Clinical trial NCT03511664
Conditions: Prostate Cancer
Keywords: Metastatic castration-resistant prostate cancer mCRPC 177Lu-PSMA-617 PSMA-617 PSMA-11 radioligand therapy
Sponsor: Endocyte
Start date: 2018-05-29; Completion date: 2023-12-14
Enrollment: 861 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

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

Sub-study A dosimetry, PK and ECG sub-study was conducted in a non-randomized cohort (AAA617+BSC/BSoC) of 30 patients at sites in Germany to provide a more complete assessment of the safety aspects of AAA617. Aside from additional assessments to collect data for dosimetry, PK, urinary metabolites and ECG, patients in the sub-study were screened for eligibility, treated and followed up similarly to the AAA617+BSC/BSoC (investigational arm) patients in the main study.

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 patient 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 refers to AAA617+BSC/BSoC (investigational arm) and BSC/BSoC only (control arm). For the sub-study, "study treatment" refers to AAA617+BSC/BSoC (also referred to as the investigational arm), as no randomization occurred in the sub-study. When discussing aspects of the study which are applicable to both the main and sub-study, the term 'randomized treatment' will be used throughout this document. The term 'study treatment' will be used only when specifically referring to the sub-study.

Patients randomized to the investigational arm began AAA617 dosing within 28 days of randomization. These patients received BSC/BSoC and 7.4 GBq (+/-10%) AAA617 once every 6 weeks (+/- 1 week) for a maximum of 6 cycles.

After the Cycle 4 treatment and prior to Cycle 5 treatment, the Investigator had to determine if:

* 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 AAA617 treatment

If the patient met all of the criteria above and agreed to continue with additional treatment of AAA617 the investigator could administer a further 2 cycles. A maximum of 6 cycles of radioligand therapy was allowed. If the patient did not meet any of the criteria or did not agree to additional AAA617 treatment, then no additional doses of AAA617 were administered after Cycle 4. After the last cycle of AAA617, patients continued BSC/BSoC alone, as long as the investigator felt they were clinically benefiting or until they required a treatment regimen not allowed in this study. For both treatment arms, the cycle duration for Cycle 1-6 was 6 weeks and for Cycle 7 and beyond, 12 weeks. From Cycle 7 onwards, all patients from both treatment arms only received BSC/BSoC.

End of treatment:

An End of Treatment (EOT) visit was scheduled approximately 30 days after the last dose of AAA617 or the date of the BSC/BSoC end of treatment decision (whichever occurred later), but before the initiation of subsequent anti-cancer treatment, outside of what was allowed on study. Once a patient discontinued the randomized treatment part of the study for any reason, an EOT visit was scheduled.

Long-term follow-up:

Patients on the active part of the study at the time of the final analysis of OS had an EOT visit at the next planned visit after implementation of V5.0/5.1 of the protocol and moved into long-term follow-up, unless they specifically withdrew consent from long-term follow-up of the study.

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 period included the collection of rPFS (if the 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 were contacted every 3 months (+/-1 month) via phone, email, or letter until a long-term follow-up study became available, until death or until withdrawal of consent, whichever occurred first.

Arms: arm 1: 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 arm 2: Patients randomized to this arm received best supportive/best standard of care (BS/BSOC) as determined by the investigator
Interventions: intervention 1: 177Lu-PSMA-617 intervention 2: Best supportive/best standard of care
Intervention descriptions: intervention 1: 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. intervention 2: Best supportive/best standard of care as defined by the local investigator

Protocol documents:
Prot_002.pdf: 
PROTOCOL NO. PSMA-617-01 / NCT03511664 
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) 
 Clinical Protocol No.: 
PSMA-617-01 
Version No.: 
7.0 
Date: 
14 September 2022 
IND No.: 
133,661 (177Lu-PSMA-617) 
133,925 or site equivalent (68Ga-PSMA-11) 
EudraCT No. 
2018-000459-41 
Phase of Study: 
Phase 3 
Investigational Products: 
177Lu-PSMA-617; 68Ga-PSMA-11 
Sponsor: 
Endocyte, Inc., A Novartis Company 
8910 Purdue Road - Suite 250 
Indianapolis, Indiana 46268 
Medical Officer: 
Novartis Pharma AG 
Oncology DU GDD 
Fabrikstr, WSJ-103.5 
CH-4002 Basel, Switzerland 
Approval: 
[signed electronically in MasterControl] 
Medical Officer Signature 
Date 
Confidentiality Statement 
By accepting receipt of this document, you (recipient) agree not to disclose the contents (in whole or in part), directly or indirectly, by 
any means except as authorized in writing by the owner, Endocyte, Inc. This document contains commercial and proprietary, or 
privileged, information and trade secrets that may not be disclosed by recipient unless such disclosure is required by federal or state 
law, and then only to the extent required by law, or allowed by Endocyte. Recipient will restrict access to this protected information 
only to those employees of recipient who are required to consider this information for purposes of your interactions with Endocyte. 
Recipient will take all steps necessary to ensure that these employees protect the information contained herein and do not disclose it to 
others. Recipient will ensure that each of its employees to whom this information is disclosed is told of its protected status and that all 
such employees agree not to disclose the information to any unauthorized person or entity. These disclosure restrictions apply equally 
to all related future information supplied to you, which Endocyte indicates as privileged or confidential. 


Page 2 of 97 
 
Protocol no. PSMA-617-01 
Endocyte, Inc., a Novartis Company 
Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
Site Principal Investigator Signature 
The investigator signature page is provided in Appendix 3 along with a link to form FDA 1572 
or equivalent if the site is outside of the United States. 


Page 3 of 97 
 
Protocol no. PSMA-617-01 
Endocyte, Inc., a Novartis Company 
Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
Table of Contents 
Site Principal Investigator Signature .......................................................................................... 2 
Table of Contents ........................................................................................................................ 3 
Revision History ......................................................................................................................... 7 
Clinical Trial Summary ............................................................................................................. 10 
List of Abbreviations and Definitions....................................................................................... 13 
1. 
Introduction ...................................................................................................................... 15 
1.1 
Background information .............................................................................................. 15 
1.2 
Summary of nonclinical studies with clinical significance ......................................... 19 
1.3 
Summary of known and potential risks and benefits ................................................... 20 
2. 
Trial Objectives and Endpoints ........................................................................................ 20 
2.1 
Trial objectives ............................................................................................................ 20 
2.1.1 
Primary objective ...............................................................................................20 
2.1.2 
Key secondary objectives ...................................................................................21 
2.1.3 
Additional secondary objectives ........................................................................21 
2.2 
Trial endpoints ............................................................................................................. 21 
2.2.1 
Alternate Primary endpoints ..............................................................................21 
2.2.2 
Key Secondary endpoints ...................................................................................21 
2.2.3 
Additional Secondary endpoints ........................................................................22 
3. 
Trial Design ...................................................................................................................... 23 
3.1 
Overview of the clinical trial design ........................................................................... 23 
3.1.1 
Study design update ...........................................................................................26 
3.2 
Rationale for the study design ..................................................................................... 26 
3.3 
Measures taken to minimize/avoid bias ...................................................................... 26 
3.4 
Description of the clinical trial .................................................................................... 26 
3.4.1 
Description of investigational medicinal product ..............................................26 
3.4.2 
Dosage and rationale for dose selection .............................................................27 
3.4.3 
Subject allocation to treatment ...........................................................................28 
3.4.4 
End of treatment visit .........................................................................................28 
3.4.5 
Duration of Subject Participation .......................................................................28 
3.5 
End of trial definition .................................................................................................. 29 
4. 
Selection and Discontinuation of Subjects ....................................................................... 29 
4.1 
Inclusion criteria .......................................................................................................... 29 
4.2 
Exclusion criteria ......................................................................................................... 31 
4.3 
Subject withdrawal of consent for study or treatment ................................................. 32 
5. 
Treatment of Subjects ....................................................................................................... 32 
5.1 
Treatment with the investigational medicinal product ................................................ 32 


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Protocol no. PSMA-617-01 
Endocyte, Inc., a Novartis Company 
Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
5.1.1 
Administration of 68Ga-PSMA-11 .....................................................................32 
5.1.2 
Administration of 177Lu-PSMA-617 ..................................................................33 
5.1.3 
Toxicity risk reduction and supportive care for 177Lu-PSMA-617 injections ...33 
5.1.4 
Management of toxicity adverse events: dosing delays and modification .........34 
5.2 
Best supportive/best standard of care .......................................................................... 35 
5.3 
Concomitant medications/ supportive care ................................................................. 36 
5.3.1 
Permitted concomitant medications/ supportive care ........................................36 
5.3.2 
Prohibited concomitant medications ..................................................................37 
5.4 
Monitoring treatment compliance ............................................................................... 37 
5.5 
Treatment discontinuation ........................................................................................... 37 
6. 
Study Assessments and Procedures .................................................................................. 37 
6.1 
Screening procedures and baseline assessments ......................................................... 37 
6.2 
Efficacy assessments ................................................................................................... 39 
6.2.1 
Radiographic imaging for tumor assessments ...................................................39 
6.2.2 
Additional Imaging Analyses .............................................................................40 
6.2.3 
RECIST criteria ..................................................................................................40 
6.2.4 
Symptomatic skeletal events ..............................................................................40 
6.2.5 
Pain score ...........................................................................................................40 
6.2.6 
Health-related quality of life ..............................................................................41 
6.2.7 
Health Economics ..............................................................................................42 
6.2.8 
Clinical progression ...........................................................................................42 
6.2.9 
PSA levels ..........................................................................................................42 
6.3 
Safety assessments....................................................................................................... 42 
6.3.1 
Clinical laboratory evaluations ..........................................................................42 
6.3.2 
Vital signs ..........................................................................................................43 
6.3.3 
Electrocardiograms ............................................................................................43 
6.3.4 
Birth Control ......................................................................................................43 
6.4 
End of treatment visit procedures ................................................................................ 43 
6.5 
Long-term follow-up procedures ................................................................................. 43 
7. 
Adverse Events ................................................................................................................. 44 
7.1 
Adverse event definitions ............................................................................................ 44 
7.2 
Evaluating and recording adverse events .................................................................... 45 
7.3 
Immediate Adverse Event Reporting .......................................................................... 46 
7.3.1 
Serious Adverse Events .....................................................................................47 
7.3.2 
Serious adverse event subject follow-up ............................................................47 
7.3.3 
Sponsor Contact Information for Immediate Reporting ....................................47 
8. 
Statistics ............................................................................................................................ 47 


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Protocol no. PSMA-617-01 
Endocyte, Inc., a Novartis Company 
Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
8.1 
Revision to the protocol and statistical analyses of rPFS and OS ............................... 48 
8.2 
Revisions to planned analyses ..................................................................................... 48 
8.3 
Sample size and power determination ......................................................................... 48 
8.4 
Analysis populations ................................................................................................... 49 
8.5 
Demographics and baseline disease characteristics .................................................... 50 
8.6 
Patient disposition ....................................................................................................... 50 
8.7 
Efficacy analyses ......................................................................................................... 50 
8.7.1 
Alternate primary endpoint efficacy analysis ....................................................50 
8.7.2 
Secondary efficacy analyses ..............................................................................52 
8.8 
Safety analyses ............................................................................................................ 53 
8.8.1 
Extent of exposure .............................................................................................53 
8.8.2 
Analysis of adverse events .................................................................................53 
8.8.3 
Analysis of laboratory assessments ....................................................................54 
8.8.4 
Analysis of vital sign data ..................................................................................54 
8.9 
IDMC and Interim Data Evaluation ............................................................................ 54 
8.9.1 
IDMC .................................................................................................................54 
8.9.2 
Formal Interim Analysis of OS ..........................................................................54 
9. 
Access to Source Data/Documents ................................................................................... 54 
10. Ethics ................................................................................................................................ 55 
10.1 Institutional Review Board/Independent Ethics Committee/ 
Research Ethics Board (IRB/IEC/REB) ...................................................................... 55 
10.2 Informed consent ......................................................................................................... 55 
10.3 Health Insurance Portability and Accountability Act .................................................. 56 
10.4 Confidentiality ............................................................................................................. 56 
11. Compliance and quality control ........................................................................................ 56 
11.1 Compliance with Monitoring and Audits .................................................................... 56 
12. Data Handling, Record Keeping, and Compliance .......................................................... 57 
12.1 Investigational medicinal product accountability ........................................................ 57 
12.2 Breaking the blind ....................................................................................................... 57 
12.3 Data collection forms and source document identification ......................................... 57 
12.4 Record maintenance and retention .............................................................................. 58 
12.5 Archiving ..................................................................................................................... 58 
13. Publication Policy ............................................................................................................. 58 
14. References ........................................................................................................................ 59 
Appendix 1 
Schedules of Assessments ............................................................................. 66 
Appendix 2 
Suggested treatment guidelines ..................................................................... 73 
Appendix 3 
Principal Investigator Signature .................................................................... 74 


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Protocol no. PSMA-617-01 
Endocyte, Inc., a Novartis Company 
Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
Appendix 4a 
Eastern Cooperative Oncology Group performance status 
scale and Karnofsky Performance Status comparison ...................................................... 75 
Appendix 4b 
Eastern Cooperative Oncology Group performance status 
scale and Karnofsky Performance Status comparison ...................................................... 76 
Appendix 5 
Common Terminology Criteria for Adverse Events ..................................... 77 
Appendix 6 
Response Evaluation Criteria in Solid Tumors ............................................. 78 
Appendix 7 
Prostate Cancer Working Group 3 Recommendations ................................. 79 
Appendix 8 
BPI-SF (sample only, not for patient use) ..................................................... 81 
Appendix 9 
 EQ-5D-5L (European Quality of Life (EuroQol) – 5 
Domain 5 Level scale) (sample only, not for patient use) ................................................ 84 
Appendix 10 
 FACT-P (Functional Assessment of Cancer Therapy – 
Prostate) (sample only, not for patient use) ...................................................................... 88 
Appendix 11 
PCCTC Bone Scan Assessment Tool ............................................................ 92 
 
List of tables 
Table 1 
Toxicity management and dose modification recommendations ............................ 34 
Table 2 
Screening procedures and baseline assessments ..................................................... 38 
Table 3 
Schedule of assessments: 177Lu-PSMA-617 plus best supportive/best standard of 
care arm (Cycle 1) ......................................................................................................................... 67 
Table 4 
Schedule of assessments: 177Lu-PSMA-617 plus best supportive/best standard of 
care arm (Cycles 2 to LTFU) ........................................................................................................ 68 
Table 5 
Schedule of assessments: Best supportive/best standard of care only arm (Cycle 1)
 
70 
Table 6 
Schedule of assessments: Best supportive/best standard of care only arm 
(Cycles 2 to LTFU) ....................................................................................................................... 71 
 
List of figures 
Figure 1 
Diagram of trial design ........................................................................................... 23 
 
 


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Protocol no. PSMA-617-01 
Endocyte, Inc., a Novartis Company 
Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
Revision History 
 
Version No. 
Date 
Summary of Changes 
1.0 
22 March 2018 
Not applicable; initial clinical trial protocol. 
1.1  
03 July 2018  
GB only amendment: 
AE assessment timing to start from consent. 
Added wording regarding birth control 
1.2  
26 September 2018  
DE only amendment: 
AE assessment timing to start from consent. 
Added wording regarding birth control 
2.0 
16 January 2019 
Incorporated GB and DE only amendment changes. 
Added statement of compliance as required by Sweden. 
Incorporated the addition of the alternative primary endpoint of 
rPFS and update to 1 rPFS analysis and 1 overall survival analysis. 
Clarified inclusion of and timing of start for best supportive/best 
standard of care. 
Clarified inclusion/exclusion criteria. 
Clarified procedures and timing 
Clarified progression of disease is not considered an AE or SAE. 
Clarified start and end timing for 68Ga-PSMA-11 TEAEs, 177Lu-
PSMA-617 TEAEs and best supportive/best standard of care dosing 
and intervention TEAEs. 
 
3.0 
01 April 2019  
• Updated sponsor name. 
• Updated background information data. 
• Clarified rPFS is an alternate primary endpoint. 
• Clarified inclusion/exclusion criteria and added specific criteria 
regarding best supportive/best standard of care options to be 
identified for patients as part of eligibility.  
• After Cycle 6, visits are now every 12 weeks (+/- 4 days) 
• Additional details regarding long-term follow were added 
including a second consent to be signed by patients who withdraw 
consent or leave the active part of the study for any reason other 
than radiographic disease progression. This now includes 
radiographic follow up. 
• Plasma testosterone was added as an acceptable form of 
testosterone testing. 
• Window for QOL and Pain questionnaires added. 
• Updated reference section 
 
4.0 
 
 
 
08 July 2019 
• Increased total number of patients randomized in the study by 64 
to ensure sufficient events in order to maintain power for total 
enrollment of 814 patients.  
• Details for confirmatory analysis of OS (based on all randomized 
patients on an Intent to Treat (ITT) basis i.e., all patients enrolled 
since the start of the study) and the rPFS analysis based on 
randomized patients on or after March 5th, 2019 were added. 


Page 8 of 97 
 
Protocol no. PSMA-617-01 
Endocyte, Inc., a Novartis Company 
Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
 
 
 
 
 
 
• Adjusted the allocation of alpha between rPFS and OS while still 
maintaining the original power for both rPFS (approximately 
85%) and OS (90%). Allocated alpha=0.004 to rPFS, 0.001 to 
interim OS and alpha of 0.02 to 0.025 for OS. Previously, 
allocation was rPFS=0.001 and OS=0.023. 
• Additional imaging analyses details were added for 
study 68Ga PSMA 11 scan data and the role of the Independent 
Review with reviewer variability assessment, as well as 
Quantitative Analysis was added to assess tumor burden and 
tumor characteristics with rPFS, OS, and other response measures, 
as determined by PCWG3 criteria. 
•  Further clarification on the start and end timing for 68Ga-PSMA-
11 TEAEs, 177Lu-PSMA-617 TEAEs and best supportive/best 
standard of care dosing and intervention TEAEs. 
• Additional wording to clarify intent to collect radiographic 
imaging for patients who stop treatment for reasons other than 
radiographic progression, 
5.0 
26 April 2021 
• Extend Long-Term Follow-Up for up to an additional 12 months 
after V5.0 of the protocol is implemented at each site. 
• Reduce the procedures required for each Long-Term Follow-Up 
visit. 
• Add the requirement to report Serious Adverse Events related to 
the study drug during Long-Term Follow-Up as well as reporting 
details of renal toxicities and secondary malignancies. 
• Updated Serious Adverse Event reporting to reflect the change to 
Novartis Safety vs PrimeVigilance. 
• Update footers and headers so that all pages read V5.0. In V4.0 
pages 73 to 95 still read “V3.0”. No change was made to the 
content of these pages from V3.0 to V4.0; the error was 
typographical.  
6.0 
26 May 2022 
• 
Extend the Long-Term Follow-Up for patients on this study to 
ensure consistent collection of long-term safety data until a new 
long-term safety follow-up study is available (to comply with 
FDA Postmarketing Requirement; estimated in 2Q2023). 
7.0 
14 September 2022 
The purpose of this protocol amendment V7 is to document 
the gap between the last visit of the patient under protocol 
amendment V5 and the first visit of the patient under protocol 
amendment V6 as there might be a time gap due to late 
finalization of protocol amendment V6.  
 
Details of the protocol amendments are as follows: 
·        V5 extended the long-term follow-up by one 
year.  
·        V6 extended further the long-term follow-up until 
a separate long-term follow-up study is available. 
 
Despite the time gap between these two protocol amendments 
V5 and V6, we suggest to continue the patient on the trial in 
order to comply with FDA post marketing requirements, so 
we continue to collect long-term safety data (with the same 
patient ID) for reconsented patient. 


Page 9 of 97 
 
Protocol no. PSMA-617-01 
Endocyte, Inc., a Novartis Company 
Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
An additional addendum of the informed consent is released 
with this protocol amendment V7 to document the patient's 
understanding to continue on study. 


Page 10 of 97 
 
Protocol no. PSMA-617-01 
Endocyte, Inc., a Novartis Company 
Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
Clinical Trial Summary 
Protocol 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) 
Clinical phase: 
Phase 3 
Objectives: 
The primary objective of this study is to compare the two alternate primary 
endpoints of radiographic progression-free survival (rPFS) and overall survival (OS) 
in patients with progressive PSMA-positive mCRPC who receive 177Lu-PSMA-617 
in addition to best supportive/best standard of care versus patients treated with best 
supportive/best standard of care alone. 
Key secondary objectives are an arm-to-arm comparison of the following: 
• 
Response Evaluation Criteria in Solid Tumors (RECIST) response 
• 
Time to a first symptomatic skeletal event (SSE)  
Additional Secondary Objectives: 
• 
Safety and tolerability of 177Lu-PSMA-617 
• 
Health-related quality of life (HRQoL; EQ-5D-5L, FACT-P and Brief Pain 
Inventory – Short Form (BPI-SF)) 
• 
Health economics 
• 
Progression-free survival (PFS) (radiographic, clinical, or prostate-specific 
antigen [PSA] progression-free survival) 
• 
Biochemical response as measured by PSA. Alkaline phosphatase [ALP] 
levels and lactate dehydrogenase [LDH] levels will also be measured. 
Study design: 
Patients with PSMA positive scans will be randomized in a 2:1 ratio to receive either 
177Lu-PSMA-617 plus best supportive/best standard of care or to receive best 
supportive/best standard of care only. Best supportive/best standard of care will be 
determined by the treating physician/investigator but will exclude investigational 
agents, cytotoxic chemotherapy, immunotherapy, other systemic radioisotopes, and 
hemi-body radiotherapy. Novel androgen axis drugs [NAADs] (such as abiraterone 
or enzalutamide) are allowed.  
The care of cancer patients must include cancer specialists accomplished in the care 
of patients with advanced prostate cancer, (e.g., medical, radiation oncologists) with 
a clear understanding of the PCWG3 2+2 rules for progression, management of 
adverse events (AEs) related to the natural course of the disease, as well as pre-
existing AEs and study-related AEs. 
The study is open-label and patients will be monitored throughout the 6 to 10-month 
treatment period for survival, disease progression, and adverse events. 
rPFS will be analyzed in these patients once 364 events have accrued. At time of the 
rPFS primary analysis, there will also be an interim analysis of OS. 
 
Before final analysis of alternate primary endpoint OS: 
When a patient discontinues from the treatment portion of the study, they will have 
an end of treatment visit and will then continue to be followed in long-term follow-
up.  
A long-term follow-up period will include the collection of rPFS survival and 
information about new treatments, along with the patient’s response to these 
treatments, adverse events assessment, and hematology and chemistry testing. 
During follow-up, patients will be contacted every 3 months (±1 month) via phone, 
email, or letter for up to 24 months or until 508 deaths have occurred.  
Patients who withdraw their consent to participate in the treatment portion of the 
study or come off the treatment portion of the study for any reason other than 


Page 11 of 97 
 
Protocol no. PSMA-617-01 
Endocyte, Inc., a Novartis Company 
Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
radiographic disease progression will be asked for permission to continue long-term 
status updates which may include, in addition to the above, collection of 
radiographic images (bone scans and CT scans and/or MRIs). 
These patients will be asked to sign a separate consent detailing what kind of long-
term follow-up assessments and study updates they will agree to. They will also be 
able to designate a contact person (e.g. study doctor, local doctor, friend, or family 
member) who may be contacted on their behalf to obtain follow-up status updates. 
After final analysis of alternate primary endpoint OS: 
All randomized patients on the active part of the study after the final analysis of 
alternate primary endpoint OS will have an EOT visit at the next planned visit after 
implementation of V5.0 of the protocol and will move into long-term follow-up. All 
patients in long-term follow-up will continue to be followed on this study under the 
same patient ID until a long-term safety follow-up study is available in the 
respective country, until death or until withdrawal of consent, whichever occurs first. 
The long-term follow-up period in this study will include the collection of survival 
and new treatment information, adverse events assessment for renal toxicity and 
secondary malignancies, and results of hematology and chemistry testing. During 
follow-up, patients will be followed for safety and survival. They will be seen or 
contacted by a clinician every 3 months (±1 month) via phone, in person or via 
telemedicine visit, email or letter until a long-term safety follow-up study is 
available for enrollment, until death or until withdrawal of consent, whichever 
occurs first. Every opportunity to continue to collect long-term safety data should be 
made for each willing participant, regardless of gap between release of protocol 
amendment v5.0 and v6.0. 
The planned enrollment for this study is 814 patients. 
Study population: 
The study population includes 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 regimens. Patients 
treated with only 1 prior taxane regimen are eligible if the patient is unwilling or the 
patient’s physician deems the patient unsuitable to receive a second regimen.  
Investigational product: 
Patients randomized to receive the investigational product will receive 7.4 GBq 
(±10%) 177Lu-PSMA-617 intravenously every 6 weeks (±1 week) for a maximum of 
6 cycles. After 4 cycles, patients will be assessed for (1) evidence of response, (2) 
residual disease, and (3) tolerance to 177Lu-PSMA-617. If the patient meets the 
criteria above and agrees to continue with additional treatment of 177Lu-PSMA-617 
radioligand therapy, the investigator may administer 2 additional cycles. A 
maximum of 6 cycles of radioligand therapy is allowed. After the last cycle of 177Lu-
PSMA-617, patients can continue best supportive/best standard of care alone. 
If the patient does not meet all of the criteria or does not agree to additional 177Lu-
PSMA-617 treatment, then no additional doses of 177Lu-PSMA-617 will be 
administered after Cycle 4. These patients can continue on best supportive/best 
standard of care alone after Cycle 4. 
Assessment schedule: 
Radiographic imaging will be done every 8 weeks (±4 days) during the first 
24 weeks of treatment and every 12 weeks (± 4 days) thereafter, regardless of 
treatment delays, through the End of Treatment visit.  
The previous 2 PSA values will be noted before randomization. Serum/plasma 
testosterone and PSA levels will be measured up to 3 days prior to Day 1 of each 
cycle. Hematology and chemistry will be done weekly during Cycle 1 (up to 3 days 
prior to each time point) and up to 3 days prior to Days 1, 15, and 29 in Cycles 2 to 6 
(i.e. every two weeks). After Cycle 6, hematology and chemistry will be done every 
12 weeks (±4 days) until the patient starts long-term follow-up.  
Patients will complete the BPI-SF, EQ-5D-5L and FACT-P questionnaires about 
their pain level and HRQoL during screening and prior to treatment on Day 1 of 


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each cycle and through the End of Treatment visit. Patients will be monitored 
throughout the study for SSEs. 
After the final analysis of OS, patients in the active part of the study will have an 
end of treatment (EOT) visit and move into long-term follow-up. Long-term follow-
up will be extended on this study until a long-term safety follow-up study is 
available in the respective country (estimated in 2nd quarter of 2023). 
Statistical methodology: 
Subsequent to the implementation of measures to minimize early dropouts from the 
best supportive/best standard of care alone arm, the primary analysis of rPFS will 
focus on patients randomized on or after March 5th, 2019; rPFS will be analyzed in 
these patients once 364 events have accrued and the alpha level applied will be 
0.004 1-sided. At time of the rPFS analysis, there will be an interim analysis of OS 
and the alpha level applied will be 0.001 1-sided; unlike rPFS, the analysis of OS 
will include all randomized patients (i.e., including those randomized before March 
5th, 2019). Following the analysis of rPFS and the interim analysis of OS, a final 
analysis of OS will be performed when 508 deaths have accrued and the alpha level 
applied will be 0.02 1-sided. 
This trial has at least 90% overall power and an overall Type I error rate of at most 
0.025 1-sided. 
After the final analysis of OS is performed, additional analyses of the primary 
endpoints (e.g. OS) will be presented descriptively without statistical inference and 
at the same nominal alpha level used for the primary analysis for each endpoint. 
Duration of Study: 
Total duration of the study will be up to approximately 66 months.  
 


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List of Abbreviations and Definitions 
Abbreviation 
Term/Definition 
ANC 
Absolute neutrophil count 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ASCO 
American Society of Clinical Oncology 
BPI-SF 
Brief Pain Inventory – Short Form 
CFR 
United States Code of Federal Regulations 
CR 
Complete response 
CRF 
Case Report Form 
CSR 
Clinical study report 
CT  
Computed tomography  
CTCAE 
Common Toxicity Criteria for Adverse Events 
DCR 
Disease control rate 
DOR 
Duration of response 
ECOG  
Eastern Cooperative Oncology Group  
EOT 
End of Treatment 
EQ-5D-5L 
European Quality of Life (EuroQol) – 5 Domain 5 Level scale 
EudraCT 
European Union Drug Regulating Authorities Clinical Trial 
FACT-P 
Functional Assessment of Cancer Therapy – Prostate 
GCSF 
Granulocyte colony-stimulating factors 
FDA 
Food and Drug Administration 
FAS 
Full Analysis Set 
68Ga 
Gallium-68 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
Hazard ratio 
HRQoL 
Health-related quality of life 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonization 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
IV 
Intravenous 


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Abbreviation 
Term/Definition 
LDH 
Lactate dehydrogenase 
177Lu 
Lutetium-177 
mCRPC 
Metastatic castration-resistant prostate cancer 
NAAD 
Novel androgen axis drug (such as abiraterone or enzalutamide) 
ORR 
Overall response rate 
OS 
Overall survival 
PCWG3 
Prostate Cancer Clinical Trials Working Group 3 
PD 
Progressive disease 
PFS 
Progression-free survival 
PR 
Partial response 
PSA 
Prostate specific antigen 
PSMA 
Prostate-specific membrane antigen 
REB 
Research Ethics Board 
RECIST 
Response Evaluation Criteria in Solid Tumors 
rPFS 
Radiographic progression-free survival 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable disease 
SSE 
Symptomatic Skeletal Event 
TEAE 
Treatment-emergent adverse event 
SOD 
Sum of the diameter 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 
90Y 
Yttrium-90 
 


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Protocol no. PSMA-617-01 
Endocyte, Inc., a Novartis Company 
Version no.: 7.0 
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This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
The following clinical protocol describes the scientific rationale, objectives, design, statistical 
considerations, and organization of the planned trial including the plan to assure the safety and 
health of the trial participants. Additional details for conducting the clinical trial are provided in 
documents referenced in the protocol, such as an Investigator's Brochure (IB), the Pharmacy 
Manual, or in the Appendices. 
The format and content of this clinical trial protocol complies with the Guideline for Good 
Clinical Practice (GCP) [E6(R2)] issued by the International Conference on Harmonization of 
Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) as well as 
applicable local regulations, i.e. LVFS 2011:19 (Sweden), and the latest version of the 
Declaration of Helsinki. The study will be conducted according to this clinical trial protocol. 
  
The term subject, participant, and patient are used interchangeably throughout this protocol and 
are used to denote an individual who participates in a clinical trial, either as a recipient of the 
investigational product(s) or as a control. 
1. 
INTRODUCTION 
1.1 
Background information 
Prostate cancer and unmet medical need 
An estimated 1.1 million men worldwide were diagnosed and 307,000 died due to prostate 
cancer in 2012. Almost 70% of the cases are diagnosed in more developed regions due to the use 
of prostate-specific antigen (PSA) testing, but there is only modest variation in mortality rates 
globally which is driven by metastatic, and often castration-resistant disease (Ferlay et al 2013, 
Bray et al 2012). 
There is an urgent need for more effective treatments to improve outcomes for patients with 
metastatic castration-resistant prostate cancer (mCRPC). Prostate cancer is the third leading 
cause of cancer mortality in United States (US) men (Siegel et al 2017), driven by prostate 
cancer patients who no longer respond to hormonal therapy. Once patients reach the mCRPC 
stage, their expected overall survival is low as was seen in the randomized phase 3 study of 
cabozantinib vs prednisone in men with mCRPC who had received prior docetaxel and 
abiraterone acetate and/or enzalutamide; the median overall survival of the prednisone control 
arm was 9.8 months (Smith et al 2016). Post-docetaxel mCRPC patients have an annual death 
rate of 73% (Scher et al 2015).  
The median age at diagnosis of mCRPC is 70 years (Flaig et al 2016). Metastatic prostate cancer 
has a predilection for bone. As a result, approximately 90% of mCRPC patients develop bone 
metastases (Kirby et al 2011), and 49% of them will develop a serious skeletal event within 
2 years (Saad et al 2004). Common presentations include bone pain, bone marrow failure, 
fatigue, or complications such as fractures and cord compression. These presentations typically 
require radiation or bone surgery, which can significantly impair physical, emotional, and 
functional well-being (Weinfurt et al 2005). These patients, many of whom are elderly, can be 
extremely symptomatic and at risk of serious oncological complications. They can be a 
considerable challenge in the clinic due to the symptoms of metastatic soft tissue and visceral 
disease, general frailty, bone marrow impairment, and because they have exhausted approved 


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agents. In mCRPC patients facing advanced illness with little hope for a cure, the focus of 
treatment shifts from active anti-cancer treatment to palliative care for relief of physical 
symptoms, maintaining function, and attempting to improve their health-related quality of life 
(Cella et al 2009). Therefore, in addition to tracking essential clinical outcomes, it is also 
important to assess and evaluate changes in HRQoL of such fragile patients as they receive 
treatment. 
Several agents have been approved for the treatment of mCRPC, and NCCN, ASCO, ESMO, and 
APCCC guidelines provide some consensus and guidance for their use. Regardless, none of these 
therapies are proven to prolong survival after enzalutamide or abiraterone. In practice, 
abiraterone acetate or enzalutamide are often used in the first-line mCRPC setting; Sipuleucel-T 
is best used in mildly asymptomatic small volume disease; and 223Radium is used to treat men 
with bone-only disease. Taxane-based chemotherapy is most often used today after abiraterone 
or enzalutamide and for symptomatic patients, particularly with visceral disease. Docetaxel is 
used more commonly that cabazitaxel. Because both agents have a typical chemotherapy side 
effect profile, they are often not considered for patients due to comorbidity, poor hematological 
reserve, or patient refusal (Zielinski et al 2014).  
Six small published series with a total of 499 patients have examined the efficacy of either 
abiraterone or enzalutamide in men previously exposed to a taxane and either abiraterone or 
enzalutamide. These modern hormonal agents produced only modest activity, including PSA 
decline >50% in 4% to 22% of patients, a median PFS of 2.7 to 4.6 months and a median OS of 
7.2 to 12.2 months (Azad et al 2015, Cheng et al 2015, Badrising et al 2014, Brasso et al 2015, 
Loriot et al 2013, Noonan et al 2013). It’s important to note that this is in contrast with the level 
of anti-tumor activity demonstrated in the pivotal clinical trials for these agents that led to 
approval. In that setting, patients had only received prior docetaxel and had not been exposed to 
prior therapy with either abiraterone or enzalutamide. As these modern hormonal agents have 
been used in earlier lines of therapy, the use of a second agent following docetaxel has resulted 
in diminished efficacy, likely due to cross resistance. 
Therefore, there are limited options available to patients who fail or refuse taxane-based 
chemotherapy, particularly if alternative agents currently approved in this setting (abiraterone 
and enzalutamide) have been used earlier in the disease. 
Prostate-specific membrane antigen  
Prostate-specific membrane antigen (PSMA) is a transmembrane protein, also known as folate 
hydrolase or glutamate carboxypeptidase II. PSMA is highly overexpressed in nearly all prostate 
cancers, but has restricted, and several hundred-fold lower, expression in some normal tissues 
such as the duodenal mucosa, proximal renal tubules, and salivary glands (Bostwick et al 1998, 
Ghosh and Heston 2004, Mannweiler et al 2009). Additionally, PSMA overexpression also 
correlates with advanced, high-grade, metastatic, androgen-independent disease (Ross et al 
2003). The differential expression of PSMA from tumor to non-tumor tissue has resulted in 
numerous targeted strategies involving both disease localization using radioactive imaging as 
well as therapeutic intervention, and therefore may be an attractive target for men with mCRPC. 
In addition to the expression pattern, the functionality of PSMA plays an equally important role 
in its value as a tumor-specific targeting mechanism. Specifically, the binding of a high affinity 


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ligand to PSMA, such as the targeting moiety in 177Lu-PSMA-617, leads to internalization 
through endocytosis and a sustained retention of the ligand and its bound radioactive cargo 
within the cancer cell (Rajasekaran et al 2003). This functional feature of PSMA allows for the 
development of low-molecular-weight targeted radiopharmaceuticals with favorable 
pharmacokinetic and tumor penetration properties, rather than being restricted to antibody-based 
targeting strategies (Haberkorn et al 2016). 
The result of both selective expression and ligand-based uptake using PSMA as a target is a 
reduction in background uptake and off-target toxicities as well as an increase in the amount of 
radioactivity that localizes at the tumor site. 
177Lu-PSMA-617 mechanism of action 
The novel PSMA-targeted radioligand therapy 177Lu-PSMA-617 consists of the PSMA-binding 
ligand glutamate-urea-lysine and a DOTA-chelator, which are connected by a naphthyl-
containing linker. By design, 177Lu-PSMA-617 exhibits high PSMA binding affinity and 
internalization, prolonged tumor retention, and rapid kidney clearance (Benešová et al 2015). 
PSMA-617 was uniquely developed for both imaging and radioligand therapy of prostate cancer 
and can be radiolabeled with gallium-68 (68Ga), lutetium-177 (177Lu), indium-111, copper-64, 
scandium-44, actinium-225, or yttrium-90 (90Y). 
177Lu, the radioactive cargo being delivered by PSMA-617, has physical properties that make it 
an ideal radionuclide for the treatment of mCRPC. 177Lu is a medium-‐energy β‐-emitter (490 
keV) with a maximum energy of 0.5 MeV and a maximal tissue penetration of <2 mm. The 
shorter β‐range of 177Lu provides better irradiation of small tumors, in contrast to the longer 
β-range of 90Y (Emmett et al 2017). The shorter path length also acts to direct the energy within 
the tumor rather than in the surrounding normal tissues, while the path length is still sufficient to 
create bystander and crossfire effects within the tumor lesion. 177Lu has a relatively long physical 
half‐life of 6.6 days that combines with the intratumoral retention of 177Lu-PSMA-617 to reduce 
the necessary dosing frequency. It is these physical properties, and the benefit of PSMA-
targeting, that allow for the delivery of effective activities of 177Lu to prostate cancer cells. 
177Lu-PSMA-617 for metastatic castration-resistant prostate cancer 
The novel therapeutic drug 177Lu-PSMA-617 was developed by the German Cancer Research 
Center, Deutsches Krebsforschungszentrum (DKFZ) in collaboration with University Hospital 
Heidelberg for the treatment of patients with metastatic prostate cancer (Kratochwil et al 2015, 
Hillier et al 2009). Based on preclinical data that demonstrated high PSMA binding affinity and 
compound internalization, prolonged tumor uptake, rapid kidney clearance, and high tumor-to-
background ratio, 177Lu-PSMA-617 proceeded into clinical development at investigative sites in 
Germany. 
Data evaluations based on compassionate use according to the German Medicinal Product Act, 
AMG §13 2b, Clinical Trial Notification (Australia) regulations, and other countries where 
expanded access programs are in place per local regulations, reported a favorable safety profile 
and promising results for PSA response rates of systemic radioligand therapy with 177Lu-PSMA-
617 in patients with mCRPC. 
Dosimetry data suggest that 177Lu-PSMA-617 is targeted to PSMA-expressing tissue, which may 
include the salivary glands, kidneys, and small and large bowel. The highest exposure is to 


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salivary glands, however in the prospective study xerostomia appears low grade and occurs at a 
rate of approximately 87% in treated patients. Clearance of 177Lu PSMA-617 from the kidney 
occurs rapidly. To date nephrotoxicity has not been notable in any safety series. There are no 
reports of Grade 3/4 nephrotoxicity in the literature. The exposure to normal bone marrow tissue 
is predictably low as it does not express PSMA and corresponds with normal plasma clearance. 
There was some evidence of reversible hematological toxicity that occurred following 
177Lu-PSMA-617 treatment that manifested as leukopenia and thrombocytopenia, with rates of 
0 to 40% and 4% to 67% respectively.  
The first published clinical series of 177Lu-PSMA-617 consisted of 10 patients (Ahmadzadehfar 
et al 2015) treated between November 2013 and January 2014, with 5.6 GBq/150mCi (4.1–6.1 
GBq/110–165 mCi). PSA decline >50% occurred in 50% of subjects, which increased to 60% 
after 2 cycles of 6 GBq/160 mCi (4.1–7.1 GBq/110–190 mCi). The level of PSA decline >50% 
(most commonly used to assess tumor response in these studies) has remained remarkably 
consistent across several clinical series when 2 or more doses of ≥6 GBq/160 mCi are given. 
Hofman presented the first prospective open-label, single-arm, non-randomized Phase 2 study of 
177Lu-PSMA-617 in 50 metastatic castration-resistant prostate cancer patients dosed with up to 4 
cycles of 4–8 GBq/110–220 mCi administered every 6 weeks (Hofman et al 2018, Hofman et al 
2019). The primary endpoints of this study were to evaluate both safety and efficacy, as 
measured by PSA response, bone pain score, quality of life measurements, imaging response and 
survival. 
Of the screened patients, 70% were identified as PSMA-positive via PET imaging and eligible 
for treatment. Most subjects had been exposed to at least 1 taxane chemotherapy and either 
abiraterone or enzalutamide in the mCRPC setting. In this heavily pre-treated patient population 
with few therapeutic alternatives, 64% of patients on 177Lu-PSMA-617 showed a PSA response 
defined by a reduction in PSA of at least 50%, and 44% had a reduction of PSA of 80% or more. 
In 27 patients with measurable disease, the objective response rate in measurable disease as 
defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria was 56% (complete 
response [CR] and partial response [PR]). Median overall survival was 13.3 months (95% 
confidence interval [CI] 10.5-18.0). Therapy with 177Lu-PSMA-617 was well tolerated. These 
safety and efficacy data also translated into significantly improved quality of life scores and 
reduction in pain scores. 
In summary, over 40 compassionate use publications and prospective Phase 2 clinical trial data 
describe the use of 177Lu-PSMA-617 in patients who have been exposed to approved agents. In 
the post-taxane, post-androgen axis inhibitor setting 177Lu-PSMA-617 has demonstrated a well-
established, predictable, well tolerated safety profile. Clinical series indicate the most common 
adverse effects, predominately Grade 1-2, of 177Lu-PSMA-617 treatment are dry mouth, nausea, 
vomiting, diarrhea, constipation, fatigue, anemia, thrombocytopenia and neutropenia. The 
incidence of Grade 3/4 toxicity in the series was very low, and mainly restricted to reversible 
hematological events. Efficacy has been demonstrated on multiple clinically significant 
endpoints, including PSA response, soft tissue lesion response measured by RECIST, PFS, OS, 
pain and quality of life. No standard dose and schedule have been developed. 


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The preliminary clinical evidence indicates 177Lu-PSMA-617 may demonstrate clinical benefit in 
patients with mCRPC in a setting where patients had been exposed to chemotherapy and NAADs 
and there is no recommended standard of care. 
This Phase 3 study will assess the efficacy of 177Lu-PSMA-617 in patients with progressive 
PSMA-positive mCRPC by measuring overall survival and rPFS in a randomized, prospective, 
open-label trial. 
1.2 
Summary of nonclinical studies with clinical significance 
In vitro PSMA affinity and internalization studies 
According to Benešová et al, the results of the binding assay of PSMA-617 in PSMA-positive 
LNCaP cells demonstrated a very high binding affinity, with an equilibrium dissociation constant 
(Ki) value of 2.34 ± 2.94 nM. The internalization of PSMA-617 is highly effective with an 
internalized fraction of 17.51 ± 3.99 percent of the added activity/106 LNCaP cells (n = 3) at 
37°C (Benešová et al 2015). 
Organ distribution in mice bearing PSMA-positive LNCaP tumors 
The organ distribution with 177Lu-PSMA-617 in mice showed a high specific uptake in LNCaP 
tumors and in the murine kidneys, as expected. Importantly, the high initial kidney uptake is 
almost completely cleared within 24 hours whereas the tumor uptake remained high or even 
tended to slightly increase during that time frame. Other organs such as the liver, lung and spleen 
demonstrated low uptake at 24 hours after injection (Benešová et al 2015). 
Biodistribution in Wistar rats 
Pharmacokinetic evaluation of 177Lu-PSMA-617 in normal healthy male Wistar rats exhibited 
major renal clearance with no significant uptake in any of the major organ/tissue (Das et al 
2016). More than 80% of the injected activity was excreted within 3 hours post-injection. 
Retention of residual activity was observed in intestine, liver, kidneys and skeleton at 24 hours 
post-administration. However, uptake in these organs, except skeleton, was observed to 
gradually decrease with the time. 
Repeat-dose toxicity in Wistar rats 
The toxicity of non-radioactive PSMA-617 administered once weekly by intravenous (IV) 
administration to male Wistar rats over 22 days was tested in a toxicology study. The animals 
were treated with 40, 160, or 400 µg PSMA-617/kg b.w. by IV bolus injection on test days 1, 8, 
15, and 22. The control group was treated with physiological saline. The no-observed-adverse-
effect-level was found to be above 400 µg PSMA-617/kg body weight administered once weekly 
by IV bolus injection (Leuschner 2016). The estimated mass of the PSMA-617 precursor which 
is applied per treatment cycle is likely to be approximately 150 to 250 µg. Using the NOAEL for 
repeat dosing of PSMA-617 of 400 µg/kg in rats, this accounts for a safety margin of 
approximately 16-27-fold, assuming that the average patient has a body surface are of 1.7 m2. 
However, considering that a more intensive dosing schedule was tested in rats, relative to the 
proposed, and well-studied, clinical regimen of once every 6 to 8 weeks, this safety margin may 
be a conservative estimate. 


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1.3 
Summary of known and potential risks and benefits 
Preclinical work, dosimetry studies, and clinical experience with 177Lu-PSMA-617 since 2013, 
suggest positive response rates and a favorable safety profile in patients with mCRPC 
(Kratochwil et al 2016, Rahbar et al 2017, Kulkarni et al 2016, Haug et al 2016, Rathke et al 
2017, Soydal et al 2016, Rathore et al 2016, Rahbar et al 2016a, Ahmadzadehfar et al 2016, 
Fendler et al 2017, Ferdinandus et al 2017, Rahbar et al 2016b, Yadav et al 2017). 
Dosimetry studies have confirmed that 177Lu PSMA-617 is targeted and normal tissues that 
express PSMA are exposed to radiation (Delker et al 2016). These tissues are salivary glands, 
renal, and small and large bowel. Renal absorbed dose is cleared rapidly, and exposure appears 
similar to that seen with 177Lu-DOTATATE. The exposure to normal bone marrow tissue should 
be low and correspond with normal plasma clearance. 
Nephrotoxicity has not been notable in any safety series. There are no reports of Grade 3/4 
nephrotoxicity in the literature. There was some evidence of reversible hematological toxicity 
that occurred following 177Lu-PSMA-617 treatment that manifested as leukopenia and 
thrombocytopenia, with rates of 0 to 40% and 4% to 67% respectively. Rahbar (2017) reported 
177Lu-PSMA-617 was associated with asymptomatic Grade 3 or 4 leukopenia, anemia, 
thrombocytopenia in 3%, 10%, 4%, respectively. Mild reversible xerostomia occurred in 8% of 
subjects. No significant diarrhea or renal impairment were reported from a retrospective review 
of doctor reports (Rahbar et al 2017). 
Hofman et al. presented results from the first prospective clinical trial with 177Lu-PSMA-617 
(Hofman et al 2019). In the trial, 50 mCRPC patients were dosed with up to 4 cycles of 4–
8 GBq. Prospective common toxicity criteria for adverse events (CTCAE) v4 safety data was 
defined. He found his regimen to be well-tolerated. The most common non-hematological 
toxicities attributed to 177Lu-PSMA-617 occurring in >25% of patients included transient G1-2 
dry mouth (66%), G1-2 nausea (48%), G1-3 fatigue (38%), and G1-2 vomiting (26%). The most 
common hematological toxicities attributed to 177Lu-PSMA-617 occurring in >25% of patients 
included G1-3 lymphocytopenia (72%), G1-4 thrombocytopenia (38%), G1-3 neutropenia (30%) 
and G1-3 anemia (28%). G3-4 toxicities attributed to 177Lu-PSMA-617 were infrequent with 
lymphocytopenia (32%), thrombocytopenia (10%), anaemia (10%), neutropenia (6%) and fatigue 
(2%).  
Potential risks of 177Lu-PSMA-617 include the effects of radiological toxicity, namely 
xerostomia, fatigue, myelosuppression and mild nausea and vomiting. 
Additional details of the nonclinical and clinical experience with 177Lu-PSMA-617 are provided 
in the IB.  
2. 
TRIAL OBJECTIVES AND ENDPOINTS  
2.1 
Trial objectives 
2.1.1 
Primary objective 
The primary objective of this study is to compare the two alternate endpoints of radiographic 
progression free survival (rPFS) and overall survival (OS) in patients with progressive PSMA-


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positive mCRPC who receive 177Lu-PSMA-617 in addition to best supportive/standard of care 
versus patients treated by best supportive/best standard of care alone. 
2.1.2 
Key secondary objectives 
Key secondary objectives are an arm-to-arm comparison of the following: 
1. RECIST response to include: 
a. Overall Response Rate (ORR) as measured by RECIST v1.1 criteria 
b. Disease control rate (DCR) as measured by RECIST v1.1 criteria  
2. Time to a first symptomatic skeletal event (SSE) 
2.1.3 
Additional secondary objectives 
1. Safety and tolerability of 177Lu-PSMA-617 
2. Periodic assessment of health-related quality of life to evaluate impact of intervention on 
patient well-being (HRQoL; EuroQol 5-dimensions 5-level [EQ-5D-5L] questionnaire, 
Functional Assessment of Cancer Therapy – Prostate [FACT-P] questionnaire and Brief 
Pain Inventory – Short Form [BPI-SF]) 
3. Health Economics 
4. Progression-free survival (PFS) (radiographic, clinical, or PSA progression-free survival) 
5. Biochemical response as measured by PSA. Alkaline phosphatase [ALP] and lactate 
dehydrogenase [LDH] levels will also be collected. 
 
2.2 
Trial endpoints 
2.2.1 
Alternate Primary endpoints 
rPFS and OS are designated as alternate primary endpoints. rPFS is defined as the time from the 
date of randomization to the date of radiographic disease progression as outlined in Prostate 
Cancer Working Group 3 (PCWG3) Guidelines (Scher et al 2016) or death from any cause. OS 
is defined as the time from randomization to the date of death from any cause. 
rPFS will be assessed locally by each site. Additionally, patient scans will be collected for 
independent central review. The independent central review will be used to support the primary 
rPFS analysis. The local rPFS assessment will be supportive.  
The statistical design of the study is such that, to be declared positive, the study would be 
required to reach statistical significance on either the primary analysis of rPFS or OS at the 
respective allocated alpha level; it is not required to statistically meet both rPFS and OS to be 
declared a positive study. Alpha allocation and recycling is used to ensure control of the overall 
Type I error rate.  
2.2.2 
Key Secondary endpoints 
The key secondary endpoints include the following: 


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1. RECIST response to include: 
a. Objective response rate (ORR) (CR + PR) as measured by RECIST v1.1 response in 
soft tissue, lymph node and visceral lesions. Duration of Response (DOR) will also be 
measured in patients with a CR or PR from date of first response to the date of 
RECIST progression or death. 
b. Disease Control Rate (DCR) (CR + PR + stable disease [SD]) as measured by 
RECIST v1.1 response in soft tissue, lymph node and visceral lesions.  
2. The time to a first SSE defined as date of randomization to 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 from any cause, whichever occurs first. 
2.2.3 
Additional Secondary endpoints 
1. To evaluate the safety and tolerability of 177Lu-PSMA-617 
2. Aspects of HRQoL will be reported using the EuroQol 5-dimensions 5-level [EQ-5D-5L] 
questionnaire, Functional Assessment of Cancer Therapy – Prostate [FACT-P] 
questionnaire and Brief Pain Inventory – Short Form [BPI-SF] 
3. Health economics 
4. Progression-free survival is defined as the date of randomization to the date of first 
evidence of radiographic progression, clinical progression, PSA progression, or death 
from any cause, whichever occurs first. 
a. Radiographic progression is defined as the date of radiographic disease 
progression as outlined in the Prostate Cancer Working Group 3 (PCWG3) 
Guidelines. 
b. Unequivocal clinical progression. Unequivocal evidence of clinical progression is 
defined as:  
 Marked escalation in cancer related pain that is assessed by the 
investigator to indicate the need for other systemic chemotherapy 
 Immediate need for initiation of new anticancer treatment, surgical or 
radiological intervention for complications due to tumor progression even 
in the absence of radiological progression 
 Marked deterioration in ECOG performance status to ≥ Grade 3 and/or in 
the opinion of the investigator ECOG deterioration indicates clinical 
progression 
 In the opinion of the investigator, it is in the best interest of the patient to 
discontinue treatment due to clinical progression  
c. PSA progression is defined as the date that a ≥ 25% increase in PSA and an 
absolute increase of 2 ng/mL or more from the nadir is documented and 
confirmed by a second consecutive value obtained 3 or more weeks later. Rises in 
PSA within the first 12 weeks will be ignored in the absence of other evidence of 
disease progression (PCWG3 Guidance). Where no decline from baseline is 


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documented, PSA progression is 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 
of treatment. 
5. Biochemical response endpoints:  
a. Proportion of subjects who are PSA responders, defined as a patient who has 
achieved a ≥50% decrease from baseline that is confirmed by a second PSA 
measurement ≥4 weeks.  
b. Alkaline phosphatase [ALP] and lactate dehydrogenase [LDH] levels will also be 
collected. 
3. 
TRIAL DESIGN 
3.1 
Overview of the clinical trial design 
This is a Phase 3, open-label, international, randomized study to evaluate the efficacy and safety 
of 177Lu-PSMA-617 in patients with progressive PSMA-positive mCRPC, when administered in 
addition to best supportive/best standard of care as compared to best supportive/best standard of 
care alone (Figure 1). 
 
 
Figure 1 
Diagram of trial design 
ECOG = Eastern Cooperative Oncology group; EQ-5D-5L = European Quality of Life (EuroQol) – 5 Domain 5 
Level scale; FACT-P = Functional Assessment of Cancer Therapy – Prostate; mCRPC = metastatic castration-
resistant prostate cancer; PSMA+ = prostate-specific membrane antigen positive; RECIST = Response Evaluation 
Criteria in Solid Tumors  


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Best supportive/best standard of care includes available care for the eligible patient according to 
best institutional practice and at the discretion of the investigator. Novel androgen axis drugs 
[NAADs] (i.e., enzalutamide or abiraterone) are allowed. 
Investigational agents, cytotoxic chemotherapy, immunotherapy, other systemic radio isotopes 
(e.g. radium-223) or hemi-body radiotherapy treatment may not be administered on study. 
At screening, potential subjects will be assessed for eligibility and will undergo a 68Ga-PSMA-11 
PET/computed tomography (CT) scan to evaluate PSMA positivity. Only patients with PSMA-
positive cancer will be randomized in a 2:1 ratio to receive either 177Lu-PSMA-617 plus best 
supportive/best standard of care (investigational arm) or to receive best supportive/best standard 
of care alone (BS/BSC-only arm). Randomization will be stratified by 4 factors (Section 3.4.3). 
Patients randomized to the investigational arm must begin 177Lu-PSMA-617 dosing within 
28 days after randomization. These patients will receive best supportive/best standard of care and 
7.4 GBq (±10%) 177Lu-PSMA-617 once every 6 weeks (±1 week) for a maximum of 6 cycles.  
After the Cycle 4 dose of 177Lu-PSMA and prior to Cycle 5 Day 1, the investigator should 
determine if: 
• The patient shows evidence of response (i.e. radiological, PSA, clinical benefit) and  
• Has signs of residual disease on CT with contrast/MRI or bone scan and 
• Has shown good tolerance to the 177Lu-PSMA-617 treatment. 
 
If the patient meets all of the criteria above, and agrees to continue with additional treatment of 
177Lu-PSMA-617, the investigator may administer a further 2 cycles. A maximum of 6 cycles of 
radioligand therapy is allowed. If the patient does not meet any of the criteria or does not agree 
to additional 177Lu-PSMA-617 treatment, then no additional doses of 177Lu-PSMA-617 will be 
administered after Cycle 4. After the last cycle of 177Lu-PSMA-617, patients can continue best 
supportive/best standard of care alone. 
Best supportive/best standard of care for each patient will be selected at the discretion of the 
patient’s physician, prior to randomization and will be administered per the physician’s orders 
and continued until the patient comes off the treatment part of the study and enters the long-term 
follow-up stage. 
A patient may choose to discontinue randomized treatment part of the study at any time.  
Before final analysis of alternate primary endpoint OS: 
If a patient chooses only to discontinue from the randomized treatment in the study for a reason 
other than radiographic progression, the patient will be asked to confirm if they consent to 
continue to be followed for long-term safety, rPFS, and survival follow-up. The patient will 
continue to be followed for long-term follow-up unless they specifically withdraw consent from 
long-term follow-up of the study. An End of Treatment (EOT) visit should occur once a patient 
discontinues randomised treatment for any reason (patient or investigator decision, going on to 
long-term follow-up, etc.). 


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The EOT visit should occur approximately 30 days from the last dose of 177Lu-PSMA-617 or the 
date of the best supportive/best standard of care end of treatment decision (whichever occurs 
later), but before the initiation of subsequent anti-cancer treatment, outside of what is allowed on 
study. 
If a patient discontinues randomized treatment for any reason other than radiographic 
progression, they will be asked for permission to continue collecting radiographic images (bone 
scans and CT scans and/or MRIs) for the purpose of continuing to assess rPFS. 
After the EOT visit, patients will enter the long-term follow-up period. The long-term follow-up 
period will include the collection of rPFS (if discontinuing for reasons other than radiographic 
progression), survival and information about new treatments, along with the patient’s response to 
these treatments, adverse events assessment, and results of hematology and chemistry testing. 
During follow-up, patients will be followed for safety and survival. They will be contacted every 
3 months (±1 month) via phone, email, or letter for up to 24 months or until 508 deaths have 
occurred. 
Patients who withdraw their consent to participate in the study for any reason other than 
radiographic disease progression will be asked for permission to continue long-term status 
updates which may include, in addition to the above, collection of radiographic images (bone 
scans and CT scans and/or MRIs). 
These patients will be asked to sign a separate consent detailing what kind of long-term follow-
up assessments and study updates they will agree to. They will also be able to designate a contact 
person (i.e. study doctor, local doctor, friend or family member) who may be contacted on their 
behalf to obtain follow-up status updates. 
For any of these patients who are unable to sign the second consent (i.e. does not return to the 
site, etc.) every effort will be made to document the extent of long-term follow-up they will 
agree to. This will be documented in their source records.  
After final analysis of alternate primary endpoint OS: 
All randomized patients on the active part of the study, after the final analysis of the OS primary 
endpoint will have an EOT visit at the next planned visit after implementation of V5.0 of the 
protocol at the site and will move into long-term follow-up. All patients in long-term follow-up 
will continue to be followed on this study under, the same patient ID, until a long-term safety 
follow-up study is available in the respective country, until death or until withdrawal of consent, 
whichever occurs first. Every opportunity to continue to collect long-term safety data should be 
made for each willing participant, regardless of time gap between release of protocol amendment 
v5 and v6.0. 
The long-term follow-up period will include the collection of survival and new treatment 
information, adverse events assessment for renal toxicity and secondary malignancies, and 
results of hematology and chemistry testing. During follow-up, patients will be followed for 
safety and survival. They will be seen or contacted by a clinician every 3 months (±1 month) via 
phone, in person or via telemedicine visit, email or letter on this study until a long-term safety 
follow-up study is available, until death or until withdrawal of consent, whichever occurs first. 
This study will enroll approximately 814 patients involving about 110 sites worldwide. 


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3.1.1 
Study design update 
The trial was originally designed to randomize 750 patients, targeting the primary analysis of 
rPFS with 457 events, an interim analysis of OS, to be conducted contemporaneously with the 
primary analysis of rPFS, and a final analysis of OS with 489 deaths. 
However, shortly after commencement of the trial, a high, early dropout rate amongst those 
randomized to BS/BSC only became evident with the majority of these dropouts withdrawing 
consent to follow-up. This meant that rPFS data could not be collected for these patients which 
consequently could result in bias in the analysis of rPFS. Remedial measures to curtail this 
phenomenon were implemented and made effective on March 5th, 2019. As part of the plan to 
address the early withdrawal of consent in the BS/BSC-only arm, the primary analysis of rPFS 
was altered to focus on patients prospectively randomized on or after March 5th, 2019; therefore, 
rPFS will be analyzed in these patients once 364 events have accrued. At time of the rPFS 
primary analysis, there will also be an interim analysis of OS; this OS analysis will be on an 
intent to treat (ITT) basis and will include all randomized patients (i.e., including those 
randomized before March 5th, 2019). Following the analysis of rPFS and the interim analysis of 
OS, a final ITT analysis of the OS primary objective will be performed when 508 deaths have 
accrued. To achieve these analyses, the total number of subjects randomized into the trial was 
increased from N=750 to N=814. The revisions described do not alter the hypothesized treatment 
effects for rPFS and OS upon which the study was originally powered. 
3.2 
Rationale for the study design 
The primary objective of this study is to compare the two alternate endpoints of rPFS and overall 
survival (OS) in patients with progressive PSMA-positive mCRPC who receive 177Lu-PSMA-
617 in addition to best supportive/standard of care versus patients treated by best supportive/best 
standard of care alone. The statistical design of the study is such that, to be declared positive, the 
study would be required to reach statistical significance on either rPFS or OS at the respective 
allocated alpha level; it is not required to statistically meet both rPFS and OS to be declared a 
positive study. Secondary endpoints have been defined by PCWG3 as well as FDA and EMEA 
guidance. In view of the highly symptomatic nature of advanced mCRPC both validated pain 
(BPI-SF) and HRQoL (EQ-5D-5L and FACT-P) measurements will be collected using various 
questionnaires. 
3.3 
Measures taken to minimize/avoid bias 
Patients will be randomized to 1 of 2 treatment arms. Randomization will be stratified to avoid 
bias in treatment selection (Section 3.4.3). Treatment will be open-label. 
Reading of the baseline 68Ga-PSMA-11 PET/CT scan will be done by central readers for 
consistency. 
3.4 
Description of the clinical trial 
3.4.1 
Description of investigational medicinal product  
The 68Ga-PSMA-11 radiopharmaceutical will be administered intravenously at a dose of 111 - 
185 MBq (3 - 5 mCi). For background and additional details on 68Ga-PSMA-11, refer to the 
68Ga-PSMA-11 Investigator’s Brochure.  


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Refer to the Fendler et al 2017 publication “68Ga-PSMA PET/CT: Joint EANM and SNMMI 
procedure guideline for prostate cancer imaging: version 1.0 guideline” for an overview of 68Ga-
PSMA-11 recommendations. Details of the patient preparation and administration can be found 
in the Imaging Manual. 
The 177Lu-PSMA-617 solution for injection consists of a sterile solution in glass vials containing 
7.4 (±0.74) GBq of 177Lu-PSMA-617 at time of injection. 
Refer to the 177Lu-PSMA-617 IB for additional details of the investigational medicinal product 
including the pharmacological class and action, the dosage form including excipients, and any 
available packaging and labelling. 
3.4.2 
Dosage and rationale for dose selection 
In the investigational arm, patients will receive best supportive/best standard of care regimen and 
IV 7.4 GBq (±10%) 177Lu-PSMA-617 once every 6 weeks (±1 week) for a maximum of 6 cycles. 
After 4 cycles patients will be reassessed to determine if a further 2 cycles can be given for a 
maximum of 6 cycles (Section 3.1). 
The basic principle of 177Lu-PSMA-617 radioligand therapy is to systemically deliver low dose 
rate radiation specifically to multiple PSMA positive prostate cancer lesions, while sparing 
normal tissues. To date, 11 dosimetry studies have been conducted and published in over 100 
patients. The results are consistent across the studies and demonstrate exposure that correlates 
well with the expected rapid clearance of a small molecule, and the limited distribution pattern of 
a PSMA-targeted radionuclide. The primary sites of non-tumor uptake were the salivary glands, 
lacrimal glands, and kidneys, with excretory mechanisms contributing to exposure in the kidneys 
where approximately 50% of the injected dose is cleared within 48 hours (Kratochwil et al 
2016). PSMA-negative tissues like the bone marrow, are exposed transiently to 177Lu-PSMA-617 
while in circulation, however this exposure is minimized due to its rapid elimination.  
177Lu-PSMA-617 is well tolerated according to the clinical experience that has been documented 
in 42 publications, summarizing the safety and or efficacy information from over 800 subjects. 
Across these studies doses have ranged from 1.1-12.0 GBq, and schedules have typically 
followed an administration schedule of once every 4 to 12 weeks, for 1-9 cycles. The majority of 
these publications have used a regimen of 4 cycles of 6 GBq every 8 weeks, as published by the 
German Radiopharmaceutical Society in 2015. However, efficacy and safety information from 
the prospective phase 2 study suggested that dosing of 6-8 GBq every 6 weeks for 4 cycles was 
well tolerated and efficacious (Hofman et al 2018). 
Clinical series now show reports of more than 4 cycles of 177Lu PSMA-617 being administered 
safely as a means to maximize the benefit to the patient (Rahbar et al 2018, Kulkarni et al 2018, 
Bräuer et al 2017, Yordanova et al 2017). In addition, a recent review suggests optimal dosing of 
6 cycles of 177Lu-PSMA-617 administered every 6 weeks in a decreasing scale reaching a total 
cumulative absorbed dose of 44 GBq (Emmett et al 2017). Six fractions of 7.4 GBq, delivers a 
similar total dose of 44.4 GBq.  
In the ANZUP1603 study in 200 Australian patients (NCT03392428), which is comparing 177Lu-
PSMA-617 with cabazitaxel, the dose starts at 8.5 GBq 177Lu-PSMA-617 and reduces by 0.5 
GBq per cycle, i.e. 8.5, 8, 7.5, 7, 6.5, 6 (cycle #6). A maximum of 6 cycles given every 6 weeks 


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is what is being evaluated, which equates to a cumulative dose that is similar to that for this 
proposed study.  
The clinical safety review and detailed analyses of the radiation exposure support the intended 
dose and frequency of 177Lu-PSMA-617 administration in this clinical trial. 
3.4.3 
Subject allocation to treatment 
Patients will be randomized by an interactive response system in a 2:1 ratio to the investigational 
treatment arm (177Lu-PSMA-617 plus best supportive/best standard of care) or the best 
supportive/best standard of care-only arm using a permuted block scheme. Randomization will 
be stratified by the following factors: 
• LDH (≤ 260 IU/L vs. > 260 IU/L) 
• Presence of liver metastases (yes vs. no) 
• ECOG score (0 or 1 vs. 2) 
• Inclusion of NAAD in best supportive/best standard of care at time of randomization (yes 
vs no) 
3.4.4 
End of treatment visit 
An EOT visit should occur once a patient discontinues the treatment part of the study for any 
reason (patient or investigator decision, going on to long-term follow-up, etc.).  
This visit should occur approximately 30 days from the last dose of 177Lu-PSMA-617 or the date 
of the best supportive/best standard of care end of treatment decision (whichever occurs later), 
but before the initiation of subsequent anti-cancer treatment, outside of what is allowed on study. 
3.4.5 
Duration of Subject Participation 
Patients may continue treatment until radiographic progressive disease, withdrawal of consent, 
the occurrence of unacceptable toxicity, or a determination by the investigator the patient is not 
clinically benefiting. As per the patient’s physician, when the participant requires care that is not 
allowed on study, the participant will discontinue treatment and enter the long-term follow-up 
period. While the patient and/or physician may decide prematurely to cease taking randomized 
therapy at any time, full follow-up of all randomized patients for the intended duration of the 
trial is planned by design for the collection of rPFS and OS data. 
It is anticipated that it will take approx. 14 months to randomize the required 814 patients in the 
study. After the last patient is randomized patients will be followed for up to 24 months or at 
least until 508 deaths have occurred. The maximum duration of the study, from first date of 
randomization to last follow-up, will therefore be approximately 38 months.  
After final analysis of the OS primary endpoint, long-term follow-up will be extended until a 
separate long-term safety follow-up study is available in the respective country, until patient 
death or until patient withdrawal of consent, whichever occurs first. The maximum duration of 
the study, from first date of randomization to last follow-up, will therefore be up to 
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3.5 
End of trial definition 
The trial and long-term follow-up procedures are expected to continue at least until 508 deaths 
have occurred. Long-term follow-up for safety and survival will continue until a separate long-
term safety follow-up study is available. For timing of the rPFS and OS analyses and any rules 
for early statistical curtailment, refer to Section 8.1. 
4. 
SELECTION AND DISCONTINUATION OF SUBJECTS 
Written informed consent must be obtained prior to any study-related procedures. The 
Investigator will ensure that the participant is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study as well as the 
participant’s financial responsibility. While full follow-up is intended in the ITT population for 
the planned duration of the trial, participants must also be notified that they are free to 
discontinue from the study at any time. The participant will be given the opportunity to ask 
questions and allowed time to consider the information provided. A copy of the signed written 
informed consent form (ICF) will be given to the participant for their review and signature.  
4.1 
Inclusion criteria 
To qualify for enrollment, patients must meet the following criteria: 
1. Patients must have the ability to understand and sign an approved 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 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 PET/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.). 


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11. Patients must have progressive mCRPC. Documented progressive mCRPC will be based 
on at least 1 of the following criteria: 
a. 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. 
b. 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. 
c. Progression of bone disease: evaluable disease or new bone lesions(s) by bone scan 
(2+2 PCWG3 criteria, Scher et al 2016). 
12. 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. 
13. Patients must have recovered to ≤ Grade 2 from all clinically significant toxicities related 
to prior therapies (i.e. prior chemotherapy, radiation, immunotherapy, etc.). 
14. Patients must have adequate organ function: 
a. Bone marrow reserve: 
• White blood cell (WBC) count ≥2.5 × 109/L (2.5 × 109/L is equivalent to 
2.5 × 103/µL and 2.5 × K/µL and 2.5 × 103/cumm and 2500/µL) OR absolute 
neutrophil count (ANC) ≥1.5 × 109/L (1.5 × 109/L is equivalent to 1.5 × 103/µL 
and 1.5 × K/µL and 1.5 × 103/cumm and 1500/µL) 
• Platelets ≥100 × 109/L (100 × 109/L is equivalent to 100 × 103/µL and 100 × K/µL 
and 100 × 103/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 × ULN is permitted 
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤3.0 × 
ULN OR ≤5.0 × ULN for patients with liver metastases 
c. Renal:  
• Serum/plasma creatinine ≤1.5 x ULN or creatinine clearance ≥50 mL/min 
15. Albumin >3.0 g/dL (3.0 g/dL is equivalent to 30 g/L) 
[Inclusion #16 has been removed] 
17. HIV-infected patients who are healthy and have a low risk of AIDS-related outcomes are 
included in this trial. 


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18. 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. 
19. The best standard of care/ best supportive care options planned for this patient: 
a. Are allowed by the protocol  
b. Have been agreed to by the treating investigator and patient 
c. Allow for the management of the patient without 177Lu-PSMA-617 
4.2 
Exclusion criteria 
Patients who meet any of the following criteria will be excluded from the study: 
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 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. 


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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.  
 
4.3 
Subject withdrawal of consent for study or treatment 
A patient may choose to withdraw his consent for participation in the study at any time at which 
time all follow-up procedures will end.  
Before final analysis of alternate primary endpoint OS: 
If a patient chooses only to discontinue from the randomized treatment in the study, the patient 
will be asked to confirm if they consent to continue to be followed for long-term safety, rPFS (if 
discontinuing for reasons other than radiographic progression), and survival follow-up. This may 
include blood work results, radiographic follow up and information about new treatments and his 
response to these treatments. Patients may also choose to be followed for survival only long-term 
follow-up.  
After final analysis of alternate primary endpoint OS: 
All randomized subjects on the active part of the study after the final analysis of the OS primary 
endpoint, will have an EOT visit and will move into long-term follow-up. This may include 
collection of survival and new treatment information, adverse events assessment for renal 
toxicity and secondary malignancies, and results of hematology and chemistry testing. Patients 
may choose to be followed for survival only long-term follow-up. 
All randomized patients on the active part of the study at the time of final analysis of the 
alternate primary endpoint OS are to be followed for safety and survival on this study, under the 
same patient ID, until a long-term safety follow-up study is available, until death, or until 
withdrawal of consent, whichever occurs first. Every opportunity to continue to collect long-term 
safety data should be made for each willing participant, regardless of time gap between release of 
protocol amendment v5.0 and v6.0. 
5. 
TREATMENT OF SUBJECTS  
5.1 
Treatment with the investigational medicinal product 
5.1.1 
Administration of 68Ga-PSMA-11 
For background and additional details on 68Ga-PSMA-11, refer to the 68Ga-PSMA-11 
Investigator’s Brochure. The 68Ga-PSMA-11 radiopharmaceutical will be administered 
intravenously at a dose of 111 - 185 MBq (3 - 5 mCi). 
Refer to the Fendler et al 2017 publication “68Ga-PSMA PET/CT: Joint EANM and SNMMI 
procedure guideline for prostate cancer imaging: version 1.0 guideline” for an overview of 68Ga-
PSMA-11 recommendations. Details of the patient preparation and administration can be found 


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in the Imaging Manual. 
 
5.1.2 
Administration of 177Lu-PSMA-617 
Once every 6-weeks (± 1 week), 7.4 GBq (±10%) 177Lu-PSMA-617 will be administered. A 
7.4 GBq dose is equivalent to 200 mCi or 7400 MBq. 
Treatment with 177Lu-PSMA-617 must be performed in accordance with national and/or local 
radiation and safety requirements. 
A saline flush with ≥10 mL of normal saline must be administered to ensure patency of the 
intravenous line before administering with 177Lu-PSMA-617 administration. 
177Lu-PSMA-617 will be administered slowly by intravenous route and followed by a saline 
flush. The time of administration must be recorded. The total activity administered must be 
measured (GBq). 
Vital signs will be collected 15(+/- 5) minutes before and at 30(+/- 5) and 60(+/- 5) minutes 
following administration.  
Patients should also be monitored for any evidence of pain or burning sensation during the 
injection. Patients should be encouraged to maintain a good fluid intake on the day of treatment 
and following therapy. 
Date and time of patient discharge following 177Lu-PSMA-617 administration should be 
recorded. 
A decision to order 177Lu-PSMA-617 should be communicated to the sponsor or designee no 
later than 10 business days prior to the planned administration for each cycle.  
 
5.1.3 
Toxicity risk reduction and supportive care for 177Lu-PSMA-617 injections 
Supportive care should be provided as deemed necessary by the treating physician. 
Oral hygiene 
Patients should be advised to use sodium bicarbonate mouthwash during the first 3 days of each 
cycle. 
Nausea and vomiting 
Mild nausea and vomiting may occur without prophylactic therapy and antiemetic treatment is 
recommended. Oral or IV ondansetron (or equivalent) and/or dexamethasone or equivalent 
institutional anti-emetic regimen should be administered on the day of 177Lu-PSMA-617 
administration. If oral administration is given, it should occur at least 30 minutes before dosing 
and, if by injection, at least 15 minutes prior to infusing 177Lu-PSMA-617. 
Additionally, dexamethasone and domperidone/metoclopramide or institutional anti-emetic 
regimen may be administered on Days 2 and 3 of each cycle if required at the discretion of the 
investigator. 
Other anti-emetics should be used as required as per standard clinical practice.  


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Additional suggested treatment guidelines 
A listing of additional suggested treatment guidelines can be found in Appendix 2. These are to 
be used at the discretion of the investigator. 
5.1.4 
Management of toxicity adverse events: dosing delays and modification 
Within the first few days of treatment the most common adverse events (AEs) are general fatigue 
and an increase in bone pain. Symptomatic hematologic toxicity may occur but is not common. 
Every effort should be made to keep the treatment cycle of 6 weeks (±1 week) at the prescribed 
doses. Physical exams, assessment of toxicities, along with hematology and chemistry results 
must all be assessed prior to dosing with 177Lu-PSMA-617. At the discretion of the investigator, 
a dose of 177Lu-PSMA-617 may be delayed or reduced. Table 1 provides dose modification 
recommendations. Only one reduction in administered activity is permitted. If a patient has 
further toxicity that would require an additional reduction in administered activity, treatment 
with 177Lu-PSMA-617 must be discontinued. Once a dose is reduced, treatment with 177Lu-
PSMA-617 should not be re-escalated. 
If a treatment delay due to adverse event or toxicity management persists for >4 weeks, treatment 
with 177Lu-PSMA-617 must be discontinued. If treatment with 177Lu-PSMA-617 is discontinued 
due to an AE, abnormal laboratory value, or toxicity, treatment with best supportive/best 
standard of care may continue at the discretion of the investigator if the patient has not 
radiographically progressed as measured by PCWG3 criteria. 
 
Table 1 Toxicity management and dose modification recommendations 
Event 
Grade 
Management recommendations 
Anemia, leukopenia, or neutropenia: 
• 
Hemoglobin <10 g/dL 
• 
WBC count <3.0 × 109/L 
• 
ANC <1.5 × 109/L 
≥Grade 2 
Hold 177Lu-PSMA-617 administration until improvement 
to Grade 1 or baseline. 
Manage as deemed appropriate by investigator. The use 
of growth factors is permitted but should be discontinued 
once the AE resolves to Grade 1 or baseline. Checking 
hematinic levels (iron, B12, and folate) and providing 
supplementation is advocated. Transfusions may be given 
as clinically indicated for anemia. 
 
Thrombocytopenia  
(platelet count of < 75 x 109/L) 
≥ Grade 2  
Hold 177Lu-PSMA-617 administration until improvement 
to Grade 1 or baseline. 
 
Transfusions may be given as clinically indicated for 
thrombocytopenia. 
Hematological toxicity (except 
lymphocytopenia that responds to 
medical intervention) 
Grade 3 or 
Grade 4 
Hold 177Lu-PSMA-617 administration until improvement 
to Grade 1 or baseline. 
Reduce 177Lu-PSMA-617 dose by 20% on the next cycle 
Serum/plasma creatinine increased 
≥40% from baseline AND calculated 
creatinine clearance decreased >40% 
from baseline 
 
Reduce 177Lu-PSMA-617 dose by 20% on the next cycle 


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Table 1 Toxicity management and dose modification recommendations 
Event 
Grade 
Management recommendations 
Salivary gland toxicity 
≥ Grade 2 
Reduce 177Lu-PSMA-617 dose by 20% on the next cycle 
Non-hematological, clinically 
significant toxicity not otherwise stated  ≥ Grade 2 
Hold 177Lu-PSMA-617 administration until resolved to 
Grade 1 or baseline 
Electrolyte or metabolic abnormalities 
that are correctable within a 48 hr 
period without sequela  
≥ Grade 2 
Hold 177Lu-PSMA-617 administration until resolved to 
Grade 1 or baseline 
Gastrointestinal toxicity (not amenable 
to medical intervention) 
≥ Grade 3 
Hold 177Lu-PSMA-617 administration until resolved to 
Grade 2 or baseline 
Reduce 177Lu-PSMA-617 dose by 20% on the next cycle 
Fatigue 
≥ Grade 3 
Hold 177Lu-PSMA-617 administration until resolved to 
Grade 2 or baseline 
Pain 
≥ Grade 3 
Hold 177Lu-PSMA-617 administration until resolved to 
Grade 2 or baseline 
Spinal cord compression 
 
Hold 177Lu-PSMA-617 administration until the 
compression has been adequately treated and 
hematological parameters have returned to Grade 1 or 
baseline and ECOG performance status has returned to 
baseline at the time the next cycle administration is due 
Fracture in weight bearing bones 
 
Hold 177Lu-PSMA-617 administration until fracture is 
adequately stabilized/treated and hematological 
parameters have returned to Grade 1 or baseline and 
ECOG performance status has returned to baseline at the 
time the next cycle administration is due 
AST or ALT >5 × ULN in the absence 
of liver metastases 
 
Discontinue 177Lu-PSMA-617 
Renal toxicity 
≥ Grade 3 
Discontinue 177Lu-PSMA-617 
Any serious AE that requires drug 
discontinuation or treatment delay of 
>4 weeks 
 
Discontinue 177Lu-PSMA-617 
Any unacceptable toxicity 
 
Discontinue 177Lu-PSMA-617 
Note: Hematologic parameters (i.e., CBC with differential analysis) will be monitored every week in Cycle 1 only. 
Cycles 2 to 6, it will be monitored every 2 weeks. After Cycle 6, it will be monitored every 12 weeks. 
AE = adverse event; ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate 
aminotransferase; ECOG = Eastern Cooperative Oncology Group; Lu = Lutetium; PSMA = prostate-specific 
membrane antigen; ULN = upper limit of normal; WBC = white blood cell 
5.2 
Best supportive/best standard of care 
The care of cancer patients must include cancer specialists accomplished in the care of patients 
with advanced prostate cancer, (e.g., medical, radiation oncologists) with a clear understanding 
of the PCWG3 2+2 rules for progression, management of AEs related to the natural course of the 
disease, as well as pre-existing AEs and study-related AEs. 
The best supportive/best standard of care for the patient in either arm should be administered as 
per physician’s orders and protocol at the institution, and whenever feasible, best supportive/best 
standard of care should be optimized for all study participants prior to randomization. Patients 


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will continue to be treated with best supportive/best standard of care until they require a 
treatment regimen not allowed on this study or have radiographic progressive disease as 
measured by PCWG3 criteria. 
Other treatments for prostate cancer, not specifically excluded as part of the study, should be 
used in accordance with the routine clinical practice and at the discretion of the investigator. 
These may include, but are not limited, to any of the interventions mentioned below. 
Supportive measures (pain meds, hydration, transfusions, etc.), and ketoconazole are allowed on 
study. 
Hormonal agents (single or combinations), estrogens including diethylstilbestrol (DES) and 
estradiol are allowed on study. 
Luteinizing hormone-releasing hormone (LHRH) analogue for testosterone suppression 
including both agonists and antagonists are allowed on study.  
Any corticosteroid such as dexamethasone, prednisone, etc. and 5-alpha reductases including 
finasteride and dutasteride is allowed on study. 
Abiraterone, enzalutamide, apalutamide or any other NAAD is allowed on study. 
Radiation in any external beam or seeded form is allowed on the study. This can include 
stereotactic body radiation therapy (SBRT) or palliative external beam or radiation involving 
seeds but no systemic radiopharmaceuticals. Y90 beads are allowed for approaches to liver 
metastasis as they are FDA approved.  
Bone targeted agents including zoledronic acid, denosumab and any bisphosphonates are allowed 
on study. 
It is important to recognize that combinations of any, and all, of the above are allowed on the 
study and can be modified over time as needed. 
5.3 
Concomitant medications/ supportive care 
5.3.1 
Permitted concomitant medications/ supportive care 
Consideration should be given to using concomitant bone health agents such as bisphosphonates 
on either arm of the study. Patients receiving bisphosphonates, denosumab, zoledronic acid or 
similar therapy prior to randomization may be maintained on this therapy during the study. 
Bisphosphonates denosumab, zoledronic acid or similar therapy can be stopped or started at the 
discretion of the investigator throughout the study. 
Patients must maintain castrate levels of serum/plasma testosterone either by chemical castration 
or by having had an orchiectomy. 
Medications for myelosuppression 
Blood transfusion or erythropoietin stimulation agents are allowed throughout the study after 
randomization. Routine prophylaxis with GCSF/granulocyte-macrophage colony-stimulating 
factor and erythropoietin is not recommended. Nevertheless, use is permitted at the investigator’s 
discretion. 
Refer to Section 5.1.4 for guidance on the management of toxicity. 


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5.3.2 
Prohibited concomitant medications 
Investigational agents, cytotoxic chemotherapy, immunotherapy, other systemic radio isotopes 
(e.g., radium-223), or hemi-body radiotherapy treatment may not be administered on study. 
5.4 
Monitoring treatment compliance 
The investigational medicinal product will be administered only at the investigational site under 
the direction of the investigator. Compliance with 177Lu-PSMA-617 therapy will be monitored 
and ensured. 
5.5 
Treatment discontinuation 
Patients may discontinue the treatment part of the study for any of the following reasons: 
• Evidence of tumor progression by radiological assessment as measured by PCWG3 
criteria 
• Unacceptable toxicity 
• Patient non-compliance or voluntary withdrawal 
• Required use of a prohibited treatment 
• Evidence that the patient is no longer clinically benefiting 
• At the sponsor’s or investigator’s discretion 
Patients that discontinue treatment due to unacceptable toxicity should return to the clinic for the 
End of Treatment visit. Participants who discontinue 177Lu-PSMA-617 due to unacceptable 
toxicity may continue to receive best supportive/best standard of care alone during the treatment 
part of the study until they discontinue the treatment part of the study and enter long-term follow-
up.  
 
Before final analysis of alternate primary endpoint OS: 
If a patient discontinues the treatment part of the study for any reason other than radiographic 
progression, they will be asked for permission to continue collecting radiographic images (bone 
scans and CT scans and/or MRIs) for the purpose of continuing to assess rPFS, unless they 
specifically withdraw consent from continued participation in the study.  
 
After final analysis of alternate primary endpoint OS: 
If a patient discontinues the treatment part of the study for any reason other than radiographic 
progression, no additional scanning will be required. 
6. 
STUDY ASSESSMENTS AND PROCEDURES 
6.1 
Screening procedures and baseline assessments 
Screening procedures and baseline assessments will be performed within 4 weeks of 
randomization except for baseline imaging. Any procedure or assessment done within this time 
frame may be accepted as the baseline procedure or assessment. Baseline medical imaging (CT 
with contrast/ MRI, and bone scan) is to be performed within 28 days of start of treatment. Any 


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medical imaging done within this time frame may be accepted as the baseline imaging. The 
screening procedures are detailed in Table 2. 
Table 2 Screening procedures and baseline assessments 
Screening Procedure or 
Baseline Assessment 
Notes 
Informed consent 
As per local/central IRB/IEC/REB timing requirements but prior to the 
performance of any study specific procedures. 
Inclusion/exclusion criteria 
Refer to Section 4.1 and Section 4.2 for additional details. 
Medical history 
Collect medical history, including the following details about prior 
prostate cancer treatment(s): 
• 
Date of initial diagnosis 
• 
Approximate start and stop date of each therapy 
• 
Date and type of progression (e.g. PSA, radiological, bone, or 
no clinical benefit) 
• 
Site of progression (new lesions, existing lesions, or both) when 
available 
Prior/concomitant 
medication review 
 
Full physical examination 
Should be performed by a qualified medical practitioner. 
Height 
 
Weight 
 
ECOG performance score 
Refer to Appendix 4 for the ECOG performance score scale.  
Vital signs  
Includes: blood pressure, pulse, and respiratory rate 
CT with contrast/MRI 
CT with contrast /MRI tumor assessments should include evaluations of 
the chest, abdomen, and pelvis using the RECIST v1.1 criteria with 
caveats outlined in the PCWG3 recommendations 
The radiological technique used for measurement of the baseline 
images should also be the radiological technique used for each 
reassessment. 
99mTc diphosphonate bone 
scan 
Baseline and follow up radiological disease assessments must include 
bone scans performed with technetium-99m labeled diphosphonates as 
per the local standard of care for patients with prostate cancer. Use the 
PCCTC bone scan assessment tool or equivalent to document lesions 
(included in Appendix 11).  
Histology 
Pathology report of the most recent biopsy required at enrollment.  
Disease pattern 
Bone, visceral, soft tissue, and lymph nodes 
12-lead ECG 
 
Hematology  
Refer to Section 6.3.1 for list of tests 
Chemistry  
Refer to Section 6.3.1 for list of tests 
Urinalysis, macroscopic 
(microscopic when 
indicated) 
Refer to Section 6.3.1 for list of tests 


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Table 2 Screening procedures and baseline assessments 
Screening Procedure or 
Baseline Assessment 
Notes 
Serum/plasma testosterone 
 
PSA 
Includes PSA results and dates of 2 previous measurements. Prior 
measurements are needed to assess PSA velocity/doubling time. 
BPI-SF, EQ-5D-5L and 
FACT-P 
Baseline pain score assessment (BPI-SF) and HRQoL (EQ-5D-5L, 
FACT-P) assessments. HRQoL assessments may be either self-
completed by the subject or administered via face-to-face interview and 
completed by a caretaker/clinician. 
Best supportive/best 
standard of care 
determination 
To be decided prior to randomization, as part of screening. 
PSMA PET/CT scan 
To be done once all other eligibility requirements are confirmed. The 
metastatic lesion requirement may be confirmed at the same time as the 
baseline 68Ga-PSMA-11 PET/CTa scan. 
Baseline 68Ga-PSMA-11 PET/CTa scan must be done within 4 weeks (+ 
2 weeks) of start of treatment but not within the 6 days prior to start of 
treatment. 
Study eligibility based on PSMA positivity will be determined by 
central readers. 
Screening registration 
Initial screening registration should take place after the patient has 
signed the Informed Consent Form. It should be completed once all 
screening assessments have been completed and results confirmed 
except for metastatic lesion requirement and PSMA positivity.  
Study enrollment 
Study enrollment should take place after screening registration is 
completed and once the metastatic lesion requirement is confirmed by 
the site and PSMA positivity has been confirmed by the central readers. 
Patients randomized to the investigational arm are to begin dosing with 
177Lu-PSMA-617 within 28 days after randomization. 
a 
For background and additional details on 68Ga-PSMA-11, refer to the 68Ga-PSMA-11 Investigator’s 
Brochure. 
BPI-SF = Brief Pain Inventory – Short Form; CT= computed tomography; ECG = electrocardiography; 
ECOG = Eastern Cooperative Oncology Group; EQ-5D-5L = European Quality of Life (EuroQol) – 5 Domain 5 
Level scale; FACT-P = Functional Assessment of Cancer Therapy – Prostate; HRQoL = Health-related quality of 
life; IEC = Independent Ethics Committee; IRB = Institutional Review Board; MRI = magnetic resonance 
imaging; PCCTC = Prostate Cancer Clinical Trials Consortium; PET = positron emission tomography; PSA = 
prostate-specific antigen; PSMA = prostate-specific membrane antigen; REB = Research Ethics Board; RECIST 
= Response Evaluation Criteria in Solid Tumors;  
6.2 
Efficacy assessments 
For the timing of efficacy assessments, refer to the schedule of assessments provided in 
Appendix 1. 
6.2.1 
Radiographic imaging for tumor assessments 
Radiologic assessment should follow PCWG3 guidelines. Periodic radiographic imaging will 
include both: 


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• CT with contrast/MRI imaging 
• Bone scans with technetium-99m labeled diphosphonates 
CT with contrast/MRI tumor assessments should include evaluations of the chest, abdomen, and 
pelvis.  
Disease progression by bone scan will be defined as at least 2 new bone lesions at the first post-
treatment scan, with at least two additional lesions on the next (confirmatory) scan (2+2 PCWG3 
criteria, Scher et al 2016). For scans after the first post-treatment scan, at least two new lesions 
relative to the first post-treatment scan confirmed on a subsequent scan (2+2 PCWG3 criteria). If 
the second scan confirms the metastases, then the date of progression is the date of the scan when 
the first 2 new metastases were documented. 
6.2.2 
Additional Imaging Analyses 
The baseline eligibility 68Ga-PSMA-11 scan data will be used for additional exploratory 
analyses. The 68Ga-PSMA-11 PET/CT and corresponding diagnostic CT/MRI scans will be used 
in a retrospective Independent Review assessing inter-reviewer variability. The Independent 
Review will serve to evaluate the reading procedure for 68Ga-PSMA-11 PET/CT scans by 
assessing the variability and reproducibility of visual assessment. Visual assessment will be 
independently performed by three reviewers on 68Ga-PSMA-11 PET/CT scans and 
corresponding diagnostic CT/MRI scans. 
In addition, Quantitative Analysis will also be performed to assess tumor burden and tumor 
characteristics on 68Ga-PSMA-11 PET/CT scans at the time of enrolment. The association of 
these baseline data with rPFS, OS, and other efficacy endpoints will be assessed in exploratory 
analyses. 
An imaging charter will provide a detailed and expanded description of the planned analyses. 
  
6.2.3 
RECIST criteria 
The responses of soft tissue, lymph node, and visceral lesions to treatment will be characterized 
using the RECIST v1.1 criteria with caveats outlined in the PCWG3 recommendations (see 
Appendix 6 and Appendix 7). 
6.2.4 
Symptomatic skeletal events 
The time to the first SSE will measure the time to the first new symptomatic pathological bone 
fracture, spinal cord compression, tumor-related orthopedic surgical intervention, requirement 
for radiation therapy to relieve bone pain or death from any cause, whichever occurs first. 
6.2.5 
Pain score 
Pain will be assessed using the Brief Pain Inventory – Short Form (BPI-SF).  
The Brief Pain Inventory- Short Form will be used as part of this study to assess the severity of 
pain and the impact of pain on daily functions. Full details regarding the BPI-SF, its validation 
and clinical application are available in the Brief Pain Inventory User Guide (Cleeland 2009). 
A copy of the BPI-SF questionnaire is provided in Appendix 8. 


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6.2.6 
Health-related quality of life 
The ECOG Performance Status scale will be used to assess patients’ ability to perform daily 
living tasks and their range of basic physical ability. A copy of the ECOG scale is provided in 
Appendix 4. 
The EQ-5D-5L questionnaire will also be administered as a part of this study to assess HRQoL. 
EQ-5D is an international, validated, standardized, generic questionnaire for describing and 
valuing HRQoL (Rabin 2001). EQ-5D was developed by the EuroQol Group in order to provide 
a simple, generic measure of health for clinical and economic appraisal (EuroQoL Group 1990). 
This instrument generates a preference-based health-state utility score (EQ-5D utility index) and 
an overall health-state score based on a visual analogue scale (EQ-5D VAS).  
EQ-5D is designed for self-completion by respondents and is ideally suited for use in clinics and 
face-to-face interviews. It is cognitively undemanding, taking only a few minutes to complete. 
Instructions to respondents are included in the questionnaire. The most recent version of EQ-5D 
is the EQ-5D-5L, which was developed to improve the instrument’s sensitivity and to reduce 
ceiling effects. The number of dimensions (mobility, self-care, usual activities, pain/discomfort, 
anxiety/depression) has not changed, however the new version includes five levels of severity in 
each of the existing dimensions in place of three (EuroQoL Group 2015). Full details regarding 
the EQ-5D-5L questionnaire, including references, are available at the EQ-5D website: 
https://euroqol.org/eq-5d-instruments/eq-5d-5l-about. 
A copy of the EQ-5D-5L questionnaire is provided in Appendix 9 
The FACT-P questionnaire will also be administered as part of this study to specifically assess 
the HRQoL of prostate cancer patients. The FACT-P is made up of 2 parts: the FACT-G 
(general) questionnaire with 27 questions, and the Prostate Cancer Subscale (PCS) with an 
additional 12 questions. The FACT-G (Functional Assessment of Cancer Therapy – General) 
questionnaire is one of the most widely used HRQoL instruments and measures HRQoL in four 
different domains: Physical well-being, Functional well-being, Emotional well-being, and 
Social/Family well-being (Cella et al 1993). The PCS is designed specifically to measure 
prostate cancer-specific quality of life. Each item in both the FACT-G and PCS is rated on a 0 to 
4 Likert-type scale, and then combined to produce subscale scores for each domain, as well as 
global quality of life score with higher scores representing better QoL. The FACT system has a 
number of advantages as a method of measuring QoL: 
• Questionnaires have been developed to reflect patients’ concerns 
• Measurements are reliable, reproducible, and have been validated in numerous studies 
(Cella et al 1993, Esper et al 1997) 
• Available in over 45 different languages 
• Designed for patient self-administration, but can also be administered by interview 
format (Webster et al 2003) 
Full details regarding the FACT-P questionnaire, including references, are available at the 
FACIT website: http://www.facit.org/FACITOrg/Questionnaires. 
A copy of the questionnaire (FACT-P version 4) is provided in Appendix 10. 


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HRQoL will be periodically assessed at baseline, prior to administration of each cycle of 177Lu-
PSMA-617, and through the End of Treatment visit. 
6.2.7 
Health Economics 
A health economics (HE) sub-study will be performed. Core health resource use information will 
be collected, using case report forms (CRFs) on days in hospital and any outpatient visits. Data 
collected on concomitant medication may also be used in the economic analysis.  
For the economic modelling, costs will be imputed on the basis of representative country unit 
costs at the point of analysis using standard fee schedules. Health outcomes will be assessed in 
terms of quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios. Quality 
adjustments will be based on patients’ responses to the EQ-5D health status measure which will 
be administered at baseline, before each cycle of therapy, and each point of follow-up as part of 
the QoL questionnaire. 
 
6.2.8 
Clinical progression 
Clinical progression will be assessed by the investigator. The following criteria should be used to 
determine when a patient has met the standard for unequivocal evidence of clinical progression:  
• Marked escalation in cancer-related pain that is assessed by the investigator to indicate 
the need for other systemic chemotherapy 
• Immediate need for initiation of new anticancer treatment, surgical, or radiological 
intervention for complications due to tumor progression even in the absence of 
radiological progression 
• Marked deterioration in ECOG performance status to ≥ Grade 3 and a finding of the 
investigator that the deterioration indicates clinical progression 
• In the opinion of the investigator, it is in the best interest of the patient to discontinue 
treatment due to clinical progression 
6.2.9 
PSA levels 
Local labs will measure PSA levels. Increases and decreases will be tracked to assess PSA 
responses as per PCWG3 (Appendix 7). 
6.3 
Safety assessments 
6.3.1 
Clinical laboratory evaluations 
Local labs will perform hematology, chemistry, serum/plasma testosterone, and urinalysis 
testing.  


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Chemistry, urinalysis, and hematology testing will include the following: 
Chemistry 
*total carbon 
dioxide or 
equivalent is 
acceptable 
 
** urea is 
acceptable 
• 
Sodium 
• 
potassium 
• 
total and direct bilirubin 
• 
ALP 
• 
AST 
• 
ALT 
 
• 
LDH 
• 
blood urea 
nitrogen**  
• 
creatinine 
• 
uric acid 
• 
phosphorus 
• 
chloride 
• 
bicarbonate* 
• 
calcium 
• 
glucose 
• 
total protein 
• 
albumin 
Urinalysis 
• 
urine pH 
• 
protein content 
• 
specific gravity 
• 
appearance and color 
 
• 
glucose 
• 
ketones 
 
 
Hematology 
• 
complete blood count (white blood cell count and differential) 
• 
red blood cell count 
• 
hemoglobin 
• 
hematocrit 
• 
platelet count 
 
6.3.2 
Vital signs 
Blood pressure, pulse and respiratory rate will be assessed. 
6.3.3 
Electrocardiograms 
A 12-lead ECG will be done at screening. 
6.3.4 
Birth Control 
It is recommended that male patients who are sexually active practice an effective barrier method 
of birth control (e.g, condom and spermicidal jelly). Effective birth control methods should be 
used from day of the 68Ga-PSMA-11 dose, throughout study treatment and for at least 6 months 
following the last dose of 177Lu-PSMA-617. 
6.4 
End of treatment visit procedures 
The assessments and procedures to be done at the EOT visit are defined in the Schedule of 
Assessments tables, provided in Appendix 1. 
6.5 
Long-term follow-up procedures 
Before final analysis of alternate primary endpoint OS: 
A long-term follow-up period will collect, long-term follow-up specific self-reported AE 
assessments, rPFS (if discontinuing for reasons other than radiographic progression), survival 
and treatment updates from patients every 3 months (± 1 month) via phone, email, or letter. 
Hematology and chemistry blood work results will also be collected. Patients who withdraw their 
consent to participate in the treatment portion of the study or come off the treatment portion of 
the study for any reason other than radiographic disease progression will be asked for permission 


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to continue long-term status updates which may include, in addition to the above, collection of 
radiographic images (bone scans and CT scans and/or MRIs). 
These patients will be asked to sign a separate consent detailing what kind of long-term follow-
up assessments and study updates they will agree to. They will also be able to designate a contact 
person (i.e. study doctor, local doctor, friend or family member) who may be contacted on their 
behalf to obtain follow-up status updates. 
For any of these patients who are unable to sign the second consent (i.e. does not return to the 
site, etc.) every effort will be made to document the extent of long-term follow-up they will 
agree to. This will be documented in their source records.  
After final analysis of alternate primary endpoint OS: 
All randomized patients on the active part of the study at the time of final analysis of the 
alternate primary endpoint OS will have an EOT visit at the next planned visit after 
implementation of V5.0 of the protocol and will move into long-term follow-up. All patients in 
long-term follow-up will continue to be followed on this study, under the same patient ID, until a 
separate long-term safety follow-up study is available in the respective country, until death or 
until withdrawal of consent, whichever occurs first. 
The long-term follow-up period will include the collection of survival and new treatment 
information, adverse events assessment for renal toxicity and secondary malignancies, and 
results of hematology and chemistry testing. During follow-up, patients will be followed for 
safety and survival. They will be seen or contacted by a clinician every 3 months (±1 month) via 
phone, in person or via telemedicine visit, email or letter on this study until a long-term safety 
follow-up study is available, until death or until withdrawal of consent, whichever occurs first. 
Every opportunity to continue to collect long-term safety data should be made for each willing 
participant, regardless of time gap between release of protocol amendment v5.0 and v6.0. 
7. 
ADVERSE EVENTS 
7.1 
Adverse event definitions 
The following definitions comply with the ICH E2A guidance, Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting, and the safety definitions of 
the World Health Organization (WHO) International Drug Monitoring Center. 


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Term 
Definitionsa 
Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the 
use of a medicinal product, whether or not considered related to the medicinal product. 
Progression of disease is not considered an AE or SAE for this study.  
Adverse Drug 
Reaction  
For an investigational medicinal product all noxious and unintended response to a 
medicinal product related to any dose should be considered adverse drug reactions.  
Response in this context means that a causal relationship between a medicinal product 
and an adverse event is at least a reasonable possibility. 
Serious Adverse Event 
(SAE) or  
Adverse Drug 
Reaction 
A serious adverse event or reaction is any untoward medical occurrence that at any 
dose:  
• 
results in death; except for deaths due to progression of disease 
• 
is life-threatening;  
• 
requires inpatient hospitalization or prolongation of existing hospitalization;  
• 
results in persistent or significant disability/incapacity; or  
• 
is a congenital anomaly/birth defect. 
NOTE: The term "life-threatening" in the definition of "serious" refers to an event in 
which the patient was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it were more severe.  
Unexpected Adverse 
Drug Reactionb 
An adverse reaction, the nature or severity of which is not consistent with the applicable 
product information (i.e., Investigator's Brochure for an unapproved investigational 
medicinal product). 
a 
ICH E2A, Clinical Safety Data Management: Definitions and Standards for Expedited Reporting. 
b 
Also referred to as a Suspected Unexpected Serious Adverse Reaction (SUSAR). 
AE = adverse event; SAE = serious adverse event 
7.2 
Evaluating and recording adverse events 
Before final analysis of alternate primary endpoint OS: 
All AEs will be graded according to CTCAE v5.0. All AE monitoring and SAE recording and 
reporting will begin at the time of consent and will continue up to and including 30 days after the 
last dose of 177Lu-PSMA-617 or the date of best supportive/best standard of care end of 
treatment decision, whichever is later. For patients that are not randomized, AE monitoring will 
continue up to and including 6 days after administration of 68Ga-PSMA-11. 
All AEs and abnormal test findings, regardless of suspected causal relationship to 68Ga-PSMA-
11, 177Lu-PSMA-617, and/or best supportive/best standard of care, will be recorded in the 
patients’ case histories. For all AEs sufficient information will be obtained to permit an adequate 
determination of the outcome of the event and an assessment of the casual relationship between 
the AE and 68Ga-PSMA-11, 177Lu-PSMA-617, and/or best supportive/best standard of care. AEs 
or abnormal test findings felt to be associated with 68Ga-PSMA-11, 177Lu-PSMA-617, and/or 
best supportive/best standard of care will be followed until the event or its sequelae or the 
abnormal test finding resolves or stabilizes at a level acceptable to the investigator. 
The investigator will promptly review AEs and abnormal test findings to determine if: 1) the 
abnormal test finding should be classified as an AE; 2) there is a reasonable possibility that the 


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AE was caused by 68Ga-PSMA-11, 177Lu-PSMA-617, and/or best supportive/best standard of 
care; and 3) the AE meets the criteria for a serious adverse event (SAE). If the final 
determination of causality is “unknown and of questionable relationship to the study drug” the 
adverse event will be classified as associated with the use of the study drug for reporting 
purposes. If the final determination of causality is “unknown but not related to the study drug” 
the determination and rationale will be documented in the patient’s case history. 
After final analysis of alternate primary endpoint OS: 
All AEs will be graded according to CTCAE v5.0. All AE monitoring and SAE recording and 
reporting will begin at the time of consent and will continue up to and including 30 days after the 
last dose of 177Lu-PSMA-617 or the date of best supportive/best standard of care end of 
treatment decision, whichever is later. In addition, SAE recording and reporting will be 
continued in the long-term follow-up period. During long-term follow-up, SAEs are to be 
reported only if the investigator suspects a causal relationship to the study treatment.  
SAEs experienced after the 30-day period following the last administration of randomized 
treatment, including during long-term follow-up, should be reported to Novartis Safety if the 
investigator suspects a causal relationship to the study treatment. 
During long-term follow-up, for all renal toxicities, secondary malignancies and all SAEs, 
sufficient information will be obtained to permit an adequate determination of the outcome of the 
event and an assessment of the casual relationship between the AE and 177Lu-PSMA-617, and/or 
best supportive/best standard of care. SAEs, renal toxicities and secondary malignancies felt to 
be associated with 177Lu-PSMA-617, and/or best supportive/best standard of care will be 
followed until the event or its sequelae or the abnormal test finding resolves or stabilizes at a 
level acceptable to the investigator. 
The investigator will promptly review AEs and abnormal test findings to determine if: 1) the 
abnormal test finding should be classified as an AE; 2) there is a reasonable possibility that the 
AE was caused by, 177Lu-PSMA-617, and/or best supportive/best standard of care; and 3) the AE 
meets the criteria for a serious adverse event (SAE). If the final determination of causality is 
“unknown and of questionable relationship to the study drug” the adverse event will be classified 
as associated with the use of the study drug for reporting purposes. If the final determination of 
causality is “unknown but not related to the study drug” the determination and rationale will be 
documented in the patient’s case history. Renal toxicities and secondary malignancies will be 
recorded as AEs. Any AE determined to meet the criteria for a serious adverse event and 
considered related to the study drug (even a questionable relationship) should be recorded as an 
AE and reported as an SAE. 
 
7.3 
Immediate Adverse Event Reporting 
Endocyte will ensure that all relevant safety information as required by local and/or national 
laws, directives and/or regulations are reported to the appropriate Competent Authorities as well 
as the Principal Investigator and/or IRBs/Ethics Committees. 


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7.3.1 
Serious Adverse Events 
SAEs require expeditious handling and MUST IMMEDIATELY be reported upon discovery so 
the sponsor may comply with regulatory requirements. 
Any SAE, regardless of causal relationship, must be reported to the Sponsor Contact listed in the 
Sponsor Contact section (Section 7.3.3) immediately (no later than 24 hours after the investigator 
becomes aware of the SAE) by emailing or faxing a completed SAE form to the number/email 
indicated. Compliance with this time requirement is essential so that the sponsor may comply 
with its regulatory obligations. 
Follow-up information relating to an SAE must be reported to the Sponsor Contact in 
Section 7.3.3 within 24 hours of receipt by the investigator by emailing or by faxing a completed 
SAE form to the number indicated. The patient should be observed and monitored carefully until 
the condition resolves or stabilizes or its cause is identified. 
SAEs which are: 1) associated with 68Ga-PSMA-11, 177Lu-PSMA-617, and/or best 
supportive/best standard of care; 2) fatal or life-threatening; and 3) unexpected, will be reported 
to the principal investigator and/or IRBs/Ethics Committee/Research Ethics Boards (REBs) and 
the Regulatory Authorities within 7 days of awareness of the respective information. Other SAEs 
which are: 1) associated with the investigational drug or study treatment; 2) non-fatal or non-life-
threatening; and 3) unexpected will be reported to the principal investigator and/or IRBs/Ethics 
Committee/REBs and Regulatory Authorities within 15 days of awareness of the respective 
information. 
7.3.2 
Serious adverse event subject follow-up 
Follow-up information to a reported SAE will be submitted to the principal investigator and/or 
IRBs/Ethics Committees and Competent Authorities in accordance with local regulations and 
international guidelines. If the results of the follow-up investigation show that an SAE that was 
initially determined to not require reporting does, in fact, meet the requirements for reporting, the 
investigator will report the SAE to the principal investigator and/or IRBs/Ethics 
Committees/REBs in accordance with local regulations and international guidelines. 
7.3.3 
Sponsor Contact Information for Immediate Reporting 
Serious adverse events and follow-up information should be reported on a completed serious 
adverse event report form to Novartis Safety. Detailed instructions regarding the submission 
process can be found in the Change in Safety Reporting Process Training provided to each site 
detailing the reporting of SAEs to Novartis Safety. 
8. 
STATISTICS 
This section outlines the general study design, study endpoints, and statistical analysis strategy 
for the study.  
All statistical analyses will be carried out using SAS version 9.4 (or later). The SAP will be 
written and finalized prior to the first planned analysis and without knowledge of any 
by-treatment group accumulated data. The SAP will provide a detailed and expanded description 


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of the statistical methods outlined in this protocol. Additional analyses, such as important 
subgroups, will be described. 
After the final analysis of OS is performed, additional analyses of the primary endpoints (e.g. 
OS) will be presented descriptively without statistical inference and at the same nominal alpha 
level used for the primary analysis for each endpoint. Final safety analyses will be performed 
when the last patient is followed on this study until a long-term safety follow-up study is 
available in the respective country, dies or withdraws consent, whichever occurs first. 
8.1 
Revision to the protocol and statistical analyses of rPFS and OS 
The trial was originally designed to randomize 750 patients, targeting the primary analysis of 
rPFS with 457 events with a 1-sided alpha level of 0.001, an interim analysis of OS with a 1-
sided alpha level of 0.001, to be conducted contemporaneously with the primary analysis of 
rPFS, and a final primary analysis of OS with 489 deaths with a 1-sided alpha of 0.023. 
However, shortly after commencement of the trial, a high early dropout rate amongst those 
randomized to BS/BSC-only arm became evident with the majority of these dropouts 
withdrawing consent to follow-up. This meant that rPFS data could not be collected for these 
patients which consequently could result in bias in the analysis of rPFS. Remedial measures to 
curtail this phenomenon were implemented and made effective on March 5th, 2019. As part of 
the plan to address the early withdrawal of consent in the BS/BSC-only arm, the primary analysis 
of rPFS was altered to focus on patients prospectively randomized on or after March 5th, 2019; 
therefore, rPFS will be analyzed in these patients once 364 events have accrued with a 1-sided 
alpha level of 0.004. At time of this rPFS primary analysis, there will be an interim analysis of 
OS with a 1-sided alpha level of 0.001; this OS analysis will be on an ITT basis and will include 
all randomized patients (i.e., including those randomized before March 5th, 2019). Following the 
analysis of rPFS and the interim analysis of OS, a final ITT primary analysis of OS will be 
performed when 508 deaths have accrued with a 1-sided alpha level of 0.020. To achieve these 
analyses, the total number of subjects randomized into the trial was increased from N=750 to 
N=814. The revisions described do not alter the hypothesized treatment effects for rPFS and OS 
upon which the study was originally powered. 
8.2 
Revisions to planned analyses 
Subsequent to the protocol revision, if further changes are made to primary and/or key secondary 
hypotheses, or the statistical methods related to those hypotheses, then the protocol will be 
further amended (consistent with ICH Guideline E9). Any changes to exploratory or non-
confirmatory analyses made after the protocol has been finalized, along with an explanation as to 
when and why they occurred, will be listed in the Clinical Study Report (CSR). |Any post hoc 
exploratory analyses will be clearly identified in the CSR. Full details will be in the SAP. Any 
deviations from the statistical plan will be described and justified in a protocol amendment 
and/or in the CSR. 
8.3 
Sample size and power determination 
The sample size was determined based on the alternate primary endpoints of rPFS and overall 
survival. Planned enrollment for this study is approximately 814 subjects. 


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Under the null hypothesis for survival, median survival is assumed to be 10 months on 
177Lu PSMA-617 and best supportive/best standard of care (active) for a hazard ratio (HR) of 
1.00. Under the alternative hypothesis, median overall survival on active is assumed to be 
13.7 months for a HR of 0.7306.  
Under the null hypothesis for rPFS, median rPFS is assumed to be 4 months on 177Lu-PSMA-617 
and best supportive/best standard of care (active) for a hazard ratio (HR) of 1.00. Under the 
alternative hypothesis, median rPFS on active is assumed to be 6 months for a HR of 0.67.  
Based on a non-linear patient accrual profile over 14 months, a total of 814 patients randomized 
and followed on an ITT basis for a minimum of 13 months is expected to yield 508 deaths. This 
number of events provides at least 90% power to test the hypothesis that the HR for OS is 0.7306 
or better with a 1-sided alpha level of at least 0.020. 
For rPFS, a total of approximately 557/814 patients are expected to be randomized on or after 
5 March 2019, these being the patients to be included in the primary analysis of rPFS; with a 
minimum of approximately 6 months follow-up, these patients are expected to yield 364 rPFS 
events which will be sufficient to provide 84% power to test the hypothesis that the HR of rPFS 
is or 0.67 or better with a 1-sided alpha level if 0.004. At the time of this rPFS analysis, 341 
deaths are expected amongst all randomized patients. These interim OS data will be analyzed 
with a 1-sided alpha level of 0.001. Central independent assessments will be used to determine 
rPFS events. 
The alpha level applicable to OS in the final analysis will depend upon the earlier rPFS and 
interim OS results: 
• if p<0.004 1-sided is achieved for rPFS and p<0.001 1-sided is achieved for interim OS, 
then the alpha level for the final analysis of OS will be raised to 0.025 1-sided. 
• if p<0.004 1-sided is achieved for rPFS but p<0.001 1-sided is not achieved for interim 
OS, then the alpha level for the final analysis of OS will be 0.024 1-sided. 
• if p<0.004 1-sided is not achieved for rPFS but p<0.001 1-sided is achieved for interim 
OS, then the alpha level for the final analysis of OS will be raised to 0.021 1-sided. 
• if p<0.004 1-sided is not achieved for rPFS and p<0.001 1-sided is not achieved for 
interim OS, then the alpha level for the final analysis of OS will remain at 0.020 1- sided. 
This design provides at least 90% power for OS and 84% power for rPFS; with an overall Type I 
error rate ≤0.025 1-sided.  
The observed HRs that will meet p<0.004 for rPFS and the interim analysis of OS are 0.745 and 
0.701 respectively; and the observed HR that will meet p<0.020 to p<0.025 in the final analysis 
of OS are 0.824 to 0.823. 
8.4 
Analysis populations 
Analysis datasets are defined as follows: 
• Full Analysis Set (FAS): All randomized patients. OS will be assessed on an ITT basis 
and related data will be summarized by randomized treatment. 


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• PFS Analysis Set (PFS-FAS): All patients randomized on or after March 5th, 2019. The 
primary analysis of rPFS will be based on this dataset on an ITT basis and related data 
will be summarized by randomized treatment. 
• Response Evaluable Analysis Set: The subset of patients in the PFS-FAS with evaluable 
disease by RECIST at baseline. Soft tissue response as measured by RECIST will be 
assessed in this dataset. 
• Safety Analysis Dataset: There will be two safety datasets 
o The subset of patients who received as least one dose of 68Ga-PSMA-11.  
o The subset of patients in the FAS who received as least one dose of randomized 
therapy. Patient safety data in this dataset will be summarized by treatment 
received. 
8.5 
Demographics and baseline disease characteristics 
Demographic and baseline disease characteristic data will be summarized in the FAS and PFS-
FAS for each treatment with frequency distributions and/or descriptive statistics (mean, standard 
deviation, median, range, and/or relevant percentiles). Formal statistical tests comparing 
treatment groups will not be provided. 
8.6 
Patient disposition 
All patients who discontinue from the study will be identified, and the extent of their 
participation in the study will be reported. This will be done for the FAS and the PFS-FAS. If 
known, a reason for their discontinuation will be given. Reporting of patient disposition will 
include: 
• A summary of data on patient discontinuation 
• A summary of data on overall qualification status of all patients 
• An account of all significant protocol deviations 
All patients enrolled in the study will be accounted for in the summation. The number of patients 
who do not qualify for analysis, who die, or who discontinue before treatment begins, will be 
specified. 
8.7 
Efficacy analyses 
8.7.1 
Alternate primary endpoint efficacy analysis 
8.7.1.1 
rPFS 
Radiographic progression-free survival (rPFS) is defined as the time from the date of 
randomization to the date of radiographic disease progression as outlined in Prostate Cancer 
Working Group 3 (PCWG3) Guidelines (Scher et al 2016) or death from any cause. rPFS as 
determined by the independent central assessment will be used for this analysis. The primary 
analysis of rPFS will be based upon the PFS-FAS and will take place once 364 rPFS events have 
been reached. The allocated alpha level for the rPFS analysis is 0.004 1-sided. 


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Patients who are alive without radiographic progression at the analysis data cut-off or are lost to 
follow-up at the time of analysis will be censored for rPFS at the time of their last radiographic 
assessment or at the data cut-off date. rPFS data will be displayed using Kaplan Meier curves 
from which median rPFS times will be estimated for both treatment arms. 
A stratified log-rank test model will be the primary statistical methodology used to analyze rPFS 
in the PFS-FAS dataset, stratified for the randomization stratification factors.  
Supportive analyses of rPFS will be performed in terms of (i) a stratified Cox regression model 
on the PFS-FAS dataset with a single covariate for randomized treatment, and stratifying again 
for the randomization stratification factors; and (ii) the same as (i) but based upon the FAS 
dataset. The HR and CI from (i) will be used as an adjunct to the primary stratified log rank test 
p-value to provide the quantification of the treatment effect on rPFS. 
 
8.7.1.2 
OS 
Overall survival (OS) is defined as the time from the date of randomization to the date of death 
from any cause and will be assessed in the FAS. A formal interim analysis of OS is planned to 
occur at the time of the rPFS analysis (with 364 rPFS events in PFS-FAS); it is anticipated that 
approximately 341 deaths will have accrued in the FAS at the time of the rPFS analysis in the 
PFS-FAS. The allocated alpha level for OS in this interim analysis is 0.001 1-sided. The final 
analysis of OS is event driven and will take place once 508 deaths have occurred in the FAS. As 
described in Section 8.3, the allocated alpha level for the final OS analysis will be between 0.020 
and 0.025 1-sided, depending on the results of the earlier primary rPFS analysis and interim OS 
analysis. 
Patients who are lost to follow-up or are alive at the time of the OS analysis (for both interim and 
final analyses) will be censored at the time they were last known to be alive or at the date of 
event cut-off for the OS analysis. OS data will be displayed using Kaplan Meier curves from 
which median OS will be estimated for both treatment arms. 
OS will be analyzed using the same statistical methodology as described for the primary analysis 
of rPFS. Supportive analyses of OS will be performed at the interim and final in terms of Cox 
regression model on the FAS dataset with a single covariate for randomized treatment, stratifying 
for the randomization stratification factors. The HR and CI from these analyses be used as an 
adjunct to the primary stratified log rank test p-values to provide the quantification of the 
treatment effect on OS. 
 
8.7.1.3 
Statistical Interpretation of Alternate Primary Endpoints 
The statistical design of the study is such that, to be declared positive, the study would be 
required to reach statistical significance on either the primary analysis of rPFS or OS at the 
respective allocated alpha level; it is not required to meet both rPFS and OS to be declared a 
statistically positive study.  
Note, this applies to OS assessed at either the interim or the final analysis, i.e. for the study to be 
declared statistically positive requires rPFS to meet its allocated alpha level or OS to meet its 


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allocated alpha level at either (i) the formal OS interim analysis (conducted at the time of the 
rPFS analysis) or (ii) at the final OS analysis with 508 deaths.  
Alpha allocation and recycling are used to ensure control of the overall Type I error rate as 
described in Section 8.3. 
8.7.2 
Secondary efficacy analyses 
Key secondary endpoints 
Key secondary endpoints will be subject to Type I error control. These endpoints are: 
1. RECIST ORR and DCR 
2. Time to SSE  
The primary evaluation of these endpoints will be assessed in the PFS-FAS dataset. Time to SSE 
will be analyzed using a Cox regression model with a single covariate for randomized treatment, 
stratifying for the randomization stratification factors. ORR and DCR will be analyzed using 
logistic regression with a single covariate for randomized treatment and stratification for the 
randomization stratification factors. The odds ratio (active: control), its 95% confidence interval 
and associated 2-sided p-value will be presented. The DOR for binary response endpoint ORR 
will also be summarized and presented using Kaplan-Meier curves. 
To control the overall Type I error rate, if either alternate primary endpoint is met, then the key 
secondary endpoints will be assessed using the Hochberg closed test procedure at the alpha level 
applicable to the successful alternate primary endpoint. This procedure is reasonable given the 
positive correlation between the two key secondary endpoints. 
Supportive analyses of ORR, DCR and time to SSE will be performed in the FAS dataset using 
the same methods as described for the primary evaluation of these endpoints. 
Additional Secondary Endpoints 
Additional Secondary Endpoints will be assessed at the nominal 5% level, i.e. there will be no 
alpha control applied. These endpoints will be assessed in PFS-FAS with the exception of safety 
which will be assessed using the Safety analysis sets and are: 
1. To evaluate the safety and tolerability of 177Lu-PSMA-617  
2. Aspects of HRQoL will be self-reported by patients (or via interview format) using the 
EQ-5D-5L and FACT-P questionnaires, and pain will be assessed by patients using the 
BPI-SF. 
3. Health economics 
4. PFS as defined as the date of randomization to the date of first evidence of radiographic 
progression, clinical progression, PSA progression, or death from any cause, whichever 
occurs first.  
5. Biochemical response endpoints:  
d. Proportion of subjects who are PSA responders, defined as a patient who has 
achieved a ≥50% decrease from baseline that is confirmed by a second PSA 
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e. Alkaline phosphatase [ALP] and lactate dehydrogenase [LDH] levels will also be 
collected. 
Event-free survival endpoints (e.g., PFS, time to pain worsening) will be analyzed using a Cox 
regression model in the same manner as described for time to SSE except using a 2-sided p-
value. DCR will be analyzed in the same manner as ORR and HRQoL will be analyzed in the 
same manner as pain score over time. Time to pain improvement response after initial pain 
worsening will be analyzed using mixture distribution methodology akin to that described by 
Ellis et al 2008. 
8.8 
Safety analyses 
All safety evaluations will be based on the Safety Analysis Set. 
8.8.1 
Extent of exposure 
The duration of exposure and dose intensity will be calculated. The relationship between dose 
intensity, duration of exposure, and frequency and severity of adverse events will be explored by 
data tabulation. 
8.8.2 
Analysis of adverse events 
The frequency of treatment emergent adverse events (TEAEs) and SAEs will be tabulated by 
Medical Dictionary for Regulatory Activities (MedDRA) preferred term and system organ class. 
The maximum NCI CTCAE grade and frequency of AEs will be summarized. 
A 68Ga-PSMA-11 TEAE is defined as an AE that was not present prior to dosing with 
68Ga-PSMA-11 but appeared following dosing or was present at time of initial dosing but 
worsened during or after dosing. The treatment-emergent period will be defined as the period 
from the date of 68Ga-PSMA-11 dosing up to 6 days after the date of 68Ga-PSMA-11 dosing as 
long as prior to the first dose of 177Lu-PSMA-617 for the investigational arm and Cycle 1 Day 1 
for the best supportive/best standard of care-only arm. Adverse events reported as “possibly”, 
“probably”, or “definitely” related to 68Ga-PSMA-11 that occur beyond the 6-day reporting 
window but occur before the initiation of randomized treatment are also 68Ga-PSMA-11 TEAEs. 
Unrelated 68Ga-PSMA-11 adverse events that occur beyond 6 days will not be TEAEs. 
A randomized treatment TEAE is defined as an AE that was not present prior to initiation of 
randomized treatment, defined as first dose of 177Lu-PSMA-617 for the investigational arm and 
Cycle 1 Day 1 for the BS/BSC arm, but appeared following treatment, or was present at 
treatment initiation but worsened during treatment. An AE that was present at treatment initiation 
but resolved and then reappeared while the patient was on treatment is a TEAE (regardless of the 
intensity of the AE when the treatment was initiated). The treatment-emergent period will be 
defined as the period from the initiation of randomized treatment up to 30 days after the date of 
the last dose or intervention of randomized treatment or the day prior to the initiation of 
subsequent anticancer treatment, whichever occurs first.  
Adverse events leading to permanent discontinuation of study drug and/or leading to death will 
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8.8.3 
Analysis of laboratory assessments 
Laboratory values and change from baseline will be summarized by visit and treatment using 
descriptive statistics. Shift tables of the worst on-study laboratory toxicity based on CTCAE v5.0 
grading relative to baseline will be presented by treatment group. Subject listings of laboratory 
toxicities ≥ Grade 3 will be provided. 
8.8.4 
Analysis of vital sign data 
Vital sign data (observed and change from baseline) will be summarized using descriptive 
statistics by time point and treatment. Abnormal findings from physical examinations will be 
assessed for clinical significance which will be included in the AE listings and summaries. 
8.9 
IDMC and Interim Data Evaluation  
8.9.1 
IDMC 
An IDMC will be convened to review accumulating safety and safeguard patient interest in the 
study. Safety data monitoring will be conducted quarterly by the IDMC. These safety reviews 
will commence following the completion of the first three months of study accrual. 
In addition, a summary of efficacy data will also be provided to the IDMC at the time of routine 
safety data reviews; these efficacy data will be provided for information only, no statistical 
analyses will be conducted. The only analyses of efficacy data are those formally planned for 
rPFS in the PFS-FAS at 364 events, interim OS (in the FAS) at the time of the rPFS analysis and 
final OS (in the FAS) with 508 deaths. 
The IDMC will review these formal efficacy analyses. The IDMC may recommend early 
curtailment of trial on the basis of meeting one of the preplanned formal efficacy analyses or due 
to the emergence of an unforeseen safety concern placing patient safety at risk. 
An IDMC Charter will be approved and finalized by the IDMC members prior to the initiation of 
any formal efficacy analysis. 
The IDMC can recommend a course of action, but the sponsor will make the final decision 
regarding whether or not to continue or stop the trial, based on any analysis for reasons related to 
safety or efficacy. 
8.9.2 
Formal Interim Analysis of OS 
As described above in Section 8.3, one formal interim analysis is planned for OS in the FAS to 
take place at the time of the primary rPFS analysis in the PFS-FAS. The allocated alpha level for 
the interim OS analysis is 0.001 1-sided. Regardless of whether a positive result is attained at this 
time, for either rPFS or interim OS, patient follow-up will continue until 508 OS events have 
accrued in the FAS at which time a final OS analysis will be performed.  
9. 
 ACCESS TO SOURCE DATA/DOCUMENTS 
During the course of the study, a representative of Endocyte or its designee will be contacting 
and/or visiting the study sites to monitor the progress of the study. Contacts with the investigator 
and on-site visits for the purpose of data audits, including the comparison of source documents 


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with case report forms (CRFs) and study agent accountability logs, will occur. The principal 
investigator or his/her representative will need to be available to the representative of Endocyte 
or its designee during these visits. 
By signing the protocol, the investigator acknowledges that, within legal and regulatory 
restrictions and institutional and ethical considerations, Endocyte, its designee, or responsible 
government agencies (as required by law) may review or copy source documents in order to 
verify case report form (CRF) data. 
10. 
ETHICS 
10.1 
Institutional Review Board/Independent Ethics Committee/ Research 
Ethics Board (IRB/IEC/REB) 
The investigator will obtain approval from the IRB/IEC/REB of the proposed clinical protocol 
and ICF for study recruitment and the approval will be provided to Endocyte or its designee prior 
to beginning the clinical trial. The only circumstance in which a deviation from the 
IRB/IEC/REB-approved clinical protocol/ICF may be initiated in the absence of prospective 
IRB/IEC approval is to eliminate an apparent immediate hazard to the research participants. In 
such circumstances, the investigator will promptly notify the IRB/IEC/REB of the deviation. 
The investigator will promptly notify Endocyte of any regulatory inspection relating to this 
study, including either the institution or the IRB/IEC/REB, and will promptly provide Endocyte 
with a copy of any inspection report. 
10.2 
Informed consent 
The investigator will make certain that an appropriate informed consent process is in place to 
ensure that potential participants, or their authorized representatives, are fully informed about the 
nature and objectives of the clinical study, the potential risks and benefits of study participation, 
and their rights as research participants. The investigator, or his/her authorized designee, will 
obtain the written, signed ICF of each participant, or the participant’s authorized representative, 
prior to performing any protocol-specific procedures on the participant. The date and time that 
the participant, or the participant’s authorized representative, signs the ICF and a narrative of the 
issues discussed during the informed consent process will be documented in the participant’s 
case history. The investigator will retain the original copy of the signed ICF, and a copy will be 
provided to the participant, or to the participant’s authorized representative. 
The investigator will make certain that appropriate processes and procedures are in place to 
ensure that ongoing questions and concerns of enrolled participants are adequately addressed and 
that the participants are informed of any new information that may affect their decision to 
continue participation in the clinical study. In the event of substantial changes to the clinical 
study or the risk-to-benefit ratio of study participation, the investigator will obtain the informed 
consent of enrolled participants for continued participation in the clinical study. 


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10.3 
Health Insurance Portability and Accountability Act 
Preparation of the Health Insurance Portability and Accountability Act (HIPAA) authorization 
form is the responsibility of the investigator and must include all elements required by the United 
States (US) Department of Health and Human Service’s Privacy Rule. Prior to the beginning of 
the study, the investigator must have the IRB or the appropriate institution privacy board’s 
written approval/favorable opinion of the HIPAA authorization form. 
The HIPAA authorization must be signed and personally dated by the participant or their legally 
acceptable representative. 
For sites located outside of the US, local regulations regarding protection of individually 
identifiable health information must be followed. 
10.4 
Confidentiality 
All records will be kept confidential and the participant’s name will not be released at any time. 
Participant records will not be released to anyone other than Endocyte or its designee(s) and 
responsible government agencies. Data sets for each participant will be identified by a unique 
number. If participant records are sent to Endocyte or its affiliates or designees, the participant’s 
name or other identifying information will be masked and participant registration number or 
other unique identifier substituted. 
11. 
COMPLIANCE AND QUALITY CONTROL 
Independent auditing of the clinical study for protocol and GCP compliance may be conducted 
periodically at selected clinical sites by the Endocyte, Inc. Quality Assurance. 
The purpose of the sponsor’s audit is to evaluate trial conduct and compliance with the protocol, 
standard operating procedures, GCP, and the applicable regulatory requirements. 
Site monitoring visits will be conducted periodically at each clinical site. During site monitoring 
visits the following but not exhaustive list of points will be reviewed: patient informed consent, 
patient recruitment and follow-up, AE reporting including SAE documentation, outcome events 
documentation and reporting, investigational drug allocation, storage and accountability, 
concomitant therapy use, and quality of data. 
11.1 
Compliance with Monitoring and Audits 
Representatives of Endocyte or its designee must be allowed to visit (scheduled in advance) all 
study site locations periodically to assess the data, quality, and study integrity. On site, they will 
review study records and directly compare them with CRFs and discuss the conduct of the study 
with the investigator and verify that the facilities remain acceptable. It is the responsibility of the 
investigator (or designee) to be present or available for consultation during such monitoring 
visits. 
In addition, the study may be evaluated by Endocyte (or designee’s) internal auditors and 
government inspectors who must be allowed access to CRFs, source documents, investigational 
medication records, and other study files. The sponsor’s (or designee’s) audit reports will be kept 


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confidential to the extent permitted by law. The investigator must notify Endocyte promptly of 
any inspections scheduled by regulatory authorities and promptly forward copies of inspection 
reports to Endocyte. The investigator agrees to promptly take any reasonable steps that are 
requested by Endocyte as a result of monitoring or auditing activities to address deficiencies in 
study conduct or documentation. In the event that Endocyte is unable to secure compliance with 
the Statement of investigator or study protocol and prematurely terminates a trial site, Endocyte 
will notify the FDA (as required by 21 CFR § 312.56) the site’s IRB/IEC/REB, and other 
regulatory authorities, as required. 
12. 
DATA HANDLING, RECORD KEEPING, AND COMPLIANCE 
12.1 
Investigational medicinal product accountability 
At the completion of the study, there will be a final reconciliation of drug shipped, drug 
consumed, and drug destroyed. 
12.2 
Breaking the blind 
Not applicable. 
12.3 
Data collection forms and source document identification 
All source data will be retained by the trial site to ensure that, if requested, a monitor, auditor, or 
regulatory agency has access to the source documents. 
Source data are the clinical findings and observations, laboratory and test data, and other 
information contained in source documents. Source documents are the original records (and 
certified copies of original records) including, but not limited to, hospital medical records, 
physician or office charts, physician or nursing notes, participant diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, x-rays, biopsy reports, 
ultrasound reports, pharmacy records, or any other similar reports or records of any procedures 
performed in accordance with the protocol. Source documentation may also include any sponsor 
CRF when source data is recorded directly onto a CRF.  
The health-related quality of life questionnaires will utilize electronic Clinical Outcome 
Assessments (eCOA) technology for direct entry of the patient’s responses. The eCOA will serve 
as source data. 
A CRF will be completed for each participant enrolled into the clinical study. Patients are to be 
identified by, year of birth, patient screening number and patient enrollment number. Information 
recorded on the CRF must match the source data recorded on the source documents. 
The investigator will review, approve, and sign/date completed CRFs. Their signature serves as 
attestation ensuring that all clinical and laboratory data entered on the CRF are complete, 
accurate, and authentic. This review and sign-off may be delegated to a qualified physician 
appointed as a sub-investigator by the principal investigator. The transfer of duties must be 
recorded on the Delegation Log (kept on file at the site) and all sub-investigators must be listed 
on FDA Form 1572 or equivalent regulatory statement. The investigator must ensure that all 


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sub-investigators are familiar with the protocol and all study-specific procedures and have 
appropriate knowledge of the study agent(s). 
12.4 
Record maintenance and retention  
The investigator will maintain records in accordance with GCP guidelines including the 
following: 
• IRB/IEC/REB correspondence (including approval notifications) related to the clinical 
protocol, including copies of adverse event reports and annual or interim reports 
• All versions of the IRB/IEC/REB approved clinical protocol and corresponding ICFs and, 
if applicable, participant recruitment advertisements 
• Normal value(s)/range(s) for medical/laboratory/technical procedures or tests included in 
the clinical protocol and laboratory certification 
• Instructions for on-site preparation and handling of the investigational drug, study 
treatment, and other study-related materials if not addressed in the clinical protocol; 
• Participant screening and enrollment logs and signed ICFs 
• Investigational drug accountability records, including documentation of drug return or 
destruction 
• A summary of the final clinical study results 
12.5 
Archiving 
Endocyte and the investigator will retain the records and reports associated with the clinical trial 
as required by local regulatory requirements after the marketing application is approved for the 
investigational drug. If a marketing application is not submitted or approved for the 
investigational drug the information will be retained until two years after investigations under the 
Investigational New Drug Application/Clinical Trial Application have been discontinued and the 
FDA/EMA/CA notified. 
13. 
PUBLICATION POLICY 
Endocyte and the investigators are committed to the publication and widespread dissemination of 
the results of this study. This study represents a joint effort between Endocyte and the 
investigators, and as such, the parties agree that the recommendation of any party concerning 
manuscripts or texts shall be taken into consideration in the preparation of final scientific 
documents for publication or presentation. All proposed publications and presentations by the 
investigators or their personnel and associates resulting from or relating to this study must be 
submitted to Endocyte for review 60 days before submission for publication or presentation. 
If the proposed publication or presentation contains patentable patient matter, which, at 
Endocyte’s sole discretion, warrants intellectual property protection, Endocyte may delay any 
publication or presentation for up to 60 days after approval for the purpose of pursuing such 
protection. 


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14. 
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Wegen S, Eppard E, Kürpig S, Essler M, Yordanova A, Hauser S, et al. Treatment response 
according to PSA changes in patients undergo more than one cycle of 177Lu-PSMA-617 
therapy. Eur J Nucl Med Mol Imaging. 2016;43(Suppl 1):S213 EPW14. 
Weinfurt et al 2005 
Weinfurt KP, Li Y, Castel LD, Saad F, Timbie JW, Glendenning GA, et al. The significance of 
skeletal-related events for the health related quality of life of patients with metastatic prostate 
cancer. Ann Oncol. 2005;16(4):579–84. 


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Protocol no. PSMA-617-01 
Endocyte, Inc., a Novartis Company 
Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
Yadav et al 2017 
Yadav MP, Ballal S, Tripathi M, Damle NA, Sahoo RK, Seth A, et al. 177Lu-DKFZ-PSMA-617 
therapy with metastatic castration resistant prostate cancer: safety, efficacy, and quality of life 
assessment. Eur J Nucl Med Mol Imaging. 2017;44(1):81-91. 
Yordanova et al 2017 
Yordanova A, Becker A, Eppard E, et al. The impact of repeated cycles of radioligand therapy 
using [177Lu]Lu-PSMA-617 on renal function in patients with hormone refractory metastatic 
prostate cancer. Eur J Nucl Med Mol Imaging. 2017;DOI 10.1007/s00259-017-3681-9. 
Zielinski et al 2014 
Zielinski RR, Azad AA, Chi KN, Tyldesely S. Population-based impact on overall survival after 
the introduction of docetaxel as standard therapy for metastatic castration resistant prostate 
cancer. Can Urol Assoc J. 2014 Jul;8(7-8):E520-3. 
 
 


Page 66 of 97 
 
Protocol no. PSMA-617-01 
Endocyte, Inc., a Novartis Company 
Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
Appendix 1 
Schedules of Assessments 


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Protocol no. PSMA-617-01 
Endocyte, Inc., a Novartis Company 
Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
Table 3 Schedule of assessments: 177Lu-PSMA-617 plus best supportive/best standard of care arm (Cycle 1) 
Study Period: 
Cycle 1 
Cycle Week: 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
Cycle Day: 
Day 1 
Day 8 
Day 15 
Day 22 
Day 29 
Day 36 
Concomitant medication review 
X---------------------------------------------------------------------------------------------------------------X 
AE monitoringa 
X---------------------------------------------------------------------------------------------------------------X 
Weight 
Xb 
 
 
 
 
 
ECOG 
Xb 
 
 
 
 
 
Directed physical exam 
Xb 
 
 
 
 
 
Vital signsc 
Xb 
 
 
 
 
 
EQ-5D-5L 
Xd,f  
 
 
 
 
 
FACT-P 
Xd,f 
 
 
 
 
 
BPI-SF 
Xd,f 
 
 
 
 
 
Administer 177Lu-PSMA-617 
X 
 
 
 
 
 
Best supportive/best standard of care  
As per physician’s orders 
Hematologye 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Chemistrye 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Serum/plasma testosterone 
Xb 
 
 
 
 
 
PSA 
Xb 
 
 
 
 
 
Radiographic imaging (CT with 
contrast/MRI and bone scan) 
Every 8 weeks (± 4 days) after first dose of 177Lu-PSMA-617 for the first 24 weeks (independent of dose 
delays), then every 12 weeks (± 4 days)  
a Adverse event monitoring will commence at time of consent. 
b Can be done up to 3 days prior to Day 1. For hematology and chemistry: up to 3 days prior to Days 1, 8, 15, 22, 29, and 36. 
c Blood pressure, pulse and respiratory rate will be assessed at required physical exams (up to 3 days of Day 1) and at 15(+/-5) minutes before, 30 (+/-5) minutes post,  
and 60 (+/-5) minutes post 177Lu-PSMA-617 administration. 
d To be completed prior to drug administration on Day 1. Can be completed up to 3 days prior to Day 1. 
e Hematology and chemistry to be done every week for Cycle 1 only.  
f  HRQoL and pain assessments may be self-completed by subject or administered in interview format and completed by a caretaker, clinician or site research team member. 
 
AE = adverse event; BPI-SF Brief Pain Inventory – Short Form; CT = computed tomography; ECOG = Eastern Cooperative Oncology Group; EQ-5D-5L = European Quality of 
Life (EuroQol) – 5 Domain 5 Level scale; FACT-P = Functional Assessment of Cancer Therapy – Prostate; MRI = magnetic resonance imaging; PSA = prostate-specific antigen 


Page 68 of 97 
 
Protocol no. PSMA-617-01 
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Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
Table 4 Schedule of assessments: 177Lu-PSMA-617 plus best supportive/best standard of care arm (Cycles 2 to LTFU) 
Study Period: 
Cycles 2-6* 
After Cycle 
6** 
End of 
Treatmentg 
Long-term follow-up 
(Before final analysis of 
alternate primary endpoint 
OS) 
Long-term follow-up 
Extension (after final 
analysis of primary 
alternate endpoint OS) 
Cycle Week: 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
Every 12 weeks 
(± 4 days) 
 
Every 3 months 
(± 1 month) 
Every 3 months 
(± 1 month) 
Cycle Day: 
Day 1 
Day 8 
Day 15 
Day 22 
Day 29 
Day 36 
 
 
Collect: 
• Hematology 
• Chemistry 
• Survival 
• New treatment: 
• Start/stop dates 
• Best response 
• Type of response 
• AE assessment 
• Radiographic 
imaging (only if pt 
came off the active 
part of the study for 
any reason other 
than radiographic 
disease 
progression) 
 
Collect: 
• Hematology 
• Chemistry 
• Survival 
• New treatment: 
• Start/stop dates 
• AE assessment for 
renal toxicity and 
reporting of 
secondary 
malignancies. 
• SAE reporting: 
only if the 
investigator 
suspects a causal 
relationship to 
study treatment. 
 
Concomitant 
medication review 
X------------------------------------------------------------------------------------------Xa 
 
X 
AE monitoringb 
X------------------------------------------------------------------------------------------Xa 
X 
Weight 
Xc 
 
 
 
 
 
Xc 
X 
ECOG 
Xc 
 
 
 
 
 
Xc 
X 
Directed physical 
exam 
Xc 
 
 
 
 
 
Xc 
X 
Vital signsd 
Xc 
 
 
 
 
 
Xc 
X 
EQ-5D-5L 
Xe,h  
 
 
 
 
 
Xe,h  
Xh  
FACT-P 
Xe,h 
 
 
 
 
 
Xe,h 
Xh 
BPI-SF 
Xe,h 
 
 
 
 
 
Xe,h 
Xh 
Administer 
177Lu-PSMA-617 
X 
 
 
 
 
 
 
 
Best supportive/ 
best standard of 
care  
As per physician’s orders 
 
 
Hematologyf 
Xc 
 
Xc 
 
Xc 
 
Xc 
X 
Chemistryf 
Xc 
 
Xc 
 
Xc 
 
Xc 
X 
Serum/plasma 
testosterone 
Xc 
 
 
 
 
 
Xc 
X 
PSA 
Xc 
 
 
 
 
 
Xc 
X 
Radiographic 
imaging (CT with 
contrast/MRI and 
bone scan) 
To be conducted every 8 weeks (± 4 days) after first dose of 177Lu-PSMA-617 for the 
first 24 weeks (independent of dose delays), then every 12 weeks (± 4 days)  
 


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Protocol no. PSMA-617-01 
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Version no.: 7.0 
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This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
 
* After the Cycle 4 dose of 177Lu-PSMA-617 and prior to Cycle 5 Day 1, the investigator should determine if: 
- The patient shows evidence of response (i.e. radiological, PSA, clinical benefit) and  
- Has signs of residual disease on CT with contrast/MRI or bone scan and 
- has shown good tolerance to the 177Lu-PSMA-617 treatment. 
If the patient meets the criteria above, and agrees to continue with additional treatment of 177Lu-PSMA-617, the investigator may administer a further 2 cycles. A maximum of 6 
cycles of radioligand therapy is allowed. If the patient does not meet all of the criteria or does not agree to additional 177Lu-PSMA-617 treatment, then no additional doses of 
177Lu-PSMA-617 will be administered after Cycle 4. After the last cycle of 177Lu-PSMA-617, patients can continue best supportive/best standard of care alone. 
** Cycles 2-6 are 6 weeks long. Cycle 7 Day 1 should occur after 6 full weeks from C6D1 (Day 43 of Cycle 6). Starting with Cycle 7, all cycles are 12 weeks long. The stipulated 
windows apply to C7D1 required procedures and for all cycles afterwards.  
 a Phone evaluations are allowed, but are not required for visits after Day 1 of each cycle.  
b Adverse event monitoring will commence at time of consent. 
c Can be done up to 3 days prior to Day 1. For hematology and chemistry: up to 3 days prior to Days 1, 15, and 29. 
d Blood pressure, pulse and respiratory rate will be assessed at required physical exams (up to 3 days of Day 1) and at 15(+/-5) minutes before, 30(+/-5) minutes post, and 60(+/-
5) minutes post 177Lu-PSMA-617 administration. 
e To be completed prior to drug administration (if applicable) on Day 1. Can be completed up to 3 days prior to Day 1. 
f For Cycles 2 to 6: Hematology and chemistry to be done at Days 1, 15, and 29 (every 2 weeks). After Cycle 6, to be done on Cycle 7 Day 1 and then every 12 weeks (± 4 days).  
g To be done once a patient is to enter the long-term follow-up part of the study. To occur approximately 30 days from the last dose of 177Lu-PSMA-617 or last dose or 
intervention of best supportive/best standard of care end of treatment decision, but before the initiation of subsequent anticancer treatment, outside of what is allowed on study 
h  HRQoL and pain assessments may be self-completed by subject or administered in interview format and completed by a caretaker, clinician or site research team member. 
 
 
AE = adverse event; ANC= absolute neutrophil count; BPI-SF Brief Pain Inventory – Short Form; CBC = complete blood count; CT = computed tomography; ECOG = Eastern 
Cooperative Oncology Group; EQ-5D-5L = European Quality of Life (EuroQol) – 5 Domain 5 Level scale; FACT-P = Functional Assessment of Cancer Therapy – Prostate; 
MRI = magnetic resonance imaging; PSA = prostate-specific antigen; PSMA = prostate-specific membrane antigen; WBC = white blood cell 
 
 
 


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Protocol no. PSMA-617-01 
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Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
Table 5 Schedule of assessments: Best supportive/best standard of care only arm (Cycle 1) 
Study Period: 
Cycle 1 
Cycle Week: 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
Cycle Day: 
Day 1 
Day 8 
Day 15 
Day 22 
Day 29 
Day 36 
Concomitant medication review 
X--------------------------------------------------------------------------------------------------------------X 
AE monitoringb 
X--------------------------------------------------------------------------------------------------------------X 
Weight 
Xa 
 
 
 
 
 
ECOG 
Xa 
 
 
 
 
 
Directed physical exam 
Xa 
 
 
 
 
 
Vital signsc 
Xa 
 
 
 
 
 
EQ-5D-5L 
Xd,f  
 
 
 
 
 
FACT-P 
Xd,f 
 
 
 
 
 
BPI-SF 
Xd,f 
 
 
 
 
 
Best supportive/ best standard of care 
As per physician’s orders 
Hematologye 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Chemistrye 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Serum/plasma testosterone 
Xa 
 
 
 
 
 
PSA 
Xa 
 
 
 
 
 
Radiographic imaging (CT with 
contrast/MRI and bone scan) 
Every 8 weeks (± 4 days) after Cycle 1 Day 1g for the first 24 weeks (independent of dose delays), then every 
12 weeks (± 4 days) through the End of Treatment visit 
a Can be done up to 3 days prior to Day 1. For hematology and chemistry: up to 3 days prior to Days 1, 8, 15, 22, 29, and 36. 
b Adverse event monitoring will commence at time of consent. 
c   Blood pressure, pulse and respiratory rate will be assessed at required physical exams (up to 3 days of Day 1). 
d To be completed prior to any drug administration (if applicable) on Day 1. Can be completed up to 3 days prior to Day 1. 
e Hematology and chemistry to be done every week for Cycle 1 only. 
f  HRQoL and pain assessments may be self-completed by subject or administered in interview format and completed by a caretaker, clinician or site research team member. 
g    Cycle 1 Day 1 for patients on the Best supportive/best standard of care only arm is considered as the day that the majority of the day 1 assessments are conducted 
 
AE = adverse event; BPI-SF Brief Pain Inventory – Short Form; CT = computed tomography; ECOG = Eastern Cooperative Oncology Group; EQ-5D-5L = European Quality of 
Life (EuroQol) – 5 Domain 5 Level scale; FACT-P = Functional Assessment of Cancer Therapy – Prostate; MRI = magnetic resonance imaging; PSA = prostate-specific antigen 
 


Page 71 of 97 
 
Protocol no. PSMA-617-01 
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Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
Table 6 Schedule of assessments: Best supportive/best standard of care only arm (Cycles 2 to LTFU) 
Study Period: 
Cycles 2-6** 
After Cycle 
6** 
End of 
Treatmentg 
Long-term 
follow-up (Before 
final analysis of 
alternate primary 
endpoint OS) 
Long-term 
follow-up 
Extension (After 
final analysis of 
alternate primary 
endpoint OS) 
Cycle Week: 
Week 1 
Week 
2 
Week 
3 
Week 
4 
Week 
5 
Week 
6 
Every 12 
weeks (± 4 
days) 
 
Every 3 months 
(± 1 month) 
Every 3 months 
(± 1 month) 
Cycle Day: 
Day 1 
Day 8 
Day 15 
Day 22 
Day 29 
Day 36 
 
 
Collect: 
• Hematology 
• Chemistry 
• Survival 
• New treatment: 
• Start/stop dates 
• Best response 
• Type of 
response 
• AE assessment 
• Radiographic 
imaging (only if 
pt came off the 
active part of 
the study for 
any reason other 
than 
radiographic 
disease 
progression) 
 
 
Collect: 
• Hematology 
• Chemistry 
• Survival 
• New 
treatment: 
• Start/stop 
dates 
• AE 
assessment for 
renal toxicity 
and secondary 
malignancies. 
• SAE 
reporting: 
only if the 
investigator 
suspects a 
causal 
relationship to 
study 
treatment. 
 
Concomitant 
medication review 
X-----------------------------------------------------------------------------------------------
Xa 
X 
AE monitoringb 
X-----------------------------------------------------------------------------------------------
Xa 
X 
Weight 
Xc 
 
 
 
 
 
Xc 
X 
ECOG 
Xc 
 
 
 
 
 
Xc 
X 
Directed physical 
exam 
Xc 
 
 
 
 
 
Xc 
X 
Vital signsd 
Xc 
 
 
 
 
 
Xc 
X 
EQ-5D-5L 
Xe,h  
 
 
 
 
 
Xe,h 
Xh  
FACT-P 
Xe,h 
 
 
 
 
 
Xe,h 
Xh 
BPI-SF 
Xe,h 
 
 
 
 
 
Xe,h 
Xh 
Best supportive/best 
standard of care 
As per physician’s orders 
 
 
Hematologyf 
Xc 
 
Xc 
 
Xc 
 
Xb 
X 
Chemistryf 
Xc 
 
Xc 
 
Xc 
 
Xb 
X 
Serum/plasma 
testosterone 
Xc 
 
 
 
 
 
Xb 
X 
PSA 
Xc 
 
 
 
 
 
Xb 
X 
(continued) 
 
 
 
 
 


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Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
Radiographic 
imaging (CT with 
contrast/MRI and 
bone scan) 
To be conducted every 8 weeks (± 4 days) after Cycle 1 Day 1 for the first 24 
weeks (independent of dose delays), then every 12 weeks (± 4 days) 
** Cycles 2-6 are 6 weeks long. Cycle 7 Day 1 should occur after 6 full weeks from C6D1 (Day 43 of Cycle 6). Starting with Cycle 7, all cycles are 12 weeks long. The stipulated 
windows apply to C7D1 required procedures and for all cycles afterwards.  
 
 
 
a  Phone evaluations are allowed, but are not required for visits after Day 1 of each cycle. 
b Adverse event monitoring will commence at time of consent. 
c Can be done up to 3 days prior to Day 1. For hematology and chemistry: up to 3 days prior to Days 1, 15, and 29. 
d Blood pressure, pulse and respiratory rate will be assessed at required physical exams (up to 3 days of Day 1). 
e To be completed prior to drug administration (if applicable) on Day 1. Can be completed up to 3 days prior to Day 1. 
f For Cycles 2 to 6: Hematology and chemistry to be done at Days 1, 15, and 29 (every 2 weeks). After Cycle 6, to be done every12 weeks (± 4 days).  
g To be done once a patient is to enter the long-term follow-up part of the study. To occur approximately 30 days from the date of the last dose or intervention of best 
supportive/best standard of care end of treatment decision, but before the initiation of subsequent anticancer treatment, outside of what is allowed on study. 
h  HRQoL and pain assessments may be self-completed by subject or administered in interview format and completed by a caretaker, clinician or site research team member. 
 
AE = adverse event; ANC = absolute neutrophil count; BPI-SF Brief Pain Inventory – Short Form; CBC = complete blood count; CT = computed tomography; ECOG = Eastern 
Cooperative Oncology Group; EQ-5D-5L = European Quality of Life (EuroQol) – 5 Domain 5 Level scale; FACT-P = Functional Assessment of Cancer Therapy – Prostate; 
MRI = magnetic resonance imaging; PSA = prostate-specific antigen; WBC = white blood cell count 
 
 


Page 73 of 97 
 
Protocol no. PSMA-617-01 
Endocyte, Inc., a Novartis Company 
Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
Appendix 2 
Suggested treatment guidelines  
The following are suggested guidelines for clinical support during 177Lu-PSMA-617 
administration. They are to be used at the discretion of the investigator. 
• Cooling the salivary glands from 30 min. before and up to 4 hours after the 177Lu-PSMA-
617 injection for reducing the risk of salivary glands radiation injuries is optional and 
depends on center practice. 
• 500 mL of 0.9% (i.e., normal) saline may be infused at a rate of 125 mL/hour to begin 
after administration of 177Lu-PSMA-617. Additionally, fluid intake should be encouraged 
on the day of treatment.  
• In patients with high tumor burden or gout allopurinol may be started within 7 days and 
up to 10 days following 177Lu-PSMA-617 therapy 


Page 74 of 97 
 
Protocol no. PSMA-617-01 
Endocyte, Inc., a Novartis Company 
Version no.: 7.0 
                                                                                 14 September 2022 
This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
Appendix 3 
Principal Investigator Signature 
I have read this clinical protocol, no. PSMA-617-01, in its entirety and: 
• 
I agree to implement and conduct this clinical study diligently and in strict compliance 
with the protocol, good clinical practices, and all applicable national, federal, and local 
laws and/or regulations. 
• 
I agree that this clinical protocol will not be modified by me or any member of my staff 
without the written consent of Endocyte, Inc. and, if required, I will receive approval of 
these modifications by my institution’s IRB/REB/Independent Ethics Committee (IEC). 
• 
I certify that neither I nor any member of my staff has been disqualified or debarred by the 
Food and Drug Administration (FDA), European or any other regulatory bodies for clinical 
investigations or any other purpose. 
• 
I understand that this clinical protocol and the accompanying clinical Investigator’s 
Brochure contains trade secrets and/or commercial information that are privileged and/or 
confidential and may not be disclosed unless such disclosure is required by national, 
federal, or local laws and/or regulations. 
 
Pursuant to 21 CFR § 312.53(c), each US investigator will complete and sign FDA Form 1572, 
Statement of Investigator, prior to participating in the study. The completed form, along with a 
curriculum vitae, will be returned to Endocyte and maintained on record. 
Form FDA 1572, Statement of Investigator, which must be completed, is available at: 
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM074728.pdf  
 
 
 
 
Principal Investigator Signature 
 
Date 
 
 
 
Name (Printed) 
 
 
 
 
 
Title (Printed) 
 
 
 
 


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Version no.: 7.0 
 
 
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This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
Appendix 4a Eastern Cooperative Oncology Group performance status scale 
and Karnofsky Performance Status comparison 
Eastern Cooperative Oncology Group Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature (eg, light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but unable to carry out 
any work activities.  Up and about more than 50% of waking hours. 
3 
In bed >50% of the time.  Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally confined to 
bed or chair. 
5 
Dead 


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Version no.: 7.0 
 
 
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This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
Appendix 4b Eastern Cooperative Oncology Group performance status scale 
and Karnofsky Performance Status comparison 
ECOG PERFORMANCE STATUS 
KARNOFSKY PERFORMANCE 
STATUS 
0—Fully active, able to carry on all pre-disease 
performance without restriction 
100—Normal, no complaints; no 
evidence of disease 
90—Able to carry on normal activity; 
minor signs or symptoms of disease 
1—Restricted in physically strenuous activity but 
ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work 
80—Normal activity with effort, some 
signs or symptoms of disease 
70—Cares for self but unable to carry 
on normal activity or to do active work 
2—Ambulatory and capable of all selfcare but unable to 
carry out any work activities; up and about more than 50% 
of waking hours 
60—Requires occasional assistance 
but is able to care for most of 
personal needs 
50—Requires considerable 
assistance and frequent medical care 
3—Capable of only limited selfcare; confined to bed or 
chair more than 50% of waking hours 
40—Disabled; requires special care 
and assistance 
30—Severely disabled; 
hospitalization is indicated although 
death not imminent 
4—Completely disabled; cannot carry on any selfcare; 
totally confined to bed or chair 
20—Very ill; hospitalization and 
active supportive care necessary 
10—Moribund 
5—Dead 
0—Dead 
*Karnofsky D, Burchenal J, The clinical evaluation of chemotherapeutic agents in cancer. In: MacLeod C, ed. Evaluation of Chemotherapeutic 
Agents. New York, NY: Columbia University Press; 1949:191–205. 
**Zubrod C, et al. Appraisal of methods for the study of chemotherapy in man: Comparative therapeutic trial of nitrogen mustard and 
thiophosphoramide. Journal of Chronic Diseases; 1960:11:7-33. 


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Protocol no. PSMA-617-01 
Endocyte, Inc. 
Version no.: 7.0 
 
 
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This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
Appendix 5 
Common Terminology Criteria for Adverse Events  
The complete NCI CTCAE (version 5.0) can be found at the following site:  
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_5.0/ 
 
 


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Endocyte, Inc. 
Version no.: 7.0 
 
 
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This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
Appendix 6 
Response Evaluation Criteria in Solid Tumors 
The latest RECIST guidelines (version 1.1) can be found at the following site: 
http://recist.eortc.org/wp-content/uploads/2015/03/RECISTGuidelines.pdf 
 


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Endocyte, Inc. 
Version no.: 7.0 
 
 
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This information is confidential or privileged information and trade secrets of Endocyte, Inc. 
Appendix 7 
Prostate Cancer Working Group 3 Recommendations  
The sections that apply to this trial are the criteria for prostate-specific antigen (PSA) response and 
progression, and the criteria for bone lesion “prevent/delay end points” (progression). It is based on 
the PCWG3 recommendations. Please note that not all the recommendations listed below are 
applicable to this patient population or to the specifics of this study.  
Variable 
PCWG3 (2016) 
PSA 
• 
Recognize that a favorable effect on PSA may be delayed for 12 weeks or more, even for a 
cytotoxic drug 
• 
Monitor PSA by cycle but plan to continue through early rises for a minimum of 12 weeks unless 
other evidence of progression 
• 
Ignore early rises (prior to 12 weeks) in determining PSA response 
For control/relieve/eliminate endpoints: 
• 
Describe absolute changes in PSA over time from baseline to best response 
For delay/prevent endpoints: Decline from baseline: 
• 
Record time from start of therapy to first PSA increase that is ≥25% and ≥2 ng/mL above the 
nadir, and which is confirmed by a second value 3 or more weeks later (ie, a confirmed rising 
trend) 
No decline from baseline: 
• 
PSA progression ≥25% and ≥2 ng/mL after 12 weeks 
Soft-tissue lesions For control/relieve/eliminate end points: 
Use Response Evaluation Criteria in Solid Tumors (RECIST) with caveats: 
• 
Record up to 5 lesions per site of disease 
• 
Record changes in nodal, lung, liver adrenal and central nervous system (CNS) sites separately 
• 
Only report changes in lymph nodes that were ≥1.5 cm in diameter in short axis at baseline 
• 
Record changes in pelvic (regional) nodes vs extrapelvic (distant/metastatic) nodes separately 
• 
Only report changes in visceral lesions (liver, lung, adrenal, CNS) that were ≥1.0 cm in the 
longest dimension 
• 
Record complete elimination of disease at any site separately 
• 
Confirm favorable change with second scan 
• 
Record changes using waterfall plot 
For delay/prevent end points: 
• 
Record changes in nodal and visceral disease separately 
• 
Record up to 5 lesions per site of spread 
• 
Use RECIST 1.1 criteria for progression, but clearly record type of progression (growth of 
existing lesions vs development of new lesions) separately by site. With additional requirement 
that progression at first assessment be confirmed by a second scan 6 or more weeks later. 
(Particularly important when anticipated effect on PSA is delayed or for biologic therapies) 
• 
Previously normal (<1.0 cm) lymph nodes must have grown by ≥5 mm in the short axis from 
baseline or nadir and be ≥1.0 cm in the short axis to be considered to have progressed. Nodes that 
have progressed to 1.0 to less than 1.5 cm are pathologic, subject to clinical discretion, and 
nonmeasurable. For existing pathologic adenopathy (≥1.5 cm), progression is defined per 
RECIST 1.1 


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Bone 
For control/relieve eliminate end points: 
• 
Record outcome as new lesions, no new lesions or resolved lesion 
• 
First scheduled reassessment: 
o 
No new lesions: continue therapy 
o 
New lesions: perform a confirmatory scan 6 or more weeks later 
• 
Confirmatory scan: 
o 
No new lesions: continue therapy 
o 
Additional new lesions: progression 
• 
Subsequent scheduled reassessments:  
o 
No new lesions: continue  
o 
New lesions: progression 
• 
Changes in intensity or uptake do not constitute regression or progression 
For prevent/delay end points (progression): 
• 
Exclude pseudoprogression in the absence of symptoms or other signs of progression 
• 
At least two new lesions on first post-treatment scan, with at least two additional lesions on the 
next scan (2+2 rule) 
• 
If at least two additional new lesions are seen on the next (confirmatory) scan, the date of 
progression is the date of the first post-treatment scan, when the first two new lesions were 
documented 
• 
For scans after the first post-treatment scan, at least two new lesions relative to the first post-
treatment scan confirmed on a subsequent scan 
• 
Date of progression is the date of the scan that first documents the second lesion 
• 
Changes in intensity of uptake alone do not constitute either progression or regression 
• 
Report the proportion of patients who have not progressed at fixed time intervals (6 and 12 
months) 
Symptoms 
 
Pain palliation assessment requires a patient population with clinically meaningful pain at baseline (eg, 
≥4 on a 10-point pain intensity scale) and response defined as a clinically meaningful score improvement 
at a subsequent time point (eg, a 30% relative or 2-point absolute improvement from baseline at 12 
weeks, confirmed at least 2 weeks later, without an overall increase in opiate use).  
For control/relieve eliminate end points: 
• 
Serial (eg, daily x 7 days) assessments at each time point can improve the stability of values 
Principles may be extended for any PRO for which a clinically meaningful baseline PRO score has been 
determined together with a responder definition that is based on a sustained clinically meaningful score 
improvement. 
For delay/prevent end points: 
Patients with any level of baseline pain, including no pain, are eligible to be evaluated for prevent/delay 
end points; those without pain are followed for development of pain, whereas those with baseline pain are 
followed for progression (eg, a 2-point increase without an overall decrease in opiate use). 
Pain assessment should be administered at treatment discontinuation and once again if feasible (eg, 2 to 4 
weeks later). 
Time to deterioration of physical function and/or health-related quality of life (HRQoL) scores should also 
be included, with a priori thresholds defining clinically meaningful deterioration score changes that are 
based on prior published data for the selected questionnaire. 
Refer to Scher et al 2016 for more details. 
CNS = central nervous system; HRQoL = health-related quality of life; PCWG3 = Prostate Cancer Working Group 3; PSA = 
prostate-specific antigen; RECIST = Response Evaluation Criteria in Solid Tumors. 


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Appendix 8 
BPI-SF (sample only, not for patient use)  


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Appendix 9 
 EQ-5D-5L (European Quality of Life (EuroQol) – 5 Domain 5 
Level scale) (sample only, not for patient use) 


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Appendix 10  FACT-P (Functional Assessment of Cancer Therapy – 
Prostate) (sample only, not for patient use) 


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Appendix 11 PCCTC Bone Scan Assessment Tool  


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SAP_001.pdf: 
 
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) 
NCT Number: 
NCT03511664 
 
Document Date: 
 
Statistical Analysis Plan Version 3.0 : 18 January 2021 
 
 
 
 
 
 
 
 




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Table of Contents
1.
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...............................4
2.
INTRODUCTION...........................................................................................7
2.1
Changes from the Protocol ........................................................................ 7
3.
STUDY DESIGN AND OBJECTIVES ................................................................7
3.1
Study Design........................................................................................... 7
3.2
Randomization and Blinding .................................................................... 10
3.3
Study Objectives.................................................................................... 10
3.4
Sample Size Justification......................................................................... 11
4.
PLANNED ANALYSES..................................................................................12
4.1
Interim Analyses and IDMC Oversight....................................................... 13
4.2
Sub-study Analyses................................................................................ 13
5.
GENERAL ANALYSIS DEFINITIONS ............................................................13
5.1
Study Periods and Visit Window Definitions ............................................... 19
5.1.1
Study Periods............................................................................... 19
5.1.2
Visit Windows .............................................................................. 19
5.2
Partial/Missing Dates.............................................................................. 19
5.3
Definition of Populations ......................................................................... 21
5.3.1
Efficacy Populations ..................................................................... 21
5.3.2
Safety Populations ....................................................................... 21
5.3.3
Sub-study Populations ................................................................. 22
5.4
Subgroup Definitions.............................................................................. 22
5.4.1
Analyses on subgroups................................................................. 22
5.5
Treatment Arms..................................................................................... 23
5.6
General Variable Definitions .................................................................... 23
6.
STUDY PATIENTS.......................................................................................25
6.1
Patient Disposition ................................................................................. 25
6.1.1
Sub-study..................................................................................... 26
6.2
Protocol Deviations ................................................................................ 26
6.2.1
Sub-study..................................................................................... 27
6.3
Inclusion and Exclusion Criteria ............................................................... 27
6.3.1
Sub-study..................................................................................... 27
6.4
Stratification Information........................................................................ 27
7.
BASELINE CHARACTERISTICS AND PRIOR AND CONCURRENT THERAPIES 
AND MEDICATIONS ..........................................................................................27
7.1
Demographic and baseline assessments.................................................... 27
7.2
Baseline Disease Characteristics .............................................................. 28
7.3
Medical History ...................................................................................... 28
7.4
Prior Cancer Related Therapy .................................................................. 28
7.5
Sub-study............................................................................................. 29
8.
EFFICACY EVALUATION .............................................................................30
8.1
Efficacy Variable Definitions .................................................................... 30
8.1.1
Primary Efficacy Definitions ......................................................... 30
8.1.2
Key Secondary Efficacy Definitions............................................... 32
8.1.3
Additional Secondary Efficacy Definitions .................................... 33
8.1.4
Sub-study..................................................................................... 34


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8.2
Efficacy Analyses ................................................................................... 34
8.2.1
Primary Efficacy Analyses ............................................................ 34
8.2.2
Key Secondary Efficacy Analyses.................................................. 39
8.2.3
Additional Secondary Efficacy Analyses ....................................... 41
8.2.3.1
Progression-free Survival Analysis.................................................. 41
8.2.3.2
Biochemical Response Analysis ...................................................... 42
8.2.3.3
Quality of Life (QoL) Analysis......................................................... 42
8.2.3.4
Health Economics Analysis ............................................................ 50
8.2.4
Sub-study..................................................................................... 51
9.
SAFETY EVALUATION.................................................................................52
9.1
Extent of Exposure................................................................................. 52
9.1.1
Sub-study..................................................................................... 53
9.2
Adverse Events and Deaths..................................................................... 53
9.2.1
Definition of Treatment Emergent Adverse Events (TEAEs).......... 53
9.2.2
General Convention...................................................................... 54
9.2.3
68Ga-PSMA-11 Adverse Events...................................................... 55
9.2.3.1
Sub-study................................................................................... 55
9.2.4
Randomized Treatment Adverse Events ....................................... 55
9.2.4.1
Sub-study................................................................................... 56
9.2.5
Deaths.......................................................................................... 56
9.2.5.1
Sub-study................................................................................... 56
9.2.6
Long-term Follow up Adverse Events ........................................... 56
9.2.6.1
Sub-study................................................................................... 57
9.2.7
Safety Topics of Interest.............................................................. 57
9.2.7.1
Sub-study................................................................................... 57
9.3
Clinical Laboratory Determination ............................................................ 57
9.3.1
Sub-study..................................................................................... 59
9.4
Vital Signs, Physical Findings, and ECG..................................................... 59
9.4.1
Sub-study..................................................................................... 60
9.5
Prior and Concurrent Surgical and Therapeutic Procedures .......................... 60
9.5.1
Sub-study..................................................................................... 61
9.6
Prior and Concurrent Radiotherapy........................................................... 61
9.6.1
Sub-study..................................................................................... 61
9.7
Prior and Concomitant Medications........................................................... 61
9.7.1
Sub-study..................................................................................... 62
9.8
Post-Treatment Cancer-related Therapy.................................................... 62
9.8.1
Sub-study..................................................................................... 62
10.
REFERENCES ..........................................................................................63
APPENDIX A:  QUALITY OF LIFE QUESTIONNAIRE REFERENCES ......................65
APPENDIX B:  EXAMPLES OF DATE OF BONE PROGRESSION ............................67
REVISION HISTORY .........................................................................................68


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1. LIST OF ABBREVIATIONS AND DEFINITION of TERMS
Abbreviation
Term/Definition
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
ATC
Anatomical therapeutic classification
BOR
Best overall response
BPI-SF
Brief Pain Inventory – Short Form
BSC
Best supportive care
BSoC
Best standard of care
C1D1
Cycle 1 Day 1
CI
Confidence interval
CR
Complete response
CRO
Contract Research Organization
CRF
Case Report Form
CRS
Case Retrieval Strategy
CSR
Clinical study report
CT 
Computed tomography 
CTCAE
Common Toxicity Criteria for Adverse Events
DCR
Disease control rate
DOR
Duration of response
ECG
Electrocardiogram
ECOG 
Eastern Cooperative Oncology Group 
EDoR
Expected duration of response
EMA
European Medical Agency
EOT
End of Treatment
ESA
Erythropoietin stimulating agents
EuroQoL
European Quality of Life
EQ-5D-5L
European Quality of Life (EuroQol) – 5 Domain 5 Level scale
EQ-VAS
European Quality of Life – Visual Analogue Scale
EWB
Emotional Well-Being
FACT-P
Functional Assessment of Cancer Therapy - Prostate
FACT-G
Functional Assessment of Cancer Therapy - General
FAPSI-8
Functional Assessment of Cancer Therapy Advance Prostate Symptom Index-8
FDA
Food and Drug Administration


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Abbreviation
Term/Definition
FAS
Full Analysis Set
FWB
Functional Well-Being
68Ga
Gallium-68
GM-CSF
Granulocyte macrophage colony-stimulating factor
HLGT
High level group terms
HLT
High level terms
HR
Hazard ratio
HRQoL
Health-related quality of life
ICH
International Council for Harmonization
IDMC
Independent Data Monitoring Committee
IRT
Interactive response technology
ITT
Intent to treat
LDH
Lactate dehydrogenase
LOS
Length of stay
177Lu
Lutetium-177
LTFU
Long term follow up
MAR
Missing at random
mCRPC
Metastatic castration-resistant prostate cancer
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic Resonance Imaging
NAAD
Novel androgen axis drug (such as abiraterone, enzalutamide, or apalutamide)
NCI
National Cancer Institute
NMQ
Novartis Medical Dictionary for Regulatory Activities (MedDRA) queries
OAU
Opioid analgesic use
ORR
Overall response rate
OS
Overall survival
PCS
Prostate Cancer Subscale
PCWG3
Prostate Cancer Clinical Trials Working Group 3
PD
Progressive disease
PK
Pharmacokinetics
PET
Positron emission tomography
PFS
Progression-free survival
PR
Partial response
PRO
Patient reported outcome
PRS
Prostate Cancer Subscale Pain-Related Subscale
PSA
Prostate specific antigen
PSMA
Prostate-specific membrane antigen
PT
Preferred term


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Abbreviation
Term/Definition
PWB
Physical Well-Being
QoL
Quality of life
RECIST
Response Evaluation Criteria in Solid Tumors
rPFS
Radiographic progression-free survival
SAP
Statistical analysis plan
SD
Stable disease
SFWB
Social/Family Well-Being
SMQ
Standardized Medical Dictionary for Regulatory Activities (MedDRA) queries
SOC
System organ class
SSE
Symptomatic Skeletal Event
TDRP
Time to disease-related pain
TEAE
Treatment-emergent adverse event
TFOA
Time to first use opioid analgesic
TOI
Trial Outcomes Index
TMF
Trial Master File
VAS
Visual analogue scale
WBC
White blood cell
WHO
World Health Organization


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2. Introduction
This Statistical Analysis Plan (SAP) was written for the clinical trial PSMA-617-01 and is 
based on the current protocol version 4.0 dated 08 July 2019 and current country specific 
protocol version 4.4 DE dated 22 July 2020 that supports the sub-study conducted at sites 
in Germany.  All decisions regarding the analyses, as defined in the SAP, have been made 
prior to database lock.  The ICH guideline E3 “Structure and Content of Clinical Study 
Reports” was used as a guide to the writing of this SAP.  
2.1 Changes from the Protocol
In protocol section 8.7.2, it states that the primary evaluation of the key secondary 
endpoints will be assessed in the PFS-FAS. While this is the case for the key secondary 
endpoint of time to first symptomatic skeletal event (SSE), the other key secondary 
endpoints, Overall Response Rate (ORR) and Disease Control Rate (DCR) per RECIST 1.1,
will be assessed in the Response Evaluable Analysis Set defined as the subset of patients 
in the PFS-FAS with evaluable disease by RECIST 1.1 at baseline.  In addition, the 
supportive analyses of ORR and DCR will not be performed in the FAS as the FAS would 
have included patients without RECIST evaluable disease and may result in bias due to 
the early dropout in the BSC/BSoC arm (see Section 3.1).
Furthermore , the protocol 
specified that the time to first SSE will be analyzed using a Cox regression model, 
stratifying for the randomization factors however, the primary analysis of this endpoint 
will compare the treatment arms using the stratified log-rank test.  The specific analyses 
that are planned for the key secondary endpoints are described in Section 8.2.2.   
The analysis population PFS Analysis Set (PFS-FAS) as stated in protocol section 8.4, will 
be referred in the SAP and tables, listings and figures as PFS Full Analysis Set (PFS-FAS) 
as shown in Section 5.3.1.
As stated in section 8.3 of the protocol, the alpha level applicable to overall survival (OS) 
in the final analysis will depend upon the earlier radiographic progression-free survival 
(rPFS) and interim OS results.  This implies that regardless of the interim analysis result 
of OS, final OS will be re-tested at the applicable alpha level.  However, if the interim OS 
results are met at the pre-specified alpha level, the final OS will be presented descriptively 
without statistical inference and at the same nominal alpha level as specified in Section
3.4. In the event the formal interim OS analysis is not performed, the alpha level applicable 
to the final OS analysis will only depend on the final rPFS results.  The details are further 
described in Section 4  and Section 8.2.1.
3. Study Design and Objectives
3.1 Study Design
This is a Phase 3, open-label, international, randomized study to evaluate the efficacy 
and safety of 177LuPSMA-617 in patients with progressive PSMA positive mCRPC, when 
administered in addition to best supportive/best standard of care (BSC/BSoC) as 
compared to BSC/BSoC alone (Figure 1).


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Figure 1
Diagram of trial design
ECOG = Eastern Cooperative Oncology group; EQ-5D-5L = European Quality of Life (EuroQol) – 5
Domain 5 Level scale; FACT-P = Functional Assessment of Cancer Therapy – Prostate; mCRPC = 
metastatic castration-resistant prostate cancer; PSMA+ = prostate-specific membrane antigen 
positive; RECIST = Response Evaluation Criteria in Solid Tumors
BSC/BSoC includes available care for the eligible patient according to best institutional 
practice and at the discretion of the investigator. Novel androgen axis drugs [NAADs] 
(i.e., enzalutamide, abiraterone, or apalutamide) are allowed.
Investigational agents, cytotoxic chemotherapy, immunotherapy, other systemic radio 
isotopes (e.g. radium-223) or hemi-body radiotherapy treatment may not be 
administered on study.
At screening, potential subjects will be assessed for eligibility and will undergo a 68Ga-
PSMA-11 PET/computed tomography (CT) scan to evaluate PSMA positivity. Only 
patients with PSMA-positive cancer will be randomized in a 2:1 ratio to receive either 
177Lu-PSMA-617 plus BSC/BSoC (investigational arm) or to receive BSC/BSoC only
(BSC/BSoC-only arm). Randomization will be stratified by 4 factors (Section 3.2).
Patients randomized to the investigational arm must begin 177Lu-PSMA-617 dosing within 
28 days of randomization. These patients will receive BSC/BSoC and 7.4 GBq (±10%) 
177Lu-PSMA-617 once every 6 weeks (±1 week) for a maximum of 6 cycles. 
After the Cycle 4 dose of 177Lu-PSMA-617 and prior to Cycle 5 Day 1, the investigator 
should determine if:


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•
The patient shows evidence of response (i.e. radiological, Prostate-specific 
antigen (PSA), clinical benefit) and 
•
Has signs of residual disease on CT with contrast/MRI or bone scan and
•
Has shown good tolerance to the 177Lu-PSMA-617 treatment.
If the patient meets all of the criteria above, and agrees to continue with additional 
treatment of 177Lu-PSMA-617, the investigator may administer a further 2 cycles. A 
maximum of 6 cycles of radioligand therapy is allowed.  If the patient does not meet any 
of the criteria or does not agree to additional 177Lu-PSMA-617 treatment, then no 
additional doses of 177Lu-PSMA-617 will be administered after Cycle 4. After the last 
cycle of 177Lu-PSMA-617, patients can continue BSC/BSoC alone.
BSC/BSoC for each patient will be selected at the discretion of the patient’s physician, 
prior to randomization and will be administered per the physician’s orders and continued 
until the patient comes off the treatment part of the study and enters the long-term 
follow-up stage.
A patient may choose to discontinue the randomized treatment part of the study at any 
time. If a patient chooses only to discontinue from the randomized treatment in the 
study for a reason other than radiographic progression, the patient will be asked to 
confirm if they consent to continue to be followed for long term safety, radiographic 
Progression-Free Survival (rPFS), and survival follow up.  The patient will continue to be 
followed for long term follow up unless they specifically withdraw consent from long term 
follow-up of the study. Crossover to 177Lu-PSMA-617 treatment is not allowed.
An End of Treatment (EOT) visit should occur once a patient discontinues randomized 
treatment for any reason (patient or investigator decision, going on to long term follow 
up, etc.). The EOT visit should occur approximately 30 days from the last dose of 177Lu 
PSMA-617 or the date of the best supportive/best standard of care end of treatment 
decision (whichever is later), but before the initiation of subsequent anti-cancer 
treatment, outside of what is allowed on study.
After the EOT visit, patients will enter the long-term follow-up period.  The long-term 
follow-up period will include the collection of rPFS (if discontinuing for reasons other than 
radiographic progression), survival and information about new treatments, along with 
the patient’s response to these treatments, adverse events assessment, and results of 
hematology and chemistry testing. During follow-up, patients will be followed for safety 
and survival.  They will be contacted every 3 months (±1 month) via phone, email, or 
letter for up to 24 months or until 508 deaths have occurred, whichever is sooner.
Patients who withdraw their consent to participate in the study for any reason other than 
radiographic disease progression will be asked for permission to continue long-term 
status updates which may include, in addition to the above, collection of radiographic 
images (bone scans and CT scans and/or MRIs).
These patients will be asked to sign a separate consent detailing what kind of long term 
follow up assessments and study updates they will agree to. They will also be able to 
designate a contact person (i.e. study doctor, local doctor, friend or family member) who 
may be contacted on their behalf to obtain follow up status updates.
For any of these patients who are unable to sign the second consent (i.e. does not return 
to the site, etc.) every effort will be made to document the extent of long term follow up 
they will agree to. This will be documented in their source records.
This study will enroll approximately 814 patients involving about 110 sites worldwide.
Study design update:
The trial was originally designed to randomize 750 patients, targeting the primary 
analysis of rPFS with 457 events, an interim analysis of Overall Survival (OS), to be 


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conducted contemporaneously with the primary analysis of rPFS, and a final analysis of 
OS with 489 deaths.
However, shortly after commencement of the trial, a high, early dropout rate amongst 
those randomized to BSC/BSoC only became evident with the majority of these dropouts 
withdrawing consent to follow-up. This meant that rPFS data could not be collected for 
these patients which consequently could result in bias in the analysis of rPFS. Remedial 
measures to curtail this phenomenon were implemented and made effective on 5-Mar-
2019. As part of the plan to address the early withdrawal of consent in the BSC/BSoC-
only arm, the primary analysis of rPFS was altered to focus on patients prospectively 
randomized on or after 5-Mar-2019; therefore, rPFS will be analyzed in these patients 
once 364 events have accrued. At time of the rPFS primary analysis, there will also be 
an interim analysis of OS; this OS analysis will be on an intent to treat (ITT) basis and 
will include all randomized patients (i.e., including those randomized before 5-Mar-
2019). Following the analysis of rPFS and the interim analysis of OS, a final ITT analysis 
of the OS primary objective will be performed when 508 deaths have accrued. To 
achieve these analyses, the total number of subjects randomized into the trial was 
increased from N=750 to N=814. The revisions described do not alter the hypothesized 
treatment effects for rPFS and OS upon which the study was originally powered.
Dosimetry, Pharmacokinetics and ECG Sub-study:
A dosimetry, pharmacokinetics (PK) and ECG sub-study will be conducted in a single arm, 
non-randomized cohort of approximately 30 patients at sites in Germany.  These patients
will receive the investigational treatment arm only (i.e., 177Lu-PSMA-617 plus best 
supportive/best standard of care) and will provide a complete assessment of the safety 
aspects of 177Lu-PSMA-617. To prevent biasing the results obtained from patients 
randomized in the main study, the patients enrolled in the sub-study will not be included 
in the in the analyses of the randomized main study but will be described separately from 
the main study. The data analysis of dosimetry, PK and ECG from the sub-study will be 
described in stand-alone analysis plan documents.
3.2
Randomization and Blinding 
Eligible patients will be randomized by an interactive response technology (IRT) system 
in a 2:1 ratio to the investigational treatment arm or the BSC/BSoC -only arm using a 
permuted block scheme. The approximate 30 eligible patients included in the sub-study 
will not undergo randomization as all patients will receive the investigational treatment 
arm. Randomization will be stratified by the following factors:
Presence of liver metastases (yes vs. no)
ECOG score (0 or 1 vs. 2)
Inclusion of NAAD in best supportive/best standard of care at time of 
randomization (yes vs. no) 
The study is open-label.  However, access to subject treatment allocation will be limited 
to those individuals whose roles require access to perform their study responsibilities.  
Details of what roles and which individuals have access to unblinded data will be 
documented in a separate Data Access Plan maintained by the sponsor.  Dates of access 
and reason for accesses will be recorded.  Sponsor statisticians will be blinded and 
contract research organization (CRO) statisticians assigned to the study will be 
unblinded.    
3.3 Study Objectives
Primary objective


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The primary objective of this study is to compare the two alternate endpoints of 
radiographic progression free survival (rPFS) per Prostate Cancer Clinical Trials Working 
Group 3 (PCWG3) guidelines (Scher et al 2016) and overall survival (OS) in patients with
progressive PSMA-positive mCRPC who receive 177Lu-PSMA-617 in addition to BSC/BSoC
versus patients treated by BSC/BSoC alone.
Key secondary objectives
Key secondary objectives are an arm-to-arm comparison of the following:
1. RECIST response to include:
a.
Overall Response Rate (ORR) as measured by RECIST v1.1 criteria
b.
Disease Control Rate (DCR) as measured by RECIST v1.1 criteria 
2. Time to the first symptomatic skeletal event (SSE)
Additional secondary objectives
1. Safety and tolerability of 177Lu-PSMA-617
2. Periodic assessment of health-related quality of life to evaluate impact of 
intervention on patient well-being (HRQoL; EuroQol 5-dimensions 5-level [EQ-5D-
5L] questionnaire, Functional Assessment of Cancer Therapy – Prostate [FACT-P] 
questionnaire and Brief Pain Inventory – Short Form [BPI-SF])
3. Health Economics
4. Progression-free survival (PFS) (radiographic, clinical, or PSA progression-free 
survival)
5. Biochemical response as measured by PSA. Alkaline phosphatase (ALP) and 
lactate dehydrogenase (LDH) levels will also be collected.
6. Dosimetry, PK and ECG (sub-study of approximately 30 patients)
3.4 Sample Size Justification
   
The sample size was determined based on the alternate primary endpoints of rPFS and 
overall survival. Planned enrollment for this study is approximately 814 subjects.
Under the null hypothesis for survival, median overall survival is assumed to be 10 months 
on 177Lu-PSMA-617 and best supportive/best standard of care (active) for a hazard ratio 
(HR) of 1.00. Under the alternative hypothesis, median overall survival on active is 
assumed to be 13.7 months for a HR of 0.7306. 
Under the null hypothesis for rPFS, median rPFS is assumed to be 4 months on 177Lu-
PSMA-617 and best supportive/best standard of care (active) for a HR of 1.00. Under the 
alternative hypothesis, median rPFS on active is assumed to be 6 months for a HR of 0.67. 
Based on a non-linear patient accrual profile over 14 months, a total of 814 patients 
randomized and followed on an ITT basis for a minimum of 13 months is expected to yield 


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508 deaths.  This number of events provides at least 90% power to test the hypothesis 
that the HR for OS is 0.7306 or better with a 1-sided alpha level of at least 0.020.
For rPFS, a total of approximately 557/814 patients are expected to be randomized on or 
after 5 March 2019, these being the patients to be included in the primary analysis of 
rPFS; with a minimum of approximately 6 months follow-up, these patients are expected 
to yield 364 rPFS events which will be sufficient to provide 84% power to test the 
hypothesis that the HR of rPFS is 0.67 or better with a 1-sided alpha level of 0.004. At the 
time of this rPFS analysis, 341 deaths are expected amongst all randomized patients. 
These interim OS data will be analyzed with a 1-sided alpha level of 0.001. Central 
independent assessments will be used to determine rPFS events.
The alpha level applicable to OS in the final analysis will depend upon the earlier rPFS and 
interim OS results:
if p<0.004 1-sided is achieved for rPFS and p<0.001 1-sided is achieved for interim 
OS, then the alpha level for the final analysis of OS will be raised to 0.025 1-sided.
if p<0.004 1-sided is achieved for rPFS but p<0.001 1-sided is not achieved for 
interim OS, then the alpha level for the final analysis of OS will be 0.024 1-sided.
if p<0.004 1-sided is not achieved for rPFS but p<0.001 1-sided is achieved for 
interim OS, then the alpha level for the final analysis of OS will be raised to 0.021 
1-sided.
if p<0.004 1-sided is not achieved for rPFS and p<0.001 1-sided is not achieved 
for interim OS, then the alpha level for the final analysis of OS will remain at 0.020 
1- sided.
This design provides at least 90% power for OS and 84% power for rPFS; with an overall 
-sided.  
The observed HRs that will meet p<0.004 for rPFS and the interim analysis of OS are 
0.745 and 0.701 respectively; and the observed HR that will meet p<0.020 to p<0.025 in 
the final analysis of OS are 0.824 to 0.823.
4. Planned Analyses
The analyses of the alternate primary endpoints, rPFS and OS, are event driven.  The 
formal planned analysis of rPFS is when 364 rPFS events have been observed in patients 
randomized on or after 5 March 2019 with an interim analysis of OS at the time of the 
rPFS analysis using all patients randomized since trial commencement (see Section 5.3.1
for Efficacy Populations).  A final analysis of OS, using all patients randomized, will take 
place when 508 deaths have been observed.
The statistical design of the study is such that, to be declared positive, the study would be 
required to reach statistical significance on either the primary analysis of rPFS or OS at 
the respective allocated alpha level; it is not required to meet both rPFS and OS to be 
declared a statistically positive study.
Note, this applies to OS assessed at either the interim or the final analysis, i.e. for the 
study to be declared statistically positive requires rPFS to meet its allocated alpha level or 
OS to meet its allocated alpha level at either (i) the formal OS interim analysis (conducted 
at the time of the rPFS analysis) or (ii) at the final OS analysis with 508 deaths.
The alpha level applicable to OS in the final analysis will depend upon the earlier rPFS and 
interim OS results as described in Section 3.4. If the formal interim OS analysis is met at 
the pre-specified alpha level, the final OS will only be presented descriptively without 
statistical inference at the nominal alpha level. However, if the formal interim OS analysis 
is not performed, the alpha level applicable to the OS analysis will depend on the final 
rPFS results as follows:


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if p<0.004 1-sided is achieved for rPFS, then the alpha level for the final analysis 
of OS will be raised to 0.025 1-sided.
if p<0.004 1-sided is not achieved for rPFS, then the alpha level for the final 
analysis of OS will be 0.021 1-sided.
4.1
Interim Analyses and IDMC Oversight
Safety data monitoring will be conducted quarterly by the Independent Data Monitoring 
Committee (IDMC). Safety reviews will commence following the completion of the first 
three months of study accrual.  Safety analyses to be conducted are outlined in the IDMC 
charter. The specific responsibilities and composition of the IDMC are outlined in the IDMC 
Charter.  The IDMC Charter will be approved and finalized by the IDMC members prior to 
the initiation of any formal efficacy analysis.  A summary of efficacy data will also be 
provided to the IDMC at the time of routine safety data reviews; these efficacy data will 
be provided for information only; no statistical hypothesis testing will be conducted.  
The planned analysis of rPFS and the interim analysis of OS will be overseen by the IDMC 
who may recommend stopping the study for superior efficacy at the first interim analysis 
for efficacy if the corresponding pre-specified 1-sided p-value threshold is met. The IDMC 
can recommend a course of action including early cessation if one of the alternate primary 
endpoints is met, but the sponsor will make the final decision regarding whether or not to 
continue or stop the trial, based on any analysis for reasons related to safety or efficacy.
4.2
Sub-study Analyses
The analyses of dosimetry, PK and ECG from the sub-study are described in separate 
analysis plans and are outside the scope of this SAP. All other analyses as described in 
this SAP will be performed, at the earliest, when all patients have completed study 
treatment (i.e. 177Lu-PSMA-617+BSC/BSoC) or discontinued study treatment for any 
reason.  Separate TFL shells will detail the planned outputs for the sub-study analyses. 
5. General Analysis Definitions
Data will be analyzed using SAS version 9.4 or higher. 
No tests of significance will be carried out to compare treatment arms on baseline data 
because any observed differences between them must be attributed to chance.
Descriptive statistics will be presented in tables as follows: 
• Categorical data will be summarized in contingency tables presenting frequencies 
and percentages.
• Continuous data will be summarized using number of non-missing values (n), mean, 
standard deviation, median, minimum, and maximum values.
Unless otherwise indicated, for frequency tables, patients with missing data will be 
excluded from the denominator of percentage calculations. All treatment arm comparisons 
other than the one-sided analyses described for the alternate primary endpoints, rPFS and 
OS, will be based on two-sided tests.
Tables will be created by treatment arm and for all patients combined as described at the 
beginning of sections 7, 8, and 9.
Individual patient listings will include all study-related data. The sort order of the listings 
will be by treatment, patient ID (center number-patient number), and date of assessment 
(if available).
Randomized treatment throughout this document will refer to 177Lu-PSMA-617+BSC/BSoC 
and BSC/BSoC alone for analyses pertaining to the main study and will refer to 177Lu-
PSMA-617+BSC/BSoC for analyses pertaining to the sub-study.


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Best supportive/best standard of care (BSC/BSoC):  BSC/BSoC in either arm will be 
administered as per physician’s orders and protocol at the institution and whenever 
feasible, it should be optimized prior to randomization.  Patients will continue to be treated 
with BSC/BSoC until they require a treatment regimen not allowed on study or have 
radiographic progressive disease as measured by Prostate Cancer Clinical Trials Working 
Group 3 (PCWG3) criteria.   BSC/BSoC is defined as follows:
Concomitant medications indicated as study BSC/BSoC, coded using WHO Drug 
Global dictionary.  A pre-specified list of concomitant medications, based on the 
interventions allowed as BSC/BSoC per protocol (protocol section 5.2) will be used 
to indicate and flag concomitant medications as study BSC/BSoC.  The BSC/BSoC 
flag captured on the CRF will not be used to identify concomitant medications 
indicated as study BSC/BSoC.  
Concurrent procedures other than radiotherapy indicated as study BSC/BSoC, are 
coded using the Medical Dictionary for Regulatory Activities (MedDRA).  The 
BSC/BSoC flag captured on the CRF will be used to identify concurrent procedures 
other than radiotherapy indicated as study BSC/BSoC.
Concurrent radiotherapy indicated as study BSC/BSoC.  The BSC/BSoC flag 
captured on the CRF will be used to identify concurrent radiotherapy indicated as 
study BSC/BSoC.
Reference date is the date of first dose of randomized treatment unless otherwise noted.  
Date of first dose of randomized treatment is defined as the date of first 177Lu-PSMA-617 
administration (non-zero dose) on Cycle 1 Day 1 (C1D1) or the date of first administration 
of BSC/BSoC.  
The date of first 177Lu-PSMA-617 administration will be defined as the earliest date 
of administration as captured on the 177Lu-PSMA-617 Administration CRF page with 
a non-zero dose.
The date of first administration of BSC/BSoC will be defined as the date of C1D1.
The date of first administration of a NAAD as study BSC/BSoC will be defined as 
follows:
o
= earliest start date of a NAAD indicated as study BSC/BSoC (captured on 
concomitant medications CRF) if after the date of first administration of 
BSC/BSoC, otherwise
o
= date of first administration of BSC/BSoC.
For example: if the earliest start date of a NAAD indicated as study BSC/BSoC is 
01MAR2019 and the date of first administration of BSC/BSoC is 03JAN2019, then 
the date of first administration of a NAAD as study BSC/BSoC is 01MAR2019.
The number of days until a study assessment or procedure is calculated as:
Study Day= Assessment date – Reference date +1 if assessment date is after or 
on the reference date
  Study Day= Assessment date – Reference date if assessment date is before the 
reference date
Note: The reference date for safety assessments during randomized treatment (e.g. 
adverse event onset, laboratory measurement, vital sign measurement, ECOG 
performance status, etc.) is the date of first dose of randomized treatment and the 
reference date for efficacy assessments (i.e. survival, tumor response, health related 


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quality of life) is the date of randomization.  The reference date for all assessments in 
the sub-study is the date of first dose of 177Lu-PSMA-617.
Baseline for a given variable will be defined as the last non-missing assessment, including 
unscheduled assessments, for that variable obtained prior to or on the reference date but 
before the first treatment dose, unless otherwise noted. 
For efficacy evaluations, the last non-missing assessment, including unscheduled 
assessments on or before the date of randomization is taken as “baseline” value or 
“baseline” assessment. For RECIST/PCWG3-based endpoints using CT/MRI, and bone 
scans (i.e. rPFS, ORR, DCR, duration of response, PFS), a window of 28 days from the 
start of randomized treatment will be allowed, i.e. the investigator/central review-reported 
responses will be maintained and baseline considered valid if the baseline assessment is 
within 28 days of randomized treatment start date. In the context of baseline definition, 
the efficacy evaluations also include the laboratory parameters PSA, ALP and LDH, and 
HRQoL (e.g. FACT-P).  For safety evaluations of randomized treatment (i.e. laboratory 
assessments, ECOG performance status and vital signs), the last available assessment on 
or before the date of start of randomized treatment is taken as “baseline” assessment. For 
vital signs where time of assessment is captured (e.g. pre-dose and post-dose vital sign), 
the 15 minutes pre-dose value on or before the date of start of randomized treatment is 
taken as “baseline” assessment. For safety evaluations of 68Ga-PSMA-11 (i.e. laboratory 
assessments and vital signs), the last available assessment on or before the date of 68Ga-
PSMA-11 is taken as “baseline” assessment.
In rare cases where multiple measurements meet the baseline definition, with no further 
flag or label that can identify the chronological order, then the following rule should be 
applied: If multiple values are from the same laboratory or collected for ECGs or vital 
signs, then the last value should be considered as baseline.
If patients have no value as defined, the baseline result will be considered as missing.  
Refer to the table below for specific details on the baseline definitions for key study 
parameters. 


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Parameter
Baseline Definition1
Evaluation
Baseline Height, 
Weight, Body Mass 
Index (BMI) 
the last available assessment on or 
before the date of randomization
Baseline 
demographics and 
disease 
characteristics for 
randomized 
treatment
Baseline Height, 
Weight, Body Mass 
Index (BMI) prior to 
68Ga-PSMA-11 dosing
the last available assessment on or 
before the date of 68Ga-PSMA-11
dosing
Baseline 
demographics and 
disease 
characteristics for 
68Ga-PSMA-11
Baseline ECOG score
ECOG score captured on the 
Enrollment CRF page
Note: ECOG performance is not 
collected at the time of screening, 
therefore it will not be available for 
those not enrolled.
Baseline 
demographics and 
disease 
characteristics and 
Stratification Factor 
for randomized
treatment
Baseline PSA, LDH and 
ALP
the last available assessment on or 
before the date of randomization
Baseline 
demographics and 
disease 
characteristics and 
Efficacy for 
randomized 
treatment
Baseline PSA,LDH and 
ALP prior to 68Ga-
PSMA-11 dosing
the last available assessment on or 
before the date of 68Ga-PSMA-11
dosing
Baseline 
demographics and 
disease 
characteristics for 
68Ga-PSMA-11
Baseline lesions (per 
investigator and 
central review)
the last available assessment on or 
before the date of randomization 
and/or within 28 days of start of 
randomized treatment 
Baseline disease 
characteristics and 
Efficacy for 
randomized 
treatment
Baseline lesions (per 
investigator) prior to 
68Ga-PSMA-11 dosing
the last available assessment on or 
before the date of 68Ga-PSMA-11
dosing
Baseline 
demographics and 
disease 
characteristics for 
68Ga-PSMA-11


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Baseline EQ-5D-5L, 
FACT-P and BPI-SF
the last available assessment on or 
before the date of randomization
Efficacy
Laboratory tests at 
baseline (chemistry, 
hematology, 
testosterone, 
urinalysis)
the last available assessment on or 
before the date of start of randomized 
treatment
Safety for 
randomized 
treatment
Laboratory tests at 
screening (chemistry, 
hematology, 
testosterone, 
urinalysis)
the last available assessment on or 
before the date of 68Ga-PSMA-11
dosing
Safety for 68Ga-
PSMA-11
ECOG score at 
baseline
the last available assessment on or 
before the date of start of randomized 
treatment
Safety for 
randomized 
treatment
Vital signs at baseline
the last available assessment on or 
before the date of start of randomized 
treatment or if a time assessment is 
captured, the  15 minutes pre-dose 
value on or before the date of start of 
randomized treatment
Safety for 
randomized 
treatment
Vital signs at 
screening
the last available assessment on or 
before the date of 68Ga-PSMA-11
dosing
Safety for 68Ga-
PSMA-11
ECG at baseline
the last available assessment on or 
before the date of start of randomized 
treatment
Safety for 
randomized 
treatment
ECG at screening
the last available assessment on or 
before the date of 68Ga-PSMA-11
dosing
Safety for 68Ga-
PSMA-11
1.For the sub-study, randomized treatment refers only to 177Lu-PSMA-617+BSC/BSoC.
Cycle 1 Day 1 (C1D1) is date of first study procedures, randomized treatment and 
assessments.
Date of randomization is used for the start date of “time to” endpoints for efficacy analyses.
68Ga-PSMA-11 dosing is the date 68Ga-PSMA-11 was administered.
Date of last randomized treatment administration is the date of last administration of 
randomized treatment which is the date of last administration of 177Lu-PSMA-617 or date 
of last administration of BSC/BSoC, whichever is later. For example: if the last dose 
administration of 177Lu-PSMA-617 is on 15APR2019, and the end of treatment decision 


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date for BSC/BSoC is on 17APR2019, then the date of last administration of randomized 
treatment is on 17APR2019. 
Date of last administration of 177Lu-PSMA-617 is the last date when 177Lu-PSMA-617 
was administered (non-zero dose), i.e. the latest date of administration as captured 
on the 177Lu-PSMA-617 Administration CRF page with a non-zero dose.
Date of last administration of BSC/BSoC is the end of treatment decision date 
recorded on the End of Treatment – BSC/BSoC CRF.
Date of last administration of a NAAD as study BSC/BSoC will be defined as follows:
o
= latest end date of a NAAD indicated as study BSC/BSoC (captured on 
concomitant medications CRF) if before date of last administration of 
BSC/BSoC, otherwise
o
= date of last administration of BSC/BSoC.
For example: if the latest end date of a NAAD indicated as study BSC/BSoC is 
01AUG2019 and the date of last administration of BSC/BSoC is 03OCT2019, then 
the date of last administration of a NAAD as study BSC/BSoC is 01AUG2019.
Last date of exposure to randomized treatment: The
177Lu-PSMA-617 treatment schedule
is organized in cycles of 42 days. The last date of exposure to randomized treatment is
derived to be the latest date of the last date of exposure to either 177Lu-PSMA-617 or 
BSC/BSoC. The last date of exposure to 177Lu-PSMA-617 or BSC/BSoC will be derived 
as follows: 
The
last
date of exposure to
177Lu-PSMA-617 is calculated as
(last date of
administration of Lu-PSMA-617) + (length of time interval - 1) i.e. [last date of
177Lu-PSMA-617 administration + (42-1)].
If the subject died or was lost to follow-up (i.e. discontinued early from the study) 
within the last date of administration of 177Lu-PSMA-617 + 42 days, the last date of 
exposure to 177Lu-PSMA-617 is the date of death or date of last contact, respectively.
The last date of exposure to BSC/BSoC is the last date of administration of BSC/BSoC (i.e. 
the end of treatment decision date recorded on the End of Treatment –BSC/BSoC CRF).
The last date of exposure to a NAAD as study BSC/BSoC is the last date of administration 
of a NAAD as study BSC/BSoC.
Last contact date: The last contact date is derived for patients not known to have died at 
the analysis cut-off date based on the latest date among the following:
Assessment dates (e.g. laboratory, vital signs, ECOG performance status/HRQoL 
(e.g. FACT-P), ECG, tumor imaging, end of treatment decision, etc.).
Medication and procedure dates including 177Lu-PSMA-617 administration, concomitant 
medications/therapies, concurrent surgical and therapeutic procedures (including 
radiation therapy), post-treatment cancer-related therapies after randomized treatment 
discontinuation (with non-missing medication/procedure term).
Adverse event start and end dates (with non-missing verbatim AE term present).
“Date of Last Contact” collected on the “Long Term Follow Contact” CRF.
Randomized treatment start/end date
Randomization date
The last contact date is defined as the latest complete date from the above list or the 
cut-off date, whichever comes first. The cut-off date will not be used for last contact 
date, unless the patient was seen or contacted on that date. No date post cut-off date 
will be used. Completely imputed dates (e.g. the analysis cut-off date programmatically 
imputed to replace the missing end date of a dose administration record) will not be 
used to derive the last contact date. 


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The last contact date is used for censoring of patients in the analysis of overall survival.
Time unit: A year length is defined as 365.25 days.  A month length is 30.4375 days 
(365.25/12).  If duration is reported in months, duration in days will be divided by 
30.4375.  If duration is reported in years, duration in days will be divided by 365.25.
5.1 Study Periods and Visit Window Definitions
5.1.1
Study Periods
The study consists of 3 periods: screening, treatment (with no maximum number of cycles 
defined), and a follow-up period (end of treatment, long-term follow-up). Results will be 
presented by time point and not by period.  However, the naming of the time points will 
reflect the period.  In the investigational treatment arm, a patient will be treated with 
177Lu-PSMA-617 + BSC/BSoC up to a maximum of 6 cycles, and then BSC/BSoC only for 
the duration of the on-treatment period.  Note that for cycles 1-6, cycle duration is 6 
weeks, and for cycles 7 and beyond, cycle duration is 12 weeks.
5.1.2
Visit Windows
For data collected at multiple time points, the scheduled collection date/time will be used 
to summarize the data, unless otherwise indicated.  Visits are scheduled from time of 
previous cycle’s Day 1.    
Scan assessments are scheduled from the reference date (date of first dose).  Scan dates 
are not associated with a visit number.  Dates are used for analyses and patient listings.    
Unscheduled assessments will not be taken into account in summary variable calculations, 
except for baseline assessments and unscheduled RECIST, bone scan, PSA and HRQoL 
evaluations for evaluating efficacy (Section 8). All measurements will be presented in the 
listings.
Unless otherwise indicated, if more than one measurement (a lab result for example) exists 
for a patient on a particular time point/visit, the last value obtained at that time point/visit 
will be used when summarizing the data.
Refer to protocol section 6.1 and protocol Appendix 1 for schedules of study assessments 
during each study period.
5.2 Partial/Missing Dates
In general, the database requires a valid full date, including dates used for the alternate 
primary endpoints, rPFS and OS.  However, for partial or missing dates for initial cancer 
diagnosis, prior therapies, and concomitant medication start dates, the rules shown 
below will be applied. (Concomitant medication stop dates and start and end dates for 
adverse events, concurrent radiotherapy, and concurrent surgical/therapeutic procedures 
are full date required fields.)
The imputed dates will only be used for the assignment to prior and/or concomitant 
medication or concurrent therapy and for deriving time since initial cancer diagnosis.  
The imputed dates will not be used in any other calculation and will not be listed.  
For the calculation of the time since initial cancer diagnosis, the following imputation 
rules will be applied when the date of initial cancer diagnosis is incomplete:
• If the day is missing: first day of the month.
• If the day and month are missing: first day of January.


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For the assignment of medication, therapy and procedure to prior or 
concomitant/concurrent collected on the Concomitant Medication/Therapy, Concurrent 
Surgical / Therapeutic Procedures, and Radiotherapy CRF pages, the following rules will 
be applied for incomplete dates:
• If start date is incomplete: 
o
if end date is before the date of first dose of randomized treatment, the 
start date will remain missing (i.e. prior); 
o
if end date is on or after date of first study drug administration or the 
medication is ongoing, 
if the day is missing: the start date will be imputed with the first day 
of the month; 
if the day and month are missing: the start date will be imputed with 
01 January of the year.
Note: Prior cancer related therapies, procedures and medications with missing or partial 
dates as captured on the Prior Cancer Related Surgery, Prior Radiotherapy and Prior 
Cancer Systemic Therapy CRF pages will not be imputed or included in the assignment of 
medications, procedures or therapies to prior or concomitant.  Prior cancer related 
therapies will be summarized separately as described in Section 7.4.
The following rule should be used for the imputation of the date of last administration 
(end date) for BSC/BSoC:
If the end date is completely missing and there is no End of Treatment (EOT) 
page and no death date/End of Study (EOS) date, the patient is considered as on-
going.  The patient should be treated as on-going and the cut-off date should be 
used as the end date.
After imputation, compare the imputed date with start date of BSC/BSoC, if the imputed 
date is < start date of BSC/BSoC:  Use the BSC/BSoC start date. 
The following rules will be used for imputing adverse event (AE) start dates to assign as 
treatment emergent:
If day, month and year are missing:
Completely missing start dates will not be imputed.
If day and month are missing: 
If partial start date year = year of randomized treatment start date then
o
If end date contains a full date and end date is earlier than randomized 
treatment start date then set start date = 01 January of the year 
o
Else set start date = randomized treatment start date. 
If partial start date year > year of randomized treatment start date then 01 
January of the year
If partial start date year < year of randomized treatment start date then 01 July 
of the year
If day is missing: 


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If partial start date month and year = month and year of randomized treatment 
start date then 
o
If end date contains a full date and end date is earlier than randomized 
treatment start date then set start date= first day of the month and year. 
o
Else set start date = randomized treatment start date.
If partial start date month and year > month and year of randomized treatment 
start date then first day of the month and year  
If partial start date month and year < month year of randomized treatment start 
date then 15th day of the month and year
Note: If randomized treatment start date is missing, apply the same rules but use the 
68Ga-PSMA-11 administration date instead.
For the assignment of an adverse event as a randomized treatment-emergent adverse 
event, the following rules will be applied when there is a partial date of subsequent anti-
cancer treatment as captured on the post-treatment anti-cancer therapies or procedures 
CRF pages:
if the day is missing: if the month of the partial subsequent anti-cancer treatment 
is in the same month as the date of last administration of randomized treatment 
(see Section 5), then impute using the date of last administration of randomized 
treatment.  Otherwise, impute using the first day of the month.
5.3 Definition of Populations
5.3.1
Efficacy Populations 
Full Analysis Set (FAS):  All randomized patients.  Patients will be included in the 
treatment arm to which they were randomized regardless of actual treatment 
received.  This is an intent to treat analysis set.  This analysis set will be used for 
the primary analysis of OS.
PFS Full Analysis Set (PFS-FAS):  All patients randomized on or after 5 March 
2019.  Patients will be included in the treatment arm to which they were 
randomized regardless of actual treatment received.  This analysis set will be used 
for the primary analyses of rPFS and all secondary endpoints excluding ORR and 
DCR.
Response Evaluable Analysis Set:  The subset of patients in the PFS-FAS with 
evaluable disease by RECIST at baseline (i.e. at least one target and/or non-target 
lesion per independent central review radiologist assessment used as the final 
radiology assessment. See section 8.1 for details on how the final radiology 
assessment is selected.).  Patients will be included in the treatment arm to which 
they were randomized.  Soft tissue response as measured by RECIST will be 
assessed in this dataset.  This analysis set will be used for the primary analyses of 
ORR and DCR.
5.3.2
Safety Populations 
PSMA-11 Safety Analysis Set: All patients who received a dose of 68Ga-PSMA-
11.  This includes screened patients that are not enrolled (i.e., not randomized).  
Patients enrolled will be included in the treatment arm to which they were 
randomized.


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FAS Safety Analysis Set:  The subset of patients in the FAS who received at least 
one dose of randomized treatment.  Patients will be included in the treatment arm 
corresponding to the actual treatment received.  
5.3.3
Sub-study Populations 
PSMA-11 Sub-study Analysis Set: All patients who received a dose of 68Ga-
PSMA-11 in the sub-study conducted at sites in Germany.  This includes screen 
failure patients who are not enrolled in the sub-study.
Sub-study Safety Analysis Set: All patients who received at least one dose of 
the investigational treatment (177Lu-PSMA-617+BSC/BSoC) in the sub-study 
conducted at sites in Germany.
5.4 Subgroup Definitions   
The following subgroups are defined for the study:
1.Stratification Factor (based on CRF data) – Inclusion of NAADs (e.g., enzalutamide, 
abiraterone, or apalutamide) as part of assigned BSC/BSoC treatment at start of 
study (Yes vs. No).  See Section 5.6 for derivation. 
2. Number of cycles in the 177Lu-PSMA-
5-6 cycles).
3. Stratification factor (based on CRF data) – Baseline LDH (
IU/L). See Section 5.6 for derivation.
4.  Stratification factor (based on CRF data) - Presence of liver metastases at baseline 
(Yes vs. No). See Section 5.6 for derivation.
5.  Stratification factor (based on CRF data) – ECOG score at baseline (0 or 1 vs. 2). 
See section for derivation.
6.  
7.  Race (White vs. Black or African American vs. Asian vs. Other (includes “Native 
Hawaiian or Other Pacific Islander”, “American Indian or Alaska Native” or more 
than one race reported)
5.4.1
Analyses on subgroups 
All subgroup analyses are to be considered exploratory and descriptive; p-values 
presented with efficacy results will be treated as nominal.  
Efficacy analyses The alternate primary endpoints, rPFS and OS, will be summarized and 
analyzed by the following subgroups (defined in Section 5.4) to assess the consistency of 
treatment effect provided either or both primary endpoints are statistically significant:
Inclusion of NAADs as part of assigned BSC/BSoC treatment at start of study
Baseline LDH
Presence of liver metastases at baseline
ECOG score at baseline
Age
Race
No formal statistical test of hypotheses will be performed for the subgroups.  For each 
subgroup, a stratified cox regression model will be used to estimate the treatment effect 


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stratifying for the randomization factors from IRT.  When one of the stratification factors 
is the subgroup of interest, that factor will be excluded from the stratified model.  The 
model will include three terms: treatment, subgroup (e.g. ECOG score at baseline) and 
treatment by subgroup interaction.  The HR and associated confidence interval for each 
subgroup will be estimated from the model.  Kaplan-Meier estimates as described for the 
alternate primary endpoints (Section 8.2.1) will also be provided excluding the log-rank 
test p-value.  Subgroup analyses of rPFS and OS will be presented graphically using forest 
plots.
The efficacy analyses in subgroups will only be performed if at least 10% of patients or 10 
patients are present in each class.
Key safety analyses of exposure, adverse events and clinical laboratory values 
will be performed as described in Section 9, on the FAS and PSMA-11 safety analysis sets 
(defined in Section 5.3.2) in the following subgroups (defined in Section 5.4):
Inclusion of NAADs as part of assigned BSC/BSoC treatment at start of study (FAS 
Safety Analysis Set only)
Number of cycles received in the 177Lu-PSMA-617 + BSC/BSoC treatment arm (FAS 
Safety Analysis Set only)
ECOG score at baseline (FAS Safety Analysis Set only)
Age (FAS Safety Analysis Set and PSMA-11 Safety Analysis Set)
Race (FAS Safety Analysis Set and PSMA-11 Safety Analysis Set)
The objective for carrying out these subgroup analyses is to identify potential safety issues 
that may be limited to a subgroup of patients, or safety issues that are more commonly 
observed in a subgroup of patients.  Summary tables will only be performed if at least 
10% of patients or 10 patients are present in each subgroup.
The results of the efficacy and safety subgroup analyses will be presented in separate 
tables and figures from study arm results.
Separate listings will not be created for subgroups.  
5.5 Treatment Arms
The following treatment arm labels will be used in the analysis:
Lu-PSMA-617+BSC/BSoC: 177Lu-PSMA-617 + Best supportive/best standard of 
care (investigational treatment arm)
BSC/BSoC only:  Best supportive/best standard of care only (control arm)
5.6 General Variable Definitions  
Time to withdrew consent from 177Lu-PSMA-617 (days): (Date of withdrew of consent 
from 177Lu-PSMA-617 treatment – date of randomization + 1).  
Time to withdrew consent from BSC/BSoC (days): (Date of withdrew of consent from 
BSC/BSoC – date of randomization + 1).  
Time to withdrew consent from study (days): (Date of withdrew of consent from
study – date of randomization + 1).
Age (years): year of informed consent - year of birth; calculated within clinical 
database.


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Time since initial prostate cancer diagnosis (years): (Date of informed consent - Date 
of initial prostate cancer diagnosis)/(365.25). For incomplete dates, see Section 
5.2.
Weight (kg) = weight (lb) * 0.45359237
Height (cm) = height (in) * 2.54
BMI (kg/m2) = weight[kg] / (height[m]2) using weight and height at baseline.
Best % change (where a decrease over time is desirable) = ((smallest post baseline 
assessment – baseline)/baseline) x 100
Last taxane therapy treatment-free interval (months): (randomization date - last 
taxane therapy end date)/(30.4375). For incomplete dates, the see Section 5.2. 
Taxanes included are those identified as ‘Taxane’ per WHO Drug ATC Level 4 (e.g. 
cabazitaxel, docetaxel or paclitaxel).
Baseline PSA doubling time (months):  PSA doubling time will be calculated as 
natural log of 2 (0.693) divided by the sum of the fixed slope (common to all 
patients) and the random slope (specific for the patient)  of the random coefficient 
linear model between the natural log of PSA and time of PSA measurement (Svatek 
et al., 2006).  If the PSA doubling time is less than zero (i.e. stable, nonincreasing, 
or decreasing PSA levels as defined by a negative slope from the random coefficient 
linear model), the PSA doubling time is set to 0. PSA is collected at screening visit 
and for the most recent 2 PSA measurements available prior to screening.  
Calculations will be performed only for subjects with (1) all 3 PSA values with each 
rval between the first and last PSA 
PCWG3 guidelines (Scher et al., 
2016; Pound et al., 1999).
For interpretation of PSA doubling time it should be noted that PCWG3 guidelines 
state the calculation should be based on the most recent PSA values during androgen 
deprivation therapy, and that 
.  
These additional criteria will not be applied since the information is not available.
Randomized Treatment (i.e. 177Lu-PSMA-617 and BSC/BSoC) Exposure Variables: 
Average duration of randomized treatment cycles (months) = mean across cycles of 
(date of dosing for cycle n+1 – date of dosing for cycle n)/30.4375, where n=1 to 
total number of cycles minus 1.
Duration of exposure (months) = (Date of last exposure to randomized treatment –
Reference date + 1)/30.4375.  Date of first administration to randomized treatment 
and date of last exposure to randomized treatment are defined in Section 5.  
For duration of exposure to 177Lu-PSMA-617, the date of last exposure is the date 
of last exposure to 177Lu-PSMA-617 and the reference date is the date of first 
administration of 177Lu-PSMA-617.
For duration of exposure to BSC/BSoC, the date of last exposure is the date of last 
exposure to BSC/BSoC and the reference date is the date of first administration of 
BSC/BSoC (i.e. date of C1D1).
For duration of exposure to a NAAD as study BSC/BSoC, the date of last exposure 
is the date of last exposure to a NAAD as study BSC/BSoC and the reference date 
is the date of first administration of a NAAD as study BSC/BSoC.


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Dose intensity of 177Lu-PSMA-617
Dose intensity overall (GBq/month) = (actual total dose of 177Lu-PSMA-617 during 
the study) / (actual duration of the study (months))   Note: The duration of the last 
cycle will be set to 6 weeks (or ~ 1.37 months = 42 /30.4375). 
Planned dose intensity overall (GBq/month) = (planned total dose of 177Lu-PSMA-
617 during the study) / (planned duration of the study (months))  
Relative dose intensity overall (%) = (dose intensity overall) / (planned dose 
intensity overall)
Dose intensity of 177Lu-PSMA-617 per cycle
Dose intensity per cycle (GBq/cycle) = (actual total dose of 177Lu-PSMA-617 during 
the cycle) 
Planned dose intensity per cycle (GBq/cycle) = (planned total dose of 177Lu-PSMA-
617 during the cycle) 
Relative dose intensity per cycle (%) = (dose intensity per cycle) / (planned dose 
intensity per cycle)
Randomization Stratification Factors based on CRF data
Stratification factor (based on CRF data) –
is defined as the latest LDH value on or before the date of randomization as collected 
on the laboratory CRF page.
Stratification factor (based on CRF data) - Presence of liver metastases at baseline 
(Yes vs. No) is defined as at least one target and/or non-target liver lesion on or 
before the date of randomization and/or within 28 days of start of randomized 
treatment as captured on either the target or non-target lesion CRF pages.
Stratification factor (based on CRF data) – ECOG score at baseline (0 or 1 vs. 2) is 
defined as the ECOG score captured on the Enrollment CRF page.
Stratification Factor (based on CRF data) – Inclusion of NAADs (e.g., enzalutamide, 
abiraterone, or apalutamide) as part of assigned BSC/BSoC treatment at start of 
study (Yes vs. No) is defined as having a NAAD indicated as study BSC/BSoC (see 
Section 5) on or before the date of C1D1.
6. Study Patients
6.1 Patient Disposition
Sample size flow will be displayed in a consort diagram, and the following patient data will 
be summarized in tables.


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Patient disposition for all patients who signed an informed consent:
• Number of patients who signed informed consent
• Number of patients screened
• Number of patients who were screen failures and the reason for screen failure
• Number of patients administered 68Ga-PSMA-11 (PSMA-11 Safety Analysis Set)
By treatment arm and combined:
• Number of randomized patients – Full Analysis Set
• Number of randomized patients on or after March 5, 2019 – PFS Analysis Set
o
Number (%) of patients in Response Evaluable Analysis Set
• Number of randomized patients administered study treatment (FAS Safety Analysis 
Set) 
Enrollment by country and center will be summarized for all screened patients and also by 
treatment arm using the FAS. 
End of treatment status and the end of study status for all patients in the FAS, PFS-FAS 
and in the FAS randomized prior to 5 March 2019 will be summarized, by treatment arm 
and combined:
Number (%) of patients treated, not treated and still on treatment
Number (%) of patients discontinued from 
177Lu-PSMA-617 and BSC/BSoC, 
separately and all study treatments
Number (%) for each primary reason for discontinuation from 177Lu-PSMA-617 and 
BSC/BSoC, separately 
o
Number (%) for reason for withdrawal of consent for 177Lu-PSMA-617 
and  BSC/BSoC, separately
o
Time to withdrew consent (in days) continuous and categorical (1,2-
28, 29-56, >56) 
Number (%) of patients continuing in long-term follow-up period (i.e. patients 
who agreed to long-term follow-up and have not discontinued from the study) 
Number (%) of patients discontinued from study
Number (%) for each primary reason for discontinuation from study
o
Number (%) for reason for withdrawal of consent for 177Lu-PSMA-617 
and  BSC/BSoC, separately
o
Time to withdrew consent (in days) continuous and categorical (1, 2-
28, 29-56, >56)
6.1.1
Sub-study 
Patient disposition for all patients who signed an informed consent in the sub-study will be 
summarized and will include the following: Number of patients who signed informed 
consent, Number of patients screened, Number of patients who were screen failures and 
the reason for screen failure, Number of patients administered 68Ga-PSMA-11 (PSMA-11 
Sub-study Analysis Set), Number of patients administered 177Lu-PSMA-617 and BSC/BSoC 
(Sub-study Safety Analysis Set).  End of treatment and end of study status will also be 
summarized as described above for all patients in the Sub-study Safety Analysis Set.
6.2
Protocol Deviations


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For the FAS, major protocol deviations will be summarized for each treatment arm and 
overall. The details of all deviations (major and minor) will also be listed by treatment and 
patient ID.  All Protocol deviations (major and minor) will be recorded as part of the Trial 
Master File (TMF).
Specific protocol deviation categories will be assigned to important deviations related to 
COVID-19 (e.g. missing efficacy assessments and treatment interruptions) and these will 
be summarized separately and flagged in the listings. 
6.2.1
Sub-study 
A listing of all deviations (major and minor) will be listed for the Sub-study Safety Analysis 
Set.  Specific protocol deviations related to COVID-19 will be flagged in the listing.
6.3 Inclusion and Exclusion Criteria
For all screened patients, a summary of all inclusion criteria not met and exclusion criteria 
met will be provided. An additional summary will be provided for the PSMA-11 Safety 
Analysis Set.  A listing, including the protocol version the patient was consented under and 
a flag for the FAS population, will be provided for all screened patients. 
6.3.1
Sub-study 
A listing of all inclusion criteria not met and exclusion criteria met will be provided for all 
screened patients in the sub-study. 
6.4
Stratification Information
For the FAS,PFS-FAS and the Response Evaluable Analysis Set, the number (%) of patients 
in each randomization stratum based on data obtained from the IRT system and data 
collected on the CRF (see Section 5.6) will be summarized by treatment arm and overall.  
of liver metastases (yes vs. no); ECOG score (0 or 1 vs. 2); and inclusion of NAAD in best 
supportive/standard of care (yes vs no) at time of randomization.  Discordance between 
the stratum recorded in the IRT system and the actual stratum through data collected in 
the CRF will be cross-tabulated for the FAS, PFS-FAS and Response Evaluable Analysis Set 
and listed for the FAS.
7. Baseline Characteristics and Prior and Concurrent Therapies and 
Medications
All tables in Section 7 will be presented by treatment arm and for all patients combined 
for the FAS, PFS-FAS, the Response Evaluable Analysis Set, FAS Safety Analysis Set and 
the PSMA-11 Safety Analysis Set (defined in Section 5.3) unless otherwise specified.  For 
tables using the PSMA-11 Safety Analysis Set, an additional column will be included for 
patients not enrolled (i.e. not randomized).   
7.1 Demographic and baseline assessments
Descriptive statistics of patient characteristics at baseline will be presented for the 
following:
•   
-
•   Race (White vs. Black or African American vs. Asian vs. Others (includes “Native 
Hawaiian or Other Pacific Islander, American Indian or Alaska Native”)


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•   Ethnicity 
•   Height (cm)
•   Weight (kg)
•   BMI (kg/m2)
•   ECOG performance status (0 or 1 vs. 2) Note: ECOG performance status is captured 
on the Enrollment CRF page and not collected at the time of screening.  Thus, ECOG 
performance status will not be available for those not enrolled.
7.2 Baseline Disease Characteristics
Descriptive statistics of patient disease characteristics at baseline will be presented for the 
following variables:
• Time since initial prostate cancer diagnosis (years)
• Initial Histopathological Classification
• Initial Histopathological Grade 
• Initial Gleason score
o
Categorical: 2-3,4-7,8-10, unknown
• Stage at Initial Diagnosis 
• Total Sum of Target Lesions Diameters per RECIST 1.1
• Baseline Target Lesions (Yes vs. No) and Non-Target Lesions (Yes vs. No)
• Site of disease (lung (yes/no), liver (yes/no), lymph node (yes/no), bone (yes/no), 
other (yes/no) using target and non-target lesions or bone scan assessments (bone 
only); sponsor to provide categorization)
•
• Baseline PSA
• Baseline ALP
• Baseline LDH
Note: The baseline variables ‘Total Sum of Target Lesions Diameters’, ‘Target Lesions and 
Non-Target Lesions’ will be based on the data collected on target/non-target lesion 
assessment according to RECIST 1.1 according to local investigator assessment and 
documented in the CRF. ‘Site of disease’ will be based on the data collected on either the 
target/non-target lesion assessment (per RECIST 1.1) or the bone scan assessment per 
local investigator assessment and documented in the CRF.
7.3
Medical History 
Relevant medical conditions will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA).  The MedDRA version used for reporting will be specified as a footnote 
in the applicable tables and listings.
The relevant medical conditions will be tabulated separately for active (ongoing) and not-
active conditions by system organ class (SOC) and preferred term (PT).  Medical history 
events will be marked as ongoing if still active at time of informed consent.
7.4
Prior Cancer Related Therapy


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Descriptive statistics with respect to prior therapy will be displayed.  A listing of all data 
recorded on the Prior Cancer Related Surgery, Prior Radiotherapy and Prior Cancer 
Systemic Therapy CRF pages will also be provided.
Prior cancer related surgery will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) and prior cancer systemic therapy will be coded using the WHO Drug 
Global dictionary.  The MedDRA and WHO Drug Global dictionary versions used for 
reporting will be specified as a footnote in the applicable tables and listings. 
The variables to be summarized in tables are:
Prior Prostate Cancer-related Surgery  
-
Number of patients with at least one prostate cancer-related Surgery (including 
biopsies)
-
Prior number of prostate cancer-related surgeries/biopsies
-
Reason for prior surgery (Therapeutic, Diagnostic/Biopsy, Palliative, Other)
Prior Prostate Cancer-related Radiotherapy
-
Number of patients with at least one Prostate Cancer-related Radiotherapy
-
Prior number of radiotherapies
-
Unique Sites
Prior Prostate Cancer-related Systemic Therapy:  All Therapies
-
Prior number of NAAD-containing regimens
-
Prior number of taxane-containing regimens
-
Reason for therapy
-
Number of unique agents
-
Type of prior therapy (by ATC Level 4 and WHO Drug preferred name). Type of 
prior therapy will be presented by ATC level alphabetically and preferred name is 
sorted within ATC class alphabetically.
Prior Prostate Cancer-related Systemic Therapy:  Last Taxane Therapy
Last taxane therapy is defined as the last taxane as part of a taxane-containing 
regimen, prior to study entry.
-
Reason for Therapy
-
Number of cycles
-
Duration of therapy (months): (last taxane therapy stop date – last taxane 
therapy start date + 1)/30.4375.  Incomplete dates will not be imputed.
-
Progression
-
PSA progression (yes, no, not applicable, unknown)
-
Bone progression (yes, no, not applicable, unknown)
-
Soft tissue progression (yes, no, not applicable, unknown)
-
Type(s) of progression (New lesions, existing lesions, new and existing 
lesions, not applicable, unknown)
-
Treatment-free interval (months, defined in Section 5.6)
-
Best overall response (BOR) to last taxane-therapy (Complete response (CR), 
Partial response (PR), Stable disease (SD), Progressive Disease (PD), Not 
Available, Unknown)
-
Duration of historic BOR (CR or PR) (months): (date of progression (earliest of 
PSA, bone or soft tissue) - date of best response (CR or PR) + 1)/30.4375. 
Incomplete dates will not be imputed.
-
Reason last taxane therapy ended
7.5 Sub-study
Baseline demographics and baseline disease characteristics will be summarized for the 
Sub-study Safety Analysis Set and will be summarized and listed for PSMA-11 sub-study 
analysis set.  Medical history and prior cancer therapy will be listed for the PSMA-11 Sub-
study Analysis Set.


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8. Efficacy Evaluation
8.1
Efficacy Variable Definitions
In general, time to event and duration endpoints (e.g. rPFS), in number of days, is 
calculated as:
Days = event/censor date – reference date (e.g. randomization date) +1.  If a patient has 
no assessment after first dose, censoring is at date of randomization.  See Section 5 for 
converting time units.
Radiographic imaging will be assessed locally by each site and entered into the CRF.
Additionally, patient scans will be collected for independent central review and data will be 
enter into the imagining CRF at the vendor. The independent central review will be used 
for the primary analyses of radiographic progression-free survival per PCWG3, overall 
response rate, disease control rate and duration of response using RECIST 1.1 and 
progression-free survival. The final radiology assessment as determined by the 
independent reviewer and described in the imagining review charter will be used for the 
analysis of these endpoints.  At the time of analysis and prior to database lock, the two 
independent radiologists (radiologist 1 and radiologist 2) will each perform a global read 
and make a final determination of rPFS for the patient.  If there is a difference in patient 
level determination of progressive disease (PD) between the two independent radiologists, 
a third radiologist will adjudicate the final assessment.  The adjudicator will select which 
of the two independent radiologists’ reads (radiologist 1 or radiologist 2) he/she agrees 
with more for RECIST/PCWG3 PD determination.  The selected radiology read (i.e. 
radiologist 1 or radiologist 2) by the adjudicator will be the final radiology assessment for 
the patient.  If there is no adjudication, the final radiology assessment defaults to 
radiologist 1.  Refer to Imagining Review Charter for more details.
The local radiographic imaging assessment will be used for patient management at the 
site and will be compared to central assessments to evaluate concordance as described in 
the IDMC charter and mock tables. The local investigator assessment as captured on the 
CRF will be used as a sensitivity analysis for radiographic progression-free survival only.
8.1.1
Primary Efficacy Definitions
Overall Survival (OS) (months):  (Date of death/censor - Date of randomization + 
1)/30.4375.  OS is defined as the time (in months) from the date of randomization to the 
date of death due to any cause.  If the patient is not known to have died, then OS will be 
censored. The censoring date is date of last contact (see Section 5), i.e. the date the 
patient was last known to be alive).
Radiographic progression-free survival (rPFS) (months): (Date of radiographic 
PD/death/censor – date of randomization + 1) / 30.4375.  rPFS is defined as the time (in 
months) from the date of randomization to the date of radiographic disease progression 
as outlined in PCWG3 Guidelines (Scher et al 2016; protocol Appendix 7, RECIST v1.1; 
FDA guidance, 2007; EMA guideline, 2012) or death due to any cause.  
o
Note:  
In the investigational treatment arm, a patient continues to be in the 
treatment period of the study on BSC/BSoC after receiving their final 
dose of 177Lu-PSMA-617.   


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Patients are at risk of the different types of rPFS events for different 
lengths of time:
- RECIST v1.1 (Soft tissue) PD can occur up through last scan, which 
can be during long term follow-up (LTFU).  
- Bone PD can occur up to scan prior to last scan (with confirmation 
at last scan), which can be during LTFU.
- Death can occur up through 24 weeks past the last study scan, or 
if no post treatment scans, up to 24 weeks after the first randomized 
treatment dose (based on the 2 missed visits censoring rule)
Date of radiographic progressive disease (radiographic PD) event: date of the first 
CT/MRI/bone scan PD/death due to any cause occurs with no more than 1 
immediately prior missing assessment.
o
RECIST 1.1 PD
Assessment in which Overall RECIST v1.1 Response is PD 
Date of PD is date of first appearance of the new lesion(s), if 
applicable.
o
Bone scan PD must be confirmed as follows (rules allow for a flare effect at 
the first post-treatment scan).  See examples in Appendix B:
Rule 1 (Progression at week 8 confirmed at week 16):  If there are 
at least two new lesions on the first post-treatment scan, they must 
be confirmed with at least two additional lesions on the next scan 
(2+2 rule).  The date of progression is the date of the first post-
treatment scan.  
Rule 2 (Progression at week 16 or later confirmed at next scan):  For 
scans after the first post-treatment scan, there must be at least two 
new lesions relative to the first post-treatment scan (treating as a 
new baseline) that remain persistent (confirmed) on a subsequent 
scan. The date of progression is the date of the scan that first 
documents the second lesion compared to first post-treatment scan. 
Date of Censoring for rPFS: 
o
The censoring date is the date when the last evaluable radiographic 
assessment (CT/MRI/bone scan) determined a lack of progression.   
o
If there were no evaluable assessments, censoring occurs at the date of 
randomization.  
o
Patients who have 2 or more consecutive missed tumor assessments 
immediately prior to progressive disease (PD) or death will be censored at 
the date of the last evaluable tumor assessment prior to those missing 
tumor assessments.  Study scans are every 8 weeks +/- 4 days for the first 
24 weeks, then every 12 weeks +/- 4 days and are scheduled relative to 
date of first dose of randomized treatment.  Thus, subjects are considered 
as having 2 missed assessments if:
(2 missed visits, 117 = 16 weeks + 4 days + 1; 229 = 24 weeks + 8 weeks + 4 
days + 1)
last evaluable 


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(2 missed visits, 145 = 20 weeks + 4 days + 1; 313 = 24 weeks + 20 weeks + 4 
days +1)  
174 days
(2 missed visits, 173 = 24 weeks + 4 days + 1) 
8.1.2
Key Secondary Efficacy Definitions
RECIST responses for patients with measurable disease at baseline (RECIST guidelines 
v1.1, Eisenhauer et al., 2009)
Overall Response Rate (ORR) = Proportion of patients with a best overall response 
(BOR) of Complete Response (CR) or Partial Response (PR).  ORR is based on 
RECIST v1.1 response for patients with measurable disease at baseline.
Patients with no evaluable RECIST evaluations after baseline will be considered 
non-responders.
Soft tissue CR or PR needs to be confirmed at the next scan that is evaluable at least 
4 weeks later. The following rules will be taken into account to define the BOR:
o
CR = at least two determinations of CR at least 4 weeks or later
o
PR = at least two determinations of PR or better (i.e. CR) at least 4 weeks 
or later apart (and not qualifying for CR)
o
SD = at least one Stable Disease (SD) assessment or better (i.e. CR or PR) 
> 6 weeks after first dose of randomized treatment (and not qualifying for 
CR or PR)
o
Non-CR/Non-PD = at least one non-CR/non-PD assessment (or better) > 6 
weeks after first dose of randomized treatment (and not qualifying for CR 
or PD).
o
PD = Progressive Disease (PD) at first evaluable scan after first dose of 
randomized treatment (and not qualifying for CR, PR or SD)
Disease Control Rate (DCR) = Proportion of patients with BOR of CR, PR, SD, or Non-
CR/Non-PD according to RECIST v1.1.
o
Same rules for no post baseline evaluations and for confirmation of CR and 
PR
o
Also, best response of SD or Non-CR/No-PD must be at least 6 weeks after 
date of first dose.  
Duration of response (DOR) (months) (only for patients with a tumor response of 
CR or PR): (Date of RECIST PD/death/censor – Date of Best Overall Response + 
1)/30.4375.) DOR is defined as the duration between the date of first documented 
best overall response and the date of first documented radiographic progression  
or death due to any cause.  Date of Best Overall Response is the date of the first 
RECIST response of CR or PR of the confirmed response endpoint Overall Response 
Rate.  Censoring rules are the same as for rPFS, except using only soft tissue scan 
dates (excluding bone scan dates).
Time to first symptomatic skeletal event (SSE, months): (Date of SSE/censor – Date 
of randomization + 1)/30.4375.  Time to first SSE is defined as the time (in months) 
from the date of randomization to the date of the SSE or death from any cause.  SSE 
date is 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 occurs first.  SSE 


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data for this endpoint is collected up through EOT visit.
Censoring date is date of the last study visit (on or before EOT visit).
8.1.3
Additional Secondary Efficacy Definitions
Progression-free 
survival 
(PFS) 
(months): 
 
(Date 
of 
first 
radiographic 
progression/clinical 
progression/PSA 
progression/death/censor 
–
Date 
of 
randomization + 1)/30.4375. PFS is 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 occurs first.  The dates of radiographic, clinical 
and PSA progression are defined as follows:
o Date of radiographic progression:  defined in Section 8.1.1.
o Date of clinical progression: earliest date of assessment for when the investigator 
indicates clinical progression has occurred.
o Date of PSA progression: Where a decline from baseline is documented, date that a 
(from all scheduled and unscheduled visits prior to the current visit being 
evaluated) is documented and confirmed by a second value obtained 3 or more 
weeks later. Rises in PSA within the first 12 weeks of date of first dose of 
randomized treatment will be ignored. 
Where no decline from baseline is documented, PSA progression is defined as a 
of 2 ng/mL or more after 12 weeks from the date of first dose of randomized 
treatment (with confirmation obtained 3 or more weeks later) as specified in 
PCWG3 guidelines. 
o Date of censoring for PFS: Censoring date is the same as defined for rPFS.
PSA doubling time (months):  PSA doubling time will be calculated as natural log of 2 
(0.693) divided by the sum of the fixed slope (common to all patients) and the random 
slope (specific for the patient) of the random coefficient linear model between the 
natural log of PSA and time of PSA measurement (Svatek et al., 2006).  If the PSA 
doubling time is less than zero (i.e. stable, nonincreasing, or decreasing PSA levels as 
defined by a negative slope from the random coefficient linear model), the PSA 
doubling time is set to zero.   The calculation will be based on (1) latest baseline PSA 
.2 ng/mL, (2) at least three consecutive (scheduled and 
unscheduled) post-
guidelines (Scher et al., 2016; Pound et al., 1999).  
If the baseline PSA value prior to first dose of randomized treatment is missing or < 
0.2 ng/mL, PSA doubling time will be missing.     
For interpretation of PSA doubling time it should be noted that PCWG3 guidelines state 
the calculation should be based on the most recent PSA values during androgen 
deprivation therapy.  These additional criteria will not be applied.
PSA response
decrease in PSA from baseline that 
weeks later. All scheduled and unscheduled PSA assessments will be used to determine 
and confirm PSA response.
PSA > 80% decrease


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used to determine and confirm a
Duration of PSA response (only for patients with response) (months): (date of PSA 
progression/censor – Date of PSA response + 1)/30.4375. Duration of PSA response 
is defined as the duration (in months) between the date of first document PSA response 
defined above. The censoring date is the date of last PSA assessment.  
8.1.4
Sub-study
For all efficacy variable derivations, the date of first dose of 177Lu-PSMA-617+BSC/BSoC, 
as defined in Section 5, will be used as the reference date instead of the date of 
randomization.  All efficacy derivations will be based on local investigator assessment; no 
central assessments will be performed. 
8.2
Efficacy Analyses 
The primary analysis of rPFS per independent central review will be based on the PFS-FAS 
while the primary analysis of OS will be based on the FAS. The analyses of the secondary 
efficacy endpoints will be performed on the PFS-FAS , defined in Section 5.3, except for 
soft tissue response (ORR and DCR) as measured by RECIST 1.1, for which the primary 
analysis will be performed on the Response Evaluable Efficacy Analysis Set.  The 
randomization stratification factors from the IRT system will be used for all efficacy 
analyses unless otherwise specified.
All data summaries will be presented by treatment arm.
8.2.1
Primary Efficacy Analyses
The alternate primary efficacy endpoints are OS and rPFS (defined in Section 8.1.1).  For 
the primary analysis of rPFS with an interim analysis of OS, and final analysis of OS (see 
Section 4), the analyses described below will be done using 1-sided tests of treatment 
differences.    If the formal interim OS analysis is met at the pre-specified alpha level, the 
final OS will only be presented descriptively without statistical inference at the nominal 
alpha level specified in Section 3.4. However, if the interim analysis of OS is not performed, 
the alpha level applicable to the OS analysis will depend on the final rPFS results as 
described in Section 4.
Overall Survival
The null hypothesis for OS, as stated in Section 3.4, will be tested at a one-sided level of 
significance.  The primary analysis is to test the null hypothesis and compare the two 
treatment arms using a stratified log-rank test stratifying for the randomization 
stratification factors. The alternate primary efficacy variable, OS, will be analyzed at the 
interim analysis and final analysis as defined in Section 4.
The primary analysis of OS at the interim and final analysis will be based on the FAS 
population.  The OS distribution will be estimated using the Kaplan-Meier method, and 
Kaplan-Meier curves (including number at risk and confidence limits), median, 25th
percentile, and 75th percentile and associated 99.8% confidence intervals at the interim 
analysis and 95% or 96% confidence intervals at the final analysis (depending on the 
earlier rPFS and interim OS results, Section 3.4 or depending on the final rPFS results if 
the interim OS analysis is not performed, Section 4) will be presented for each treatment 
arm.  The OS Kaplan-Meier estimate along with 99.8% confidence intervals at the interim 
analysis and 95% or 96% confidence intervals at the final analysis, will be presented at 
different time points (e.g. 6, 12, and 18 months) for each treatment arm. The one-sided 
p-value from the log-rank test will be presented at the interim and final analysis.


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A supportive analysis will be performed in terms of a stratified Cox regression model with 
a single covariate for randomized treatment arm, stratifying again for the randomization 
stratification factors.  The hazard ratio for OS will be calculated, along with its 99.8% 
confidence interval at the interim analysis and its 95% or 96% confidence interval at the 
final analysis, from the stratified Cox model.  The HR and CI from this model will be used 
as an adjunct to the primary stratified log-rank test p-value to provide the quantification 
of the treatment effect on OS.
The following data will be provided for the analysis of OS:
Median follow-up (months) with 95% CI using the Kaplan-Meier method, censoring for 
deaths, and range
Kaplan-Meier curves with 99.8% confidence limits at interim and 95% or 96% 
confidence limits at final and number at risk 
Number (%) events and censored, reason censored (alive, lost to follow-up, withdrew 
consent)
Kaplan-Meier median, 25th percentile, and 75th percentile with 99.8% CIs at interim 
and 95% or 96% CIs at final 
Overall Survival rates and standard errors at 6 months, 12 months, and 18 months 
with 99.8% CIs at interim and 95% or 96% CIs at final
Cox regression HR (active: control) with 99.8% CI at interim and 95% or 96% CI at 
final
Log-rank test 1-sided p-value
Visual checks of the proportional hazard assumption will be performed based on the Plots 
(SURVIVAL LOGSURV LOGLOGS) generated by LIFETEST procedure in SAS.  No formal 
analysis will be generated.  If the proportional hazard assumption doesn’t hold, additional 
methods may be explored to assess the treatment effect.  Further details will be provided 
in a separate post-hoc analysis plan. 
Radiographic Progression-Free Survival
The null hypothesis for rPFS per independent central review, as stated in Section 3.4, will 
be tested at a one-sided level of significance.  The primary analysis is to test the null 
hypothesis and compare the two treatment arms using a stratified log-rank test stratifying 
for the randomization stratification factors. The alternate primary efficacy variable, rPFS, 
will be analyzed when 364 rPFS events have occurred (Section 4).
The primary analysis of rPFS will be based on the PFS-FAS population.  The rPFS 
distribution will be estimated using the Kaplan-Meier method, and Kaplan-Meier curves 
(including number at risk and confidence limits), median, 25th percentile, and 75th
percentile and associated 99.2% confidence intervals will be presented for each treatment 
arm.  The rPFS Kaplan-Meier estimate along with 99.2% confidence intervals will be 
presented at different time points (e.g. 3, 6, and 12 months) for each treatment arm. The 
one-sided p-value from the log-rank test will be presented.
A supportive analysis will be performed in terms of a stratified Cox regression model with 
a single covariate for randomized treatment arm, stratifying again for the randomization
stratification factors.  The hazard ratio for rPFS will be calculated, along with its 99.2% 
confidence interval, from the stratified Cox model.  The HR and CI from this model will be 
used as an adjunct to the primary stratified log-rank test p-value to provide the 
quantification of the treatment effect on rPFS.
The following data will be provided for the analysis of rPFS:
Median follow-up (months) with 95% CI using the Kaplan-Meier method, censoring for 
radiographic progressions or deaths, and range
Kaplan-Meier curves with 99.2% confidence limits and number at risk 


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Number (%) events and censored, reason censored (ongoing without event, event 
documented after 2 or more missed tumor assessments, adequate assessment not 
available)
Kaplan-Meier median, 25th percentile, and 75th percentile with 99.2% CIs
rPFS rates and standard errors at 3 months, 6 months, and 12 months with 99.2% CIs
Cox regression HR (active: control) with 99.2% CI
Log-rank test 1-sided p-value
Visual checks of the proportional hazard assumption will be performed based on the Plots 
(SURVIVAL LOGSURV LOGLOGS) generated by LIFETEST procedure in SAS.  No formal 
analysis will be generated.  If the proportional hazard assumption doesn’t hold, additional 
methods may be explored to assess the treatment effect.  Further details will be provided 
in a separate post-hoc analysis plan. 
Sensitivity and supportive analyses for rPFS:
For all sensitivity and supportive analyses of the alternate primary endpoints, rPFS and 
OS, the nominal one-sided p-value will be provided without any statistical inference.
First Sensitivity analysis of rPFS:  This sensitivity analysis is the same as the primary rPFS 
analysis (Section 8.1.1) except with additional rPFS events as follows:
o
Includes events regardless of intervening missed assessments.
o
Bone PDs are indicated by one of the following per PCWG3 guidelines:
Rule 1 (Progression at week 8 and confirmed at week 16): same as 
Rule 1 described in Section 8.1.1.
Modified Rule 2 (Progression at week 16 or later without
confirmation):  PD can still only occur at the second post treatment 
scan or later.  The date of bone PD is the date when there are at 
least two new lesions relative to the first post-treatment scan without 
confirmation.
o
Includes all radiographic PD and deaths captured in the study, including 
scans not centrally read that are captured on the LTFU CRF page. 
This sensitivity analysis will use the PFS-FAS population and will compare the two 
treatment arms using the same analysis conventions described in Section 8.2.1. 
Second Sensitivity analysis:
This sensitivity analysis is the same as the primary rPFS 
analysis except with additional censoring as follows:
o
Deaths occurring after start of a new anti-cancer therapy will be censored 
at start date of new therapy.
This sensitivity analysis will use the PFS-FAS population and will compare the two 
treatment arms using the same analysis conventions described in Section 8.2.1.
Third Sensitivity analysis:  This sensitivity analysis is the same as the primary rPFS 
analysis except rPFS will be defined from the date of first dose of randomized treatment.  
This sensitivity analysis will use the PFS-FAS population and will compare the two 
treatment arms using the same analysis conventions described in Section 8.2.1.
Fourth Sensitivity analysis:
This sensitivity analysis is the same as the primary rPFS 
analysis except using local investigator assessments.  This sensitivity analysis will use the 
PFS-FAS population and will compare the two treatment arms using the same analysis 
conventions described in Section 8.2.1.
Sensitivity analyses to assess the impact of COVID-19:


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The impact of missing PCWG3 (bone scans) and/or RECIST assessments on the primary 
rPFS analysis caused by COVID- 19 will be evaluated by the existing first sensitivity 
analysis.  
The following analyses of rPFS will be used to estimate the treatment effect in the 
absence of the COVID-19 virus:
Analysis as per the primary rPFS analysis but censoring COVID-19 related deaths 
at the last adequate assessment prior to the death.  
An analysis as per the ‘first sensitivity analysis' but censoring COVID-19 related 
deaths at the date of death.
For the analyses above, the patients with COVID-19 related deaths will be determined in 
a blinded fashion by clinical review of the data and will be documented prior to database 
lock.
The same analyses conventions used for the primary analyses of rPFS, as described in 
section 8.2.1, will be performed (without p-values).
Supportive analyses of rPFS:  
rPFS will be derived in all patients randomized (FAS population) using the same 
conventions as described in Section 8.1.1 but will consider patients randomized before 
March 5, 2019 who withdrew consent from the study (i.e. no further data on radiographic 
progression is available) as (1) censored at time of withdrawal and (2) a rPFS event at the 
time of withdrawal.  
The following data will be summarized using the FAS:
o
(1): Number (%) rPFS events (radiographic PD, deaths) and censored, 
reason censored (ongoing without event, withdrew consent, event 
documented with two or more missed tumor assessments, adequate 
assessment not available) 
o
(2): Number (%) rPFS events (radiographic PD, deaths, withdrew consent) 
and censored, reason censored (ongoing without event, withdrew consent, 
event documented with two or more missed tumor assessments, adequate 
assessment not available)  
Missing tumor assessments: The number of patients with at least one missing/not 
evaluable tumor assessment (TA) based on independent central review will be presented 
together with the following breakdown categories: number of patients with 1, 2, 3, 4, 5, 
>5 missing/not evaluable TAs.   The purpose of this analysis is to gain an insight as to 
whether the TAs have been carried out in accordance with the protocol and to understand 
if any meaningful discrepancies exist between the pattern of missing assessments by 
treatment arms.  Timing of all tumor assessments will be depicted graphically and 
displayed by treatment arm.
Since the planned tumor assessments are every 8 weeks in the first 24 weeks from C1D1
and every 12 weeks thereafter, the following time windows (in weeks) will be constructed 
for each patient from the date of randomization: (note the open parenthesis such as (12, 
20] indicates that week 12 doesn’t belong to this interval and week 12+1 day belongs to 
that interval)
Until ~24 weeks post randomization [0, 12], (12, 20], (20, 28]
After ~24 weeks post randomization (28, 42], (42, 54], (54, 66], …
where ‘0’ is the patient’s date of randomization. Every time-window (with the exception of 
the initial, broader one) is centered at the scheduled time of a TA, i.e., around week 16, 
week 24 for second and third window respectively, etc. A patient will be considered ‘at 
risk’ of missing a TA for any one of these time-windows if the patient either:


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is ‘on study’ for at least the first 4 weeks of the time-window for the first 24 
weeks (8 weeks for the first time window), or at least the first 6 weeks of time-
window thereafter, i.e., if the patient is ongoing at the time of the scheduled TA, 
or
discontinued treatment due to documented disease progression within the specific 
time window.
For example, if a patient discontinued due to documented disease progression during Week 
24, then the patient would have been ‘at risk’ of a missing/not evaluable TA for the [20, 
28] week time window. 
For the purpose of this analysis, ‘not evaluable’ TAs (i.e., evaluations with an overall tumor 
response of ‘not evaluable’ per central independent review) will be considered to be 
missing. However, a clear distinction between ‘truly missing’ and ‘present but not 
evaluable’ needs to be made in the derived dataset to allow for both a combined analysis, 
i.e. missing and not evaluable treated the same, and separate analyses.
TAs performed after a documented radiographic disease progression per independent 
central review will not be considered. In other words, the final time-window for which a 
patient would be at risk of a missing/not evaluable scan would be that during which the 
documented radiographic progression occurred.
For patients without documented radiographic progression per independent central review, 
all TAs are considered up to the earliest of the following dates: death, the analysis cut-off, 
discontinuation due to disease progression, withdrawal of consent or loss to follow-up.
Concordance between local and central review: A summary on censoring reasons will be 
produced for rPFS by investigator and central radiology.  The censoring patterns will be 
compared between investigator and central review.  A comparison of rPFS event 
type/censor between local radiology review and central radiology review will be provided 
using the PFS-FAS population.
Sensitivity and supplementary analyses for OS:
Supplementary analysis of OS:
A supplementary descriptive analysis of OS will be performed using the PFS-FAS 
population.  This analysis will use the same analysis conventions described in Section 8.2.1
but will be descriptive with the nominal p-value presented.
Sensitivity analyses to assess the impact of COVID-19:
The following analyses of OS will be used to estimate the treatment effect in the absence 
of the COVID-19 virus:
Analysis as per the primary OS analysis but censoring COVID-19 related deaths 
at the date of death.
For the analyses above, the patients with COVID-19 related deaths will be determined in 
a blinded fashion by clinical review of the data and will be documented prior to database 
lock.
The same analyses conventions used for the primary analyses of OS, as described in 
section 8.2.1, will be performed (without p-values).
Subgroup analyses for rPFS and OS:
If either of the primary efficacy analyses of the alternate endpoints are statistically 
significant, the alternate primary endpoints of rPFS and/or OS will be summarized for 
subgroups, as specified in Section 5.4.1.  Subgroup analyses of rPFS and OS will be 
presented graphically using forest plots.


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8.2.2
Key Secondary Efficacy Analyses
Refer to Section 8.2 for analysis sets and presentation of summary statistics.  To control 
the overall Type I error rate, if either alternate primary endpoint is met (see Section 4), 
then the key secondary endpoints will be assessed using the Hochberg closed test 
procedure at the alpha level applicable to the successful alternate primary endpoint. This 
procedure is reasonable given the positive correlation between the key secondary 
endpoints. 
The alpha level applicable to the analysis of the key secondary endpoints will depend on 
the statistically significant results of the final rPFS or the statistically significant results of 
OS at either the interim or final analysis as follows:  
Analysis of Key Secondary Endpoints at Interim and Final OS Analysis
Final rPFS/Interim OS Analysis
Final OS Analysis
Scenario
Final 
rPFS
1-sided
p-value
Interim 
OS
1-sided
p-value
2-sided alpha
(CI)
for Key
Secondary
Endpoints
Final 
OS
1-sided
p-value
2-sided 
alpha
(CI)
for Key
Secondary
Endpoints
A
p<0.004
p<0.001
0.01
(99%)
Not re-tested1
Not re-tested2
B
p<0.004
NS
Not tested3
p<0.024
0.048
(95.2%)
NS
Not tested4
C
NS
p<0.001
0.002
(99.8%)
Not re-tested1
Not re-tested2
D
NS
NS
Not tested3
p<0.02
0.040
(96%)
NS: Not statistically significant at pre-specified alpha level.
CI: Confidence interval
1.
Final OS will not be re-tested if the interim OS is met.  The final OS results will be presented 
descriptively including 95% CI and the nominal p-value.
2.
The key secondary endpoints will not be re-tested if the final OS is met however, the results 
will be presented descriptively including 95% CI and the nominal p-value.
3.
The key secondary endpoints will not be tested if interim OS is not met however, the results 
will be presented descriptively including 95% CI and the nominal p-value.
4.
If the key secondary endpoints are tested when final OS is not met using the successful 
rPFS 1-sided (2-sided) alpha level of 0.004 (0.008), there will be, at most, a type I error
inflation of 0.004 because the rPFS alpha level has already been allocated to the final OS 
test.  Therefore, if final OS is not met, the key secondary endpoints will only be presented 
descriptively including 95% CI and the nominal p-value.


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Analysis of Key Secondary Endpoints at Final rPFS/Final OS Analysis
Final rPFS/Final OS Analysis
Scenario
Final rPFS
1-sided
p-value
Final
OS
1-sided
p-value
2-sided alpha
(CI)
for Key
Secondary
Endpoints
A
p<0.004
p<0.025
0.05
(95%)
B
p<0.004
NS
Not tested1
C
NS
p<0.021
0.042
(95.8%)
D
NS
NS
Not tested2
NS: Not statistically significant at pre-specified alpha level.
CI: Confidence interval
1.
If the key secondary endpoints are tested when final OS is not met using the successful 
rPFS 1-sided (2-sided) alpha level of 0.004 (0.008), there will be, at most, a type I error 
inflation of 0.004 because the rPFS alpha level has already been allocated to the final OS 
test.  Therefore, if final OS is not met, the key secondary endpoints will only be presented 
descriptively including 95% CI and the nominal p-value.
2.
The key secondary endpoints will not be tested if final OS is not met however, the results 
will be presented descriptively including 95% CI and the nominal p-value.
A table summarizing the results of the Hochberg closed test procedure will be provided 
indicating the applicable alpha level used.
Key secondary endpoints subject to Type I error control: 
1. RECIST response:  ORR and DCR 
2. Time to SSE 
Time to Symptomatic Skeletal Event
Time to SSE (defined in Section 8.1.2) will be summarized and analyzed in the same 
manner as described for  rPFS (both primary and supportive analyses using the alpha 
levels and confidence intervals as described in the table above) using the PFS-FAS, except 
using 2-sided p-values from the stratified log-rank test as the primary comparison.  An 
additional analysis will be done on the FAS population using the same methods as for the 
primary analysis.
Overall Response and Disease Control Rate
Percent change of sum of diameters of target lesions (in mm) from baseline per 
independent central review will be summarized as follows:
Continuous variable summaries of baseline and best % change from baseline
Overall response rate and disease control rate per independent central review (defined in 
Section 8.1.2) will be analyzed using logistic regression with a single covariate for 
randomized treatment arm and stratification for the randomization stratification factors. 
The following will be reported:
Odds ratio (active: control) with  CI as described in the table above 
The associated 2-sided p-value  
DOR will be displayed using Kaplan-Meier curves, median, 25th percentile, and 75th
percentile with 95% CIs, number (%) events and censored, and will be analyzed 
using mixture distribution methodology (Ellis et al. 2008) outlined below.


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The primary analysis of RECIST ORR and DCR will be on the Response Evaluable Analysis 
Set.  
Mixture distribution analysis for duration of response
Duration of Response (DOR) per independent central review will be analyzed in the 
Response Evaluable Analysis Set using mixture distribution methodology (Ellis et al. 2008).  
To avoid an inflated estimate of duration of response that occurs when estimating only in 
the subset of patients that have a response, the following methods, paraphrasing from 
Ellis et al., will be used.  Treatment arm differences in duration of response will be analyzed 
using a mixture distribution to test the hypothesis that the expected duration of response 
(EDoR) is equal for the experimental treatment, E, and the control treatment, C, that is:
                  Ho: R = EDoRE/EDoRC = 1  versus   Ha: R = EDoRE/EDoRC
The test will be performed as follows.
(i)  Estimate the proportions of patients with RECIST response as
                                           pE = rE/NE   and   pC = rC/NC                                          (2)
Where rE and rC are the number of patients responding to treatment arms E and C;
    
NE and NC are the number of all patients in each treatment arm.
(ii)  Estimate the mean duration of response in each treatment arm, M E and M C, and their 
standard errors, using a time to event probability distribution, in responding patients, 
some of which may be censored in response. This can be done using SAS PROC LIFEREG 
for distributions such as the exponential, the Weibull, the gamma, the Normal, and the log 
Normal.   The choice in the distribution will be made based upon overall data (ignoring 
randomized treatment arm) prior to the planned analysis after the database is locked. 
(iii)  Combine the estimates from step (i) and (ii) to calculate estimates of R and 
Var[ln(R)].  Then assess the difference between treatment arms E and C using the test 
statistic:
8.2.3
Additional Secondary Efficacy Analyses
Refer to Section 8.2 for analysis sets and presentation of summary statistics.  The 
Additional Secondary Endpoints will be assessed and presented at the nominal 5% level, 
i.e., there will be no alpha control applied at the planned analyses as described in Section 
4.  These endpoints are PFS, Biochemical Response (PSA response endpoints, LDH and 
ALP assessments), Health-related QoL, and Health Economics.  Analysis will be performed 
on the PFS-FAS population
8.2.3.1
Progression-free Survival Analysis 


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PFS (defined in Section 8.1.3), will be summarized and analyzed in the same manner as 
those described for the alternate primary endpoint rPFS using the PFS-FAS, except using 
2 sided p-values from the Cox regression model instead of the p-value from the Log-Rank 
test.  Radiographic progressions per independent central review will be used.  No 
sensitivity analyses will be performed for PFS.  Additionally, the following will be 
presented:
Number and % of PFS events that are due to death, radiographic progression, 
clinical progression (including the primary criteria of clinical progression), and PSA 
progression
8.2.3.2
Biochemical Response Analysis
All biochemical response analyses will be performed using the PFS-FAS.  PSA, ALP, and 
LDH values will be summarized descriptively as follows:
Continuous variable summary statistics for baseline, each time point, and % 
change from baseline for each treatment arm 
Plots of the mean (±standard error) values over time for PSA, ALP, and LDH.
Summary statistics of PSA doubling time with 95% CI for the mean PSA doubling 
time
  Summary statistics of maximum % change from baseline
  
decrease and PSA > 80% decrease)
  Waterfall plot of the maximum % change from baseline in PSA for each patient
  
same as DOR (Section 8.2.2).
Unscheduled labs will not be included in tables but will be provided in listings.
Treatment arm differences of % change from baseline in PSA, ALP, and LDH across all 
time points will be analyzed using mixed effects general linear models for repeated 
measures, under the assumption of Missing at Random (MAR).  The fixed effects will 
include treatment arm, time (as a categorical variable), treatment by time interaction, and 
randomization stratification factors.  An unstructured variance-covariance matrix for the 
repeated measures for a single patient will be used.  In case of problems with fitting the 
model, as an alternative, a heterogeneous Toeplitz and AR(1) structures will be considered 
to reduce the number of parameters of the model.  If necessary for the model fit, the 
outcome variables might be transformed.  Details of any transformations used will be 
provided in the CSR. The differences in least square means between the treatment arms 
and corresponding 95% confidence interval at selected time points will be presented.
For PSA response, analyses will be the same as those described for binary outcome ORR 
(Section 8.2.2).   
Duration of PSA response will be analyzed using a mixture distribution analysis, as 
described for DOR (Section 8.2.2).
8.2.3.3
Quality of Life (QoL) Analysis
For QoL analyses, patient reported outcomes (PROs) will be assessed using the 
questionnaires EQ-5D-5L, FACT-P, and BPI-SF.


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Analyses will be done on the PFS-FAS, and all results will be reported by treatment arm.  
QoL measures are collected on Day 1 of each treatment cycle and at the EOT visit.  
Analyses over time will include time up through EOT visit.  
For analysis of each outcome, only patients with a baseline value and at least one post 
baseline time point will be included.  As with all efficacy analyses, main models will be 
adjusted for randomization stratification factors.  Type I error is not controlled in the 
multiple health related QoL analyses.  Thus, all p-values presented will be unadjusted and 
are nominal and descriptive.
8.2.3.3.1
EQ-5 Dimension-5 Level (EQ-5D-5L) Questionnaire
The EQ-5D-5L is shown in protocol Appendix 9.  The higher the EQ-VAS score, the better 
the QoL.   The higher the EQ-5D items, the worse the QoL.
     Description and Scoring
The EQ-5D-5L consists of the EQ-5D descriptive system and the EQ visual analogue scale 
(EQ-VAS). The EQ-5D-5L descriptive system comprises the following 5 dimensions: 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.  The EQ-VAS 
records the respondent’s self-rated health on a vertical, visual analogue scale.   
Each of the five dimension-scales contain five levels, with level 1 indicating no problems, 
level 2 indicating slight problems, level 3 indicating moderate problems, level 4 indicating 
severe problems, and level 5 indicating unable to/extreme problems. 
The EQ-VAS is scored by assigning an integer value, ranging from 0 (Worst imaginable 
health state) to 100 (Best imaginable health state), corresponding to the mark placed by 
the patient on the VAS. Ambiguous answers (e.g., two marks placed on the scale by a 
patient) should be treated as missing values.                 
Scale name
Number 
of 
items
Item 
range*
Descriptive System Dimension
Mobility
1
1-5
Self-Care
1
1-5
Usual Activities
1
1-5
Pain/Discomfort
1
1-5
Anxiety/Depression
1
1-5
Health State Evaluation
EQ-VAS*
1
0-100
* EQ-VAS is a continuous visual analog scale, with integer scores ranging from 0 to 100.
A utility score will be obtained by using a weighted combination of the levels of the five 
dimension-scales. The weights are based on value sets which are country-specific.  The 
country specific code for the U.K. will be used for all sites in this study since the health 
economics modeling will target the U.K. population for developing the core economic 
model. Each patient’s 5 digit health states code (response to question 1,2,3,4, and 5 


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concatenated (ex., 41325 results in a utility score of 0.193)) is converted to a utility 
score using the EQ-5D-5L value set, available in the cross-walk index value calculator 
which can be downloaded from the web site https://euroqol.org/eq-5d-instruments/eq-5d-5l-
about/valuation/crosswalk-index-value-calculator/ . (Scroll to the bottom of the web page and 
download the Excel file. Use the sheet labelled ‘EQ-5D-5L Value Sets.’)
Since utility score depends on the combination of all items’ responses, any missing 
response results in a missing utility score.  If a patient dies, for analysis he will be 
assigned a score of 0 on the date of death.  In the U.K. value set, 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’).
Analysis
For each of the five dimension-scales, frequency count and percentage of each reporting 
level (1 to 5) over time will be presented.
Utility score and EQ-VAS, will be summarized as continuous variables and will be presented 
for each time point.  For EQ-VAS and Utility score, a plot of the mean values with standard 
errors by treatment group at each time point (showing number of subjects at each visit), 
will be constructed.
The proportion of patients and associated 95% CI who experience any improvement 
relative to baseline in utility score (an increase of .001 or more) at any time up through 
EOT will be summarized for each treatment.
Similarly, the proportion of patients with worsening relative to baseline, indicated by no 
change or any decrease in score, will be summarized.
Time to worsening for utility score is defined as the time (in months) from randomization 
to the first occurrence of worsening in score relative to baseline (no change or any 
decrease), clinical disease progression (excluding radiographic and PSA progression), or 
death, whichever is earlier.  If no event is experienced, the censoring date will be time of 
the last QoL assessment.  
Survival curves for the time to worsening (months) for each treatment arm will be 
computed using the Kaplan-Meier method. The two treatment arms will be compared 
using a cox regression analysis stratified for randomization stratification factors (LDH <
260 UI/L vs >, liver metastases (yes vs no), ECOG (0-1 vs 2), Inclusion of NAAD in 
BSC/BSoC at time of randomization (yes vs no)).  The 25th percentile of and median time 
to worsening will be presented, in case less than 50% of subjects experienced worsening 
for some variables. 
Change from baseline in utility score will also be analyzed using general linear models for 
repeated measures. Baseline value (as a continuous variable), treatment arm, time (as 
visit number), treatment by time interaction, baseline by time interactions, and 
randomization stratification factors as main effects will be the fixed factors. A general 
(unstructured) variance-covariance matrix for the repeated measures for a single patient 
will be used. In case of problems with fitting the model, as an alternative, a 
heterogeneous Toeplitz and AR(1) structures will be considered to reduce the number of 
the parameters of the model.  The differences in least square means between the 
treatment arms and corresponding 95% confidence interval at selected time points will 
be presented.


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8.2.3.3.2
FACT-P
The Functional Assessment of Cancer Therapy – Prostate (FACT-P) is shown in protocol 
Appendix 10.  The higher the FACT-P score (for all subscales and total scales), the better 
the QoL.
     Description
Scale/Sub-scale Name
Number of 
Items
Scale Range
FACT-P Item 
numbers
Threshold for 
worsening*
Subscale
Physical Well-Being (PWB)
7 items
0-28
GP1-GP7
3
Social/Family 
Well-Being 
(SFWB)
7 items
0-28
GS1-GS7
3
Emotional Well-Being (EWB)
6 items
0-24
GE1-GE6
3
Functional Well-Being (FWB)
7 items
0-28
GF1-GF7
3
Prostate 
Cancer 
Subscale 
(PCS)
12 items
0-48
All items in 
“Additional 
Concerns” 
section
3
PCS 
pain-related 
subscale 
(PRS)
4 items
0-16
P1, P2, P3, 
GP4
2
FACT 
Advanced 
Prostate 
Symptom Index-8
(FAPSI-
8)**
8 items
0-32
GP1, 
GP4, 
GE6, C2, P2, 
P3, P7, P8
3
Total Scale
Trial Outcomes Index (TOI) 
score
3 subscales
0-104
PWB, 
FWB, 
PCS
9
FACT-G (General)
4 subscales
0-108
PWB, SFWB, 
EWB, FWB
9
FACT-P Total 
39 items
0-156
All
10
*Minimally important difference for both 1) decrease from baseline for within subject 
change and 2) between group differences for treatment comparisons.
** Symptom index of important clinician-rated symptoms/concerns to monitor when 
assessing value of treatment for advanced prostate cancer (FAPSI-8; Yount et al. 2003)
     Scoring
Scoring of FACT-P subscales and total scores (Trial Outcome Index (TOI), FACT-G Total 
Score (G for general), and FACT-P Total Score (P for prostate)) are shown below.  These 
are from the FACT-P Scoring Guidelines (Version 4).  Item codes in scoring guidelines are 
shown on the FACT-P form in Appendix 10 of the protocol.
FACT-P Instructions:  




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Subscale
Item 
Code
Reverse 
item?
Item 
response
Item 
Score
Prostate Cancer 
Subscale (PCS)
Score range:
0-48
C2
4
-
=
C6
0
+
=
P1
4
-
=
P2
4
-
=
P3
4
-
=
P4
0
+
=
P5
0
+
=
P6
4
-
=
P7
4
-
=
BL2
4
-
=
P8
4
-
=
BL5
0
+
Sum individual item scores:
Multiply by 12:
Divide by number of items answered:
= PC Subscale score
To derive a FACT-P Trial Outcome Index (TOI):
Score range: 0-104
+
+
=
= FACT-P TOI
(PWB score)
(FWB score)
(PCS score)
To derive a FACT-G Total score:
Score range: 0-108
+
+
+
=
= FACT-G Total score
(PWB 
score)
(SFWB 
score)
(EWB 
score)
(FWB 
score)
To derive a FACT-P Total score:
Score range: 0-156
+
+
+
+
=
= FACT-P Total score
(PWB 
score)
(SFWB 
score)
(EWB 
score)
(FWB 
score)
(PCS 
score)
To derive Pain-related subscale (PRS):
Subscale
Item 
Code
Reverse 
item?
Item 
response
Item 
Score
Pain-related 
subscale
Score range:
0-16
P1
4
-
=
P2
4
-
=
P3
4
-
=
GP4
4
-
=
Sum individual item scores:
Multiply by 4:
Divide by number of items answered:
= PR Subscale score


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To derive FACT Advanced Prostate Symptom Index-8 (FAPSI-8):
Using the 8 items GP1, GP4, GE6, C2, P2, P3, P7, P8, do the following:
  Reverse code individual items as needed following guidelines in scores above.
  Sum individual item scores.
  Multiply by 8.
  Divide by the number of items answered.
     Analysis
For each FACT-P related total scale and subscale described in the table in the Description 
section above, will be summarized as continuous variables and will be presented for each 
time point.  A plot of the mean values with standard errors by treatment group at each 
time point (showing number of subjects at each visit), will be constructed for FACT-P
total scale only.
Subscale analysis criteria:
When a treatment difference in the time to worsening in FACT-P total score results in a p 
<0.05, the FACT-P total subscales defined above (PWB, SFWB, EWB, FWB, PCS) will be 
analyzed to determine which are associated with the differences.
The proportion of patients that experience improvement relative to baseline in FACT-P
total score indicated by a >10 point increase at any time up through EOT will be 
summarized as described in Section 8.2.3.3.1 for EQ-5D-5L utility score, and 
subsequently for the subscales when the .05 criteria described above is met.
The proportion of patients that experience worsening relative to baseline in FACT-P total 
score indicated by a >10 point decrease will be summarized similarly.  
  
Time to worsening for FACT-P total score is defined as the time (in months) from 
randomization to the first occurring of a >10 point decrease in FACT-P compared to 
baseline, clinical disease progression (excluding radiographic and PSA progression), or 
death.  If no event is experienced, the censoring date will be time of the last QoL 
assessment.  
Survival analyses will be conducted as described in Section 8.2.3.3.1 for EQ-5D-5L utility 
score, and subsequently for the subscales when the .05 criteria described above is met. 
Change from baseline in FACT-P total score will also be analyzed using general linear 
models for repeated measures produced as described in Section 8.2.3.3.1for EQ-5D-5L 
utility score, and subsequently for the subscales (PWB, SFWB, EWB, FWB, PCS) when 
the .05 criteria described above is met.
The same analyses as described for FACT-P total score will be performed for the PRS, 
FAPSI-8, TOI, and FACT-G, except using the appropriate threshold values as defined in 
the Description table above and plots for TOI and FACT-G only.  No subscale analyses 
will be performed if p<0.05. 




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The Pain Intensity Scale, Pain Interference Scale, and the four individual pain intensity 
items in the table above, will be summarized as continuous variables and will be 
presented for each time point.  A plot of the mean values with standard errors by 
treatment group at each time point (showing number of subjects at each visit), will be 
constructed for Pain Intensity Scale, Pain Interference Scale and Worst Pain Intensity 
Scale, only.
Time to worsening of Worst Pain Intensity (item 3), also called Time to Disease Related 
Pain (TDRP), Pain Intensity Scale, and Pain Interference Scale are defined as the time (in 
months) from randomization to the first occurring of 1) an increase of worsening 
threshold (in the table above) compared to baseline, 2) clinical disease progression 
(excluding radiographic and PSA progression), or 3) death.  If no event is experienced, 
the censoring date will be time of the last BPI-SF assessment.  
Survival analyses of time to worsening of Worst Pain Intensity, Pain Intensity Scale, and 
Pain Interference Scale will be conducted as described in Section 8.2.3.3.1 for EQ-5D-5L 
utility score.  
Additionally, the time to improvement following initial pain worsening in Pain Intensity 
Scale and Pain Interference Scale will be analyzed using mixture distribution 
methodology described in Section 8.2.2.  Time to pain improvement is defined as time 
from worsening of intensity or interference to a score < baseline.
Change from baseline in Worst Pain Intensity, Pain Intensity Scale, and Pain Interference 
Scale will also be analyzed using general linear models for repeated measures as 
described in Section 8.2.3.3.1 for EQ-5D-5L utility score.
8.2.3.4
Health Economics Analysis
The health economics analysis will be done by a separate vendor and is not a part of this 
SAP; however, data relating to health resource utilization, feeding into the health 
economics analysis, will be summarized using the PFS-FAS as described in this section. 
All data relating to health resource utilization will be listed.
Health resource utilization data will be used to support health economic evaluations.  
Study specific analyses will focus on descriptive statistics of the variables described 
below occurring during the randomized treatment period and will be summarized by 
treatment arm as described in Section 5 for categorical and continuous variables.  
Survival analyses of time to disease-related pain and time to first use of opioid 
analgesics will be conducted similarly as described in Section 8.2.3.3.1 for EQ-5D-5L 
utility score.
1. Hospital admissions
Number of hospitalizations both as a categorical variable and a continuous 
variable
Hospitalizations (yes/no) (admitted as in-patient) 
LOS per hospitalization episode will be estimated and the total LOS in the 
hospital per patient will be summarized.
Total Number of symptomatic skeletal events (SSEs; includes symptomatic 
pathological bone fracture, spinal cord compression, tumor-related 
orthopedic surgical intervention, or requirement for radiation therapy to 


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relieve bone pain; captured in 3 CRFs: Adverse Events, Concurrent 
Surgical/Therapeutic Procedures, and Radiotherapy)  
Number of hospitalizations for SSEs
2. Duration of time in hospital following 177Lu-PSMA-617 administration (hours) is the 
time span of patient discharge as captured on the 177Lu-PSMA-617 administration 
CRF.
3. Concomitant drug category use (frequency of administration, dose (listed only); total 
number of days administered = end date-start date + 1).  The list of concomitant 
drugs as captured on the concomitant medication/therapy CRF page to include in 
each category will be 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
(8)
Opioid analgesics use for cancer-related pain
1. Time to disease-related pain (TDRP or Time to worsening of 
Worst Pain Intensity as defined in Section 8.2.3.3.3)
2. Time to first use of opioid analgesics (TFOA, defined below)
4. Therapeutic interventions (frequency; total number of days administered = end/stop 
date – start date + 1)
Local external beam radiotherapy, including palliative external radiation as 
captured on the concurrent radiotherapy CRF page.
Blood transfusion (full blood or derivates).  The list of concomitant blood 
tranfusions captured on the concomitant medication/therapy CRF page to 
include will be pre-specified and flagged prior to the pre-planned analyses.
Variable definitions:
Time to first use of opioid analgesic (TFOA) – TFOA is defined as days from 
randomization to the first occurrence of first need of pain and opioid analgesic use (OAU) 
as indicated in concurrent medications), clinical disease progression (excluding 
radiographic and PSA progression), or death.   If no event is experienced, censoring date 
is the later of date of last visit and last concomitant medication recorded.
8.2.4
Sub-study
At the time of the final analysis of cumulative safety data of the sub-study patients (Section 
4.2), limited efficacy data (excluding patient reported outcomes) will be summarized 


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descriptively (i.e. no hypothesis testing will be performed) for the 
177Lu-PSMA-
617+BSC/BSoC arm using the Sub-study Safety Analysis Set. 
9. Safety Evaluation
Safety analyses will be presented using the PSMA-11 Safety Analysis Set or the FAS Safety 
Analysis Set except for study drug exposure (specifics in Section 9.1), 68Ga-PSMA-11 
adverse events (PSMA-11 Safety Analysis Set only), randomized treatment adverse events 
and adverse events during long-term follow-up (FAS Safety Analysis Set only) and 
prior/concurrent/post-therapies (specifics in Section 9.5, 9.6 and 9.7).  Safety analyses of 
laboratory values and vital signs using the PSMA-11 Safety Analysis Set will only include 
assessments done at screening.
For the PSMA-11 and FAS safety analysis sets, tables will show results by treatment arm 
and for all patients combined.  For the PSMA-11 Safety Analysis Set, an additional column 
will be included for patients not enrolled (i.e. not randomized).    
Listings will be created by treatment arm.
9.1
Extent of Exposure
68GA-PSMA-11 Exposure
For the PSMA-11 Safety Analysis Set, the variables to be summarized for 68GA-PSMA-11
exposure are:
68GA-PSMA-11 activity injected-decay corrected dose (MBq)
68GA-PSMA-11 activity injected-decay corrected dose per body weight (MBq/kg)
Randomized Treatment Exposure, Summary of Cycles
For the FAS Safety Analysis Set, summary of treatment cycles variables to be included 
are:
     Randomized treatment exposure, for both treatment arms:
Duration of exposure to randomized treatment (months) (definition in Section 5.6)
Number of cycles started per patient (both as categorical and continuous variable) 
Average duration of randomized treatment cycles (months) (definition in Section 
5.6)
Number of patients with at least one cycle delayed 
Number of cycles delayed with reasons for delay
177Lu-PSMA-617 exposure, for the Lu-PSMA-617 + BSC/BSoC arm:
Number of patients with at least one dose interrupted (omitted) with the reasons for 
interruption overall and by cycle
Number of patients with at least one dose reduced with the reasons for dose 
reduction overall and by cycle
Randomized Treatment Exposure, By Cycle and Across Cycles Combined
177Lu-PSMA-167 exposure, for the Lu-PSMA-617 + BSC/BSoC arm


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For the FAS Safety Analysis Set investigational treatment arm, 177Lu-PSMA-167 exposure 
variables to be summarized (definitions in Section 5.6) are:
Cumulative dose (GBq) of patient for the entire study overall
Dose intensity per cycle (GBq/cycle) for each cycle
Dose intensity (GBq/month) for the entire study overall
Relative cycle dose intensity (%) for each cycle
Relative dose intensity (%) for the entire study overall
BSC/BSoC exposure, for both treatment arms
For the FAS Safety Analysis Set (both treatment arms), variables to be tabulated for 
BSC/BSoC for the entire study and for each treatment cycle are:
Concomitant medications indicated as study BSC/BSoC, coded using WHO Drug 
Global dictionary.  The WHO Drug Global dictionary version used for reporting will 
be specified as a footnote in the applicable tables and listings. A pre-specified list 
of concomitant medications, based on the interventions allowed as BSC/BSoC per 
protocol (protocol section 5.2) will be used to indicate and flag concomitant 
medications as study BSC/BSoC.  The BSC/BSoC flag captured on the CRF will not 
be used to identify concomitant medications indicated as study BSC/BSoC.
Concurrent procedures other than radiotherapy indicated as study BSC/BSoC, 
coded using MedDRA.  The MedDRA version used for reporting will be specified as 
a footnote in the applicable tables and listings.  The BSC/BSoC flag captured on the 
CRF will be used to identify concurrent procedures other than radiotherapy 
indicated as study BSC/BSoC.
Concurrent radiotherapy indicated as study BSC/BSoC. The BSC/BSoC flag 
captured on the CRF will be used to identify concurrent radiotherapy indicated as 
study BSC/BSoC.
Additionally, a summary of the number (%) of patients who received a NAAD as study 
BSC/BSoC, type of NAAD received (by WHO Drug preferred name) and duration of 
exposure will be provided by treatment arm and overall using the FAS Safety Set.  All 
concomitant medications, concurrent procedures and radiotherapies flagged as study 
BSC/BSoC will be listed.
9.1.1
Sub-study
68GA-PSMA-11 exposure will be summarized using the PSMA-11 Sub-study Analysis Set.  
Study treatment and 177Lu-PSMA-617 exposure will be summarized as described above 
using the Sub-study Safety Analysis Set.
9.2
Adverse Events and Deaths
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) preferred term (PT) and system organ class (SOC) and will be graded according 
to the National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE criteria 
[v5.0]). The MedDRA version used for reporting will be specified as a footnote in the 
applicable tables and listings.
9.2.1
Definition of Treatment Emergent Adverse Events (TEAEs)
68GA-PSMA-11


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A
68Ga-PSMA-11 TEAE is defined as an AE that was not present prior to dosing with 
68Ga-PSMA-11 but appeared following dosing, or was present at time of dosing but 
worsened during or after dosing. 
The treatment-emergent period will be defined as the period from the date of 68Ga-PSMA-
11 dosing up to 6 days after the date of 68Ga-PSMA-11 dosing as long as prior to the first 
dose of 177Lu-PSMA-617 for the investigational arm and prior to Cycle 1 Day 1 for the 
BSC/BSoC arm.
AEs reported as “possibly”, “probably”, or “definitely” related to 68Ga-PSMA-11 that occur 
beyond the 6-day reporting window but occur before the initiation of randomized treatment 
are also 68Ga-PSMA-11 TEAEs. Unrelated 68Ga-PSMA-11 AEs that occur beyond 6 days will 
not be TEAEs.
Randomized treatments
A randomized treatment TEAE is defined as an AE that was not present prior to initiation 
of randomized treatment, defined as first dose of 177Lu-PSMA-617 for the investigational 
arm and Cycle 1 Day 1 for the BSC/BSoC arm, but appeared following treatment, or was 
present at treatment initiation but worsened during treatment. An AE that was present at 
treatment initiation but resolved and then reappeared while the patient was on treatment 
is a TEAE (regardless of the intensity of the AE when the treatment was initiated). 
The treatment-emergent period will be defined as the period from the date of initiation of 
randomized treatment up to 30 days after the date of the last administration of randomized 
treatment or the day prior to the initiation of subsequent anticancer treatment, whichever 
occurs first.
9.2.2
General Convention
Any treatment-emergent event as defined in Section 9.2.1 missing the assessment of 
relatedness will be considered study drug-related.
In case a patient experienced the same event more than once, the maximum toxicity 
grade will be presented.
In all AE tables except the ones presented by Cycles, multiple occurrences of the same 
adverse events occurring in one individual are counted only once.
In all AE tables presented by cycle of onset, multiple occurrences of the same adverse 
events occurring in one individual within one cycle are counted only once.
AE summaries for 68GA-PSMA-11 and Randomized Treatment will include AEs occurring 
during the treatment-emergent period whereas AE summaries for Long-term Follow up 
will include new and existing AEs during the long-term follow-up period captured on the 
Long-Term Follow up CRF page. All AEs will be listed along with the information collected 
on those AEs. AEs will be summarized by number and percentage of patients having at 
least one AE, having at least one AE in each primary SOC and for each PT using MedDRA 
coding. The total number of events will also be provided.  A patient with multiple 
occurrences of an AE will be counted only once in the respective AE category. A patient 
with multiple CTCAE toxicity grades for the same preferred term will be summarized under 
the maximum CTCAE toxicity grade recorded for the event. AE with missing CTCAE toxicity 
grade will be included in the total across all grades of the summary table.
In all AE summaries, the primary SOC will be presented alphabetically and the PTs will be 
sorted within primary SOC in descending frequency. The sort order for the PT will be based 
on their frequency in the 177Lu-PSMA-617+BSC/BSoC arm for randomized treatment and 
long-term follow-up AE summaries and the frequency in the overall column for 68Ga-PSMA-
11 AE summaries.


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9.2.3
68Ga-PSMA-11 Adverse Events
A summary table using the PSMA-11 Safety Analysis Set including the number of patients 
with at least one event, and the total number of events will be presented for the following 
variables: 
• TEAE1
• serious TEAE1
• grade 3/4/5 TEAE2
• drug-related TEAE1
• serious drug-related TEAE1
• drug-related grade 3/4/5 TEAE2
• fatal TEAE2
1AE variables to be tabulated by SOC and PT by grade including a total across all grades 
and all grades 3/4/5.
2AE variables to be tabulated by SOC and PT.
A summary of serious and non-serious adverse events with number of occurrences will be 
produced (an occurrence is defined as >1 day between start and prior end date of record 
of same preferred term).
A listing will include the participant identifier, age, race, verbatim, preferred term, duration 
of the event, toxicity grade, seriousness, action taken regarding 68Ga-PSMA-11, outcome, 
relationship to study drug, and start and end date. Non-treatment-emergent adverse 
events will be flagged.   
9.2.3.1
Sub-study
Similar analyses as described in Section 9.2.3 will be done using the PSMA-11 Sub-study 
Analysis Set.
9.2.4
Randomized Treatment Adverse Events
A summary table using the FAS Safety Analysis Set including the number of patients with 
at least one event, and the total number of events will be presented for the AE variables 
below.   
• TEAE1, 3                      
• Serious TEAE1, 3
• Grade 3/4/5 TEAE2
• Drug-related TEAE1
• Serious drug-related TEAE1
• Drug-related grade 3/4/5 TEAE2
• TEAE leading to reduction of 177Lu-PSMA-617 dose1  or of BSC/BSoC1
• TEAE leading to interruption of 177Lu-PSMA-617 treatment1  or of BSC/BSoC1
• TEAE leading to permanent discontinuation of 177Lu-PSMA-617 treatment1 or of 
BSC/BSoC1
• Fatal TEAE2


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1AE variables to be tabulated by SOC and PT by grade (including a total across all grades 
and all grades 3/4/5).
2AE variables to be tabulated by SOC and PT.
3TEAEs are to be tabulated by SOC and PT, including a total across all grades and all grades 
3/4/5), and by 177Lu-PSMA-167 cycle of onset.
A summary of serious and non-serious adverse events with number of occurrences will be 
produced (an occurrence is defined as >1 day between start and prior end date of record 
of same preferred term).
A listing for each patient will include the same variables as mentioned above in Section 
9.2.3 except will include action taken regarding 177Lu-PSMA-617 and action taken 
regarding Best supportive/Best standard of care. Non-treatment-emergent adverse events 
will be flagged.
To help evaluate the impact of the COVID-19 virus on the safety, the incidence of COVID-
19 related adverse event preferred terms will be presented incorporating (a) COVID-19 
related adverse events with an onset date prior to the start of the outbreak (i.e. pre-2020) 
and (b) all COVID-19 related adverse events occurring before the data cut-off. All COVID-
related AEs will be included in the listings.
9.2.4.1
Sub-study
Similar analyses as described in Section 9.2.4 (excluding TEAEs by 177Lu-PSMA-167 cycle 
of onset due to the small number of patients) will be performed using the Sub-study Safety 
Analysis Set.  All AEs will be listed including COVID-related AEs.
9.2.5
Deaths
Summaries of all deaths, including deaths within 6 weeks and 3 months (12 weeks) of 
randomization (using the FAS and FAS Safety Set), on-treatment deaths or within 30 days 
of randomized treatment discontinuation (using the FAS Safety Set), and 68Ga-PSMA-11 
on-treatment deaths (using the PSMA-11 Safety Analysis Set) will be provided including 
the primary cause of death (including deaths due to COVID-19).  All deaths will be listed 
and will include the details for ‘other cause’.
9.2.5.1
Sub-study
A summary of all deaths and on-treatment deaths will be provided using the Sub-study 
Safety Analysis Set.  A summary of 68Ga-PSMA-11 on-treatment deaths will be provided 
using the PSMA-11 Sub-study Analysis Set.  All deaths in the sub-study will be listed.
9.2.6
Long-term Follow up Adverse Events
During LTFU, new and existing AEs will continue to be followed, capturing only AE term 
and grade.  
A summary table including the number of patients with at least one event, and the 
total number of events will be presented for the AE variables captured on the Long 
Term Follow-Up – Adverse Events CRF page below using the FAS Safety Analysis Set.   
• AE1                        
• Grade 3/4/5 AE2
• Fatal AE2


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1AE variables to be tabulated by SOC and PT by grade including a total across all grades 
and all grades 3/4/5.
2AE variables to be tabulated by SOC and PT.
A listing will include the participant identifier, age, race, verbatim, preferred term, and 
toxicity grade.
9.2.6.1
Sub-study
A listing of all AEs captured during long-term follow up will be provided.
9.2.7
Safety Topics of Interest
A safety topic of interest is a grouping of adverse events that are of scientific and medical 
concern specific to 68Ga-PSMA-11 and 177Lu-PSMA-617. These groupings are defined on a 
program level using MedDRA terms, SMQs (standardized MedDRA queries), HLGTs (high 
level group terms), HLT (high level terms) and PTs (preferred terms). Customized SMQs 
(Novartis MedDRA queries, NMQ) may also be used. A NMQ is a customized group of search 
terms which defines a medical concept for which there is no official SMQ available or the 
available SMQ does not completely fit the need. It may include a combination of single 
terms and/or an existing SMQ, narrow or broad. The groups are defined according to the 
MedDRA terms defined in the program Case Retrieval Strategy (CRS) document and will 
be summarized. The latest version of the CRS document available at the time of the 
analyses will be used. For each specified safety topic of interest, number and percentage 
of patients with at least one event of the safety topic of interest occurring during the on 
treatment period will be summarized.
Summaries of these Safety Topics of Interest during 68Ga-PSMA-11 treatment period 
(using PSMA-11 Safety Analysis Set) and during randomized treatment period (using the 
FAS Safety Analysis Set) will be provided by treatment arm, (specifying grade, SAE, 
relationship, leading to treatment discontinuation (if applicable), leading to dose 
interruption (if applicable), hospitalization, death etc.). 
A listing of all grouping levels down to the MedDRA preferred terms used to define each 
Safety Topic of Interest will be generated.
9.2.7.1
Sub-study
A listing of Safety Topics of Interest during 68Ga-PSMA-11 treatment period (using PSMA-
11 Sub-study Analysis Set) and during 177Lu-PSMA-617treatment period (using the Sub-
study Safety Analysis Set) will be provided.
9.3
Clinical Laboratory Determination
Local labs will perform hematology, chemistry, serum testosterone, and urinalysis testing.
The following laboratory parameters are to be summarized:


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• Testosterone
• Chemistry
sodium
potassium
total and direct 
bilirubin
ALP
AST
ALT
LDH
blood urea 
nitrogen2
creatinine
urate
phosphate
chloride
Bicarbonate1
calcium
glucose
total protein
albumin
•Urinalysis3
urine pH
protein content
specific gravity
appearance and 
color
glucose
ketones
•
Hematology
complete blood count (white blood cell count and 
differential)
red blood cell count
hemoglobin
hematocrit
platelet count
1. total carbon dioxide or equivalent is acceptable
2. urea is acceptable
3. Urinalysis parameters are only collected at screening. Appearance and color, glucose, ketones 
and protein content are captured as free-text and will only be listed (not summarized).
Hematology, chemistry and serum testosterone laboratory values and the change from 
baseline during randomized treatment will be summarized for each parameter by visit. 
Shift tables of the worst post-baseline on-treatment laboratory toxicity based on 
CTCAE v5.0 grading relative to baseline will be presented as well as the frequency of grade 
3/4 toxicities. For laboratory tests where CTCAE grades are not defined, shift tables using 
low/normal/high/(low and high) classification to compare baseline to worst post-baseline 
on-treatment value will be presented. Frequency statistics for qualitative laboratory 
parameters will also be presented by visit. The summaries will include all laboratory 
assessments collected no later than 30 days after the last administration of randomized 
treatment (i.e. on-treatment).
The mean (±standard error) values over time will be plotted for hemoglobin, hematocrit, 
platelets, WBC, absolute neutrophil count, AST, ALT, BUN, and creatinine by treatment 
arm. 
An additional summary of hematology, chemistry and serum testosterone laboratory 
values at screening will be provided for the PSMA-11 Safety Analysis Set.
provided.  Values outside of the laboratory’s reference range will be flagged. Values 
collected later than 30 days after the last randomized treatment date will also be flagged. 
If laboratory values are provided as ‘<X’ (i.e. below limit of detection) or ‘>X’, prior to 
conversion of laboratory values to SI unit, these numeric values are set to X. The patient 
listings will indicate the CTCAE grade. 
During long-term follow up, hematology and chemistry are collected every 3 months. Shift 
tables of the worst post-baseline laboratory toxicity during LTFU based on CTCAE v5.0 


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grading relative to baseline will be presented as well as the frequency of grade 3/4 
toxicities. For laboratory tests where CTCAE grades are not defined, shift tables using 
low/normal/high/(low and high) classification to compare baseline to worst post-baseline 
value during LTFUP will be presented.  These will be displayed in similar tables separately 
for LTFU using the FAS Safety Analysis Set.  Laboratory assessments collected during LTFU 
will be included in the listings.
Liver function parameters 
Liver function parameters of interest are total bilirubin (TBL), ALT, AST and alkaline 
phosphatase (ALP). The number (%) of patients with worst post-baseline values will be 
summarized by treatment arm using the FAS Safety Analysis Set only.  The following 
summaries will be produced during the randomized treatment and long-term follow up, 
separately:
•
ALT > 3xULN 
•
ALT > 5xULN
•
ALT > 8xULN
•
ALT > 10xULN
•
ALT > 20xULN
•
AST > 3xULN 
•
AST > 5xULN
•
AST > 8xULN
•
AST > 10xULN
•
AST > 20xULN
•
ALT or AST > 3xULN 
•
ALT or AST > 5xULN
•
ALT or AST > 8xULN
•
ALT or AST > 10xULN
•
ALT or AST > 20xULN
•
TBL > 2xULN
•
TBL > 3xULN
•
Concurrent ALT > 3xULN & TBL > 2xULN
•
Concurrent AST > 3xULN & TBL > 2xULN
•
Concurrent ALT or AST > 3xULN & TBL > 2xULN
•
Concurrent ALT or AST > 3xULN & TBL > 2xULN & ALP < 2xULN
•
For single parameters (e.g. AST>3xULN), the worst value post-baseline is considered.  For 
the combination of various parameters, the lab values need to be from the same 
assessment (concurrent assessment). Concurrent measurements are those occurring on 
the same date. In addition, a listing of all TBL, ALT, AST and ALP values for subjects with 
a post-baseline TBL > 2xULN, ALT> 3xULN or AST > 3xULN will be provided using the FAS 
Safety Analysis Set. Values meeting the criteria during randomized treatment and LTFU 
will be listed.
9.3.1
Sub-study 
Shift tables as described above will be presented using the Sub-study Safety Analysis Set.  
Listings of all laboratory data will be provided using the PSMA-11 Sub-study Analysis Set. 
Hematology and chemistry data collected during long-term follow up will be listed using 
the Sub-study Safety Analysis Set. 
9.4
Vital Signs, Physical Findings, and ECG
Vital signs (blood pressure, pulse, and respiratory rate) and weight, will be summarized 
by visit (observed and change from baseline during randomized treatment). The 
summaries will include all assessments collected no later than 30 days after the last 




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Set. The MedDRA version used for reporting will be specified as a footnote in the applicable 
tables and listings.
Procedures as captured on the Concurrent Surgical / Therapeutic Procedures CRF page will 
be classified as prior and/or concurrent. Prior procedures are all procedures occurring 
before the date of the first randomized drug administration (prior to first dose of 177Lu-
PSMA-617 for the investigational arm and prior to Cycle 1 Day 1 for the BSC/BSoC arm). 
Concurrent procedures are all procedures continued or started on or after the date of the 
first randomized study drug administration but not more than 30 days after end of 
randomized treatment Assignment will be done after applying the imputation rules as 
specified in Section 5.2 for partial start and end dates.
Prior and concurrent surgical and therapeutic procedures will be tabulated separately by 
system organ class and preferred term. All procedures will be listed including all details 
from the concurrent surgical and therapeutic procedures CRF page. 
9.5.1
Sub-study
Prior and/or concurrent surgical and therapeutic procedures during 
177Lu-PSMA-
617+BSC/BSoC treatment period will be summarized using the Sub-study Safety Analysis 
Set. 
9.6
Prior and Concurrent Radiotherapy
Descriptive statistics of prior and concurrent radiotherapy as captured on the Radiotherapy 
CRF page will be summarized using the FAS Safety Set.  Prior radiotherapy are all 
radiotherapies occurring before the date of the first randomized drug administration (prior 
to first dose of 177Lu-PSMA-617 for the investigational arm and prior to Cycle 1 Day 1 for 
the BSC/BSoC arm). Concurrent radiotherapy are all radiotherapies that continued or 
started on or after the date of the first administration of randomized treatment but no 
more than 30 days after the end of randomized treatment.  Assignment will be done after 
applying the imputation rules as specified in Section 5.2 for partial start and end dates. 
Prior and concurrent radiotherapy will be tabulated separately. The variables to be 
summarized in tables are:
-
Number of patients with at least one prior (concurrent) radiotherapy
-
Number of prior (concurrent) radiotherapies
-
Unique Sites
All prior and concurrent radiotherapies recorded on the Radiotherapy CRF will be listed.
9.6.1
Sub-study
Prior and concurrent radiotherapy will be summarized using the Sub-study Safety Analysis 
Set.
9.7
Prior and Concomitant Medications
Prior and concomitant medications during the randomized treatment period will be coded 
using the WHO Drug Global dictionary and will be summarized using the FAS Safety 
Analysis Set.  The WHO Drug Global dictionary version used for reporting will be specified 
as a footnote in the applicable tables and listings.
The medications as captured on the Concomitant Medication/Therapy CRF page will be 
classified as prior and/or concomitant during randomized treatment period. Prior 
medications are all medications taken before the date of the first randomized drug 
administration (prior to first dose of 177Lu-PSMA-617 for the investigational arm and prior 
to Cycle 1 Day 1 for the BSC/BSoC arm). Concomitant medications are all medications 
continued or started on or after the date of the first randomized study drug administration 
but not more than 30 days after end of randomized treatment. Assignment will be done 


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after applying the imputation rules as specified in Section 5.2 for partial start and end 
dates.
The number and percentage of patients will be tabulated by ATC level 4 and Preferred 
Term, by prior or concomitant medications during randomized treatment period.
Prior and concomitant medications during the 68Ga-PSMA-11 dosing period will be 
summarized separately using the PSMA-11 Safety Analysis Set. Medications as captured 
on the Concomitant Medication/Therapy CRF page will be classified as prior and/or 
concurrent to 68Ga-PSMA-11 dosing.  Medications prior to 68Ga-PSMA-11 dosing are all 
medications occurring before the date of 68Ga-PSMA-11 dosing.  Medications concurrent 
to 68Ga-PSMA-11 dosing are all medications continued or started on or after the date of 
68Ga-PSMA-11 but not more than 6 days after administration or start of randomized 
treatment.
A listing of all medications recorded on the concomitant medications CRF page will 
provide details including flag for Best Supportive/Best Standard of Care, indication, dose, 
route, frequency, and start and stop dates.
9.7.1
Sub-study
Prior and/or concurrent medications during 177Lu-PSMA-617+BSC/BSoC treatment period 
will be summarized using the Sub-study Safety Analysis Set.  Prior and concomitant 
medications during the 68Ga-PSMA-11 dosing period will be listed using the PSMA-11 Sub-
study Analysis Set. 
9.8
Post-Treatment Cancer-related Therapy
Drug or other non-radiation therapies will be classified according to WHO Drug Global 
dictionary and will be summarized using the FAS. The WHO Drug Global dictionary version 
used for reporting will be specified as a footnote in the applicable tables and listings.
The number and percentage of participants receiving a post- treatment cancer-related 
therapy since discontinuation of randomized treatment will be displayed by preferred term 
within each ATC.  Post-treatment anti-cancer therapy summaries will be sorted 
alphabetically by preferred term within ATC class.
Best response to post treatment anti-cancer therapy and type of response will be 
summarized.
Descriptive statistics of post-treatment radiotherapy received after the randomized 
treatment period will be summarized.  The variables to be summarized in tables are:
-
Number of patients with at least one post-treatment radiotherapy
-
Number of post-treatment radiotherapies
-
Unique Sites
A listing of all data recorded on the post-treatment disease assessment, post-treatment 
radiotherapy, and post-treatment anti-cancer therapies CRFs will be provided.
9.8.1
Sub-study
Post-treatment cancer-related therapy since discontinuation of 177Lu-PSMA-
617+BSC/BSoC will be listed using the Sub-study Safety Analysis Set.


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10.
REFERENCES
• Cella D, Nichol MB, Eton D, Nelson JB, Mulani P. Estimating Clinically Meaningful 
Changes for the Functional Assessment of Cancer Therapy—Prostate: Results from 
a Clinical Trial of Patients with Metastatic Hormone-Refractory Prostate Cancer. 
Value in Health 12(1): 124-129, 2009.
• Cella D, Zagari MJ, Vandoros C, Gagnon DD, Hurtz HJ, and Nortier JWR. Epoetin Alfa 
Treatment Results in Clinically Significant Improvements in Quality of Life in Anemic 
Cancer Patients When Referenced to the General Population. JCO 21(2): 366-373, 
2003
• Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, dd. June 
14, 2010 - National Cancer Institute.
• Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid 
tumors: Revised RECIST guideline (version 1.1). European Journal of Cancer 
2009;45:228-247.
• Ellis S, Carroll KJ, Pemberton K. Analysis of duration of response in oncology trials. 
Contemp Clin Trials. Jul 2008;29(4):456-65.
• European Medicines Agency.  Appendix 1 to the guideline on the evaluation of 
anticancer medicinal products in man.  Methodological consideration for using 
progression-free survival (PFS) or disease-free survival (DFS) in confirmatory 
trials.  Science Medicines Health.  13 Dec 2012.   
http://www.ema.europa.eu/docs/en GB/document library/Scientific guideline/20
13/01/WC500137126.pdf
• EQ-5D-5L User Guide: https://euroqol.org/wp-content/uploads/2016/09/EQ-5D-
5L UserGuide 2015.pdf
• Fitzmaurice 
G, 
Laird 
N, 
Ware 
J. 
Applied 
Longitudinal 
Analysis, 
2004; 
https://content.sph.harvard.edu/fitzmaur/ala/
• Lin DY, Feuer EJ, Etzioni R, Way Y.  Estimating medical costs from incomplete follow-
up 
data. 
 
Biometrics. 
 
Jun 
1997; 
53(2):419-434.  
http://dlin.web.unc.edu/files/2013/04/LinEA97.pdf
• Mihaylova B, Briggs A, O’Hagan A, Thompson SG.  Review of statistical methods for 
analyzing healthcare resources and costs.  Health Economics.  2011; 20:897-916. 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3470917/pdf/hec0020-0897.pdf
• Newcombe RG. Interval estimation for the difference between independent 
proportions: Comparison of eleven methods. Statistics in Medicine 1998;17:873–
90.
• Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC.  Natural 
history of progression after PSA elevation following radical prostatectomy. Journal 
of the American Medical Association. 05 May 1999; 281(17): 1591-1597.
• Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, et al. Trial Design and 
Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations 
from the Prostate Cancer Clinical Trials Work Group 3. J Clin Oncol 
2016;34(12):1402–18.
• Svatek RS, Shulman M, Choudhary PK, Benaim E. Critical Analysis of Prostate-
Specific Antigen Doubling Time Calculation Methodology. Cancer 2006;106:1047–
53. 
• U.S. Department of Health and Human Services, Food and Drug Administration, 
Center for Drug Evaluation and Research, and Center for Biologics Evaluation and 
Research.  Guidance for industry.  Clinical trial endpoints for the approval of cancer 


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drugs and biologics.  May 2007.
https://www.fda.gov/downloads/Drugs/Guidances/ucm071590.pdf
•
Yount S, Cella D, Banik D, Ashraf T, Shevrin D.  Brief assessment of priority 
symptoms in hormone refractory prostate cancer:  The FACT advanced prostate 
symptom index (FAPSI).  Health and Quality of Life Outcomes.  21 Nov 2003; 
1:69  
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC305353/pdf/1477-7525-1-69.pdf


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Appendix A:  Quality of Life Questionnaire References
     References regarding EQ-5D-5L
Full scoring details for the EQ-5D-5L are described at the site https://euroqol.org/wp-
content/uploads/2016/09/EQ-5D-5L UserGuide 2015.pdf
The derivation and performance of the value set for conversion of questionnaire 
responses to a utility score is described in the manuscript 
http://eprints.whiterose.ac.uk/121473/1/Devlin et al-2017-Health Economics.pdf
Repeated measures analysis of PROs: Fitzmaurice G, et al., 2004.  (full reference in 
Section 10)
     References regarding the FACT-P
Manual of the Functional Assessment of Chronic Illness Therapy (FACIT) Measurement 
System, version 4.0 (November 1997) is located on-line at www.facit.org
Minimally important differences in FACT-P related scales
Score type
Source
Total 
possible 
score
Range 
of 
MID
MID 
used in 
analyses
Physical well-
being (PWB)
Cella et al. Qual Life Res 2002; 11: 
207-221; Yost et al. Eval Health Prof 
2005; 28: 172-191
28
2-3
3
Social/family 
well-being 
(SFWB)
Yost et al. Eval Health Prof 2005; 28: 
172-191
28
2-3
3
Emotional well-
being (EMB)
Yost et al. Eval Health Prof 2005; 28: 
172-191
24
2-3
3
Functional 
well-being 
(FWB)
Cella et al. Qual Life Res 2002; 11: 
207-221; Yost et al. Eval Health Prof 
2005; 28: 172-191
28
2-3
3
FACT-G total 
scorea
Cella et al. Value Health 2009; 12: 
124-129
108
9
Prostate cancer 
subscale 
(PCS) score
Cella et al. Value Health 2009; 12: 
124-129
48
2-3
3
FACT-P
total scoreb
Cella et al. Value Health 2009; 12: 
124-129
156
6-10
10
Pain-related 
subscale 
(PRS)c
Cella et al. Value Health 2009; 12: 
124-129
16
1-2
2
TOI score
Yost et al. Eval Health Prof 2005; 28: 
172-191
104
5-9
9
FAPSI-8
Cella et al. Value Health 2009; 12: 
124-129
32
2-3
3
Notes: (a) Composite of the scores on the PWB+SFWB+EWB+FWB (b) Composite of 
the scores PWB+SFWB+EWB+FWB+PCS. Impaired QoL has been defined arbitrarilty in 
published literature as a FACT-
-128, of the 156 maximum score (c) 
Calculated using the 4 questions on pain in the FACT-P, but the scores are reversed 


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such that higher score indicates better health and less pain. A decrease in score 
signifies pain progression
Change thresholds for deterioration on the FACT-P PCS, TOI, and FACT-P Total scales are 
based upon Cella et al. 2009, which provided clinically meaningful change estimates in a 
prostate cancer sample based upon an anchoring methodology. The FACT-G scales 
(PWB, SFWB, EWB, FWB, and the FACT-G) were not addressed in that article, and so the 
clinically meaningful change estimates for those scales are derived from an earlier 
reference, which reports normative values from a large sample from the general 
population for the FACT-G scales. Standard errors (once normalized back to their original 
scales from the zero to 100 scale reported in the article) for the PWB, SFWB, EWB, FWB, 
and the FACT-G were 5.35, 6.80, 4.78, 6.83, and 18.04, respectively. Taking one half 
the standard deviation is equivalent to finding a 0.5 effect size. Using this distributional 
technique to find the clinically meaningful change estimates produced values of about 3 
points for PWB, SFWB, EWB, and FWB and about 9 points for the FACT-G.


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Appendix B:  Examples of Date of Bone Progression
Cases 1, 2 and 3 represent the date of bone progression by Rule 2 and Case 4 represents 
the date of bone progression by Rule 1, as described in Section 8.1.1.  In Case 5, even 
though there are 2 new lesions compared to baseline at Week 24, there is only 1 new 
lesion compared to Week 8 thus indicating that there is no bone progression.