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

In the Main Study, "randomized treatment" refers to the investigational arm (AAA617+BSC/BSoC) and the control arm (BSC/BSoC). In the sub-study, "study treatment" refers to the investigational arm (AAA617+BSC/BSoC) without randomization:

1. A randomized treatment-emergent adverse event (TEAE) is any adverse event that occurs from the start of randomized treatment to 30 days after the last administration of randomized treatment or prior to the initiation of subsequent anticancer treatment.
2. A study treatment-emergent adverse event (TEAE) is any adverse event that occurs from the start of study treatment to 30 days after the last administration of study treatment or prior to the initiation of subsequent anticancer treatment.

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

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 evaluable disease at baseline per central review assessment.

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.

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 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).

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.

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).

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.

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.

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.

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).

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 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 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 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 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 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.

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.

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 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.

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 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.

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.

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.

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

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).

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.

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).