Randomized Phase II Trial of Niraparib With Standard Combination Radiotherapy and Androgen Deprivation Therapy (ADT) in High Risk Prostate Cancer (With Initial Phase I) (NADIR*) *Randomized Phase II Trial of Niraparib With Standard Combination Androgen DeprIvation Therapy (ADT) and Radiotherapy in High Risk Prostate Cancer (With Initial Phase I)
Phase: PHASE1
Conditions: Prostate Adenocarcinoma, Stage IIC Prostate Cancer AJCC v8, Stage III Prostate Cancer AJCC v8, Stage IIIA Prostate Cancer AJCC v8, Stage IIIB Prostate Cancer AJCC v8, Stage IIIC Prostate Cancer AJCC v8, Stage IVA Prostate Cancer AJCC v8
Sponsor: NRG Oncology

NRG ONCOLOGY 
NRG-GU007 
(ClinicalTrials.gov NCT #: 04037254) 
PHASE III RANDOMIZED STUDY OF CONCURRENT CHEMOTHERAPY AND 
PELVIC RADIATION THERAPY WITH OR WITHOUT ADJUVANT 
CHEMOTHERAPY IN HIGH-RISK PATIENTS WITH EARLY-STAGE CERVICAL 
CARCINOMA FOLLOWING RADICAL HYSTERECTOMY 
Amendment 4: May 24, 2022 
 

NRG-GU007 
 
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NRG ONCOLOGY  
 
NRG-GU007  
(ClinicalTrials.gov NCT #04037254) (07-APR-2020) 
 
 
RANDOMIZED PHASE II TRIAL OF NIRAPARIB WITH STANDARD 
COMBINATION RADIOTHERAPY AND ANDROGEN DEPRIVATION THERAPY 
(ADT) IN HIGH RISK PROSTATE CANCER (WITH INITIAL PHASE I) (NADIR*) 
*Randomized Phase II Trial of Niraparib With Standard Combination Androgen DeprIvation 
Therapy (ADT) and Radiotherapy In High Risk Prostate Cancer (With Initial Phase I)             
 
This trial is part of the National Clinical Trials Network (NCTN) program, which is sponsored 
by the National Cancer Institute (NCI). The trial will be led by NRG Oncology with the 
participation of the network of NCTN organizations: the Alliance for Clinical Trials in 
Oncology; ECOG-ACRIN Medical Group; and SWOG. 
 
Coordinating Center:  
NRG Oncology 
Four Penn Center; 1600 JFK Blvd; Suite 1020; Philadelphia, PA 19103 
 
Study Team (24-MAY-2022) 
Principal Investigator/ Medical Oncology 
Dror Michaelson, MD, PhD 
Massachusetts General Hospital 
55 Fruit Street, Yaw 7E  
Boston, MA 02114 
617-726-1594/FAX 617-726-3440 
DMichaelson1@mgh.harvard.edu 
 
Translational Science Co-Chair 
Phuoc T. Tran, MD, PhD 
University of Maryland School of Medicine 
850 W. Baltimore Street 
Baltimore MD 21201 
410-369-5233/FAX 410-347-0870 
phuoc.tran@som.umaryland.edu   
 
Statistician 
Theodore Karrison, PhD  
University of Chicago and NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
773-702-9326 
karrisont@nrgoncology.org 
 
Radiation Oncology Co-Chair 
Zachary Zumsteg, MD 
Samuel Oschin Comprehensive Cancer Center 
8700 Beverly Blvd, AC1004 
Los Angeles, CA 90048 
310-423-2523/FAX 310-423-6161  
zachary.zumsteg@cshs.org 
 
Medical Physics Co-Chair 
Rajat Kudchadker, PhD 
Department of Radiation Physics 
1400 Pressler St. Unit 1420 
University of Texas MD Anderson Cancer 
Center 
Houston, TX 77030-3722 
713-563-2538/FAX 713-563-6949 
rkudchad@mdanderson.org 
 

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STUDY CHAMPIONS 
SWOG Champion 
David VanderWeele, MD, PhD 
Northwestern University 
Chicago, IL 
312-926-2413 
david.vanderweele@northwestern.edu   
 
 
 
NRG Oncology Contact Information (24-MAY-2022) 
Data Management 
For questions concerning eligibility or 
data submission 
Margaret Kennish 
Jennifer Petrask, BS, LPN 
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
215-574-3909; petraskj@nrgoncology.org 
215-574-3240; kennishm@nrgoncology.org 
RTQA 
For questions concerning RT data 
submission 
 
Joanne Hunter, BS, RT(T)(R) 
IROC Philadelphia-RT QA Center 
ACR Clinical Research Center 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
215-574-3222 
hunterj@nrgoncology.org 
RT Credentialing 
 
http://irochouston.mdanderson.org 
OR 
IROC-Credentialing@mdanderson.org 
RT data submission to TRIAD 
Triad-Support@acr.org 
Protocol Development: 
For questions concerning protocol and 
informed consent versions & 
amendments 
Carol Lam 
NRG Oncology, 50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
215-717-0848 
lamc@nrgoncology.org 
Genitourinary Committee Chair 
Felix Feng, MD 
University of California, San Francisco  
1825 4th Street, First Floor, Rm M2267 
San Francisco, CA 94143 
415-353-7183/FAX 415-353-7182 
felix.feng@ucsf.edu 
 
 
 
 
 
 
 

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Protocol Agent 
Agent 
Supply 
NSC # 
IND # 
IND Sponsor 
Niraparib 
Janssen 
804335 
Exempt 
 
 
 
NRG Oncology 
GnRH Agonist: 
leuprolide, 
goserelin, 
buserelin, 
triptorelin 
Commercial 
N/A 
 
 
Participating Sites 
 U.S. 
 Canada 
 Approved International Member Sites 
 
 
Document History 
 
Version Date 
Amendment 4 
May 24, 2022 
Amendment 3 
November 09, 2020 
Amendment 2 
April 07, 2020 
Amendment 1 
June 18, 2019 
Initial 
April 30, 2019 
 
 
 
 
  
 
 
This protocol was designed and developed by NRG Oncology. It is intended 
to be used only in conjunction with institution-specific IRB approval for 
study entry.  No other use or reproduction is authorized by NRG Oncology 
nor does NRG Oncology assume any responsibility for unauthorized use of 
this protocol. 

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NRG ONCOLOGY 
 
NRG-GU007 
 
Randomized Phase II Trial of Niraparib with Standard Combination Radiotherapy and 
Androgen Deprivation Therapy (ADT) in High Risk Prostate Cancer  
(With Initial Phase I) 
 
CONTACT INFORMATION:  (24-MAY-2022) 
For regulatory requirements: 
For patient enrollments: 
For data submission: 
Regulatory documentation must 
be submitted to the Cancer 
Trials Support Unit (CTSU) via 
the Regulatory Submission 
Portal. 
Regulatory Submission Portal: 
(Sign in at 
https://www.ctsu.org, and select 
Regulatory > Submission.)  
 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately by phone or email: 
1-866-651-CTSU (2878), or 
CTSURegHelp@coccg.org to 
receive further instruction and 
support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-CTSU 
(2878) for regulatory assistance. 
Please refer to the patient 
enrollment section of the protocol 
for instructions on using the 
Oncology Patient Enrollment 
Network (OPEN) which is 
accessed at 
https://www.ctsu.org/OPEN_SYS
TEM/ or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN-related questions 
by phone or email : 1-888-823-
5923, or at 
ctsucontact@westat.com. 
 
 
Data collection for this study 
will be done exclusively through 
Medidata Rave.  Refer to the 
data submission section of the 
protocol for further instructions.  
 
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific page located on the CTSU members’ website (https://www.ctsu.org).  Access 
to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program - 
Identity and Access Management (CTEP-IAM) registration system and requires user log in with a 
CTEP-IAM username and password.  
For clinical questions (i.e. patient eligibility or treatment-related), contact the Study Data Manager 
of the Lead Protocol Organization 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
 
 
 

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TABLE OF CONTENTS  
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SCHEMA .........................................................................................................................................7 
1. OBJECTIVES ..............................................................................................................................9 
1.1 
Primary Objective ....................................................................................................9 
1.2 
Secondary Objectives ...............................................................................................9 
1.3 
Exploratory Objective ..............................................................................................9 
2. BACKGROUND .........................................................................................................................9 
2.1 
Rationale ..................................................................................................................9 
2.2 
Why This Trial Is Important ..................................................................................10 
2.3 
Pertinent Data .........................................................................................................10 
3. PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILITY CRITERIA ........................12 
3.1 
Patient Selection Guidelines ..................................................................................12 
3.2 
Eligibility Criteria ..................................................................................................13 
3.3 
Ineligibility Criteria ...............................................................................................14 
4. REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP ..................16 
5. TREATMENT PLAN/Regimen description..............................................................................19 
5.1 
Systemic Therapy ...................................................................................................21 
5.2 
Radiation Therapy ..................................................................................................22 
5.3 
General Concomitant Medication and Supportive Care Guidelines ......................32 
5.4 
Duration of Therapy ...............................................................................................33 
6. TREATMENT MODIFICATIONS/MANAGEMENT .............................................................33 
6.1 
Dose Modifications for GnRH Agonists (Leuprolide, Goserelin, Buserelin, 
Triptorelin) .............................................................................................................33 
6.2 
Dose Modifications for Niraparib ..........................................................................33 
7. 
ADVERSE EVENTS REPORTING REQUIREMENTS .................................................37 
7.1       Protocol Agents ......................................................................................................37 
7.2       Adverse Events and Serious Adverse Events ........................................................37 
7.3 
Adverse Events for Investigational Study Agent Provided by Janssen .................38 
7.4 
Adverse Events for Commercial Study Agents .....................................................40 
7.5 
Expedited Reporting of Adverse Events ................................................................40 
7.6 
Routine Reporting Requirements for Adverse Events ...........................................44 
7.7 
Pregnancy ...............................................................................................................44 
8. REGISTRATION AND STUDY ENTRY PROCEDURES   ...................................................45 
8.1 
Cancer Trials Support Unit Registration Procedures   ...........................................46 

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8.2 
RT-Specific Pre-Registration Requirements   ........................................................50 
8.3       Patient Enrollment .................................................................................................51 
9. 
DRUG INFORMATION ...................................................................................................52 
9.1  
Commercial Agents: GnRH Agonists (leuprolide, goserelin, buserelin, 
triptorelin) ..............................................................................................................52 
9.2 
Investigational Study Agent: Niraparib (IND exempt) ..........................................52 
10. Pathology/Biospecimen ...........................................................................................................55 
10.1 
Biospecimen Submission Tables ...........................................................................55 
11. Special Studies (Non-Tissue) ...................................................................................................58 
12. Modality Reviews ....................................................................................................................58 
12.1    Radiation Therapy Quality Assurance Reviews .....................................................58 
12.2    Medical Oncology Modality Quality Assurance Reviews ......................................59 
13. DATA AND RECORDS .........................................................................................................59 
13.1 
Data Management/Collection ................................................................................59 
13.2 
Summary of Data Submission  ..............................................................................60 
13.3 
Data Quality Portal  ...............................................................................................61 
13.4 
Global Reporting/Monitoring ................................................................................61 
14. STATISTICAL CONSIDERATIONS ....................................................................................61 
14.1 
Study Design ..........................................................................................................61 
14.2 
Study Endpoints .....................................................................................................65 
14.3 
Primary Objectives Study Design ..........................................................................66 
14.4 
Study Monitoring of Primary Objectives ...............................................................67 
14.5 
Accrual/Study Duration Considerations ................................................................67 
14.6 
Dose Level Guidelines ...........................................................................................67 
14.7 
Secondary Analyses ...............................................................................................68 
14.8 
Exploratory Hypothesis and Endpoints .................................................................68 
14.9 
Gender/Ethnicity/Race Distribution .......................................................................69 
REFERENCES ..............................................................................................................................71 
APPENDIX I .................................................................................................................................75 
APPENDIX II (07-APR-2020) ......................................................................................................77 
APPENDIX III ...............................................................................................................................78 
 
 
 

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NRG-GU007 
SCHEMA 
 
PHASE I SCHEMA 
Histologically confirmed adenocarcinoma of prostate at high risk for recurrence determined by 
Gleason score (Gleason ≥ 9, PSA ≤ 150 ng/mL, any T-stage) 
 
↓ 
GnRH agonist androgen suppression therapy*  
+ 
Niraparib** 
+ 
Dose Escalated IMRT 
*GnRH agonist androgen suppression therapy is not allowed prior to registration in Phase I. 
**See Dose Level chart in Section 5.1. 
 
 

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PHASE II SCHEMA 
 
Histologically confirmed adenocarcinoma of prostate at high risk for recurrence determined by 
Gleason score 
↓ 
STRATIFICATION  
 
Gleason Score: 
 
Gleason ≥ 9, PSA ≤ 150 ng/mL, any T-stage 
 
Gleason 8, PSA < 20 ng/mL, and ≥ T2 
 
Gleason 8, PSA ≥ 20-150 ng/mL, any T-stage 
 
Gleason 7, PSA ≥ 20-150 ng/mL, any T-stage  
 
RT: Standard fractionation vs. hypofractionation 
 
RANDOMIZE (1:1) 
↓ 
↓ 
Arm 1*  
GnRH Agonist Androgen Suppression 
Therapy 
+ 
Dose Escalated IMRT 
 
 
Arm 2* 
GnRH Agonist Androgen Suppression 
Therapy 
+ 
Dose Escalated IMRT 
+ 
Niraparib** 
*See Section 5.1 for drug treatment details and Section 5.2 for radiation therapy details. GnRH 
agonist androgen suppression therapy can begin prior to registration in Phase II 
**Dosing per Phase I results  
 

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1. OBJECTIVES 
1.1 
Primary Objective 
1.1.1 Phase I: To establish the preferred dose of niraparib in combination with radiation and 
ADT 
1.1.2 Phase IIR: To compare the disease-free state, defined as PSA remaining < 0.1 ng/ml at 
the end of ADT therapy in men with high risk prostate cancer treated with standard 
therapy with or without the addition of niraparib 
 
1.2 
Secondary Objectives 
1.2.1 To further establish the safety and toxicity profile of standard treatment with radiation 
and androgen deprivation therapy specifically, two years from initiation of ADT, plus 
niraparib at the phase II dose 
1.2.2 To compare the overall survival, prostate cancer-specific survival, local/regional or 
distant progression, and distant metastatic disease rates of standard therapy with or 
without the addition of niraparib. Although the clinical benefit of niraparib in 
combination with radiotherapy and ADT has not yet been established, the intent of 
offering this treatment is to provide a possible therapeutic benefit, and thus the patient 
will be carefully monitored for tumor response and symptom relief in addition to dose, 
safety and tolerability. 
 
1.3 
Exploratory Objective 
1.3.1 To identify genomic biomarkers of response to combination therapy with radiation, ADT 
and PARP inhibition 
 
2. BACKGROUND 
2.1 
Rationale 
High level evidence has established the use of long-term ADT with radiation therapy as 
standard of care for men with locally advanced prostate cancer.  However, in men with 
the highest recurrence rates, the failure rate may exceed 50%, and a substantial number of 
men will still progress to life threatening complications from prostate cancer.   
 
The control arm in this study will consist of involved field radiation therapy plus standard 
long-term ADT for 24 months. Prior studies have demonstrated that PSA nadir is a strong 
predictor of outcome in men treated with standard therapy (D'Amico 2012; Zelefsky 
2013).  PSA nadir values of > 0.5 ng/ml were associated with higher rates of disease-
specific and all-cause  mortality among men treated with radiation with or without short-
term ADT ( D'Amico 2012).  In another study, among men treated with ADT, failure to 
achieve PSA < 0.3 ng/ml was highly prognostic for death related to prostate cancer 
(Zelefsky 2013).  Thus, PSA nadir appears to be a surrogate for survival related to 
prostate cancer and may be considered as an intermediate marker for assessing the 
efficacy of novel agents in this disease context. Here, we further require that men sustain 
very low PSA until the end of the 2-year post-ADT therapy interval, in order to identify 
those likely to be in a ‘disease-free’ state. 
 
The initial experimental arm in this study will add the potent PARP inhibitor, niraparib, 

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to standard therapy in men with high risk prostate cancer. 
 
2.2 
Why This Trial Is Important 
With current standard of care therapy, a substantial percentage of men with high risk, 
localized prostate cancer will ultimately progress to metastatic disease despite maximal 
treatment. The aim of our study is to identify additional therapeutic interventions that will 
improve outcomes in this patient population. The design of this trial will utilize the 
intermediate endpoint of PSA nadir to assess whether the addition of the PARP inhibitor 
niraparib appears promising.  Our intent would be to rapidly advance a promising 
systemic agent to definitive phase 3 testing.  Positive phase 3 results would alter standard 
of care treatment for high risk localized prostate cancer. 
 
2.3 
Pertinent Data 
Neoadjuvant/concomitant/adjuvant androgen deprivation therapy (ADT) with a long 
acting GnRH agonist improves survival when added to primary radiation therapy for men 
with prostate cancer at high risk for relapse. Three notable studies have established the 
role of long term ADT with a GnRH agonist. An EORTC trial enrolled 415 subjects with 
locally advanced disease and showed a 16% overall survival benefit with three years of 
ADT (78% vs. 62% survival at five years, p = 0.001) (Bolla 1997). RTOG 85-31 enrolled 
977 patients and demonstrated a non-significant 4% overall survival benefit (75% vs. 
71%, p = 0.52) at five years (Pilepich 1997) and a significant 10% overall survival 
benefit at 10 years (49% vs. 39%, p = 0.002) with the addition of indefinite ADT 
(Pilepich 2005). A subsequent EORTC trial was designed to demonstrate equivalence of 
6 months and 3 years of ADT but instead showed a significant 5 year overall survival 
advantage for the longer term ADT group (15% vs. 19% mortality) (Pilepich 1997). 
 
As a result of these studies, high level evidence strongly supports the use of long-term 
ADT with radiation therapy as standard of care for men with locally advanced prostate 
cancer.  However, not all men are at similar risk of adverse outcome.  Therefore, risk 
stratification is crucial in determining appropriate treatment for men with localized 
prostate cancer (Albertsen 2005; Chism 2004; D'Amico 2002; Pisansky 1997; Symon 
2003). Prognostic factors include clinical stage, Gleason score, and the level of PSA 
(Albertsen 2005; Chism 2004; D'Amico 2002; Pisansky 1997; Symon 2003).  In men 
with the highest recurrence rates, the failure rate with regard to PSA relapse is 40% to 
65% (Albertsen 2005; Chism 2004; D'Amico 2002; Pisansky 1997; Symon 2003). 
Despite the addition of ADT to radiation therapy, a substantial subset of these men may 
progress to life threatening complications related to prostate cancer.  Additional 
treatments at the time of definitive therapy may prevent subsequent relapse and 
progression. 
 
When studied in the neoadjuvant setting with prostatectomy, standard ADT alone is not 
associated with improvement in PSA failure rate (Fair 1997; Klotz 1999; Meyer 1999). 
Pathologic complete responses are rarely observed in response to standard ADT.  To 
explain this lack of efficacy, a leading hypothesis suggests that GnRH agonist therapy 
alone does not adequately suppress prostate tissue androgens (Mostaghel 2014). 
Consequently, preliminary studies have studied more intensive androgen blockade.  

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Abiraterone acetate, a CYP17 (cytochrome P450 c17) inhibitor, reduces all sources of 
serum androgens to undetectable or near undetectable levels.  Taplin and colleagues 
demonstrated that in prostate tissue as well, levels of androgens were significantly lower 
with GnRH agonist therapy plus abiraterone than with GnRH agonist therapy alone 
(Taplin 2014).   
 
Despite the lack of benefit with the combination of ADT and radical prostatectomy, there 
is clear demonstration of improved survival when ADT is combined with radiation.  In 
part this may be explained by the demonstration that androgen signaling increases 
prostate cancer specific DNA repair, while androgen suppression inhibits DNA repair and 
renders prostate cancer cells preferentially more sensitive to radiation induced damage 
and cell death ( Goodwin 2013; Polkinghorn 2013).   
 
There is great interest in targeting DNA repair mechanisms in tumor cells.  Normal 
cellular physiology is characterized by elaborate DNA repair mechanisms for both single 
and double stranded DNA breaks.  Single stranded breaks in DNA are addressed by 
nucleotide excision, base excision and mismatch excision repair.  The nuclear enzyme 
PARP (poly ADP-ribose polymerase) efficiently recognizes, and subsequently facilitates 
repair of, single stranded DNA breaks.  A number of other proteins, including BRCA1, 
BRCA2 and ATM, are integral components of double-stranded DNA repair pathways.  
When the pathways for both single stranded and double stranded repair are 
simultaneously disrupted, the impact on cells may be profound.  This notion of synthetic 
lethality has most directly been verified in breast and ovarian tumors that are BRCA 
deficient, and which manifest particular sensitivity to PARP inhibition (O'Connor 2015; 
Yap 2011).  Following clinical trials that confirmed efficacy, the PARP inhibitor olaparib 
was FDA-approved in 2014 for women with BRCA-deficient ovarian cancer.  Niraparib 
was approved in 2017 for maintenance treatment of ovarian cancer following response to 
platinum-based chemotherapy.  Several other potent PARP inhibitors are in late stages of 
clinical development, including talazoparib (BMN-673; Medivation, San Francisco, CA, 
USA), veliparib (ABT-888; Abbvie, North Chicago, IL, USA), and rucaparib 
(AGO14699; Clovis, Boulder, CO, USA), in a variety of malignancies. 
 
The potential role of PARP inhibition in prostate cancer was introduced in a landmark 
study in 50 patients with advanced metastatic prostate cancer (Mateo 2015).  In total, 
approximately one third of men responded to therapy with olaparib, but much more 
striking was the finding that among 16 men with deficiencies in DNA repair pathways 
(including deletions and/or deleterious mutations in BRCA1, BRCA2, ATM, Fanconi’s 
anemia genes, and/or CHEK2), 88% responded to therapy.  Two important conclusions 
from this study were that: 1) a substantial percentage of men with advanced prostate 
cancer, perhaps up to 25%-30%, may have either germline or sporadic mutations in DNA 
repair pathway genes within the tumors; and 2) these patients have a remarkably 
favorable response rate to PARP inhibition.  The great excitement generated by this study 
has led to rapid development of late stage clinical trials of various PARP inhibitors in 
advanced prostate cancer. 
 
The role of PARP inhibition has not been investigated in the treatment of localized 

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prostate cancer.  There is a particularly compelling rationale for combining PARP 
inhibition with radiation therapy and ADT in prostate cancer. In preclinical models, 
PARP inhibitors improve efficacy of radiation therapy by blocking DNA repair 
mechanisms (Brock 2004; Chalmers 2004).  Various animal models have confirmed these 
results, such as the HCT-116 colon cancer xenograft model, in which the addition of 
veliparib to radiation, compared with radiation alone, nearly doubled median survival 
while veliparib alone had no demonstrable activity (Donawho 2007).  Whereas efficacy 
of PARP inhibitors alone may require innate DNA repair deficiencies within tumors, the 
efficacy of PARP inhibitors when combined with radiation may not, but this has yet to be 
explored comprehensively.  The best data to suggest that biomarkers of response to 
radiation and PARP1 inhibition will differ from biomarkers of response to PARP1 
inhibition alone is from preclinical studies in breast cancer (Chalmers 2004).  Across a 
large panel of cell lines, members of our team demonstrated that treatment with a PARP1 
inhibitor radiosensitized the majority of breast cancer cell lines independent of BRCA 
mutation status, suggesting that determinants of synthetic lethality to monotherapy with 
PARP1 inhibitor were not effective predictors of response to combination therapy with 
radiation plus a PARP1 inhibitor.  Finally, ADT may induce a conditional synthetic lethal 
phenotype with PARP inhibition in hormone naïve prostate cancers where DNA damage 
could then further be augmented by radiation therapy. 
 
In this trial, we propose to study the combination of niraparib with standard radiation and 
ADT in men with high risk prostate cancer.  A phase I component will be utilized to 
establish the preferred dose of niraparib in combination with radiation and ADT. Given 
that the purpose of the phase I component is to establish safety and the maximum 
tolerated dose of niraparib in combination with radiation and ADT, the phase I 
component will enroll only patients with Gleason 9-10 disease, the subgroup with the 
highest risk of recurrence and cancer-specific mortality in RTOG 0521 (unpublished 
NRG Oncology data). After safety and a maximum tolerated dose have been established, 
a  randomized phase II will then compare clinical outcomes with standard radiation and 
ADT with and without niraparib in a broader group of high-risk prostate cancer patients.  
Additionally, we will profile tumor and blood samples from these patients, and determine 
predictors of treatment response.  Specifically, somatic DNA damage repair status will be 
determined at the initiation of therapy.  We hypothesize that PARP inhibition added to 
radiation and ADT for high risk prostate cancer will improve outcomes relative to 
standard therapy with radiation and ADT. 
 
 
3. PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILITY CRITERIA 
 
 
Note: Per NCI guidelines, exceptions to inclusion and exclusion criteria are not 
permitted.  For questions concerning eligibility, please contact the Biostatistical/Data 
Management Center (see protocol cover page). For radiation therapy-related eligibility 
questions, please contact RTQA (see protocol cover page).  
 
3.1 
Patient Selection Guidelines 
Although the guidelines provided below are not inclusion/exclusion criteria, investigators 

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should consider these factors when selecting patients for this trial. Investigators also 
should consider all other relevant factors (medical and non-medical), as well as the risks 
and benefits of the study therapy, when deciding if a patient is an appropriate candidate 
for this trial. 
3.1.1 Patients must have the psychological ability and general health that permits completion of 
the study requirements and required follow up. 
3.1.2 Submission of tumor tissue is required for all patients. Investigators should check with 
their site Pathology department regarding release of biospecimens before approaching 
patients about participation in the trial. (See Section 10 for details.)  
 
3.2 
Eligibility Criteria (24-MAY-2022) 
A patient cannot be considered eligible for this study unless ALL of the following 
conditions are met. 
3.2.1 Histologically confirmed (within 180 days prior to registration) adenocarcinoma of the 
prostate at high risk for recurrence as determined by the following criteria, according to 
AJCC 8th edition:  
Phase I enrollment 
 Gleason ≥ 9, PSA ≤ 150 ng/mL, any T-stage 
 
Phase II enrollment 
 Gleason ≥ 9, PSA ≤ 150 ng/mL, any T-stage 
 Gleason 8, PSA < 20 ng/mL, and ≥ T2 
 Gleason 8, PSA ≥ 20-150 ng/mL, any T-stage 
 Gleason 7, PSA ≥ 20-150 ng/mL, any T-stage 
3.2.2 No distant metastases as evaluated by: 
 Bone scan 90 days prior to registration;  
 Lymph node assessment by CT or MR of pelvis or nodal sampling within 90 days prior 
to registration (Please note: Lymph nodes will be considered negative (N0) if they are 
< 1.5 cm short axis). 
3.2.3 History/physical examination within 90 days prior to registration  
3.2.4 Age ≥ 18;  
3.2.5 ECOG performance status of 0 or 1 within 180 days prior to registration; 
3.2.6 Pretreatment serum PSA, obtained prior to any androgen suppression therapy and within 
180 days of registration. 
3.2.7 Phase I patients: Prior androgen suppression for prostate cancer is not allowed prior to 
registration.   
Phase II patients: Prior androgen suppression for prostate cancer is allowed ≤ 45 days 
prior to registration.  
3.2.8  Adequate hematologic, renal, and hepatic function within 90 days prior to registration 
defined as follows: 
 Hemoglobin ≥ 9.0 g/dL 
 Platelets ≥ 100, 000 cells/mm3 
 ANC ≥ 1.5 X 109/L    

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 Serum creatinine ≤1.5 x upper limit of normal (ULN) OR a calculated creatinine 
clearance ≥30 mL/min estimated using the following Cockcroft-Gault equation: 
 
Creatinine Clearance (mL/min) = 
[140-Age (years)] x Weight (kg)    
                                          
 
72 x serum creatinine (mg/dL) 
 
 AST and ALT ≤3.0 x ULN  
 Serum albumin ≥3 g/dL 
 Serum potassium ≥3.5 mmol/L 
 Serum total bilirubin ≤1.5 × ULN or direct bilirubin ≤1 x ULN (Note: in subjects 
with Gilberts syndrome, if total bilirubin is >1.5 x ULN, measure direct and indirect 
bilirubin, and if direct bilirubin is ≤1.5 x ULN, subject may be eligible) 
3.2.9 Men of child-producing potential must be willing to consent to use effective 
contraception while on treatment and for at least 3 months afterwards. 
3.2.10 The patient or a legally authorized representative must provide study-specific informed 
consent prior to study entry. 
 
3.3 
Ineligibility Criteria (09-NOV-2020) 
Patients with any of the following conditions are NOT eligible for this study. 
3.3.1 PSA > 150 ng/mL 
3.3.2 Definitive clinical or radiologic evidence of metastatic disease 
3.3.3 Pathologically positive lymph nodes or nodes > 1.5 cm short axis on CT or MR imaging. 
3.3.4 Prior radical prostatectomy, cryosurgery for prostate cancer, or bilateral orchiectomy for 
any reason. 
3.3.5 Any active malignancy within 2 years of study registration that may alter the course of 
prostate cancer treatment.  
3.3.6 Prior systemic therapy for prostate cancer; note that prior therapy for a different cancer is 
allowable  
3.3.7 Prior radiotherapy, including brachytherapy, to the region of the prostate that would result 
in overlap of radiation therapy fields. 
3.3.8 Current treatment with first generation anti-androgens (bicalutamide, nilutamide, 
flutamide). For patients enrolled to phase II, if prior anti-androgens were administered, a 
washout period of > 30 days is required prior to enrollment. 
3.3.9 Severe, active co-morbidity, defined as follows:  
 Unstable angina and/or congestive heart failure requiring hospitalization within 
the last 6 months 
 Transmural myocardial infarction within the last 6 months 
 Acute bacterial or fungal infection requiring intravenous antibiotics at the time of 
registration 
 Uncontrolled Acquired Immune Deficiency Syndrome (AIDS) based upon current 
CDC definition 

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 Presence of uncontrolled hypertension (persistent systolic blood pressure [BP] 
≥160 mmHg or diastolic BP ≥100 mmHg). Subjects with a history of 
hypertension are allowed, provided that BP is controlled to within these limits by 
anti-hypertensive treatment. 
3.3.10 Prior allergic reaction to the drugs involved in this protocol (including known allergies, 
hypersensitivity or intolerance to the excipients of niraparib. Please see Niraparib IB for 
details.) 
3.3.11 HIV positive with CD4 count < 200 cells/microliter.  
 Note that patients who are HIV positive are eligible, provided they have a CD4 
count ≥ 200 cells/microliter within 90 days prior to registration. Patients receiving 
treatment with highly active antiretroviral therapy (HAART) will not be eligible 
due to concern for radiosensitization. 
 Note also that HIV testing is not required for eligibility for this protocol. This 
exclusion criterion is necessary because the treatments involved in this protocol 
may be affected by these drugs. 
3.3.12  Any history or current diagnosis of MDS/AML. 
 
3.3.13 Prior or current treatment with PARP inhibitor. 
 
 

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4. REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP  
(09-NOV-2020) 
 
PRE-TREATMENT ASSESSMENTS  
 
Assessment 
Prior to registration 
Prior to treatment 
Biopsy with Gleason score 
≤ 180 days 
 
Nodal staging per pelvic CT or MR 
or nodal sampling/dissection   
≤ 90 days 
 
H&P, vital signs (heart rate, blood 
pressure) 
≤ 90 days 
 
Bone scan 
≤ 90 days 
 
ECOG performance status 
≤ 180 days 
 
Serum PSA (prior to GnRH agonist 
therapy) 
≤ 180 days 
 
CBC with diff (to include ANC, 
plt, Hgb)  
≤ 90 days 
 
CMP (to include AST, ALT, total 
bilirubin, albumin, creatinine, 
potassium) 
≤ 90 days 
 
Concomitant Medications 
At baseline any time prior to 
registration 
 
For DDR sub-study  
 H&E stained slide from 
primary tumor 
 FFPE block from primary 
tumor 
 
Obtained pre-treatment 
and submitted per 
Section 10.1 
For WGS-SNPs sub-study  
 Whole blood for DNA 
 
Obtained pre-treatment 
and submitted per 
Section 10.1 
For banking for future research (for 
pts who consent to biobanking) 
 Serum 
 Plasma 
 Urine 
 
Ph I pts and Ph II pts 
randomized to 
niraparib: Prior to 
niraparib start 
Ph II pts not 
randomized to 
niraparib: 8 weeks prior 
RT start 
 
 

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ASSESSMENTS DURING TREATMENT-Phase I 
 
Assessment 
Prior to 
RT Start 
Months 1, 2, 
3, 4, 5, 6, 9, 12 
 
Months 15, 18, 
21, 24  
 
At Month 24 
History/physical/ 
performance status/vital 
signs(heart rate, blood 
pressure) 
Vital signs should be 
documented in patient 
chart and reported as AEs 
if appropriate. 
 
X*** 
X 
 
Disease Assessment 
 
 X* 
X 
 
PSA 
 
 X* 
X 
 
CMP (to include AST, 
ALT, total bilirubin, 
albumin, creatinine, 
potassium) 
 
X 
As clinically 
indicated 
 
CBC (to include ANC, 
plt, Hgb) 
 
X** 
As clinically 
indicated 
 
AE evaluation 
 
X 
X 
 
Prostate MRI  
X 
 
 
 
Prostate Biopsy 
 
 
 
Recommended 
*Disease assessments and PSA required at months 3, 6, 9, and 12 only 
**Obtain weekly during month 1 and then every two weeks for months 2 and 3 then monthly 
starting with month 4 
*** Monitor heart rate and blood pressure weekly for the first two months, then monthly until 
end of treatment. See Section 6.2 for details. 
 
 
 
 

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ASSESSMENTS DURING TREATMENT-Phase II 
 
 
 
Both ARMS 
ARM 2 
 
Assessment 
Prior to 
RT Start 
Months 3, 6, 9, 
12, 15, 18, 21, 
24 from start 
of GnRH 
Agonist 
Androgen 
Suppression 
Therapy 
During 
Niraparib:  
Months 1, 2, 3, 
4, 5, 6, 9, 12 of 
Niraparib 
treatment*  
At Month 24 
History/physical/ 
performance status/vital 
signs (heart rate, blood 
pressure) 
Vital signs should be 
documented in patient 
chart and reported as AEs 
if appropriate. 
 
X 
X*** 
 
Disease Assessment 
 
X 
 
 
PSA 
 
X 
 
 
CMP (to include AST, 
ALT, total bilirubin, 
albumin, creatinine, 
potassium) 
 
 
As clinically 
indicated 
X 
 
CBC (to include ANC, 
Plt, Hgb) 
 
 
As clinically 
indicated 
X** 
 
AE evaluation 
 
X 
X 
 
Prostate MRI  
X 
 
 
 
Prostate Biopsy 
 
 
 
Recommended 
*These times are relative to the start of niraparib 
**Obtain weekly during month 1 and then every two weeks for months 2 and 3 then monthly 
starting with month 4 
*** For patients randomized to niraparib arm, monitor heart rate and blood pressure weekly for 
the first two months, then monthly until end of treatment. See section 6.2 for details. 
 
 
 
 
 
 

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ASSESSMENT IN FOLLOW UP 
 
Assessments 
Beginning month 30: Q 6 months x 3 years, 
then annually for 3 years 
History/physical/PS 
X 
Disease assessment 
X 
PSA 
X 
AE evaluation 
X 
For banking for future research (for pts who 
consent to biobanking) 
 Serum 
 Plasma 
Within 7 days after completing niraparib (Phase 
I pts and Phase II, Arm 2 pts) or 12 months of 
ADT (Phase II, Arm 1 pts) and, if applicable, at 
recurrence.  See Section 10. 
 
 
Definition of Disease Assessments 
PSA examinations during and following treatment will be the primary method for assessing 
response to treatment.  Radiographic imaging, including bone scan and CT or MRI of the 
abdomen/pelvis, will be done at baseline and thereafter as clinically indicated. A prostate biopsy 
at 24 months following the initiation of ADT is strongly recommended for assessment of 
complete response. 
 
Treatment failure is the presence of one of the following:  
 Biochemical failure – defined by the Phoenix definition (PSA ≥ 2 ng/ml over the nadir 
PSA, the presence of local, regional, or distant recurrence 
 Local failure – defined as biopsy proven recurrence within the prostate gland 
 Regional or distant metastasis – defined as imaging or biopsy demonstrated evidence for 
regional or distant metastatic disease.  Biopsy is not required to define metastasis; 
however, in the absence of rising PSA, biopsy is strongly encouraged. 
 
5. TREATMENT PLAN/REGIMEN DESCRIPTION  
 
All study subjects will be treated with GnRH agonist androgen suppression therapy. 
GnRH agonist androgen suppression therapy will continue for 24 months. 
 
Phase I:  GnRH agonist androgen suppression therapy cannot begin prior to registration, 
and niraparib will begin at the same time as GnRH agonist androgen suppression therapy. 
Niraparib and GnRH agonist androgen suppression therapy must begin 8 weeks (+/-7 
days) prior to RT. Niraparib will be administered for 12 months. 
 
 
Phase I Dose Levels  
Dosing will begin at Level 1 and proceed according to the dose escalation algorithm 
described in Section 14.1.1. 

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Dose Level 
GnRH Agonist 
Suppression Therapy 
Dose 
Escalated 
IMRT* 
Niraparib 
1 
24 months 
70 Gy in 28 
fractions or 
79.2 Gy in 44 
fractions 
100 mg PO once daily for 
12 months beginning with 
GnRH agonist androgen 
suppression therapy 
(including during IMRT) 
2 
24 months 
70 Gy in 28 
fractions or 
79.2 Gy in 44 
fractions  
200 mg PO once daily 
beginning with GnRH 
agonist androgen 
suppression therapy.  During 
the weeks of IMRT, 
niraparib will be dosed at 
100 mg PO once daily. 
Following IMRT, niraparib 
will resume at 200 mg PO 
once daily, until a total of 12 
months of niraparib is 
completed 
3 
24 months 
70 Gy in 28 
fractions or 
79.2 Gy in 44 
fractions  
200 mg PO once daily for 
12 months beginning with 
GnRH agonist androgen 
suppression therapy 
(including during radiation) 
     0** 
24 months 
70 Gy in 28 
fractions or 
79.2 Gy in 44 
fractions 
100 mg PO once daily for 
12 months beginning with 
beginning with GnRH 
agonist androgen 
suppression therapy 
(EXCEPT during IMRT, 
when niraparib will NOT be 
administered) 
*Dose escalated radiation to prostate and pelvic lymph nodes delivered with IMRT with a 
boost to be provided with EBRT. 
**Dose Level 0 will be utilized if 2 or more DLTs are observed at Dose Level 1 and Dose 
Level 1 is closed; or provisionally if 1 DLT is observed at Dose Level 1, although Dose 
Level 1 may be re-opened pending further data. 
 
Phase II 
GnRH agonist androgen suppression therapy may be started prior to enrollment.  Dose-
escalated IMRT can begin anywhere from 56-115 days (-7 days) after initiation of GnRH 
agonist therapy androgen suppression therapy. 
Patients randomized to niraparib should receive niraparib for 8 weeks (+/- 7 days) prior to 
IMRT, and will continue niraparib for a total of 12 months. 
 

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If, for example, a patient has not yet begun GnRH agonist androgen suppression  therapy 
prior to enrollment, the patient may begin GnRH agonist androgen suppression therapy 
and niraparib together, and then start IMRT 8 weeks (+/- 7 days) later.  On the other 
hand, if a patient has already received GnRH agonist androgen suppression therapy and is 
then enrolled and randomized to begin niraparib 4 weeks after starting GnRH agonist 
androgen suppression therapy (for example), IMRT must begin 8 weeks (+/- 7 days) after 
starting niraparib and 12 weeks into GnRH agonist androgen suppression therapy.   
 
Summary of Treatment Start Times 
 
5.1 
Systemic Therapy (24-MAY-2022) 
5.1.1 Niraparib 
For the phase I regimen, niraparib will be administered per the table above. For the phase 
II regimen in Arm 2, the niraparib dose will be administered per the phase I results. 
Missed doses of niraparib, for any reason (including patient forgot, vomited, etc.) must 
not be made up and are to be counted as a missed dose.  Patients should continue to the 
next scheduled dose.   
 
5.1.2 GnRH Agonist Androgen Suppression Therapy 
GnRH agonist androgen suppression therapy (leuprolide, goserelin, buserelin, or 
triptorelin) will be administered for the phase I and II regimens. Agent selection is per 
treating physician discretion and will be administered per institutional standard and FDA-
approved labeling.  
Treatment 
Start Time 
GnRH Agonist Androgen 
Suppression Therapy 
Ph I: Same time as niraparib  
 
Ph II: Within 45 days of registration/randomization  
Niraparib 
Ph I: Same time as GnRH agonist androgen suppression 
therapy; both GnRH agonist and niraparib must begin 
within 7 days after registration and must start 56 (+/- 7) 
days prior to start of radiation 
 
Ph II, arm 2: Must begin within 7 (+/- 7) days after 
registration/randomization AND 56 (+/- 7) days prior to 
start of radiation  
Dose Escalated IMRT 
Ph I:  Must begin 56 (+/- 7 days) after initiation of GnRH 
and niraparib 
 
Ph II, arm 1:  Must begin within 56-115 days (- 7 days) 
after GnRH agonist androgen suppression therapy initiation 
 
Ph II, arm 2:   Must begin within 56-115 days (- 7 days) 
after GnRH agonist androgen suppression therapy initiation 
AND 
56 (+/- 7 days) after initiation of niraparib  

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5.2 
Radiation Therapy (09-NOV-2020) 
 
All patients will begin radiation 56-115 days (- 7 days) after the initiation of GnRH agonist 
therapy. Patients receiving niraparib will begin radiation therapy 56 days (+/- 7 days) after 
initiation of niraparib.  
 
All patients will be treated with intensity modulated radiation therapy (IMRT) to the prostate, 
seminal vesicles, and pelvic lymph nodes using daily image guidance. Treatment with a full 
bladder is strongly recommended in all patients. Physicians may elect to treat the prostate with 
either standard fractionation or hypofractionation. 
 
Patients receiving standard fraction will receive radiation delivering 45 Gy to the prostate, 
seminal vesicles, and pelvic lymph nodes  in 25 fractions, followed by a sequential prostate boost 
(+/- seminal vesicle treatment) to a total dose of 79.2 Gy in 44 total fractions (1.8 Gy/fraction). 
Patients receiving hypofractionation will receive radiation delivering 45 Gy pelvic lymph nodes 
(1.8 Gy/fraction) as above with a simultaneous integrated boost delivering 62.5 Gy to the 
prostate (+/- seminal vesicle treatment) in 25 fractions (2.5 Gy/fraction), followed by a 3 fraction 
sequential prostate boost (+/- seminal vesicle treatment) to a total dose of 70 Gy in 28 total 
fractions. 
 
A composite EBRT plan that includes both Phases 1 and 2 treatment plans must be generated and 
summed at the beginning of the patient’s treatment. 
 
 
For credentialing requirements, please refer to Section 8 of the protocol. 
 
5.2.1 Treatment Technology 
 
All patients are required to be treated with intensity modulated radiotherapy (IMRT) techniques, 
including volume modulated arc therapy (VMAT) and tomotherapy. RT should be delivered with 
megavoltage equipment at energies ≥6 MV and ≤15 MV. MRI-based linear accelerators that 
fulfill these criteria are allowed. For the fixed gantry angle IMRT technique, a minimum of five 
gantry angles and a maximum of nine gantry angles are recommended for each phase of 
treatment.  For the VMAT technique, a minimum of two arcs and a maximum of three arcs are 
recommended for each phase of treatment.. 
 
Daily image guidance with cone beam CT (CBCT), CT-on-rails, 2D-kV, 2D-MV, or MRI 
imaging is required. Fiducial markers placed in the prostate prior to simulation are preferred for 
all patients, and required for patient’s monitored with 2D-kV and 2D-MV image guidance. Intra-
fraction motion tracking, such as Calypso beacons, are not allowed given lack of compatibility 
for post-treatment MRI.  
 
 
 
 

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5.2.2 Immobilization and Simulation 
 
Simulation will be CT-based in all cases. The use of urethral contrast at the time of simulation is 
allowed but not required. Rectal contrast is discouraged because it may distend the rectum and 
artificially displace the prostate in the anterior direction. IV contrast is permitted to assist in 
identifying the pelvic vessels. Patients will be positioned supine on a flat tabletop with a 
customized thermoplastic immobilization cast or a molded foam cradle for stabilization and 
setup reproducibility. Simulation with a comfortably full bladder is strongly recommended 
for all patients able to maintain this state in order to minimize dose to the bowel and improve 
bladder dosimetry. The degree of bladder fullness should be made to duplicate the degree of 
fullness anticipated for daily treatment, i.e., if the patient is instructed to maintain a full bladder 
for treatment, he should be simulated as such. Typically this will require drinking 2-3 cups of 
water at least 30-45 minutes prior to simulation and all treatments. The rectum should be kept as 
empty as possible. An enema 1-2 hours prior to simulation is strongly recommended. CT images 
should be acquired at a slice thickness of ≤3 mm from the top of the iliac crests superiorly to the 
perineum inferiorly. Target volumes (Section 5.2.4) and normal critical structures (Section 5.2.4) 
will be defined in the slices in which they are visualized.  
 
In cases where fiducial markers are used, markers should be placed at least 5 days prior to 
simulation.  
 
If a rectal spacer will be used for treatment, it must be placed prior to simulation. If a patient will 
be treated with an endorectal balloon, the balloon should be present at simulation.  
 
5.2.3 Imaging for Structure Definition, Image Registration/Fusion and Follow-up 
 
Fusion with prostate or pelvis MRI is highly encouraged to aid in target delineation, particularly 
with respect to the prostate apex. If a rectal spacer is used, an MRI with the spacer in place is 
strongly recommended for fusion with the CT simulation in order to ensure adequate delineation 
of the spacer and rectum during treatment planning.  
 
5.2.4 Definition of Target Volumes and Margins 
 
Clinical and Planning Target Volumes 
 
Note: All structures must be named for digital RT data submission as listed in the table below.  
The structures marked as “Required” in the table must be contoured and submitted with the 
treatment plan. Structures marked as “Required when applicable” must be contoured and 
submitted when applicable. 
 
Resubmission of data may be required if labeling of structures does not conform to the standard 
DICOM name listed.  Capital letters, spacing and use of underscores must be applied exactly as 
indicated. 
 
 

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  Standard Fractionation 
 
Standard Name 
 
Description 
 
Validation 
Required/Required when 
applicable/Optional 
CTV_4500 
CTV to receive 45 Gy 
Required 
CTV_7920 
CTV to receive 79.2 Gy 
Required  
PTV_4500 
PTV to receive 45 Gy 
Required 
PTV_7920 
 
PTV to receive 79.2 Gy 
Required 
PTV_4500PRV10 
 
Volume defined to control 
intermediate dose spillage, ring 
from 0.1cm to 1.0 cm from 
PTV_4500 
 
Required  
PTV_7920PRV10 
 
Volume defined to control 
intermediate dose spillage, ring 
from 0.1cm to 1.0 cm from 
PTV_7920 
 
Required  
 
 
 
Hypofractionation 
 
Standard Name 
 
Description 
 
Validation 
Required/Required when 
applicable/Optional 
CTV_4500 
CTV to receive 45 Gy 
Required 
CTV_7000 
CTV to receive 70 Gy 
Required  
PTV_4500  
PTV to receive 45 Gy  
Required  
PTV_7000 
PTV to receive 70 Gy 
Required  
PTV_4500PRV10 
 
Volume defined to control 
intermediate dose spillage, ring 
from 0.1cm to 1.0 cm from 
PTV_4500 
 
Required  
PTV_7000PRV10 
 
Volume defined to control 
intermediate dose spillage, ring 
from 0.1cm to 1.0 cm from 
PTV_7000 
 
Required  
 

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Detailed Specifications  
Target volumes: The definitions of volumes will be in accordance with the 1999 
ICRUReport#62. 
 
CTV_4500: The CTV_4500 will include any portion of the seminal vesicle not included in a 
higher dose CTV, and the obturator, external iliac, proximal internal iliac and common iliac 
nodes, using the vascular structures, up to a level corresponding to the top of L4-L5. Please refer 
to the Pelvic Lymph Node Volumes for Prostate Cancer Atlas on the NRG Oncology Web site 
(https://www.nrgoncology.org/Portals/0/Scientific%20Program/CIRO/Atlases/Prostate%20Pelvi
c%20Lymph%20Nodes.ppt). The presacral nodes from L5-S1 to S3 may be included if desired 
depending on whether the dose constraints to the rectum are achievable (see Normal Structure 
Constraints and Compliance Criteria Table). The inferior extent of the external iliac lymph nodes 
is at the top of the femoral heads. The inferior extent of the obturator lymph nodes is at the top of 
the symphysis pubis. The CTV_4500 will include a 7 mm margin in 3-dimensions to the 
contoured iliac vessels, but not extend outside of the true pelvis, into adjacent bone, into the 
pelvic musculature, nor into adjacent identifiable organs, such as the bladder, rectum or other 
bowel.  
 
PTV_4500: The PTV_4500 margins should be a minimum of 5 mm and a maximum of 8 mm 
margin around CTV_4500 in all dimensions. Margins can either be uniform in all directions, or 
asymmetric within the 5-8 mm range. Using different margins for the part of CTV_4500 that 
covers the pelvic lymph nodes and the part of CTV_4500 that covers the prostate and seminal 
vesicles is allowed, as long as all margins are within a 5-8 mm range. Additionally, a margin as 
small as 3 mm can be used posteriorly near the rectum.  
 
CTV_7000: The CTV_7000 includes the entire prostate and proximal 1 cm of the seminal 
vesicles in all cases. In patients with known seminal vesicle invasion or at very high risk of 
seminal vesicle invasion, the CTV_7000 can include the entire prostate and seminal vesicles as 
long as rectal and bowel dose constraints can be met. This structure should be used for 
patients undergoing hypofractionation only.  
 
PTV_7000: The PTV_7000 will provide a margin around the CTV_7000 to compensate for the 
variability of treatment set up and internal organ motion. A range of 4-6 mm around the 
CTV_7000 can be utilized. Margins can either be uniform in all directions, or asymmetric. 
Individual selection of a PTV margin should be based on the institution’s level of confidence in 
patient set-up and the type of image guidance. A smaller margin of 3 mm is permitted posteriorly 
near the rectum. Careful consideration should be made when defining the margin in 3 
dimensions. This structure should be used for patients undergoing hypofractionation only. 
 
CTV_7920: The CTV_7920 includes the entire prostate and proximal 1 cm of the seminal 
vesicles in all cases. In patients with known seminal vesicle invasion or at very high risk of 
seminal vesicle invasion, the CTV_7920 can include the entire prostate and seminal vesicles as 
long as rectal and bowel dose constraints can be met. This structure should be used for 
patients undergoing standard fractionation only.  
 

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PTV_7920: The PTV_7920 will provide a margin around the CTV_7920 to compensate for the 
variability of treatment set up and internal organ motion. A range of 4-6 mm around the 
CTV_7920 can be utilized. Margins can either be uniform in all directions, or asymmetric. 
Individual selection of a PTV margin should be based on the institution’s level of confidence in 
patient set-up and the type of image guidance. A smaller margin of 3 mm is permitted posteriorly 
near the rectum. Careful consideration should be made when defining the margin in 3 
dimensions. This structure should be used for patients undergoing standard fractionation 
only. 
 
PTV_4500PRV10: This volume is ring structure including only the area in between a symmetric 
0.1cm expansion around PTV_4500 and a 1cm expansions around PTV_4500. 
 
PTV7000PRV10: This volume is ring structure including only the area in between a symmetric 
0.1cm expansion around PTV_7000 and a 1cm expansions around PTV_7000. This structure 
should be used for patients undergoing hypofractionation only. 
 
PTV7920PRV10: This volume is ring structure including only the area in between a symmetric 
0.1cm expansion around PTV_7920 and a 1cm expansions around PTV_7920. This structure 
should be used for patients undergoing standard fractionation only. 
 
Definition of Critical Structures and Margins 
Note: All structures must be named for digital RT data submission as listed in the table below.  
The structures marked as “Required” in the table must be contoured and submitted with the 
treatment plan. Structures marked as “Required when applicable” must be contoured and 
submitted when applicable.   
 
Resubmission of data may be required if labeling of structures does not conform to the standard 
DICOM name listed.  Capital letters, spacing and use of underscores must be applied exactly as 
indicated. 
 
Normal Critical Structures 
The normal tissues will be contoured and considered as solid organs. See the ITC web site 
(http://atc.wustl.edu) to view examples of target and normal tissue contours. Normal critical 
structures to be defined on the treatment planning CT scan will include the following:  
 
Standard Name 
 
Description 
 
Validation 
Required/Required 
when 
applicable/Optional 
Bladder 
Bladder 
Required 
Rectum 
Rectum 
Required 
Sigmoid 
S-shaped loop of bowel 
connecting the rectum 
to the descending colon 
in the left pelvis 
Required 

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Spc_Bowel 
Potential space of both 
small and large bowel, 
excluding the rectum 
and sigmoid 
Required 
Femur_L 
Left femur 
Required 
Femur_R 
Right femur 
Required 
Femurs 
Femur_L + Femur_R 
 
Required 
PenileBulb 
Entire penile bulb 
Required 
SeminalVes 
Seminal Vesicles 
Required 
SemVes_Prox 
1 cm Proximal Seminal 
Vesicles 
Required 
External 
External Patient 
Contour 
Required 
 
Detailed Specifications 
-Bladder: Contoured from the base to the dome 
-Rectum: From its origin at the rectosigmoid flexure superiorly or the bottom of the SI joints, 
whichever is more inferior, to the anus at the inferior-most extent of the ischial tuberosities. The 
length is usually about 10-15 cm. 
-Sigmoid: The loop of large bowel, typically S-shaped, connecting the rectum distally to the 
descending colon in the left pelvis proximally.  
-Spc_Bowel: The potential bowel space including all large and small bowel loops in a bowel bag 
excluding the rectum and sigmoid. The borders are the abdominal wall anteriorly, pelvic 
sidewalls laterally (excluding the pelvic lymph node regions), superiorly to one cut above the last 
axial CT image on which the lymph nodes are outlined and outlining around the sides of the 
bladder near the top of the bladder to encompass the bowel that may fall into these regions). 
-Bilateral femora: The proximal femur from the lowest level of the ischial tuberosities (right or 
left) and superiorly to the top of the ball of the femur, including the trochanters. 
-PenileBulb: The entire penile bulb, consisting of the proximal corpus spongiosum. 
-SeminalVes: The entire length of the seminal vesicles. 
-SemVes_Prox: Proximal 1 cm of the seminal vesicles. 
-External: External patient contour encompassing all patient anatomy with a single contour on 
each slice. 
 
5.2.5 Dose Prescription 
Note: The information provided in this section can be used for adjusting the dose constraints for 
treatment planning purposes.  This table together with the planning priority table should be used 
during dose optimization.  It is important to remember that ideal plans might not be achievable in 
all cases.  Thus, the Compliance Criteria table could be different than the information given here.   
 
Cases will be scored using the Compliance Criteria table. 
 
 

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STANDARD FRACTIONATION 
Target 
Standard Name 
Dose (Gy) Fraction 
Size (Gy) 
# of 
fractions  
Frequency Dose specification 
technique 
PTV_4500 
45 
1.8 
25 
Daily 
Covering 95% of 
PTV 
PTV_7920 
79.2 
1.8 
44 
Daily 
Covering 95% of 
PTV 
 
HYPOFRACTIONATION 
Target 
Standard Name 
Dose (Gy) Fraction 
Size (Gy) 
# of 
fractions  
Frequency Dose specification 
technique 
PTV_4500 
45 
1.8 
25 
Daily 
Covering 95% of 
PTV 
PTV_7000 
70 
2.5 
28 
Daily 
Covering 95% of 
PTV 
 
Dose Specifications 
 
Standard fractionation 
Dose for Phase 1 will be 45.0 Gy at 1.8 Gy per fraction in both arms. Once Phase 1 is completed, 
a cone down boost to the prostate and proximal seminal vesicles will be delivered in Phase 2 to 
34.2 Gy at 1.8 Gy per fraction, for a total prostate dose of 79.2 Gy.  
 
 Phase 1: Treat pelvic lymph nodes, prostate, and seminal vesicles 
o 45 Gy in 25 fractions to cover 95% of PTV_4500 and PTV_7920 
o Minimum PTV dose for a volume of 0.03cc is 95% of prescription (42.8 Gy) 
 
 Phase 2: Prostate or prostate/seminal vesicle boost 
o 34.2 Gy in 19 fractions to PTV_7920 such that prescriptions dose on the plan sum 
covers 95% of the PTV_7920 
o Minimum PTV_7920 dose on the plan sum for a volume of 0.03cc is 95% of 
prescription (75.2 Gy) 
o Maximum dose for a volume of 0.03cc within PTV_7920 on the plan sum should be 
≤107% of prescription (84.7 Gy). The maximum dose should not overlap with organs 
at risk such as the bowel, bladder or rectum. 
 
Hypofractionation 
Dose for Phase 1 will be a simultaneous integrated boost treatment delivering 45.0 Gy at 1.8 Gy 
per fraction to the pelvic lymph nodes and 62.5 Gy at 2.5 Gy per fraction to the prostate and 
proximal seminal vesicles in both arms. Once Phase 1 is completed, a cone down boost to the 
prostate will be delivered in Phase 2 to 7.5 Gy at 2.5 Gy per fraction, for a total prostate dose of 
70 Gy.  
 
 Phase 1: Treat pelvic lymph nodes, prostate, and seminal vesicles 
o 45 Gy in 25 fractions to cover 95% of PTV_4500 
o Minimum PTV dose for a volume of 0.03cc is 95% of prescription (42.8 Gy for 

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PTV_4500) 
 
 Phase 2: Prostate or prostate/seminal vesicle boost 
o 7.5 Gy in 3 fractions such that 70 Gy covers 95% of the PTV_7000 in the plan sum 
o Minimum PTV_7000 dose for a volume of 0.03cc is 95% of prescription (66.5 Gy) 
on the plan sum 
o Maximum dose for a volume of 0.03cc within the PTV_7000 should be ≤107% of 
prescription (74.9 Gy) on the plan sum. The maximum dose should not overlap with 
organs at risk such as the bowel, bladder or rectum. 
 
5.2.6 Compliance criteria 
 
The compliance criteria listed here will be used to score each case.  Given the limitations 
inherent in the treatment planning process, the numbers given in this section can be different than 
the prescription table. Goal constraints are given, and meeting these should be attempted. Plans 
meeting the goal constraints can be viewed as ideal plans. However, even if achieving the goal 
constraints is not possible, the Per Protocol and Variation Acceptable categories are both 
considered to be acceptable.  The Per Protocol cases can be viewed as near ideal plans not 
meeting goal constraints, and the Variation Acceptable category can include more challenging 
plans that do not fall at or near the ideal results.  A final category, called Deviation 
Unacceptable, results when cases do not meet the requirements for either Per Protocol or 
Variation Acceptable. Plans falling in this category are considered to be suboptimal and 
additional treatment planning optimization is recommended. 
 
Normalization of Dose: The plan is normalized such that 95% of the PTV_4500 volume 
receives prescription dose of 45 Gy and 95% of the PTV_7000/PTV_7920 volume receives 
prescription dose of 70 Gy/79.2 Gy. Please note the PTV_4500 and PTV_7000/PTV_7920 will 
overlap. Therefore, the target volume constraints for PTV_4500 should be evaluated based on 
Phase 1, the first 25 fractions. PTV_7000/PTV_7920 and all normal organ structures should be 
evaluated based on the plan sum of Phase 1 and Phase 2.  
 
Note: Deviation Unacceptable occurs when dose limits for Variation Acceptable are not 
met 
 
Target Volume Constraints and Compliance Criteria 
Name of 
Structure 
Dosimetric parameter 
Per Protocol Variation 
Acceptable 
PTV_4500 
 
D95%[Gy] 
>=45 
>=42.8 
D99%[Gy] 
>=42.8 
>=41.9 
PTV_7000 
D95%[Gy] 
>=70 
>=66.5 
D99%[Gy] 
>=66.5  
>=65.1 
D0.03cc[Gy] 
<=74.9 
<=75.6 
PTV_7920 
D95%[Gy] 
>=79.2  
>=75.2 
D99%[Gy] 
>=75.2 
>=73.7 
D0.03cc[Gy] 
<=84.7  
<=85.5 
 

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Per Protocol range is excluded from Variation Acceptable range. 
 
Normal Structure Constraints and Compliance Criteria 
 
Standard Fractionation 
Name of 
Structure 
Dosimetric parameter 
Per Protocol 
Variation 
Acceptable 
Rectum 
D0.03cc[%] 
<=104 
<=106 
V80Gy[cc] 
<=3 
<=7 
V75Gy[%] 
<=8 
<=15 
V70Gy[%] 
<=10 
<=20 
V60Gy[%] 
<=20 
<=35 
V50Gy[%] 
<=30 
<=40 
Bladder 
D0.03cc[%] 
<=105 
<=107 
V80Gy[%] 
<=2 
<=10 
V75Gy[%] 
<=5 
<=20 
V70Gy[%] 
<=10 
<=25 
V60Gy[%] 
<=20 
<=40 
V50Gy[%] 
<=30 
<=50 
Sigmoid 
D0.03cc[Gy] 
<=54 
<=60 
V50Gy[cc] 
<=45 
<=60 
Spc_Bowel 
D0.03cc[Gy] 
<=48.2 
<=53 
V45Gy[cc] 
<=50 
<=90 
Femurs 
D0.03cc[Gy] 
<=45 
<=55 
 
Hypofractionation 
Name of 
Structure 
Dosimetric parameter 
Per Protocol 
Variation 
Acceptable 
Rectum 
D0.03cc[%] 
<=104 
<=106 
V70Gy[cc] 
<=5 
<=12 
V65Gy[%] 
<=8 
<=15 
V60Gy[%] 
<=10 
<=20 
V50Gy[%] 
<=20 
<=35 
V40Gy[%] 
<=30 
<=40 
Bladder 
D0.03cc[%] 
<=105 
<=107 
V71Gy[%] 
<=2 
<=10 
V65Gy[%] 
<=5 
<=20 
V60Gy[%] 
<=10 
<=25 
V50Gy[%] 
<=25 
<=50 
Sigmoid 
D0.03cc[Gy] 
<=50 
<=56 
V50Gy[cc] 
<=45 
<=60 
Spc_Bowel 
D0.03cc[Gy] 
<=48.2 
<=53 
V45Gy[cc] 
<=50 
<=90 
Femurs 
D0.03cc[Gy] 
<=40 
<=50 
 

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Recommended dose acceptance criteria for other normal tissue, but not to be used for plan 
score. 
 
Name of 
Structure 
Dosimetric parameter 
Per Protocol 
Variation 
Acceptable 
PenileBulb 
Mean[Gy] 
<=50 
<=60 
 
Delivery Compliance criteria 
 
 
Per Protocol 
Variation Acceptable 
Start date  
 
56-115 days after 
GnRH 
antagonist/agonist 
initiation AND 56 
days after 
niraparib 
56-115 days (- 7 
days)after GnRH 
antagonist/agonist 
initiation AND 56 
days after niraparib 
(+/- 7 days) 
Overall Radiation Treatment time 
Standard Fractionation 
60-65 days 
      66-70 days 
Overall Radiation Treatment time 
Hypofractionation 
37-40 days 
41-45 days 
Interruptions 
0-2 unplanned 
treatment days 
missed (not 
including 
holidays) 
3-5 unplanned 
treatment days missed 
(not including 
holidays) 
 
 
5.2.7 Treatment Planning Priorities and Instructions 
 
- Critical Structure and Target priorities must be listed in order of decreasing importance 
 
The following list is given as an example 
1. 
Rectum 
2. 
Spc_Bowel 
3. 
Sigmoid 
4. 
PTV_7920/PTV_7000 
5. 
Bladder 
6. 
PTV_4500 
7. 
Femur_L and Femur_R 
8. 
PenileBulb 
 
Acceptable choices of algorithm are listed at  
http://rpc.mdanderson.org/RPC/Services/Anthropomorphic_%20Phantoms/Phantoms.htm 
Review TPS (Treatment Planning Systems) approved for calculation of dose with heterogeneities 
 
-Dose matrix resolution 

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Dose grid size should be ≤ 3 mm in all directions. 
 
5.2.8 Patient specific QA 
For IMRT/VMAT delivery, although an automated MU verification calculation may be 
permitted subject to protocol credentialing and approval, a direct measurement of the dose 
distribution from the designated treatment system shall be performed prior to delivery of the first 
fraction.  All components of the inverse-plan verification technique, including the planning 
system, treatment machine, and detector hardware and analysis procedure, shall be credentialed 
according to guidelines established by IROC-Houston for protocols utilizing inverse planning. 
 
For IMRT/VMAT delivery, patient specific QA is highly recommended. Any patient-specific 
QA performed should follow your institutional guidelines. The recommended minimum patient 
specific QA criterion is for 90% of the comparison points to pass a ±3%/3mm Gamma Index 
analysis. 
 
5.2.9 Treatment Localization/IGRT 
 
All patients are required to have daily image guidance prior to each fraction with 3D CBCT or 
2D kV imaging. Intrafraction tracking, such as with Calypso beacons is not allowed since this 
will preclude post-treatment MRI. 3D CBCT is strongly preferred, as this allows assessment of 
both rectal and bladder filling. Matching should either focus on the prostate-rectum interface or 
on fiducials in patients that have them. Fiducials are strongly recommended for 3D CBCT 
patients. If 2D KV imaging is used, then fiducial markers are required. If Calypso beacons are 
utilized, then 3D CBCT to evaluate for bladder and rectal filling is recommended but not 
required. 
 
 
5.3 
General Concomitant Medication and Supportive Care Guidelines 
 
5.3.1 Permitted Supportive/Ancillary Care and Concomitant Medications 
 
All supportive therapy for optimal medical care will be given during the study period at 
the discretion of the attending physician(s) within the parameters of the protocol and 
documented on each site’s source documents as concomitant medication.  
 
5.3.2 Prohibited Therapies 
 Investigational agents other than the study drugs 
 Other anticancer therapies 
 Other agents that target the androgen axis (eg, antiandrogens such as 
enzalutamide and apalutamide, or CYP17 inhibitors such as ketoconazole) 
 Testosterone 
 
Administration of radiation therapy other than the radiation therapy specified in this 
protocol. (Radiation protocol therapy is outlined in Section 5.2.) 
 Chemotherapy 
 Immunotherapy 
 Diethylstilbestrol (DES) or similar estrogen receptor agonists 
 Pomegranates and pomegranate juice 

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 Spironolactone 
 Radiopharmaceuticals such as radium-223 (223Ra), strontium (89Sr), or 
samarium (153Sm) 
 Strong inducers of CYP3A4 (eg, rifampin) 
 
5.3.3 Participation in Other Trials  
Patients are not to participate in other therapeutic trials.  However, trials that do not add 
experimental agents are allowed (e.g. imaging trials, quality of life, etc). 
 
5.4 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue as 
specified in the above treatment modality sections or until one of the following criteria 
applies: 
 
Disease progression, 
 
Intercurrent illness that prevents further administration of treatment, 
 
Unacceptable adverse event(s), as described in Section 7 
 
Patient decides to withdraw consent for participation in the study, or 
 
General or specific changes in the patient’s condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
6. TREATMENT MODIFICATIONS/MANAGEMENT 
 
6.1 
Dose Modifications for GnRH Agonists (Leuprolide, Goserelin, Buserelin, 
Triptorelin) 
There are no modification guidelines for GnRH agonist therapy.  All patients should 
be dosed with standard dosing for the full 24 months of treatment.  Please refer to the 
FDA-approved package inserts for each GnRH agonist. 
 
6.2 
Dose Modifications for Niraparib (09-NOV-2020) 
 
The dosing schedule for the phase I portion of the study is provided in Section 5 above.   
 
Dose modifications will occur according to the following schedule: 
 
Dose 
Level 
Niraparib Starting Dose 
Reduced Niraparib Dose 
0 
100 mg daily, except during the 
weeks of radiation when drug will 
be held 
Off study treatment 
1 
100 mg daily 
100 mg daily, except during the weeks 
of radiation when drug will be held 
2 
200 mg daily, except during 
weeks of radiation therapy, when 
it will 100 mg daily 
100 mg daily 
3 
200 mg daily, including during 
weeks of radiation therapy 
200 mg daily, except during weeks of 
radiation therapy, when it will 100 mg 

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daily 
 
 
Dosing of niraparib will continue until 12 months after initiation. 
Hematologic Toxicities 
The site should consider discontinuation of niraparib if: 
 Hematologic toxicity has not recovered to Grade 1 or baseline after prolonged (greater than 
1 week) period of dose interruption. 
 A diagnosis of MDS/AML is confirmed by a hematologist. 
 
Niraparib Dose Modifications for Anemia 
For the management of anemia, supportive measures such as blood transfusions may be performed 
as deemed necessary by the investigator per institutional standard-of-care. If more than 1 blood 
transfusion is given within 4 weeks, the sponsor should be notified. For Grade ≥3 anemia, niraparib 
should be interrupted until resolution to Grade <3. 
 
Weekly monitoring and/or interruption are not required if at baseline grade, eg, subject with 
baseline Hgb 9.1 (Grade 2 anemia) does not need to be monitored weekly for Grade 1 or 2 
anemia. 
Toxicity Grade 
Dose of Niraparib 
Grade 1 
No Change, consider weekly monitoring. 
Grade 2 
At least weekly monitoring and consider interrupting until 
≤Grade 1 or baseline and then resume at same dose with 
recommendation of weekly monitoring for 28 days after restart.  
Grade ≥3  
Interrupt until ≤Grade 1 or baseline, then: 
 Resume at 200 mg or 1 dose-level reduction (at the discretion 
of the investigator). 
 If subject was already reduced dose at 100 mg, discuss with PI 
prior to resuming treatment. 
 
Weekly monitoring is required until resolution to Grade 1 or 
baseline. Weekly monitoring is recommended for 28 days after 
restarting dose. 
Second occurrence Grade 
≥3 
Interrupt until ≤Grade 1 or baseline and restart at 1 dose-level 
reduction. Weekly monitoring is required until resolution to 
Grade 1 or baseline. Weekly monitoring is recommended for 28 
days after restarting dose. 
 
If subject was on 100 mg, discuss with PI prior to resuming 
treatment. 
Third occurrence Grade ≥3 
Permanently discontinue  
Notes: 
 
For subjects with a platelet count ≤10,000 cells/µL, prophylactic platelet transfusion may be 
considered. For subjects taking anti-coagulant or anti-platelet therapy, consider the 

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35 
 
risk/benefit of interrupting these drugs or prophylactic transfusion at an alternative threshold 
such as ≤20,000 cells/µL. 
 
If subject requires platelet transfusion or has neutropenic fever or neutropenia requiring 
granulocyte-colony stimulating factor for Grade ≥3 AE deemed to be related to niraparib 
toxicity, interrupt study drug and restart at 1 dose-level reduction after resolution to Grade 1 
or baseline. If the subject was previously dose-reduced for the same hematologic toxicity, 
discontinue niraparib. 
 
If standard of care treatment with radiation and/or GnRH agonist therapy is stopped for any 
reason, then niraparib should be discontinued as well. 
 
Hypertensive Crisis 
Hypertension, including hypertensive crisis, has been reported with the use of niraparib. 
Pre-existing hypertension should be adequately controlled before starting niraparib 
treatment.  
 
For patients taking niraparib, monitor blood pressure and heart rate weekly for the first two 
months and then monthly until end of treatment. Sites should complete blood pressure and heart 
rate at in-person visits whenever possible.  
 
Patients may complete this monitoring at home if they are unable to complete this on site. 
Patients must keep a blood pressure and heart rate diary if they are doing so. A blood pressure 
device will be provided for those patients who are completing at home monitoring and do not 
have one. Site instruction will be provided. Patients will be instructed to record blood pressure 
and heart rate and return the diary at each visit. Please see section 9.2.5 and Appendix III for 
details. 
 
Monitoring compliance will be conducted by the site. Patients will notify their treating physician 
if their blood pressure or heart rate is abnormal, which will be determined by the treating 
physician.  
 
Hypertension should be medically managed with antihypertensive medicinal products as 
well as adjustment of the niraparib dose, if necessary. In the niraparib clinical program, most 
cases of hypertension were controlled adequately using standard antihypertensive treatment with 
or without niraparib dose adjustment. Niraparib should be discontinued in case of hypertensive 
crisis or if medically significant hypertension cannot be adequately controlled with 
antihypertensive therapy. 
 
Hypertension Monitoring and Management 
 Abbreviations: Angiotensin Converting Enzyme (ACE) Inhibitors, Angiotensin II Receptor 
 Blockers (ARB), selective beta blockers (BB), Dihydropyridine calcium channel blockers 
(DHP-CCP) 
 Only doses of niraparib will be modified for hypertension. 
 In case of persistent or severe hypertension, despite the optimal use of antihypertensive medicinal 
products and niraparib dose reduction, niraparib should be permanently discontinued. 
 Hypertension should be graded using the NCI CTCAE v5.0. Please note: patients may have 
baseline hypertension meeting CTCAE grading criteria on study entry. Should patients require 

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36 
 
increase in dosing of BP medication or increased number of medications, they should then be 
noted to have hypertension related to study drug, with grading as per CTCAE v5.0 criteria. 
 Baseline grade of hypertension should also be recorded in the patient’s record. 
 
CTCAE 
Grade v 5.0 
Antihypertensive Therapy 
Blood Pressure 
Monitoring 
Niraparib Dose 
Modification 
Grade 1 
Consider early initiation of BP 
medication for BP > 140/90 
mmHg that is confirmed on a 
second reading. 
Niraparib can cause 
rapid escalation in BP, and 
early initiation of BP 
management can reduce 
likelihood of HTN-related 
complications. 
Continue standard BP 
monitoring per treating 
MD. 
None 
Grade 2 
Initiate BP medication for first 
line treatment. 
Suggestions: ACE inhibitor 
or Calcium Channel Blocker 
Escalate dose of medication in 
stepwise fashion until 
BP is controlled or at a 
maximum dose 
If BP is not controlled to 
< 140/90 mmHg with one 
maximized drug regimen, then 
add a second agent. 
Niraparib does not need to 
be held unless otherwise 
clinically necessary 
Consider blood pressure 
management specialist consult 
Increase frequency of 
monitoring until stabilized 
to BP <140/90 mmHg 
None. Do not hold 
niraparib unless 
otherwise clinically 
necessary 
Grade 3 
Maximize 2 drug regimen 
 Suggestions: 
ACE-inhibitor + Calcium 
Channel Blocker 
 
Escalate doses of existing 
medication until BP is 
controlled or at a maximum 
dose. 
If BP is not controlled to 
< 140/90 mmHg with two drug 
regimen, then add a third 
agent. 
Additional antihypertensive 
drugs, up to a total of 4, may 
be maximized for blood 
pressure control 
Increase frequency of 
monitoring until stabilized 
to BP <140/90 mmHg 
Do not hold niraparib 
unless BP is not 
decreased to less than 
150/100 mmHg 48 hours 
after multi-drug therapy 
is instituted or if clinical 
symptoms worsen (e.g. 
headache). 
If BP is not controlled to 
less than 150/100 
mmHg with maximal 
therapy or if clinical 
symptoms worsen, then 
hold niraparib until 
maximum effect of the 
antihypertensive agents 
is achieved. 

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Consider consult with a blood 
pressure management 
specialist if greater than 3 
drugs are required for BP 
control. 
If BP is reduced to less 
than 140/90 within 28 
days, niraparib may be 
resumed at prior dose. If 
reoccurrence of Grade 3 
hypertension, dose reduce 
niraparib. 
Grade 4 
Hospitalize patient for ICU 
management, IV therapy as 
necessary 14 days are allowed 
to maximize the full effect of 
antihypertensive agents. 
Intensive BP monitoring 
(hospitalization if 
necessary) 
Discontinue niraparib 
 
Posterior Reversisble Encephalopathy Syndrome 
There have been rare reports of niraparib-treated patients developing signs and symptoms 
that are consistent with Posterior Reversible Encephalopathy Syndrome (PRES). PRES is 
a rare neurologic disorder that can present with the following signs and symptoms 
including seizures, headache, altered mental status, visual disturbance, or cortical 
blindness, with or without associated hypertension. A diagnosis of PRES requires 
confirmation by brain imaging, preferably magnetic resonance imaging. In patients 
developing PRES, treatment of specific symptoms including control of hypertension is 
recommended, along with discontinuation of niraparib. The safety of reinitiating 
niraparib therapy in patients previously experiencing PRES is not known. 
 
Myelodysplatic Syndrome/Acute Myeloid Leukemia 
If MDS and/or AML are confirmed while on treatment with niraparib, then niraparib 
should be permanently discontinued and the patient should be treated appropriately. 
 
7. ADVERSE EVENTS REPORTING REQUIREMENTS 
 
Adverse Event reporting begins at the time a patient signs consent; please report all 
AEs that start after consent is signed. Report serious adverse events that meet 
expedited reporting criteria via CTEP-AERS. 
 
7.1  Protocol Agents 
 
 
Investigational Agents 
The investigational agent administered in NRG-GU007, niraparib, is exempt and 
distributed by a third party distributor. For niraparib, determination of whether an 
adverse event meets expedited reporting criteria, see the reporting table in Section 7.5 
of the protocol. 
 
Commercial Agents 
The commercial agents in NRG-GU007 are FDA-approved GnRH agonists.  
 
7.2 Adverse Events and Serious Adverse Events 
7.2.1 This study will utilize the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 for CTEP-AERS (CTEP Adverse Event Reporting System) CAERs 

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reporting of adverse events (Aes), located on the CTEP web site, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. All 
appropriate treatment areas should have access to a copy of the CTCAE version 5.0. 
 
7.2.2 Definition of an Adverse Event (AE) 
Any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related.  Therefore, an AE can be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not 
considered related to the medicinal (investigational) product (attribution of unrelated, 
unlikely, possible, probable, or definite). (International Conference on Harmonisation 
[ICH], E2A, E6).  
 
For multi-modality trials, adverse event reporting encompasses all aspects of protocol 
treatment including radiation therapy, surgery, device, and drug. 
 
Due to the risk that niraparib may have an effect on sperm, the impregnation of a study 
participant’s partner must be reported via CTEP-AERS in an expedited manner. 
 
7.3 
Adverse Events for Investigational Study Agent Provided by Janssen (09-NOV-
2020) 
Please refer to the niraparib Investigator Brochure for comprehensive information. 
 

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Very Common (>10%) 
Common (1-10%) 
Very Rare (< 1%) 
Decrease in red blood cells; 
may cause anemia 
Tachycardia 
MDS 
Decrease in blood cells; 
may increase risk of 
bleeding 
Leukopenia 
AML 
Neutropenia, Neutropenic 
infection 
Hypokalemia 
Neutropenic Sepsis 
Constipation 
Dry mouth 
Hypertensive crisis 
Nausea 
Anxiety 
PRES 
Vomiting 
Depression 
 
Decreased appetite 
Nose bleeds 
 
Abdominal pain 
Rash 
 
Diarrhea 
Muscle pain 
 
Dyspepsia 
Peripheral edema 
 
Insomnia 
Swelling or irritation of 
lining of throat or intestinal 
tract 
 
Headache 
Increases in AST, ALT, 
GGT, ALP – may indicate 
damage to liver cells 
 
Fatigue 
Increase in kidney test 
called blood creatinine 
 
Urinary tract infection 
Decrease in weight 
 
Bronchitis 
 
 
 
Conjunctivitis 
 
Back pain 
 
 
Arthralgia 
 
 
Dyspnea 
 
 
Nasopharyngitis 
 
 
Hypertension 
 
 
Dizziness 
 
 
Cough 
 
 
Asthenia 
 
 
Heart Palpitations 
 
 
Dysgeusia 
 
 
 
The following situations should be reported as adverse events on the case report form and if any 
of these events meet the criteria for seriousness, they should be reported expeditiously via CTEP-
AERS: 
 Overdose of the medicinal product 
 Suspected abuse/misuse of the medicinal product 
 Inadvertent or accidental exposure of the medicinal product 
 Medication error, with or without patient exposure (e.g. name confusion) 
 Suspected transmission of any infectious agent via administration of the medicinal 

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product 
 Drug exposure during pregnancy (paternal) 
 
7.3.1 Adverse Events of Special Interest 
Adverse events of special interest are events that Janssen is actively monitoring as a 
result of a previously identified signal (even if non-serious). Janssen identified the 
following as AESI specific for prostate trials (this may not be reflected in the current IB 
version):   
 Grade 3-4 Anemia 
 Grade 3-4 Thrombocytopenia 
 Grade 3-4 Neutropenia 
 Acute Myeloid Leukemia 
 Myelodysplastic Syndrome  
Any adverse event of special interest should be reported to Janssen within 24 hours of 
becoming aware of the event.  
 
7.4 
Adverse Events for Commercial Study Agents  
Refer to the package insert for detailed pharmacologic and safety information 
 
7.5 
Expedited Reporting of Adverse Events 
 
Adverse Event reporting begins at the time a patient signs consent; please report all 
Aes that start after consent is signed. Report serious adverse events that meet 
expedited reporting criteria via CTEP-AERS. 
 
All serious adverse events that meet expedited reporting criteria defined in the reporting 
table below will be reported via the CTEP Adverse Event Reporting System, CTEP-
AERS, accessed via the CTEP web site,  
https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613 
 
Submitting a report via CTEP-AERS serves as notification to the NRG 
Biostatistical/Data Management Center and satisfies NRG requirements for expedited 
adverse event reporting. 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be 
made to the NRG Oncology by phone at 1-215-574-3191. An electronic report must be 
submitted immediately upon re-establishment of the Internet connection. 
 
7.5.1 Expedited Reporting Methods 
 Per CTEP NCI Guidelines for Adverse Events Reporting, a CTEP-AERS 24-hour 
notification must be submitted within 24 hours of learning of the adverse event.  Each 
CTEP-AERS 24-hour notification must be followed by a complete report within 5 
days.  
 Supporting source documentation is requested by NRG as needed to complete 
adverse event review. Supporting source documentation should include the protocol 
number, patient ID number, and CTEP-AERS ticket number on each page. Contact 

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NRG Oncology at 1-215-574-3191 for source documentation assistance. 
 A serious adverse event that meets expedited reporting criteria outlined in the AE 
Reporting Tables but is assessed by the CTEP-AERS as “an action not 
recommended” must still be reported to fulfill NRG safety reporting obligations. Sites 
must bypass the “NOT recommended” assessment; the CTEP-AERS allows 
submission of all reports regardless of the results of the assessment.  
7.5.2 Expedited Reporting Requirements for Adverse Events  
 
Phase 1:  Expedited Reporting Requirements for Adverse Events that Occur within 
30 Days of the Last Administration of the Niraparib 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not they are 
considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be 
considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH 
E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-AERS 
within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific Protocol 
Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” – The AE must initially be reported via CTEP-AERS within 24 hours of learning of the 
AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” – A complete expedited report on the AE must be submitted within 10 calendar days of learning 
of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention and have 
an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
 
All Grade 3, 4, and Grade 5 Aes 
Expedited 10 calendar day reports for: 
 
Grade 2 Aes resulting in hospitalization or prolongation of hospitalization 

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2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, rounded UP to the 
nearest whole day, after the agent/intervention was last administered.  Footnote “1” above applies after this reporting period. 
Effective Date:  May 5, 2011 
Additional Protocol-Specific Instructions to Expedited Reporting Requirements 
Please see Section 7.3.1 
 
Phase II, Arm 2: Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for 
Adverse Events that Occur within 30 Days of the Last Administration of Niraparib1,2 
 
Starting 30 days after last dose of niraparib expeditiously report Aes reasonably 
related to niraparib per footnote 1 in the table below.  
 
For Aes unrelated to niraparib during the period of GnRH only therapy starting 30 
days after last dose of niraparib should be reported per the Ph II, Arm 1 table.  
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not they are 
considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be 
considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH 
E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-AERS 
within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific Protocol 
Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” – The AE must initially be reported via CTEP-AERS within 24 hours of learning of the 
AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” – A complete expedited report on the AE must be submitted within 10 calendar days of learning 
of the AE. 

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1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention and have 
an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
 
All Grade 4, and Grade 5 Aes 
Expedited 10 calendar day reports for: 
 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
 
Grade 3 adverse events 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, rounded UP to the 
nearest whole day, after the agent/intervention was last administered.  Footnote “1” above applies after this reporting period. 
Effective Date:  May 5, 2011 
Additional Protocol-Specific Instructions to Expedited Reporting Requirements 
Please see Section 7.3.1 
 
Phase II, Arm 1:  Any Phase Study Utilizing a Commercial Agent1 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they are considered 
related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be 
considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH 
E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-AERS 
within the timeframes detailed in the table below. 
Attribution 
Grade 4 
Grade 5 
Unexpected 
Expected 
Unexpected 
Expected 
Unrelated 
Unlikely 
 
10 day 
10 day 
Possible 
Probable 
Definite 
24-h/5 day 
 
24-h/5 day 
24-h/5 day 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” – The AE must initially be reported via CTEP-AERS within 24 hours of learning of 
the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o “10 Calendar Days” – A complete expedited report on the AE must be submitted within 10 calendar days of 
learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention 
and have an attribution of possible, probable, or definite require reporting as follows:  

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Expedited 24-hour notification followed by complete report within 5 calendar days for: 
 
Unexpected Grade 4 and all Grade 5 Aes 
 
 
7.5.3 Reporting to the Site IRB/REB 
Investigators will report serious adverse events to the local Institutional Review Board 
(IRB) or Research Ethics Board (REB) responsible for oversight of the patient according 
to institutional policy. 
7.5.4 Secondary Malignancy  
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A 
secondary malignancy is not considered a metastasis of the initial neoplasm.  
 
CTEP requires all secondary malignancies that occur during or subsequent to treatment 
with an agent under an NCI IND/IDE be reported via CTEP-AERS. In addition, 
secondary malignancies following radiation therapy must be reported via CTEP-AERS. 
Three options are available to describe the event: 
 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
 
Myelodysplastic syndrome (MDS) 
 
Treatment-related secondary malignancy 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in each protocol.  
 
Second Malignancy:  
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT 
a metastasis from the initial malignancy).  Second malignancies require ONLY routine 
reporting via CDUS unless otherwise specified. 
 
7.6 
Routine Reporting Requirements for Adverse Events 
All Adverse Events must be reported in routine study data submissions.  Aes reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
 
7.7 
Pregnancy 
Although not an adverse event in and of itself, pregnancy as well as its outcome must be 
documented via CTEP-AERS.  In addition, the Pregnancy Information Form included 
within the NCI Guidelines for Adverse Event Reporting Requirements must be 
completed and submitted to NRG Oncology.  Any pregnancy occurring in a patient’s 
partner from the time of consent to 90 days after the last dose of study drug must be 
reported within 24 hours of awareness and then followed for outcome.  Newborn infants 
should be followed until 30 days old.  Please see the “NCI Guidelines for Investigators: 
Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and DCP INDs and 
IDEs” (at http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm) for more 
details on how to report pregnancy and its outcome to CTEP.  
 

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8. REGISTRATION AND STUDY ENTRY PROCEDURES  (24-MAY-2022) 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually. To register, all individuals must obtain a Cancer Therapy Evaluation 
Program (CTEP) Identity and Access Management (IAM) account at 
https://ctepcore.nci.nih.gov/iam. In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must complete their annual 
registration using CTEP’s web-based Registration and Credential Repository (RCR) at 
https://ctepcore.nci.nih.gov/rcr.    
RCR utilizes five person registration types. 
 IVR — MD, DO, or international equivalent; 
 NPIVR — advanced practice providers (e.g., NP or PA) or graduate level researchers 
(e.g., PhD); 
 AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications , 
such as the Roster Update Management System [RUMS], OPEN, Rave, acting as a 
primary site contact, or with consenting privileges; 
 Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored trials; 
and 
 Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
RCR requires the following registration documents: 
Documentation Required 
IVR NPIVR AP 
A 
AB 
FDA Form 1572 
✔ 
✔ 
 
 
 
Financial Disclosure Form 
✔ 
✔ 
✔ 
 
 
NCI Biosketch (education, training, employment, license, 
and certification) 
✔ 
✔ 
✔ 
 
 
GCP training 
✔ 
✔ 
✔ 
 
 
Agent Shipment Form (if applicable) 
✔ 
 
 
 
 
CV (optional) 
✔ 
✔ 
✔ 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and Cancer Trials Support Unit (CTSU) websites and applications. In addition, IVRs and 
NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) covering their 
practice sites on the FDA Form 1572 in RCR to allow the following: 
 Addition to a site roster; 
 Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN; 
 Act as the site-protocol Principal Investigator (PI) on the IRB approval. 
 
In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN must be rostered at the 

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enrolling site with a participating organization.  
 
Additional information is located on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm. For questions, please contact the RCR 
Help Desk by email at RCRHelpDesk@nih.gov. 
 
8.1 
Cancer Trials Support Unit Registration Procedures  (24-MAY-2022) 
Permission to view and download this protocol and its supporting documents is restricted 
and is based on person and site roster assignment housed in the CTSU Regulatory 
Support System (RSS). 
 
This study is supported by the NCI Clinical Trials Support Unit (CTSU). 
 
IRB Approval  
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical 
Trials Network (NCTN) and NCI Community Oncology Research Program (NCORP) 
Research Bases after March 1, 2019, all U.S.-based sites must be members of the NCI 
Central Institutional Review Board (NCI CIRB). In addition, U.S.-based sites must 
accept the NCI CIRB review to activate new studies at the site after March 1, 2019. Local 
IRB review will continue to be accepted for studies that are not reviewed by the CIRB, or 
if the study was previously open at the site under the local IRB. International sites should 
continue to submit Research Ethics Board (REB) approval to the CTSU Regulatory 
Office following country-specific regulations.  
Sites participating with the NCI CIRB must submit the Study Specific Worksheet (SSW) 
for Local Context to the CIRB using IRBManager to indicate their intent to open the study 
locally. The NCI CIRB’s approval of the SSW is automatically communicated to the 
CTSU Regulatory Office, but sites are required to contact the CTSU Regulatory Office at 
CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI CIRB 
approvals across their Signatory Network. Site preferences can be set at the network or 
protocol level. Questions about establishing site preferences can be addressed to the 
CTSU Regulatory Office by email or calling 1-888-651-CTSU (2878). 
Sites using their local IRB or REB, must submit their approval to the CTSU Regulatory 
Office using the Regulatory Submission Portal located in the Regulatory section of the 
CTSU website. Acceptable documentation of local IRB/REB approval includes: 
 Local IRB documentation; 
 IRB-signed CTSU IRB Certification Form; and/or 
 Protocol of Human Subjects Assurance Identification/IRB 
Certification/Declaration of Exemption Form. 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the 
IRB/REB approval) must meet the following criteria in order for the processing of the 
IRB/REB approval record to be completed: 
 Holds an active CTEP status; 

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 Active status at the site(s) on the IRB/REB approval on at least one participating 
organization’s roster; 
 If using NCI CIRB, active on the NCI CIRB roster under the applicable CIRB 
Signatory Institution(s) record; 
 Includes the IRB number of the IRB providing approval in the Form FDA 1572 in 
the RCR profile;  
 Lists all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 
in the RCR profile; and 
 Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements for Protocol NRG-GU007 Site Registration 
Additional site requirements to obtain an approved site registration status include: 
 An active Federal Wide Assurance (FWA) number; 
 An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO); 
 An active roster affiliation with the NCI CIRB roster under at least one CIRB 
Signatory Institution (US sites only); and 
 Compliance with all protocol-specific requirements (PSRs). 
 This is a study with a radiation and/or imaging (RTI) component and the enrolling 
site must be aligned to an RTI provider. To manage provider associations or to add 
or remove associated providers, access the Provider Association page from the 
Regulatory section on the CTSU members’ website at 
https://www.ctsu.org/RSS/RTFProviderAssociation. Sites must be linked to at 
least one Imaging and Radiation Oncology Core (IROC) credentialed provider to 
participate on trials with an RTI component. Enrolling sites are responsible for 
ensuring that the appropriate agreements and IRB approvals are in place with their 
RTI provider. An individual with a primary role on a treating site roster can update 
the provider associations, though all individuals at a site may view provider 
associations. To find who holds primary roles at your site, view the Person Roster 
Browser under the RUMS section on the CTSU website. 
 
 IROC Credentialing Status Inquiry (CSI) Form – this form is submitted to IROC 
to begin the modality credentialing process.  
 
To complete protocol-specific credentialing the RT/I provider or enrolling site should 
follow instructions in protocol section 8.2 to submit documentation or other materials to 
the designated IROC Quality Control (QC) center. Upon the IROC QA center approving 
the RTI provider for the study modality IROC will automatically send the approval to the 
Regulatory Support System (RSS) to comply with the protocol-specific requirement., 
unless otherwise noted at the bottom of the IROC Credentialing Approval notification. 
IROC will continue to copy the provider and/or enrolling site on modality approvals. 
Upon site registration approval in RSS, the enrolling site may access OPEN to complete 
enrollments. The enrolling site will select their credentialed provider treating the subject 
in the OPEN credentialing screen and may need to answer additional questions related to 

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treatment in the eligibility checklist.   
 
Additional Requirements for sites in Canada 
All institutions in Canada must conduct this trial in accordance with International 
Conference on Harmonization-Good Clinical Practice (ICH-GCP) Guidelines. This trial is 
being conducted under a Clinical Trial Application (CTA) with Health Canada. As a result 
essential documents must be retained for 25 years following the completion of the trial at 
the participating site (25 years post final analysis, last data collected, or closure notification 
to REB, whichever is later), or until notified by the sponsor, NRG Oncology, that 
documents no longer need to be retained.    
 
 
Prior to clinical trial commencement, sites in Canada must also complete and submit the 
following documents via the Regulatory Submission portal on the CTSU website. 
 Clinical Trial Site Information Form,  
 Qualified Investigator Undertaking Form  
 Research Ethics Board Attestation Form 
 Protocol Signature Page  
 Investigator Brochure Signature Page  
 Delegation of Tasks (DTL) Log  
 List of Laboratories  
 SIV/Training Confirmation of Completion Form – Research Associate (please 
refer to the activation memo for details)  
 SIV/Training Confirmation of Completion Form – Qualified Investigator (please 
refer to the activation memo for details)  
 IRB/REB approved consent (English and native language versions)*. Must be 
submitted and reviewed by NRG regulatory 
(CanadianRegulatory@NRGOncology.org) prior to submission to local 
IRB/REB. 
 
*Translation of documents is critical. The institution is responsible for all translation 
costs. All regulatory documents, including the IRB/REB approved consent, must be 
provided in English and in the native language. Certification of the translation is optimal 
but due to the prohibitive costs involved NRG will accept, at a minimum, a verified 
translation. A verified translation consists of the actual REB approved consent document 
in English and in the native language, along with a cover letter on organizational 
letterhead/stationery that includes the professional title, credentials, and signature of the 
translator as well as signed documentation of the review and verification of the 
translation by a neutral third party. The professional title and credentials of the neutral 
third party translator must be specified as well. 
 
The following items are collected By NRG Oncology Regulatory on a yearly or biyearly 
basis:   
 IRB/REB Membership Roster  
 Laboratory Certificates and Normal Values  
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Requirements for the Initial Shipment of Niraparib for ALL sites 
Institutions must electronically complete (versus hand write) a Study Agent 
Shipment Form (SASF) available on the protocol web site Institutions must submit 
the SASF via the Regulatory Submission Portal on the CTSU website as soon as the 
individual responsible for the study agent has been identified.  
Downloading Site Registration Documents:   
Download the site registration forms from the protocol-specific page located on the 
CTSU members’ website. Permission to view and download this protocol and its 
supporting documents is restricted to institutions and its associated investigators and staff 
on a participating roster. To view/download site registration forms:  Log in to the CTSU 
members’ website (https://www.ctsu.org) using your CTEP-IAM username and 
password; 
 Click on Protocols in the upper left of your screen 
o Enter the protocol number in the search field at the top of the protocol tree, 
or 
o Click on the By Lead Organization folder to expand, then select NRG 
Oncology and protocol number NRG-GU007; 
 
Click on Documents, Protocol Related Documents, and use the Document Type 
filter and select Site Registration to download and complete the forms provided. 
(Note: For sites under the CIRB initiative, IRB data will load automatically to the 
CTSU as described above.)  
 
Submitting Regulatory Documents:  
Submit required forms and documents to the CTSU Regulatory Office via the 
Regulatory Submission Portal on the CTSU members’ website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website go 
to the Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission 
Portal should alert the CTSU Regulatory Office immediately by phone or email: 1-
866-651-CTSU (2878), or CTSURegHelp@coccg.org in order to receive further 
instruction and support. 
 
Checking Site’s Registration Status: 
Site’s registration status may be verified on the CTSU members’ CTSU website.  
 Click on Regulatory  at the top of the screen; 
 Click on Site Registration; and  
 Enter the sites 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, 

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Protocol Status, and/or IRB Type. 
Note: The status shown only reflects institutional compliance with site registration 
requirements as outlined within the protocol. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling investigator’s 
status with the NCI or their affiliated networks. 
 
 
8.2 RT-Specific Pre-Registration Requirements  (24-MAY-2022) 
For detailed information on the specific technology requirement required for this study, 
please refer to the table below and utilize the web link provided for detailed instructions. 
The check marks under the treatment modality columns indicate whether that specific 
credentialing requirement is required for this study. Specific credentialing components 
may require you to work with various QA centers; however, IROC Houston will notify 
your institution when all credentialing requirements have been met and the institution is 
RT credentialed to enter patients onto this study.  This document must be uploaded by the 
site to the CTSU Regulatory Submission Portal for RSS to be updated.   
 
RT   
Credentialing 
Requirements 
Web Link for Credentialing Procedures and Instructions 
http://irochouston.mdanderson.org 
Treatment Modality 
 
Photon 
Key Information 
Credentialing 
Status Inquiry 
Form 
    X 
To determine if your institution has completed the 
requirements above, please complete a “Credentialing 
Status Inquiry Form” found under Credentialing on the 
IROC Houston QA Center website 
(http://irochouston.mdanderson.org). 
Facility 
Questionnaire 
    X 
The IROC Houston electronic facility questionnaire (FQ) 
should be completed or updated with the most recent 
information about your institution.  To access this FQ, email 
irochouston@mdanderson.org to receive your FQ link. 
Phantom 
Irradiation 
     X 
An IMRT Head & Neck phantom study provided by the 
IROC Houston QA Center must be successfully completed. 
Instructions for requesting and irradiating the phantom are 
found on the IROC Houston web site 
(http://irochouston.mdanderson.org).  
Credentialing Notification Issued to: 
Institution 
     X 
Institution will be credentialed for the treatment modality 
that they intend to use on all patients. IROC Houston QA 
Center will notify the institution and NRG Headquarters 
that all desired credentialing requirements have been met. 
 
8.2.1 Digital RT Data Submission to NRG Using TRIAD 
Transfer of Images and Data (TRIAD) is the American College of Radiology’s 
(ACR) image exchange application. TRIAD provides sites participating in clinical 
trials a secure method to transmit images. TRIAD anonymizes and validates the 

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images as they are transferred. 
TRIAD Access Requirements: 
 A valid Cancer Therapy Evaluation Program (CTEP) Identity and Access 
Management (IAM) (CTEP-IAM) account.  
 Registration type of: Associate (A), Associate Plus (AP), Non-Physician 
Investigator (NPIVR), or Investigator (IVR). Refer to the CTEP Registration 
Procedures section for instructions on how to request a CTEP-IAM account 
and complete registration in RCR. 
 TRIAD Site User role on an NCTN or ETCTN roster. 
All individuals on the Imaging and Radiation Oncology Core provider roster have access 
to TRIAD, and may submit images for credentialing purposes, or for enrollments to 
which the provider is linked in OPEN. 
 
TRIAD Installation: 
To submit images, the individual holding the TRIAD Site User role will need to 
install the TRIAD application on their workstation. TRIAD installation 
documentation is available at https://triadinstall.acr.org/triadclient/. 
This process can be done in parallel to obtaining your CTEP-IAM account 
username and password and RCR registration. 
For questions, contact TRIAD Technical Support staff via email TRIAD-
Support@acr.org or 1-703-390-9858. 
 
8.3 
Patient Enrollment (24-MAY-2022) 
Patient registration can occur only after evaluation for eligibility is complete, eligibility 
criteria have been met, and the study site is listed as ‘approved’ in the CTSU RSS.  Patients 
must have signed and dated all applicable consents and authorization forms.   
 
8.3.1 Oncology Patient Enrollment Network (OPEN) 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and 
with the LPOs registration/randomization systems or the Theradex Interactive Web 
Response System (IWRS) for retrieval of patient registration/randomization assignment. 
OPEN will populate the patient enrollment data in NCI’s clinical data management 
system, Medidata Rave. 
Requirements for OPEN access:   
 A valid CTEP-IAM account; 
 To perform enrollments or request slot reservations:  Must be on an LPO roster, 
ETCTN corresponding roster, or participating organization roster with the role of 

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Registrar. Registrars must hold a minimum of an Associate Plus (AP) registration 
type; 
 Have an approved site registration for the protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR.  
Prior to accessing OPEN, site staff should verify the following: 
 Patient has met all eligibility criteria within the protocol stated timeframes; and  
 All patients have signed an appropriate consent form and Health Insurance 
Portability and Accountability Act (HIPAA) authorization form (if applicable). 
Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. You may print this confirmation for your records.  
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ 
website. Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org. For any additional questions, contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
In the event that the OPEN system is not accessible, participating sites can contact NRG 
web support for assistance with web registration: websupport@acr.org or call the NRG 
Registration Desk at 215-574-3191, Monday through Friday, 8:30 a.m. to 5:00 p.m. ET. 
The registrar will ask the site to fax in the eligibility checklist and will need the registering 
individual’s e-mail address and/or return fax number. This information is required to assure 
that mechanisms usually triggered by the OPEN web registration system (e.g. drug 
shipment and confirmation of registration) will occur.  
 
9. DRUG INFORMATION  
 
9.1  
Commercial Agents: GnRH Agonists (leuprolide, goserelin, buserelin, triptorelin) 
Sites must refer to the package insert for detailed dosing, pharmacologic and safety 
information.  
 
9.2 
Investigational Study Agent: Niraparib (IND exempt) (24-MAY-2022) 
To supplement the toxicity information contained in this document, investigators must 
obtain the current version of the investigator brochure for comprehensive pharmacologic 
and safety information. The Investigator Brochure can be obtained from the CTSU by 
completing the Request for Clinical Brochure form. This form can be found on the CTSU 
website under documents > site registration. 
 
9.2.1 Adverse Events 
 
See Section 7.3 and consult the investigator brochure for comprehensive information. 
 

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9.2.2 Dosage Selected, Preparation, and Schedule of Administration 
Niraparib is administered orally on a once daily dosing schedule as outlined in Section 5.1. 
Niraparib can be taken with or without food.  
 
Preparation and Safe Handling 
Niraparib may have adverse effects on a fetus in utero. Caregivers should handle 
niraparib with protection (eg, gloves).  
9.2.3 Agent Storage and Stability 
Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C to 30°C 
(59°F to 86°F). 
9.2.4 Supply, Packaging, Accountability, and Drug Ordering  
Niraparib will be distributed by a vendor, Clinical Research Services, a division of 
RxCrossroads by McKesson. Niraparib will be packaged as 100 mg capsules in 93 count 
bottles. Niraparib must be stored in a secure area and administered only to subjects enrolled 
in the clinical study in accordance with the conditions specified in this protocol.  
Patients will be asked to bring their medication bottle and a pill diary at the 1, 2, 3, 4, 5, 6, 
9, and 12 month visits, regardless of whether the bottle is empty. A pill count and 
evaluation of the pill diary will be completed to assess compliance. The pill diary is located 
in Appendix I and on the CTSU website.  
 
Janssen will supply niraparib free of charge to subjects on study in the U.S. and Canada.  
The investigator, or responsible party designated by the investigator, must maintain a 
careful record of the receipt, distribution, and return of all drugs received from Clinical 
Research Services according to good clinical practices. Sites are encouraged to use the NCI 
Investigational Agent Accountability Record available on the CTEP website or their 
institutional drug accountability log. 
 
At the completion of the study, unused supplies will be destroyed at the site according to 
the institution's policy for drug destruction.  Sites should complete the drug destruction 
form located on the CTSU website under protocol-specific page and send the form to 
Clinical Research Services (see below for contact information). 
 
The Study Agent Shipment Form (SASF), available on the CTSU website, under the NRG-
GU007 study page must be completed and submitted to the CTSU Regulatory Office via 
the Regulatory Submission Portal as soon as the individual responsible for the study agent 
has been identified. 
 
The drug supply will not be shipped by Clinical Research Services until the subject has 
been registered. NRG Oncology will notify Clinical Research Services to initiate each of 
these shipments after registration of the subject.  Clinical Research Services will ship drug 
for subjects registered to phase I and to subjects randomized to Arm II in the phase II 
portion.   
 
Each shipment includes a sufficient supply of niraparib for 180 days of treatment. Each 
patient can receive up to 2 shipments.  At approximately 6 months, McKesson will contact 
the study site to confirm their requirement for additional study drug for the patient and 

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arrange a day and time of delivery. 
 
Upon notification of a new subject enrollment, Clinical Research Services will call the site 
contact to confirm that the site’s shipment is being processed. Clinical Research Services’ 
distribution team will monitor packages throughout the duration of transit via the FedEx 
website and FedEx One Call Solution (live support). Real-time monitoring enables 
McKesson to mitigate potential delivery delays. 
 
Clinical Research Services will ship drug to sites in the U.S. and Canada, according to the 
following schedule: 
 
NRG-GU007 Shipment Schedule 
Subject 
Registered 
Initial e-order 
sent by NRG 
Initial e-order 
received by CRS 
(before 2 p.m. ET) 
Initial order shipped by 
CRS 
Initial order received at 
site 
Monday 
Monday 
Monday 
Monday 
Tuesday 
Tuesday 
Tuesday 
Tuesday 
Tuesday 
Wednesday 
Wednesday 
Wednesday 
Wednesday 
Wednesday 
Thursday  
Thursday 
Thursday 
Thursday 
Thursday 
Friday  
Friday 
Friday 
Friday 
Monday 
Tuesday 
 
For orders intended for sites in the U.S., Clinical Research Services will ship the order “same 
day” for all orders received before 2 p.m. ET, Monday through Thursday, via FedEx Priority 
Overnight/FedEx International Priority. Orders received after 2 p.m. ET, Monday through 
Wednesday, will be processed and shipped the next business morning. 
 
Drug deliveries are restricted during weekends and holidays. Clinical Research Services 
observes the following holidays: New Year’s Day, Memorial Day, Independence Day, Labor 
Day, Thanksgiving Day, the Friday following Thanksgiving Day, Christmas Eve, and 
Christmas Day. Sites should plan ahead to accommodate subjects being treated during 
restricted times. 
 
Please contact the Clinical Research Services program manager listed below directly for 
shipment tracking information and for anticipated delivery dates or if a shipment has 
not been received by the expected date.  
 
Questions about supply and delivery should be directed to: 
 
Clinical Research Services, a division of RxCrossroads by McKesson 
845 Regent Blvd. 
Suite 100B 
Irving, TX 75063 
Email: clinicalresearchservices@mckesson.com  
Phone:  Toll Free 800-693-4906  
 
9.2.5    Blood Pressure Monitors 
Patients receiving niraparib who do not have their own blood pressure monitor will be 

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provided one in order to monitor their heart rate and blood pressure at home according to 
the protocol requirements in section 6.2. Ordering instructions are posted on the CTSU 
website. 
 
10. PATHOLOGY/BIOSPECIMEN 
10.1 
Biospecimen Submission Tables (09-NOV-2020) 
10.1.1 Mandatory Specimen Submissions  
See detailed specimen collection/processing/shipping on the protocol-specific page of the CTSU 
website, www.ctsu.org. 
Required Study #1: Analysis of DDR mutations associated with PARPi therapy response 
1) The synthetic lethality shown in breast, ovarian and prostate cancer that are deficient in 
homologous recombination (HR) repair and which manifest as exquisite sensitivity to PARP 
monotherapy is the impetus for us to perform integrated HR and DDR biomarker analysis in this trial.  
We propose to identify genomic biomarkers of response to combination therapy with radiation, ADT 
and PARP inhibition from tumor.   
 
Biomarker Assay Description  
Next generation sequencing (NGS) using the FoundationOne® platform will be used to determine 
patient’s mutation status.  FoundationOne® is a comprehensive genomic profile that applies next-
generation sequencing in a unique manner to identify all four types of genomic alterations across 
genes known to be unambiguous drivers of solid tumors with high accuracy. The test simultaneously 
sequences the coding region of 315 cancer-related genes plus introns from 28 genes often rearranged 
or altered in cancer to a typical median depth of coverage of greater than 500x. Each covered read 
represents a unique DNA fragment to enable the highly sensitive and specific detection of genomic 
alterations that occur at low frequencies due to tumor heterogeneity, low tumor purity and small tissue 
samples. FoundationOne detects all classes of genomic alterations, including base substitutions, 
insertions and deletions (indels), copy number alterations (CNAs) and rearrangements using a small, 
routine FFPE sample (including core or fine needle biopsies).   
 
A. Specimens and Processing: 
Formalin Fixed Paraffin Embedded (FFPE) tumor specimens will be collected and prepared 
following standard pathology practices and sent to the NRGBB. The NRGBB will provide the FFPE 
tissue to FoundationOne at the end of the study. 
Prior to starting the assay, a Hematoxylin and Eosin (H&E) stained slide is prepared, and then 
reviewed by a board certified pathologist to confirm disease ontology and to ensure that adequate 
tissue (0.6 mm3), tumor content (≥20% tumor) and sufficient nucleated cells are present to proceed 
with the assay.   
 
Data on the Clinical Utility of the Integrated Assay 
 
A. Background information:  
FoundationOne is a validated comprehensive genomic profile (CGP) for solid tumors. The test is 
designed to provide physicians with clinically actionable information to guide treatment decisions 
for patients based on the genomic profile of their disease. Since the genomic profile will not be 
prepared and results will not be available until the end of the study, the profile will not guide 
treatment decisions for patients enrolled on this trial. 
 
B. Biomarker Distribution:  
FoundationOne® provides a genetic profile for each specimen submitted. 

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C. Assay Cutpoints:  
Not applicable (no cutpoints are to be used by Foundation Medicine to identify patients for study). 
 
2) Forms: ST Form and copy of pathology report with accession number and date of procedure 
visible. All other PHI information should be redacted.  
 
3) Shipping: Sites are responsible for all FFPE shipping costs. Sites can ship FFPE samples Monday-
Friday. Instructions for packing and shipping FFPE material is included with the protocol documents 
included on the CTSU website, www.ctsu.org.  
 
Ship FFPE samples to:  
Attn: NRG Oncology Biospecimen Bank – San Francisco 
UCSF box 1800 
2340 Sutter Street- Room S341 
San Francisco, CA 94115 
415-476-7864/Fax 415-476-5271 
Email: NRGBB@ucsf.edu 
 
Specimen Type  
Collection Time Points 
 
Collection Information 
and Requirements/ 
Instructions for Site 
Shipping  
 
H&E Stained Slide 
from primary tumor 
 
Pre-treatment 
H&E stained slides 
Slides can be duplicate 
cut H&Es, they do not 
have to be the diagnostic 
slides. H&E slides cannot 
be returned to sites. 
 
Ship to NRGBB-San 
Francisco 
(use cold packs during 
warm weather) 
FFPE Block from 
primary tumor  
 
 
Pre-treatment 
Paraffin-embedded block. 
Must be same block as 
H&E being submitted. 
Unstained slides are NOT 
an acceptable alternative 
for this study. For 
patients who consent to 
banking, the FFPE tissue 
will be kept at the 
Biospecimen bank 
 
Ship to NRGBB-San 
Francisco 
(use cold packs during 
warm weather) 
 
10.1.2 Optional Specimen Submissions 
(Patients must be offered the opportunity to consent to optional specimen collection. If the 
patient consents to participate, the site is required to submit the patient’s specimens as specified 
per protocol. Sites are not permitted to delete the specimen component from the protocol or from 
the sample consent.) 
 
See detailed specimen collection/processing/shipping on the protocol-specific page of the CTSU 
website, www.ctsu.org. 
 

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This study will include collection of biospecimens for future analyses. An amendment for any 
correlative science studies to be performed on biological samples will be submitted to CTEP, 
NCI for review and approval according to NCTN guidelines or via the Navigator portal after the 
trial has been reported. Amendments to the protocol and/or proposals for use of banked tissue or 
blood samples will include the appropriate background, experimental plans with assay details, 
and a detailed statistical section. Samples for testing will not be released for testing until the 
appropriate NCI approvals have been obtained. 
 
Specimen Collection for Biobanking for Potential Future Research   
Forms: ST Form 
Kits: Frozen Specimen kits can be requested from the NRGBB-SF at NRGBB@ucsf.edu. Allow 5-10 
business days for kits. Sites must have IRB approval before requesting kits.  
Shipping: One prepaid return label provided for each case for batch shipping all frozen biospecimens 
only. Batch shipments can be made once sites have collected the post treatment samples or with other 
cases.  
Shipping Days: Frozen specimens should be shipped on dry ice by priority overnight Monday-Wednesday 
for US Sites, or Monday-Tuesday for Canadian sites.  
  
Processing: Instructions for processing and shipping are included with the protocol documents included 
on the CTSU website, www.ctsu.org.  
 
Ship all specimens to:  
Attn: NRG Oncology Biospecimen Bank Staff– San Francisco 
UCSF – Dept of Radiation Oncology 
2340 Sutter Street- Room S341 
San Francisco, CA 94115 
 
 
For questions, please contact the San Francisco Bank at:  
Email: NRGBB@ucsf.edu 
415-476-7864/Fax 415-476-5271 
Specimen Type  
Collection Time 
Points 
 
Collection Information and  
Requirements/Instructions 
for Site 
Shipping 
 
WHOLE BLOOD: 
5-10 mL of 
anticoagulated 
whole blood in 
EDTA tube 
(purple/ lavender 
top) and freeze 
 
Pre-Treatment prior to 
radiation therapy 
  
Mix whole blood and aliquot a 
minimum of 1.5ml of whole 
blood into three (3) 2 ml 
cryovials.  
Storage: Freeze at -80°C and 
ship frozen with serum and 
plasma 
Batch ship on Dry Ice 
by Priority Overnight 
Courier to NRGBB -
SF 
SERUM: 5-10 mL 
of whole blood in 
1 red-top tube and 
centrifuge  
 
 
Pre-Treatment 
Ph I pts and Ph II pts 
randomized to 
niraparib: Prior to 
niraparib start 
Process serum and aliquot a 
minimum of 0.5 mL per aliquot 
into five (5) 1 mL cryovials.  
Storage: Freeze at -80°C and 
ship frozen with whole blood 
and plasma. 
 
Batch ship on Dry Ice 
by Priority Overnight 
Courier to NRGBB -
SF 

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Ph II pts not 
randomized to 
niraparib: 8 weeks prior 
RT start 
 
Post-Treatment 
Within 7 days after 
completing niraparib or 
12 months of ADT 
administration 
 
At recurrence, if 
applicable.  
PLASMA: 5-10 
mL of 
anticoagulated 
whole blood in 
THREE (3) EDTA 
tubes (purple/ 
lavender top) and 
centrifuge  
 
Pre-Treatment 
Ph I pts and Ph II pts 
randomized to 
niraparib: Prior to 
niraparib start 
 
Ph II pts not 
randomized to 
niraparib: 8 weeks prior 
RT start 
 
Post-Treatment  
Within 7 days after 
completing niraparib or 
12 months of ADT 
administration 
 
At recurrence, if 
applicable.  
Process plasma as per special 
instructions in Appendix II and 
aliquot a minimum of 4.0 ml 
per aliquot into two 5 ml 
Cryovials and the remaining 
plasma into five 
2 ml cryovials (See Appendix 
II).  
Storage: Freeze and store at -
80°C until ready to batch ship 
frozen with blood and serum. 
Batch ship on Dry Ice 
by Priority Overnight 
Courier to NRGBB -
SF 
Urine  
 
 
Pre-Treatment  
Ph I pts and Ph II pts 
randomized to 
niraparib: Prior to 
niraparib start 
 
Ph II pts not 
randomized to 
niraparib: 8 weeks prior 
RT start 
One 10 mL urine aliquot in one 
sterile 15 ml polypropylene 
centrifuge tube.  
Store frozen at -80°C. (-20° C 
is allowed for short term 
storage).  
Batch ship on Dry Ice 
by Priority Overnight 
Courier to NRGBB -
SF 
 
11. SPECIAL STUDIES (NON-TISSUE) 
Not applicable to this study. 
 
12. MODALITY REVIEWS 
12.1 Radiation Therapy Quality Assurance Reviews 
The Radiation Oncology Co-Chair, Dr. Zach Zumsteg, or NRG Oncology Headquarters 

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approved designee will perform an RT Quality Assurance Review after IROC 
Philadelphia-RT has received complete data in TRIAD. The RT reviews will be ongoing 
and performed remotely. The final cases will be reviewed within 3 months after this study 
has reached the target accrual or as soon as IROC-Philadelphia RT has received complete 
data in TRIAD for all cases enrolled, whichever occurs first. The scoring mechanism is: Per 
Protocol, Variation Acceptable, and Unacceptable Deviation. 
 
12.2 Medical Oncology Modality Quality Assurance Reviews 
The Study Chair, Dr. Dror Michaelson, or NRG Oncology Headquarters approved designee 
will perform a Systemic Therapy Assurance Review for niraparib for all patients who 
receive or are to receive systemic therapy in this trial.  The goal of the review is to evaluate 
protocol compliance.  The review process is contingent on timely submission of niraparib 
treatment data as specified in Section 12.1. The scoring mechanism is: 1) Per Protocol, 2) 
Acceptable Variation, 3) Unacceptable Deviation, and 4) Not Evaluable.   
 
Dr. Michaelson/designee will perform a Quality Assurance Review after NRG 
Headquarters has received complete data for cases enrolled. The reviews will be ongoing 
and performed remotely. The final cases will be reviewed within 3 months after this study 
has reached the target accrual or as soon as NRG Headquarters has received complete data 
for all cases enrolled, whichever occurs first. 
 
13. DATA AND RECORDS 
13.1 
Data Management/Collection (24-MAY-2022) 
Medidata Rave is a clinical data management system being used for data collection for 
this trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system 
and role assignments. Requirements to access Rave via iMedidata: 
 
A valid CTEP-IAM account; and  
 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, 
Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
 
Rave role requirements: 
o Rave CRA or Rave CRA (Lab Admin) role, must have a minimum of an 
Associate Plus (AP) registration type; 
o Rave Investigator role, must be registered as an Non-Physician 
Investigator (NPIVR) or Investigator (IVR); and 
o Rave Read Only role, must have at a minimum an Associates (A) 
registration type. 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types 
and documentation required. 
Upon initial site registration approval for the study in Regulatory Support System (RSS), 
all persons with Rave roles assigned on the appropriate roster will be sent a study 
invitation email from iMedidata. To accept the invitation, site staff  either click on the 
link in the email or log in to iMedidata via the CTSU members’ website  under Data 
Management > Rave Home and click to accept the invitation in the Tasks pane located in 

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the upper right corner of the iMedidata screen. Site staff will not be able to access the 
study in Rave until all required Medidata and study specific trainings are 
completed. Trainings will be in the form of electronic learnings (eLearnings), and can be 
accessed by clicking on the eLearning link in the Tasks pane located in the upper right 
corner of the iMedidata screen. If an eLearning is required for the study and has not yet 
been taken, the link to the eLearning will appear under the study name in the Studies pane 
located in the center of the iMedidata screen; once the successful completion of the 
eLearning has been recorded, access to the study in Rave will be granted, and a Rave 
EDC link will replace the eLearning link under the study name.  
Site staff that have not previously activated their iMedidata/Rave account at the time of 
initial site registration approval for the study in RSS will receive a separate invitation 
from iMedidata to activate their account. Account activation instructions are located on 
the CTSU website in the Data Management section under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance). Additional information 
on iMedidata/Rave is available on the CTSU members’ website in the Data Management 
> Rave section at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-
823-5923 or by email at ctsucontact@westat.com.   
 
13.2 
Summary of Data Submission (07-APR-2020) 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who 
will enroll in future studies using similar agents. Adverse events are reported in a routine 
manner at scheduled times during the trial using Medidata Rave®. Additionally, certain 
adverse events must be reported in an expedited manner for more timely monitoring of 
patient safety and care. See Section 7 for information about expedited and routine 
reporting.   
Summary of Data Submission: Refer to the CTSU website. 
Summary of Dosimetry Digital Data Submission 
 
DICOM DIGITAL 
DATA  
DICOM CT Data Set 
DICOM RT Structure 
DICOM RT Dose (2) 
DICOM RT Plan 
 
Due within 1 week of the start of 
RT 
 
TRIAD submission time point = 
          RT DIGITAL PLAN  
 
  
 
All required structures MUST be  labeled  per the tables in 
Section  Sections 5.2.4 
Digital Data Submission Information Form (DDSI)  
Upon submission of the digital data via TRIAD, complete an online Digital Data Submission 
form  https://www.irocqa.org/Resources/TRIAD 
DVH Analysis Worksheet  
Available on the CTSU website and submitted via TRIAD with the RT Digital Data listed. 
 
Submit Digital RT Data via TRIAD; see Section 8 for TRIAD account access and 
installation instructions. 

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13.3 
Data Quality Portal (18-JUN-2019) 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data Management. 
The Rave Home section displays a table providing summary counts of Total 
Delinquencies and Total Queries. DQP Queries, DQP Delinquent Forms and the 
DQP Reports modules are available to access details and reports of unanswered 
queries, delinquent forms, and timeliness reports. Review the DQP modules on a 
regular basis to manage specified queries and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and have access to 
the CTSU website. Staff that have Rave study access can access the Rave study 
data using a direct link on the DQP. 
To learn more about DQP use and access, click on the Help icon displayed on the 
Rave Home, DQP Queries, and DQP Delinquent Forms modules. 
Note: Some Rave protocols may not have delinquent form details or reports specified on 
the DQP. A protocol must have the Calendar functionality implemented in Rave by the 
Lead Protocol Organization for delinquent form details and reports to be available on the 
DQP. Site staff should contact the LPO Data Manager for their protocol regarding 
questions about Rave Calendaring functionality.   
 
13.4 
Global Reporting/Monitoring 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to 
CTEP on a quarterly basis by FTP burst of data.  Reports are due January 31, April 30, 
July 31, and October 31.  Instructions for submitting data using the CDUS can be found 
on the CTEP Web site (http://ctep.cancer.gov/reporting/cdus.html). 
 
14. STATISTICAL CONSIDERATIONS 
14.1 
Study Design (18-JUN-2019) 
14.1.1 Phase I Design 
To evaluate the safety and tolerability of the combined regimen, a phase I trial will be 
conducted.  Dose limiting toxicities (DLTs) will be defined by NCI CTCAE version 5.  
Any treatment-related gastrointestinal or genitourinary Grade 3 or higher adverse events 
(AE) lasting > 1 week, despite maximal medical interventions, will be considered a DLT.  
Additionally, any treatment-related Grade 4 AEs lasting > 1 week will be considered a 
DLT.  Relationship to treatment will be determined by the responsible clinician, and 
specifics of each putative DLT will be reviewed by the study chairs prior to formal 
declaration of DLT.  The evaluation window for DLTs will be from inception of 
combined ADT and niraparib therapy through 6 months of treatment.  Three dose tiers 
will be considered as described in Section 5.1. The dose-identification scheme will 
proceed as follows: 
 

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Background 
 The basic treatment schedule is 8 weeks daily niraparib (PO) + ADT (GnRH agonist), 
then 6-8 weeks niraparib + ADT + RT, then niraparib + ADT for total duration of 12 
months   
 The proposed DLT window is the first 6 months of therapy 
 Safety has already been established for 200 mg of niraparib given concurrently with ADT 
 Given the myelosuppression of niraparib as a single agent, although in platinum treated 
patients, when given with pelvic RT, myelosuppression can be expected to dictate the 
MTD 
 Thus, the part of the regimen for which safety must be more clearly established begins 
after the first 8 weeks of therapy, when patients start to receive concurrent niraparib 
and RT 
Note: For the remainder of this summary, we break the treatment schedule into three parts: 
Part 1: the first 8 weeks of niraparib + ADT  
Part 2: the 6-8 weeks following part 1 when patients receive niraparib + ADT + RT  
Part 3: the period following part 2 when patients receive niraparib + ADT until 12 
months of therapy have been completed 
 
The following is a summary of the four dose levels.  Though we don’t include it in the table, note 
that patients will also receive concurrent ADT throughout parts 1-3.   
 
Part 1 
Part 2 
Part 3 
Level 0 
100 mg niraparib 
0 mg niraparib + RT 
100 mg niraparib 
Level 1 (starting 
dose) 
100 mg niraparib 
100 mg niraparib + 
RT 
100 mg niraparib 
Level 2 
200 mg niraparib 
100 mg niraparib + 
RT 
200 mg niraparib 
Level 3 
200 mg niraparib 
200 mg niraparib + 
RT 
200 mg niraparib 
 
 
 
 
 
Dose escalation scheme 
1. Enroll 3 patients at dose level 1 and observe for 2 months (i.e. until the completion of part 1).  
Once all 3 of these patients have completed part 1, enroll up to 3 additional patients at dose level 
1.     
 If none of the first 3 patients experience a DLT by the time the second cohort of patients 
reaches part 2, the second cohort may continue with part 2 of dose level 1. 
 If 1 of the first 3 patients experiences a DLT before the second cohort reaches part 2, the 
second cohort should proceed to part 2 of dose level 0.  Note that these patients will 
become “level 0” patients, since the regimen they receive will be identical to that of dose 
level 0.  No additional patients should be enrolled at dose level 1 until the first 3 have 
been observed for the full 6-month DLT window. 
 If 2 or more of the first 3 patients experience a DLT before the second cohort of patients 
have reached part 2, the second cohort should proceed to part 2 of dose level 0, and dose 
level 1 (and levels 2 and 3) should be permanently closed. 
 Escalation to dose level 2 should follow the safety guidelines outlined below. 

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2a. If dose level 1 is closed, either permanently or temporarily (i.e. until the first 3 patients 
complete the “full” evaluation period) for reasons outlined above, up to 6 patients may be 
enrolled at dose level 0 (including those who were moved to dose level 0 due to toxicity in the 
first cohort at dose level 1). Escalation should follow the safety guidelines outlined below.   
 
2b. If initial evidence suggests dose level 1 is safe (i.e. the criteria for escalation have been met), 
enroll up to 6 patients at dose level 2 (since part 2 of dose level 2 is the same as that for dose 
level 1) and observe.  Escalation/de-escalation should follow the safety guidelines outlined 
below.   
 
3. If appropriate, enroll 3 patients at dose level 3 and observe until the completion of part 1.  
Once all 3 of these patients have completed part 1 of dose level 3, enroll up to 3 additional 
patients at dose level 3.   
 If none of the first 3 patients experience a DLT by the time the second cohort of patients 
reaches part 2, the second cohort may continue with part 2 of dose level 3. 
 If 1 of the first 3 patients experiences a DLT before the second cohort reaches part 2, the 
second cohort should proceed to part 2 of dose level 2.  Note that these patients will 
become “level 2” patients, since the regimen they receive will be identical to that of dose 
level 2.  No additional patients should be enrolled at dose level 3 until the first 3 have 
been observed for the full 6-month DLT window. 
 If 2 or more of the first 3 patients experience a DLT before the second cohort of patients 
have reached part 2, the second cohort should proceed to part 2 of dose level 2, and dose 
level 3 should be permanently closed. 
 De-escalation should follow the safety guidelines outlined below. 
4. Once all dose levels are permanently closed and all patients have been observed for the full 6-
month DLT window, identify the recommended phase II dose (RP2D).  The RP2D will be the 
highest dose at which at least 6 patients have been enrolled and < 33% of patients have 
experienced a DLT. 
 
Additional safety guidelines 
 Dose levels at which 6 or more patients have been treated should be permanently closed 
to new patients.     
 A maximum of 12 patients may be enrolled at a dose level; however, this number may 
only exceed 6 in situations where a second cohort of patients has been enrolled to a dose 
level and at least 1 of the first 3 patients at that dose level subsequently experiences a 
DLT before the second cohort of patients has reached part 2 of the treatment (in which 
case the second cohort of patients would be moved to the previous dose level). 
 If 1 DLT is observed on a dose level, no more patients may be added to this dose level 
until the full DLT evaluation period has been completed on the first 3 patients. 
 After the first 3 patients have been fully evaluated for DLT, if 1 out of 3 DLTs have been 
observed, then up to 3 additional patients may be accrued to the dose level (not to exceed 
a maximum of 6 total patients at this dose level).  
 New patients should not be assigned to a dose level at which 4 or more patients have 
been fully evaluated and ≥ 33% of the patients have experienced a DLT. 

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 New patients should not be assigned to a dose level above a dose level where ≥ 33% of 
the fully evaluated patients have experienced a DLT. 
 After the first 3 patients have been fully evaluated for DLT, if 1 out of 3 DLTs have been 
observed, then at least 1 additional patient must complete the full evaluation period 
before an escalation decision can be made. 
 The dose can be escalated if 0/3 DLTs are observed among a fully evaluated  cohort or 
1/4 among a fully evaluated cohort. 
 
NOTES:  
 
If any patients experience protocol-defined DLTs during the pre-radiation portion 
of the study treatment, they will be considered unevaluable for safety and 
tolerability of the combined regimen.  Such patients will be discontinued from 
study treatment, and should be replaced with another patient. 
 
The duration of the phase I trial is projected to last between 2.3 to 3.3 years.  
 
After the start of the accrual, NRG Headquarters will provide current toxicity data to 
the study chairs every two weeks. The study chairs will follow up any report of an 
SAE or DLT with the site investigators.   The study team, including the study 
chairs, study statisticians, data managers and protocol administrator, as well as a 
representative from any site with a patient currently within the DLT window, will 
hold monthly conference calls to review the overall conduct of the study. Data on 
treatment dose delivery, adverse events reported, patient demographics and 
eligibility will be assembled and reviewed.  At each meeting, consideration will 
also be given to the rate of accrual.  When a decision on dose de-
escalation/escalation must be made, the study team will hold a special conference 
call to review information including the categorization and grading of reported 
adverse events, determination of the dose-limiting toxicities, etc. The decision to 
de-escalate or escalate will be made by consensus of the study team in accordance 
with the decision rules outlined in the protocol.  Brief minutes of each meeting 
will be written to document the review of information and any decision made. The 
meeting minutes will be submitted to the NRG Early Phase Protocol Monitoring 
Oversight Committee for review. 
 
Any patient who has not experienced a DLT and withdraws from the trial before 
completion of the 6-month DLT evaluation window will be considered 
unevaluable for safety and tolerability.  Such patients will be discontinued from 
study treatment, and should be replaced with another patient. 
 
14.1.2 
Phase II Design 
The objective of the phase II trial is to determine whether the combination of 
niraparib with radiation and ADT is sufficiently promising to warrant phase III 
testing.  The dose of niraparib will be the MTD established in phase I.  The triple 
combination will be compared to a concurrent, randomized control arm consisting of 
RT and ADT without niraparib.  Randomization will be stratified according to the 
eight strata defined in the study schema (4 risk groups x 2 types of RT).  The primary 
endpoint, considered a good surrogate for disease-specific survival, is maintenance of 
PSA <0.1 for 2 years from the start of ADT.  

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From observations in RTOG 0521 (conducted among the same patient population as 
this trial), at the end of ADT, 32% of patients maintained a PSA < 0.1. These patients 
exhibited a lower frequency of distant metastasis, consistent with other studies 
evaluating functions of PSA as surrogate endpoints for later clinical disease endpoints 
(Denham 2008; D’Amico 2012; Royce 2017). Specifically, among patients who 
maintained the low PSA state, subsequent incidence of distant metastatic disease is 
currently about 5%. Among men with PSA exceeding 0.1 during or at completion of 
ADT, about 20% subsequently have experienced distant metastatic disease. Overall 
survival rates through 6 years post-trial entry are 88% among those who maintained 
low PSA through 2 years post-RT, compared to 81% among those who had PSA 
exceeding 0.1 by 2 years. 
More mature data from a trial in the same class of patients (but for which the 
proposed endpoint is not available and thus conventional ‘PSA failure’ status by the 
Phoenix definition was used) also indicates that early avoidance of PSA progression 
is indicative of longer term prognosis. Among patients from the long-term ADT arm 
of RTOG 9202 who were free of conventional PSA failure at 2 years, subsequent 5-
year overall survival (i.e., 7 years from diagnosis) was 76%, compared to 54% among 
those who had PSA failure during the 2-year treatment interval. As expected, this 
difference was almost wholly due to avoidance of prostate cancer death, as the 
difference in cumulative incidence of prostate cancer death was over 20% (4% vs. 
28%), while the difference in other cause-death was negligible (20% vs. 18%) 
(unpublished, submitted manuscript). Thus it is anticipated that this endpoint will 
provide an informative evaluation of whether the experimental regimen will lead to 
material gains in clinical endpoints, and thus whether a larger scale trial is warranted.  
 
14.2 
Study Endpoints 
14.2.1 Primary Endpoint: Maintenance of a disease-free state characterized by PSA values 
sustained below 0.1 ng/ml for 2 years following initiation of ADT. 
14.2.2 Secondary Endpoints 
 Overall survival, i.e., time from randomization until death from any cause.   
 Prostate cancer-specific survival, defined as time from randomization until death 
from prostate cancer.  Patients who die from other causes will be censored as of the 
time of death.   
 Pathologic complete response among patients undergoing 12-core biopsy at 24 
months. 
 Time to local/regional or distant progression.  Patients who die prior to development 
of local/regional or distant progression will be censored at the time of death. 
 Time to distant metastases, defined as time from randomization until detection of 
distant metastatic disease.  Patients who die prior to development of distant 
metastases will be censored at the time of death. 
 Biochemical progression-free survival (bPFS), defined as PSA > 2 ng/ml over the 
nadir PSA, the presence of local, regional, or distant recurrence, or death from 
prostate cancer.  Patients who receive salvage androgen deprivation therapy prior to 
the occurrence of a bPFS event will be censored at the time of salvage treatment.  
Patients who die from causes other than prostate cancer will be censored as of the 

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time of death. 
 Adverse events, which  will be categorized as early (within 90 days of completion of 
radiotherapy) or late (more than 90 days after the completion of radiotherapy). 
14.2.3 Exploratory Endpoints 
 Targeted exome sequencing of the genes most commonly altered in prostate cancer, 
including DNA repair genes (BRCA2, BRCA1, ATM, PALB2, RAD51B, and 
RAD51C) and more commonly detected alterations (p53 mutation, ETS gene fusions, 
and PTEN loss). 
 Transcriptome-wide analysis of gene expression using a high-density Affymetrix 
oligonucleotide array to profile the transcriptome of tumor samples 
 Whole blood samples will be analyzed for single nucleotide polymorphisms 
previously associated with prostate cancer risk. Plasma samples will be assessed for 
baseline and post-therapy alterations in a targeted gene panel and for reversion 
mutations in DNA repair genes as early biomarkers of treatment resistance. 
 
14.3 
Primary Objectives Study Design 
14.3.1 Primary Hypothesis and Endpoints 
The primary endpoint is maintenance of a disease-free state characterized by PSA values 
sustained below 0.1 ng/ml until the completion of treatment; specifically, for two years 
following the start of ADT. PSA levels will be assessed prior to the start of RT, at the end 
of RT, and every three months for 24 months. Based on data from RTOG 0521, it is 
hypothesized that treatment with ADT and RT alone achieves a 30% disease-free rate at 
24 months and that the addition of niraparib will increase this percentage to 50%, i.e., a 
20% absolute improvement.   
14.3.2 How Primary Endpoints Will Be Analyzed 
A modified intent-to-treat (mITT) analysis will be conducted that includes all randomized 
patients except those deemed to have been inappropriately randomized due to ineligibility 
and those lost to follow-up prior to 2 years.  In order to be considered a responder, all 
PSA values obtained up to and including the two-year landmark must be < 0.1 ng/ml. 
Patients who die prior to two years from prostate cancer will be counted as failures.  
Patients who die from causes other than prostate cancer will be considered non-evaluable 
for the primary endpoint. It is not anticipated that early deaths will diminish the cohort in 
any meaningful way, but cumulative incidence of deaths and other events that render 
patients unevaluable for the primary endpoint will be estimated to assess any impact on 
statistical power and whether adjustments to the sample size are required. 
 
Patients still under follow-up but who have a missing PSA value at two years or more 
than two missing values prior to two years will also be counted as failures.   The 
proportion of patients disease-free at 24 months will be compared in the two treatment 
arms using a non continuity-corrected chi-square test.  As a secondary analysis, a logistic 
regression model will be fit to adjust for the stratification factors (risk group and type of 
RT). 
14.3.3 Sample Size and Power Calculations 
Assuming that high-risk patients targeted for enrollment in this trial have a true response 
rate to ADT+RT of 30% for this endpoint, then for 85% power at a one-sided type I error 
rate of 5%, 85 patients per arm (170 total) are required to detect a 20% absolute 

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improvement (to 50%) in the 2-year rate of maintained low PSA with the addition of 
niraparib. With an assumed ineligibility rate of 5%, a maximum of 90 patients per 
arm will be accrued, for a total maximum of 180 patients. 
 
14.4 
Study Monitoring of Primary Objectives 
14.4.1 Interim Analysis for the DMC 
The NRG Oncology Data Monitoring Committee (DMC) will review the study twice a year 
with respect to patient accrual and morbidity. The DMC also will review the study on an 
“as needed” basis. A formal futility rule will be employed. If at 50% of trial endpoint 
information, the response rate in the experimental regimen is equal to or less than that in 
the standard treatment, then discontinuation of accrual (if relevant) and further 
experimental agent treatment will be considered. This futility rule is associated with a 
minimal power loss of typically less than 2% (Wierand 1987). At this juncture an O’Brien-
Fleming (O’Brien 1979) efficacy bound will also be employed. If the z-statistic exceeds 
2.37 in favor of niraparib (one-sided p<0.0089), then early termination of the trial for 
efficacy will be considered.  This boundary will maintain the overall type I error rate at 5% 
(one-sided) with a slight adjustment of the final critical p-value to 0.047. 
14.4.2 Safety 
Because this is a novel combination in this setting, two additional comprehensive safety 
evaluations will be conducted during the Phase II portion.  After 50 randomized patients 
(25 per arm) reach 6 months on study, we will summarize and compare the frequency of 
specific adverse events of concern. Grade 3 and grade 4 estimated frequencies in the 
experimental arm will be compared to threshold values, with particular regard to CBC 
values, gastrointestinal and genitourinary adverse events. The overall adverse event 
frequency distributions will also be compared between the standard and experimental arms 
to assess tolerability of the regimen, as well as any likely impact on compliance, using chi-
square and Fisher exact tests.  Note that accrual to the trial will not be suspended during 
these evaluations unless a major concern is identified. If no major concerns arise and the 
study continues, another comprehensive safety evaluation will then be performed after 100 
randomized patients (50 per arm) reach 6 months on study.   
 
Second primary malignancies will be recorded throughout the trial, with observed 
incidence compared between arms and to expected incidence based on age-standardized 
national rates. 
 
14.5 
Accrual/Study Duration Considerations (18-JUN-2019) 
 
 The phase I portion will enroll cohorts of 3-6 patients at an expected rate of 3 patients 
every 2 months.   Given the requirement for suspensions of accrual, the duration of the 
phase I trial is projected to last between 2.3 to 3.3 years, and phase II enrollment will then 
proceed seamlessly. Based on recent history with high-risk prostate cancer, accrual of 10-
15 patients per month is readily achievable during phase II.  It is projected that the phase 
II study will complete accrual in 18 months.  The last patient enrolled will be followed 
for two years, giving a total study duration for the phase II trial of 3.5 years. 
 
14.6 
Dose Level Guidelines 
 
These are specified in Sections 5.1, 6.1, and 6.2 above. 

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14.7 
Secondary Analyses  
Analysis of secondary time-to-event endpoints will consist of comparison of Kaplan-
Meier (Kaplan 1958) curves using a logrank test for overall survival, prostate-cancer 
specific survival, and biochemical progression-free survival (bPFS).  Cumulative 
incidence curves for time to local/regional or distant progression, time to distant 
metastases, and death from prostate cancer and their associated competing risk will be 
compared using the Fine-Gray test (Dignam 2008).  Cox (1972) regression models will 
also be fit to assess and adjust for the effects of the stratification variables and other 
covariates.  The proportional hazards assumption will be tested using graphical methods 
(Kay 1997) and Schoenfeld residuals (Grambsch 1994), and if violated an alternative 
metric, such as comparison of restricted means at 3 years, will be performed (Karrison 
1997).  The restricted means will be compared both unadjusted and adjusted for the 
stratification factors (Karrison 2018). 
The proportion of patients with complete pathologic response (pCR) at 24 months will be 
compared using a chi-square test. Assuming that in this high risk population the expected 
positive biopsy rate is 25%, then for 80% power at one-sided type I error rate of 5%, 45 
patients per arm (90 total) will be required to detect an absolute reduction of 20% (to 5%) 
in the 2-year pCR rate. If a biopsy participation rate of at least 60% can be achieved 
among trial enrollees, then this sample size will be obtained. It is anticipated that greater 
participation may be achieved, which will allow for adequate power over a range of 
control group biopsy positivity rates and reductions due to the addition of niraparib. 
Adverse event (AE) rates in the two treatment arms will be summarized by time of 
occurrence (early vs. late), type, grade, and attribution to treatment.  For each type of AE, 
the worst grade occurring during the early treatment period, late treatment period, or 
entire treatment period will be determined.  For each time period, treatment group 
comparisons will be conducted using chi-square or Fisher exact tests.. 
 
14.8 
Exploratory Hypothesis and Endpoints  
Exploratory endpoints/objectives are: 
 Targeted exome sequencing of the genes most commonly altered in prostate cancer, 
including DNA repair genes (BRCA2, BRCA1, ATM, PALB2, RAD51B, and 
RAD51C) and more commonly detected alterations (p53 mutation, ETS gene fusions, 
and PTEN loss). 
 Transcriptome-wide analysis of gene expression using a high-density Affymetrix 
oligonucleotide array to profile the transcriptome of tumor samples. 
 Whole blood samples will be analyzed for single nucleotide polymorphisms 
previously associated with prostate cancer risk. Plasma samples will be assessed for 
baseline and post-therapy alterations in a targeted gene panel and we will assess for 
reversion mutations in DNA repair genes as early biomarkers of treatment resistance. 
 
Descriptive statistics will be generated summarizing the frequency of gene alterations, 
mutations, and gene expression levels. The percentage of patients with baseline or post-
therapy alterations in targeted genes will be reported and the association between the 
occurrence of reversion mutations in DNA repair genes and clinical outcomes will be 

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assessed using logistic regression models for dichotomous endpoints (disease-free state, 
pCR), and Cox regression or competing risk regression modeling for time-to-event data. 
 
14.9 
Gender/Ethnicity/Race Distribution  
Phase I (assumes maximum 36 patients enrolled) 
 
 
Racial Categories 
DOMESTIC PLANNED ENROLLMENT REPORT 
Ethnic Categories 
Not Hispanic or 
Latino 
Hispanic or Latino 
 
Total 
Female 
Male 
Female 
Male 
American Indian/Alaska 
Native 
N/A 
0 
N/A 
0 
0 
Asian 
N/A 
1 
N/A 
0 
1 
Native Hawaiian or Other 
Pacific Islander 
N/A 
0 
N/A 
0 
0 
Black or African American 
N/A 
4 
N/A 
0 
4 
White  
N/A 
23 
N/A 
4 
27 
More Than One Race 
N/A 
0 
N/A 
0 
0 
Total 
N/A 
28 
N/A 
4 
32 
 
 
 
Racial Categories 
INTERNATIONAL (including Canadian participants) 
PLANNED ENROLLMENT REPORT 
Ethnic Categories 
Not Hispanic or 
Latino 
Hispanic or Latino 
 
Total 
Female 
Male 
Female 
Male 
American Indian/Alaska 
Native 
N/A 
0 
N/A 
0 
0 
Asian 
N/A 
1 
N/A 
0 
1 
Native Hawaiian or Other 
Pacific Islander 
N/A 
0 
N/A 
0 
0 
Black or African American 
N/A 
1 
N/A 
0 
1 
White  
N/A 
2 
N/A 
0 
2 
More Than One Race 
N/A 
0 
N/A 
0 
0 
Total 
N/A 
4 
N/A 
0 
4 
 

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Phase II 
 
 
Racial Categories 
DOMESTIC PLANNED ENROLLMENT REPORT 
Ethnic Categories 
Not Hispanic or 
Latino 
Hispanic or Latino 
 
Total 
Female 
Male 
Female 
Male 
American Indian/Alaska 
Native 
N/A 
1 
N/A 
0 
1 
Asian 
N/A 
2 
N/A 
0 
2 
Native Hawaiian or Other 
Pacific Islander 
N/A 
1 
N/A 
0 
1 
Black or African American 
N/A 
21 
N/A 
0 
21 
White  
N/A 
122 
N/A 
13 
135 
More Than One Race 
N/A 
2 
N/A 
0 
2 
Total 
N/A 
149 
N/A 
13 
162 
 
 
 
Racial Categories 
INTERNATIONAL (including Canadian participants) 
PLANNED ENROLLMENT REPORT 
Ethnic Categories 
Not Hispanic or 
Latino 
Hispanic or Latino 
 
Total 
Female 
Male 
Female 
Male 
American Indian/Alaska 
Native 
N/A 
1 
N/A 
0 
1 
Asian 
N/A 
3 
N/A 
0 
3 
Native Hawaiian or Other 
Pacific Islander 
N/A 
0 
N/A 
0 
0 
Black or African American 
N/A 
2 
N/A 
0 
2 
White  
N/A 
10 
N/A 
1 
11 
More Than One Race 
N/A 
1 
N/A 
0 
1 
Total 
N/A 
17 
N/A 
1 
18 
 
 
 
 

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APPENDIX I 
PATIENT’S PILL DIARY: NIRAPARIB 
 
NRG-GU007: Randomized Phase II Trial of Niraparib With Standard Combination Radiotherapy and 
Androgen Deprivation Therapy (ADT) in High Risk Prostate Cancer (With Initial Phase I) 
 
Today’s date:  
Patient Initials:  
Patient Study ID: CASE #  
 
 
Instructions to patient: Place the date and number of pills taken in the appropriate column. Complete one page for 
each 30 days of treatment for a total of 365 days. Be sure to bring the pill diary to your appointments as 
instructed. 
 
Take ( ___) pills each day and at the same time each day with or without food unless you have been instructed 
by your physician to take less or to stop taking the drug for a period of time. If you forget to take pills on one 
day do NOT take a double dose the next day just chart that no pills were taken on that date (0). Feel free to 
make any comments during treatment. 
Month #  
 
DATE 
DAY 
NUMBER OF PILLS TAKEN 
DAILY 
COMMENTS 
 
1 
 
 
 
2 
 
 
 
3 
 
 
 
4 
 
 
 
5 
 
 
 
6 
 
 
 
7 
 
 
 
8 
 
 
 
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SITE USE ONLY: NUMBER OF PILLS TAKEN:
 
TOTAL DOSE TAKEN (# PILLS X 100mg): 
 
 

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APPENDIX II (07-APR-2020) 
PLASMA PROCESSING GUIDELINES 
 
Collect THREE 10mL EDTA tubes.  Fill tubes completely.   
Mix gently by inverting the tubes ten (10) times.   
 
SPIN #1 
Centrifuge at room temperature for 10 min at 1600 (±150) g.  If centrifuge uses rpm (revolutions 
per minute), see centrifuge instructions for the conversion to g.  Centrifugation at 4°C is 
acceptable. 
 
To ensure stability of the sample, time between draw and preservation should not exceed 4 
hours. 
 
After centrifugation, transfer supernatant of the EDTA tubes to two fresh 15mL centrifuge tubes 
without disturbing the cellular layer using a disposable pipette. Be sure to pre-label the transfer 
tubes.   
 
Discard EDTA tubes. 
 
SPIN #2 CRITICAL STEP 
Centrifugation separates plasma from leukocytes and erythrocytes. Leaving sufficient residual 
plasma in the tubes after the centrifugation and not disturbing the leukocyte layer when pipetting 
is a critical step in the sample preparation process.  Be careful not to disturb leukocyte layer in 
the tubes when transferring the plasma 
 
Centrifuge the plasma in the 15mL centrifuge tubes at room temperature for 10 min at 3000 
(±150) g. 
 
CRITICAL STEP 
The 2nd centrifugation is intended to remove any residual intact blood cells carried over from the 
1st centrifugation step.  
 
After centrifugation, transfer supernatant to a fresh 15mL centrifuge tube without disturbing the 
cellular layer using a disposable pipette. Be sure to pre-label the transfer tubes. 
 
CRITICAL STEP 
Expect ~4 mL plasma per 10 mL of whole blood.   Leave a residual volume of about 0.3mL (~7 
mm) on the bottom of the 15mL tube to avoid contaminating the plasma with cells. 
 
After transferring the plasma to a new 15mL centrifuge tube as described, gently mix plasma.  
 
Transfer plasma into each of the two 5 mL cryovials and the remainder into five 2 mL cryovials. 
All plasma should be retained.   
 
Immediately after processing, place cryovials into a storage box and freeze upright. Store 
samples at -80°C or lower in a non-self-defrosting freezer until shipment. 

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APPENDIX III- PATIENT BLOOD PRESSURE AND HEART RATE DIARY  
(09-NOV-2020) 
Today’s Date ___________________________ 
Site Name:____________________ 
Patient Name ______________________________ 
Patient Study ID _________________ 
Instructions:  
You will receive instruction to use the blood pressure device and take a heart rate reading (if not provided 
by the blood pressure device) from the study team. 
 
Heart Rate: 
1. Your blood pressure device gives you your heart rate.  
2. If your blood pressure device does not have a heart rate reading, manually take your heart rate. 
 
Blood Pressure:  
1. Make sure you know how to use your blood pressure monitor and that the cuff that goes on your arm 
is the proper size. 
2. Your blood pressure readings have two numbers. The first number is the pressure in your blood 
vessels during a heart beat (systolic), and the second number is the pressure in the vessels when the 
heart rests in between beats (diastolic). These numbers are usually written with a slash in between 
them (for example, normal blood pressure is 120/80). 
3. Take your blood pressure at the same time of day and, if possible, in the morning before activity 
(such as making breakfast, dressing ,etc.). It is important to take your blood pressure when you are at 
rest. This means should be sitting still for at least 10 minutes before taking your blood pressure. 
4. Record the date, time, and record your blood pressure reading. 
 Your treating physician will monitor and interpret your blood pressure log. 
 Home blood pressure monitoring is not a substitute for professional measurements. 
5. Please contact your local doctor’s office for instructions, if the follow occur; 
 If your systolic pressure is greater than 170 OR your diastolic blood pressure is greater than 110, 
 If your heart rate is greater than 120 or lower than 50. 
6. Please bring this form to every clinic visit or appointment.  
 
WEEKLY 
MONTH/WEEK DATE TIME 
BLOOD 
PRESSURE 
HEART 
RATE/PULSE 
COMMENTS 
1/1 
 
 
 
 
 
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2/4 
 
 
 
 
 
 
 

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DATE 
TIME 
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PRESSURE 
HEART 
RATE/PULSE 
COMMENTS 
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