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The CUSP Group, LLC
A Uro-Oncology Trial Management Organization ESCALATE, A Phase III Randomized Study Comparing Enzalutamide or Darolutamide with Radium-223 vs Enzalutamide or Darolutamide with Placebo **and the Effect upon Symptomatic Skeletal Event-Free Survival for**
mCRPC Patients STUDY NUMBER: PC18-1005  
VERSION  
  
 DATE FINAL:  
1.2 04 MAY 2020  
NCT04237584  
| VERSION                      | 1.2                                                                                                                                                                                                                                                                                    |
|------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| DATE FINAL:                  | 04 MAY 2020                                                                                                                                                                                                                                                                            |
| mCRPC Patients STUDY NUMBER: | PC18-1005                                                                                                                                                                                                                                                                              |
| STUDY DRUG(S):               | Radium-223, Darolutamide, Enzalutamide                                                                                                                                                                                                                                                 |
| SPONSOR/CRO:                 | MANA RBM 1401 Wewatta St. Unit 813 Denver, CO 80202 pmanasco@manarbm.com Neal D. Shore, MD, FACS                                                                                                                                                                                       |
| INVESTIGATORS:               | Lead-Principal Investigator Carolina Urologic Research Center 823 82nd Parkway Suite B Myrtle Beach, SC 29579 1-843-455-1220 NShore@gsuro.com A Oliver Sartor, MD Co-Principal Investigator Tulane University 1415 Tulane Ave. New Orleans, LA 70112 1-504-988-7869 osartor@tulane.edu |  
| Confidential                |             |
|-----------------------------|-------------|
| STUDY DRUG: RADIUM-223      | PC18-1005   |
| Final Protocol: 04 MAY 2020 | VERSION 1.2 |
| Page 1 of 102               |             |  
The CUSP Group, LLC  
  
  
A Uro-Oncology Trial Management Organization ESCALATE, A Phase III Randomized Study Comparing Enzalutamide or Darolutamide with Radium-223 vs Enzalutamide or Darolutamide with Placebo **and the Effect upon Symptomatic Skeletal Event-Free Survival for**
mCRPC Patients This clinical study **shall be conducted in compliance with the protocol, as referenced herein,** and all applicable local, national, and international regulatory requirements to include, but not be limited to:
- **International Conference on Harmonisation (ICH) Guidelines on Good Clinical**
Practice (GCP)
- **Ethical principles that have their origins in the Declaration of Helsinki**
- **Food and Drug Administration (FDA) Code of Federal Regulation (CFR):**
o **Title 21CFR Part 50 & 45 CFR Part 46, Protection of Human Subjects** o **Title 21CFR Part 54, Financial Disclosure by Clinical Investigators**
o **Title 21CFR Part 56, Institutional Review Boards**
o **Title 21CFR Part 312, Investigational New Drug Application**
o **Title 45 CFR Parts 160, 162, and 164, Health Insurance Portability and**
Accountability Act (HIPAA)
As the Study Lead-Principal, Study Co-Principal **and/or Site Principal Investigator**, I understand that my signature on the protocol constitutes my agreement and understanding of my responsibilities to conduct the clinical study in accordance with **the protocol and applicable** regulations. Furthermore, it constitutes my understanding and agreement that any changes initiated by myself, without prior agreement in writing from the Sponsor, shall be defined as a deviation from the protocol, and shall be formally documented as such.  
*The CUSP Group, LLC*  
  
  
A Uro-Oncology Trial Management Organization ESCALATE, A Phase III Randomized Study Comparing Enzalutamide or Darolutamide with Radium-223 vs Enzalutamide or Darolutamide with Placebo **and the Effect upon Symptomatic Skeletal Event-Free Survival for**
mCRPC Patients  
| STUDY NUMBER:                                                                 | PC18-1005                              |                  |
|-------------------------------------------------------------------------------|----------------------------------------|------------------|
| STUDY DRUG:                                                                   | Radium-223, Darolutamide, Enzalutamide |                  |
| VERSION                                                                       | 1.2                                    |                  |
| DATE FINAL:                                                                   | 04 MAY 2020                            |                  |
| Neal D. Shore, MD                                                             |                                        |                  |
| ________________________________                                              | ______________________________________ | ________________ |
| Study Lead-Principal Investigator                                             | Study Lead-Principal Investigator      | Date             |
| Neal D. Shore, MD, FACS                                                       | Signature                              |                  |
| Carolina Urologic Research Center                                             | 05-05-2020                             |                  |
| A. Oliver Sartor, MD                                                          |                                        |                  |
| ________________________________                                              | ______________________________________ | ________________ |
| Study Co-Principal Investigator A. Oliver Sartor, MD Tulane University        | 05-05-2020                             |                  |
| Study Co-Principal Investigator                                               | Date                                   |                  |
| Signature                                                                     |                                        |                  |
| Penelope Manasco, MD                                                          |                                        |                  |
| ________________________________                                              | ______________________________________ | ________________ |
| Sponsor Representative Penelope Manasco, MD MANA RBM                          | 05-05-2020                             |                  |
| Sponsor Representative                                                        | Date                                   |                  |
| Signature                                                                     |                                        |                  |
| Thomas Paivanas, MHSA                                                         |                                        |                  |
| ________________________________                                              | ______________________________________ | ________________ |
| Trials Management Organization                                                | Trials Management Organization         | Date             |
| Thomas Paivanas, MHSA The CUSP Group, LLC/ CUSP Clinical  Research Consortium | 05-05-2020                             |                  |
| Signature Confidential                                                        |                                        |                  |
| STUDY DRUG: RADIUM-223                                                        |                                        | PC18-1005        |
| Final Protocol: 04 MAY 2020                                                   |                                        | VERSION 1.2      |
| Page 3 of 102                                                                 |                                        |                  |  
  
  
A Uro-Oncology Trial Management Organization ESCALATE, A Phase III Randomized Study Comparing Enzalutamide or Darolutamide with Radium-223 vs Enzalutamide or Darolutamide with Placebo **and the Effect upon Symptomatic Skeletal Event-Free Survival for**
mCRPC Patients  
| STUDY NUMBER:   | PC18-1005   |
|-----------------|-------------|
| VERSION         | 1.2         |
| DATE FINAL:     | 04 MAY 2020 |  
By signing this protocol acceptance page, I confirm I have read, understand, and agree to conduct the study in accordance with the current protocol.  
___________________________ _______________________________ _________________
Site Principal Investigator Name (Please Print)
Site Principal Investigator Signature Date  
Confidential  
STUDY DRUG: RADIUM-223 PC18-1005  
Final Protocol: 04 MAY 2020 VERSION 1.2  
Page 4 of 102  
| Protocol            | Changes Made                                                                                                                                                                                                                                                                                     | Sections Affected                                             |
|---------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------|
| Version 1.1         | Redundant Schedule of                                                                                                                                                                                                                                                                            | Section 8.2: Schedule of                                      |
| Assessments removed | Assessments removed.                                                                                                                                                                                                                                                                             |                                                               |
| 1.1                 | Addition of footnotes ab and ac.                                                                                                                                                                                                                                                                 | Appendix C                                                    |
| 1.1                 | Added PCWG3 expectations for Screening and RECIST/PCWG3  expectations for Pre-R2 visit.                                                                                                                                                                                                          | Sections 10.2 and 10.4                                        |
| 1.1                 | Revised Inclusion #13                                                                                                                                                                                                                                                                            | Inc/Exc: pages 13 and 34.                                     |
| 1.1                 | Moved Abbrev. PE from  Q12Week imaging to Cycle 4,  Day 1 only.                                                                                                                                                                                                                                  | Schedule of Assessments  Appendix C. Sections 10.5 and  10.6. |
| 1.2                 | Added estimated creatinine  clearance >/= 30 mL/min by  Cockroft-Gault calculation to  inclusion 9.                                                                                                                                                                                              | Synopsis and 3.1 Inclusion  Criteria                          |
| 1.2                 | Added specific details from full  prescribing information for  (Xofigo, Xtandi, and Nubeqa) regarding allowed dose  modifications and special  precautions.                                                                                                                                      | Section 9- Dose Modifications                                 |
| 1.2                 | Added language to allow remote  and telemedicine visits: "Visits  may be split over multiple days if  needed and may be conducted via  remote visits (non-clinic) or via  telemedicine visits as needed to  facilitate visit completion and  infection control (e.g. limit  COVID-19 exposure)." | Section 10.1                                                  |  
| 1.2                               | Removed TUG at screening. It is  only needed at Lead-in RT1 Day  1 (prior to RT1 first dose).                     | Section 10.2   |
|-----------------------------------|-------------------------------------------------------------------------------------------------------------------|----------------|
| 1.2                               | Updated Enza compliance to:  "Enzalutamide or Darolutamide  Estimated Compliance (RT1  Days 28, 56, and 84 only)" | Section 10.3   |
| 1.2                               | Updated Enza compliance to:  "Enzalutamide or Darolutamide  Estimated Compliance"                                 | Section 10.4   |
| 1.2                               | Updated Enza compliance to:  "Enzalutamide or Darolutamide  Estimated Compliance"                                 | Section 10.5   |
| 1.2                               | Updated Enza compliance to:  "Enzalutamide or Darolutamide  Estimated Compliance"                                 | Section 10.8   |
| 1.2                               | Updated Enza compliance to:  "Enzalutamide or Darolutamide  Estimated Compliance"                                 | Section 10.9   |
| 1.2                               | Added sentence providing more                                                                                     | Section 13.6.1 |
| detail on safety interim analysis |                                                                                                                   |                |  
| PROTOCOL SYNOPSIS Title of Study: ESCALATE, A Phase III Randomized Study Comparing Enzalutamide or  Darolutamide with Radium-223 vs Enzalutamide or Darolutamide with  Placebo and the Effect upon Symptomatic Skeletal Event-Free Survival for  mCRPC Patients Study Number: PC18-1005 Sponsor: MANA RBM Study The total duration of the study is 50 months: 18 months  Duration: recruitment, 30 months follow-up, and a 2 month closeout period. Phase of Study: III Study Centers: This study will be conducted at approximately 20 sites Number of  Approximately 499 patients are planned to be randomized 1:1 to open-label  Patients: enzalutamide or darolutamide (Randomization #1 [R1]; Randomized Treatment #1,  [RT1]) and approximately 414 of these patients will be subsequently randomized  1:1 to double-blind radium-223 or placebo (Randomization #2 [R2]; Randomized  Treatment #2, [RT2]) while continuing enzalutamide or darolutamide androgen  receptor blocker (ARB) therapy. Objectives: Primary Objective The primary objective of this study is to: - To compare the symptomatic skeletal event-free survival (SSE-FS) of  patients on radium-223 vs. placebo while taking randomized ARB  therapy. Secondary Objectives The secondary objectives of this study are to: - Assess overall survival (OS) - Assess time to chemotherapy initiation after RT2 Cycle 1, Day 1  (C1D1) - Assess radiographic progression-free survival (rPFS) after RT2 C1D1 - Determine the safety profile of androgen receptor blocker (ARB)  therapy with or without radium-223 - Assess occurrence of AESI: bone fractures (pathologic and nonpathologic) Exploratory Objectives The exploratory objectives of this study are to: - Compare the safety and cognitive function of enzalutamide and  darolutamide from RT1 randomization through 12 weeks of enzalutamide  or darolutamide (prior to RT2)   |
|---|  
| Determine skeletal progression using PCWG3 criteria for progression based   |                                                                              |                            |
|-----------------------------------------------------------------------------|------------------------------------------------------------------------------|----------------------------|
| .                                                                           | upon 99Tc bone scan imaging after RT2 randomization                          |                            |
| Determine the time to PSA progression following RT2 randomization           |                                                                              |                            |
| .                                                                           | Determine the total alkaline phosphatase (ALP) response rate every 12        |                            |
| .                                                                           | weeks following RT2 randomization                                            |                            |
| .                                                                           | Assess time to total ALP progression                                         |                            |
| .                                                                           | Assess time to lactate dehydrogenase (LDH) progression                       |                            |
| .                                                                           | Assess further correlative biomarkers in the patient population              |                            |
| .                                                                           | Assess frequency of the following adverse events that are listed as warnings |                            |
| for the study drugs (cardiovascular, seizures, falls, weakness, cognitive   |                                                                              |                            |
| function)                                                                   |                                                                              |                            |
| Study Schema:                                                               | ICF, Eligibility Criteria, Screening Assessments                             |                            |
| I/E Met (except Inc 12-15)?                                                 |                                                                              |                            |
| J. Yes                                                                      |                                                                              |                            |
| RT1= 12 Weeks Open-Label                                                    | R1: Randomize to RT1.                                                        |                            |
| Enzalutamide (Enza)                                                         |                                                                              |                            |
| Darolytamide (Darol                                                         | ontinue RT1 for 12 weeks?                                                    |                            |
| Q Yes                                                                       |                                                                              |                            |
| ≥ 30% PSA decrease at any time during initial 12 weeks?                     | 1                                                                            | End of                     |
| . Yes                                                                       | Study Drug                                                                   |                            |
| Visit                                                                       |                                                                              |                            |
| Pre-RT2 Assessments                                                         |                                                                              |                            |
| Inclusion 12-15 met?                                                        | End of Study                                                                 |                            |
| (Administrative                                                             |                                                                              |                            |
| - Yes                                                                       | Assessment, at the                                                           |                            |
| time of permanent                                                           |                                                                              |                            |
| RTZ= Double-Blind                                                           | R2: Randomize to RT2                                                         |                            |
| (Ra-223 or Placebo)                                                         | Discontinuation                                                              |                            |
| nue with Prior Enza or Dar                                                  | Continue RT2, until 1) 6 cycles                                              | from Study)                |
| with Enza or Dara                                                           | re completed (or)                                                            |                            |
| permanently stopped, or 2)                                                  | Study Drug                                                                   |                            |
| Administer RT2 up to 6 cycles, and                                          | Radiological Progression or                                                  |                            |
| continue with Q12 Week Imaging Visits                                       | Prohibited Treatment Initiated                                               |                            |
| Follow-up                                                                   | Q12 Week Progression Follow-up visits                                        | Rdiological Progression of |
|                                                                             |                                                                              |                            |
| until either Radiological Progression                                       | Prohibited Treatment Initiated?                                              |                            |
| occurs or Prohibited Treatment Initiated                                    | Yes                                                                          |                            |
| Survival                                                                    | Overall Survival visits every six                                            |                            |  
| Randomization  to Treatments Study Design:   | This is a randomized, multi-center, Phase III, double-blind, placebo-controlled  study in patients with mCRPC. Screening Patients will be screened -42 to -2 days prior to starting RT1 treatment with an  androgen receptor blocker (ARB).  R1  Following successful screening for first randomization (i.e., R1 I/E are met),  patients will be randomized (R1) 1:1 to open-label randomized treatment 1 (RT1)  with one of ARB's: enzalutamide or darolutamide. Patients may not switch RT1  ARB treatment during the study. RT1: Day 1, Day 28, Day 56 and Day 84 Ensure patient is taking bone health agent (BHA) at or before first RT1 dose and continues on BHA throughout RT1 and RT2 treatment periods. Patients must  receive at least 12 weeks of RT1 prior to Pre-R2 visit and before starting  randomized, double-blinded Ra-223 or placebo (RT2). Patients will have serial  PSAs performed at least every 4 weeks during the first 12 weeks of RT1 therapy.Confidential   |
|----------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Final Protocol: 04 MAY 2020 VERSION 1.2  
Page 9 of 102
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pre-r2

Pre-R2 baseline assessments will be done after 12-16 weeks of RT1 have been completed and no less than 14 days prior to RT2 (C1D1) to review safety parameters and establish baseline values prior to C1D1. Imaging assessments (CT, MRI, Bone Scan) should only be done for patients that have a documented ≥ 30% PSA decline at any time during the first *12 weeks of RT1.* Subjects must meet additional inclusion criteria 12-15 in order to be qualified for the second randomization (R2). Only subjects that complete the initial 12 weeks of run-in RT1 should be evaluated for the additional inclusion criteria. Prior inclusion criteria 1-11 do not need to be re-evaluated. All subjects that complete the lead-in RT1 treatment should perform the second series of Cognitive function testing, even if they do not qualify for R2, prior to discontinuation.
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r2

If the all (R2) randomization conditions are all met, subjects will be eligible for
(R2) randomization and should start the 1st cycle of (RT2) Ra-223 or placebo
(C1D1) within 14 days following the pre-R2 safety laboratory blood draw. Patients eligible for RT2 will be centrally randomized in a 1:1 ratio to receive either radium-223 dichloride or placebo (saline) administered IV on Day 1 of each cycle for 6, 28-day cycles, and will continue with their open-label, randomized ARB and BHA throughout the RT2 treatment period. The placebo will be administered in precisely the same fashion as the active drug.
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rt2 up to 6 cycles

Randomized, Double-Blind Ra-223 or Placebo Cycles 1-6: q **28 days** First RT2 cycle (C1D1) must occur within 14 days after the pre-R2 safety laboratory blood draw. Ideally, subsequent RT2 cycles 2-6 should be scheduled to occur every 28 days +/- 7 days following the previous cycle, but dosing may be delayed up to 4 weeks per cycle (maximum 8 weeks between cycles). Patients will continue with their open-label, randomized ARB irrespective of Ra223/placebo delays. Subjects should continue on BHA throughout the RT2 treatment period. Safety laboratory assessments must be completed within 14 days of each cycle and results assessed for safety to proceed with next cycle before administration.
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q12-week rt2 imaging

After the first administration of RT2 at C1D1, patients will be assessed radiologically by CT or MRI and bone scan every 12 weeks, until either:  
| 1)   | radiological progression defined as soft tissue progression per RECIST 1.1 or  bone progression per PCWG3 or   |
|------|----------------------------------------------------------------------------------------------------------------|  
| 2)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | a prohibited treatment has begun.   |             |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------|-------------|
| The 12-week visits start 12 weeks +/- 7 days after RT2 Cycle 1, Day 1 and must  remain on this schedule independent of other study visits. The same imaging  modality should be used for all assessments (CT or MRI). The RECIST and  PCWG3 tumor assessments should be completed by the same trained rater  throughout the study.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                     |             |
| Telephone End of Study Drug(s) Telephone End of Study Drug Visits are required 30 days +/- 7 days after last dose  of study drug(s) (Ra-223/Placebo, Enzalutamide, and Darolutamide) are administered or at the last clinic visit if patient declines further participation.  Q12-Week Progression Follow-up After RT2 cycles are either stopped or (6) cycles completed, patients without radiological progression that have not started a prohibited treatment will continue  to have clinic visits every 12 weeks (continuing with the same schedule based on  C1D1). Enzalutamide or Darolutamide may continue during the Q12-Week  Progression Follow-up period. PSA progression alone is not considered progression  in this protocol [Scher et al. 2016]. Clinical progression will be assessed by the site  investigator on any scheduled or unscheduled visit. Overall Survival Patients that demonstrate radiological progression or start a prohibited treatment  will be followed for SSE's, AESIs, and overall survival. Enzalutamide or  Darolutamide may continue during the Overall Survival period. Patients in this  phase of the study will be evaluated every 6 months +/- 1 month after the last Q12- Week Visit is performed until death or the end of the study. Patients may be  contacted during outpatient visits or by telephone and/or chart review. End of Study: When patients permanently discontinue the study due to any reason (screen failure,  lost to follow-up, withdrawn consent, etc.), an End of Study visit will be done to  capture the reason for screen failure, reason for permanent discontinuation, study  disposition, and to assess AEs.Confidential |                                     |             |
| STUDY DRUG: RADIUM-223                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                     | PC18-1005   |
| Final Protocol: 04 MAY 2020                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                     | VERSION 1.2 |
| Page 11 of 102                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                     |             |  
| Study Drugs,  Doses, and  Modes of  Administration:   | Randomized Treatment #1, RT1 Ensure patient is taking a bone health agent (BHA) at the time of starting RT1.  Patients eligible to receive RT1 will be randomized (R1) in a 1:1 ratio to receive open-label enzalutamide (160 mg PO QD) [available commercially through  prescription] or darolutamide (600 mg PO BID) [provided through the study] for  mCRPC. Dose reductions of RT1 will be allowed per protocol (see dose-reduction  guidelines). Once receiving RT1, subjects should continue RT1 on study until toxicity, or other reason listed in section 3.4. Patients who do not have a ≥ 30% PSA decline at any time during the RT1 period  will not be randomized to RT2 and will be discontinued from the study. Patients  must receive RT1 at least 12 weeks and meet all R2 conditions to proceed to the  second double-blind randomized treatment phase. Randomized Treatment #2, RT2 Patients eligible to receive RT2 will be randomized (R2) in a 1:1 ratio to receive  double-blind RT2 (radium-223 or placebo) that will be administered IV on Day 1  of each cycle for 6, 28-day cycles). RT2 active and placebo treatments will be  administered in precisely the same fashion on Day 1 of each cycle for 6, 28-day  cycles. Patients will continue with their open-label, randomized ARB and bone  health agent. Randomized (Ra-223 or Placebo) will be blinded to patient and study staff  /investigators who perform any study related procedures/tasks. Designated trained,  unblinded individual or individuals will prepare and administer radium-223 at 55  kBq/kg IV or placebo via intravenous infusion on Day 1 of a 28-day cycle for a  total of 6 cycles. No dose reductions will be allowed, but treatment can be held for  up to 4 weeks. If the hold is the result of a treatment-related AE and lasts for >4  weeks, then treatment will be permanently discontinued. No less than 3 weeks and  no more than 8 weeks is allowed between doses. Patients will be evaluated for  toxicity within 14 days prior to each cycle. Radiological assessments will be  performed every 12 weeks following Cycle 1 Day 1, as defined in Appendix C,  page 94. Patients will continue on RT2 for up to 6 cycles or until patient has a  reason for discontinuation as listed in Section 3.5 of the protocol. Upon radiographic progression, further treatments are decided by the site  investigator according to standard local practice. Radium-223 or placebo may  continue at the discretion of the site investigator (if the maximum of 6 doses have  not been reached) if they believe it to be in the patient's best interest. If patient  continues on Ra-223 or placebo after radiological progression, the Q12 Week  Imaging visits will not be done, and the patient will move into Overall Survival  phase after all Ra-223 or Placebo cycles are completed. Enzalutamide or Confidential   |
|-------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Final Protocol: 04 MAY 2020 VERSION 1.2  
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| darolutamide may be continued after progression if the treating investigator  considers that the patient is still receiving benefit.  PSA progression alone is not considered progression in this protocol [Scher et al. 2016]. Clinical progression will be assessed by the site investigator on any scheduled or  unscheduled visit.   |                                                                                                                                                                                                                                                                               |             |                                               |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------|-----------------------------------------------|
| Inclusion                                                                                                                                                                                                                                                                                                                                | Patients must meet all of the following inclusion criteria in order to be qualified for  the first randomization (R1) to Open-label Enzalutamide or Darolutamide (Lead-in                                                                                                     |             |                                               |
| Criteria:                                                                                                                                                                                                                                                                                                                                | Phase):                                                                                                                                                                                                                                                                       | 1.          | Able and willing to provide informed consent. |
| 2.                                                                                                                                                                                                                                                                                                                                       | Histologically or cytologically confirmed diagnosis of prostate  adenocarcinoma.                                                                                                                                                                                              |             |                                               |
| 3.                                                                                                                                                                                                                                                                                                                                       | Men ≥ 18 years.                                                                                                                                                                                                                                                               |             |                                               |
| 4.                                                                                                                                                                                                                                                                                                                                       | ECOG performance status of 0 or 1 at screening.                                                                                                                                                                                                                               |             |                                               |
| 5.                                                                                                                                                                                                                                                                                                                                       | Metastatic to bone with ≥ 2 bone metastases (area of increased  uptake on 99mTc bone scan); equivocal lesions on the bone scan must  be confirmed by standard X-ray, CT, or MRI.                                                                                              |             |                                               |
| 6.                                                                                                                                                                                                                                                                                                                                       | Patients must have progressive metastatic castration-resistant  prostate cancer (mCRPC) at screening and on androgen deprivation  therapy (ADT) as evidenced by either: a.For patients who manifest disease progression solely as a  rising prostate-specific antigen (PSA) level - documentation  of a sequence of two rising PSA values at a minimum of 1- week apart with the Screening value ≥1 ng/ml (see Appendix  D); b.For patients with disease progression manifested in the bone,  irrespective of progression by rising PSA - defined by the  appearance of 2 or more new skeletal lesions demonstrated  by 99Tc bone imaging. Ambiguous results should be  confirmed by other imaging modalities than bone scan and xray (e.g.: CT-scan or MRI). c.For patients with disease progression manifested at nodal  sites, irrespective of progression by rising PSA - progression defined per RECIST 1.1.                                                                                                                                                                                                                                                                               |             |                                               |
| 7.                                                                                                                                                                                                                                                                                                                                       | Ongoing ADT with luteinizing hormone-releasing hormone (LHRH)  agonist or antagonist or bilateral orchiectomy.                                                                                                                                                                |             |                                               |
| 8.                                                                                                                                                                                                                                                                                                                                       | Use of bone health agents (denosumab or zoledronic acid or other  bisphosphonates) starting any time prior to R1 unless  contraindicated or considered not in the best interest of the patient. A  waiver must be approved by the medical monitor if bone health Confidential |             |                                               |
| STUDY DRUG: RADIUM-223                                                                                                                                                                                                                                                                                                                   |                                                                                                                                                                                                                                                                               | PC18-1005   |                                               |
| Final Protocol: 04 MAY 2020                                                                                                                                                                                                                                                                                                              |                                                                                                                                                                                                                                                                               | VERSION 1.2 |                                               |
| Page 13 of 102                                                                                                                                                                                                                                                                                                                           |                                                                                                                                                                                                                                                                               |             |                                               |  
| agents cannot be used. Bone health agents should be continued  throughout both RT1 and RT2 treatment periods.                                                                                                                                                                                                                                                                                                                                                         |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                                            |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------|
| 9.                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Adequate bone marrow and organ function as defined by: a. Hemoglobin ≥ 10.0 g/dL b. Absolute neutrophil count (ANC) ≥ 1.5 x 109 /L c. Platelets ≥ 100 x 109 /L d. Serum creatinine ≤ 1.95 mg/dL e. Estimated creatinine clearance >/= 30 mL/min/1.73m2 by  Cockroft-Gault calculation  f. Alanine aminotransferase (ALT) ≤ 175 U/L g. Aspartate aminotransferase (AST) ≤ 100 U/L h. Total bilirubin ≤ 1.8 mg/dL (unless the patient a diagnosis  of Gilbert's disease or a similar syndrome involving slow  conjugation of bilirubin; in patients with Gilbert's, the total  bilirubin should be less than 6 mg/dL if patient has Gilbert's  and the elevation should be seen in the unconjugated or  indirect bilirubin measurement) i. LDH ≤ 224 U/L at screening. j. Albumin ≥ 2.5 g/dL |                                                                            |
| 10. Fertile male patients, defined as all males physiologically capable of  conceiving offspring with female partners of child-bearing potential,  must be willing to use condoms plus spermicidal agent during the  study treatment period and for 6 months after the last dose of study  drug, and not father a child or donate sperm during this period. 11. The treating site investigator deems RT1 (Enzalutamide or  Darolutamide) treatment safe and feasible. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                                            |
| Subjects must meet the remaining inclusion criteria in order to be qualified for the  second randomization (R2). Only subjects that complete the initial 12 weeks of runin RT1 should be evaluated. Prior inclusion criteria do not need to be re-evaluated:  12. Patients must have a documented ≥ 30% decline of PSA at any time  during the 12 weeks of RT1. 13. Patients must have no evidence of visceral metastatic disease at the  time of RT2 randomization. 14. Ongoing treatment with RT1 and bone health agents at time of RT2  randomization. 15. The treating site investigator deems RT2 (Ra-223 dichloride)  treatment safe and feasible.                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                                            |
| Exclusion                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Patients who meet any of the following criteria will be excluded from study entry:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                            |
| Criteria:                                                                                                                                                                                                                                                                                                                                                                                                                                                             | 1.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Pathological finding consistent with small cell carcinoma of the prostate. |  
| 2.   | Prior chemotherapy for CRPC. Prior docetaxel for hormone-sensitive  disease is permitted under the following conditions: started within 3 months  of ADT initiation, given for a maximum of 6 cycles and progression  occurred > 6 months after the last dose of docetaxel.   |
|------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 3.   | Prior treatment for mCRPC or CRPC. However, the following therapies are  permitted and not exclusionary: Sipuleucel-T, 5-alpha-reductase inhibitors,  estrogens, or older antiandrogens (such as flutamide, bicalutamide, or  nilutamide).                                    |
| 4.   | Prior treatment for more than 2 months with CYP17 inhibitors (e.g.  abiraterone or orteronel).                                                                                                                                                                                |
| 5.   | Prior treatment for more than 2 months with agents inhibiting androgen  receptor signaling (e.g. enzalutamide, apalutamide, or darolutamide).                                                                                                                                 |
| 6.   | Prior hemibody or whole-body external radiotherapy. Other types of prior  external radiotherapy and brachytherapies are allowed.                                                                                                                                              |
| 7.   | Prior therapy with radionuclides (e.g., radium-223, strontium-89, samarium153, rhenium-186, rhenium-188, actinium-225 and lutetium-177).                                                                                                                                                                                                                                                                               |
| 8.   | Current involvement in any drug or device trial involving investigational  agent or medical device within the last 28 days prior to R1.                                                                                                                                       |
| 9.   | In general, any prior investigational agent for nmCRPC/mCRPC; however, may be reviewed by medical monitor/PIs for waiver consideration, on a  case-by-case basis.                                                                                                             |
| 10. Hypersensitivity to compounds related to enzalutamide, darolutamide, or  Ra-223. 11. A blood transfusion ≤ 28 days prior to R1. 12. Major surgical procedures ≤ 28 days or minor surgical procedures ≤7 days  prior to R1. No waiting period is required following port-a-cath placement. 13. Patients with visceral metastases, clinical evidence of central nervous  system metastases, or leptomeningeal tumor spread as demonstrated via  CT/MRI of chest, abdomen, pelvis, and CNS (if needed). CT/MRI of the  CNS only performed if suspicion of CNS metastases or leptomeningeal  tumor spread. Nodules < 1 cm alone will not be considered visceral  metastases. Renal masses < 3 cm will not be considered exclusionary. 14. Serious active infection at the time of screening or another serious  underlying medical condition that would impair the ability of the patient to  receive protocol treatment. 15. Presence of other active cancers, or history of treatment for invasive cancer  ≤2 years of R1. Patients with Stage I/II cancer who have received definitive  local treatment and are considered unlikely to recur are eligible. All  patients with previously treated in situ carcinoma (i.e., non-invasive) and  superficial bladder cancer are eligible, as are patients with history of nonmelanoma skin cancer. 16. Any other serious or unstable illness, or medical, social, or psychological  condition, that could jeopardize the safety of the subject and/or his/her      |                                                                                                                                                                                                                                                                               |  
| compliance with study procedures, or may interfere with the subject's  participation in the study or evaluation of the study results."   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |
|------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Optional blood samples (i.e., plasma and serum samples) will be collected from                                                           |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |
| Correlative                                                                                                                              | patients that provide consent.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |
| Testing:                                                                                                                                 | Samples will be collected at 3 timepoints:  - Pre-RT1: Prior to enzalutamide or darolutamide dosing - Pre-R2: After 12-week Lead-in enzalutamide or darolutamide, and - Following confirmed radiographic progression or prior to initiation of a prohibited anti-cancer treatment, whichever occurs earlier Blood samples will be sent to a central biorepository. Samples may also be  analyzed for exploratory biomarkers to evaluate predictive biomarkers and to assess  correlation with disease activity, effects of study drug, and clinical outcomes.                                                                                      |
| Cognitive  Testing and  Patient  Reported  Outcomes                                                                                      | Cognitive Function testing (CANTAB battery of Cognitive Function Tests) and  patient reported outcomes (FACT-P and FACT-Cog) will be done to determine  changes that may occur during the study in relation to exposure to different  treatments. Data collection will be done electronically at the following timepoints:  - Screening (practice) - Lead-in RT1,  - Pre-R2                                                                                                                                                                                                                                                                        |
| Statistical                                                                                                                              | The following stratification variables will be used in the RT2 randomization                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |
| Methodology:                                                                                                                             | process: - PSA response (≥90% vs < 90% decline at any time from initiation of RT1) - ECOG Score 1 or 0 at Pre RT2 visit - Prior docetaxel use (yes vs no) The primary endpoint of this 1:1 randomized Phase III study is SSE-FS with the  following assumptions:  - The ERA-223 study (published data) suggests that the median SSE-FS rate  for the placebo control arm is 24 months, as per the Bayer adjustment of -4  months. - HR = 0.70 - Median SSE-FS for enzalutamide of 34.3 months (under the exponential  assumption).  - Two-sided alpha = 0.05  - Power = 0.80 - Cumulative drop-out rate by the end of the study = 10% Confidential |  
Final Protocol: 04 MAY 2020 VERSION 1.2  
Page 16 of 102  
| We anticipate:   | Total Number  of Patients  Randomized at R2   |                             |                             |     |
|------------------|-----------------------------------------------|-----------------------------|-----------------------------|-----|
| Power            | Recruitment Period  (months)                  | Follow-up  Period  (months) | Expected  Number of  Events |     |
| 80%              | 18                                            | 32                          | 246                         | 414 |  
| Descriptive statistics, including mean, median, standard deviations and ranges for  all continuous measures will be tabulated and reported. Percentages and  frequencies for all categorical measures will also be presented. Time-to-events  endpoints will be reported using Kaplan-Meier estimates, with 95% CI for median  time-to-event.   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
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pc18-1005 contact information

| PC18-1005 CONTACT INFORMATION Sponsor/CRO MANA RBM Contact Information: MANA RBM 1401 Wewatta St. Unit 813 Denver, CO 80202 919-556-9456 support@manarbm.com Study Principal Investigators: Neal D. Shore, MD, FACS Study Lead-Principal Investigator Carolina Urologic Research Center 823 82nd Parkway Suite B Myrtle Beach, SC 29579 843-455-1220 NShore@gsuro.com A. Oliver Sartor, MD co principal investigator Study Co-Principal Investigator Tulane University 1415 Tulane Ave. New Orleans, LA 70112 504-988-7869 osartor@tulane.edu Thomas Paivanas, MHSA 4440 Sleaford Rd Annandale VA 22003 703-764-4984 Tom@cuspgroup.netTrial Management Organization CUSP Group/CUSP Clinical Research  Consortium   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| LIST OF ABBREVIATIONS ADT Androgen deprivation therapy AE Adverse event AESI Adverse Event of Special Interest ALP Alkaline phosphatase ALT Alanine aminotransferase ANC Absolute neutrophil count ARB AST BCT BHA Androgen Receptor Blocker Aspartate aminotransferase Blood Collection Tube Bone Health Agents BP Blood pressure Bq Becquerel BUN Blood urea nitrogen C1D1 Cycle 1, Day 1 of Ra-223 or Placebo CBC Complete blood count CBR Clinical benefit rate CFR Code of Federal Regulations CI Confidence interval CMP Comprehensive metabolic profile CO2 Carbon dioxide CR Complete response CT CTC ctDNA DNA ENZA Computed tomography Circulating Tumor Cells Circulating Tumor DNA Deoxyribonucleic Acid Enzalutamide EBRT External beam radiotherapy ECOG Eastern Cooperative Oncology Group  eCRF eICF eISF eTMF Electronic case report form Electronic informed consent form Electronic investigator site file Electronic trial master file FDA Food and Drug Administration GCP Good Clinical Practice GMP Good Manufacturing Practice HIPAA Health Insurance Portability and Accountability Act HR Hazard ratio HSPC Hormone-sensitive prostate cancer IB Investigator's Brochure ICF Informed consent form ICH International Conference on Harmonization IDMC Independent Data Monitoring CommitteeConfidential STUDY DRUG: RADIUM-223   | PC18-1005   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------|
| Final Protocol: 04 MAY 2020                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | VERSION 1.2 |
| Page 19 of 102                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |             |  
| LIST OF ABBREVIATIONS IRB IV LDH LHRH mCRPC MRI Investigational review board Intravenous Lactate dehydrogenate Luteinizing hormone-releasing hormone Metastatic castration-resistant prostate cancer Magnetic resonance imaging NCI CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events NE Not evaluable ORR Objective response rate OS Overall survival PCWG Prostate Cancer Clinical Trials Working Group PD Progressive disease PS Performance Status PHI Protected health information PR Partial response PSA Prostate-specific antigen RECIST 1.1 Response Evaluation Criteria in Solid Tumors version 1.1 RNA Ribonucleic Acid rPFS Radiographic progression-free survival R1 First Randomization- 1:1, Open-Label RT1 Randomized Treatment #1 (Open-Label Darolutamide or Enzalutamide) R2 Second Randomization- 1:1, Double-Blind RT2 Randomized Treatment #2 (Double-Blind Ra-223 or Placebo) SAE Serious adverse event SAR Suspected adverse reaction SD Stable disease SSE Symptomatic skeletal event SSE-FS Symptomatic skeletal event free survival SUSAR Suspected Unexpected Serious Adverse Reaction UAE Unexpected adverse event UCP Unequivocal clinical progression ULN Upper limit of normal USPI US package insert WBC White blood cell   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| TABLE OF CONTENTS                                                                                                                     |                                                                                                                                                |
|---------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------|
| 1.                                                                                                                                    | INTRODUCTION ...........................................................................................................................25     |
| 1.1                                                                                                                                   | Background .                                                                                                                                   |
| Clinical Studies with radium-223 ......................................................................................26             |                                                                                                                                                |
| 1.1.1                                                                                                                                 |                                                                                                                                                |
| 1.1.2                                                                                                                                 | Clinical Safety Summary .............................................................................................................27        |
| 1.2                                                                                                                                   | Radium-223 in combination with other therapies                                                                                                 |
| 1.3                                                                                                                                   | The response of bone metastases to enzalutamide ..........................................................30                                   |
| 1.4                                                                                                                                   | Rationale for the Study ........................................................................................................30             |
| 2.                                                                                                                                    | STUDY OBJECTIVES                                                                                                                               |
| 2.1                                                                                                                                   | Primary Objective ...................................................................................................................31        |
| 2.2                                                                                                                                   | Secondary Objectives                                                                                                                           |
| 2.3                                                                                                                                   | Exploratory Objectives .....................................................................................................32                 |
| 2.4                                                                                                                                   | Endpoints                                                                                                                                      |
| 2.4.1                                                                                                                                 | Primary Endpoint ...........................................................................................................................32 |
| 2.4.2                                                                                                                                 | Secondary Endpoints                                                                                                                            |
| 2.4.3                                                                                                                                 | Exploratory Endpoints                                                                                                                          |
| 3.                                                                                                                                    | STUDY PATIENT POPULATION AND DISCONTINUATION                                                                                                   |
| 3.1                                                                                                                                   | Inclusion Criteria ..................................................................................................................34        |
| Exclusion Criteria ................................................................................................................36 |                                                                                                                                                |
| 3.2                                                                                                                                   | Discontinuation from Randomized Treatments ............................................................37                                      |
| 3.3                                                                                                                                   |                                                                                                                                                |
| 3.4                                                                                                                                   | Required Discontinuation from Randomized (RT1) Treatment (Darolutamide                                                                         |
| or Enzalutamide)                                                                                                                      |                                                                                                                                                |
| 3.5                                                                                                                                   | Required Discontinuation from Randomized (RT2) Treatment (Ra-233 or                                                                            |
| Placebo)                                                                                                                              |                                                                                                                                                |
| 3.6                                                                                                                                   | Q12-Week Progression Follow-up ..................................................................................38                            |
| 3.7                                                                                                                                   | Overall Survival Phase                                                                                                                         |
| CORRELATIVE TESTING ...................................................................................................39             |                                                                                                                                                |
| 4.                                                                                                                                    |                                                                                                                                                |
| 4.1.1                                                                                                                                 | Planned Use for Biorepository Samples ............................................................................39                           |
| 4.1.2                                                                                                                                 | Biorepository Sample Collection Times ..........................................................................39                             |
| 4.1.3                                                                                                                                 | Biorepository Sample Collection Information ...............................................................39                                  |
| COGNITIVE TESTING AND EPRO .............................................................................39                            |                                                                                                                                                |
| 5.                                                                                                                                    |                                                                                                                                                |
| 6.                                                                                                                                    | STUDY REGISTRATION ...............................................................................................40                           |
| 7.                                                                                                                                    | STUDY DESIGN...................................................................................................................40              |
| STUDY MEDICATIONS                                                                                                                     |                                                                                                                                                |
| 8.                                                                                                                                    |                                                                                                                                                |  
Confidential  
| 8.1                                                                                                                                         | Randomized Treatment #1, RT1 .........................................................................................44               |
|---------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------|
| 8.2                                                                                                                                         | Randomized Treatment #2, RT2.....................................................................................45                    |
| 8.3                                                                                                                                         | Blinding and Unblinding the Study ...............................................................................45                    |
| 8.3.1                                                                                                                                       | Treatment Assignment Unblinding for Blinded Studies ............................................45                                     |
| 8.4                                                                                                                                         | Concomitant Medications ..............................................................................................46               |
| 8.4.1                                                                                                                                       | Required Concomitant Medications .............................................................................46                       |
| Permitted Concomitant Medications and Treatments .................................................47                                        |                                                                                                                                        |
| 8.4.2                                                                                                                                       |                                                                                                                                        |
| 8.4.3                                                                                                                                       | Prohibited Concomitant Medications ..........................................................................47                        |
| 8.4.4                                                                                                                                       | Cautionary Medications .................................................................................................48             |
| 9.                                                                                                                                          | DOSE MODIFICATIONS                                                                                                                     |
| 9.1                                                                                                                                         | Dose and schedule modifications                                                                                                        |
| 9.1.1                                                                                                                                       | R-223                                                                                                                                  |
| 9.1.2                                                                                                                                       | Enzalutamide                                                                                                                           |
| 9.1.3                                                                                                                                       | Darolutamide                                                                                                                           |
| 10.                                                                                                                                         | STUDY ASSESSMENTS AND EVALUATIONS                                                                                                      |
| 10.1                                                                                                                                        | OVERVIEW                                                                                                                               |
| 10.2                                                                                                                                        | Screening                                                                                                                              |
| 10.3                                                                                                                                        | Lead-In RT1 (enzalutamide or darolutamide) Therapy Phase (12 weeks                                                                     |
| duration)                                                                                                                                   |                                                                                                                                        |
| Pre-R2 Assessments, at 12-16 weeks after RT1 initiation, within 14 days                                                                     |                                                                                                                                        |
| 10.4                                                                                                                                        | prior to RT2 randomization. ........................................................................................................52 |
| 10.5                                                                                                                                        | Ra-223 or Placebo Administration Cycles 1-6 (every 4 weeks)                                                                            |
| 12-Week Imaging Visits ..................................................................................................................54 |                                                                                                                                        |
| 10.6                                                                                                                                        |                                                                                                                                        |
| 10.7                                                                                                                                        | Telephone End of Study Drug Visit                                                                                                      |
| 10.8                                                                                                                                        | Q12 Week Progression Follow-up Visits ..............................................................................54                 |
| 10.9                                                                                                                                        | OVERALL SURVIVAL                                                                                                                       |
| 10.10                                                                                                                                       | End of Study Administrative Assessments ..............................................................................56               |
| 10.11                                                                                                                                       | Lost to Follow-up.                                                                                                                     |
| 11.                                                                                                                                         | DRUG FORMULATION, AVAILABILITY, ADMINISTRATION, AND                                                                                    |
| TOXICITY INFORMATION                                                                                                                        |                                                                                                                                        |
| 11.1                                                                                                                                        | RADIUM-223                                                                                                                             |
| 11.1.1                                                                                                                                      | Labelling, Packaging, and Supply ........................................................................................57            |
| 11.1.2                                                                                                                                      | General warning                                                                                                                        |
| RADIATION PROTECTION                                                                                                                        |                                                                                                                                        |
| 11.1.3                                                                                                                                      |                                                                                                                                        |
| 11.1.4                                                                                                                                      | Preparation and Administration of Radium-223                                                                                           |
| 11.1.5                                                                                                                                      | Precautions and Risks Associated with radium-223 ........................................................59                            |  
| 11.2                                                                                                                                | Enzalutamide                                                                                                                                      |
|-------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------|
| 11.2.1                                                                                                                              | Labelling, Packaging, and Supply ....................................................................................60                           |
| 11.3                                                                                                                                | Darolutamide                                                                                                                                      |
| 11.3.1                                                                                                                              | Labelling, Packaging, and Supply .....................................................................................60                          |
| 1.4                                                                                                                                 | Accountability for All Study Drugs ...................................................................................60                          |
| 12.                                                                                                                                 | RESPONSE EVALUATIONS AND MEASUREMENTS ........................................61                                                                  |
| 13.                                                                                                                                 | STATISTICAL CONSIDERATIONS                                                                                                                        |
| 13.1                                                                                                                                | Statistical Design .....................................................................................................................61        |
| Stratification factors                                                                                                              |                                                                                                                                                   |
| 13.2                                                                                                                                | Sample Size Considerations                                                                                                                        |
| 13.3                                                                                                                                |                                                                                                                                                   |
| 13.4                                                                                                                                | Analysis Population ..............................................................................................................62              |
| 13.5                                                                                                                                | DATA ANALYSIS                                                                                                                                     |
| 13.5.1                                                                                                                              | Demographics and Baseline Characteristics ...................................................................62                                   |
| 13.5.2                                                                                                                              | Efficacy Analysis ...........................................................................................................................63   |
| 13.5.3                                                                                                                              | Safety Analysis ...............................................................................................................................63 |
| Analysis Time Points ............................................................................................................64 |                                                                                                                                                   |
| 13.6                                                                                                                                | Planned Interim Analyses ...................................................................................................64                    |
| 13.6.1                                                                                                                              |                                                                                                                                                   |
| 13.6.2                                                                                                                              | Final Analysis ......................................................................................................................64           |
| 13.7                                                                                                                                | Primary Completion Date ................................................................................................64                        |
| Independent Data Monitoring Committee ......................................................................64                      |                                                                                                                                                   |
| 13.8                                                                                                                                | Steering Committee ..............................................................................................................64               |
| 13.9                                                                                                                                |                                                                                                                                                   |
| 14.                                                                                                                                 | SAFETY REPORTING AND ANALYSES ..................................................................64                                                |
| 14.1                                                                                                                                | Definitions                                                                                                                                       |
| 14.1.1                                                                                                                              | A Adverse Events .............................................................................................................................65  |
| 14.1.2                                                                                                                              | Adverse Events of Special Interest ...................................................................................65                          |
| Serious Adverse Event                                                                                                               |                                                                                                                                                   |
| 14.1.3                                                                                                                              |                                                                                                                                                   |
| 14.1.4                                                                                                                              | Suspected Unexpected Serious Adverse Reactions (SUSAR)                                                                                            |
| 14.2                                                                                                                                | Recording and Reporting of Adverse Events .......................................................................66                               |
| 14.2.1                                                                                                                              | Recording of Adverse Events ..................................................................................................66                  |
| 14.2.2                                                                                                                              | Reporting Period for Adverse Events ...............................................................................67                             |
| 14.2.3                                                                                                                              | Assessment of Adverse Events ..........................................................................................68                         |
| 14.3                                                                                                                                | Recording and Reporting of Adverse Events of Special Interest ..........................68                                                        |
| 14.4                                                                                                                                | Recording of Adverse Events and Serious Adverse Events ......................................68                                                   |
| 14.4.1                                                                                                                              | Diagnosis versus Signs and Symptoms                                                                                                               |
| 14.4.2                                                                                                                              | Persistent or Recurrent Adverse Events ................................................................................69                         |
| 14.4.3                                                                                                                              | Abnormal Laboratory Values ............................................................................................69                         |
| 14.4.4                                                                                                                              | D DEATHS                                                                                                                                          |
| Confidential                                                                                                                        |                                                                                                                                                   |
| STUDY DRUG:  RADIUM-223                                                                                                             | PC18-1005                                                                                                                                         |
| Final Protocol:  04 MAY 2020                                                                                                        | VERSION 1.2                                                                                                                                       |  
| Hospitalization, Prolonged Hospitalization, or Surgery 70 Pre-Existing Medical Conditions 70 New Cancers 70 Radium-223 Overdose 71   |                                                                                                                                                                                                                          |
|--------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 14.5                                                                                                                                 | Sponsor Serious Adverse Event Reporting Requirements 71 Sponsor Assessment of Suspected Unexpected Serious Adverse Reactions 71 Sponsor Reporting for Clinical Studies Under an Investigational New Drug  Application 72 |
| 15.                                                                                                                                  | ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS 72                                                                                                                                                                     |
| 15.1                                                                                                                                 | Institutional Review Board Approval 72                                                                                                                                                                                   |
| 15.2                                                                                                                                 | Regulatory Approval 72                                                                                                                                                                                                   |
| 15.3                                                                                                                                 | Informed Consent 72                                                                                                                                                                                                      |
| 15.4                                                                                                                                 | Patient Confidentiality 73                                                                                                                                                                                               |
| 15.5                                                                                                                                 | Site Investigator and Staff Information 74                                                                                                                                                                               |
| 15.6                                                                                                                                 | Financial Information 74                                                                                                                                                                                                 |
| 16.                                                                                                                                  | RESEARCH RETENTION AND DOCUMENTATION OF THE STUDY 74                                                                                                                                                                     |
| 16.1                                                                                                                                 | Amendments to the Protocol 74                                                                                                                                                                                            |
| 16.2                                                                                                                                 | Documentation Required to Initiate the Study 75                                                                                                                                                                          |
| 16.3                                                                                                                                 | Study Documentation and Storage 75                                                                                                                                                                                       |
| 16.4                                                                                                                                 | Data Collection 77                                                                                                                                                                                                       |
| 16.5                                                                                                                                 | Study Monitoring, Auditing, and Inspecting 77                                                                                                                                                                            |
| 16.6                                                                                                                                 | Quality Assurance and Quality Control 77                                                                                                                                                                                 |
| 16.7                                                                                                                                 | Disclosure and Publication Policy 78                                                                                                                                                                                     |
| 17.                                                                                                                                  | REFERENCES 79                                                                                                                                                                                                            |
| 18.                                                                                                                                  | APPENDICES 82                                                                                                                                                                                                            |
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list of appendices

| Appendix A:   | ECOG Performance Status Criteria 82                                                              |
|---------------|--------------------------------------------------------------------------------------------------|
| Appendix B:   | Guidelines for Fertile Male Patients 90                                                          |
| Appendix C:   | Schedule of Assessments 91                                                                       |
| Appendix D:   | Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1  and PCWG3 Bone Progression 96 |
| Appendix E:   | Remote Risk Based Monitoring and Trial Method (MANA Method)…101                                  |
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1. introduction 1.1 background

Prostate cancer is responsible for the deaths of over 300,000 men annually world-wide [Ferlay et al. 2015]. Recurrent and advanced stages of the disease are initially treated with suppression of testosterone production through either orchiectomy or androgen deprivation therapy (ADT).  
Despite low levels of circulating testosterone, the disease progresses and is termed castrationresistant prostate cancer (CRPC). The majority of CRPC patients have or will develop metastatic disease (mCRPC). Many patients with metastatic disease will experience clinically relevant events related to bone metastases, including pain, pathological fractures, and spinal cord compression. Since the regulatory approval of docetaxel chemotherapy in 2004 [Tannock et al. 2014], several life-prolonging treatments have become commercially available for mCRPC - including cabazitaxel, sipuleucel-t, radium-223, and novel androgen-targeted therapies (abiraterone acetate and enzalutamide)[Flaig et al. 2016). Despite the utilization of these drugs, increased benefit by early intensification in this setting has not been well established.
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enzalutamide

Enzalutamide, a targeted androgen-receptor inhibitor that blocks binding of androgen to the androgen receptor, translocation to the nucleus, and DNA binding [Tran et al. 2009]. It has been FDA-approved for patients with mCRPC based on data from multiple phase III trials, including AFFIRM [Scher et al. 2012], PREVAIL [Beer et al. 2014], and TERRAIN [Shore et al. 2016], and approved for non-metastatic CRPC based on the PROSPER study [Hussain et al. 2018]. Enzalutamide demonstrated superiority to placebo for the treatment of mCRPC including median rPFS (20.0 vs. 5.4 months; hazard ratio 0.32, 95% CI: 0.28–0.37; p < 0.0001) and OS (35.3 vs. 31.3; hazard ratio 0.77, 95% CI 0.67–0.88; p = 0.0002) [Beer et al. 2017] in chemotherapy naïve patients and OS (18.4 vs. 13.6 months; hazard ratio 0.63; 95% CI: 0.53,0.75; P<0.001) in patients with prior chemotherapy exposure. The TERRIAN study further validated enzalutamide as a standard of care for mCRPC with a median progression-free survival of 15.7 months to 5.8 months in the bicalutamide arm (hazard ratio 0.44; 95% CI: 4.8, 8.1; p<0.0001).
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darolutamide

Darolutamide, a novel androgen receptor antagonist, was approved for non-metastatic castrationresistant prostate cancer on July 30, 2019 based on the ARAMIS study (NCT02200614), a multicenter, double-blind, placebo-controlled clinical trial in 1,509 patients with non-metastatic castration resistant prostate cancer. Patients were randomized (2:1) to receive either 600 mg darolutamide orally twice daily (n=955) or matching placebo (n=554). All patients received a gonadotropin-releasing hormone (GnRH) analog concurrently or had a previous bilateral orchiectomy. Twelve patients with previous seizure histories were treated on the darolutamide arm. The primary endpoint was metastasis free survival (MFS), defined as the time from randomization to first evidence of distant metastasis or death from any cause within 33 weeks after the last evaluable scan, whichever occurred first. The median MFS was 40.4 months (95% CI: 34.3, not reached) for patients treated with darolutamide compared with 18.4 months (95% CI: 15.5, 22.3) for those receiving placebo (hazard ratio 0.41; 95% CI: 0.34, 0.50; p<0.0001). OS data has yet to mature. Alpha Particle-emitting therapy Radium-223 Radium-223 dichloride ([Radium-223], Xofigo®, Bayer Consumer Care AG) is an FDA approved alpha particle-emitting radioactive therapeutic agent indicated for the treatment of patients with CRPC, symptomatic bone metastases and no known visceral metastatic disease. Radium-223 mimics calcium and forms complexes with the bone mineral hydroxyapatite preferentially in areas of increased bone turnover, such as bone metastases. The high linear energy transfer of alpha particle emitters induces double-strand DNA breaks in adjacent cells, resulting in an anti-tumor effect on bone metastases. The alpha particle range from radium-223 dichloride is less than 100 micrometers (less than 10 cell diameters). This limited range of penetration depth minimizes damage to the surrounding normal tissue, including bone marrow, resulting in minimal myelosuppression. Radium-223 also acts by interrupting the vicious circle of interaction between the tumor microenvironment and the prostate cancer cells.
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clinical studies with radium-223

The Phase I dose escalation study of radium-223 consisted of 25 breast and prostate cancer patients with osteoblastic lesions who were injected with a single dose of the agent. Pharmacokinetic studies demonstrated that within 24 hours, <1% of the administered dose remained in circulation and was predominantly eliminated via the gastrointestinal tract. Pain relief was reported by 52%, 60%, and 56% of patients after either 1, 4, or 8 weeks, respectively. 28% of patients experienced a "flare" phenomenon. There was a significant decline in alkaline phosphatase among the prostate patient cohort. No dose limiting toxicities (defined as platelets <20 x 109/L, or neutrophils <0.5 x 109/L) were experienced. Myelosuppression was mild and reversible with a nadir 2-4 weeks after drug administration. However, non-hematologic toxicity consisting of transient diarrhea (40% of patients), fatigue (25% of patients), and nausea or vomiting (20% of patients) occurred. The Phase II double-blind, placebo-controlled trial randomized 64 men with CRPC to receive four intravenous (IV) injections of either 50 kBecquerel (Bq)/kg of radium-223 or placebo every 4 weeks. The primary endpoints were change in bone-alkaline phosphatase and time to skeletalrelated events (SREs). At 4 weeks alkaline phosphatase levels were -65% in the radium-223 arm and +9.3% in the placebo arm (p<0.0001). Time to SREs was not statistically significantly different (14 versus 11 weeks, p=0.26). There was a statistically significant change in time to prostate-specific antigen (PSA) progression of 26 versus 8 weeks and a median change in relative PSA (-24% versus +45%). There was a trend to improvement in overall survival (OS) (65.3 versus 46.4 weeks, p=0.066), but the difference did not reach statistical significance.  
Final Protocol: 04 MAY 2020 VERSION 1.2 Page 26 of 102 Hematological toxicity was comparable in the two arms and noted only in the first 4 weeks of treatment with radium-223. The Phase III placebo-controlled trial (ALSYMPCA) planned to randomize 921 men with symptomatic bone-metastatic CRPC in a 2:1 ratio to receive 6 injections at 4-week intervals of either radium-223 (50 kBq/kg) or placebo. Entry criteria included at least two metastatic bone lesions, no visceral metastases, and either prior docetaxel treatment or inability to receive docetaxel. The primary endpoint was OS, with secondary endpoints of time to first SSE, time to alkaline phosphatase progression, alkaline-phosphatase response, alkaline-phosphatase normalization, time-to-PSA-progression, safety endpoints, and quality-of-life. The study was designed with 90% power to detect a hazard ratio (HR) for death of 0.76 at 5% significance level. The two arms were well balanced in terms of baseline demographics. The trial was halted at an interim analysis after 809 patients had been randomized (541 on radium-223 and 268 on placebo) based on the fact that the OS for patients on the radium-223 arm was significantly longer than for patients on the placebo arm. At the planned interim analysis, 63% of the patients receiving radium-223 had received all 6 injections in comparison to 47% in the placebo arm. Median survival was significantly increased from 11.2 months to 14.0 months with a HR of 0.695 (p= 0.00185) in favor of radium-223. In the final analysis, radium-223 prolonged median OS compared with placebo, irrespective of previous docetaxel use (previous docetaxel use, HR 0.70, 95% confidence interval [CI] 0.56-0.88; p=0.002; no previous docetaxel use, HR 0.69, 0.52-0.92; p=0.01). Furthermore, radium-223 significantly prolonged the median time to first SSE compared to placebo (15.6 months vs. 9.8 months; hazard ratio, 0.66; 95% CI, 0.52 to 0.83; P<0.001) and demonstrated favorable ALP outcomes, including time in total ALP increase (hazard ratio, 0.17; 95% CI, 0.13 to 0.22; P<0.001), ALP response (P<0.001), and ALP normalization (P<0.001).
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clinical safety summary enzalutamide

Enzalutamide carries the following warnings and precautions in the US prescribing information: * Seizures occurred in 0.4% of patients taking enzalutamide in clinical studies. In patients predisposed to seizures, 2.2% of patients taking enzalutamide experienced a seizure. * Posterior Reversible Encephalopathy Syndrome was reported in post-approval use. Symptoms included seizure, headache, lethargy, confusion, blindness and other visual and neurology disturbances. * Hypersensitivity reactions including edema of the face occurred in 0.5% of patients treated with enzalutamide in clinical trials. * Ischemic Heart Disease was reported in 2.7% of patients treated 1.2% of patients on placebo. * Falls and Fractures occurred in 10% of patients treated with enzalutamide compared to 4% of patients treated with placebo. The most common adverse events, occurring in more than 10% of patients and >/= 2% over placebo included asthenia/fatigue, decreased appetite, hot flush, arthralgia, dizziness/vertigo, hypertension, headache and weight loss. Drug interactions with CYP2C8 inhibitors (increase enzalutamide concentrations) and CYP3A4 inducers (decrease enzalutamide concentrations) were reported in the Package Insert. In addition, recommendations to avoid CYP3A4, CYP 2C9, and CYP2C19 substrates with narrow therapeutic indices (e.g. warfarin).
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darolutamide

The most common adverse reactions (≥2%) in patients who received darolutamide were fatigue, pain in extremity, and rash. Ischemic heart disease (4.0%) and heart failure (2.1%) were more common on the darolutamide arm. The most frequent adverse events that required dose-interruptions were hypertension (0.6%), diarrhea (0.5%), and pneumonia (0.5%). The most frequent adverse events that required dose-reductions were fatigue (0.7%), hypertension (0.3%), and nausea (0.3%). The most frequent adverse events requiring permanent treatment discontinuation were cardiac failure (0.4%) and death (0.4%). The most common laboratory abnormalities (all grades) were neutrophil count decreased (20%), AST increased (23%) and bilirubin increased (16%). Radium-223 Warnings reported in the US package insert include the following: * Bone Marrow Suppression- 2% of patients taking Radium-223 experienced bone marrow failure or ongoing pancytopenia * Hematologic evaluation prior to treatment. Prior to first treatment the absolute neutrophil count should be >1.5x109/L, platelets should be >=100x109/L and hemoglobin >=10g/dL. Prior to subsequent doses, the ANC should be >=1x109/L and platelets >=50x109/L. * Concomitant use with chemotherapy: the safety and efficacy has not been established * Increased fractures and mortality in combination with abiraterone plus prednisone/prednisolone (discussed in section 1.2)  
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* Administration and radiation protection. Administration of Radium-223 is associated with potential risks to other persons from radiation or contamination from spills of bodily fluids.  
* Fluid status-dehydration occurred in 3% of patients taking Radium-223 and 1% of placebotreated patients
* Injection site reactions: erythema, pain and edema at the injection site occurred in 1% of patients taking Radium-223 Adverse events (AEs) have been assessed for any man who received ≥ 1 injection of radium-223. There were 762 patients in the safety assessment population in studies of radium-223. AEs were observed in 88% of the radium-223 patients and 94% of placebo-treated patients. Serious adverse events (SAEs) were higher in the placebo group (43% versus 55%) and treatment discontinuation due to AEs was higher in the placebo group (13% versus 20%). Grade 3/4 hematologic toxicities were comparable between the two arms: neutropenia (3% versus 1%), thrombocytopenia (6% versus 2%), anemia (13% versus 13%). Non-hematologic grade 3/4 toxicities included bone pain (21% versus 26%), nausea (2% in either cohort), diarrhea (2% in either cohort), vomiting (2% in either cohort), fatigue (5% versus 6%), and bone pain (21% versus 26%). A statistically higher percentage of patients had meaningful improvement in quality of life with radium-223 over placebo.
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1.2 radium-223 in combination with

The ALSYMPCA study showed that the addition of radium-223 to the best standard of care, including local external-beam radiation therapy (EBRT), treatment with glucocorticoids, antiandrogens, ketoconazole, or estrogens, extended OS compared to patients receiving standard of care plus placebo [Parker et al. 2013]. Notably, enzalutamide or abiraterone plus corticosteroid were not included in the study. Data from the expanded access program in Europe suggested that patients receiving concomitant radium-223 and enzalutamide or abiraterone plus corticosteroid lived longer than those individuals without such concomitant therapy [Jim et al. 2010]. This is further strengthened by data from the radium-223 US expanded access programs.  
A combination trial of abiraterone plus prednisone/prednisolone in concurrent combination with radium-223 (ERA-223) reported results in 2018. This randomized double-blind, placebocontrolled Phase III ERA-223 trial investigated whether administering radium-223 dichloride
(radium-223) in combination with abiraterone acetate plus prednisone/prednisolone increased symptomatic skeletal event free survival (SSE-FS). The trial has enrolled 806 patients who are randomized in a 1:1 ratio to receive study treatment (either radium-223 dichloride or placebo in addition to abiraterone acetate plus prednisone/prednisolone for the first six cycles followed by abiraterone acetate plus prednisone/prednisolone thereafter) until an on-study symptomatic skeletal event (SSE) occurs (or other withdrawal criteria are met). The study completed enrollment in September 2016. On November 14th, 2017, an Independent Data Monitoring Committee (IDMC) recommended to unblind the Phase ERA223 III trial due to the observation of an imbalance concerning more fractures and deaths events in the treatment arm investigating radium-223 in combination with abiraterone acetate and prednisone/prednisolone. In November 2017, Bayer had informed health authorities worldwide as well as investigators and healthcare professionals about the preliminary findings of an increased incidence of fractures and death in the Phase III ERA-223 study. Of note, only 39% and 42% of subjects received concurrent denosumab or bisphosphonate treatment in the radium-223 and placebo arms, respectively (Smith at al. 2019). The FDA finalized its assessment of the Phase III ERA-223 trial results in August 2018 and the indication remains unchanged - Xofigo is indicated for the treatment of patients with castrationresistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease.  
As a consequence of the results of the ERA-223 trial there was an update in the SmPC concerning Warnings and Precautions - Increased Fractures and Mortality in Combination with Abiraterone plus Prednisone/Prednisolone: Xofigo is not recommended in combination with abiraterone acetate plus prednisone/prednisolone. Currently, the PEACE III study (NCT02194842) is ongoing and designed to answer the question of whether radium-223 in addition to enzalutamide improves radiological progression-free survival in patients with asymptomatic or mildly symptomatic mCRPC. This study initiates radium-223 and enzalutamide concurrently and does not address the optimal timing of radium223. Following the unblinding of ERA-223, the PEACE III study was amended to mandate bone protective agents, either denosumab or zoledronic acid [Tombal et al. 2019]. subsequently published that subjects initiating bone protective agents at least 6 weeks before their first injection of radium-223 had significantly lower rates of bone fractures, regardless of the use of Ra-223. Of the subjects receiving enzalutamide and radium-223, 13 of 39 (33%) without a bone protective agent reported a fracture, while only 1 of 33 (3%) on a bone protective agent reported a fracture. There was no difference in the rate of fractures between enzalutamide and radium-223 in patients that received a bone protective agent; however, the number of patients evaluated was low.
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1.3 the response of bone

Patients responding to enzalutamide therapy often have bone lesions that exhibit the bone flare phenomenon on a bone scan [Ryan et al. 2011]. The flare phenomenon is captured on bone scan as increased deposition within the hydroxyapatite associated with healing bone and represents an osteosclerotic reaction, with deposition of hydroxyapatite and presumably diminution of tumor size. Within the bone, there is an increase in elements to which radium-223 binds, while at the same time bone metastases are decreasing in size. This enhanced stromal/tumor ratio in bone is theoretically ideal for radium-223 therapy. This hypothesis has not been examined in preclinical or clinical studies.
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1.4 rationale for the study

Thousands of patients with bone predominant mCRPC experience disease progression after an initial response to enzalutamide or abiraterone acetate and the next treatment choice is unclear due to the availability of multiple therapies. Clinical and disease characteristics often dictate and/or limit potential options. No randomized controlled studies have suggested one therapy might be preferable to another in this setting or have established the ideal timing of radium-223, a novel radiopharmaceutical targeting bone metastases. The optimal time to add radium-223 to an active hormone treatment regimen such as enzalutamide or darolutamide has not been well established. Recent data from ERA-223, a trial adding concomitant radium-223 or placebo to abiraterone acetate, demonstrated an increased risk of fractures in the radium-223 group [Smith et al. 2019]. The fracture risk was dramatically reduced when bone-protective agents were used. A post-hoc analysis showed that both groups of patients with alkaline phosphatase flares during the study had a lower proportion of fractures, compared to those without flares [Smith et al. 2019]. The ongoing PEACE-III study is investigating concurrent enzalutamide and radium-223 and only mandated bone health agents subsequent to the release of the ERA-223 fracture data. The hypothesis we are testing in this study is whether layering radium-223 following 16 weeks of enzalutamide or darolutamide exposure in patients demonstrating a biochemical response improves disease outcomes. By adding radium-223 following a potential bone flare phenomenon (first 12-14 weeks of therapy with an androgen receptor blocker), maximizing patients expected to have durable response to systemic therapy, and using bone protective agents during treatment, we aim to demonstrate an optimal time to add radium-223 in the mCRPC landscape. In this study, the efficacy of adding radium-223 after an initial PSA decline ≥30% at any time during a 12-week lead-in period of enzalutamide or darolutamide, will be assessed via time to symptomatic skeletal event-free survival (SSE-FS). In the PREVAIL study, the prognostic importance of PSA response was demonstrated; subjects experiencing an initial PSA response during enzalutamide treatment had better outcomes than those that did not, including time to PSA progression, rPFS, and overall survival. (Armstrong et al. 2018). As radium-223 targets the bone only, this study will select for patients that demonstrate systemic control of their disease (i.e. a biochemical response during oral therapy) to enable higher likelihood of patient benefit. SSE-FS is a clinically meaningful endpoint defined as the first occurrence of a symptomatic pathologic fractures, external beam radiation therapy to relieve skeletal symptoms, spinal cord compression, or tumor-related orthopedic surgical intervention, or death from any cause.
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2. study objectives 2.1 primary

The primary objective of this study is to:
- To compare the symptomatic skeletal event-free survival (SSE-FS) of patients on radium-223 vs. placebo while taking randomized ARB therapy.
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2.2 secondary objectives

The secondary objectives of this study are to:
- Assess overall survival (OS)
- Assess time to chemotherapy initiation after RT2 Cycle 1, Day 1 (C1D1)  
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- Assess radiographic progression-free survival (rPFS) after RT2 C1D1 - Determine the safety profile of androgen receptor blocker (ARB) therapy with or without radium-223
- Assess occurrence of AESI: bone fractures (pathologic and non-pathologic)
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2.3 exploratory objectives

The exploratory objectives of this study are to:
- Compare the safety and cognitive function of enzalutamide and darolutamide from RT1 randomization through 12 weeks of enzalutamide or darolutamide (prior to RT2)
- Determine skeletal progression using PCWG3 criteria for progression based upon 99Tc bone scan imaging after RT2 randomization
- Determine the time to PSA progression following RT2 randomization
- Determine the total alkaline phosphatase (ALP) response rate every 12 weeks following RT2 randomization
- Assess time to total ALP progression - Assess time to lactate dehydrogenase (LDH) progression - Assess further correlative biomarkers in the patient population - Assess changes in cognitive function following RT2 randomization
- Assess frequency of the following adverse events that are listed as warnings for the study drugs (cardiovascular, seizures, falls, weakness, cognitive function)
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2.4 endpoints primary endpoint

The primary endpoint is the symptomatic skeletal event-free survival (SSE-FS).  
Symptomatic skeletal events are defined as the duration of time from RT2 until any one of the following:
- the first use of external-beam radiation therapy to relieve skeletal tumor-related symptoms
- the occurrence of new symptomatic pathologic bone fractures.  
- the occurrence of new symptomatic spinal cord compression
- a tumor-related orthopedic surgical intervention For calculating the cumulative incidence of SSE over time, the time to SSE is defined as the time elapsed between the day of C1D1 after Randomization 2 to the day of SSE recorded for each patient. Patients who are alive and without evidence of an SSE at their last study visit will be censored at that visit date. Patients who die without an SSE will be considered as having a completed event at the date of their death.
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secondary endpoints

The secondary efficacy endpoints are:
- Overall survival (OS) defined as the time from RT2 randomization until death on study.  
Patients who are alive at the time of data cut-off will be censored at the last date known to be alive.  
- Time to chemotherapy initiation defined as the time from RT2 to initiation of docetaxel or cabazitaxel treatment, whichever occurs earlier.  
- Radiological progression-free survival (rPFS) defined as time to the first occurrence of bone scan progression per PCWG3 criteria, and/or progression by CT/MRI per RECIST 1.1 criteria, or death from any cause following RT2. Radiological progression is interpreted by local assessment only.  
- Determine the safety profile of androgen receptor blockers (enzalutamide or darolutamide) with or without radium-223 using adverse event rates, electronic patient reported outcomes, and cognitive testing.  
- Assess occurrence of AESI: fractures (pathologic and non-pathologic)
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exploratory endpoints

Exploratory efficacy endpoints include:
- Compare the safety of enzalutamide and darolutamide after 12 weeks of enzalutamide or darolutamide (pre-RT2) using adverse event rates, electronic patient reported outcomes, and cognitive testing.  
o Compare the proportion of subjects meeting criteria for cognitive impairment after 12 weeks of enzalutamide or darolutamide (pre-RT2) by comparing objective neurocognitive tests (CANTAB modules). Cognitive impairment is defined per the International Cognition and Cancer Task Force guidelines as meeting one of the following: 1) ≥1.5 SDs below (age- and education-adjusted) norm on ≥2 cognitive domain modules; or 2) ≥2 SDs below norm on ≥1 cognitive domain module Wefel et al. 2011].  
o Compare the average decline in maximally changed cognitive domain in patients in each treatment group after 12 weeks of enzalutamide or darolutamide (preRT2) using objective neurocognitive testing (CANTAB modules).  
o Compare subjective cognitive function between treatment arms by comparing FACT-Cog total scores after 12 weeks of enzalutamide or darolutamide (preRT2).  
o Compare overall quality of life between treatment arms by comparing FACT-P
between arms after 12 weeks of enzalutamide or darolutamide (pre-RT2)
- Time to first skeletal progression using PCWG3 criteria for progression using 99Tc bone scan imaging after RT2 C1D1.  
- Time to PSA progression defined as:
o For patients with a PSA decline from R2 randomization, an initial PSA increase of at least 25% and 2 ng/mL above the nadir, which is confirmed by a second value 3 or more weeks later (i.e., a confirmed rising trend).  
- Assess frequency of the following adverse events that are listed as warnings for the study drugs (cardiovascular, seizures, falls, weakness, cognitive function)
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3. study patient population and

Patients must meet all of the following inclusion criteria in order to be qualified for the first randomization (R1) to Open-label Enzalutamide or Darolutamide (Lead-in Phase):
1. Able and willing to provide informed consent. 2. Progressive mCRPC at screening with histologically or cytologically confirmed diagnosis of prostate adenocarcinoma.  
3. Men ≥ 18 years. 4. ECOG performance status of 0 or 1 at screening.  
5. Metastatic to bone with ≥ 2 bone metastases (area of increased uptake on 99mTc bone scan); equivocal lesions on the bone scan must be confirmed by standard Xray, CT, or MRI.  
6. Patients must have progressive castration-resistant prostate cancer (CRPC) on androgen deprivation therapy (ADT) as evidenced by either of:
a.For patients who manifest disease progression solely as a rising prostatespecific antigen (PSA) level - documentation of a sequence of two rising PSA values at a minimum of 1-week apart with the Screening value ≥1 ng/ml (see Appendix D);
b.For patients with disease progression manifested in the bone, irrespective of progression by rising PSA - defined by the appearance of 2 or more  
Final Protocol: 04 MAY 2020 VERSION 1.2 Page 34 of 102 o For patients without a PSA decline from R2 randomization, a PSA increase of at least 25% and 2 ng/mL above the pre-RT2 value.  
- Total alkaline phosphatase (ALP) response rate. Total ALP response is defined as the proportion of patients who had elevated total ALP at R2 randomization which has normalized at least 12 weeks after R2 randomization.  
- Time to total alkaline phosphatase (ALP) progression defined as:
o In patients without a total ALP decline from R2 randomization: a ≥25% increase from the value at R2 randomization at least 12 weeks following R2 randomization, o In patients with an initial total ALP decline from the value at RT2 randomization:
≥25% increase above the nadir value, which is confirmed by a second value obtained 3 or more weeks later
- Time to lactate dehydrogenase (LDH) progression defined as o In patients with normal LDH at RT2 randomization: one abnormally elevated value confirmed by a second abnormal value obtained 3 or more weeks later.  
o In patients with LDH above ULN at RT2 randomization: ≥25% increase from the value at RT2 randomization
- Assess further correlative biomarkers in the patient population new skeletal lesions demonstrated by 99Tc bone imaging. Ambiguous results should be confirmed by other imaging modalities than bone scan and x-ray (e.g.: CT-scan or MRI).  
c.For patients with disease progression manifested at nodal sites, irrespective of progression by rising PSA - progression defined per RECIST 1.1.  
7. Ongoing ADT with luteinizing hormone-releasing hormone (LHRH) agonist or antagonist or bilateral orchiectomy.  
8. Use of bone health agents (denosumab or zoledronic acid or other bisphosphonates) starting any time prior to R1 unless contraindicated or considered not in the best interest of the patient. A waiver must be approved by the medical monitor if bone health agents cannot be used. Bone health agents should be continued throughout both RT1 and RT2 treatment periods.  
9. Adequate bone marrow and organ function as defined by:
a.Hemoglobin ≥ 10.0 g/dL
b.Absolute neutrophil count (ANC) ≥1.5 x 109/L c.Platelets ≥100 x 109/L
d.Serum creatinine ≤1.95 mg/dL e.Estimated creatinine clearance >/= 30 mL/min/1.73m2 by Cockroft-Gault calculation f. Alanine aminotransferase (ALT) ≤ 175 U/L g.Aspartate aminotransferase (AST) ≤ 100 U/L h.Total bilirubin ≤ 1.8 mg/dL (unless the patient a diagnosis of Gilbert's disease or a similar syndrome involving slow conjugation of bilirubin; in patients with Gilbert's, the total bilirubin should be less than 6 mg/dl if patient has Gilbert's and the elevation should be seen in the unconjugated or indirect bilirubin measurement)
i. LDH ≤ 224 U/L at screening j. Albumin ≥2.5 g/dL
10. Fertile male patients, defined as all males physiologically capable of conceiving offspring with female partners of child-bearing potential, must be willing to use condoms plus spermicidal agent during the study treatment period and for 6 months after the last dose of study drug, and not father a child or donate sperm during this period.  
11. The treating site investigator deems RT1 (Enzalutamide or Darolutamide)
treatment safe and feasible.  
Subjects must meet the remaining inclusion criteria in order to be qualified for the second randomization (R2). Only subjects that complete the initial 12 weeks of run-in RT1 should be evaluated. Prior inclusion criteria do not need to be re-evaluated:
12. Patients must have a documented ≥ 30% decline of PSA at any time during the 12 weeks of RT1.  
13. Patients must have no evidence of visceral metastatic disease at the time of RT2 randomization.  
14. Ongoing treatment with RT1 and bone health agents at time of RT2 randomization.  
15. The treating site investigator deems RT2 (Ra-223 dichloride) treatment safe and feasible.
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3.2 exclusion criteria

Patients who meet any of the following criteria will be excluded from study entry and will be considered Screen Failures (cannot be randomized to R1). These are only evaluated prior to the first randomization (R1) and do not need to be re-evaluated for R2:
1. Pathological finding consistent with small cell carcinoma of the prostate 2. Prior chemotherapy for CRPC. Prior docetaxel for hormone-sensitive disease is permitted under the following conditions: started within 3 months of ADT initiation, given for a maximum of 6 cycles and progression occurred > 6 months after the last dose of docetaxel.  
3. Prior treatment for mCRPC or CRPC. However, the following therapies are permitted and not exclusionary: Sipuleucel-T, 5-alpha-reductase inhibitors, estrogens, or older antiandrogens (such as flutamide, bicalutamide, or nilutamide).  
4. Prior treatment for more than 1 month with CYP17 inhibitors (e.g. abiraterone or orteronel)
5. Prior treatment for more than 2 months with agents inhibiting androgen receptor signaling (e.g. enzalutamide, apalutamide, or darolutamide).  
6. Prior hemibody or whole-body external radiotherapy. Other types of prior external radiotherapy and brachytherapies are allowed.  
7. Prior therapy with radionuclides (e.g., radium-223, strontium-89, samarium-153, rhenium-186, rhenium-188, actinium-225 and lutetium-177).  
8. Current involvement in any drug or device trial involving investigational agent or medical device within the last 28 days prior to R1.  
9. In general, any prior investigational agent for nmCRPC/mCRPC; however, may be reviewed by medical monitor/PIs for waiver consideration, on a case-by-case basis.  
10. Hypersensitivity to compounds related to enzalutamide, darolutamide, or Ra223 11. A blood transfusion ≤ 28 days prior to R1. 12. Major surgical procedures ≤ 28 days or minor surgical procedures ≤7 days prior to R1.  
No waiting period is required following port-a-cath placement.  
13. Patients with visceral metastases, clinical evidence of central nervous system metastases or leptomeningeal tumor spread as demonstrated via CT/MRI of chest, abdomen, pelvis, and CNS (if needed). CT/MRI of the CNS only performed if suspicion of CNS metastases or leptomeningeal tumor spread. Nodules <1 cm alone will not be considered visceral metastases. Renal masses <3cm will not be considered exclusionary.  
14. Serious active infection at the time of screening or another serious underlying medical condition that would impair the ability of the patient to receive protocol treatment.  
15. Presence of other active cancers, or history of treatment for invasive cancer ≤2 years of study entry. Patients with Stage I/II cancer who have received definitive local treatment and are considered unlikely to recur are eligible. All patients with previously treated in situ carcinoma (i.e., non-invasive) and superficial bladder cancer are eligible, as are patients with history of non-melanoma skin cancer.  
16. Any other serious or unstable illness, or medical, social, or psychological condition, that could jeopardize the safety of the subject and/or his/her compliance with study procedures, or may interfere with the subject's participation in the study or evaluation of the study results.
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3.3 discontinuation from randomized treatments

Following permanent discontinuation of darolutamide, enzalutamide, or Ra-223 or Placebo, patients will have a Telephone End of Study Drug visit, which will include protocol-required safety follow-up assessments 30 days after the last dose of study medication unless the patient specifically declines further follow-up, in which case the data from last visit will be used. Study site personnel must document the patient's decision in the clinical records.
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3.4 required discontinuation from randomized

The primary reasons that require patients to permanently discontinue darolutamide or enzalutamide are as follows:
- Adverse event or inter-current illness: any intolerable adverse event (including toxicity related to ARB) that cannot be ameliorated by the use of adequate medical intervention or that in the opinion of the Site Investigator or Medical Monitor would lead to undue risk if study treatment were continued.  
- Gross noncompliance with protocol: the Medical Monitor or Lead-Principal Investigator may request permanent treatment discontinuation in the event of a major protocol deviation, lack of cooperation, or noncompliance.
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3.5 required discontinuation from randomized

The primary reasons that require patients to permanently discontinue the double-blind, randomized Ra-223 or placebo treatment regimen are as follows:
- Radiological disease progression; however, investigators may continue RT2 treatment through 6 cycles until it no longer clinically benefits the patient as defined per PCWG3. PSA progression is not considered progression in this protocol (Scher et al. 2016).  
- Adverse event or inter-current illness: any intolerable adverse event (including toxicity related to Ra-223) that cannot be ameliorated by the use of adequate medical intervention or that in the opinion of the Site Investigator or Medical Monitor would lead to undue risk if study treatment were continued.  
- Gross noncompliance with protocol: the Medical Monitor or Lead-Principal Investigator may request permanent treatment discontinuation in the event of a major protocol deviation, lack of cooperation, or noncompliance.  
- Required use of a prohibited concomitant therapy (section 8.4.3).  
- Death - Lost to follow-up
- Sponsor discontinuation of study: the Sponsor reserves the right to terminate the study.  
The Sponsor will terminate this study following completion of the study objectives, or earlier if deemed necessary.  
- Patient decision: patients may permanently discontinue any of the randomized study drug treatments at any time for any reason.
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3.6 q12-week progression follow-up

After Ra-223 or placebo (RT2) treatment is completed or discontinued, patients should continue RT1 and have follow-up visits every 12 weeks, until radiological progression, or until a prohibited treatment (section 8.4.3) is initiated. The visits should remain on the same Q12-Week (Imaging) schedule based on Cycle 1, Day 1. All new reportable AEs occurring during this period must be reported and followed until resolution, unless, in the opinion of the Site Investigator, these values are not likely to improve. In this case, the Site Investigator must record his or her reasoning for this decision in the patients' medical records and as a comment in the electronic Case Report Form (eCRF). Once 12-week follow-up visits are no longer required, the patient enters into the Overall Survival phase. All patients who have Grade 3 or 4 hematological laboratory abnormalities (per National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] v 5.0) at the time of discontinuation must be followed until the laboratory values have returned to Grade 1 or 2, unless it is, in the opinion of the Site Investigator, not likely that these values are to improve. In this case, the Site Investigator must record his or her reasoning for making this decision in the patients' medical records and as a comment in the eCRF.
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3.7 overall survival phase

Patients that have radiological progression or that start a prohibited treatment (section 8.4.3) will be followed every 6 months (+/- 1 month) after the last Q12-Week visit was performed (during randomized (RT2) treatment or during follow-up). Patients will be followed by outpatient visits, telephone contacts, and/or chart review. Only adverse events identified by the Site Investigator to be related to darolutamide, enzalutamide, radium-223, SSE-related AEs, and Adverse Events of Special Interest will need to be reported.
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4. correlative testing planned use

Subject participation in the central biorepository is optional and will not alter their participation in the overall study. Sample collection and storage at a central biorepository will enable for future interrogation of prostate cancer biomarkers. At this time the ultimate use of these samples has not been determined; samples may be used to perform various types of analyses, and these analyses will vary depending upon evolving research needs. Potential investigations utilizing stored saliva, serum, plasma, buffy coats, or other tissues include but are not limited to proteins, various metabolites, and others. Samples may also be analyzed for exploratory biomarkers to evaluate predictive biomarkers and to assess correlation with disease activity, effects of study drug, and clinical outcomes.
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biorepository sample collection times

Samples will be collected at 3 timepoints:
- Pre-RT1: Prior to enzalutamide or darolutamide obtained through study. - Pre-R2: After 12-week Lead-in enzalutamide or darolutamide (RT1), and
- At the next visit after radiographic progression is confirmed or initiation of a prohibited treatment, whichever occurs earlier
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biorepository sample collection information

Details regarding the biorepository sample collection and site responsibilities are available in the laboratory manual.
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5. cognitive testing and epro

Studies assessing the effect of ADT on the cognitive function of men with prostate cancer have reported mixed results.[McGinty et al. 2014, Alibhai et al. 2010, Joly et al. 2006, Jim et al. 2010] One recent prospective, controlled study of the effect of ADT on cognitive function suggests that treatment with ADT is associated with a decline in cognitive function [Gonzalez et al. 2015]. Additionally, the investigators found a specific SNP that may be associated with increased risk of cognitive dysfunction during treatment but not in untreated men.[Gonzalez et al. 2015] Furthermore, a recent population-based cohort study of men with prostate cancer receiving ADT suggests that ADT may be associated with an increased risk of Alzheimer's disease.[Nead et al. 2016] Whether the cognitive effects associated with treatments with oral therapies that directly  
Final Protocol: 04 MAY 2020 VERSION 1.2 Page 39 of 102 bind the AR in the central nervous system after crossing the blood brain barrier (enzalutamide) when compared with AR targeting agents that do not cross the blood brain barrier (darolutamide), has not been adequately described. In this study we will assess objective neurocognitive changes associated with treatment with AR targeting agents that do (enzalutamide) and do not (darolutamide) cross the blood brain barrier. Objective neurocognitive change will be compared between arms and longitudinally over time using modules from CANTAB neurocognitive tablet-based tests. A battery of CANTAB cognitive function tests will be used. In addition, we will compare subjective quality of life and neurocognitive effects during treatment with darolutamide and enzalutamide using the ePRO instruments FACT-P and FACT-COG. Data collection will be done electronically at the following timepoints:
- Screening (practice)
- Pre-RT1 (prior to enzalutamide or darolutamide given through the study)
- Pre-R2 (12 weeks post- enzalutamide or darolutamide)
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6. study registration

The study will be listed on ClinicalTrials.gov by MANA RBM. Yearly updates and reporting on final study results will be the responsibility of MANA RBM.
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7. study design

This is a multi-center, Phase III study in patients with mCRPC.
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screening

Patients will be screened -42 to -2 days prior to starting RT1 treatment with an androgen receptor blocker.
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r1

Following successful screening for first randomization (i.e., R1 I/E are met), patients will be randomized (R1) 1:1 to open-label randomized treatment 1 (RT1) with either enzalutamide or darolutamide. Patients may not switch RT1 ARB treatment during the study.
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rt1 day 1 day 28

Ensure patient is taking bone health agent (BHA) at or before first RT1 dose and continues on BHA throughout RT1 and RT2 treatment periods. Patients must receive at least 12 weeks of RT1 prior to Pre-R2 visit and before starting randomized, double-blinded Ra-223 or placebo (RT2).  
Patients will have serial PSAs performed at least every 4 weeks during the first 12 weeks of RT1 therapy.
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pre-r2

Pre-R2 baseline assessments will be done after at least 12-16 weeks of RT1 have been completed and no less than 14 days prior to C1D1 of RT2 to review safety parameters and establish baseline values prior to C1D1. Imaging assessments (CT, MRI, Bone Scan) should only be done for patients that have a documented ≥ 30% PSA decline at any time during the first 12 weeks of RT1.  
Subjects must meet additional inclusion criteria 12-15 in order to be qualified for the second randomization (R2). Only subjects that complete the initial 12 weeks of run-in RT1 should be evaluated for the additional inclusion criteria. Prior inclusion criteria 1-11 do not need to be reevaluated. *All subjects that complete the lead-in RT1 treatment should perform the second* series of Cognitive function testing, even if they do not qualify for R2, prior to discontinuation. R2: If the all (R2) randomization conditions are all met, subjects will be eligible for (R2)
randomization and should start the 1st cycle of (RT2) Ra-223 or placebo (C1D1) within 14 days following the pre-R2 safety laboratory blood draw. Patients eligible for RT2 will be centrally randomized in a 1:1 ratio to receive either radium-223 dichloride or placebo (saline) administered IV on Day 1 of each cycle for 6, 28-day cycles, and will continue with their open-label, randomized ARB and bone health agent(s). The placebo will be administered in precisely the same fashion as the active drug.
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rt2 up to 6 cycles

First RT2 cycle (C1D1) must occur within 14 days after the pre-R2 safety laboratory blood draw. Ideally, subsequent RT2 cycles 2-6 should be scheduled to occur every 28 days +/- 7 days following the previous cycle, but dosing may be delayed up to 4 weeks per cycle (maximum 8 weeks between cycles). Patients will continue with their open-label, randomized ARB irrespective of Ra-223/placebo delays. Subjects should continue on BHA throughout the RT2 treatment period. Safety laboratory assessments must be completed within 14 days of each cycle and results assessed for safety to proceed with next cycle before administration.
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q12-week rt2 imaging

After the first administration of RT2 at C1D1, patients will be assessed radiologically by CT or MRI and bone scan every 12 weeks, until either: 3) radiological progression defined as soft tissue progression per RECIST 1.1 or bone progression per PCWG3 or 4) a prohibited treatment has begun. The 12-week visits start 12 weeks +/- 7 days after RT2 Cycle 1, Day 1 and must remain on this schedule independent of other study visits. The same imaging modality should be used for all assessments (CT or MRI). The RECIST and PCWG3 tumor assessments should be completed by the same trained rater throughout the study.
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telephone end of study drug(s)

Telephone End of Study Drug visits are required 30 days +/- 7 days after last dose of study drug(s) (Ra-223/Placebo, Enzalutamide, and Darolutamide) are administered or at the last clinic visit if patient declines further participation.
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q12-week progression follow-up

After RT2 cycles are either stopped or (6) cycles completed, patients without radiological progression that have not started a prohibited treatment will continue to have clinic visits every 12 weeks (continuing with the same schedule based on C1D1). Enzalutamide or Darolutamide may continue during the Q12-Week Progression Follow-up period. PSA progression alone is not considered progression in this protocol [Scher et al. 2016]. Clinical progression will be assessed by the site investigator on any scheduled or unscheduled visit.
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overall survival

Patients that demonstrate radiological progression or start a prohibited treatment will be followed for SSE's, AESIs, and overall survival Enzalutamide or Darolutamide may continue during the Overall Survival period. Patients in this phase of the study will be evaluated every 6 months +/- 1 month after the last Q12-Week Visit is performed until death or the end of the study. Patients may be contacted during outpatient visits or by telephone and/or chart review.
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end of study

When patients permanently discontinue the study due to any reason (screen failure, lost to follow-up, withdrawn consent, etc.), an End of Study visit will be done to capture the reason for screen failure, reason for permanent discontinuation, study disposition, and to assess AEs.
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8. study medications 8.1 randomized

Ensure patient is taking a bone health agent at time of Randomization 1 (R1). Patients eligible to receive RT1 will be randomized (R1) in a 1:1 ratio to receive open-label enzalutamide (160 mg PO QD) [available commercially through prescription] or darolutamide (600 mg PO BID) [provided through the study] for mCRPC. Dose reductions of RT1 will be allowed per protocol (see dose-reduction guidelines). Once receiving RT1, subjects should continue RT1 on study until toxicity, or other reason listed in section 3.4. Patients who do not have a ≥ 30% PSA decline at any time during the RT1 period will not be randomized to RT2 and will be discontinued from the study. Patients must receive RT1 at least 12 weeks and meet all R2 conditions to proceed to the second double-blind randomized treatment phase.
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8.2 randomized treatment #2 rt2

Patients eligible to receive RT2 will be randomized (R2) in a 1:1 ratio to receive double-blind RT2 (radium-223 or placebo) that will be administered IV on Day 1 of each cycle for 6, 28-day cycles). RT2 active and placebo treatments will be administered in precisely the same fashion on Day 1 of each cycle for 6, 28-day cycles. Patients will continue with their open-label, randomized ARB and bone health agent. Randomized (Ra-223 or Placebo) will be blinded to patient and study staff /investigators who perform any study related procedures/tasks. Designated trained, unblinded individual or individuals will prepare and administer radium-223 at 55 kBq/kg IV or placebo via intravenous infusion on Day 1 of a 28-day cycle for a total of 6 cycles. No dose reductions will be allowed, but treatment can be held for up to 4 weeks. If the hold is the result of a treatment-related AE and lasts for >4 weeks, then treatment will be permanently discontinued. No less than 3 weeks and no more than 8 weeks is allowed between doses. Patients will be evaluated for toxicity within 14 days prior to each cycle. Radiological assessments will be performed every 12 weeks following Cycle 1 Day 1, as defined in Appendix C. Patients will continue on RT2 for up to 6 cycles or until patient has a reason for discontinuation as listed in Section 3.5 of the protocol. Upon radiographic progression, further treatments are decided by the site investigator according to standard local practice. Radium-223 or placebo may continue at the discretion of the site investigator (if the maximum of 6 doses have not been reached) if they believe it to be in the patient's best interest. If patient continues on Ra-223 or placebo after radiological progression, the Q12 Week Imaging visits will not be done, and the patient will move into Overall Survival phase after all Ra-223 or Placebo cycles are completed. Enzalutamide or darolutamide may be continued after progression if the treating investigator considers that the patient is still receiving benefit.  
PSA progression alone is not considered progression in this protocol [Scher et al. 2016]. Clinical progression will be assessed by the site investigator on any scheduled or unscheduled visit.
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8.3 blinding and unblinding the

Patients will be randomized to receive radium-223 or placebo in a double-blind fashion. Ideally, there should be at least 2 staff members at each study site who are unblinded in order to allow the individuals to serve as back-up for each other. All treating physicians, clinical staff, patients, and the sponsor personnel will be blinded as to which treatment a patient is randomized, except for designated and trained unblinded representatives who will perform drug ordering, drug accountability, preparation of placebo, dose calibration, and administration of Ra-223/Placebo.  
There is no intention to routinely unblind individual patients at any time. Individual requests for safety unblinding require the approval of the Medical Monitor. If the investigator decides that unblinding is warranted, the investigator should contact the Medical Monitor prior to unblinding unless this could delay emergency treatment of the participant. The Site Investigator may hold administration of radium-223/placebo while waiting for a decision on unblinding to be made. Approval may be obtained by contacting the Medical Monitor directly. Upon approval by the Medical Monitor, appropriate MANA RBM staff member will break the blind and will provide the site with the patient's treatment assignment.  
Examples of circumstances requiring unblinding include:
- A life-threatening, unexpected AE (e.g. SUSAR) that is thought to be related to radium223 unblinding would change or influence treatment decisions
- In the event of a suspected unexpected serious adverse reaction - Medication error, such as an accidental overdose, that would warrant unblinding in order to more effectively manage toxicity
- Regulatory reporting requirement (e.g. in the event of a safety signal in a treatment arm.) - Unblinding influences current treatment decisions (e.g. Ra-223 is a reasonable treatment option for a patient following disease progression)
Site Investigators may only unblind patients under emergency unblinding rules (See unblinding rules document for further details.). If a patient is unblinded by the Site Investigator, he must discontinue Ra-223/Placebo and enter the Overall Survival phase. The occurrence of a SAE or progressive disease (PD) should not routinely precipitate the immediate unblinding. However, if emergency unblinding is necessary for the treatment of an SAE, study treatment can be unblinded. Should blinding be broken for a patient, the Medical Monitor should be contacted by the Site Investigator within one working day of the premature unblinding to discuss its rationale. The study will be unblinded for analysis purposes at the time of final analysis.
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8.4 concomitant medications

At each visit, the patient will be asked about new and ongoing medications taken after the time of the initial informed consent.
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required concomitant medications

- Androgen Deprivation Therapy **(ADT)**: all patients who have not had a bilateral orchiectomy are required to remain on a LHRH agonist (e.g. leuprolide, goserelin) or antagonist (e.g. degarelix).  
- Bone Health Agent **(BHA)**: all patients are required to take concomitant bone health agents (e.g.,denosumab, zoledronate, or other bisphosphonates) starting prior to the LeadIn RT1 phase and continuing throughout the study unless the site investigator determines there is a contraindication for treatment and requests a medical waiver. All waivers must be approved by the Medical Monitor.
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permitted concomitant medications and treatments

All concomitant medications and treatments should be documented in the relevant section of the case report form. Premedication with anti-emetics is allowed according to standard practice guidelines. Medications may be administered for maintenance of existing conditions prior to screening or for a new condition that develops while on study, including but not limited to the following:
- During the duration of the study, other concomitant treatments including but not limited to treatments such as such as analgesics, corticosteroids, estrogens (e.g., stilboestrol), older antiandrogens (bicalutamide, flutamide, and nilutamide), and ketoconazole are permitted throughout the study according to routine clinical practice at the discretion of the site Investigator.  
- Herbal therapies are **not restricted** on study. - Blood transfusions are allowed throughout the study after R2. - Receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor use, as recommended according to practice guidelines.  
- EBRT is allowed at the discretion of the Site Investigator.  
Other medications considered necessary for the patient's safety and well-being may be given at the discretion of the Site Investigator with the exception of those listed in Section 8.4.3.
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prohibited concomitant medications

The following treatments are prohibited while in this study:
- Any other investigational therapy
- Radiopharmaceuticals other than study-provided radium-223
- Darolutamide, if RT1 is enzalutamide - Enzalutamide, if RT1 is darolutamide - Hemi-body and total body radiation
- Chemotherapy (estramustine (EmcytTM) is considered a chemotherapy)
- Novel CYP17 inhibitors (e.g. abiraterone or orteronel) - Other novel agents inhibiting androgen receptor signaling (e.g. apalutamide) (ErleadaTM) - Immunotherapy
- Bone marrow stimulating agents [sargramostin (Leukine), filgrastim (NeupogenTM),
pegfilgrastim (NeulastaTM) and epoetin alpha (EpogenTM, ProcritTM)]
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cautionary medications

- PI should review all concomitant medications that have potential drug-drug interactions with the study medications - Ra-223, enzalutamide, and darolutamide to determine if treatment with the study medications is safe.
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9. dose modifications

If toxicity occurs, the toxicity will be graded utilizing the NCI CTCAE v 5.0 (http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE), and appropriate supportive care treatment will be administered to decrease the signs and symptoms thereof. No dose reductions of radium-223 will be allowed. Treatment can be held for up to 4 weeks. If the hold lasts for >4 weeks (>8 weeks between cycles), then treatment will be permanently discontinued. Dose reductions of enzalutamide or darolutamide will be allowed at the discretion of the site investigator during the study, per current full prescribing information.
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9.1 dose and schedule modifications

Dose and schedule modifications are based on recommendations from the investigator's brochure of study medications. At each visit during the treatment period, patients should first be evaluated for the occurrence of adverse events and laboratory abnormalities. Specific recommendations for management of possible adverse events are provided below.
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ra-223

Every effort should be made to administer the full dosing regimen of Ra223 dichloride. Adjustment of dose level is not permitted.
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9.1.1.1 special warnings

- Patients with evidence of compromised bone marrow reserve e.g. following prior cytotoxic chemotherapy and/or radiation treatment (EBRT) should be treated with caution. An increased incidence of hematological adverse reactions such as neutropenia and thrombocytopenia was observed in these patients during the phase III study. - Crohn's disease and ulcerative colitis: safety and efficacy of Ra-223 in patients with Crohn's disease and with ulcerative colitis have not been studied. Due to the fecal excretion of Ra-223, radiation may lead to aggravation of acute inflammatory bowel disease. Ra-223 should only be administered after a careful benefit-risk assessment in patients with acute inflammatory bowel disease. - Osteonecrosis of the jaw: in patients treated with bisphosphonates and Ra-223, an increased risk of development of osteonecrosis of the jaw (ONJ) cannot be excluded. In the phase III ALSYMPCA study, cases of ONJ have been reported in 0.67% of patients (4/600) in the Ra223 arm compared to 0.33% patients (1/301) in the placebo arm. However, all patients with ONJ were also exposed to prior or concomitant bisphosphonates (e.g. zoledronic acid) and prior chemotherapy (e.g. docetaxel).  
Final Protocol: 04 MAY 2020 VERSION 1.2 Page 48 of 102
- Secondary malignant neoplasms: Ra-223 contributes to a patient's overall long-term cumulative radiation exposure. Therefore, long-term cumulative radiation exposure may be associated with an increased risk of cancer and hereditary defects. In particular, the risk for osteosarcoma, myelodysplastic syndrome and leukemia may be increased. No cases of Ra223-induced cancer have been reported in clinical trials in follow-up of up to three years
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9.1.1.2 dose delay

Dosing delay may be instituted under the following circumstances: Myelosuppression: treatment-related changes in hematology parameters may occur: - If a patient experiences CTCAE v4 Grade ≥ 3 neutropenia, thrombocytopenia, or anemia lasting > 14 days, further Ra223 administrations must be discontinued. - If a patient experiences CTCAE v4 Grade ≥ 3 neutropenia, thrombocytopenia, or anemia the administration of Ra233 should be delayed until recovery to Grade 2 or better. - Before subsequent administrations, the ANC should be ≥ 1.0 x 109/L and the platelet count ≥ 50 x 109/L. Gastrointestinal events: - Diarrhea should be treated as per local practice. A further dose of Ra223 should not be given before diarrhea is recovered to CTCAE v4 Grade 2 or baseline levels. - Nausea or vomiting should be treated as per local practice. A further dose of Ra223should not be given before nausea or vomiting is recovered to CTCAE v.4 Grade 2 or baseline levels. Spinal Cord Compression: In patients with untreated imminent or established spinal cord compression, treatment with standard of care, as clinically indicated, should be completed before starting or resuming treatment with Ra223. Surgical Intervention:
If surgery is required, the patient should continue with study treatment, if this is considered safe in the treating Investigator's opinion. The surgeon needs to be notified that the patient has been given radioactive drug, and needs to follow the guidelines for radioactive protection. Non-pathological fractures: For traumatic fractures in weight-bearing bones during treatment phase, the Ra223 administration should be delayed for 2-4 weeks from the time of fracture. Orthopedic stabilization of fractures should be performed before starting or resuming treatment with Ra223. Pathological fractures: Pathological fractures may occur as the result of either progressive disease or increased physical activity associated with significant pain palliation. Pathologic fractures are to be treated in a manner that attempts to maintain the best functional status and quality of life. Study treatment may continue as planned. Any Other Toxicity: Local practice will apply.
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enzalutamide

If a patient experiences ≥ Grade 3 toxicity or an intolerable adverse reaction, that does not improve with adequate medical intervention, dosing should be withheld for one week or until symptoms improve to ≤ Grade 2.Enzalutamide may be restarted at the original dose (160 mg/day) or at a reduced dose (120 mg or 80 mg) if warranted. After dose reduction, based on patient tolerance, enzalutamide may be reincreased to a maximum dose of 160 mg/day at Investigator discretion. Enzalutamide must be interrupted during the evaluation of symptoms suspicious of PRES (headache, lethargy, confusion, blindness and other visual and neurological disturbances, with or without associated hypertension). Restarting treatment at a reduced dose or after treatment interruption for > 2 weeks must be discussed with the Medical Monitor.
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darolutamide

NUBEQA (Darolutamide): If a patient experiences a greater than or equal to Grade 3 toxicity or an intolerable adverse reaction, withhold dosing or reduce to 300 mg twice daily until symptoms improve. Then the treatment may be resumed at a dose of 600 mg twice daily. Dose reduction below 300 mg twice daily is not recommended
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10. study assessments and evaluations

All patients should visit the study center on the days and windows specified within this protocol. The complete Schedule of Assessments for this study is shown in Appendix C, page 94. Visits may be split over multiple days if needed and may be conducted via remote visits (non-clinic) or via telemedicine visits as needed to facilitate visit completion and infection control (e.g. limit COVID-19 exposure).
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screening assessments that can be

- CT scan of the chest, abdomen and pelvis (preferred modality) given with IV contrast unless contraindicated. An MRI may be used in place of a CT scan. The same modality must be used throughout the study.  
- MRI or CT scan of the brain, if indicated by clinical symptoms, ≤4 weeks prior to randomization
- Begin prescription/insurance process for obtaining commercial Enzalutamide (for all subjects, in case RT1 is Enzalutamide)
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screening assessments that can be

- Physical examination - Demographics
- ECOG performance status (see Appendix A), page 77.  
- Vital signs measurements of height (first visit only), weight, resting heart rate, blood pressure, respiratory rate, and temperature)
- Concomitant medication review - all ongoing medications. - Prior anticancer/relevant medication and procedure history review- including history of androgen deprivation therapy, orchiectomy, radical prostatectomy, history of prior bisphosphonate/ denosumab use, vitamin D, calcium, anticancer medications, and exclusionary medications.  
- Cognitive Assessments Practice (Battery of CANTAB Cognitive Function Tests) - ePRO Assessments (FACT-P, FACT-COG)
- 12-lead ECG
- Screening bone fracture risk assessment: This includes a history of prior fractures, comorbidities, prior bone density assessment (particularly the most recent bone density assessment prior to screening).  
- Past and ongoing medical history Screening assessments that can be done up to ≤14 **days prior to Lead-in RT1:**
- CBC: including hemoglobin, hematocrit, white blood cell (WBC) with 3-part differential, and platelets
- CMP: including glucose, blood urea nitrogen (BUN), creatinine, estimated creatinine clearance (Cockcroft-Gault), sodium, potassium, chloride, calcium, carbon dioxide
(CO2), aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, total protein, and albumin.  
- ALP and LDH
- PSA
- Research biomarkers, with optional patient consent
- If not already taking, start treatment with bone health agent if not contraindicated.  
- Eligibility review If all I/E are met (except inclusion criteria **12-15), subject may proceed to Randomization** (R1). PCWG3 read of Screening Bone scan will be performed for all subjects that get randomized to R2, so that 2+2 rule can be evaluated.
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10.3 lead-in rt1 (enzalutamide or

- Lead-In RT1/: Day 1 only, prior to first dose of RT1
- ePRO Assessments (FACT-P, FACT-COG) - ECOG performance status
- TUG (timed up and go)
- Cognitive Assessments (Battery of CANTAB Cognitive Function Tests)
- Enzalutamide or Darolutamide Estimated Compliance (RT1 Days 28, 56, and 84 only)
- All RT1 visits (Day 1, Day 28, Day 56, and Day 84)
- Darolutamide Dispensation (if applicable) - Darolutamide Accountability (if applicable) - PSA blood sample will be collected at least every 4 weeks (+/- 7 days) - Adverse event evaluation - Assessment of bone fractures (AESIs) and SSEs
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10.4 pre-r2 assessments at 12-16

- Abbreviated Physical Exam
- Vital signs: weight, resting heart rate, blood pressure, respiratory rate, and temperature.  
- ECOG performance status
- ePRO Assessments (FACT-P, FACT-COG)
- Cognitive Assessments (Battery of CANTAB Cognitive Function Tests) - TUG (timed up and go) - 12-lead ECG - Adverse event (AE) assessment
- Concomitant medication review - CBC including hemoglobin, hematocrit, WBC with 3-part differential and platelets
- CMP including glucose, BUN, creatinine, estimated creatinine clearance (CockcroftGault), sodium, potassium, chloride, calcium, CO2, AST, ALT, total bilirubin, total protein, and albumin.  
- ALP and LDH - PSA
- Research biomarkers, with optional patient consent - Assessment of bone fractures (AESIs) and SSEs
- Review of other anti-cancer therapies - Bone fracture assessment
- SSE evaluation
- Enzalutamide or Darolutamide Estimated Compliance - Darolutamide Dispensation (if applicable)
- Darolutamide Accountability (if applicable)
NOTE:
- A CT or MRI and Bone scan should only be done for subjects that meet inclusion criterion 12. After imaging results are available, subjects should continue to be reviewed for inclusion 13-15.  
- RECIST/PCWG3 assessments associated with the Pre-R2 CT or MRI and Bone scans must be done for patients that meet (all) Inc/Exc. (including inclusion criteria 12-15) and randomize to R2.