medicine	Munich		Germany
69	Rostock University Medical Center, Clinic and Polyclinic for Nuclear Medicine	Rostock		Germany
70	The Netherlands Cancer Institute	Amsterdam		Netherlands
71	St. Antonius Hospital	Nieuwegein		Netherlands
72	Radboud University Medical Center	Nijmegen		Netherlands
73	Universitair Medisch Centrum Utrecht	Utrecht		Netherlands
74	VA Caribbean Healthcare System	San Juan		Puerto Rico
75	Sahlgrenska University Hospital, Department of Oncology	Gothenburg		Sweden
76	Skane University Hospital	Lund		Sweden
77	Karolinska University Hospital	Stockholm		Sweden
78	Norrlands Universitetssjukhus	Umeå		Sweden
79	Uppsala University Hospital, Department of Oncology	Uppsala		Sweden
80	Bristol Hematology & Oncology Center	Bristol		United Kingdom
81	Beatson West of Scotland Cancer Center	Glasgow		United Kingdom
82	Royal Surrey County Hospital NHS Foundation Trust	Guildford		United Kingdom
83	Guy's Hospital	London		United Kingdom
84	Royal Free London NHS Foundation Trust Royal Free Hospital	London		United Kingdom
85	St Bartholomew's Hospital, West Smithfield	London		United Kingdom
86	University College London Hospitals NHS Foundation Trust	London		United Kingdom
87	University Hospital Southampton NHS Foundation Trust	Southampton		United Kingdom
88	Institute of Cancer Research	Sutton		United Kingdom

Sponsors and Collaborators

• Endocyte

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol - Apr 26, 2021
• Statistical Analysis Plan - Jan 18, 2021

More Information

Publications

• Iravani A, Violet J, Azad A, Hofman MS. Lutetium-177 prostate-specific membrane antigen (PSMA) theranostics: practical nuances and intricacies. Prostate Cancer Prostatic Dis. 2020 Mar;23(1):38-52. doi: 10.1038/s41391-019-0174-x. Epub 2019 Oct 8. Review.

• Responsible Party: Endocyte
• ClinicalTrials.gov Identifier: NCT03511664
• Other Study ID Numbers: PSMA-617-01; 2018-000459-41; CAAA617A12301
• First Posted: Apr 30, 2018
• Last Update Posted: Aug 11, 2022
• Last Verified: Aug 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Endocyte: Metastatic castration-resistant prostate cancer; mCRPC; 177Lu-PSMA-617; PSMA-617; PSMA-11; radioligand therapy
• Additional relevant MeSH terms: Prostatic Neoplasms; 177Lu-PSMA-617

Study Results

Participant Flow

Recruitment Details	The study was conducted in 86 sites across 9 countries. Belgium (3); Canada (7); Denmark (3); France (6); Netherlands (4); Sweden (5); UK (9); US (45); Germany (4, for the sub-study only)

Arm/Group Title	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC)	Best Supportive/Best Standard of Care (BS/BSOC) Alone
Arm/Group Description	Patients randomized to receive the investigational product received 7.4 GBq (+/- 10%) 177Lu-PSMA-617 intravenously every 6 weeks (+/- 1 week) for a maximum of 6 cycles. Best supportive/best standard of care (BS/BSOC) might be used	Patients randomized to this arm received best supportive/best standard of care (BS/BSOC) as determined by the investigator
Period Title: Overall Study
STARTED	551	280
FAS Safety Analysis Set	529	205
Progression-Free Survival (PFS) Full Analysis Set (PFS-FAS)	385	196
Response Evaluable Analysis Set	319	120
COMPLETED	329	167
NOT COMPLETED	222	113

Baseline Characteristics

Arm/Group Title	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC)	Best Supportive/Best Standard of Care (BS/BSOC) Alone	Total
Arm/Group Description	Patients randomized to receive the investigational product received 7.4 GBq (+/- 10%) 177Lu-PSMA-617 intravenously every 6 weeks (+/- 1 week) for a maximum of 6 cycles. Best supportive/best standard of care (BS/BSOC) might be used	Patients randomized to this arm received best supportive/best standard of care (BS/BSOC) as determined by the investigator	Total of all reporting groups
Overall Participants	551	280	831
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	69.7 (7.4)	70.5 (7.8)	70.0 (7.6)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	551 100%	280 100%	831 100%
Race/Ethnicity, Customized (Number) [Number]
White	486 88.2%	235 83.9%	721 86.8%
Black or African American	34 6.2%	21 7.5%	55 6.6%
Asian	9 1.6%	11 3.9%	20 2.4%
Other	2 0.4%	0 0%	2 0.2%
Missing	20 3.6%	13 4.6%	33 4%

Outcome Measures

1. Primary Outcome

Title	Radiographic Progression-free Survival (rPFS)
Description	Radiographic progression-free survival (rPFS) was defined as the time (in months) from the date of randomization to the date of radiographic disease progression based on the central review assessment per the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria or death due to any cause. Patients who were alive without radiographic progression at the analysis data cut-off were censored for rPFS at the time of their last evaluable radiographic assessment. Date of censoring for rPFS: 1) The censoring date was the date when the last evaluable radiographic assessment (CT/MRI/bone scan) determined a lack of progression; 2) If there were no evaluable assessments, censoring occurred at the date of randomization; 3) Patients who had 2 or more consecutive missed tumor assessments immediately prior to PD or death were censored at the date of the last evaluable tumor assessment prior to those missing tumor assessments.
Time Frame	From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)

Outcome Measure Data

Analysis Population Description

PFS Full Analysis Set (PFS-FAS)

Arm/Group Title	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC)	Best Supportive/Best Standard of Care (BS/BSOC) Alone
Arm/Group Description	Patients randomized to receive the investigational product received 7.4 GBq (+/- 10%) 177Lu-PSMA-617 intravenously every 6 weeks (+/- 1 week) for a maximum of 6 cycles. Best supportive/best standard of care (BS/BSOC) might be used	Patients randomized to this arm received best supportive/best standard of care (BS/BSOC) as determined by the investigator
Measure Participants	385	196
Median (99.2% Confidence Interval) [Months]	8.7	3.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC), Best Supportive/Best Standard of Care (BS/BSOC) Alone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	Log Rank
	Comments	one-sided stratified log-rank test
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.40
	Confidence Interval	(2-Sided) 99.2%; 0.29 to 0.57
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Overall Survival (OS)
Description	Overall Survival (OS) was defined as the time (in months) from the date of randomization to the date of death due to any cause. If the patient was not known to have died, then OS was censored. The censoring date was date of the last study visit, or contact, until the cut-off date. The cut-off date was not used for last contact date, unless the patient was seen or contacted on that date.
Time Frame	From date of randomization until date of death from any cause, assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS)

Arm/Group Title	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC)	Best Supportive/Best Standard of Care (BS/BSOC) Alone
Arm/Group Description	Patients randomized to receive the investigational product received 7.4 GBq (+/- 10%) 177Lu-PSMA-617 intravenously every 6 weeks (+/- 1 week) for a maximum of 6 cycles. Best supportive/best standard of care (BS/BSOC) might be used	Patients randomized to this arm received best supportive/best standard of care (BS/BSOC) as determined by the investigator
Measure Participants	551	280
Median (95% Confidence Interval) [Months]	15.3	11.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC), Best Supportive/Best Standard of Care (BS/BSOC) Alone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Log Rank
	Comments	one-sided stratified log-rank test
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.62
	Confidence Interval	(2-Sided) 95%; 0.52 to 0.74
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Number of Participants With Treatment Emergent Adverse Events
Description	The distribution of adverse events (AE) was done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs) and Serious Adverse Event (TESAEs), through the monitoring of relevant clinical and laboratory safety parameters.
Time Frame	From randomization till 30 days safety follow-up, assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)

Outcome Measure Data

Analysis Population Description

FAS Safety Analysis Set

Arm/Group Title	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC)	Best Supportive/Best Standard of Care (BS/BSOC) Alone
Arm/Group Description	Patients randomized to receive the investigational product received 7.4 GBq (+/- 10%) 177Lu-PSMA-617 intravenously every 6 weeks (+/- 1 week) for a maximum of 6 cycles. Best supportive/best standard of care (BS/BSOC) might be used	Patients randomized to this arm received best supportive/best standard of care (BS/BSOC) as determined by the investigator
Measure Participants	529	205
Adverse Events (AEs)	501 90.9%	150 53.6%
Serious Adverse Events (SAEs)	192 34.8%	57 20.4%

4. Secondary Outcome

Title	Overall Response Rate (ORR)
Description	Overall Response Rate (ORR) was defined as the proportion of participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR). ORR was based on RECIST 1.1 response for patients with measurable disease at baseline per central review assessment.
Time Frame	From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)

Outcome Measure Data

Analysis Population Description

Response Evaluable Analysis Set

Arm/Group Title	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC)	Best Supportive/Best Standard of Care (BS/BSOC) Alone
Arm/Group Description	Patients randomized to receive the investigational product received 7.4 GBq (+/- 10%) 177Lu-PSMA-617 intravenously every 6 weeks (+/- 1 week) for a maximum of 6 cycles. Best supportive/best standard of care (BS/BSOC) might be used	Patients randomized to this arm received best supportive/best standard of care (BS/BSOC) as determined by the investigator
Measure Participants	319	120
Count of Participants [Participants]	95 17.2%	2 0.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC), Best Supportive/Best Standard of Care (BS/BSOC) Alone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	Chi-squared
	Comments	Two-sided Wald's Chi-square test (stratified)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	24.99
	Confidence Interval	(2-Sided) 95%; 6.05 to 103.24
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Disease Control Rate (DCR)
Description	Disease control rate (DCR) was defined as the proportion of participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) or Stable Disease (SD) according to RECIST v1.1 per central review assessment.
Time Frame	From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)

Outcome Measure Data

Analysis Population Description

Response Evaluable Analysis Set

Arm/Group Title	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC)	Best Supportive/Best Standard of Care (BS/BSOC) Alone
Arm/Group Description	Patients randomized to receive the investigational product received 7.4 GBq (+/- 10%) 177Lu-PSMA-617 intravenously every 6 weeks (+/- 1 week) for a maximum of 6 cycles. Best supportive/best standard of care (BS/BSOC) might be used	Patients randomized to this arm received best supportive/best standard of care (BS/BSOC) as determined by the investigator
Measure Participants	319	120
Count of Participants [Participants]	284 51.5%	80 28.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC), Best Supportive/Best Standard of Care (BS/BSOC) Alone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	Chi-squared
	Comments	Two-sided Wald's Chi-square test (stratified)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	5.79
	Confidence Interval	(2-Sided) 95%; 3.18 to 10.55
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Duration of Response (DOR)
Description	Duration of Response (DOR) was defined as the duration between the date of first documented Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) and the date of first documented radiographic progression or death due to any cause as per central review assessment.
Time Frame	From first documented evidence of CR or PR (the response prior to confirmation) until time of documented disease progression or death due to any cause, whichever comes first, assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)

Outcome Measure Data

Analysis Population Description

PFS Full Analysis Set (PFS-FAS). Only participants for whom BOR was CR or PR and evaluable Duration of Response events (Progression or Death) included in the analysis.

Arm/Group Title	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC)	Best Supportive/Best Standard of Care (BS/BSOC) Alone
Arm/Group Description	Patients randomized to receive the investigational product received 7.4 GBq (+/- 10%) 177Lu-PSMA-617 intravenously every 6 weeks (+/- 1 week) for a maximum of 6 cycles. Best supportive/best standard of care (BS/BSOC) might be used	Patients randomized to this arm received best supportive/best standard of care (BS/BSOC) as determined by the investigator
Measure Participants	95	2
Median (95% Confidence Interval) [Months]	9.8	10.6

7. Secondary Outcome

Title	Time to First Symptomatic Skeletal Event (SSE)
Description	Time to first Symptomatic Skeletal Event (SSE) was defined as the time (in months) from the date of randomization to the date of the SSE or death from any cause. The SSE date was the date of first new symptomatic pathological bone fracture, spinal cord compression, tumor-related orthopedic surgical intervention, requirement for radiation therapy to relieve bone pain, or death due to any cause, whichever occurred first. SSE data for this endpoint were collected up through EOT visit. The censoring date was date of the last study visit (on or before the EOT visit).
Time Frame	From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)

Outcome Measure Data

Analysis Population Description

PFS Full Analysis Set (PFS-FAS)

Arm/Group Title	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC)	Best Supportive/Best Standard of Care (BS/BSOC) Alone
Arm/Group Description	Patients randomized to receive the investigational product received 7.4 GBq (+/- 10%) 177Lu-PSMA-617 intravenously every 6 weeks (+/- 1 week) for a maximum of 6 cycles. Best supportive/best standard of care (BS/BSOC) might be used	Patients randomized to this arm received best supportive/best standard of care (BS/BSOC) as determined by the investigator
Measure Participants	385	196
Median (95% Confidence Interval) [Months]	11.5	6.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC), Best Supportive/Best Standard of Care (BS/BSOC) Alone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	Log Rank
	Comments	Two-sided stratified log-rank test
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.50
	Confidence Interval	(2-Sided) 95%; 0.40 to 0.62
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	Progression-free survival (PFS) was defined as the time (in months) from the date of randomization to the date of first evidence of radiographic, clinical or PSA progression or death due to any cause, whichever occurred first.
Time Frame	From date of randomization until date of progression or date of death from any cause, whichever come first, assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)

Outcome Measure Data

Analysis Population Description

PFS Full Analysis Set (PFS-FAS)

Arm/Group Title	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC)	Best Supportive/Best Standard of Care (BS/BSOC) Alone
Arm/Group Description	Patients randomized to receive the investigational product received 7.4 GBq (+/- 10%) 177Lu-PSMA-617 intravenously every 6 weeks (+/- 1 week) for a maximum of 6 cycles. Best supportive/best standard of care (BS/BSOC) might be used	Patients randomized to this arm received best supportive/best standard of care (BS/BSOC) as determined by the investigator
Measure Participants	385	196
Median (95% Confidence Interval) [Months]	5.9	2.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC), Best Supportive/Best Standard of Care (BS/BSOC) Alone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	Log Rank
	Comments	Two-sided stratified log-rank test
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.30
	Confidence Interval	(2-Sided) 95%; 0.24 to 0.38
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Best Percentage Change From Baseline in Prostate-specific Antigen (PSA) Level
Description	Best percentage change from baseline in PSA level was defined as the maximum percent decrease at any time post-baseline, including only patients with a baseline value and at least one non-missing post-baseline value (scheduled and unscheduled).
Time Frame	From date of randomization till 30 days safety fup, assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)

Outcome Measure Data

Analysis Population Description

PFS Full Analysis Set (PFS-FAS). Only participants with an evaluable post-baseline and baseline samples were included in the analysis.

Arm/Group Title	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC)	Best Supportive/Best Standard of Care (BS/BSOC) Alone
Arm/Group Description	Patients randomized to receive the investigational product received 7.4 GBq (+/- 10%) 177Lu-PSMA-617 intravenously every 6 weeks (+/- 1 week) for a maximum of 6 cycles. Best supportive/best standard of care (BS/BSOC) might be used	Patients randomized to this arm received best supportive/best standard of care (BS/BSOC) as determined by the investigator
Measure Participants	333	138
Mean (Standard Deviation) [Percentage change]	-20.9 (142.6)	50.4 (118.4)

10. Secondary Outcome

Title	Percentage of Participants Achieving Prostate-specific Antigen (PSA) Response
Description	PSA response was defined as the proportion of patients who had a >= 50% decrease in PSA from baseline confirmed by a PSA measurement >= 4 weeks later.
Time Frame	From date of randomization till 30 days safety fup, assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)

Outcome Measure Data

Analysis Population Description

PFS Full Analysis Set (PFS-FAS)

Arm/Group Title	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC)	Best Supportive/Best Standard of Care (BS/BSOC) Alone
Arm/Group Description	Patients randomized to receive the investigational product received 7.4 GBq (+/- 10%) 177Lu-PSMA-617 intravenously every 6 weeks (+/- 1 week) for a maximum of 6 cycles. Best supportive/best standard of care (BS/BSOC) might be used	Patients randomized to this arm received best supportive/best standard of care (BS/BSOC) as determined by the investigator
Measure Participants	385	196
Number (95% Confidence Interval) [Percentage of participants]	46.0 8.3%	7.1 2.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC), Best Supportive/Best Standard of Care (BS/BSOC) Alone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	Chi-squared
	Comments	Two-sided Wald's Chi-square test (stratified)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	11.19
	Confidence Interval	(2-Sided) 95%; 6.3 to 20.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Prostate-specific Antigen 80 (PSA80) Response
Description	PSA80 response was defined as the proportion of participants who had a >= 80% decrease in PSA from baseline confirmed by a PSA measurement >= 4 weeks later.
Time Frame	From date of randomization till 30 days safety fup, assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)

Outcome Measure Data

Analysis Population Description

PFS Full Analysis Set (PFS-FAS)

Arm/Group Title	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC)	Best Supportive/Best Standard of Care (BS/BSOC) Alone
Arm/Group Description	Patients randomized to receive the investigational product received 7.4 GBq (+/- 10%) 177Lu-PSMA-617 intravenously every 6 weeks (+/- 1 week) for a maximum of 6 cycles. Best supportive/best standard of care (BS/BSOC) might be used	Patients randomized to this arm received best supportive/best standard of care (BS/BSOC) as determined by the investigator
Measure Participants	385	196
Number (95% Confidence Interval) [Percentage of participants]	33.0 6%	2.0 0.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC), Best Supportive/Best Standard of Care (BS/BSOC) Alone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	Chi-squared
	Comments	Two-sided Wald's Chi-square test (stratified)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	23.6
	Confidence Interval	(2-Sided) 95%; 8.6 to 65.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Duration of PSA Response
Description	Duration of PSA response was defined as the duration between the date of first document PSA response (i.e. >= 50% decrease in PSA from Baseline) and the earliest date of PSA progression, where date of PSA progression was defined as: 1) Where a decline from baseline was documented, date that a >= 25% increase in PSA and an absolute increase of 2 ng/mL or more from the nadir was documented and confirmed by a second consecutive value obtained at least 3 weeks later. Rises in PSA within the first 12 weeks of the date of first dose of randomized treatment were ignored; 2) Where no decline from baseline was documented, PSA progression was defined as a >= 25% increase from the baseline value along with an increase in absolute value of 2 ng/mL or more after 12 weeks from the date of first dose of randomized treatment (without confirmation) as specified in the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) guidelines.
Time Frame	From date of first documented PSA response till 30 days safety fup, assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)

Outcome Measure Data

Analysis Population Description

PFS Full Analysis Set (PFS-FAS). Only participants with PSA progression were included in the analysis.

Arm/Group Title	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC)	Best Supportive/Best Standard of Care (BS/BSOC) Alone
Arm/Group Description	Patients randomized to receive the investigational product received 7.4 GBq (+/- 10%) 177Lu-PSMA-617 intravenously every 6 weeks (+/- 1 week) for a maximum of 6 cycles. Best supportive/best standard of care (BS/BSOC) might be used	Patients randomized to this arm received best supportive/best standard of care (BS/BSOC) as determined by the investigator
Measure Participants	177	14
Median (95% Confidence Interval) [Months]	8.9	4.4

13. Secondary Outcome

Title	Best Percentage Change From Baseline in Alkaline Phosphatase (ALP) Level
Description	Best percentage change from baseline in alkaline phosphatase (ALP) level was defined as the maximum percent decrease at any time post-baseline, including only patients with a baseline value and at least one non-missing post-baseline value (scheduled and unscheduled).
Time Frame	From date of randomization till 30 days safety fup, assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)

Outcome Measure Data

Analysis Population Description

PFS Full Analysis Set (PFS-FAS). Only participants with an evaluable post-baseline and baseline samples were included in the analysis.

Arm/Group Title	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC)	Best Supportive/Best Standard of Care (BS/BSOC) Alone
Arm/Group Description	Patients randomized to receive the investigational product received 7.4 GBq (+/- 10%) 177Lu-PSMA-617 intravenously every 6 weeks (+/- 1 week) for a maximum of 6 cycles. Best supportive/best standard of care (BS/BSOC) might be used	Patients randomized to this arm received best supportive/best standard of care (BS/BSOC) as determined by the investigator
Measure Participants	372	172
Mean (Standard Deviation) [Percentage change]	-14.4 (46.3)	0.6 (33.8)

14. Secondary Outcome

Title	Best Percentage Change From Baseline in Lactate Dehydrogenase (LDH) Level
Description	Best percentage change from baseline in lactate dehydrogenase (LDH) level was defined as the maximum percent decrease at any time post-baseline, including only patients with a baseline value and at least one non-missing post-baseline value (scheduled and unscheduled).
Time Frame	From date of randomization till 30 days safety fup, assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)

Outcome Measure Data

Analysis Population Description

PFS Full Analysis Set (PFS-FAS). Only participants with an evaluable post-baseline and baseline samples were included in the analysis.

Arm/Group Title	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC)	Best Supportive/Best Standard of Care (BS/BSOC) Alone
Arm/Group Description	Patients randomized to receive the investigational product received 7.4 GBq (+/- 10%) 177Lu-PSMA-617 intravenously every 6 weeks (+/- 1 week) for a maximum of 6 cycles. Best supportive/best standard of care (BS/BSOC) might be used	Patients randomized to this arm received best supportive/best standard of care (BS/BSOC) as determined by the investigator
Measure Participants	371	168
Mean (Standard Deviation) [Percentage change]	-23.1 (23.8)	-9.2 (28.2)

15. Secondary Outcome

Title	Time to Worsening in BPI-SF Pain Intensity Scale
Description	Time to worsening in BPI-SF pain intensity scale was defined as the time from randomization to the first occurring of an increase of worsening threshold (>=30% of baseline or >=2-point increase) at any time up through EOT visit compared to baseline, clinical disease progression, or death.
Time Frame	From date of randomization until date of End of Treatment (EoT), assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)

Outcome Measure Data

Analysis Population Description

PFS-Full analysis set. Only participants with an evaluable events were included in the analysis.

Arm/Group Title	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC)	Best Supportive/Best Standard of Care (BS/BSOC) Alone
Arm/Group Description	Patients randomized to receive the investigational product received 7.4 GBq (+/- 10%) 177Lu-PSMA-617 intravenously every 6 weeks (+/- 1 week) for a maximum of 6 cycles. Best supportive/best standard of care (BS/BSOC) might be used	Patients randomized to this arm received best supportive/best standard of care (BS/BSOC) as determined by the investigator
Measure Participants	328	166
Median (95% Confidence Interval) [Months]	5.9	2.2

16. Secondary Outcome

Title	Time to Improvement After Worsening in BPI-SF Pain Intensity Scale
Description	Time to improvement after worsening in BPI-SF pain intensity scale was defined as the time from worsening of Pain Intensity score to a Pain Intensity score <= baseline.
Time Frame	From date of randomization until date of End of Treatment (EoT), assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)

Outcome Measure Data

Analysis Population Description

PFS-Full analysis set. Only participants with an evaluable events were included in the analysis.

Arm/Group Title	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC)	Best Supportive/Best Standard of Care (BS/BSOC) Alone
Arm/Group Description	Patients randomized to receive the investigational product received 7.4 GBq (+/- 10%) 177Lu-PSMA-617 intravenously every 6 weeks (+/- 1 week) for a maximum of 6 cycles. Best supportive/best standard of care (BS/BSOC) might be used	Patients randomized to this arm received best supportive/best standard of care (BS/BSOC) as determined by the investigator
Measure Participants	144	76
Median (95% Confidence Interval) [Months]	2.8	4.2

17. Secondary Outcome

Title	Time to Worsening in BPI-SF Pain Interference Scale
Description	Time to worsening in BPI-SF pain interference scale was defined as the time from randomization to the first occurring of 1) an increase of worsening threshold (>=30% of baseline or >=2-point increase) at any time up through EOT visit compared to baseline, 2) clinical disease progression, or 3) death.
Time Frame	From date of randomization until date of End of Treatment (EoT), assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)

Outcome Measure Data

Analysis Population Description

PFS-Full analysis set. Only participants with an evaluable events were included in the analysis.

Arm/Group Title	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC)	Best Supportive/Best Standard of Care (BS/BSOC) Alone
Arm/Group Description	Patients randomized to receive the investigational product received 7.4 GBq (+/- 10%) 177Lu-PSMA-617 intravenously every 6 weeks (+/- 1 week) for a maximum of 6 cycles. Best supportive/best standard of care (BS/BSOC) might be used	Patients randomized to this arm received best supportive/best standard of care (BS/BSOC) as determined by the investigator
Measure Participants	330	166
Median (95% Confidence Interval) [Months]	5.0	2.3

18. Secondary Outcome

Title	Time to Improvement After Worsening in BPI-SF Pain Interference Scale
Description	Time to improvement after worsening in BPI-SF pain interference scale was defined as the time from worsening of Pain Interference score to a Pain Interference score <= baseline.
Time Frame	From date of randomization until date of End of Treatment (EoT), assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)

Outcome Measure Data

Analysis Population Description

PFS-Full analysis set. Only participants with an evaluable events were included in the analysis.

Arm/Group Title	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC)	Best Supportive/Best Standard of Care (BS/BSOC) Alone
Arm/Group Description	Patients randomized to receive the investigational product received 7.4 GBq (+/- 10%) 177Lu-PSMA-617 intravenously every 6 weeks (+/- 1 week) for a maximum of 6 cycles. Best supportive/best standard of care (BS/BSOC) might be used	Patients randomized to this arm received best supportive/best standard of care (BS/BSOC) as determined by the investigator
Measure Participants	176	72
Median (95% Confidence Interval) [Months]	3.0	2.8

19. Secondary Outcome

Title	Time to Worsening in BPI-SF Worst Pain Intensity Scale (Time to Disease Related Pain)
Description	Time to worsening in BPI-SF worst pain intensity scale (time to disease related pain) was defined as the time from randomization to the first occurring of worsening exceeding the threshold threshold (>=30% of baseline or >=2 point increase) at any time up through EOT visit compared to baseline, clinical disease progression, or death.
Time Frame	From date of randomization until date of End of Treatment (EoT), assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)

Outcome Measure Data

Analysis Population Description

PFS-Full analysis set. Only participants with an evaluable events were included in the analysis.

Arm/Group Title	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC)	Best Supportive/Best Standard of Care (BS/BSOC) Alone
Arm/Group Description	Patients randomized to receive the investigational product received 7.4 GBq (+/- 10%) 177Lu-PSMA-617 intravenously every 6 weeks (+/- 1 week) for a maximum of 6 cycles. Best supportive/best standard of care (BS/BSOC) might be used	Patients randomized to this arm received best supportive/best standard of care (BS/BSOC) as determined by the investigator
Measure Participants	332	169
Median (95% Confidence Interval) [Months]	5.0	2.0

20. Secondary Outcome

Title	Change From Baseline in BPI-SF (Brief-Pain Inventory - Short Form) Pain Intensity Scale
Description	The BPI-SF is a generic pain assessment tool used in research and practice for pain assessment in musculoskeletal conditions. The higher the BPI-SF score, the worse the pain. The BPI-SF consists of 4 questions regarding pain intensity (worst pain intensity, least pain intensity, average pain intensity and pain right now), 2 questions on the use of analgesics, and 7 questions on how the level pain has interfered with the subject's life (General Activity, Mood, Walking Ability, Normal Work, Relations with other people, Sleep, Enjoyment of Life). Intensity items consist of an 11-response rating scale scored from 0 ("No Pain") to 10 ("Pain As Bad As You Can Imagine"). BPI-SF Pain intensity is the mean of non-missing items of the 4 individual scales, if there are 3 or more items not missing; otherwise this scale is set to missing.
Time Frame	Baseline (BL), Cycle 2 to Cycle 13 (Week 1 Day 1), End of Treatment (EoT) (cycle duration for Cycle 1-6 = 6 weeks and for Cycle 7 and beyond = 12 weeks)

Outcome Measure Data

Analysis Population Description

PFS Full Analysis Set (PFS-FAS). Only participants with non-missing score both at Baseline and at post-baseline visits were included in the analysis.

Arm/Group Title	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC)	Best Supportive/Best Standard of Care (BS/BSOC) Alone
Arm/Group Description	Patients randomized to receive the investigational product received 7.4 GBq (+/- 10%) 177Lu-PSMA-617 intravenously every 6 weeks (+/- 1 week) for a maximum of 6 cycles. Best supportive/best standard of care (BS/BSOC) might be used	Patients randomized to this arm received best supportive/best standard of care (BS/BSOC) as determined by the investigator
Measure Participants	385	196
Cycle 2, Week 1, Day 1 change from BL	-0.59 (2.037)	0.21 (2.404)
Cycle 3, Week 1, Day 1 change from BL	-0.62 (1.924)	0.02 (2.033)
Cycle 4, Week 1, Day 1 change from BL	-0.42 (2.017)	0.26 (2.383)
Cycle 5, Week 1, Day 1 change from BL	-0.49 (1.957)	0.55 (3.144)
Cycle 6, Week 1, Day 1 change from BL	-0.41 (1.897)	0.10 (2.740)
Cycle 7, Week 1, Day 1 change from BL	-0.48 (2.011)	-0.32 (1.585)
Cycle 8, Week 1, Day 1 change from BL	-0.18 (1.759)	-1.10 (2.205)
Cycle 9, Week 1, Day 1 change from BL	-0.70 (2.157)	0.13 (1.780)
Cycle 10, Week 1, Day 1 change from BL	0.02 (1.513)	0.50 (1.768)
Cycle 11, Week 1, Day 1 change from BL	-0.40 (0.956)	0.75 (1.768)
Cycle 12, Week 1, Day 1 change from BL	-1.00 (0.354)
Cycle 13, Week 1, Day 1 change from BL	-0.75 (NA)
End of Treatment (EoT) change from BL	0.46 (2.415)	0.50 (2.405)

21. Secondary Outcome

Title	Change From Baseline in BPI-SF (Brief-Pain Inventory - Short Form) Pain Interference Scale
Description	"The BPI-SF is a generic pain assessment tool used in research and practice for pain assessment in musculoskeletal conditions. The higher the BPI-SF score, the worse the pain. The BPI-SF consists of 4 questions regarding pain intensity (worst pain intensity, least pain intensity, average pain intensity and pain right now), 2 questions on the use of analgesics, and 7 questions on how the level pain has interfered with the subject's life (General Activity, Mood, Walking Ability, Normal Work, Relations with other people, Sleep, Enjoyment of Life). Interference items consist of scores from 0 ("Does Not Interfere") to 10 ("Completely Interferes"). BPI-SF Interference scale is the mean of non-missing items of the 7 items on pain interference, if there are 4 or more items not missing; otherwise this scale is set to missing."
Time Frame	Baseline (BL), Cycle 2 to Cycle 13 (Week 1 Day 1), End of Treatment (EoT) (cycle duration for Cycle 1-6 = 6 weeks and for Cycle 7 and beyond = 12 weeks)

Outcome Measure Data

Analysis Population Description

PFS Full Analysis Set (PFS-FAS). Only participants with non-missing score both at Baseline and at post-baseline visits were included in the analysis.

Arm/Group Title	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC)	Best Supportive/Best Standard of Care (BS/BSOC) Alone
Arm/Group Description	Patients randomized to receive the investigational product received 7.4 GBq (+/- 10%) 177Lu-PSMA-617 intravenously every 6 weeks (+/- 1 week) for a maximum of 6 cycles. Best supportive/best standard of care (BS/BSOC) might be used	Patients randomized to this arm received best supportive/best standard of care (BS/BSOC) as determined by the investigator
Measure Participants	385	196
Cycle 2, Week 1, Day 1 change from BL	-0.40 (2.167)	0.58 (2.700)
Cycle 3, Week 1, Day 1 change from BL	-0.35 (2.348)	-0.15 (2.216)
Cycle 4, Week 1, Day 1 change from BL	-0.33 (2.249)	0.21 (2.762)
Cycle 5, Week 1, Day 1 change from BL	-0.32 (2.223)	0.52 (3.480)
Cycle 6, Week 1, Day 1 change from BL	-0.28 (2.166)	0.49 (3.354)
Cycle 7, Week 1, Day 1 change from BL	-0.22 (1.882)	0.06 (2.570)
Cycle 8, Week 1, Day 1 change from BL	0.18 (1.926)	-0.26 (1.291)
Cycle 9, Week 1, Day 1 change from BL	-0.15 (1.751)	0.12 (1.667)
Cycle 10, Week 1, Day 1 change from BL	0.62 (2.141)	1.50 (1.313)
Cycle 11, Week 1, Day 1 change from BL	-0.06 (1.334)	0.36 (4.748)
Cycle 12, Week 1, Day 1 change from BL	-0.89 (0.914)
Cycle 13, Week 1, Day 1 change from BL	-0.43 (NA)
End of Treatment (EoT) change from BL	0.73 (2.756)	0.29 (2.385)

22. Secondary Outcome

Title	Time to Worsening in FACT-P Total Score
Description	Time to worsening was defined as the time from randomization to the first occurring of a >=10 point decrease in FACT-P total score compared to baseline, clinical disease progression, or death.
Time Frame	From date of randomization until date of End of Treatment (EoT), assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)

Outcome Measure Data

Analysis Population Description

PFS-Full analysis set

Arm/Group Title	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC)	Best Supportive/Best Standard of Care (BS/BSOC) Alone
Arm/Group Description	Patients randomized to receive the investigational product received 7.4 GBq (+/- 10%) 177Lu-PSMA-617 intravenously every 6 weeks (+/- 1 week) for a maximum of 6 cycles. Best supportive/best standard of care (BS/BSOC) might be used	Patients randomized to this arm received best supportive/best standard of care (BS/BSOC) as determined by the investigator
Measure Participants	385	196
Median (95% Confidence Interval) [Months]	5.7	2.2

23. Secondary Outcome

Title	Change From Baseline in FACT-P (Functional Assessment of Cancer Therapy - Prostate) Total Score
Description	The FACT-P total score (range 0-156) consist of five subscales (Physical (0-28), Functional (0-28), Social (0-28), and Emotional Well-being (0-24)) and a functional well-being and prostate cancer subscale (range 0-48). Higher scores indicate higher degree of functioning and better quality of life.
Time Frame	Baseline (BL), Cycle 2 to Cycle 13 (Week 1 Day 1), End of Treatment (EoT) (cycle duration for Cycle 1-6 = 6 weeks and for Cycle 7 and beyond = 12 weeks)

Outcome Measure Data

Analysis Population Description

PFS Full Analysis Set (PFS-FAS). Only participants with non-missing score both at Baseline and at post-baseline visits were included in the analysis.

Arm/Group Title	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC)	Best Supportive/Best Standard of Care (BS/BSOC) Alone
Arm/Group Description	Patients randomized to receive the investigational product received 7.4 GBq (+/- 10%) 177Lu-PSMA-617 intravenously every 6 weeks (+/- 1 week) for a maximum of 6 cycles. Best supportive/best standard of care (BS/BSOC) might be used	Patients randomized to this arm received best supportive/best standard of care (BS/BSOC) as determined by the investigator
Measure Participants	385	196
Cycle 2, Week 1, Day 1 change from BL	3.6 (16.63)	-7.2 (17.85)
Cycle 3, Week 1, Day 1 change from BL	3.8 (17.48)	-2.6 (14.00)
Cycle 4, Week 1, Day 1 change from BL	5.4 (15.93)	-1.3 (18.40)
Cycle 5, Week 1, Day 1 change from BL	4.0 (16.24)	-5.9 (27.83)
Cycle 6, Week 1, Day 1 change from BL	4.1 (15.22)	-5.0 (26.87)
Cycle 7, Week 1, Day 1 change from BL	4.9 (16.47)	-2.9 (17.89)
Cycle 8, Week 1, Day 1 change from BL	3.8 (15.87)	-13.0 (32.76)
Cycle 9, Week 1, Day 1 change from BL	3.8 (14.22)	6.9 (5.92)
Cycle 10, Week 1, Day 1 change from BL	0.0 (18.27)	0.2 (14.14)
Cycle 11, Week 1, Day 1 change from BL	-0.8 (20.99)	8.2 (33.71)
Cycle 12, Week 1, Day 1 change from BL	10.3 (12.11)
Cycle 13, Week 1, Day 1 change from BL	30.0 (NA)
End of Treatment (EoT) change from BL	-9.4 (21.64)	-10.4 (18.59)

24. Secondary Outcome

Title	Time to Worsening in EQ-5D-5L Utility Score
Description	Time to worsening for utility score was defined as time from randomization to the first occurrence of worsening in utility score relative to baseline (no change or any decrease), clinical disease progression, or death.
Time Frame	From date of randomization until date of End of Treatment (EoT), assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)

Outcome Measure Data

Analysis Population Description

PFS-Full analysis set

Arm/Group Title	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC)	Best Supportive/Best Standard of Care (BS/BSOC) Alone
Arm/Group Description	Patients randomized to receive the investigational product received 7.4 GBq (+/- 10%) 177Lu-PSMA-617 intravenously every 6 weeks (+/- 1 week) for a maximum of 6 cycles. Best supportive/best standard of care (BS/BSOC) might be used	Patients randomized to this arm received best supportive/best standard of care (BS/BSOC) as determined by the investigator
Measure Participants	385	196
Median (95% Confidence Interval) [Months]	1.0	0.5

25. Secondary Outcome

Title	Change From Baseline in the European Quality of Life (EuroQol) - 5 Domain 5 Level Scale (EQ-5D-5L) Utility Score
Description	The EQ-5D-5L is a standardized participant completed questionnaire that measures health-related quality of life. EQ-5D-5L consists of two components: a health state profile and an optional visual analogue scale (VAS). EQ-5D health state profile is comprised of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: 1= no problems, 2= slight problems, 3=moderate problems, 4= severe problems, and 5= extreme problems. Higher scores indicated greater levels of problems across each of the five dimensions. A utility score was obtained by using a weighted combination of the levels of the five dimension-scales. The weights were based on value sets which were country-specific for the U.K. Utility scores ranges from the lowest possible score for a living patient of -0.594 (when all responses are '5') to 1 (when all responses are '1').If a patient died, he was assigned a score of 0 on the date of death.
Time Frame	Baseline (BL), Cycle 2 to Cycle 13 (Week 1 Day 1), End of Treatment (EoT) (cycle duration for Cycle 1-6 = 6 weeks and for Cycle 7 and beyond = 12 weeks)

Outcome Measure Data

Analysis Population Description

PFS Full Analysis Set (PFS-FAS). Only participants with non-missing score both at Baseline and at post-baseline visits were included in the analysis.

Arm/Group Title	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC)	Best Supportive/Best Standard of Care (BS/BSOC) Alone
Arm/Group Description	Patients randomized to receive the investigational product received 7.4 GBq (+/- 10%) 177Lu-PSMA-617 intravenously every 6 weeks (+/- 1 week) for a maximum of 6 cycles. Best supportive/best standard of care (BS/BSOC) might be used	Patients randomized to this arm received best supportive/best standard of care (BS/BSOC) as determined by the investigator
Measure Participants	385	196
Cycle 2, Week 1, Day 1 change from BL	0.0221 (0.17693)	-0.0897 (0.24973)
Cycle 3, Week 1, Day 1 change from BL	0.0297 (0.18817)	-0.0331 (0.14155)
Cycle 4, Week 1, Day 1 change from BL	0.0292 (0.17713)	-0.0818 (0.23752)
Cycle 5, Week 1, Day 1 change from BL	0.0398 (0.16827)	-0.0673 (0.28633)
Cycle 6, Week 1, Day 1 change from BL	0.0342 (0.17950)	-0.0110 (0.17842)
Cycle 7, Week 1, Day 1 change from BL	0.0252 (0.16127)	-0.0088 (0.09081)
Cycle 8, Week 1, Day 1 change from BL	0.0285 (0.18017)	-0.0296 (0.14964)
Cycle 9, Week 1, Day 1 change from BL	0.0100 (0.17447)	0.0087 (0.08167)
Cycle 10, Week 1, Day 1 change from BL	0.0134 (0.15764)	-0.0655 (0.09263)
Cycle 11, Week 1, Day 1 change from BL	0.0464 (0.16858)	0.0250 (0.19940)
Cycle 12, Week 1, Day 1 change from BL	0.1118 (0.13833)
Cycle 13, Week 1, Day 1 change from BL	0.0640 (NA)
End of Treatment (EoT) change from BL	-0.0939 (0.22698)	-0.0900 (0.21223)

26. Secondary Outcome

Title	Change From Baseline in the European Quality of Life (EuroQol) - 5 Domain 5 Level Scale (EQ-5D-5L) EQ-VAS
Description	The EQ-5D-5L is a standardized participant completed questionnaire that measures health-related quality of life. EQ-5D-5L consists of two components: a health state profile and an optional visual analogue scale (VAS). EQ VAS records the patient's self-rated health on a vertical visual analogue 0-100 scale, where the endpoints are labelled 'The best health you can imagine' and 'The worst health you can imagine'. The higher the EQ-VAS score, the better the QoL.
Time Frame	Baseline (BL), Cycle 2 to Cycle 13 (Week 1 Day 1), End of Treatment (EoT) (cycle duration for Cycle 1-6 = 6 weeks and for Cycle 7 and beyond = 12 weeks)

Outcome Measure Data

Analysis Population Description

PFS Full Analysis Set (PFS-FAS). Only participants with non-missing score both at Baseline and at post-baseline visits were included in the analysis.

Arm/Group Title	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC)	Best Supportive/Best Standard of Care (BS/BSOC) Alone
Arm/Group Description	Patients randomized to receive the investigational product received 7.4 GBq (+/- 10%) 177Lu-PSMA-617 intravenously every 6 weeks (+/- 1 week) for a maximum of 6 cycles. Best supportive/best standard of care (BS/BSOC) might be used	Patients randomized to this arm received best supportive/best standard of care (BS/BSOC) as determined by the investigator
Measure Participants	385	196
Cycle 2, Week 1, Day 1 change from BL	1.8 (19.98)	-7.2 (20.31)
Cycle 3, Week 1, Day 1 change from BL	1.4 (19.82)	-3.8 (21.50)
Cycle 4, Week 1, Day 1 change from BL	2.8 (19.18)	-1.7 (18.73)
Cycle 5, Week 1, Day 1 change from BL	4.0 (17.30)	-8.5 (28.88)
Cycle 6, Week 1, Day 1 change from BL	2.1 (19.61)	3.2 (19.43)
Cycle 7, Week 1, Day 1 change from BL	3.6 (20.64)	5.9 (12.79)
Cycle 8, Week 1, Day 1 change from BL	0.6 (17.18)	13.8 (16.60)
Cycle 9, Week 1, Day 1 change from BL	0.1 (19.68)	6.3 (20.82)
Cycle 10, Week 1, Day 1 change from BL	2.9 (13.97)	-8.0 (2.83)
Cycle 11, Week 1, Day 1 change from BL	5.8 (10.33)	-9.0 (28.28)
Cycle 12, Week 1, Day 1 change from BL	4.5 (13.03)
Cycle 13, Week 1, Day 1 change from BL	-5.0 (NA)
End of Treatment (EoT) change from BL	-8.9 (22.07)	-10.1 (21.49)

27. Secondary Outcome

Title	Number of Participants Hospitalized as In-patient
Description	The number of hospitalizations (yes/no) (admitted as in-patient) was collected as part of the hospital admission for health economic evaluations.
Time Frame	From date of randomization till 30 days safety fup, assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)

Outcome Measure Data

Analysis Population Description

PFS Full Analysis Set (PFS-FAS)

Arm/Group Title	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC)	Best Supportive/Best Standard of Care (BS/BSOC) Alone
Arm/Group Description	Patients randomized to receive the investigational product received 7.4 GBq (+/- 10%) 177Lu-PSMA-617 intravenously every 6 weeks (+/- 1 week) for a maximum of 6 cycles. Best supportive/best standard of care (BS/BSOC) might be used	Patients randomized to this arm received best supportive/best standard of care (BS/BSOC) as determined by the investigator
Measure Participants	385	196
Yes	157 28.5%	59 21.1%
No	228 41.4%	137 48.9%

28. Secondary Outcome

Title	Duration of Time in Hospital Following 177Lu-PSMA-617 Administration
Description	The duration of time in hospital following 177Lu-PSMA-617 administration (hours) was the time span of patient discharged as captured on the 177Lu-PSMA-617 administration Case Report Form (CRF).
Time Frame	From date of randomization till 30 days safety fup, assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)

Outcome Measure Data

Analysis Population Description

PFS Full Analysis Set (PFS-FAS)

Arm/Group Title	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC)	Best Supportive/Best Standard of Care (BS/BSOC) Alone
Arm/Group Description	Patients randomized to receive the investigational product received 7.4 GBq (+/- 10%) 177Lu-PSMA-617 intravenously every 6 weeks (+/- 1 week) for a maximum of 6 cycles. Best supportive/best standard of care (BS/BSOC) might be used	Patients randomized to this arm received best supportive/best standard of care (BS/BSOC) as determined by the investigator
Measure Participants	341	0
Mean (Standard Deviation) [Hours]	28.25 (46.578)

29. Secondary Outcome

Title	Concomitant Drug Use for Health Economics Analysis
Description	The list of concomitant drugs as captured on the concomitant medication/therapy CRF page to include in each category was pre-specified and flagged prior to the pre planned analyses. (1) Bisphosphonates (including but not limited to zoledronic acid, alendronic acid, etc.), denosumab, and other bone targeted therapies), (2) Corticosteroids for systemic use (3), Antifungals for systemic use (i.e. ketoconazole), (4) ESA (erythropoietin stimulating agents, i.e. epoetin alfa), (5) Granulocyte macrophage colony-stimulating factor (GM-CSF), (6) Novel androgen axis drugs (NAADs; i.e. enzalutamide, abiraterone, apalutamide), (7) Antiemetics and (8) Opioid analgesics use for cancer-related pain.
Time Frame	From date of randomization till 30 days safety fup, assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)

Outcome Measure Data

Analysis Population Description

PFS Full Analysis Set (PFS-FAS)

Arm/Group Title	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC)	Best Supportive/Best Standard of Care (BS/BSOC) Alone
Arm/Group Description	Patients randomized to receive the investigational product received 7.4 GBq (+/- 10%) 177Lu-PSMA-617 intravenously every 6 weeks (+/- 1 week) for a maximum of 6 cycles. Best supportive/best standard of care (BS/BSOC) might be used	Patients randomized to this arm received best supportive/best standard of care (BS/BSOC) as determined by the investigator
Measure Participants	385	196
Yes	169 30.7%	88 31.4%
No	216 39.2%	108 38.6%
Yes	246 44.6%	113 40.4%
No	139 25.2%	83 29.6%
Yes	1 0.2%	4 1.4%
No	384 69.7%	192 68.6%
Yes	8 1.5%	2 0.7%
No	377 68.4%	194 69.3%
Yes	7 1.3%	3 1.1%
No	378 68.6%	193 68.9%
Yes	188 34.1%	115 41.1%
No	197 35.8%	81 28.9%
Yes	232 42.1%	45 16.1%
No	153 27.8%	151 53.9%
Yes	199 36.1%	96 34.3%
No	186 33.8%	100 35.7%

30. Secondary Outcome

Title	Therapeutic Interventions for Health Economics Analysis
Description	The list of therapeutic interventions was pre-specified and flagged prior to the pre planned analyses as captured on: 1) the concurrent radiotherapy CRF page to include local external beam radiotherapy (inclusive of palliative external radiation), 2) on the concomitant medication/therapy CRF page to include blood transfusion (full blood or derivates).
Time Frame	From date of randomization till 30 days safety fup, assessed up to 43 months (Final OS analysis cut-off date = 27-Jan-2021)

Outcome Measure Data

Analysis Population Description

PFS Full Analysis Set (PFS-FAS)

Arm/Group Title	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC)	Best Supportive/Best Standard of Care (BS/BSOC) Alone
Arm/Group Description	Patients randomized to receive the investigational product received 7.4 GBq (+/- 10%) 177Lu-PSMA-617 intravenously every 6 weeks (+/- 1 week) for a maximum of 6 cycles. Best supportive/best standard of care (BS/BSOC) might be used	Patients randomized to this arm received best supportive/best standard of care (BS/BSOC) as determined by the investigator
Measure Participants	385	196
Yes	63 11.4%	37 13.2%
No	322 58.4%	159 56.8%
Yes	74 13.4%	13 4.6%
No	311 56.4%	183 65.4%

Adverse Events

Time Frame	From first dose of study treatment up to 30 days after last dose (maximum 27 months).
Adverse Event Reporting Description	Adverse Events (AEs) and All-cause mortality were collected in the FAS Safety Analysis Set
Arm/Group Title	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC)		Best Supportive/Best Standard of Care (BS/BSOC) Alone
Arm/Group Description	Patients randomized to receive the investigational product received 7.4 GBq (+/- 10%) 177Lu-PSMA-617 intravenously every 6 weeks (+/- 1 week) for a maximum of 6 cycles. Best supportive/best standard of care (BS/BSOC) might be used		Patients randomized to this arm received best supportive/best standard of care (BS/BSOC) as determined by the investigator
All Cause Mortality
	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC)		Best Supportive/Best Standard of Care (BS/BSOC) Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	66/529 (12.5%)		19/205 (9.3%)
Serious Adverse Events
	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC)		Best Supportive/Best Standard of Care (BS/BSOC) Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	192/529 (36.3%)		57/205 (27.8%)
Blood and lymphatic system disorders
Anaemia	15/529 (2.8%)		1/205 (0.5%)
Bone marrow failure	1/529 (0.2%)		0/205 (0%)
Febrile neutropenia	2/529 (0.4%)		0/205 (0%)
Leukopenia	2/529 (0.4%)		0/205 (0%)
Neutropenia	1/529 (0.2%)		0/205 (0%)
Pancytopenia	6/529 (1.1%)		0/205 (0%)
Thrombocytopenia	3/529 (0.6%)		0/205 (0%)
Cardiac disorders
Arrhythmia	1/529 (0.2%)		0/205 (0%)
Atrial fibrillation	1/529 (0.2%)		0/205 (0%)
Cardiac failure	1/529 (0.2%)		0/205 (0%)
Cardiac failure congestive	2/529 (0.4%)		0/205 (0%)
Cardio-respiratory arrest	0/529 (0%)		1/205 (0.5%)
Cardiomyopathy	1/529 (0.2%)		0/205 (0%)
Myocardial infarction	1/529 (0.2%)		0/205 (0%)
Supraventricular tachycardia	0/529 (0%)		1/205 (0.5%)
Ventricular tachycardia	2/529 (0.4%)		0/205 (0%)
Congenital, familial and genetic disorders
Vascular malformation	1/529 (0.2%)		0/205 (0%)
Ear and labyrinth disorders
Vertigo	1/529 (0.2%)		0/205 (0%)
Endocrine disorders
Adrenal insufficiency	1/529 (0.2%)		0/205 (0%)
Inappropriate antidiuretic hormone secretion	0/529 (0%)		1/205 (0.5%)
Eye disorders
Vision blurred	1/529 (0.2%)		0/205 (0%)
Gastrointestinal disorders
Abdominal pain	4/529 (0.8%)		1/205 (0.5%)
Ascites	1/529 (0.2%)		0/205 (0%)
Constipation	5/529 (0.9%)		1/205 (0.5%)
Diarrhoea	0/529 (0%)		1/205 (0.5%)
Duodenal ulcer	1/529 (0.2%)		0/205 (0%)
Dysphagia	1/529 (0.2%)		1/205 (0.5%)
Gastric haemorrhage	1/529 (0.2%)		0/205 (0%)
Gastrointestinal haemorrhage	0/529 (0%)		1/205 (0.5%)
Gastrooesophageal reflux disease	1/529 (0.2%)		0/205 (0%)
Haematemesis	1/529 (0.2%)		0/205 (0%)
Intestinal perforation	1/529 (0.2%)		0/205 (0%)
Intestinal pseudo-obstruction	1/529 (0.2%)		0/205 (0%)
Large intestinal obstruction	1/529 (0.2%)		0/205 (0%)
Lower gastrointestinal haemorrhage	1/529 (0.2%)		1/205 (0.5%)
Nausea	3/529 (0.6%)		1/205 (0.5%)
Rectal haemorrhage	1/529 (0.2%)		0/205 (0%)
Small intestinal obstruction	1/529 (0.2%)		1/205 (0.5%)
Stomatitis	1/529 (0.2%)		0/205 (0%)
Upper gastrointestinal haemorrhage	1/529 (0.2%)		0/205 (0%)
Volvulus	0/529 (0%)		1/205 (0.5%)
Vomiting	5/529 (0.9%)		1/205 (0.5%)
General disorders
Asthenia	0/529 (0%)		1/205 (0.5%)
Disease progression	2/529 (0.4%)		1/205 (0.5%)
Euthanasia	1/529 (0.2%)		0/205 (0%)
Fatigue	2/529 (0.4%)		0/205 (0%)
General physical health deterioration	0/529 (0%)		1/205 (0.5%)
Generalised oedema	1/529 (0.2%)		0/205 (0%)
Influenza like illness	0/529 (0%)		1/205 (0.5%)
Malaise	1/529 (0.2%)		0/205 (0%)
Multiple organ dysfunction syndrome	1/529 (0.2%)		0/205 (0%)
Oedema	0/529 (0%)		1/205 (0.5%)
Oedema peripheral	1/529 (0.2%)		0/205 (0%)
Pain	5/529 (0.9%)		1/205 (0.5%)
Pyrexia	7/529 (1.3%)		0/205 (0%)
Systemic inflammatory response syndrome	1/529 (0.2%)		0/205 (0%)
Hepatobiliary disorders
Acute hepatic failure	1/529 (0.2%)		0/205 (0%)
Bile duct stenosis	1/529 (0.2%)		0/205 (0%)
Cholecystitis	1/529 (0.2%)		0/205 (0%)
Cholestasis	1/529 (0.2%)		0/205 (0%)
Hepatic failure	1/529 (0.2%)		0/205 (0%)
Hepatic lesion	1/529 (0.2%)		0/205 (0%)
Hepatocellular injury	0/529 (0%)		2/205 (1%)
Infections and infestations
Appendicitis	2/529 (0.4%)		0/205 (0%)
Bacterial sepsis	1/529 (0.2%)		0/205 (0%)
Bronchitis	1/529 (0.2%)		0/205 (0%)
COVID-19	1/529 (0.2%)		0/205 (0%)
Diverticulitis	1/529 (0.2%)		0/205 (0%)
Enterococcal bacteraemia	1/529 (0.2%)		0/205 (0%)
Enterocolitis infectious	1/529 (0.2%)		0/205 (0%)
Escherichia sepsis	1/529 (0.2%)		0/205 (0%)
Extradural abscess	1/529 (0.2%)		0/205 (0%)
Fungaemia	1/529 (0.2%)		0/205 (0%)
Herpes zoster	1/529 (0.2%)		0/205 (0%)
Infection	3/529 (0.6%)		2/205 (1%)
Kidney infection	1/529 (0.2%)		0/205 (0%)
Klebsiella sepsis	1/529 (0.2%)		0/205 (0%)
Lower respiratory tract infection	1/529 (0.2%)		0/205 (0%)
Osteomyelitis	1/529 (0.2%)		0/205 (0%)
Pharyngitis	0/529 (0%)		1/205 (0.5%)
Pneumonia	7/529 (1.3%)		3/205 (1.5%)
Pyelonephritis	1/529 (0.2%)		0/205 (0%)
Pyelonephritis acute	1/529 (0.2%)		0/205 (0%)
Sepsis	10/529 (1.9%)		2/205 (1%)
Septic shock	2/529 (0.4%)		0/205 (0%)
Staphylococcal bacteraemia	1/529 (0.2%)		0/205 (0%)
Urinary tract infection	13/529 (2.5%)		1/205 (0.5%)
Urosepsis	3/529 (0.6%)		0/205 (0%)
Viral infection	1/529 (0.2%)		0/205 (0%)
Wound infection	1/529 (0.2%)		0/205 (0%)
Injury, poisoning and procedural complications
Acetabulum fracture	1/529 (0.2%)		0/205 (0%)
Fall	1/529 (0.2%)		1/205 (0.5%)
Femoral neck fracture	1/529 (0.2%)		0/205 (0%)
Femur fracture	1/529 (0.2%)		0/205 (0%)
Hip fracture	1/529 (0.2%)		0/205 (0%)
Muscle strain	0/529 (0%)		1/205 (0.5%)
Overdose	1/529 (0.2%)		0/205 (0%)
Rib fracture	0/529 (0%)		1/205 (0.5%)
Spinal fracture	2/529 (0.4%)		0/205 (0%)
Subdural haematoma	4/529 (0.8%)		2/205 (1%)
Wound complication	0/529 (0%)		1/205 (0.5%)
Investigations
Blood creatinine increased	0/529 (0%)		1/205 (0.5%)
Metabolism and nutrition disorders
Cachexia	1/529 (0.2%)		0/205 (0%)
Decreased appetite	1/529 (0.2%)		0/205 (0%)
Dehydration	5/529 (0.9%)		1/205 (0.5%)
Failure to thrive	2/529 (0.4%)		0/205 (0%)
Hypervolaemia	0/529 (0%)		1/205 (0.5%)
Hypocalcaemia	1/529 (0.2%)		0/205 (0%)
Hypoglycaemia	1/529 (0.2%)		1/205 (0.5%)
Hypokalaemia	2/529 (0.4%)		1/205 (0.5%)
Hyponatraemia	0/529 (0%)		1/205 (0.5%)
Hypophosphataemia	0/529 (0%)		1/205 (0.5%)
Tumour lysis syndrome	1/529 (0.2%)		0/205 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/529 (0.4%)		0/205 (0%)
Back pain	9/529 (1.7%)		3/205 (1.5%)
Bone pain	6/529 (1.1%)		2/205 (1%)
Flank pain	1/529 (0.2%)		0/205 (0%)
Intervertebral disc compression	1/529 (0.2%)		0/205 (0%)
Intervertebral disc protrusion	1/529 (0.2%)		0/205 (0%)
Neck pain	2/529 (0.4%)		0/205 (0%)
Osteolysis	1/529 (0.2%)		0/205 (0%)
Pain in extremity	1/529 (0.2%)		0/205 (0%)
Pathological fracture	1/529 (0.2%)		0/205 (0%)
Spinal pain	1/529 (0.2%)		0/205 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases to central nervous system	2/529 (0.4%)		0/205 (0%)
Metastases to meninges	1/529 (0.2%)		0/205 (0%)
Nervous system disorders
Brain oedema	0/529 (0%)		1/205 (0.5%)
Cauda equina syndrome	1/529 (0.2%)		1/205 (0.5%)
Cerebellar infarction	1/529 (0.2%)		0/205 (0%)
Cerebral haemorrhage	1/529 (0.2%)		0/205 (0%)
Cerebral infarction	1/529 (0.2%)		0/205 (0%)
Cognitive disorder	1/529 (0.2%)		0/205 (0%)
Diplegia	0/529 (0%)		1/205 (0.5%)
Dizziness	2/529 (0.4%)		0/205 (0%)
Dysarthria	1/529 (0.2%)		0/205 (0%)
Encephalopathy	0/529 (0%)		1/205 (0.5%)
Haemorrhage intracranial	2/529 (0.4%)		0/205 (0%)
Headache	2/529 (0.4%)		0/205 (0%)
Hypoglossal nerve paralysis	1/529 (0.2%)		0/205 (0%)
Ischaemic stroke	3/529 (0.6%)		0/205 (0%)
Loss of consciousness	1/529 (0.2%)		0/205 (0%)
Metabolic encephalopathy	1/529 (0.2%)		1/205 (0.5%)
Myelopathy	0/529 (0%)		1/205 (0.5%)
Pachymeningitis	1/529 (0.2%)		0/205 (0%)
Paraesthesia	2/529 (0.4%)		0/205 (0%)
Peripheral motor neuropathy	1/529 (0.2%)		0/205 (0%)
Radiculopathy	2/529 (0.4%)		0/205 (0%)
Seizure	1/529 (0.2%)		0/205 (0%)
Spinal cord compression	6/529 (1.1%)		10/205 (4.9%)
Spinal cord disorder	0/529 (0%)		1/205 (0.5%)
Syncope	4/529 (0.8%)		0/205 (0%)
Transient ischaemic attack	1/529 (0.2%)		0/205 (0%)
Tremor	1/529 (0.2%)		0/205 (0%)
Psychiatric disorders
Confusional state	2/529 (0.4%)		1/205 (0.5%)
Delirium	1/529 (0.2%)		1/205 (0.5%)
Mental status changes	3/529 (0.6%)		0/205 (0%)
Mixed anxiety and depressive disorder	1/529 (0.2%)		0/205 (0%)
Renal and urinary disorders
Acute kidney injury	9/529 (1.7%)		6/205 (2.9%)
Dysuria	1/529 (0.2%)		0/205 (0%)
Haematuria	11/529 (2.1%)		1/205 (0.5%)
Hydronephrosis	1/529 (0.2%)		1/205 (0.5%)
Malignant urinary tract obstruction	1/529 (0.2%)		0/205 (0%)
Nephrolithiasis	1/529 (0.2%)		0/205 (0%)
Renal tubular acidosis	1/529 (0.2%)		0/205 (0%)
Urinary retention	5/529 (0.9%)		2/205 (1%)
Urinary tract obstruction	4/529 (0.8%)		0/205 (0%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	1/529 (0.2%)		0/205 (0%)
Penile pain	1/529 (0.2%)		0/205 (0%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	1/529 (0.2%)		0/205 (0%)
Chronic obstructive pulmonary disease	1/529 (0.2%)		0/205 (0%)
Dyspnoea	5/529 (0.9%)		1/205 (0.5%)
Epistaxis	1/529 (0.2%)		0/205 (0%)
Haemoptysis	1/529 (0.2%)		0/205 (0%)
Hypoxia	1/529 (0.2%)		0/205 (0%)
Pleural effusion	2/529 (0.4%)		1/205 (0.5%)
Pneumonia aspiration	1/529 (0.2%)		0/205 (0%)
Pulmonary embolism	6/529 (1.1%)		2/205 (1%)
Pulmonary hypertension	0/529 (0%)		1/205 (0.5%)
Surgical and medical procedures
Neck dissection	1/529 (0.2%)		0/205 (0%)
Pain management	1/529 (0.2%)		0/205 (0%)
Vascular disorders
Aortic stenosis	1/529 (0.2%)		0/205 (0%)
Arteriosclerosis	0/529 (0%)		1/205 (0.5%)
Deep vein thrombosis	3/529 (0.6%)		0/205 (0%)
Embolism	2/529 (0.4%)		0/205 (0%)
Hypotension	4/529 (0.8%)		0/205 (0%)
Orthostatic hypotension	1/529 (0.2%)		0/205 (0%)
Other (Not Including Serious) Adverse Events
	177Lu-PSMA-617 Plus Best Supportive/Best Standard of Care (BS/BSOC)		Best Supportive/Best Standard of Care (BS/BSOC) Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	501/529 (94.7%)		150/205 (73.2%)
Blood and lymphatic system disorders
Anaemia	160/529 (30.2%)		26/205 (12.7%)
Leukopenia	66/529 (12.5%)		4/205 (2%)
Lymphopenia	75/529 (14.2%)		8/205 (3.9%)
Neutropenia	45/529 (8.5%)		3/205 (1.5%)
Thrombocytopenia	91/529 (17.2%)		9/205 (4.4%)
Gastrointestinal disorders
Abdominal pain	29/529 (5.5%)		6/205 (2.9%)
Constipation	103/529 (19.5%)		23/205 (11.2%)
Diarrhoea	100/529 (18.9%)		5/205 (2.4%)
Dry mouth	205/529 (38.8%)		1/205 (0.5%)
Nausea	185/529 (35%)		33/205 (16.1%)
Vomiting	97/529 (18.3%)		12/205 (5.9%)
General disorders
Asthenia	34/529 (6.4%)		16/205 (7.8%)
Fatigue	227/529 (42.9%)		47/205 (22.9%)
Oedema peripheral	50/529 (9.5%)		13/205 (6.3%)
Pain	28/529 (5.3%)		9/205 (4.4%)
Pyrexia	30/529 (5.7%)		7/205 (3.4%)
Infections and infestations
Urinary tract infection	52/529 (9.8%)		1/205 (0.5%)
Injury, poisoning and procedural complications
Fall	37/529 (7%)		12/205 (5.9%)
Investigations
Blood creatinine increased	28/529 (5.3%)		4/205 (2%)
Weight decreased	57/529 (10.8%)		18/205 (8.8%)
Metabolism and nutrition disorders
Decreased appetite	111/529 (21%)		30/205 (14.6%)
Hypocalcaemia	36/529 (6.8%)		7/205 (3.4%)
Hypokalaemia	39/529 (7.4%)		7/205 (3.4%)
Hypophosphataemia	28/529 (5.3%)		7/205 (3.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	117/529 (22.1%)		26/205 (12.7%)
Back pain	121/529 (22.9%)		28/205 (13.7%)
Bone pain	55/529 (10.4%)		15/205 (7.3%)
Pain in extremity	45/529 (8.5%)		12/205 (5.9%)
Nervous system disorders
Dizziness	42/529 (7.9%)		9/205 (4.4%)
Headache	36/529 (6.8%)		4/205 (2%)
Psychiatric disorders
Insomnia	28/529 (5.3%)		9/205 (4.4%)
Renal and urinary disorders
Haematuria	37/529 (7%)		8/205 (3.9%)
Respiratory, thoracic and mediastinal disorders
Cough	42/529 (7.9%)		13/205 (6.3%)
Dyspnoea	50/529 (9.5%)		19/205 (9.3%)
Vascular disorders
Hypertension	30/529 (5.7%)		12/205 (5.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.