Conditions: Metastatic Castration Resistant Prostate Cancer
Keywords: CRPC PARP inhibitor PARPi BRCA ATM HRD TRITON homologous recombination DNA repair DNA defect DNA anomaly germline somatic mCRPC
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 405
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine how participants with metastatic castration-resistant prostate cancer, and evidence of a homologous recombination gene deficiency, respond to treatment with rucaparib versus treatment with physician's choice of abiraterone acetate, enzalutamide, or docetaxel.

Detailed description:

Arms:
arm 1: Oral rucaparib (monotherapy). arm 2: Oral abiraterone acetate (monotherapy, given in combination with prednisone). Oral enzalutamide (monotherapy). Intravenous docetaxel (monotherapy, given in combination with prednisone or prednisolone).

Interventions: intervention 1: Rucaparib intervention 2: Abiraterone acetate or Enzalutamide or Docetaxel
Intervention descriptions: intervention 1: Rucaparib will be administered daily. intervention 2: Abiraterone acetate and enzalutamide will be administered daily. Docetaxel will be administered every 3 weeks.

Protocol document:
Prot_000.pdf: 
 
 
ClinicalTrials.gov Oﬃcial Title: A Study of Rucaparib Versus 
Physician's Choice of Therapy in PaƟents With MetastaƟc 
CastraƟon-resistant Prostate Cancer and Homologous 
RecombinaƟon Gene Deﬁciency (TRITON3) 
 
 
ClinicalTrials.gov IdenƟﬁer Number: NCT02975934    
 
 
 
Document Date: 18 February 2022 
 
 
 
Document: Clinical Study Protocol CO-338-063 
 
 
Study Title: TRITON3: A MulƟcenter, Randomized, Open-label 
Phase 3 Study of Rucaparib versus Physician’s Choice of 
Therapy for PaƟents with MetastaƟc CastraƟon-resistant 
Prostate Cancer Associated with Homologous RecombinaƟon 
Deﬁciency 








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PROTOCOL ACCEPTANCE FORM 
Protocol: 
CO-338-063 
Title: 
TRITON3: A Multicenter, Randomized, Open-label Phase 3 Study of 
Rucaparib versus Physician’s Choice of Therapy for Patients with Metastatic 
Castration-resistant Prostate Cancer Associated with Homologous 
Recombination Deficiency 
 
Date: 
18 February 2022 
Version: 
Amendment 4 
 
 
I have carefully read this protocol and agree that it contains all of the necessary information 
required to conduct this study. I agree to conduct this study as described and according to the 
Declaration of Helsinki, ICH Guidelines for GCP, and all applicable regulatory requirements. 
 
 
 
  
Investigator’s Signature 
 Date 
 
(dd month yyyy) 
 
  
Name (printed) 
  


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1 
SYNOPSIS 
Sponsor 
Clovis Oncology, Inc. 
Name of Finished Product 
Rucaparib tablets  
Name of Active Ingredient 
Rucaparib camsylate (CO-338) 
Study Title 
TRITON3: A Multicenter, Randomized, Open-label Phase 3 Study of Rucaparib versus 
Physician’s Choice of Therapy for Patients with Metastatic Castration-resistant Prostate 
Cancer Associated with Homologous Recombination Deficiency 
Study Number 
CO-338-063  
Study Phase 
Phase 3 
Rationale 
Deoxyribonucleic acid (DNA) is constantly damaged by both endogenous and exogenous 
(environmental) assaults. Normal cells repair single-strand breaks (SSBs) in DNA through a 
process known as base excision repair (BER).1 While there are several variations of BER, all 
pathways rely on the activity of poly (adenosine diphosphate [ADP]-ribose) polymerase 
(PARP) enzymes. SSBs that are not repaired result in stalled replication forks and the 
development of double-strand breaks (DSBs), which are in turn repaired by homologous 
recombination (HR) DNA repair, a complex process involving multiple proteins, including 
those encoded by breast cancer susceptibility gene 1 and 2 (BRCA1 and BRCA2), as well as 
ataxia telangiectasia mutated serine/threonine kinase (ATM), RAD51, Fanconi anemia core 
complex, and ataxia telangiectasia and RAD3-related (ATR) protein, among others.1 
Homologous recombination defects or PARP inhibition on their own can be overcome by a 
cell, but the combination is fatal, a concept termed “synthetic lethality”, and which forms the 
basis of the therapeutic approach of using PARP inhibition to kill cancer cells with a 
HR-deficient background.1-3 
Prostate cancer is the most common malignancy among men in the United States, and the 
second-most common cause of cancer-related mortality, with approximately 30,000 men dying 
of the disease each year.4 Based upon GLOBOCAN 2012 estimates, prostate cancer is the 
second leading malignancy diagnosis and fifth leading cause of death from cancer in men in 
worldwide, with 307,000 deaths estimated in 2012.5 The course of prostate cancer from 
diagnosis to death is often a series of clinical states progressing from localized disease to 
metastatic castration-resistant prostate cancer (mCRPC), a disease state characterized by 
resistance to standard androgen deprivation therapies (ADT) and that accounts for the majority 
of prostate cancer deaths.  


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Homologous recombination deficiency (HRD) has been observed in many carcinomas, 
including prostate cancer. Men with a germline mutation in BRCA2 are at increased risk for 
developing prostate cancer, estimated at 2.5 to 8.6-fold compared with non-carriers.6 Men with 
prostate cancer and a germline mutation in BRCA2 typically develop disease at a younger age, 
have more aggressive features and higher mortality rates. While less common in prostate 
cancer, germline mutations in BRCA1 are also associated with more aggressive disease.7 In 
addition to germline mutations in BRCA1/2, somatic mutations in BRCA1/2 and other 
homologous recombination repair (HRR) genes (eg, ATM, Fanconi anemia, complementation 
group A [FANCA]) have been shown to occur in advanced prostate cancer, suggesting that a 
significant percentage of patients with mCRPC may benefit from approaches exploiting a 
deficiency in HRR, such as treatment with a PARP inhibitor (PARPi).8 A recent clinical study 
reported that 16 of 49 evaluable patients with advanced heavily pre-treated mCRPC had a 
response to the PARPi olaparib. Among the 16 evaluable patients in this study with HRR gene 
mutations, 14 (88%) had a response. Consistent with previous findings, gene mutations were 
most commonly observed in BRCA2 and ATM.9 These findings provide compelling evidence 
for use of a PARPi in a selected population of mCRPC patients with predicted loss-of-function 
mutations in BRCA1/2 and ATM. 
Androgen deprivation therapy is the standard first-line systemic treatment for metastatic 
prostate cancer. It is highly active with clinical, radiographic and prostate-specific antigen 
(PSA) responses for most patients – but almost all men will eventually progress to mCRPC. 
Over the last 10 years, multiple therapies have been shown to confer a survival benefit for 
patients with mCRPC and were approved on this basis, including docetaxel, cabazitaxel, 
Sipuleucel-T, radium Ra 223 dichloride, and two agents that target the androgen receptor (AR) 
pathway, abiraterone acetate and enzalutamide.10-14 More recently, abiraterone has 
demonstrated a survival advantage for patients with metastatic high-risk castration-sensitive 
prostate cancer,15 and in separate studies, both enzalutamide and apalutamide have 
demonstrated improvement in metastasis-free survival in patients with non-metastatic 
castration-resistant prostate cancer.16, 17 Based on their tolerability and proven efficacy in the 
pre-chemotherapy setting, abiraterone acetate and enzalutamide are often used as first-line 
therapies for mCRPC; however, patients progress on these agents after a median duration of 
16 to 18 months on treatment. Some patients receive a second regimen of AR-directed 
therapy; however, response rates are low in this setting.18-21 For many patients who have 
progressed on AR-directed therapy, systemic chemotherapy is the next treatment option. 
Treatment options include docetaxel (75 mg/m2 every 3 weeks) plus prednisone, cabazitaxel 
plus prednisone, radium Ra 223 dichloride, and sipuleucel-T. The two latter agents are 
generally well-tolerated and thus reasonable treatment options for patients prior to receiving 
treatment with chemotherapy or for patients with bone-only disease. 
Despite clinical benefit from AR-directed therapy and chemotherapy, mCRPC patients 
eventually develop progressive disease. Novel therapies that provide robust clinical benefit 
and have a good safety profile are still needed for patients with advanced mCRPC, and a 
targeted therapy such as a PARPi for the subset of patients who exhibit features of HRD 
represents an attractive option. 
Primary Objective: 
• To assess the efficacy of rucaparib versus physician’s choice of treatment based on 
radiographic progression free survival (rPFS) in mCRPC patients with HRD who 


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progressed on prior AR-directed therapy and have not yet received chemotherapy in the 
castration-resistant setting.  
Secondary Objectives: 
• To assess overall survival (OS) 
• To assess objective response rate (ORR) using modified Response Evaluation Criteria in 
Solid Tumors (RECIST) Version 1.1 in patients with measurable (nodal or visceral) 
disease 
• To assess duration of response (DOR) using modified RECIST Version 1.1 in patients with 
measurable (nodal or visceral) disease 
• To assess time to PSA progression 
• To assess PSA response ≥ 50% (all patients) 
• To assess PSA response ≥ 90% (all patients) 
• To evaluate Patient-reported Outcome (PRO) using the following instruments: 
- 
EuroQol 5 dimensions 5 level questionnaire (EQ-5D-5L),  
- 
Functional Assessment of Cancer Therapy–Prostate (FACT-P),  
- 
Analgesic drug score, and  
- 
Brief Pain Inventory–Short Form (BPI-SF) instruments  
• To assess clinical benefit rate (CBR) 
• To assess sparse pharmacokinetics (PK)  
• To assess safety and tolerability 
Exploratory Objectives: 
• To assess concordance in BRCA/ATM gene mutation status in matched Pre-Screening 
biopsy tissue, archival primary and metastatic tumor tissue, and plasma circulating 
cell-free tumor DNA (ctDNA) 
• To assess changes in the molecular profile over time of matched pre and post-treatment 
tumor or plasma samples 
• To evaluate loss of heterozygosity (LOH) in metastatic disease site biopsy and archival 
primary and metastatic tumor tissue samples 
• To evaluate mechanisms of response and resistance in ctDNA and progression tumor tissue 
samples. 
Study Design 
This is a Phase 3, multicenter, randomized, study of rucaparib versus physician’s choice of 
second-line AR-directed therapy (abiraterone acetate or enzalutamide) or docetaxel as 
treatment for mCRPC patients who have progressed on one prior AR-directed therapy 
(abiraterone acetate, enzalutamide, apalutamide, or investigational AR-targeted agent) and 
have not yet received chemotherapy in the castration-resistant setting. Patients who received 
prior PARPi treatment will be excluded. This study will enroll mCRPC patients with 


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deleterious mutations in BRCA1/2 or ATM genes. The primary endpoint is rPFS by central 
independent radiology review (IRR; rPFSirr) using modified RECIST Version 1.1/ Prostate 
Cancer Working Group Guidelines Version 3 (PCWG3) criteria. 
This study consists of a Pre-Screening Phase, Screening Phase, Randomization, Treatment 
Phase, Post-Treatment Phase, and Cross-over Phase (if applicable). Patients will receive 
rucaparib monotherapy or physician’s choice of comparator therapy (pre-designated prior to 
randomization) in the Treatment Phase, and will undergo procedures and assessments 
including regular safety and efficacy evaluations during the entire conduct of the study. 
Patients randomized to the control arm in the Treatment Phase will have the opportunity to 
receive treatment with rucaparib in the Cross-over Phase. 
Pre-Screening Phase 
The purpose of the Pre-Screening Phase is to perform central plasma and tumor tissue testing 
to identify patients with qualifying deleterious BRCA1/2 or ATM gene mutations. If a patient 
has a qualifying deleterious BRCA1/2 or ATM gene mutation identified from local testing, the 
Pre-Screening Phase is not required and the patient should proceed to the Screening Phase. 
To enter the Pre-Screening Phase, patients should have evidence of radiographic or 
biochemical disease progression, and be eligible for this study as their immediate next therapy. 
Patient tissue and plasma samples should be submitted simultaneously during Pre-Screening. 
Tissue submitted for Pre-Screening testing should be from a newly obtained metastatic biopsy, 
if there is a lesion suitable for biopsy and the patient consents to this procedure. A biopsy or 
resection of a visceral or nodal site of metastasis is preferred; however, biopsy of primary 
tumor or of a site of bony metastasis is also acceptable. If a metastatic biopsy is not feasible, 
archival tissue samples should be submitted, if available. To reduce the chance of test failure, 
archival tissue should be < 3 years old.  
Screening Phase 
The purpose of the Screening Phase is to perform study-specific screening assessments, other 
than testing for qualifying deleterious BRCA1/2 or ATM gene mutations. All patients must 
have a deleterious gene mutation in BRCA1/2 or ATM in order to enter the Screening Phase. 
Mutations may be identified by local testing, or through central testing provided by the 
sponsor during the Pre-Screening Phase. For local test results, the classification of the 
mutation as deleterious must be documented in the patient’s medical record.  
Randomization 
Eligible patients will be randomized 2:1 to receive rucaparib (600 mg twice a day [BID]) or 
physician’s choice of either docetaxel or AR-directed therapy (abiraterone acetate or 
enzalutamide, whichever the patient has not yet received). The physician’s choice of agent in 
the control arm must be prespecified prior to randomization. 
Treatment Phase 
Rucaparib will be administered at a starting dose of 600 mg BID and comparator treatments 
according to labelling and local practice. Tumor assessments by computed tomography 
(CT)/magnetic resonance imaging (MRI) and bone scans will be performed during the 
Screening Phase, at the end of every 8 calendar weeks (± 7 days) from Study Day 1 (Week 1) 
up to 24 weeks and every 12 calendar weeks (± 7 days) thereafter, and at the Treatment 
Discontinuation Visit, if applicable. Modified RECIST Version 1.1 criteria will be used to 
document radiographic response in soft tissue (visceral and nodal) disease and PCWG3 criteria 


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will be used to document radiographic progression of bone lesions. Any drug modifications 
(interruption, dose reduction, or discontinuation) should be documented in the electronic case 
report form (eCRF) and source documents. If study treatment is interrupted, tumor 
assessments will not be delayed and will proceed on the regular study schedule. Copies of all 
radiographic scans will be submitted for central IRR until after the analysis of the primary 
endpoint has been performed, at which time IRR will be discontinued and all radiographic 
scans will be evaluated by the investigator for radiographic progression. 
Patients will receive study drug until radiographic disease progression is confirmed by IRR 
until analysis of the primary endpoint has been performed, or by investigator assessment after 
analysis of the primary endpoint has been performed and IRR is discontinued, based on 
modified RECIST Version 1.1 (for nodal/visceral lesions only) and PCWG3 (for bone lesions 
only) criteria, unequivocal clinical disease progression, unacceptable toxicity or inability to 
tolerate further treatment, loss to follow-up, or withdrawal of consent. Patients in the docetaxel 
arm will receive study drug for a maximum of 10 cycles only and so may not be actively on 
treatment at the time of disease progression. PSA rise without evidence of confirmed 
radiographic progression is strongly discouraged as a criterion to start a new systemic 
antineoplastic therapy during the first 12 weeks of therapy and is discouraged as a criterion to 
start a new systemic antineoplastic therapy throughout the study. Radiographic assessments 
will continue until confirmation of radiographic disease progression, irrespective of whether 
the patient has discontinued study drug treatment or initiated subsequent anticancer therapy. 
Palliative radiation for treatment of painful bony metastases and initiation of bisphosphonates 
or other approved bone-targeting agents are allowed and should not result in discontinuation of 
study drug therapy. 
If a patient demonstrates radiographic progression while receiving treatment with study drug, 
but continues to derive clinical benefit per investigator assessment, then continuation of 
treatment beyond progression is permitted. In such cases, the patient must consent prior to 
continuing treatment with study drug. 
Safety and efficacy data will be periodically reviewed by an Independent Data Monitoring 
Committee (IDMC). 
Post-treatment Phase 
Upon treatment discontinuation, patients will have a Treatment Discontinuation Visit, a 
28-day Follow-up Visit, and then will proceed to long-term follow-up. An optional tumor 
biopsy will be collected prior to the start of subsequent anticancer therapy from patients who 
experience radiographic disease progression or unequivocal clinical disease progression and 
provide appropriate consent.  
Radiographic tumor assessments (using the same methodology as was used at initial study 
screening [eg, CT scan and bone scan]) will continue until radiographic disease progression is 
confirmed by IRR, irrespective of whether the patient has initiated subsequent anticancer 
therapy. Once the analysis of the primary endpoint has been performed, radiographic scans 
will continue to be performed by the investigator as per the protocol schedule of assessments 
until radiographic disease progression is determined by the investigator; scans will no longer 
be submitted to or read by IRR. 
Ongoing serious adverse events (SAEs), adverse events of special interest (AESIs), and 
treatment-related Grade 3/4 adverse events (AEs) will be followed until either resolution or 
stabilization has been determined or until lost to follow-up. After the 28-day Follow-up Visit, 


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only SAEs assessed as potentially related to study drug should be reported per Clovis 
Oncology Pharmacovigilance (PV) requirements and captured in the Clovis Oncology PV 
database.  
After the 28-day Follow-up Visit, AESIs of myelodysplastic syndrome (MDS) and acute 
myeloid leukemia (AML), irrespective of causality, should be reported per Clovis 
Oncology PV requirements and captured in the Clovis Oncology PV database. 
• AESIs of pneumonitis or similar events (ie, interstitial lung disease, pulmonary fibrosis, 
acute interstitial pneumonitis, alveolitis necrotizing, alveolitis, hypersensitivity 
pneumonitis, and organizing pneumonia) should be reported up to, but not beyond, the 
28-Day Follow-up Visit (28-days after the last dose of rucaparib). After the 28-day 
Follow-up Visit, only pneumonitis or similar events meeting the criteria for an SAE and 
assessed as potentially related to study drug should be reported per Clovis Oncology PV 
requirements. 
 
All patients will be followed for survival and subsequent treatments every 12 weeks 
(± 14 days) relative to the last dose of study drug until death, loss to follow-up, withdrawal of 
consent, or study closure. 
Cross-over Phase 
Patients randomized to comparator therapy will be given the opportunity to cross-over to 
receive rucaparib therapy after radiographic progression is confirmed by IRR until analysis of 
the primary endpoint has been performed, or by investigator assessment after analysis of the 
primary endpoint has been performed and IRR is discontinued. After providing consent, 
patients will be assessed to ensure criteria are met for the Cross-over Phase. If eligible, the 
patient will have protocol assessments per the rucaparib Treatment Phase, as well as including 
the Post-Treatment Phase. 
Blinding 
This is an open-label study; the study drugs will not be blinded or masked to the investigator 
or patient, so each will know the treatment being administered. A Blinding Plan will be put in 
place to limit the knowledge of aggregate efficacy data by sponsor personnel. 
Number of Patients 
The total enrollment planned for this study is approximately 400 patients. A total of 
approximately 300 patients with a deleterious BRCA1/2 gene mutation will be randomized 
and approximately 100 patients with a deleterious ATM gene mutation may be randomized. 
This is a multicenter, multinational study. Patients will be randomized across approximately 
150 study sites worldwide. 
Inclusion Criteria: 
All patients enrolling into the study must meet all of the following inclusion criteria: 
1. Have signed an Institutional Review Board/Independent Ethics Committee-approved 
informed consent form prior to any study-specific evaluation 
2. Male ≥18 years of age at the time the informed consent form is signed 


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3. Have a histologically or cytologically confirmed adenocarcinoma or poorly differentiated 
carcinoma of the prostate (pure small-cell histologies or pure high-grade neuroendocrine 
histologies are excluded; neuroendocrine differentiation is allowed) that is metastatic 
4. Surgically or medically castrated, with serum testosterone levels of ≤ 50 ng/dL (1.73 nM). 
If currently being treated with luteinizing hormone–releasing hormone (LHRH) analogs 
(patients who have not undergone an orchiectomy), therapy must be continued throughout 
the study 
5. Eligible for treatment with physician’s choice of comparator treatment, selected prior to 
randomization, per the corresponding prescribing information 
6. Evidence of disease progression after treatment with 1 prior next-generation AR-targeted 
therapy (abiraterone acetate, enzalutamide, apalutamide, or investigational AR-targeted 
agent); treatment with the older anti-androgen therapies such as bicalutamide, flutamide, 
and nilutamide are not counted toward this limit 
7. Disease progression after initiation of most recent therapy is based on any of the following 
criteria: 
a. Rise in PSA: a minimum of two consecutive rising levels, with an interval of ≥ 1 week 
between each determination. The most recent screening measurement must have been 
≥ 2 ng/mL 
b. Transaxial imaging: new or progressive soft tissue masses on CT or MRI scans as 
defined by modified RECIST Version 1.1 
c. Radionuclide bone scan: at least 2 new metastatic lesions  
8. All patients must have a deleterious gene mutation in BRCA1/2 or ATM. Mutations may 
be identified by local testing, or through central testing by the sponsor of plasma or tumor 
tissue. For local test results, the classification of the mutation as deleterious must be 
documented in the patient’s medical record 
9. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1  
10. Have adequate organ function confirmed by the following clinical laboratory values 
obtained within 14 days prior to the first dose of study drug: 
a. Bone Marrow Function 
i. 
Absolute neutrophil count (ANC) ≥ 1.5 × 109/L 
ii. Platelets > 100 × 109/L  
iii. Hemoglobin ≥ 10 g/dL independent of transfusion within 14 days 
b. Hepatic Function 
i. 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × the 
upper limit of normal (ULN) 
ii. Bilirubin ≤ 1.5 × ULN (< 2 x ULN if hyperbilirubinemia is due to Gilbert’s 
syndrome) 
c. Renal Function  
i. 
Estimated glomerular filtration rate (GFR) ≥ 45 mL/min using the Cockcroft-Gault 
formula 
11. Male patients who are committed to undertaking the following measures for the duration 
of the study and after the last dose of study drug for the time period specified: 


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a. Use a condom during sex while being treated and for 3 months after the last dose of 
study drug 
b. Do not make semen donations during treatment and for 3 months after the last dose of 
rucaparib 
c. Those with female partners of childbearing potential may be enrolled if they are: 
i. 
Documented to be surgically sterile (ie, vasectomy); 
ii. 
Committed to practicing true abstinence during treatment and for 3 months after 
the last dose of study drug; or 
iii. 
Committed to using a highly effective method of contraception (refer to protocol) 
with their partner during treatment and for 3 months following the last dose of 
study drug 
12. Have a life expectancy of at least 6 months 
Exclusion Criteria: 
Patients will be excluded from participation if any of the following criteria apply: 
1. Active second malignancy, with the exception of curatively treated non-melanoma skin 
cancer, carcinoma in situ, or superficial bladder cancer 
a. Patients with a history of malignancy that has been completely treated, and currently 
with no evidence of that cancer, are permitted to enroll in the study provided all 
therapy was completed > 6 months prior and/or bone marrow transplant (BMT) 
> 2 years prior to first dose of rucaparib 
2. Prior treatment with any PARPi 
3. Prior treatment with chemotherapy (eg docetaxel, mitoxantrone, cyclophosphamide, 
platinum-based agents) for mCRPC. Prior treatment with docetaxel (or other taxane 
chemotherapy) administered for castration-sensitive disease is permitted  
4. Symptomatic and/or untreated central nervous system (CNS) metastases. Patients with 
asymptomatic, previously treated CNS metastases are eligible provided they have been 
clinically stable (not requiring steroids for at least 4 weeks prior to first dose of study drug) 
and have appropriate scans at screening assessment 
5. Symptomatic or impending spinal cord compression unless appropriately treated, clinically 
stable, and asymptomatic 
6. Pre-existing duodenal stent and/or any gastrointestinal disorder or defect that would, in the 
opinion of the investigator, interfere with absorption of study drug 
7. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome 
(AIDS)-related illness, or history of chronic hepatitis B or C, with the exception of patients 
with sustained virologic response after completion of treatment for hepatitis C 
8. Received treatment with chemotherapy, antibody therapy, immunotherapy, gene therapy, 
angiogenesis inhibitors, or experimental drugs within < 14 days prior to first dose of study 
drug. Treatment with hormonal therapies (with the exception of LHRH analog) must be 
discontinued at least 7 days prior to the first dose of study drug 
9. Adverse effect of prior therapy not resolved to National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) Grade 1 or below with the exception 


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of alopecia. Ongoing Grade 2 non-hematologic toxicity related to most recent treatment 
regimen may be permitted with prior advanced approval from the sponsor 
10. Initiated low-dose corticosteroid, bisphosphonate, or denosumab therapy or adjusted low-
dose corticosteroid, bisphosphonate, or denosumab dose/regimen within < 28 days prior to 
first dose of study drug. Patients on a stable low-dose corticosteroid, bisphosphonate or 
denosumab regimen are eligible and may continue treatment 
11. Non-study related minor surgical procedure within < 5 days, or major surgical procedure 
within < 21 days, prior to first dose of study drug; in all cases, the patient must be 
sufficiently recovered and stable before treatment administration 
12. Presence of any other condition that may increase the risk associated with study 
participation or may interfere with the interpretation of study results, and, in the opinion of 
the investigator, would make the patient inappropriate for entry into the study 
No waivers of these inclusion or exclusion criteria will be granted by the investigator and the 
sponsor or its designee for any patient enrolling into the study. 
Inclusion/exclusion for entry into the Cross-over Phase of the study are described in the 
protocol. 
Randomization 
Eligible patients will be randomized 2:1 to receive rucaparib (600 mg BID) or physician’s 
choice (specified prior to randomization) of either docetaxel or AR-directed therapy 
(abiraterone acetate or enzalutamide, whichever the patient has not yet received). 
Randomization will occur by a central randomization procedure using an Interactive Response 
System (IXRS). The following will be included as randomization stratification factors at study 
entry to ensure treatment groups are balanced: 
• ECOG Status 0 vs 1 
• Presence of hepatic metastases or not 
• BRCA1 vs BRCA2 vs ATM gene mutation 
Study Treatment 
Rucaparib: 
The starting dose and schedule of rucaparib is 600 mg ingested BID. Patients may take 
rucaparib with or without food. Each dose should be taken with at least 8 oz (240 mL) of water 
as close to 12 hours apart as possible, preferably at the same times every day. Rucaparib may 
be provided as 200, 250 and 300 mg (as free base) dose strength tablets. Tablets should be 
swallowed whole. 
Dose holds or reductions are permitted in the event of unacceptable toxicity.  
Abiraterone acetate plus prednisone: 
The starting dose of abiraterone is 1,000 mg orally once a day (QD). No food should be eaten 
for at least 2 hours before and 1 hour after dosing. Abiraterone should be swallowed whole 
with water. Prednisone should be administered concomitantly at a dose of 10 mg orally daily. 
Enzalutamide: 
The starting dose of enzalutamide is 160 mg orally QD. Enzalutamide may be taken with or 
without food. Enzalutamide should be swallowed whole with water. 


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Docetaxel plus prednisone or prednisolone: 
Docetaxel at a dose of 75 mg/m2 should be administered intravenously (IV) every 3 weeks, for 
up to a maximum of 10 cycles (whereupon no additional study treatment shall be given, but 
assessments continue). Docetaxel is given in combination with prednisone or prednisolone 
5 mg BID. 
Patients will continue with study drug treatment until radiographic disease progression is 
confirmed by IRR until analysis of the primary endpoint has been performed, or by 
investigator assessment after analysis of the primary endpoint has been performed and IRR is 
discontinued, using modified RECIST Version 1.1 and PCWG3 (for bone lesions only) 
criteria, unequivocal clinical disease progression, unacceptable toxicity or inability to tolerate 
further treatment, loss to follow-up, or withdrawal of consent. 
Dose modifications of comparator drugs are permitted according to the label and local 
institution treatment guidelines. 
If a patient receiving study drug has met criteria for confirmed radiographic disease 
progression by modified RECIST Version 1.1 and/or PCWG3 criteria, but the patient 
continues to derive clinical benefit per the investigator, then continuation of treatment will be 
permitted with additional consent. 
Concomitant Medications 
During the study, supportive care (eg, antiemetics; analgesics for pain control) may be used at 
the investigator’s discretion and in accordance with institutional procedures. Supportive care 
must be recorded for each patient in the appropriate section of the eCRF.  
Erythropoietin, darbepoetin alfa, and/or hematopoietic colony-stimulating factors for treatment 
of cytopenias should be administered per standard of care and according to institutional 
guidelines. Transfusion thresholds for blood product support will be in accordance with 
institutional guidelines. 
Palliative radiotherapy for the treatment of painful bony metastasis is permitted during the 
study. Treatment with rucaparib should be held prior to initiation of radiation therapy and until 
the patient has recovered from any radiation-related toxicity. Radiotherapy to soft-tissue 
lesions (either target or non-target) renders these inevaluable by RECIST Version 1.1, and is 
therefore discouraged during the Treatment Phase of the study.  
For patients who have not undergone an orchiectomy and are currently being treated with 
LHRH analogs at the time of consent, therapy must be continued throughout the study. 
No other anticancer therapies (including chemotherapy, radiation, antibody, immunotherapy, 
gene therapy, angiogenesis inhibitors, or other experimental drugs) of any kind will be 
permitted while the patient is participating in the study with the exception of LHRH analogs 
and palliative radiotherapy for painful bony metastases. 
Initiation of bisphosphonates or other approved bone targeting agents is allowed, if clinically 
indicated, and should not result in study treatment discontinuation unless patient has 
radiographic evidence of disease progression. 
Herbal and complementary therapies should not be encouraged because of unknown side 
effects and potential drug interactions. 
Based on the results from the cytochrome P450 (CYP) interaction clinical study CO-338-044, 
rucaparib is a moderate inhibitor of CYP1A2, and a weak inhibitor of CYP2C9, CYP2C19, 


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and CYP3A, and showed no clinically significant effect on P-gp. Caution should be exercised 
in the concomitant use of drugs that are sensitive substrates of the above CYP enzymes. 
Although in vitro rucaparib metabolism mediated by CYP3A4 was slow, a significant 
contribution of CYP3A4 in vivo cannot be excluded. Caution should be used for concomitant 
use of strong CYP3A4 inhibitors or inducers. 
Patients taking warfarin should have international normalized ratio (INR) monitored regularly 
according to standard institutional practices, and those patients taking phenytoin should have 
therapeutic drug level monitored. 
In vitro, rucaparib is a potent inhibitor of MATE 1 and MATE2-K, a moderate inhibitor of 
OCT1, and a weak inhibitor of OCT2. As inhibition of these transporters could decrease renal 
elimination and decrease liver uptake of metformin, caution is advised when metformin is 
co-administered with rucaparib.  
Treatment Discontinuation Criteria 
A patient must be discontinued from treatment with study drug if any of the following apply: 
• unequivocal clinical disease progression;  
• unacceptable toxicity or inability to tolerate further treatment;  
• loss to follow-up;  
• withdrawal of consent. 
Efficacy Assessments 
Soft tissue (visceral and nodal) disease will be evaluated for evidence of radiographic response 
based on modified RECIST Version 1.1 criteria. Bone lesions will be followed and evaluated 
for evidence of radiographic progression based on PCWG3 criteria. Additionally, PSA 
response will be evaluated. 
Tumor assessments will be performed during screening (baseline), at the end of every 
8 calendar weeks (± 7 days) relative to Study Day 1 (Week 1) up to 24 weeks, then every 
12 calendar weeks (± 7 days), until confirmed radiographic disease progression by modified 
RECIST Version 1.1 and/or PCWG3 (for bone lesions only) criteria, loss to follow-up, 
withdrawal, or study closure. Tumor assessments will continue to be performed until 
radiographic disease progression is confirmed by IRR. After the primary endpoint analysis is 
performed, confirmation of radiographic progression by IRR will no longer occur and only 
investigator-assessed radiographic progression performed. If a complete response (CR) or 
partial response (PR) is noted, confirmatory scans should be performed at least 4 weeks after 
the initial response was first documented. 
Tumor assessments should consist of clinical examination and appropriate imaging techniques 
(ie, CT scans of the chest, abdomen, and pelvis with appropriate slice thickness per modified 
RECIST Version 1.1); other studies (MRI, X-ray, positron emission tomography (PET)/CT, 
and ultrasound) may also be performed if required. If a site can document that the CT 
performed as part of a PET/CT is of identical diagnostic quality to a diagnostic CT (with IV 
and oral contrast) then the CT portion of the PET/CT can be used for RECIST Version 1.1 
measurements. Radionuclide bone scanning (whole body) should be performed using 99mTc-
methylene diphosphonate (MDP) or hydroxydiphosphonate (HDP). All sites of disease should 
be followed and the same methods used to detect lesions at baseline are to be used to follow 


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the same lesions throughout the clinical study. If a patient has known brain metastases, this 
disease should be evaluated at each required assessment time. 
Copies of CT and bone scans (and other imaging, as appropriate) from the Treatment Phase of 
the study will be submitted for IRR for all patients. Once the analysis of the primary endpoint 
has been performed, radiographic scans will continue to be performed by the investigator as 
per the protocol schedule of assessments until radiographic disease progression is determined 
by the investigator; scans will no longer be submitted to or read by IRR. After analysis of the 
primary endpoint, investigator-assessed radiographic disease progression will be used for 
cross-over eligibility evaluation. Radiographic assessments from the Cross-over Phase will not 
be submitted for IRR. 
PSA will be measured locally at Screening, each clinic visit, and at the Treatment 
Discontinuation Visit. 
Safety Assessments 
Safety and tolerability will be assessed based on the following: 
• Incidence, type, seriousness, and severity of AEs reported; 
• Clinical laboratory investigations (hematology, serum chemistry and urinalysis); 
• Vital signs (blood pressure, pulse, and body temperature); 
• 12-lead electrocardiograms (ECGs); 
• Physical examinations; and 
• ECOG performance status 
Statistical Methods 
Sample Size Justification 
The total enrollment planned is approximately 400 patients, with approximately 300 patients 
in the subgroup with a deleterious BRCA1/2 mutation and approximately 100 patients in the 
subgroup with a deleterious ATM mutation. The median rPFS is assumed to be 6 months for 
the control arm and 10 months for rucaparib in the subgroup of patients with a deleterious 
BRCA1/2 mutation and 9 months for rucaparib in the total population. A sample size of 
approximately 300 patients in the subgroup with a deleterious BRCA1/2 mutation should 
result in approximately 200 events of rPFS, which will provide approximately 90% power to 
detect a hazard ratio (HR) of 0.6 at a one-sided 0.025 significance level. A sample size of 
approximately 400 total patients should result in approximately 270 events of rPFS, which will 
provide approximately 90% power to detect a HR of 0.67 at a one-sided 0.025 significance 
level. 
Step-down Procedure of Primary and Secondary Endpoints and General Statistical 
Considerations 
The primary and key secondary endpoints will first be tested among the patients with a 
deleterious BRCA1/2 mutation and then in the intent-to-treat (ITT) Population (ie, BRCA + 
ATM) using an ordered step-down multiple comparisons procedure. The primary endpoint of 
rPFSirr (rPFS by independent radiology review) in the subgroup of patients with a deleterious 
BRCA1/2 mutation will be tested first at a two-sided 0.05 significance level. If rPFSirr in the 
subgroup of patients with a deleterious BRCA1/2 mutation is statistically significant, then 


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rPFSirr will be tested in the ITT Population. Continuing in an ordered step-down manner, the 
key secondary endpoints of OS and ORR (by IRR) will be tested at the two-sided 0.05 
significance level. To preserve the overall Type 1 error rate, statistical significance will only 
be declared for a secondary endpoint if the primary endpoints and previous secondary 
endpoints are also statistically significant in the ordered step-down procedure. 
Quantitative variables will be summarized using descriptive statistics. For variables registered 
on a continuous scale, the following will be presented: N, mean, standard deviation (StD), 
median, minimum and maximum. Categorical variables will be presented using frequencies 
and percentages. The Kaplan-Meier methodology will be used to summarize time-to-event 
variables. The stratified HR from the Cox proportional hazards model will be used to estimate 
the HR between the randomized treatment groups for the primary endpoint.  
Primary Efficacy Analysis 
rPFSirr is defined as the time from randomization to the first objective evidence of 
radiographic progression, or death due to any cause (whichever occurs first). Radiographic 
disease progression includes soft tissue disease progression as per modified 
RECIST Version 1.1 and confirmed progression of bone disease per PCWG3 criteria. rPFS, as 
assessed by the investigator (rPFSinv), is defined similarly and will be supportive of the 
primary endpoint, rPFSirr.  
Secondary Efficacy Analyses 
Overall survival time will be calculated as the time from randomization to death (by any 
cause) +1 day. Patients who have not died will be censored on the date the patient was last 
known to be alive. OS will be analyzed at the time of the primary analysis (interim OS 
analysis) and again for a final OS analysis when maturity is reached.  
ORR is defined as the proportion of patients with a confirmed response of CR or PR using 
modified RECIST Version 1.1 (ie, CR or PR by IRR assessment and no progression in bone 
per PCWG3). Per RECIST Version 1.1, to be assigned a best overall response of CR or PR, 
changes in tumor measurements must be confirmed by repeat assessments that should be 
performed no less than 4 weeks after the criteria for response are first met. 
DOR is defined as the time from the date that a PR or CR is first reported to the time that 
disease progression is documented including that in bone (modified RECIST 
Version 1.1/PCWG3 criteria). 
Time to PSA progression is defined as the time from randomization to the date that a ≥ 25% 
increase and absolute increase of ≥ 2 ng/mL above the nadir (or baseline value for patients 
who did not have a decline in PSA) in PSA was measured. The increase must be confirmed by 
a second consecutive assessment conducted at least 3 weeks later. 
Confirmed PSA response is defined as ≥ 50% (or ≥ 90%) reduction in PSA from baseline to 
lowest post-baseline PSA result, with a consecutive assessment conducted at least 3 weeks 
later. PSA response will be calculated for all patients with PSA values at baseline and at least 
one post-baseline assessment. PSA will be assessed by a local laboratory. 
CBR is defined as the combination of CR, PR, and stable disease (SD) as defined by modified 
RECIST Version 1.1 with no progression in bone per PCWG3 criteria. 
Safety Analyses 
AEs, clinical laboratory results, vital signs, ECOG performance status, body weight, and 
concomitant medications/procedures will be tabulated and summarized. AEs will be 


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summarized overall and separately for SAEs, AESIs, AEs leading to discontinuation, AEs 
leading to death, and Grade 3 or higher AEs graded using NCI-CTCAE Version 4.03 or 
higher. Body weight and vital signs will be summarized descriptively (N, mean, StD, median, 
minimum, and maximum). ECOG performance status will be summarized categorically.  
An IDMC will review safety and efficacy data on a periodic basis to ensure an acceptable 
overall risk and benefit for patients participating in the study. 
Independent Data Monitoring Committee 
An IDMC with multidisciplinary representation will regularly evaluate benefit-risk during the 
study, and recommend any potential changes to study conduct. No formal efficacy or futility 
interim analyses for early stopping are planned; however, OS will be analyzed at the time of 
the primary analysis (interim OS analysis) and again for a final OS analysis when maturity is 
reached. The IDMC may recommend that the study be stopped if there is excessive toxicity 
observed in the rates of serious and/or Grade 3 and 4 AEs. 
Date of Protocol Amendment 4 Approval:  
18 February 2022 


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TABLE OF CONTENTS 
1 SYNOPSIS ........................................................................................................................... 5 
LIST OF IN-TEXT TABLES ....................................................................................................23 
LIST OF IN-TEXT FIGURES ...................................................................................................24 
2 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................................25 
3 INTRODUCTION ...............................................................................................................30 
3.1 
Investigational Product .............................................................................................30 
3.2 
Background and Rationale for PARP Inhibition .......................................................30 
3.3 
Metastatic Castration-resistant Prostate Cancer ........................................................30 
3.3.1 
Treatment of Metastatic, Castration-resistant Prostate Cancer .........................31 
3.4 
Prior Experience with Rucaparib ..............................................................................32 
3.4.1 
Nonclinical Experience with Rucaparib ..........................................................32 
3.4.2 
Clinical Experience with Rucaparib ................................................................33 
3.5 
Rationale for this Study of Rucaparib .......................................................................43 
4 STUDY OBJECTIVES .......................................................................................................45 
4.1 
Primary Objective ....................................................................................................45 
4.2 
Secondary Objectives ...............................................................................................45 
4.3 
Exploratory Objectives .............................................................................................45 
5 INVESTIGATIONAL PLAN ..............................................................................................46 
5.1 
Overall Study Design and Plan .................................................................................46 
5.1.1 
Pre-Screening Phase .......................................................................................46 
5.1.2 
Screening Phase .............................................................................................47 
5.1.3 
Randomization ...............................................................................................47 
5.1.4 
Treatment Phase .............................................................................................48 
5.1.5 
Post-treatment Phase ......................................................................................49 
5.1.6 
Cross-over Phase ............................................................................................50 
5.1.7 
Post-progression Treatment Phase ..................................................................50 
5.2 
Study Schema ..........................................................................................................50 
5.3 
End of Study ............................................................................................................53 
6 STUDY POPULATION SELECTION ................................................................................53 
6.1 
Number of Patients and Sites....................................................................................53 
6.2 
Inclusion Criteria .....................................................................................................53 
6.3 
Exclusion Criteria ....................................................................................................55 
6.4 
Criteria for Rucaparib Cross-over Treatment Eligibility Following 
Radiographic Progression on or after Comparator Arm Therapy ..............................56 
6.5 
Patients or Partners of Patients Including Those of Reproductive Potential ...............57 
6.5.1 
Patients Not on Rucaparib ..............................................................................58 
6.6 
Waivers of Inclusion/Exclusion Criteria ...................................................................58 


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7 STUDY TREATMENT(S) ..................................................................................................58 
7.1 
Description of Treatment(s) and Storage ..................................................................58 
7.1.1 
Investigational Drug Product - Rucaparib .......................................................59 
7.1.2 
Comparator Therapeutic Drug Products ..........................................................59 
7.2 
Packaging and Labeling ...........................................................................................59 
7.2.1 
Rucaparib .......................................................................................................59 
7.2.2 
Comparator Therapy .......................................................................................60 
7.3 
Blinding ...................................................................................................................60 
7.4 
Method of Assigning Patients to Treatment Groups ..................................................60 
7.5 
Preparation and Administration of Protocol-specified Treatment ..............................60 
7.5.1 
Rucaparib .......................................................................................................61 
7.5.2 
Single-agent Docetaxel ...................................................................................64 
7.5.3 
Single-agent Abiraterone Acetate ...................................................................64 
7.5.4 
Single-agent Enzalutamide .............................................................................64 
7.5.5 
Re-treatment and Dose Modification for All Comparator Therapy ..................64 
7.5.6 
Cross-over to Rucaparib Treatment ................................................................65 
7.5.7 
Continuation of Study Drug beyond Disease Progression ...............................65 
7.6 
Treatment Compliance .............................................................................................65 
7.6.1 
Rucaparib Treatment Compliance ...................................................................65 
7.6.2 
Comparator Therapy Treatment Compliance ..................................................66 
7.7 
Accountability of Protocol-specified Treatment .......................................................66 
8 PRIOR AND CONCOMITANT THERAPY .......................................................................67 
8.1 
Supportive Care .......................................................................................................67 
8.2 
Radiotherapy ............................................................................................................67 
8.3 
Luteinizing Hormone-releasing Hormone Analogs ...................................................67 
8.4 
Anticancer or Experimental Therapy ........................................................................68 
8.5 
CYP450 Isoenzyme Inhibitors, Inducers, and Substrates ..........................................68 
8.6 
Therapies to Control Bone Loss ...............................................................................68 
8.7 
Anticoagulants .........................................................................................................68 
8.8 
Other Concomitant Medications ...............................................................................68 
9 STUDY PROCEDURES AND ACTIVITIES BY VISIT .....................................................69 
9.1 
Schedule of Assessments..........................................................................................69 
9.2 
Informed Consent.....................................................................................................79 
9.3 
Pre-Screening Phase .................................................................................................79 
9.4 
Screening Phase .......................................................................................................80 
9.4.1 
Screening: Up to 28 Days Prior to Randomization: .........................................80 
9.4.2 
Screening: Up to 14 Days Prior to Randomization: .........................................81 
9.5 
Treatment Phase .......................................................................................................81 


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9.5.1 
Patients Randomized to Rucaparib, Physician’s Choice of Abiraterone 
Acetate or Enzalutamide or Cross-over to Rucaparib ......................................81 
9.5.2 
Patients Randomized to Physician’s Choice of Docetaxel ...............................85 
9.6 
Post-treatment Phase (Randomized Treatment/ Cross-over to Rucaparib) .................86 
9.6.1 
Treatment Discontinuation Visit .....................................................................86 
9.6.2 
28-day Safety Follow-up Visit (Randomized Treatment/ Cross-over to 
Rucaparib) ......................................................................................................87 
9.6.3 
Long-term Follow-up (Randomized Treatment/ Cross-over to 
Rucaparib) ......................................................................................................88 
9.7 
Informed Consent for Patients Who Cross-over to Rucaparib after Disease 
Progression on Comparator Treatment .....................................................................89 
9.8 
Screening Prior to Cross-over to Rucaparib ..............................................................89 
9.8.1 
Ongoing Assessments for Cross-over Patients: ...............................................89 
9.9 
Methods of Data Collection......................................................................................90 
9.9.1 
Medical History and Demographic/ Baseline Characteristics ..........................90 
9.10 
Prior and Concomitant Medication/ Procedure Assessments .....................................90 
9.11 
Efficacy Evaluations ................................................................................................90 
9.11.1 
Disease/ Tumor Assessments ..........................................................................90 
9.12 
Safety Evaluations ...................................................................................................91 
9.12.1 
Adverse Event Assessment .............................................................................91 
9.12.2 
Clinical Laboratory Investigations ..................................................................92 
9.12.3 
Vital Signs......................................................................................................93 
9.12.4 
12-lead Electrocardiogram ..............................................................................93 
9.12.5 
Physical Examinations, Body Weight and Height ...........................................93 
9.12.6 
ECOG Performance Status .............................................................................94 
9.13 
Biomarker Analysis – FFPE Tumor Tissue ..............................................................94 
9.14 
Biomarker Analysis – ctDNA/genomic DNA from Blood ........................................94 
9.15 
Pharmacokinetics Evaluation ...................................................................................94 
9.16 
Patient-reported Outcomes (Health and Quality of Life Questionnaires) ...................95 
10 ADVERSE EVENT MANAGEMENT ................................................................................95 
10.1 
Definition of an Adverse Event ................................................................................95 
10.2 
Definition of a Serious Adverse Event......................................................................95 
10.3 
Definition of an Adverse Event of Special Interest ...................................................96 
10.4 
Events or Outcomes Not Qualifying as Serious Adverse Events ...............................96 
10.5 
Clinical Laboratory Assessments as Adverse Events and Serious Adverse 
Events ......................................................................................................................97 
10.6 
Pregnancy or Drug Exposure During Pregnancy .......................................................97 
10.7 
Recording of Adverse Events, Serious Adverse Events, and Adverse Events of 
Special Interest.........................................................................................................97 


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10.7.1 
Onset Date of Adverse Events ........................................................................98 
10.7.2 
Resolution Date of Adverse Events.................................................................98 
10.7.3 
Intensity of Adverse Events ............................................................................98 
10.7.4 
Causal Relationship of Adverse Events to Study Drug ....................................99 
10.7.5 
Outcome and Action Taken ............................................................................99 
10.8 
Follow-up of Adverse Events, Serious Adverse Events, and Adverse Events of 
Special Interest....................................................................................................... 100 
10.9 
Potential Drug-induced Liver Injury ....................................................................... 101 
10.10 Regulatory Aspects of Serious Adverse Event and Adverse Events of Special 
Interest Reporting................................................................................................... 101 
11 PLANNED STATISTICAL METHODS ........................................................................... 101 
11.1 
General Considerations .......................................................................................... 101 
11.2 
Determination of Sample Size ................................................................................ 102 
11.3 
Analysis Populations .............................................................................................. 103 
11.4 
Patient Disposition ................................................................................................. 103 
11.5 
Demographics and Baseline Characteristics ........................................................... 103 
11.6 
Step-down Procedure of Primary and Secondary Endpoints ................................... 104 
11.7 
Efficacy Analyses .................................................................................................. 106 
11.7.1 
Primary Efficacy Analysis ............................................................................ 106 
11.7.2 
Secondary Efficacy Analyses ....................................................................... 106 
11.7.3 
Exploratory Efficacy Analyses ..................................................................... 107 
11.8 
Safety Analyses...................................................................................................... 108 
11.8.1 
Adverse Events............................................................................................. 108 
11.8.2 
Clinical Laboratory Evaluations ................................................................... 109 
11.8.3 
Vital Sign Measurements .............................................................................. 109 
11.9 
Interim Analysis ..................................................................................................... 110 
12 PATIENT DISPOSITION ................................................................................................. 110 
12.1 
Removal of Patients from the Study or Study Drug ................................................ 110 
13 STUDY ADMINISTRATION ........................................................................................... 111 
13.1 
Regulatory and Ethical Considerations ................................................................... 111 
13.1.1 
Good Clinical Practice .................................................................................. 111 
13.1.2 
Regulatory Authority Approvals ................................................................... 112 
13.1.3 
Institutional Review Board or Independent Ethics Committee Approval ....... 112 
13.2 
Patient Information and Consent ............................................................................ 113 
13.2.1 
General Aspects of Informed Consent .......................................................... 113 
13.2.2 
Informed Consent Process ............................................................................ 113 
13.3 
Patient Confidentiality ........................................................................................... 114 
13.4 
Study Monitoring ................................................................................................... 114 
13.5 
Case Report Forms and Study Data ........................................................................ 115 


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13.6 
Independent Data Monitoring Committee ............................................................... 116 
13.7 
Study Termination and Site Closure ....................................................................... 116 
13.8 
Study Protocol Amendments .................................................................................. 117 
13.9 
Retention of Study Documents ............................................................................... 117 
13.10 Quality Control and Assurance ............................................................................... 118 
13.10.1 Protocol Deviations ...................................................................................... 118 
13.10.2 Study Site Training ....................................................................................... 118 
13.10.3 Quality Assurance Audits and Inspections .................................................... 118 
13.10.4 Direct Access to Source Data/ Documents for Audits and Inspections .......... 118 
13.11 Clinical Study Report ............................................................................................. 119 
13.12 Publication and Disclosure Policy .......................................................................... 119 
13.13 Investigator Oversight ............................................................................................ 119 
14 REFERENCE LIST ........................................................................................................... 120 
15 APPENDICES ................................................................................................................... 125 
15.1 
Appendix 1 - Modified Response Evaluation Criteria in Solid Tumors Criteria 
(Version 1.1) and Prostate Cancer Working Group 3 Criteria ................................. 126 
15.2 
Appendix 2 - Eastern Cooperative Oncology Group (ECOG) Performance 
Status Scale ............................................................................................................ 133 
15.3 
Appendix 3 - Cockcroft-Gault Formula .................................................................. 134 
15.4 
Appendix 4 - Examples of Sensitive CYP Substrates (not an inclusive list) ............ 135 
15.5 
Appendix 5 - Brief Pain Inventory – Short Form (BPI-SF) ..................................... 136 
15.6 
Appendix 6 - Functional Assessment of Cancer Therapy – Prostate (FACT-P) ....... 139 
15.7 
Appendix 7 - Euro-Quality of Life 5D 5L (EQ-5D-5L) Patient-reported 
Outcome ................................................................................................................ 143 
15.8 
Appendix 8 - Analgesic Use Questionnaire ............................................................ 147 
 
LIST OF IN-TEXT TABLES 
Table 1. Treatment-emergent AEs (All Grades and ≥ Grade 3) Reported in ≥ 20% of 
Ovarian Cancer Patients in Combined Studies CO-338-010 and CO-338-017 ...... 39 
Table 2. Treatment-emergent AEs Reported in ≥ 20% of Patients (All Grades) in Any 
Treatment Group in Study CO-338-014 - Safety Population ................................ 40 
Table 3. Change from Baseline in Laboratory Parameters in Patients Treated with 
600 mg BID Rucaparib (Study CO-338-014) ....................................................... 42 
Table 4. Rucaparib Dose Reduction Steps ......................................................................... 64 
Table 5. Schedule of Assessments for Patients Randomized to Rucaparib or Physician’s 
Choice of Abiraterone Acetate or Enzalutamide .................................................. 70 
Table 6. Schedule of Assessments for Patients Randomized to Physician’s Choice of 
Docetaxel ............................................................................................................ 73 


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Table 7. Schedule of Assessments for Patients Who Cross over to Rucaparib after 
Physician’s Choice Comparator ........................................................................... 76 
Table 8. Requirements for Confirmation of Radiographic Disease Progression in Bone 
per Investigator’s Assessment ............................................................................. 91 
 
LIST OF IN-TEXT FIGURES 
Figure 1. Pre-Screening Study Schema ............................................................................... 51 
Figure 2. Study Schema: Screening, Treatment, and Post-treatment Phases ........................ 52 
Figure 3. Ordered Step-down Procedure ........................................................................... 105 
 


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2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADP 
adenosine diphosphate 
ADT 
androgen deprivation therapy 
AE 
adverse event 
AESI 
adverse event of special interest 
AIDS 
acquired immunodeficiency syndrome 
ALCOA+ 
Attributable, Legible, Contemporaneous, Original or Certified Copy, Accurate, and 
‘Plus’ (+) Complete, Consistent, Enduring, and Available 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
ANCOVA 
analysis of covariance 
AR 
androgen receptor 
AST 
aspartate aminotransferase 
ATM 
ataxia telangiectasia mutated serine/threonine kinase 
ATR 
ataxia telangiectasia and RAD3-related 
AUC 
area under the concentration-time curve 
BCRP 
breast cancer resistance protein 
BER 
base excision repair 
BID 
twice a day 
BMT 
bone marrow transplant 
BPI-SF 
Brief Pain Inventory–Short Form 
BRCA 
breast cancer 1 or breast cancer 2 gene 
BRCA1/2 
breast cancer 1 or breast cancer 2 gene 
BRIP1 
BRCA1-interacting protein 
BUN 
blood urea nitrogen 
CA-125 
cancer antigen-125 
CBR 
clinical benefit rate 
CDK12 
cyclin-dependent kinase 12 
CFR 
Code of Federal Regulations 
CHEK2 
checkpoint kinase 2 
CI 
confidence interval 
CLIA 
Clinical Laboratory Improvement Amendments  
Cmax 
maximum plasma concentration 
Cmin 
trough concentration 
CMH 
Cochran-Mantel-Haenszel 


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CNS 
central nervous system 
CO2 
bicarbonate 
CR 
complete response 
CRO 
contract research organization 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating cell-free tumor DNA 
CYP 
cytochrome P450 
DILI 
drug-induced liver injury 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
DSB 
double-strand breaks 
EC 
European Commission 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EMA 
European Medicines Agency 
EOC 
epithelial ovarian cancer 
EQ-5D-5L 
EuroQol 5 dimensions 5 level questionnaire 
EU 
European Union 
FACT-P 
Functional Assessment of Cancer Therapy–Prostate 
FANCA 
Fanconi anemia, complementation group A 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
FSH 
follicle-stimulating hormone 
FTC 
fallopian tube cancer 
gBRCA 
germline breast cancer 1 or 2 gene mutation 
GCIG 
Gynecologic Cancer InterGroup 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GFR 
glomerular filtration rate 
Hct 
hematocrit 
HDL 
high density lipoprotein 
HDP 
hydroxydiphosphonate 
HDPE 
high-density polyethylene 


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Hgb 
hemoglobin 
HIPAA 
Health Information Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
HRD 
homologous recombination deficiency 
HRR 
homologous recombination repair 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug Application 
INN 
International Nonproprietary Name 
INR 
international normalized ratio 
invPFS 
investigator-assessed progression-free survival 
IRB 
Institutional Review Board 
IRR 
central independent radiology review 
ITT 
intent-to-treat 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
IV 
intravenous(ly) 
IXRS 
Interactive Response System 
LD 
longest diameter 
LDH 
lactate dehydrogenase 
LDL 
low density lipoprotein 
LHRH 
luteinizing hormone–releasing hormone 
LOH 
loss of heterozygosity 
MATE 
multidrug and toxin extrusion protein 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
mCRPC 
metastatic castration-resistant prostate cancer 
MCV 
mean corpuscular volume 
MDP 
methylene diphosphonate 
MDS 
myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
Modified 
RECIST 
Response Evaluation Criteria in Solid Tumors modified according to PCWG3 
guidelines (used for evaluation of nodal/visceral disease, excluding bone disease) 


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Modified 
RECIST/PCWG3 
Response Evaluation Criteria in Solid Tumors modified according to PCWG3 
guidelines, combined with evaluation of bone disease according to PCWG3 
MRI 
magnetic resonance imaging 
NBN 
nibrin 
NCI 
National Cancer Institute 
OCT 
organic cationic transporter 
ORR 
objective response rate 
OS 
overall survival 
PALB2 
partner and localizer of BRCA2 
PARP 
poly (ADP-ribose) polymerase 
PARPi 
PARP inhibitor 
PCWG3 
Prostate Cancer Working Group Guidelines Version 3 
PD 
progressive disease (in context of disease monitoring) 
PD 
pharmacodynamic (in context of pharmacology discussion) 
PET 
positron emission tomography 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PIS 
Patient Information Sheet 
PK 
pharmacokinetic 
PPC 
primary peritoneal cancer 
PPI 
proton pump inhibitor 
PR 
partial response 
PRO 
patient-reported outcome 
PSA 
prostate-specific antigen 
PT 
Preferred Term 
PV 
pharmacovigilance 
QD 
once a day 
RAD51B 
RAD51 homolog B 
RAD51C 
RAD51 homolog C 
RAD51D 
RAD51 homolog D 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
rPFS 
radiographic progression-free survival 
rPFSinv 
radiographic progression-free survival by the investigator 
rPFSirr 
radiographic progression-free survival by IRR 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
sBRCA 
somatic breast cancer gene 1 or 2 mutation 


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SD 
stable disease 
SOC 
system organ class 
SOP 
standard operating procedure 
SSB 
single-strand break 
StD 
standard deviation 
SUSAR 
suspected unexpected serious adverse reactions 
tBRCA 
tumor tissue mutation in BRCA1 or BRCA2, includes gBRCA and sBRCA 
TEAE 
treatment-emergent adverse event 
TMZ 
temozolomide 
UDP 
uridine diphosphate 
UGT1A1 
UDP-glucuronosyl transferase 1A1 
ULN 
upper limit of normal 
Upper case 
gene/protein 
names 
Gene and protein names should be in italics and plain text, respectively, based on 
HUGO Gene Nomenclature Committee guidelines. However, in this document 
mutations which occur at both the gene and protein level are often discussed. 
Therefore for enhanced readability, gene and protein names are written in plain text 
US 
United States 
VAS 
visual analog scale 
WBC 
white blood cells 
WHO 
World Health Organization 
XO 
cross-over 
 


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3 
INTRODUCTION 
3.1 
Investigational Product 
Rucaparib (CO-338) is a small molecule inhibitor of poly (adenosine diphosphate [ADP]-ribose) 
polymerase (PARP) being developed for the treatment of cancer associated with homologous 
recombination deficiency (HRD). Rucaparib has been shown to potently inhibit PARP-1, 
PARP-2, and PARP-3 and has demonstrated activity in cells, animal models and patients with a 
breast cancer gene 1 or 2 (BRCA1 and BRCA2) mutations in both clinical and nonclinical 
studies. 
Clovis Oncology, Inc. is developing rucaparib for oral administration in patients with metastatic 
castration-resistant prostate cancer (mCRPC) associated with HRD, including patients with a 
deleterious mutations in BRCA1, BRCA2 and ataxia telangiectasia mutated serine/threonine 
kinase (ATM) and other homologous recombination repair (HRR) gene mutations.  
3.2 
Background and Rationale for PARP Inhibition 
Deoxyribonucleic acid (DNA) is constantly damaged by both endogenous and exogenous 
(environmental) assaults. Endogenous causes include spontaneous base changes, replication 
errors, and oxygen-free radicals. Exogenous agents of DNA damage include chemicals and both 
ultraviolet and ionizing radiation. A common type of DNA damage is the formation of DNA 
single-strand breaks (SSBs). Normal cells repair SSBs in DNA through a process known as base 
excision repair (BER).1 While there are several variations of BER, all pathways rely on the 
activity of PARP enzymes. In humans, the PARP family encompasses 17 enzymes, of which 
PARP-1 is the best characterized.22 SSBs that are not repaired result in stalled replication forks 
and the development of double-strand breaks (DSBs), which are in turn repaired by HRR, a 
complex process involving multiple proteins, including BRCA1 and BRCA2, as well as RAD51, 
Fanconi anemia core complex, ATM, and ataxia telangiectasia and RAD3-related (ATR) protein, 
among others.1 Thus, HRR processes act as a functional buffer to enable normal cells to survive 
the effects of PARP and BER inhibition and overcome DSB in DNA. Homologous 
recombination defects or PARP inhibition on their own can be overcome by a cell, but the 
combination is fatal, a concept termed “synthetic lethality”, which forms the basis of the 
therapeutic approach of using PARP inhibition to kill cancer cells with HRD.1-3 
3.3 
Metastatic Castration-resistant Prostate Cancer 
Prostate cancer is the most common malignancy among men in the United States (US), and the 
second-most common cause of cancer-related mortality, with approximately 30,000 men dying 
of the disease each year.4 Based upon GLOBOCAN 2012 estimates, prostate cancer is the second 
leading malignancy diagnosis and fifth leading cause of death in men worldwide, with 
307,000 deaths estimated in 2012.5 The course of prostate cancer from diagnosis to death is often 
a series of clinical states progressing from localized disease to mCRPC, a disease state 
characterized by resistance to standard androgen deprivation therapies and that accounts for the 
majority of prostate cancer deaths.  


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HRD has been observed in many carcinomas, including prostate cancer. Men with a germline 
mutation in BRCA2 are at increased risk for developing prostate cancer, estimated at 2.5 to 
8.6-fold compared with non-carriers.6 Men with prostate cancer and a germline mutation in 
BRCA2 typically develop disease at a younger age, have more aggressive features and higher 
mortality rates; while less common in prostate cancer, germline mutations in BRCA1 are also 
associated with more aggressive disease.7 In addition to germline mutations in breast cancer 1 or 
breast cancer 2 gene (BRCA1/2), somatic mutations in BRCA1/2 and other HRR genes have 
been shown to occur in advanced prostate cancer.8 A large genomic study of mCRPC identified a 
12.7% rate of mutation/deletion in BRCA2 (of which over 90% was biallelic), half of which was 
a germline mutation in BRCA2; a 7% rate of loss of ATM, an approximately 5% mutation rate of 
cyclin-dependent kinase 12 (CDK12), a previously-reported positive regulator of BRCA genes, 
and lower rates of mutation of BRCA1, Fanconi anemia, complementation group A (FANCA), 
RAD51 homolog B (RAD51B), RAD51 homolog C (RAD51C), and other HRR genes. Overall, 
almost 23% of tumors were found to have a mutation in at least one HRR gene, and over 19% of 
tumors had either a BRCA1/2 or ATM mutation, suggesting that in principle a significant 
percentage of patients with mCRPC may benefit from approaches exploiting a deficiency in 
homologous recombination repair, such as treatment with a PARP inhibitor (PARPi).8 A recent 
clinical study reported that 16 of 49 evaluable patients with advanced heavily pre-treated 
mCRPC had a response to the PARPi, olaparib. Response was defined as a Response Evaluation 
Criteria in Solid Tumors (RECIST) partial response (PR) or complete response (CR), circulating 
tumor cell reduction from 5 or more to less than 5 per 7.5 mL of blood, or 50% decrease in 
prostate-specific antigen (PSA). Fourteen of the 16 responders had a mutation in a HRR gene, 
most commonly BRCA2 and ATM.9 These findings provide compelling evidence for use of a 
PARPi in a selected population of mCRPC patients with predicted loss-of-function mutations in 
HRR genes such as BRCA1/2 and ATM. 
3.3.1 
Treatment of Metastatic, Castration-resistant Prostate Cancer 
Androgen deprivation therapy (ADT) is the standard first-line systemic treatment for metastatic 
prostate cancer. It is highly active with clinical, radiographic and PSA responses for most 
patients – but almost all men will eventually progress to mCRPC. Over the last 10 years, 
multiple therapies have been shown to confer a survival benefit for patients with mCRPC and 
were approved on this basis, including docetaxel, cabazitaxel, Sipuleucel-T, radium Ra 
223 dichloride, and two agents that target the androgen receptor (AR) pathway, abiraterone 
acetate and enzalutamide.10-14 More recently, abiraterone has demonstrated a survival advantage 
for patients with metastatic high-risk castration-sensitive prostate cancer,15 and in separate 
studies, both enzalutamide and apalutamide have demonstrated improvement in metastasis-free 
survival in patients with non-metastatic castration-resistant prostate cancer.16, 17 
Based on their tolerability and proven efficacy in the pre-chemotherapy setting, abiraterone 
acetate and enzalutamide have become common first-line therapies for mCRPC; however, 
patients progress on these agents after a median duration of 16 to18 months treatment. Response 
rates to a second regimen of AR-directed therapy are low,18-21 therefore systemic chemotherapy 
is often considered as the next treatment option for patients who have progressed on AR-directed 
therapy. Docetaxel (75 mg/m2 every 3 weeks) plus prednisone demonstrated good activity 
(45% PSA response rate and 19.2 months overall survival [OS]) in chemotherapy-naïve mCRPC 
patients who progressed on ADT, but has generally been replaced by abiraterone acetate and 


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enzalutamide as first-line treatment for mCRPC. Docetaxel appears to be less effective in the 
post-abiraterone or enzalutamide setting, with median progression-free survival (PFS) of 
approximately 4.5 months.19 It is also associated with significant toxicity, including Grade 3/4 
neutropenia, fatigue, sensory neuropathy, stomatitis, diarrhea and fatigue.14 Cabazitaxel plus 
prednisone is a treatment option following docetaxel-based treatment based on demonstrated OS 
benefit versus mitoxantrone (median of 15.1 versus 12.7 months, hazard ratio [HR] 0.70 (95% 
confidence interval [CI] 0.59-0.83, p < 0.0001) in mCRPC patients who progressed on both ADT 
and docetaxel therapy, but it is also associated with significant Grade 3/4 neutropenia and 
diarrhea.23 Radium Ra 223 dichloride received approval for treatment of mCRPC based on OS 
benefit (median of 14 versus 11.2 months for placebo) in patients who had bone, but not visceral 
disease.24 Sipuleucel-T extended median OS in mCRPC by 4.1 months compared to placebo,25 
but its effectiveness is not known in the post-abiraterone/enzalutamide and post-docetaxel 
setting. Both agents are generally well-tolerated and thus reasonable treatment options for 
patients prior to receiving treatment with chemotherapy or for patients with bone-only disease. 
Nevertheless, novel therapies that provide robust clinical benefit and have a good safety profile 
are still needed for patients with advanced mCRPC, and a targeted therapy such as a PARPi for 
the subset of patients who exhibit features of HRD represents an attractive option. 
3.4 
Prior Experience with Rucaparib 
Refer to the current rucaparib Investigator’s Brochure (IB) for the latest relevant 
nonclinical and clinical information regarding rucaparib, including the status of ongoing 
and completed clinical studies.  
An overview of data from nonclinical and clinical studies with rucaparib are summarized below. 
More current additional detail is provided in the rucaparib Investigator’s Brochure (IB). A 
summary of the benefits and risks of rucaparib treatment are also provided in the rucaparib IB. 
The nonclinical and clinical data and benefits and risks of rucaparib have been consistent over 
time. 
3.4.1 
Nonclinical Experience with Rucaparib 
The results from nonclinical studies are consistent with the anticipated mechanism of action and 
pharmacological effects of PARP inhibition.  
Pharmacological assessment demonstrated that rucaparib is a potent and selective inhibitor of 
PARP-1, PARP-2, and PARP-3 and has robust and durable in vitro and in vivo activity in 
multiple BRCA1/2 mutant cell lines and xenograft models. Rucaparib was also active in a BRCA 
wild-type model, consistent with in vitro data suggesting that rucaparib is active in cells with 
other defects in HRR through synthetic lethality. In vitro screens suggested that rucaparib has a 
limited potential for off-target effects. Safety pharmacology studies suggest that when given 
orally, rucaparib poses a low risk for causing neurobehavioral and cardiac effects in patients.  
In pharmacokinetic (PK) studies, rucaparib demonstrated species-dependent oral bioavailability, 
moderate plasma protein binding, and large volumes of distribution in nonclinical species. As a 
P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrate, rucaparib 


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demonstrated minimal penetration of rucaparib-derived radioactivity through the blood-brain 
barrier. In vitro data suggested slow metabolism by cytochrome P450 (CYP) enzymes, with 
CYP2D6 and to a lesser extent CYP1A2 and CYP3A4 contributing to the metabolism of 
rucaparib. Rucaparib was mainly excreted in feces in rats and dogs. In vitro, rucaparib reversibly 
inhibited CYP1A2, CYP2C19, CYP2C9, and CYP3A, and to a lesser extent CYP2C8, CYP2D6, 
and UDP-glucuronosyltransferase 1A1 (UGT1A1). Rucaparib induced CYP1A2, and 
down-regulated CYP2B6 and CYP3A4 in human hepatocytes at clinically relevant exposures. 
Rucaparib is a potent inhibitor of multidrug and toxin extrusion protein 1 (MATE1) and 
MATE2-K, a moderate inhibitor of organic cationic transporter 1 (OCT1), a weak inhibitor of 
OCT2, and may inhibit P-gp and BCRP in the gut.  
Oral dosing of rucaparib in single and repeat dose toxicity studies in rats and dogs resulted in 
toxicity to the hematopoietic, lymphopoietic, and gastrointestinal systems. These toxicities were 
generally both reversible upon recovery and predictive of toxicities observed in patients. 
Rucaparib was shown to be clastogenic in an in vitro chromosomal aberration assay suggesting 
potential genotoxicity in humans. Reproductive and development toxicity studies in rat showed 
that rucaparib caused maternal toxicity and was embryo-toxic. Although no rucaparib related 
effects on sperm total count, density, motility, or morphology were identified, based on 
published studies, PARP inhibitors have the potential to impair spermatogenesis and reduce 
fertility.26-29 
3.4.2 
Clinical Experience with Rucaparib 
Rucaparib has been evaluated in Phase 1, 2, and 3 clinical studies and is being evaluated in 
ongoing Phase 1, 2, and Phase 3 clinical studies. The early clinical program assessed safety and 
efficacy of rucaparib in patients with malignancies commonly treated with chemotherapeutic 
agents. Initially, an intravenous (IV) formulation of rucaparib was administered in combination 
with a variety of chemotherapies; later, the oral formulation of rucaparib was administered in 
combination with chemotherapy and as a monotherapy. The oral formulation as monotherapy is 
the focus of current development efforts. The IV formulation is no longer in use.  
On 19 December 2016, under priority and expedited review, the US Food and Drug 
Administration (FDA) granted accelerated approval for the marketing of rucaparib (Rubraca®) 
for monotherapy treatment of patients with deleterious breast cancer susceptibility gene (BRCA) 
mutation (germline and/or somatic) associated advanced ovarian cancer who have been treated 
with 2 or more chemotherapies and on 06 April 2018 Rubraca was approved for use as 
monotherapy maintenance treatment for adult patients with recurrent epithelial ovarian (EOC), 
fallopian tube cancer (FTC), or primary peritoneal cancer (PPC) who are in response (complete 
or partial) to platinum-based chemotherapy. On 29 May 2018, the European Commission (EC) 
authorized oral rucaparib as monotherapy treatment of adult patients with platinum-sensitive, 
relapsed or progressive, BRCA-mutated (germline and/or somatic), high-grade EOC, FTC, or 
PPC, who have been treated with 2 or more prior lines of platinum-based chemotherapy, and 
who are unable to tolerate further platinum-based chemotherapy.  
The latest summary information on indications and ongoing/completed clinical studies is 
provided in the rucaparib IB. Information below is current as of 27 August 2020. 


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Six studies (A4991002, A4991005, A4991014, CO-338-010, CO-338-023 [RUCAPANC], and 
CO-338-045 [ADME]) have been completed and 6 studies in addition to the one described in this 
protocol are ongoing (CO-338-014 [ARIEL3], CO-338-017 [ARIEL2], CO-338-043 [ARIEL4], 
CO-338-044 [DDI], CO-338-052 [Phase 2 mCRPC], and CO-338-078 [hepatic impairment 
study]). 
Details of all completed, ongoing, and planned studies are described briefly below. Additional 
information is provided in the rucaparib IB. 
Completed Studies 
• A4991002: a Phase 1 open-label, dose-escalation study of IV rucaparib in combination with 
temozolomide (TMZ) in patients with advanced solid tumors (Part 1) or malignant melanoma 
(Part 2).  
• A4991005: a Phase 2, open-label study of IV rucaparib in combination with TMZ in patients 
with metastatic melanoma.  
• A4991014: a Phase 1, open-label, dose-escalation study of IV and oral rucaparib 
administered with different chemotherapeutic agents in patients with an advanced solid 
tumor. 
CO-338-023 (RUCAPANC): a Phase 2, single-arm, open-label study of monotherapy oral 
rucaparib as treatment for patients with previously treated locally advanced or metastatic 
pancreatic ductal adenocarcinoma and a known deleterious BRCA mutation.  
• CO-338-010: 3-part, open-label, Phase 1/2 study of monotherapy oral rucaparib. 
- 
Part 1: a Phase 1 portion evaluating PK and safety of escalating doses of rucaparib in 
patients with solid tumors; this portion identified 600 mg twice a day (BID) as the 
recommended starting dose for future studies (n = 56; completed).  
- 
Part 2: a Phase 2 portion evaluating the efficacy and safety of rucaparib in patients with 
relapsed, high-grade ovarian cancer associated with a BRCA mutation.  
o Part 2A enrolled patients with a gBRCA mutation who had received 2 to 4 prior 
treatment regimens (n = 42; enrollment complete).  
o Part 2B enrolled patients with a gBRCA or sBRCA mutation who received at 
least 3 prior chemotherapy regimens (n = 12; enrollment complete).  
- 
Part 3: a Phase 2 portion in patients with a relapsed solid tumor associated with a BRCA 
mutation in order to characterize the PK, food effect, and safety profile of a higher dose 
strength tablet (n = 26; enrollment complete). 
• CO-338-045 (ADME study): a Phase 1 mass balance study of [14C]-rucaparib in patients with 
an advanced solid tumor (n = 6; completed). 
 
Ongoing Studies 
• CO-338-017 (ARIEL2): a 2-part open-label Phase 2 study of monotherapy oral rucaparib for 
treatment of relapsed, high-grade ovarian cancer patients. It is designed to identify tumor 
characteristics that may predict sensitivity to rucaparib. Patients will be classified into 


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molecularly-defined subgroups, including tumor BRCA (tBRCA, inclusive of both germline 
and somatic BRCA) and BRCA-like, by a prospectively defined genomic signature.  
- 
Part 1 enrolled patients with platinum-sensitive, relapsed disease who received ≥ 1 prior 
platinum regimen (n = 204; enrollment complete).  
- 
Part 2 enrolled patients with relapsed disease who received at least 3 prior chemotherapy 
regimens (n = 287 enrollment complete).  
• CO-338-014 (ARIEL3): a Phase 3, randomized, double-blind study of monotherapy oral 
rucaparib versus placebo as switch maintenance treatment in patients with 
platinum-sensitive-, relapsed, high-grade ovarian cancer who achieved a response to 
platinum-based chemotherapy (n = 564 [randomized patients; rucaparib n = 375; placebo 
n = 189]; enrollment complete). 
• CO-338-043 (ARIEL4): a Phase 3, randomized study of rucaparib versus chemotherapy in 
patients with relapse, BRCA-mutant, high-grade epithelial ovarian, fallopian tube, or primary 
peritoneal cancer (n = 345 planned).  
• CO-338-044 (DDI study): a 2-part, Phase 1, open-label, multiple-probe drug-drug interaction 
(DDI) study to determine the effect of rucaparib on PK of caffeine, S-warfarin-, omeprazole, 
midazolam, and digoxin in patients with advanced solid tumors in Part 1, followed by 
optional continued treatment with rucaparib in Part 2 (n = 17; enrollment complete). 
• CO-338-052 (TRITON2): a Phase 2 study evaluating rucaparib for treatment of patients with 
mCRPC whose tumors are associated with HRD by enrolling mCRPC patients with 
mutations in BRCA1/2, ATM, or other HRR genes. All patients will be required to have 
progressed on prior AR-targeted therapy (abiraterone acetate, enzalutamide, or 
investigational AR-targeted agent) and also have progressed after one prior taxane-based 
chemotherapy for mCRPC (n = 350 planned; enrollment ongoing)  
• CO-338-078 (hepatic impairment study): a Phase 1, clinical pharmacology study in patients 
with an advanced solid tumor and normal or moderately impaired hepatic function to assess 
the effect of hepatic function on rucaparib PK. 
 
3.4.2.1 
Overview of Pharmacokinetics and Drug-Drug Interactions 
An overview of data are provided below and described in detail in the rucaparib IB. 
Assessment of rucaparib PK in cancer patients showed an approximate dose proportional 
exposure after once a day (QD) or BID dosing, rapid absorption with maximum plasma 
concentration (Cmax) achieved within 1.5 to 6 hours, and distribution into tissue. The oral 
bioavailability was 36% and elimination ranged from 11 to 29.8 hours. Rucaparib was 
moderately bound to human plasma proteins in vitro. 
At a dose of 600 mg BID rucaparib, steady state was achieved after approximately 1 week. The 
absolute oral bioavailability was 37.2%. In the presence of a high-fat meal, there was a slight 
delay in absorption, but an overall increase in exposure and oral bioavailability (51.7% [fed] vs. 
36.2% [fasted]). 
In vitro, CYP enzymes were shown to contribute to rucaparib metabolism. In a preliminary 
assessment of rucaparib metabolism in patients, rucaparib biotransformation pathways included 
hydroxylation or oxidation, N-demethylation, deamination, and phase II methylation. A 


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carboxylic acid metabolite (M324) and a phase II N-methylated metabolite of M324 (M338) 
were identified as major metabolites.  
POPULATION PK ANALYSES 
Drug interactions with rucaparib as a substrate were assessed in a population PK analysis. 
CYP2D6 phenotypes (poor metabolizers, intermediate metabolizers, normal metabolizers, and 
ultra‑rapid metabolizers) and CYP1A2 phenotypes (normal metabolizers and hyperinducers) did 
not significantly impact the steady-state exposure of rucaparib at 600 mg BID. Concomitant 
administration of strong CYP1A2 or CYP2D6 inhibitors did not significantly impact rucaparib 
PK. Current smokers had overlapping rucaparib exposures as compared to nonsmokers and 
former smokers. Collectively, the results suggest that CYP1A2 and CYP2D6 play limited role in 
rucaparib metabolism in vivo, and no rucaparib dose adjustment is needed when concomitantly 
administered with CYP1A2 or CYP2D6 inhibitors. 
In vitro, rucaparib is a substrate of P-gp and BCRP. Concomitant usage of strong P-gp inhibitors 
did not affect rucaparib PK. Effect of BCRP inhibition on rucaparib PK has not been studied. 
Concomitant treatment with proton pump inhibitors (PPIs) did not show clinically significant 
effect on rucaparib PK. No dose modification is recommended based on use PPIs. 
EFFECT OF RUCAPARIB ON THE PHARMACOKINETICS OF OTHER DRUGS 
In the “cocktail” drug-drug interaction study CO-338-044, the effects of steady-state rucaparib at 
600 mg BID on CYP1A2, CYP2C9, CYP2C19, CYP3A, and P-gp were evaluated with single 
oral doses of sensitive probes (caffeine, S-warfarin, omeprazole, midazolam, and digoxin, 
respectively). Data suggest that rucaparib is a moderate inhibitor of CYP1A2, a weak inhibitor of 
CYP2C9, CYP2C19, and CYP3A. Rucaparib also marginally inhibited P-gp in the gut but the 
effect is unlikely clinically significant. Details and results of study CO-338-044 are provided in 
the rucaparib IB.  
3.4.2.2 
Overview of Efficacy 
An overview of data are provided below and described in detail in the rucaparib IB. 
Efficacy analysis was based on pooled efficacy data from 106 patients with BRCA mutant 
ovarian cancer, who received two or more prior chemotherapy regimens, and who initiated 
treatment with rucaparib at 600 mg BID in Part 2A of Study CO-338-010 and Parts 1 and 2 of 
Study CO-338-017. The enrollment cut-off date was 1 October 2015 (all 42 patients enrolled) 
and the visit data cut-off date was 30 November 2015 for Study CO-338-010 Part 2A. The 
enrollment cut-off was a 1 October 2015 and the visit data cut-off was 29 February 2016 for 
Part 1 (24 patients) and Part 2 (40 patients) of Study CO‑338‑017. 
Efficacy data indicate that many patients with advanced ovarian cancer associated with a 
BRCA1/2 gene mutation and who had two or more prior therapies achieve RECIST Version 1.1 
and/or Gynecologic Cancer InterGroup (GCIG) cancer antigen-125 (CA-125) responses. The 
confirmed objective response rate (ORR) per RECIST Version 1.1 by investigator review was 
53.8% (57/106) and the confirmed response by RECIST Version 1.1 or GCIC CA-125 was 


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70.8% (75/106). The confirmed ORR per RECIST Version 1.1 by independent review was 
41.5% (44/106).  
In addition, patients without a BRCA1/2 gene mutation in tumor tissue are also deriving benefit, 
with 43% achieving RECIST Version 1.1 and/or GCIG CA-125 responses. 
In the Phase 3, randomized, double-blind study of monotherapy oral rucaparib versus placebo as 
switch maintenance treatment in patients with platinum-sensitive, relapsed, high-grade ovarian 
cancer who achieved a response to platinum-based chemotherapy (ARIEL3), the primary 
efficacy endpoint was investigator-assessed PFS (invPFS) by RECIST Version 1.1. Three patient 
populations (tBRCA, HRD, and intent-to-treat [ITT]) were evaluated in a step-down analysis.  
The primary endpoint was achieved as of 15 April 2017 with a highly statistically significant 
difference in invPFS between rucaparib treatment as compared to placebo for each of the 
3 stratified primary efficacy analysis populations (p < 0.0001 for each population). The median 
invPFS in the tBRCA population was 16.6 months (95% CI, 13.4-22.9) for the rucaparib group 
and 5.4 months (95% CI, 3.4-6.7) for the placebo group. Additional data in HRD and ITT 
populations are available in the rucaparib IB.  
For each of the 3 populations, the confirmed investigator-assessed ORR, per 
RECIST Version 1.1, in patients with measurable disease at baseline was statistically 
significantly higher in the rucaparib group compared to the placebo group. In the tBRCA 
population, the confirmed ORR was 15/40 (37.5%) for the rucaparib group and 2/23 (8.7%) for 
the placebo group (p = 0.0055). Additional data in HRD and ITT populations are available in the 
rucaparib IB.  
Three mCRPC patients with a BRCA mutation received rucaparib monotherapy in 
Study CO-338-010 or under named patient access, most of whom experienced tumor 
stabilization, decrease of PSA levels, and symptom improvement. 
3.4.2.3 
Overview of Safety 
An overview of data are provided below and described in detail in the rucaparib IB. 
Integrated Safety Analysis in the Treatment Setting (Studies CO-338-010 and CO-338-017) 
An integrated safety analysis, based on pooled safety data from 545 patients in Study 
CO-338-010 (Parts 2A and 2B) and Study CO-338-017 (ARIEL2; Parts 1 and 2) with relapsed 
ovarian cancer who were treated with 600 mg BID monotherapy rucaparib, was performed and a 
summary of treatment-emergent adverse events (TEAEs), overall and ≥ Grade 3, is presented in 
Table 1. This analysis includes data as of 1 September 2017. Overall, the median duration of 
treatment was 160.0 days (approximately 5.3 months; range, 2 to 1234 days). 
The most common TEAEs reported were primarily mild to moderate (Grade 1 to 2) in severity 
and included gastrointestinal disorders (nausea [78.5%], vomiting [45.9%], constipation [37.6], 
abdominal pain (32.5%), and diarrhea [32.3%]), asthenia/fatigue (75.0%), anemia/decreased 
haemoglobin (44.0%), ALT/AST increased (39.3%), decreased appetite (38.3%), and dysgeusia 
(36.7%).  


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The most common treatment-related TEAEs reported were primarily mild to moderate (Grade 1 
to 2) in severity and included nausea (68.3), asthenia/fatigue (67.0%), anemia/decreased 
haemoglobin (38.9%), alanine aminotransferase (ALT)/aspartate aminotransferase (AST) 
increased (36.5%), dysgeusia (34.1%), and vomiting (31.6%) as described in greater detail in the 
rucaparib IB.  
The most common TEAEs ≥ Grade 3 were anemia/decreased hemoglobin (24.2%), 
asthenia/fatigue (11.7%), ALT/AST increased (10.8%), thrombocytopenia/decreased platelets 
(6.1%), and nausea (5.3%). As of the data cut-off date, approximately 9% of patients had 
discontinued due to a treatment-related TEAE.  
In addition, photosensitivity has been reported in some patients. Photosensitivity was initially 
reported in the Phase 1 dose-escalation portion of Study CO-338-010 (n = 6; 10.7%) and based 
on these reports of photosensitivity, guidance for sun protection was included in rucaparib 
clinical studies. Of 917 patients with advanced ovarian cancer treated with rucaparib 600 mg 
BID in Studies CO-338-014 (ARIEL3), CO-338-010, and CO-338-017 (ARIEL2), 
118 patients (12.9%) experienced photosensitivity, of whom 2 patients (0.2%) experienced 
≥ Grade 3 photosensitivity as described in the rucaparib IB. Patients should use typical 
precautions when going outside, such as applying sunscreen (sun protection factor 50 or greater) 
and/or covering exposed skin with clothing and wearing a hat and sunglasses. 
Effects on cardiac channel activity in vitro and a comprehensive assessment of the effects of 
rucaparib on electrocardiogram (ECG) parameters in cancer patients demonstrated a low risk of 
cardiac effects by rucaparib. 
 
 


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Table 1. 
Treatment-emergent AEs (All Grades and ≥ Grade 3) Reported in 
≥ 20% of Ovarian Cancer Patients in Combined Studies CO-338-010 
and CO-338-017 
Preferred Terma  
600 mg BID Rucaparib (N = 409)b 
n (%) 
All Grades 
≥ Grade 3 
Nausea 
428 (78.5) 
29 (5.3) 
Asthenia/fatiguec 
409 (75.0) 
64 (11.7) 
Vomiting 
250 (45.9) 
23 (4.2) 
Anemia/decreased hemoglobinc 
240 (44.0) 
132 (24.2) 
ALT/AST increasedc 
214 (39.3) 
59 (10.8) 
Decreased appetite 
209 (38.3) 
16 (2.9) 
Constipation 
205 (37.6) 
8 (1.5) 
Dysgeusia 
200 (36.7) 
1 (0.2) 
Abdominal pain 
177 (32.5) 
22 (4.0) 
Diarrhoea 
176 (32.3) 
11 (2.0) 
Thrombocytopenia/decreased 
plateletsc 
128 (23.5) 
33 (6.1) 
Blood creatinine increased 
120 (22.0) 
3 (0.6) 
Dypsnoea 
120 (22.0) 
5 (0.9) 
Note: Data are presented by decreasing frequency for TEAEs of all grades, all causality. 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BID = twice a day; 
MedDRA = Medical Dictionary for Regulatory Activities; N or n = number of patients; 
TEAE = treatment-emergent adverse event. 
a 
Preferred Terms were based on MedDRA dictionary (version 18.1). 
b 
The data presented in this table are from: all ovarian cancer patients treated with rucaparib 600 mg BID and 
enrolled in Parts 2A and 2B of Study CO-338-010 and Parts 1 and 2 of Study CO-338-017, with a data 
cut-off date of 1 September 2018.  
c 
Combined MedDRA preferred terms 
 
Safety in the Maintenance Setting (Study CO-338-014 [ARIEL3]) 
As of the 15 April 2017 cut-off date for Study CO-338-014 (ARIEL3), a total of 561 patients 
were treated with at least 1 dose of study drug (372 patients in the rucaparib group and 
189 patients in the placebo group). The median duration of treatment was 8.3 months (range: 
0-35) in the rucaparib group and 5.5 months (range, 0 to 35) in the placebo group.  
The TEAEs that occurred in ≥ 20% of patients (all grades) in either treatment group are 
summarized by Preferred Term (PT) in Table 2. The most common TEAEs that occurred in the 
rucaparib group were nausea (75.3%), asthenia/fatigue (69.4%), dysgeusia (39.2%), and 
anemia/low or decreased hemoglobin (37.4%). Although greater incidences of these most 
common TEAEs occurred with rucaparib treatment compared to placebo, the TEAEs reported 
for the placebo group provide a general context of what events are prevalent in this patient 


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population without treatment. The most common TEAEs that reported in the placebo group were 
nausea (36.5%), asthenia/fatigue (43.9%), abdominal pain (25.9%), and constipation (23.8%). 
Grade 3 or higher TEAEs are also summarized in Table 2. Approximately half (56.2%) of the 
patients treated with rucaparib experienced a TEAE of Grade 3 or higher compared to 
approximately 15% of placebo patients. For patients in the rucaparib group, 2 TEAEs that were 
Grade 3 or higher had an incidence of > 10%: anemia/low or decreased hemoglobin (18.8%) and 
increased ALT/AST (10.5%). No Grade 4 events of increased ALT/AST were reported.  
Table 2. 
Treatment-emergent AEs Reported in ≥ 20% of Patients (All Grades) 
in Any Treatment Group in Study CO-338-014 - Safety Population 
Preferred Term(s) 
All Grades 
≥ Grade 3a 
Rucaparib 
(N = 372) 
n (%) 
Placebo 
(N = 189) 
n (%) 
Rucaparib 
(N = 372) 
n (%) 
Placebo 
(N = 189) 
n (%) 
Number of Patients With at Least One TEAE 
372 (100) 
182 (96.3) 
209 (56.2) 
28 (14.8) 
Nausea 
280 (75.3) 
69 (36.5) 
14 (3.8) 
1 (0.5) 
Asthenia/Fatigue 
258 (69.4) 
83 (43.9) 
25 (6.7) 
5 (2.6) 
Dysgeusia 
146 (39.2) 
13 (6.9) 
0 
0 
Anemia and/or low/decreased hemoglobin 
139 (37.4) 
11 (5.8) 
70 (18.8) 
1 (0.5) 
Constipation 
136 (36.6) 
45 (23.8) 
7 (1.9) 
2 (1.1) 
Vomiting 
136 (36.6) 
28 (14.8) 
15 (4.0) 
2 (1.1) 
ALT/AST Increased 
126 (33.9) 
7 (3.7) 
39 (10.5) 
0 
Diarrhea 
118 (31.7) 
41 (21.7) 
2 (0.5) 
2 (1.1) 
Abdominal pain 
111 (29.8) 
49 (25.9) 
9 (2.4) 
1 (0.5) 
Thrombocytopenia and/or low/decreased 
platelets 
104 (28.0) 
5 (2.6) 
19 (5.1) 
0 
Decreased appetite 
87 (23.4) 
26 (13.8) 
2 (0.5) 
0 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = Common 
Terminology Criteria for Adverse Events; NCI = National Cancer Institute; TEAE = treatment-emergent adverse 
event. 
a 
NCI CTCAE grade. 
 
The laboratory abnormalities were consistent with the TEAEs, with decreased hemoglobin, 
increased ALT, increased AST, and increased serum creatinine, most common (Table 3). 
Decreased platelets, neutrophils, leukocytes, lymphocytes, and increased cholesterol were 
observed to a lesser extent (Table 3). 
A decrease in hemoglobin (National Cancer Institute [NCI] Common Terminology Criteria for 
Adverse Events [CTCAE] Grade 1 to 4) from baseline was observed in 61% of patients 
(Grade 3, 13%). A decrease in lymphocytes, platelets, or neutrophils from baseline to a 
worsening CTCAE Grade occurred in 24%, 40%, and 35% of all patients, respectively). A shift 
to CTCAE Grade 3 or greater lymphocytes, platelets, or neutrophils was observed in 5%, 2%, 
and 6%, of all patients, respectively. 
Notable shifts from baseline were observed for creatinine, ALT, AST, and cholesterol 
concentrations in the majority of patients. An increase in ALT or AST from baseline to a 


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worsening CTCAE grade was observed in 73% and 61% of patients, respectively. A shift to 
CTCAE Grade 3 or greater ALT or AST was observed in 7% and 1% of all patients, 
respectively.  
Increases in ALT/AST are a known self-limiting effect of rucaparib treatment; therefore, 
management of these elevations was specified within the protocol. Elevations in ALT/AST were 
generally not accompanied by a concomitant elevation in bilirubin outside the normal range, and 
no cases met Hy’s Law criteria for drug-induced liver injury. Continued dosing with rucaparib in 
the presence of Grade 3 ALT/AST elevations is permitted if there are no other signs of liver 
toxicity.  
An increase in serum creatinine from baseline to a worsening CTCAE grade occurred in 43% of 
patients (0.3% Grade 3) using an updated version of the CTCAE (ie, version 5). In CTCAE 
version 4.03, any increase in creatinine above the baseline value is assessed as a Grade 1 toxicity 
(1 to 1.5 x baseline value) and almost all patients exhibit a shift from baseline creatinine. In 
CTCAE version 5, Grade 1 for increased creatinine is based on values greater than the upper 
limit of normal (ULN). The elevations were observed early in treatment (Day 15 of Cycle 1) and 
then stabilized with continued rucaparib treatment. Serum creatinine levels decreased with 
interruption or discontinuation of rucaparib, and increase again with resumption of treatment. 
An increase in total cholesterol from baseline to a worsening CTCAE grade occurred in 41% of 
all patients (4% Grade ≥ 3).  
Overall, rucaparib safety data at a dose of 600 mg BID in patients with ovarian cancer in 
Study CO-338-014 in the maintenance setting were consistent with the combined safety data in 
patients with ovarian cancer from Studies CO-338-010 and CO-338-017 in the treatment setting. 


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Table 3. 
Change from Baseline in Laboratory Parameters in Patients 
Treated with 600 mg BID Rucaparib (Study CO-338-014) 
 
Rucaparib 
(N=372) 
Placebo 
(N=189) 
Shift in CTCAE Grade (n [%])a 
 
Grade 1-4  
Grade 3-4 
Grade 1-4  
Grade 3-4 
Decrease in 
hemoglobinb 
224 (61.0) 
46 (12.5) 
24 (12.7) 
2 (1.1) 
Decrease in 
lymphocytesb, c 
87 (23.7) 
17 (4.6) 
31 (16.5) 
5 (2.7) 
Decrease in 
neutrophilsb, c 
128 (34.9) 
23 (6.3) 
32 (17.0) 
4 (2.1) 
Decrease in plateletsb  
145 (39.5) 
8 (2.2) 
15 (8.0) 
0 
Shift in CTCAE Grade (n [%])a 
 
Grade 1-4  
Grade 3-4 
Grade 1-4  
Grade 3-4 
Increase in ALTb 
267 (72.8) 
24 (6.5) 
7 (3.7) 
0 
Increase in ASTc, d 
223 (60.9) 
3 (0.8) 
7 (3.7) 
0 
Increase in alkaline 
phosphataseb 
116 (31.6) 
1 (0.3) 
10 (5.3) 
0 
Increase in bilirubinb 
34 (9.3) 
1 (0.3) 
3 (1.6) 
0 
Increase in cholesterolb 
152 (41.4) 
15 (4.1) 
39 (20.6) 
0 
Hyperglycemiab 
125 (34.1) 
6 (1.6) 
54 (28.6) 
0 
Increase in creatinineb, e 
156 (42.5) 
1 (0.3) 
14 (7.4) 
0 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = Common 
Terminology Criteria for Adverse Events; ULN = upper limit of normal 
a 
Shifts are based on worst grade experienced on treatment and patients who had at least a 1 grade shift from 
baseline. 
b 
rucaparib n = 367. 
c 
placebo n = 188. 
d 
rucaparib n = 366. 
e 
Evaluated using CTCAE, v5 where Grade 1 is > ULN-1.5 ULN; Grade 2 is > 1.5 × baseline to 3.0 × baseline 
or > 1.5 × ULN to 3.0 × ULN; Grade 3 is > 3.0 × baseline or > 3.0 × ULN to 6.0 × ULN; and Grade 4 is 
> 6.0 × ULN.  
 
Adverse Events of Special Interest 
Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are considered adverse 
events of special interest (AESI), as these events have been observed in patients exposed to 
cytotoxic chemotherapy (eg, platinum and anthracyclines) used for treatment of ovarian cancer 
as well as with PARP inhibitors, including rucaparib. Patients in rucaparib clinical studies 
diagnosed with MDS or AML had significant confounding risk factors including prior cytotoxic 
chemotherapy, and in some cases a deleterious BRCA mutation, which increases the risk of 
developing cancer(s). Based on these confounding factors, there is insufficient scientific 
evidence to conclude that MDS and AML are causally related to rucaparib. More information on 
AESIs of MDS/AML experienced by patients in rucaparib clinical studies is provided in the 
rucaparib IB.  


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Adverse events (AEs) of pneumonitis have been reported with PARP inhibitor treatment, 
including in clinical trials evaluating rucaparib. Currently, however, there is a lack of 
understanding of a mechanistic link between pneumonitis and PARP inhibitor treatment, and 
causality assessment is often confounded by lack of a consistent clinical pattern as well as other 
pre-disposing factors, such as cancer and/or metastases in lungs, underlying pulmonary disease, 
smoking history, and/or previous chemotherapy and radiotherapy. Clovis Oncology is seeking to 
understand whether or not there is a relationship between pneumonitis and rucaparib treatment; 
thus, Clovis Oncology is designating pneumonitis as an AESI to gather data to enable a thorough 
evaluation and assessment of the event and associated terms specified in Section 10.7. Also, refer 
to the rucaparib IB for information regarding the AESI of pneumonitis.  
3.5 
Rationale for this Study of Rucaparib 
Homologous recombination deficiency has been observed in many carcinomas, including 
prostate cancer. Men with a germline mutation in BRCA2 are at increased risk for developing 
prostate cancer, estimated at 2.5 to 8.6-fold compared with non-carriers.6 Men with prostate 
cancer and a germline mutation in BRCA2 typically develop disease at a younger age, have more 
aggressive features and higher mortality rates; while less common in prostate cancer, germline 
mutations in BRCA1 are also associated with more aggressive disease.7 Deleterious germline 
mutations in other HRR genes, including ATM, checkpoint kinase 2 (CHEK2), 
RAD51 homolog D (RAD51D) and partner and localizer of BRCA2 (PALB2),30 have also been 
reported. In addition to germline mutations, somatic mutations in the HRR genes BRCA1, 
BRCA2 and ATM, and other much less frequent mutations in BRCA1-interacting 
protein 1 (BRIP1), CDK12, CHEK2, FANCA, nibrin (NBN), PALB2, RAD51B, and RAD51C 
have been observed in advanced prostate cancer.8, 9 
Nonclinical evaluation has demonstrated sensitivity of BRCA1 and BRCA2 homozygous mutant 
cell lines to rucaparib and other PARP inhibitors (see Section 4.1 of the Investigator’s Brochure). 
In addition, sensitivity to PARP inhibition has also been observed in cells deficient or depleted in 
other components of HRR, including ATM.31 This sensitivity is the result of synthetic lethality in 
homologous recombination deficient cells (like BRCA-mutant tumors) when exposed to a 
PARPi.  
Rucaparib, olaparib, niraparib, and talazoparib, similar agents in the growing class of PARP 
inhibitors in clinical development, have demonstrated clinical activity in several studies as a 
single agent for treatment of ovarian, prostate, and breast cancer associated with a BRCA 
mutation (germline or somatic), as well as in patients without a BRCA mutation.9, 32-40  
The response to PARP inhibitors in mCRPC patients has been explored in several 
Phase 1 studies. Fong et al. provided the first description of a BRCA mutant prostate cancer 
patient responding to PARPi therapy.41 In a Phase 1 dose-escalation study of olaparib, three 
mCRPC patients were enrolled, of which one patient was a germline BRCA2 mutation carrier. 
This BRCA mutant mCRPC patient had a > 50% reduction in his PSA level, resolution of bone 
metastases, and treatment duration > 1 year. The two mCRPC patients without a germline BRCA 
mutation did not demonstrate a similar response.  


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Sandhu et al. reported on a cohort of four patients with germline BRCA2-mutant advanced 
prostate cancer treated with either olaparib (three patients) or niraparib (one patient).42 In the 
patients treated with olaparib, PSA and radiographic responses lasting 34 and 26 months were 
noted in two patients, and stable disease (SD) of 10 months was noted in the third. The patient 
treated with niraparib demonstrated primary resistance and quickly progressed; the total duration 
for niraparib treatment in that patient was 6 weeks.  
Olaparib was further evaluated in mCRPC in several Phase 2 studies. In one study that enrolled 
multiple tumor types, Kaufman et al. (2014) reported efficacy data for eight BRCA mutant 
mCRPC patients who had received a median number of two prior therapies.43 All patients had 
experienced disease progression following hormonal therapy; 75% had received prior docetaxel, 
and 50% had received prior platinum (carboplatin or cisplatin). Four patients had a confirmed PR 
(confirmed RECIST Version 1.1 ORR = 50%) and two patients (25%) had a best response of 
SD. Overall duration of response (DOR) was 327 days, PFS was 7.2 months and median OS was 
18.4 months.  
More recently, olaparib demonstrated compelling clinical activity in a Phase 2 open-label 
investigator-sponsored study9 evaluating mCRPC patients with evidence of HRD. In the Trial of 
PARP Inhibition in Prostate Cancer (TOPARP) study, which enrolled 50 mCRPC patients who 
received prior docetaxel (100%), abiraterone or enzalutamide (98%), and cabazitaxel (58%), 
olaparib demonstrated an ORR of 33% in 49 evaluable patients. Response was defined as any of 
the following: response according to modified RECIST Version 1.1; at least 50% reduction in 
PSA level; or a confirmed reduction in the circulating tumor-cell count from 5 or more cells per 
7.5 mL of blood to less than 5 cells per 7.5 mL. The ORR in patients with a mutation in a DNA 
repair gene (n = 16) was 88%, including 7/7 patients with a BRCA2 mutation and 4/5 patients 
with an ATM mutation. Median radiographic PFS (rPFS) and OS in patients classified as 
biomarker positive (with HRR gene mutation) were 9.8 months and 13.8 months, respectively, 
compared to 2.7 months and 7.5 months for patient classified as biomarker negative (no HRR 
gene mutation). 
To date, rucaparib has exhibited clinical activity and an acceptable safety profile when 
administered as monotherapy. Details of the rucaparib clinical studies and efficacy data are 
further described in Section 3.4.2 and Section 3.4.2.2, as well an in the IB (Sections 5.1 and 5.3). 
Complete and partial responses, as defined by RECIST Version 1.1 criteria, as well as durable 
SD, have been observed in patients with ovarian, breast and pancreatic cancer treated with 
monotherapy rucaparib. Robust efficacy has been observed in ovarian cancer patients with a 
BRCA mutation (germline and somatic) (Section 3.4.2.2) and in patients who have a BRCA-like 
tumor (ie, did not have a BRCA mutation, but had a high percentage of tumor genome loss of 
heterozygosity [LOH]), including patients with a deleterious mutations in RAD51C or RAD51D. 
Three mCRPC patients with a BRCA mutation received rucaparib monotherapy in 
Study CO-338-010 or under named patient access, most of whom experienced tumor 
stabilization, decrease of PSA levels, and symptom improvement. Rucaparib monotherapy has an 
established and manageable safety profile. Taken together, nonclinical and clinical data with 
rucaparib and other PARP inhibitors provide a compelling evidence for use of rucaparib in a 
selected population of mCRPC patients with predicted loss-of-function mutations in HRR genes 
such as BRCA1/2 and ATM. 


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4 
STUDY OBJECTIVES 
4.1 
Primary Objective  
The primary objective of this study is: 
To assess the efficacy of rucaparib versus physician’s choice of treatment based on rPFS in 
mCRPC patients with HRD who progressed on prior AR-directed therapy and have not yet 
received chemotherapy in the castration-resistant setting.  
4.2 
Secondary Objectives  
The secondary objectives of this study are: 
• To assess OS 
• To assess ORR using modified RECIST Version 1.1 in patients with measurable (nodal or 
visceral) disease 
• To assess DOR using modified RECIST Version 1.1 in patients with measurable (nodal or 
visceral) disease 
• To assess time to PSA progression 
• To assess PSA response ≥ 50% (all patients) 
• To assess PSA response ≥ 90% (all patients) 
• To evaluate Patient-reported Outcome (PRO) using the following instruments: 
- 
EuroQol 5 dimensions 5 level questionnaire (EQ-5D-5L),  
- 
Functional Assessment of Cancer Therapy–Prostate (FACT-P),  
- 
Analgesic drug score, and  
- 
Brief Pain Inventory–Short Form (BPI-SF)  
• To assess clinical benefit rate (CBR) 
• To assess sparse PK  
• To assess safety and tolerability 
 
4.3 
Exploratory Objectives 
Exploratory objectives in this study are:  
• To assess concordance in BRCA/ATM gene mutation status in matched Pre-Screening 
biopsy tissue, archival primary and metastatic tumor tissue, and plasma circulating cell-free 
tumor DNA (ctDNA) 
• To assess changes in the molecular profile over time of matched pre and post-treatment 
tumor or plasma samples 
• To evaluate LOH in metastatic disease site biopsy and archival primary and metastatic tumor 
tissue samples 
• To evaluate mechanisms of response and resistance in ctDNA and progression tumor tissue 
samples. 


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5 
INVESTIGATIONAL PLAN 
5.1 
Overall Study Design and Plan 
This is a Phase 3, multicenter, randomized, study of rucaparib versus physician’s choice of 
second-line AR-directed therapy (abiraterone acetate or enzalutamide) or docetaxel as treatment 
for mCRPC patients with histologically or cytologically confirmed adenocarcinoma who have 
progressed on one prior AR-directed therapy (abiraterone acetate, enzalutamide, apalutamide, or 
investigational AR-targeted agent) and have not yet received chemotherapy in the 
castration-resistant setting. Progression is defined according to the Prostate Cancer Working 
Group Guidelines Version 3 (PCWG3) criteria as a rise in PSA, new or progressive disease by 
modified RECIST Version 1.1 (Appendix 1), or two new lesions by radionuclide bone scan. 
Patients who received prior PARPi treatment will be excluded. This study will enroll mCRPC 
patients with a deleterious mutation in BRCA1/2 or ATM genes. Deleterious mutations are 
defined as protein-truncating mutations, large protein-truncating rearrangements, splice site 
mutations, deleterious missense mutations, and homozygous deletions. Mutations may be 
detected by local testing, with the result documented in the patient’s medical record, or may be 
detected through central testing provided by the sponsor during Pre-Screening. For local test 
results, the classification of the mutation as deleterious must be documented in the patient’s 
medical record. The primary endpoint is rPFS using modified RECIST Version 1.1/PCWG3 
criteria by central independent radiology review (IRR; rPFSirr). 
This study consists of a Pre-Screening Phase (Section 5.1.1), Screening Phase (Section 5.1.2), 
Randomization (Section 5.1.3), Treatment Phase (Section 5.1.4) and Post-Treatment Phase 
(Section 5.1.5). Patients will receive rucaparib monotherapy or physician’s choice of comparator 
therapy (pre-designated prior to randomization) in the Treatment Phase, and will undergo 
procedures and assessments including regular safety and efficacy evaluations during the entire 
conduct of the study. Patients randomized to the control arm will have the opportunity to receive 
treatment with rucaparib in the Cross-over Phase of the study, after confirmation of radiographic 
progression (see Section 5.1.6). 
5.1.1 
Pre-Screening Phase 
The Pre-Screening Phase is to identify eligible deleterious BRCA1/2 or ATM gene mutations 
through central testing of tumor tissue and plasma. Patients who have a qualifying deleterious 
BRCA1/2 or ATM gene mutation identified through local testing need not enter Pre-Screening 
and the patient should proceed to the Screening Phase.  
To enter Pre-Screening, patients should have evidence of radiographic or biochemical disease 
progression, and be eligible for this study as their immediate next therapy. Patient tissue and 
plasma samples should be submitted simultaneously during Pre-Screening. Tissue submitted for 
Pre-Screening testing should be from a newly obtained metastatic biopsy, if there is a lesion 
suitable for biopsy and the patient consents to this procedure. If a metastatic biopsy is not 
feasible, archival tissue samples should be submitted. To reduce the chance of test failure, 
archival tissue should be < 3 years old. If plasma or tissue samples result in test failure, sites are 
encouraged to submit additional samples, as available, in order to obtain a successful test result. 
Patients who have a qualifying deleterious BRCA1/2 or ATM gene mutation identified during 


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Pre-Screening may proceed to the Screening Phase. A study schema for the Pre-Screening Phase 
is provided in Figure 1.  
In the event that a deleterious BRCA1/2 or ATM gene mutation is identified in plasma or tumor 
tissue during the Pre-Screening Phase, the patient may be referred by the investigator for genetic 
counseling and potential germline testing per institutional guidelines. If the patient chooses to 
have germline testing performed, this result will be entered in the clinical trial database for this 
study. 
During the Pre-Screening Phase, unless otherwise required by local regulations, serious adverse 
events (SAEs) which are related to protocol-mandated assessments will be reported.  
5.1.2 
Screening Phase 
After providing consent to participate, patients with a deleterious BRCA1/2 or ATM gene 
mutation will undergo Screening assessments within 28 days prior to the first dose of study drug. 
Patients will undergo procedures and assessments during the Screening Phase as described in 
Section 9.3.  
During the Screening Phase, unless otherwise required by local regulations, SAEs which are 
related to protocol-mandated assessments will be reported.  
Additional screening assessments will include collection of the patient’s medical information and 
demographics, physical exam, laboratory safety assessments, tumor assessments, PRO 
instruments, and blood and tissue samples to support exploratory objectives as described in 
Section 9.3.  
Randomization will require prospective sponsor (or designee) review and confirmation of 
eligibility, including, but not limited to: 
• BRCA/ATM gene test result by either local or central testing  
• details of prior therapy for prostate cancer 
• screening laboratory assessments 
 
5.1.3 
Randomization 
Following confirmation of all eligibility criteria in the Screening Phase, patients will be 
randomized 2:1 to receive rucaparib or physician’s choice of docetaxel or AR-directed therapy 
(abiraterone acetate or enzalutamide, whichever the patient has not yet received). The 
physician’s choice of agent in the control arm must be prespecified prior to randomization. 
Randomization will occur by a central randomization procedure using an Interactive Response 
System (IXRS), which is described in more detail in Section 7.4. Study treatment must be 
initiated within 3 days after randomization, unless approved by sponsor or designee.  


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5.1.4 
Treatment Phase 
During the treatment phase, patients will receive rucaparib or physician’s choice (pre-designated 
prior to randomization) of docetaxel or AR-directed therapy (abiraterone acetate or 
enzalutamide) and be monitored for safety and efficacy as described in Section 9.5. 
Rucaparib will be administered as 600 mg orally BID. Abiraterone acetate will be administered 
as 1,000 mg orally QD, with prednisone administered concomitantly at a dose of 10 mg orally 
daily. Enzalutamide will be administered as 160 mg orally QD. Docetaxel will be administered at 
a dose of 75 mg/m2 IV every 3 weeks in combination with prednisone or prednisolone, given 
orally, 5 mg BID, for up to a maximum of 10 cycles. 
Patients will receive the same therapy, as appropriate, throughout the Treatment Phase, or in the 
case of docetaxel up to a maximum of 10 cycles whereupon no additional study treatment shall 
be given, but all assessments will continue to be performed until criteria for treatment 
discontinuation are met. PRO assessments should also be collected at every visit.  
Tumor assessments by computed tomography (CT)/magnetic resonance imaging (MRI) and bone 
scans will be performed during the Screening Phase, at the end of every 8 calendar weeks 
(±7 days) from Study Day 1 (Week 1) up to 24 weeks and every 12 calendar weeks (± 7 days) 
thereafter, and at the Treatment Discontinuation Visit, if applicable. Modified 
RECIST Version 1.1 criteria will be used to document radiographic response in soft tissue 
(visceral and nodal) disease and PCWG3 criteria will be used to document radiographic 
progression in bone lesions. If a CR or PR is noted, confirmatory scans should be performed at 
least 4 weeks after the initial response was first documented. Radiographic tumor assessment 
(using the same methodology as was used at initial study screening [eg, CT scan and bone scan]) 
will continue until radiographic disease progression is confirmed, irrespective of whether the 
patient has discontinued study drug treatment or initiated subsequent anticancer therapy. Any 
drug modifications (interruption, dose reduction, or discontinuation) should be documented in 
the electronic case report form (eCRF) and source documents. If study treatment is interrupted, 
tumor assessments will not be delayed and will proceed on the regular study schedule. Copies of 
all radiographic scans will be submitted for IRR until after the analysis of the primary endpoint 
has been performed, at which time IRR will be discontinued and all radiographic scans will be 
evaluated by the investigator for radiographic progression. The sponsor will inform investigators 
when submission of scans for IRR should discontinue.  
Patients will receive study drug until radiographic disease progression is confirmed by IRR until 
analysis of the primary endpoint has been performed, or by investigator assessment after analysis 
of the primary endpoint has been performed and IRR is discontinued, based on modified 
RECIST Version 1.1 and PCWG3 (for bone lesions only) criteria, unequivocal clinical disease 
progression, unacceptable toxicity or inability to tolerate further treatment, loss to follow-up, or 
withdrawal of consent. Patients in the docetaxel arm will receive study drug for a maximum of 
10 cycles only and so may not be actively on treatment at the time of disease progression. PSA 
rise without evidence of confirmed radiographic progression is strongly discouraged as a 
criterion to start a new systemic antineoplastic therapy during the first 12 weeks of therapy and is 
discouraged as a criterion to start a new systemic antineoplastic therapy throughout the study. 
Palliative radiation for the treatment of painful bony metastases and initiation of bisphosphonates 


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or other approved bone-targeting agents are allowed and should not result in discontinuation of 
study drug therapy. 
Patient safety will be monitored on a regular basis using procedures and assessments described in 
Section 9 and Section 13.4. Safety and efficacy data will be periodically reviewed by the 
Independent Data Monitoring Committee (IDMC) as described in Section 13.6.  
5.1.5 
Post-treatment Phase 
The date and reason for cessation of study drug must be documented in the eCRF and source 
documents as soon as possible. Patients will undergo procedures and assessments during the 
Post-treatment Phase as described in Section 9.6. Upon treatment discontinuation, patients will 
have a Treatment Discontinuation Visit (Section 9.6.1), a 28-day Follow-up Visit (Section 9.6.2), 
and then will proceed to long-term follow-up (Section 9.6.3). An optional tumor biopsy will be 
collected prior to the start of subsequent anticancer therapy from patients who experience 
radiographic or unequivocal clinical disease progression and who provide appropriate consent. 
For patients who had their last tumor assessment ≥ 8 weeks (≥ 12 weeks if previous scan was 
after 24 weeks on study) prior to the Treatment Discontinuation Visit, a tumor assessment must 
be performed.  
If study drug was discontinued for reasons other than centrally confirmed radiographic disease 
progression, tumor assessments (using the same methodology as was used at initial study 
screening [eg, CT scan]) will continue until radiographic disease progression is confirmed by 
IRR. Similarly, PRO will continue to be collected during this time and until radiographic disease 
progression is confirmed by IRR. Once the analysis of the primary endpoint has been performed, 
radiographic scans will continue to be performed by the investigator, as well as collection of 
PRO, as per the protocol schedule of assessments until radiographic disease progression is 
determined by the investigator; scans will no longer be submitted to or read by IRR. 
Ongoing SAEs, AESIs, and treatment-related Grade 3/4 AEs will be followed until either 
resolution or stabilization has been determined or until lost to follow-up.  
After the 28-day Follow-up Visit, only SAEs assessed as potentially related to study drug should 
be reported per Clovis Oncology Pharmacovigilance (PV) requirements and captured in the 
Clovis Oncology PV database.  
After the 28-day Follow-up Visit, AESIs of MDS and AML, irrespective of causality, should 
be reported per Clovis Oncology PV requirements and captured in the Clovis Oncology PV 
database. 
• AESIs of pneumonitis or similar events (ie, interstitial lung disease, pulmonary fibrosis, 
acute interstitial pneumonitis, alveolitis necrotizing, alveolitis, hypersensitivity pneumonitis, 
and organizing pneumonia) should be reported up to, but not beyond, the 28-Day Follow-up 
Visit (28-days after the last dose of rucaparib). After the 28-day Follow-up Visit, only 
pneumonitis or similar events meeting the criteria for an SAE and assessed as potentially 
related to study drug should be reported per Clovis Oncology PV requirements. 
 


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All patients will be followed for survival and subsequent treatments every 12 weeks (± 14 days) 
relative to the last dose of study drug until death, loss to follow-up, withdrawal of consent, or 
study closure. 
5.1.6 
Cross-over Phase 
Patients randomized to comparator therapy will be given the opportunity to cross over to receive 
rucaparib therapy after radiographic progression is confirmed by IRR until analysis of the 
primary endpoint has been performed, or by investigator assessment after analysis of the primary 
endpoint has been performed and IRR is discontinued. After providing consent, patients will be 
assessed to ensure eligibility criteria are met for the Cross-over Phase (see protocol Section 6.4). 
If eligible, the patient will have protocol assessments for a Treatment Discontinuation Visit 
performed when treatment to which the patient is randomized has been completed or is 
discontinued and then will have protocol assessments per the rucaparib Treatment Phase. 
Radiographic assessments from the Cross-over Phase will not be submitted for IRR either before 
or after the analysis of the primary endpoint has been performed. The patient will also have all 
Post-Treatment Phase assessments completed after discontinuing cross-over rucaparib, including 
a second Treatment Discontinuation Visit. 
5.1.7 
Post-progression Treatment Phase 
If a patient demonstrates radiographic progression while receiving treatment with study drug, but 
continues to derive clinical benefit per investigator assessment, then continuation of treatment 
beyond progression is permitted. In such cases, the patient must consent prior to continuing 
treatment with study drug. 
5.2 
Study Schema 
The Pre-Screening Phase study schema is provided in Figure 1.  
The study schema for Screening, Treatment, and Post-treatment Phases is provided in Figure 2. 






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5.3 
End of Study 
The study will close when the required number of rPFS events has been observed and sufficient 
follow-up for OS events has occurred. At the time the decision is made to close the study, 
individual patients who are continuing to benefit from treatment with rucaparib and who do not 
meet any of the criteria for withdrawal, will have the option of receiving rucaparib via another 
access mechanism. If a patient is continuing to receive benefit from physician’s choice standard-
of-care at the time of a decision to close the study, the study site treating the patient may remain 
open until discontinuing the treatment or the patient qualifies for cross-over to rucaparib. The 
option of receiving rucaparib via another access mechanism will be available if the patient is 
tolerating their rucaparib regimen and meets the requirements for entering the alternative access 
mechanism. In addition, if there are patients for whom long-term follow-up information is being 
collected, these patients may transition to have their long-term follow-up information captured 
via another mechanism.  
The sponsor may discontinue the study early for any reason as noted in Section 13.7. 
6 
STUDY POPULATION SELECTION 
6.1 
Number of Patients and Sites 
The total enrollment planned for this study is approximately 400 patients. A total of 
approximately 300 patients with a deleterious BRCA1/2 gene mutation will be randomized and 
approximately 100 patients with a deleterious ATM gene mutation may be randomized. These 
patients will be recruited from approximately 150 sites worldwide. Patients will be randomized 
2:1 to receive rucaparib or physician’s choice of either docetaxel or second-line AR-directed 
therapy (abiraterone acetate or enzalutamide, whichever the patient has not yet received).  
6.2 
Inclusion Criteria 
Eligible patients must meet the following inclusion criteria. Unless otherwise specified, the 
criteria below apply to all patients: 
1. Have signed an Institutional Review Board/Independent Ethics Committee-approved 
informed consent form (ICF) prior to any study-specific evaluation 
2. Male ≥ 18 years of age at the time the ICF is signed 
3. Have a histologically or cytologically confirmed adenocarcinoma or poorly differentiated 
carcinoma of the prostate (pure small-cell histologies or pure high-grade neuroendocrine 
histologies are excluded; neuroendocrine differentiation is allowed) that is metastatic 
4. Surgically or medically castrated, with serum testosterone levels of ≤ 50 ng/dL (1.73 nM). If 
currently being treated with luteinizing hormone–releasing hormone (LHRH) analogs 
(patients who have not undergone an orchiectomy), therapy must be continued throughout 
the study 
5. Eligible for treatment with physician’s choice of comparator treatment, selected prior to 
randomization, per the corresponding prescribing information 
6. Evidence of disease progression after treatment with one prior next-generation AR-targeted 
therapy (abiraterone acetate, enzalutamide, apalutamide, or investigational AR-targeted 


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agent); treatment with the older anti-androgen therapies such as bicalutamide, flutamide, and 
nilutamide are not counted toward this limit 
7. Disease progression after initiation of most recent therapy is based on any of the following 
criteria: 
a. Rise in PSA: a minimum of two consecutive rising levels, with an interval of ≥ 1 week 
between each determination. The most recent screening measurement must have been 
≥ 2 ng/mL 
b. Transaxial imaging: new or progressive soft tissue masses on CT or MRI scans as defined 
by modified RECIST Version 1.1 
c. Radionuclide bone scan: at least two new metastatic lesions  
8. All patients must have a deleterious gene mutation in BRCA1/2 or ATM. Mutations may be 
identified by local testing or through central testing by the sponsor of plasma or tumor tissue. 
For local test results, the classification of the mutation as deleterious must be documented in 
the patient’s medical record 
9. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Appendix 2) 
10. Have adequate organ function confirmed by the following clinical laboratory values obtained 
within 14 days prior to the first dose of study drug: 
a. Bone Marrow Function 
i. 
ANC ≥ 1.5 × 109/L 
ii. Platelets > 100 × 109/L  
iii. Hemoglobin ≥ 10 g/dL independent of transfusion within 14 days 
b. Hepatic Function 
i. AST and ALT ≤ 3 × the ULN 
ii. Bilirubin ≤ 1.5 × ULN (< 2 × ULN if hyperbilirubinemia is due to Gilbert’s 
syndrome) 
c. Renal Function  
i. Estimated glomerular filtration rate (GFR) ≥ 45 mL/min using the Cockcroft-Gault 
formula (Appendix 3) 
11. Male patients who are committed to undertaking the following measures for the duration of 
the study and after the last dose of study drug for the time period specified: 
a. Use a condom during sex while being treated and for 3 months after the last dose of study 
drug, 
b. Do not make semen donations during treatment and for 3 months after the last dose of 
rucaparib, 
c. Those with female partners of childbearing potential may be enrolled if they are: 
i. 
Documented to be surgically sterile (ie, vasectomy);  
ii. 
Committed to practicing true abstinence during treatment and for 3 months after the 
last dose of study drug; or 
iii. 
Committed to using a highly effective method of contraception (refer to 
Section 6.5) with their partner during treatment and for 3 months following the last 
dose of study drug  
12. Have a life expectancy of at least 6 months 
 


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6.3 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from the study: 
1. Active second malignancy, with the exception of curatively treated non-melanoma skin 
cancer, carcinoma in situ, or superficial bladder cancer 
a. Patients with a history of malignancy that has been completely treated, and currently with 
no evidence of that cancer, are permitted to enroll in the study provided all therapy was 
completed > 6 months prior and/or bone marrow transplant (BMT) > 2 years prior to first 
dose of rucaparib 
2. Prior treatment with any PARPi 
3. Prior treatment with chemotherapy (eg docetaxel, mitoxantrone, cyclophosphamide, 
platinum-based agents) for mCRPC. Prior treatment with docetaxel (or other taxane 
chemotherapy) administered for castration-sensitive disease is permitted  
4. Symptomatic and/or untreated central nervous system (CNS) metastases. Patients with 
asymptomatic, previously treated CNS metastases are eligible provided they have been 
clinically stable (not requiring steroids for at least 4 weeks prior to first dose of study drug) 
and have appropriate scans at screening assessment 
5. Symptomatic or impending spinal cord compression unless appropriately treated, clinically 
stable, and asymptomatic 
6. Pre-existing duodenal stent and/or any gastrointestinal disorder or defect that would, in the 
opinion of the investigator, interfere with absorption of study drug 
7. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome 
(AIDS)-related illness, or history of chronic hepatitis B or C, with the exception of patients 
with sustained virologic response after completion of treatment for hepatitis C 
8. Received treatment with chemotherapy, antibody therapy, immunotherapy, gene therapy, 
angiogenesis inhibitors, or experimental drugs within < 14 days prior to first dose of study 
drug. Treatment with hormonal therapies (with the exception of LHRH analog) must be 
discontinued at least 7 days prior to the first dose of study drug 
9. Adverse effect of prior therapy not resolved to CTCAE Grade 1 or below with the exception 
of alopecia. Ongoing Grade 2 non-hematologic toxicity related to most recent treatment 
regimen may be permitted with prior advanced approval from the sponsor 
10. Initiated low-dose corticosteroid, bisphosphonate, or denosumab therapy or adjusted 
low-dose corticosteroid, bisphosphonate, or denosumab dose/regimen within < 28 days prior 
to first dose of study drug. Patients on a stable low-dose corticosteroid, bisphosphonate, or 
denosumab regimen are eligible and may continue treatment 
11. Non-study related minor surgical procedure within < 5 days, or major surgical procedure 
within < 21 days, prior to first dose of study drug; in all cases, the patient must be 
sufficiently recovered and stable before treatment administration 
12. Presence of any other condition that may increase the risk associated with study participation 
or may interfere with the interpretation of study results, and, in the opinion of the 
investigator, would make the patient inappropriate for entry into the study 
 


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6.4 
Criteria for Rucaparib Cross-over Treatment Eligibility Following 
Radiographic Progression on or after Comparator Arm Therapy 
To be eligible for participation in the cross-over part of the study, patients must fulfill the 
following criteria and should initiate treatment with rucaparib ≤ 28 days after the date of the 
radiographic disease assessment by which progression is confirmed by IRR until analysis of the 
primary endpoint has been performed. Treatment with rucaparib may be permitted > 28 days 
after the date of the radiographic disease assessment by which progression is confirmed by IRR 
with prior advanced approval from the sponsor, and all cross-over eligibility criteria are met 
(Note: Once the analysis of the primary endpoint has been performed, radiographic scans will 
continue to be performed by the investigator as per the protocol schedule of assessments until 
radiographic disease progression is determined by the investigator; scans will no longer be 
submitted to or read by IRR. After analysis of the primary endpoint, investigator-assessed 
radiographic disease progression will be used for cross-over eligibility evaluation):  
1. Receive sponsor approval to cross-over from comparator therapy to rucaparib treatment 
2. Received the last dose of comparator therapy at least 14 days prior to initiation of rucaparib 
treatment (7 days prior for abiraterone acetate or enzalutamide) 
3. Have adequate organ function confirmed by the following local laboratory values ≤ 14 days 
prior to first dose of rucaparib: 
a. Bone Marrow Function 
i. 
ANC ≥ 1.5 × 109/L 
ii. 
Platelets > 100 × 109/L  
iii. 
Hemoglobin ≥ 9 g/dL independent of transfusion within 14 days 
b. Hepatic Function 
i. 
AST and ALT ≤ 3 × ULN 
ii. 
Bilirubin ≤ 1.5 × ULN (< 2 × ULN if hyperbilirubinemia is due to Gilbert’s 
syndrome) 
c. Renal Function 
i. 
Estimated GFR ≥ 45 mL/min using the Cockcroft-Gault formula (Appendix 3) 
4. All Grade 3 and 4 hematologic and non-hematologic toxicities (except alopecia, nausea, 
vomiting, or adequately controlled diarrhea) resolved to baseline or ≤ CTCAE Grade 1 
5. Male patients who are committed to undertaking the following measures for the duration of 
the study and after the last dose of rucaparib for the time period specified:  
a. Use a condom during sex while being treated and for 3 months after the last dose of 
rucaparib, 
b. Do not make semen donations during treatment and for 3 months after the last dose of 
rucaparib, 
c. Those with female partners of childbearing potential may cross-over if they are: 
i 
Documented to be surgically sterile (ie, vasectomy);  
ii 
Committed to practicing true abstinence during treatment and for 3 months after the 
last rucaparib dose; or  
iii 
Committed to using a highly effective method of contraception (refer to 
Section 6.5) with their partner during treatment and for 3 months following the last 
dose of rucaparib 


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6. Have an ECOG performance status of 0 to 1 (Appendix 2). 
7. Written consent on an Institutional Review Board (IRB)/ Independent Ethics Committee 
(IEC)-approved ICF 
 
In addition, any of the following will exclude patients from receiving rucaparib in the cross-over 
part of the study: 
1. Adverse effect of comparator therapy not resolved to CTCAE Grade 1 or below with the 
exception of alopecia. Ongoing Grade 2 non-hematologic toxicity related to comparator 
therapy may be permitted with prior approval from the sponsor 
2. Received treatment with chemotherapy, hormonal therapy (with the exception of LHRH 
analog), radiation (other than palliative radiation for treatment of painful bony metastases), 
antibody therapy, immunotherapy, gene therapy, angiogenesis inhibitors, or experimental 
drugs after discontinuation of study comparator therapy. Patients requiring urgent intervening 
systemic anticancer therapy, may be permitted to cross over, provided that criteria for 
unequivocal clinical progression are confirmed per Section 12.1, in consultation with the 
sponsor, prior to initiation of intervening systemic anticancer therapy 
3. Non-study-related minor surgical procedure within < 5 days, or major surgical procedure 
within < 21 days, prior to first dose of rucaparib in cross-over; in all cases, the patient must 
be sufficiently recovered and stable before treatment administration 
4. Withdrawal of consent during treatment with the comparator arm therapy  
5. Presence of any other condition that may increase the risk associated with study participation 
and, in the opinion of the investigator, would make the patient inappropriate for continuing in 
the study with cross-over to rucaparib treatment (including general noncompliance with 
study procedures during treatment with the comparator arm therapy, per investigator 
judgement)  
 
6.5 
Patients or Partners of Patients Including Those of Reproductive 
Potential 
Male patients are required to use a condom during sex with a partner to avoid the possibility of 
exposure of the partner to rucaparib. 
Male patients must not make semen donations for 3 months after the last dose of rucaparib. 
Male patients of reproductive potential must avoid pregnancy in partners who are women of 
childbearing potential, and such partners should not be considering getting pregnant during the 
study and for at least 3 months after treatment is discontinued or longer if requested by local 
authorities. Patients will be instructed to notify the investigator if pregnancy of female partner is 
discovered either during or within 3 months of completing treatment with study drug.  
Male patients are considered to be of reproductive potential unless permanently sterile by 
bilateral orchiectomy, or with appropriate post-vasectomy documentation of absence of sperm in 
ejaculate. 
Female partners are considered to be of childbearing potential unless one of the following 
applies: 


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• Is postmenopausal, defined as no menses for at least 12 months without an alternative 
medical cause. A high follicle-stimulating hormone (FSH) level consistently in the 
postmenopausal range (30 mIU/mL or higher) may be used to confirm a postmenopausal 
state in women not using hormonal contraception or hormonal replacement therapy; 
however, in the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient to confirm a postmenopausal state: or  
• Considered to be permanently sterile. Permanent sterilization includes hysterectomy, bilateral 
salpingectomy, and/or bilateral oophorectomy. 
 
Male patients of reproductive potential must practice highly effective methods (failure rate < 1% 
per year when used consistently and correctly) of contraception with their female partners, if of 
reproductive potential, during treatment and for 3 months following the last dose of study drug or 
longer if requested by local authorities. Highly effective contraception includes: 
• Ongoing use of combined (estrogen- and progestogen-containing) hormonal contraception 
oral, injectable, or transdermal, associated with inhibition of ovulation; 
• Ongoing use of progesterone-only oral, injectable, or implantable contraceptives associated 
with inhibition of ovulation; 
• Placement of an intrauterine device (IUD) or intrauterine hormone-releasing system (IUS); 
• Bilateral tubal occlusion;  
• Sexual abstinence as defined as complete or true abstinence, acceptable only when it is the 
usual and preferred lifestyle of the patient; periodic abstinence (eg, calendar, symptothermal, 
post-ovulation methods) is not acceptable. 
 
6.5.1 
Patients Not on Rucaparib 
Patients must practice the contraception requirements listed above and additionally apply 
appropriate requirements for treatment with physicians’ choice of comparator according to 
product labelling and local practice. 
6.6 
Waivers of Inclusion/Exclusion Criteria 
No waivers of these inclusion or exclusion criteria will be granted by the investigator and the 
sponsor or its designee for any patient enrolling into the study. 
7 
STUDY TREATMENT(S) 
7.1 
Description of Treatment(s) and Storage 
This study will assess the investigational drug rucaparib compared to comparator therapy using a 
randomized 2:1 study design. 


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7.1.1 
Investigational Drug Product - Rucaparib 
Rucaparib camsylate (also known as CO-338) is an oral formulation with a molecular weight of 
555.67 Daltons. Rucaparib tablets for oral administration will be supplied to the study sites by 
the sponsor. The starting dose of rucaparib is 600 mg ingested BID. A brief description of the 
investigational product is provided below with details in the Pharmacy Guidelines. 
Drug Name: 
Rucaparib 
INN: 
Rucaparib 
Formulation:  
(strengths expressed as 
free base) 
Tablet; film coated; 200 mg (blue, round, debossed with C2), 250 mg 
(white, rounded diamond shape, debossed with C25), 300 mg (yellow, 
oval, debossed with C3)  
How Supplied: 
200, 250, and 300 mg (as free base) strength tablets in HDPE or 
equivalent with child-resistant caps. Patients may receive one or more 
strengths.  
Storage Conditions: 
15 to 30° C (59 to 86° F).  
Abbreviation: HDPE = high density polyethylene; INN = International Nonproprietary Name. 
 
7.1.2 
Comparator Therapeutic Drug Products 
Single-agent chemotherapy will consist of docetaxel given at a dose of 75 mg/m2 docetaxel IV 
every 3 weeks given in combination with oral prednisone or prednisolone 5 mg BID, for up to a 
maximum of 10 cycles.  
The starting dose of abiraterone is 1,000 mg orally QD. No food should be eaten for at least 
2 hours before and for one hour after dosing. Prednisone should be administered concomitantly 
at a dose of 10 mg orally daily. Abiraterone should be swallowed whole with water. 
The starting dose of enzalutamide is 160 mg orally QD. Enzalutamide may be taken with or 
without food. Enzalutamide should be swallowed whole with water. 
Each of these individual drugs will either be procured by the study site or supplied by the 
sponsor. Each product will be stored according to the manufacturer’s prescribing 
information/product packaging and as described in the Pharmacy Guidelines. 
Please refer to the pharmacy manual for further details. 
7.2 
Packaging and Labeling 
7.2.1 
Rucaparib 
Rucaparib tablets are provided in 60-count high-density polyethylene (HDPE) bottles with 
child-resistant caps and should be stored in the provided containers between 15° to 30°C 
(59 to 86°F). Patients will be dispensed one or more strengths depending on their current dose of 
rucaparib. The number of bottles of each strength dispensed will be sufficient to supply at least 
28 days of treatment until the next study drug dispensing visit. 


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Rucaparib bottles will be labelled in accordance with local regulatory requirements. 
7.2.2 
Comparator Therapy 
Depending on local health authority guidelines, the comparator therapy agents will be obtained 
through commercial supply, the site pharmacy, or from the sponsor, depending on region. The 
packaging and labeling will vary depending on the source of the supply.  
Products will be labeled to meet local country requirements. Where sites source their own 
comparator therapies, they are responsible for the quality and security of the supply and for 
ensuring it is appropriately labeled and dispensed in compliance with local regulations. 
7.3 
Blinding 
This is an open-label study; the study drugs will not be blinded or masked to the investigator or 
patient, so each will know the treatment being administered. A Blinding Plan will be put in place 
to limit the knowledge of aggregate efficacy data by sponsor personnel. 
7.4 
Method of Assigning Patients to Treatment Groups 
Patients will be randomly assigned to treatment groups via IXRS. The following will be included 
as randomization stratification factors at study entry to ensure treatment groups are balanced; 
ECOG performance status and presence of hepatic metastases are important prognostic 
indicators in this patient population.44, 45  
• ECOG Status 0 vs 1 
• Presence of hepatic metastases or not 
• BRCA1 vs BRCA2 vs ATM mutation 
 
The investigator should have experience using the comparator therapy that is selected.  
Study treatment must be initiated within 3 days after randomization unless otherwise agreed 
between investigator and sponsor (or designee). 
7.5 
Preparation and Administration of Protocol-specified Treatment 
The investigator will be responsible for distributing study drug to all patients. Study drug 
(ie, rucaparib or comparator therapy) will be assigned by the IXRS according to the patient’s 
randomization assignment.  
The IXRS will manage all study drug supplied by the sponsor. The system should be accessed to 
record each dispensation of rucaparib and each administration of the comparator therapies 
according to the patient’s randomized treatment. Guidelines for the use of the IXRS will be 
provided to study sites. Study sites should follow local guidelines for the handling of comparator 
therapy. 


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7.5.1 
Rucaparib 
The starting dose of rucaparib is 600 mg ingested BID. Patients may take rucaparib with or 
without food. Each dose should be taken with at least 8 oz (240 mL) of water. Tablets should be 
swallowed whole without crushing or chewing. Tablet strength combinations shall be determined 
by the IXRS system. 
Patients should take rucaparib doses as close to 12 hours apart as possible, preferably at the same 
times every day. If a patient misses a dose (ie, does not take it within 4 hours of the scheduled 
time), the patient should skip the missed dose and resume taking rucaparib with the next 
scheduled dose. Missed or vomited doses should not be made up. 
Dosing with rucaparib may be held or reduced as described in Section 7.5.1.1 and 
Section 7.5.1.2.  
Patients will be provided a sufficient quantity of study drug for 28 days with a small overage. 
Patients will be instructed to bring their rucaparib tablets and all containers (empty, partially 
used, and/or unopened) to the next scheduled visit for reconciliation by site personnel. Partially 
used bottles may be returned to the patient according to local guidelines.  
7.5.1.1 
Rucaparib Dose Modification Criteria 
Treatment with rucaparib should be held if any of the following are observed and a dose 
reduction should be considered or implemented. 
• Grade 3 or 4 hematologic toxicity  
• Grade 3 or 4 non-hematologic toxicity (except for alopecia, nausea, vomiting, or diarrhea 
adequately controlled with systemic antiemetic/antidiarrheal medication administered in 
standard doses according to the study center routines). Grade 3 or Grade 4 ALT/AST 
elevations should be managed as described below. 
• At the discretion of the investigator, rucaparib may be held or continued if new or worsening 
unexplained pulmonary symptoms suggestive of pneumonitis (including, but not limited to, 
dyspnea) occur and while evaluation to rule out pneumonitis or confirm such a diagnosis as 
well as etiology are ongoing; these events should be managed as described below. 
• In addition, and at the discretion of the investigator, the dose of rucaparib may be held and/or 
reduced for Grade 2 toxicity not adequately controlled by concomitant medications and/or 
supportive care. 
 
MANAGEMENT OF ANEMIA INCLUDING EVALUATION FOR MDS/AML AND FOLLOW-UP OF 
PATIENTS WHO DISCONTINUE TREATMENT WITH ONGOING ANEMIA 
• If the patient develops anemia CTCAE Grade ≥ 3, rucaparib treatment should be held until 
the anemia resolves to CTCAE Grade ≤ 2 whereupon daily dosing may then be resumed at 
either the same dose or a lower dose, per investigator discretion. 
• If a patient has persistent CTCAE Grade 3 anemia despite study drug interruption, and the 
anemia is considered related to the patient’s underlying prostate cancer (eg, patient has 


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extensive bony disease or history of disease-related anemia), then resumption of study drug 
may be considered, if the patient was benefiting from treatment in the opinion of the 
investigator  
• If the duration of dosing is interrupted for > 14 consecutive days due to anemia CTCAE 
Grade ≥ 3, treatment should be permanently discontinued, unless otherwise agreed between 
the investigator and the sponsor.  
• In addition, if anemia CTCAE Grade ≥ 3 persists for > 14 consecutive days, or a dependence 
upon blood transfusion occurs, then weekly complete blood counts should be performed until 
resolution of the event.  
• If, after 42 days of interruption of rucaparib, the anemia has not recovered to CTCAE 
Grade ≤ 1 then the patient should be referred to a hematologist and analysis of the bone 
marrow with cytogenetic studies are recommended according to standard hematologic 
practice. 
- 
The bone marrow analysis should include a bone marrow aspirate (for cellular 
morphology, cytogenetic analysis, and flow cytometry) and a core biopsy (for bone 
marrow cellularity). 
 
MANAGEMENT OF RUCAPARIB TREATMENT-EMERGENT ALT/AST ELEVATIONS  
• Grade 4 ALT/AST elevations: hold rucaparib until values have returned to Grade 2 or better, 
then resume rucaparib with a dose reduction. Monitor liver function tests weekly for 3 weeks 
after rucaparib has been restarted. 
• Grade 3 ALT/AST elevations, in the absence of other signs of liver dysfunction, should be 
managed as follows:  
- 
Monitor liver function tests weekly until resolution to ≤ Grade 2. 
- 
Continuation of rucaparib with elevation of ALT/AST up to Grade 3 is permitted 
provided bilirubin is < ULN.  
- 
If patient has Grade 3 ALT/AST and continues on rucaparib, and levels do not decline 
within 2 weeks or they continue to rise, treatment interruption and resolution to ≤ Grade 2 
will be required before rucaparib can be resumed, either at the current dose or at a 
reduced dose. 
 
For patients who meet treatment interruption guidelines above, treatment with rucaparib should 
be held until the toxicity resolves to ≤ CTCAE Grade 2. Dosing BID may then be resumed at 
either the same dose or a lower dose, per investigator discretion. If treatment is resumed at the 
same dose, and the patient experiences the same toxicity, treatment should be interrupted, then 
resumed at a reduced dose following resolution of the event to ≤ CTCAE Grade 2. If the patient 
continues to experience toxicity, additional dose reduction steps are permitted; however, the 
investigator must consult with the sponsor’s medical monitor before reducing to 300 mg BID. If 
a patient continues to experience toxicity despite dose reduction steps to 300 mg BID, or if 
dosing with rucaparib is interrupted for > 14 consecutive days due to toxicity, treatment should 
be discontinued, unless otherwise agreed between the investigator and the sponsor. 


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Drug-induced liver injury (DILI) is described in the US FDA Guidance for Industry, 
Drug-Induced Liver Injury: Premarketing Clinical Evaluation,46 and should be referenced when 
managing treatment-emergent ALT/AST elevations. 
Rucaparib treatment must be interrupted if biochemical criteria for suspected DILI are met, 
according to presence of the following laboratory abnormalities: 
ALT or AST > 3 × ULN  
and  
Bilirubin > 2 × ULN 
While treatment is interrupted, the patient should be evaluated for the presence of confounding 
factors including malignant disease in the liver, coadministration of other suspect drugs, 
cholestasis, and viral or autoimmune hepatitis that could have caused the laboratory 
abnormalities. Other laboratory investigations of liver function such as international normalized 
ratio (INR) should be implemented as indicated. If no alternative cause is identified, rucaparib 
must be permanently discontinued. 
All cases of possible DILI must be reported as SAEs (see Section 10.9) and will be followed 
until all abnormalities have returned to normal or to baseline levels, or an alternative cause is 
found to explain the combination of the increased transaminases and bilirubin. 
MANAGEMENT OF NEW OR WORSENING PULMONARY SYMPTOMS 
If new or worsening unexplained pulmonary symptoms suggestive of pneumonitis (including, 
but not limited to, dyspnea) occur, or a deterioration of pulmonary function is observed, and/or 
radiologic abnormality is detected in the lungs, and this occurs in the absence of any clear 
diagnosis, a diagnostic workup (including high resolution CT scan) in consultation with a 
pulmonologist should be performed in order to rule out pneumonitis. During this time, treatment 
with rucaparib may be interrupted or continued per investigator discretion. 
Following investigation, if pneumonitis is not confirmed, treatment with rucaparib may be 
resumed/continued as deemed appropriate by the investigator and in accordance with the study 
protocol directions for management of AEs. All confirmed events of pneumonitis should be 
treated as appropriate per medical judgement and institutional guidelines. If the event resolves 
and retreatment with rucaparib is being considered, please consult the Sponsor’s Medical 
Monitor. Retreatment with rucaparib may be resumed at the current or a reduced dose, if 
appropriate.  
Refer to Sections 10.3 and 10.7 of the protocol for additional information regarding classification 
and reporting of pneumonitis (and associated events) as an AESI. 
7.5.1.2 
Rucaparib Dose Modification 
Dose reduction steps are presented in Table 4. 
Dose re-escalation upon resolution of toxicity to ≤ CTCAE Grade 1 is permitted at the discretion 
of the investigator. 


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Dose modifications (interruption, reduction, re-escalation) must be recorded for each patient in 
the appropriate section of the eCRF. 
Table 4. 
Rucaparib Dose Reduction Steps 
Starting Dose 
600 mg BID 
Dose Level - 1 
500 mg BID 
Dose Level - 2 
400 mg BID 
Dose Level - 3a 
300 mg BID 
Abbreviation: BID = twice a day. 
a 
Consult with the sponsor’s medical monitor before reducing to dose level 3. Further dose reduction may be 
possible, but requires consultation with the sponsor’s medical monitor. 
 
7.5.1.3 
General Restrictions 
Photosensitivity has been observed in patients treated with rucaparib. Patients should avoid 
spending time in direct sunlight because they burn more easily during treatment with rucaparib. 
When outdoors, patients should use typical precautions such as applying sunscreen (sun 
protection factor 50 or greater) and/or covering exposed skin with clothing and wearing a hat and 
sunglasses. 
7.5.2 
Single-agent Docetaxel 
Handling, preparation, administration, precautions, and restrictions for the use of docetaxel are to 
follow Prescribing Information provided in the Pharmacy Guidelines or approved institutional or 
local guidelines. 
7.5.3 
Single-agent Abiraterone Acetate 
Handling, preparation, administration, precautions, restrictions and other information for the use 
of each drug are in the Prescribing Information provided in the Pharmacy Guidelines or approved 
institutional or local guidelines. 
7.5.4 
Single-agent Enzalutamide 
Handling, preparation, administration, precautions, restrictions and other information for the use 
of each drug are in the Prescribing Information provided in the Pharmacy Guidelines or approved 
institutional or local guidelines. 
7.5.5 
Re-treatment and Dose Modification for All Comparator Therapy 
In the event of toxicities, dose delays and modifications should occur in accordance with the 
highest toxicity observed per the recommendations and guidelines provided in the approved 
Prescribing Information provided in the Pharmacy Guidelines or according to institutional 
guidelines or local dose reduction protocols. Dose modifications (interruption, reduction, 
re-escalation) must be recorded for each patient in the appropriate section of the eCRF.  


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7.5.6 
Cross-over to Rucaparib Treatment 
Patients initially randomized to comparator therapy have the option to cross-over to rucaparib 
treatment upon radiographic disease progression, following sponsor (or designee) approval of the 
radiology report confirming disease progression by IRR, and meeting eligibility for the 
cross-over as listed in Section 6.4. 
Once the analysis of the primary endpoint has been performed, radiographic scans will continue 
to be performed by the investigator as per the protocol schedule of assessments until 
radiographic disease progression is determined by the investigator; scans will no longer be 
submitted to or read by IRR. After analysis of the primary endpoint, investigator-assessed 
radiographic disease progression will be used for cross-over eligibility evaluation. Patients may 
cross-over to rucaparib treatment upon radiographic disease progression, following sponsor (or 
designee) approval of the radiology report confirming disease progression by the investigator, 
and provided the patient meets eligibility criteria for cross-over as listed in Section 6.4.  
Patients who cross-over to receive rucaparib will continue to have all protocol-required 
assessments as described in Section 9. Cross-over to rucaparib can occur only after toxicities 
related to the comparator have resolved or sufficiently stabilized and the patient meets all criteria 
for initiation of treatment with rucaparib. Initiation of treatment with rucaparib should normally 
occur within 28-days following the scan date resulting in confirmed radiographic disease 
progression. Deviations from this timeline must be confirmed with the Sponsor. 
7.5.7 
Continuation of Study Drug beyond Disease Progression 
If a patient (either per initial randomization or after cross-over) has met the criteria for 
radiographic disease progression, but continues to derive clinical benefit per investigator 
assessment, then continuation of treatment is permitted with additional consent. Clinical 
scenarios where continuation of study drug treatment after radiographic progression may be 
considered include a patient in whom radiographic progression develops slowly while 
disease-related symptoms remain well controlled, a patient who experiences progression in a site 
of disease that is unlikely to adversely affect prognosis (eg, enlargement of a solitary lymph 
node), or a patient with general disease control but limited progression in sites of disease that can 
be managed with local therapies such as surgery or radiation. In such cases, the decision to 
continue must be documented in the medical notes prior to continuing treatment. Patients 
continuing to receive study drug will need to provide additional consent and will continue to 
have all protocol-required assessments as described in Section 9, with the exception of 
radiographic assessments which may be performed per local standard of care. 
7.6 
Treatment Compliance 
7.6.1 
Rucaparib Treatment Compliance 
Study site personnel will review dosing information with the patient (or legally authorized 
representative) on scheduled clinic visit days, providing instructions regarding dose, dose 
frequency and the number of tablets to be taken for each dose. Patients (or legally authorized 
representative) will be instructed to keep all unused containers (empty, partially used, and/or 


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unopened) for accountability at the next scheduled clinic visits. A compliance check and tablet 
count will be performed by study personnel during clinic visits. Study site personnel will record 
compliance information in the eCRF. 
Every effort should be made to ensure patients return to the clinic with their study drug 
containers/unused study drug at each study drug dispensation visit. Study site personnel should 
conduct a verbal review of dosing with the patient and document the discussion in the patient’s 
medical record. This may serve as source documentation for the purpose of entering dosing data 
in the appropriate eCRF. 
7.6.2 
Comparator Therapy Treatment Compliance 
Comparator therapy will be managed by the study site for each patient following the institutional 
guidelines or Prescribing Information for each agent.  
For abiraterone and enzalutamide, study site personnel will review dosing information with the 
patient (or legally authorized representative) on scheduled clinic visit days, providing 
instructions regarding dose, dose frequency and the number of tablets/capsules to be taken for 
each dose. Patients (or legally authorized representative) will be instructed to keep all unused 
containers (empty, partially used, and/or unopened) for accountability for any product provided 
by the sponsor at the next scheduled clinic visits. A compliance check and tablet/capsule count 
will be performed by study personnel during clinic visits. Study site personnel will record 
compliance information in the eCRF. 
Every effort should be made to ensure patients return to the clinic with their study drug 
containers/unused study drug at each study drug dispensation visit. Study site personnel should 
conduct a verbal review of dosing with the patient and document the discussion in the patient’s 
medical record. This may serve as source documentation for the purpose of entering dosing data 
in the appropriate eCRF. 
For docetaxel, site personnel should record dosing data (changes, interruptions, etc.) in the 
source records and in the appropriate eCRF.  
7.7 
Accountability of Protocol-specified Treatment 
Study personnel will maintain accurate records of study drug receipt, dispensation, use, return, 
destruction, and reconciliation for study drugs provided by the sponsor. The IXRS will be used 
to manage study drug inventory at all sites. In order to function properly, the system will require 
real-time entry of study drug receipt, dispensation, destruction, etc. by study personnel at the 
study site. 
The site is responsible for the return or destruction of study drug supplied by the sponsor as 
required. Authorization to destroy study drug at the site that has not been dispensed to a patient 
(eg, expired study drug), must be requested from the sponsor prior to destruction. Any study drug 
supplied by the sponsor accidentally or deliberately destroyed must be accounted for. All study 
drug containers must be accounted for prior to their destruction at the study center, according to 
institutional procedures for disposal of cytotoxic chemotherapeutic drugs. Unused study drug 


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containers should be destroyed on-site if possible. If destruction on site is not possible, supply 
should be returned to the drug depot. 
During the course of the study and at completion of the study, the number of study drug 
containers received, dispensed, returned, and destroyed must be reconciled. 
For comparator therapy that is sourced locally, the study site should follow local drug 
accountability practices. 
8 
PRIOR AND CONCOMITANT THERAPY 
Patients who have received prior treatment with a PARPi including IV or oral rucaparib, prior 
treatment with chemotherapy (eg docetaxel, mitoxantrone, cyclophosphamide, platinum-based 
agents) for mCRPC are not eligible to participate in this study. Prior treatment with docetaxel (or 
other taxane chemotherapy) administered for castration-sensitive disease is permitted.  
All procedures performed (eg, thoracentesis, etc.) during the study must be documented in the 
eCRF. 
8.1 
Supportive Care 
During the study, supportive care (eg, antiemetics; analgesics for pain control) may be used at 
the investigator’s discretion and in accordance with institutional procedures. Supportive care 
must be recorded for each patient in the appropriate section of the eCRF.  
Continuation of low-dose corticosteroid therapy that has been stable prior to study entry is 
permitted (see Section 6.3). A low dose is considered 5-15 mg/day of prednisone or 
prednisolone, and 0.5-3 mg/day of dexamethasone. For corticosteroids administered in 
combination with comparator therapy during the study, see Section 7.1.2.  
Erythropoietin, darbepoetin alfa, and/or hematopoietic colony-stimulating factors for treatment 
of cytopenias should be administered according to institutional guidelines. Transfusion 
thresholds for blood product support will be in accordance with institutional guidelines. 
8.2 
Radiotherapy 
Palliative radiotherapy for the treatment of painful bony metastasis is permitted during the study. 
Treatment with rucaparib should be held prior to initiation of radiation therapy and until the 
patient has recovered from any radiation related toxicity. Radiotherapy to soft-tissue lesions 
(either target or non-target) renders these inevaluable by RECIST Version 1.1, and is therefore 
discouraged during the Treatment Phase of the study.  
8.3 
Luteinizing Hormone-releasing Hormone Analogs 
For patient who have not undergone an orchiectomy and are currently being treated with LHRH 
analogs at the time of consent, therapy must be continued throughout the study. 


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8.4 
Anticancer or Experimental Therapy 
No other anticancer therapies (including chemotherapy, radiation [except for palliative 
radiotherapy to bone metastases], antibody therapy, immunotherapy, gene therapy, angiogenesis 
inhibitors, or other experimental drugs) of any kind will be permitted while the patient is taking 
study treatment in the study (ie, unless in follow-up). Prior treatment with anticancer therapies 
must have been completed at least 14 days prior to the first dose of study drug. Prior treatment 
with hormonal therapies (with the exception of LHRH analog) must be discontinued at least 
7 days prior to the first dose of study drug.  
8.5 
CYP450 Isoenzyme Inhibitors, Inducers, and Substrates 
Based on the results from the CYP interaction clinical study CO-338-044, rucaparib is a 
moderate inhibitor of CYP1A2, and a weak inhibitor of CYP2C9, CYP2C19, and CYP3A. 
Caution should be used in patients on rucaparib taking concomitant medicines that are sensitive 
substrates of CYP1A2, CYP2C9, and/or CYP3A (Appendix 4). Patients taking phenytoin, a 
CYP2C9 substrate with a narrow therapeutic window, should have therapeutic drug level 
monitored while using concomitantly with rucaparib.  
Although in vitro rucaparib metabolism mediated by CYP3A4 was slow, a significant 
contribution of CYP3A4 in vivo cannot be excluded. Caution should be used for concomitant use 
of strong CYP3A4 inhibitors or inducers. 
8.6 
Therapies to Control Bone Loss  
Patients cannot have initiated denosumab or bisphosphonate therapy or adjusted bisphosphonate 
or demosumab dose/regimen within 28 days prior to first dose of study drug. Patients on a stable 
denosumab or bisphosphonate regimen are eligible and may continue treatment. Initiation of 
bisphosphonates or other approved bone targeting agents if clinically indicated is allowed, and 
should not result in study treatment discontinuation unless patient has radiographic evidence of 
disease progression. 
8.7 
Anticoagulants 
Rucaparib is a weak inhibitor of CYP2C9 in vivo. Caution should be exercised in patients 
receiving rucaparib and concomitant warfarin (Coumadin). Patients taking warfarin should have 
INR monitored regularly per standard institutional practice. 
8.8 
Other Concomitant Medications 
Therapies considered necessary for the patient’s well-being may be given at the discretion of the 
investigator and should be documented in the eCRF. Other concomitant medications, except for 
analgesics, chronic treatments for concomitant medical conditions, or agents required for 
life-threatening medical problems, should be avoided. Herbal and complementary therapies 
should not be encouraged because of unknown side effects and potential drug interactions, but 
any taken by the patient should be documented appropriately in the eCRF. 


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Rucaparib marginally increased digoxin AUC by 20%. Caution should be exercised for patients 
receiving rucaparib and requiring concomitant medication with digoxin. Patients taking digoxin 
should have their digoxin levels monitored after starting rucaparib and then regularly per 
standard clinical practice.  
In vitro, rucaparib is a potent inhibitor of MATE 1 and MATE2-K, a moderate inhibitor of 
OCT1, and a weak inhibitor of OCT2. As inhibition of these transporters could decrease renal 
elimination and liver uptake of metformin, caution is advised when metformin is co-administered 
with rucaparib.  
9 
STUDY PROCEDURES AND ACTIVITIES BY VISIT 
9.1 
Schedule of Assessments 
Table 5 and Table 6 summarize the procedures and assessments to be performed for patients 
randomized to rucaparib or physician's choice of comparator during the study.  
Table 7 summarizes the procedures and assessments for patients in the Cross-over Phase. Study 
procedures and assessments should be performed as close to the scheduled time as possible, but 
within ± 3 days of the scheduled time unless otherwise stated. Tumor assessment visits are 
scheduled relative to Study Day 1. 


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Table 5. 
Schedule of Assessments for Patients Randomized to Rucaparib or Physician’s Choice of 
Abiraterone Acetate or Enzalutamide 
 
Pre-
screening 
Phase 
Screening Phase 
Randomization 
Treatment Phase 
Post-Treatment Phase 
 
Week 1 Week 3 Week 5 Week 7 
Week 9 & 
every 4 weeks 
thereafter 
Procedurea 
Day -28 to 
Day -1 
Day -14 
to  
Day -
1 
Stud
y 
Day 1b 
Study 
Day 15 
Study 
Day 29 
Study 
Day 43 
Day 57 & 
every 28 days 
thereafter 
Treatment
Discontin-
uationw 
28-day 
Follow- 
upw 
Long-term
Follow-up 
Informed Consent 
Xc 
X 
 
 
 
 
 
 
 
 
 
 
BRCA1/2, ATM gene mutation 
assessment from ctDNA blood and tumor 
samplec, d 
Xc 
 
 
 
 
 
 
 
 
 
 
 
Medical/Oncology Historye 
 
X 
 
 
 
 
 
 
 
 
 
 
Blood samples for plasma ctDNA 
analysisf  
 
X 
 
 
X 
 
 
 
 
X 
 
 
Physical Examination, Weight, Heightg 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signsh 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECGi 
 
X 
 
 
 
 
 
 
 
X 
 
 
Prior/Concomitant 
Medications/Procedures  
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Tumor Assessment/CT/MRI/Bone Scanj 
 
X 
 
 
 
 
 
 
Xk 
Xl 
Xl 
Xl 
Archival Primary/ Metastatic Tumor 
Tissue Sample for retrospective testingm 
 
X 
 
 
 
 
 
 
 
 
 
 
Patient-reported outcome (BPI-SF, 
analgesic drug score, FACT-P, EQ-5D-
5L)n 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
ECOG Performance Status 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Serum Testosterone 
 
X 
 
 
 
 
 
 
 
 
 
 
PSA Measuremento 
 
X 
 
 
X 
 
X 
 
X 
X 
 
 
Clinical Laboratory Assessmentsp 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Pharmacogenomic blood sampleq 
 
 
 
 
X 
 
 
 
 
 
 
 
Randomization to Study Treatment 
 
 
 
X 
 
 
 
 
 
 
 
 
Study Drug Dispensation 
 
 
 
 
X 
 
X 
 
X 
 
 
 
Adverse Eventsr 
(X) 
(X) 
(X) 
 
X 
X 
X 
X 
X 
Xs 
Xs 
 
Plasma PK Sample (Rucaparib patients 
only) 
 
 
 
 
 
 
Xt 
 
Xt 
 
 
 


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Post-progression Tumor Biopsy 
(Optional) 
 
 
 
 
 
 
 
 
Xu 
 
Subsequent Treatments, AESIs, & 
Survivalv 
 
 
 
 
 
 
 
 
 
X 
X 
Abbreviations: AESI = adverse event of special interest, ALP = alkaline phosphatase, ALT = alanine transaminase, AML = acute myeloid leukemia, ANC = absolute 
neutrophil count, AST = aspartate transaminase, ATM = ataxia telangiectasia mutated serine/threonine kinase, BRCA1/2 = breast cancer 1 or breast cancer 2 gene, 
BPI-SF = Brief Pain Inventory – Short Form, BUN = blood urea nitrogen, CO2 = bicarbonate, CR = complete response, CT = computer tomography, ctDNA = circulating 
cell-free tumor DNA, DNA = deoxyribonucleic acid, ECG = electrocardiogram, ECOG = Eastern Cooperative Oncology Group, EQ-5D-5L = EuroQol 5 dimensions 5 level 
questionnaire, FACT-P = Functional Assessment of Cancer Therapy-Prostate, Hct = hematocrit, HDL = high density lipoprotein, HDP = hydroxydiphosphonate, 
Hgb = hemoglobin, INR = international normalized ratio, LDL= low density lipoprotein, MCH = mean corpuscular hemoglobin, MCHC = mean corpuscular hemoglobin 
concentration, MCV = mean corpuscular volume, MDP = methylene diphosphonate, MDS = myelodysplastic syndrome, MRI = magnetic resonance imaging, PET = positron 
emission tomography, PK = pharmacokinetic, PR = partial response, PV = Pharmacovigilance, RBC = red blood cell count, RECIST = Response Evaluation Criteria in Solid 
Tumors, SAE = serious adverse event, WBC = white blood cells 
a 
The study visit window is ±3 days, unless noted otherwise for a particular assessment. Study visits should take into account the patient’s study drug supply. 
b 
First dose of study drug is designated as Study Day 1 and must occur within 3 days after randomization. Procedures required on Study Day 1 may be omitted if 
completed ≤ 3 days earlier during the Screening Phase with the exception of ctDNA which will be collected during Pre-Screening and must be collected during Screening 
and on Study Day 1. 
c 
Pre-Screening is for central testing of plasma ctDNA and tumor tissue samples to identify patients with qualifying deleterious BRCA1/2 and ATM gene mutations. To 
enter Pre-Screening, patients should have evidence of radiographic or biochemical disease progression, and be eligible for this study as their immediate next therapy. Both 
plasma ctDNA and tumor tissue samples should be submitted simultaneously. If plasma or tissue testing results in failure, additional samples may be submitted, as 
available. Pre-Screening requires a separate informed consent form. 
d 
Tissue for Pre-Screening should be from biopsy or resection specimen from metastatic tumor, if there is a lesion suitable for biopsy. A biopsy or resection of a visceral or 
nodal site of metastasis is preferred; however a biopsy of primary tumor or of a site of bony metastasis is also acceptable (soft tissue biopsy preferred over bone site 
biopsy). If a metastatic biopsy is not feasible, archival tissue samples can be submitted. Archival tissue for Pre-Screening should be < 3 years old. Submission of a tumor 
block with a tumor content ≥ 30% with a minimum of 80% nucleated cellular content should be provided. 
e 
Includes demographic information. Patient’s medical record must include prior treatments received, dates of administration, date of progression and how assessed, PSA 
and radiology reports. 
f 
Blood samples for plasma ctDNA analysis during Screening, before dosing on Study Day 1, and at Treatment Discontinuation are for pharmacodynamic assessments and 
companion diagnostic development. Plasma ctDNA is required on Study Day 1 even when it was previously collected.  
g 
Height at screening only. 
h 
Vital signs (blood pressure, pulse, and temperature) to be taken on drug administration days, after the patient has been resting for at least 5 minutes. 
i 
Heart rate, pulse rate, QRS, QT, QTc, and rhythm. Investigator to review results and assess as normal or abnormal (clinically significant or not clinically significant). 
ECGs to be repeated as clinically indicated. 
j 
Tumor assessments to consist of clinical examination and appropriate imaging techniques (CT scans of the chest, abdomen and pelvis, with appropriate slice thickness); CT 
with contrast is preferred, non-contrast may be used where clinically indicated. MRI may be used in place of CT scan if requested by local authorities. Where indicated for 
neurological symptoms, MRI of spine and skull to be conducted. Radionuclide bone scanning (whole body) using 99mTc-MDP or HDP. Other studies, such as PET/CT, 
may also be performed. The same methods used to detect lesions at baseline are to be used to follow the same lesions throughout the clinical study. If a patient has known 
brain metastases, this disease should be evaluated at each required assessment.  


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k 
Disease assessment by CT/MRI and bone scans will be performed during screening, during the treatment phase, and Treatment Discontinuation, and if applicable, during 
follow up. Modified RECIST Version 1.1/PCWG3 criteria will be used. Tumor assessments will occur at the end of every 8 weeks from Study Day 1, up to 24 weeks 
(Study Weeks 9, 17, 25) and then every 12 weeks thereafter (Study weeks 37, 49, 61, etc.). If a CR or PR is noted, confirmatory scans should be performed at least 4 weeks 
after the initial response was first documented. 
l 
Radiographic assessments should continue for all patients until central confirmation of radiographic progression, including any patient who discontinued from study 
treatment for reason other than disease progression or death. Tumor assessments should be performed during the Treatment Discontinuation Visit, 28-day Follow-up, or 
during Long-term Follow-up if the reason was other than central radiographically confirmed disease progression and it has been ≥ 8 weeks (≥ 12 weeks if previous scan 
was after 24 weeks on study) since the last assessment. Tumor assessments should continue on schedule (ie, every 8 or 12 weeks) during Long-term Follow-up until central 
radiographically confirmed disease progression. After the primary endpoint analysis is performed central confirmation of radiographic progression will no longer occur; 
radiographic progression and confirmation of disease progression will be performed by the investigator.  
m 
If archival primary or metastatic tumor tissue was not submitted during Pre-Screening, a specimen should be submitted during the Screening Phase or after enrollment for 
retrospective testing by the central laboratory. Archival tissue submitted during Screening for retrospective testing can be > 3 years old. Refer to the Pathology Charter for 
detailed sample handling instructions. 
n 
The BPI-SF, analgesic drug score, FACT-P, and EQ-5D-5L instruments must be completed prior to other scheduled study procedures and dosing (if applicable). During 
long-term follow up, if possible, PROs to be collected to coincide on days when tumor assessments are performed. PRO assessments should continue to be collected until 
confirmed radiologic disease progression. 
o 
All PSA measurements are performed by the local laboratory. 
p 
Clinical laboratory assessments will be done locally. Hematology should include RBC and parameters (Hgb, Hct, MCV, MCH, MCHC) and reticulocyte count, WBC and 
differential (with ANC), and platelet count. Serum chemistry should include total protein, albumin, creatinine for estimating GFR using the Cockcroft Gault formula, BUN 
or urea, total bilirubin, ALP, ALT, AST, LDH, lipid panel (total cholesterol, LDL, HDL, and triglycerides), glucose, sodium, potassium, chloride, CO2, calcium, and 
phosphorus. Fasting is not required. Urinalysis should include protein, glucose, blood, pH, and ketones. Microscopic evaluation to assess abnormal findings, if clinically 
warranted by investigator. 
q 
If pharmacogenomic sample is not collected prior to Study Day 1, it must be collected as soon as possible thereafter. 
r 
AEs (inclusive of SAEs and AESIs) occurring after first dose of study drug through to 28 days after last dose of study drug will be recorded. In addition, SAEs occurring 
after signing of ICF that were related to a Pre-Screening or Screening procedure will also be reported. 
s 
Ongoing SAEs, AESIs and Grade 3/4 AEs will be followed to resolution or stabilization. SAEs/AESIs are collected per Clovis Oncology PV guidelines and reported in 
the Clovis Oncology PV database through the 28-day Follow-up Visit after the last dose of rucaparib. Ongoing SAEs and AESIs at the time of the 28-day Follow-up Visit 
will be followed to resolution, stabilization, or lost to follow-up. After this visit, only SAEs considered as potentially related to study drug, (including pneumonitis or 
similar events meeting the criteria for an SAE and assessed as potentially related to study drug), and AESIs of MDS and AML irrespective of causality, should be 
reported. 
t 
PK within 1 hour prior to the morning dose on Study Day 29, Day 57, Day 85, and Day 113. The PK sample should be collected close to 12 hours post the last dose (even 
if the morning dose on the specified visit days is not administered). 
u 
Optional tumor biopsy should be collected from patients at time of disease progression. Refer to the Pathology Charter for detailed sample handling instructions. 
v 
All patients discontinued from treatment, regardless of reason, should be followed for subsequent treatments and survival every 12 weeks relative to the last dose of study 
drug until death, loss to follow-up, withdrawal of consent from study, or closure of the study. Follow-up can be performed via the telephone and can be completed to 
coincide with scheduled tumor assessments and/or PRO during this period.  
w 
Patients eligible for cross-over to rucaparib will have a Treatment Discontinuation Visit after discontinuation of comparator therapy, but are not required to complete the 
28-day follow-up visit on their original study treatment.  
 
 


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Table 6. 
Schedule of Assessments for Patients Randomized to Physician’s Choice of Docetaxel 
 
 
Screening Phase 
Randomization 
Treatment Phase 
 
 
Week 
1 
Week 1 
and every 
3 weeks 
thereafter 
Week 1 
and every 
4 weeks 
thereafter 
Week 9 
and every 
8 weeks 
thereafter 
Post-Treatment Phase 
Procedurea 
Pre-
screening 
Phase 
Day -28 
to 
Day -1 
Day -14 
to  
Day -1 
Study 
Day 1 
Study 
Day 1 and 
every 21 
days 
thereafter
b 
Study 
Day 1 and 
every 
28 days 
thereafter
b 
Study 
Day 57 
and every 
56 days 
thereafter 
Treatment 
Discontinuati
onv 
28-day 
Follow-
upv 
Long-t
erm 
Follow
-up 
Informed Consent 
Xc 
X 
 
 
 
 
 
 
 
 
 
BRCA1/2, ATM gene mutation 
assessment from ctDNA blood and 
tumor samplec, d 
Xc 
 
 
 
 
 
 
 
 
 
 
Medical/Oncology Historye 
 
X 
 
 
 
 
 
 
 
 
 
Blood samples for plasma ctDNA 
analysisf 
 
X 
 
 
X 
 
 
 
X 
 
 
Physical Examination, Weight, 
Heightg 
 
X 
 
 
 
X 
 
 
X 
X 
 
Vital Signsh 
 
X 
 
 
 
X 
 
 
X 
X 
 
12-lead ECGi 
 
X 
 
 
 
 
 
 
X 
 
 
Prior/Concomitant 
Medications/Procedures  
 
X 
 
 
 
X 
 
 
X 
X 
 
Tumor Assessment/CT/MRI/Bone 
Scanj 
 
X 
 
 
 
 
 
Xk 
Xl 
Xl 
Xl 
Archival Primary/ Metastatic 
Tumor Tissue Sample for 
retrospective testingm 
X 
 
 
 
 
 
 
 
 
 
 
Patient-reported outcome (BPI-SF, 
analgesic drug score, FACT-P, 
EQ-5D-5L)n 
 
 
X 
 
 
 
X 
 
X 
X 
X 
ECOG Performance Status 
 
 
X 
 
 
X 
 
 
X 
X 
 
Serum Testosterone 
 
X 
 
 
 
 
 
 
 
 
 
PSA Measuremento 
 
X 
 
 
 
X 
 
 
X 
 
 
Clinical Laboratory Assessmentsp 
 
 
X 
 
 
X 
 
 
X 
X 
 
Pharmacogenomic blood sampleq 
 
 
 
 
X 
 
 
 
 
 
 
Randomization to Study 
Treatment 
 
 
 
X 
 
 
 
 
 
 
 


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Docetaxel Administration 
 
 
 
 
 
X 
 
 
 
 
 
Adverse Eventsr 
(X) 
(X) 
(X) 
 
 
X 
 
X 
Xs 
Xs 
 
Post-progression Tumor Biopsy 
(Optional) 
 
 
 
 
 
 
 
 
Xt 
 
 
Subsequent Treatments, AESIs, & 
Survivalu 
 
 
 
 
 
 
 
 
 
X 
X 
Abbreviations: AESI = adverse event of special interest, ALP = alkaline phosphatase, ALT = alanine transaminase, ANC = absolute neutrophil count, AML = acute myeloid 
leukemia, AST = aspartate transaminase, ATM = ataxia telangiectasia mutated serine/threonine kinase, BRCA1/2 = breast cancer 1 or breast cancer 2 gene, BPI-SF = Brief Pain 
Inventory – Short Form, BUN = blood urea nitrogen, CO2 = bicarbonate, CR = complete response, CT = computer tomography, ctDNA = circulating cell-free tumor DNA, 
DNA = deoxyribonucleic acid, ECG = electrocardiogram, ECOG = Eastern Cooperative Oncology Group, EQ-5D-5L = EuroQol 5 dimensions 5 level questionnaire, 
FACT-P = Functional Assessment of Cancer Therapy-Prostate, Hct = hematocrit, HDL= high density lipoprotein, HDP = hydroxydiphosphonate, Hgb = hemoglobin, 
INR = international normalized ratio, LDL= low density lipoprotein, MCH = mean corpuscular hemoglobin, MCHC = mean corpuscular hemoglobin concentration, 
MCV = mean corpuscular volume, MDP = methylene diphosphonate, MDS = myelodysplastic syndrome, MRI = magnetic resonance imaging, PET = positron emission 
tomography, PR = partial response, PV = Pharmacovigilance, RBC = red blood cell count, RECIST = Response Evaluation Criteria in Solid Tumors, SAE = serious adverse 
event, WBC = white blood cells 
a 
The study visit window is ±3 days, unless noted otherwise for a particular assessment. Study visits should take into account the patient’s study drug supply. 
b 
First dose of study drug is designated as Study Day 1 and must occur within 3 days after randomization. Procedures required on Study Day 1 may be omitted if 
completed ≤ 3 days earlier during the Screening Phase with the exception of ctDNA which will be collected during Pre-Screening and must be collected during Screening 
and on Study Day 1. Docetaxel administration will continue up to a maximum of 10 cycles (whereupon no study treatment shall be given, but assessments continue). 
c 
Pre-Screening is for central testing of plasma ctDNA and tissue samples to identify patients with qualifying deleterious BRCA1/2 or ATM gene mutations. To enter 
Pre-Screening, patients should have evidence of radiographic or biochemical disease progression, and be eligible for this study as their immediate next therapy. Both 
plasma ctDNA and tumor tissue samples should be submitted simultaneously. If plasma or tissue testing results in failure, additional samples may be submitted, as 
available. Pre-Screening requires a separate informed consent form.  
d 
Tissue for Pre-Screening should be from biopsy or resection specimen from metastatic tumor, if there is a lesion suitable for biopsy. A biopsy or resection of a visceral or 
nodal site of metastasis is preferred; however a biopsy of primary tumor or of a site of bony metastasis is also acceptable (soft tissue biopsy preferred over bone site 
biopsy). If a metastatic biopsy is not feasible, archival tissue samples can be submitted. Archival tissue for Pre-Screening should be < 3 years old. Submission of a tumor 
block with a tumor content ≥ 30% with a minimum of 80% nucleated cellular content should be provided.  
e 
Includes demographic information. Patient’s medical record must include prior treatments received, dates of administration, date of progression and how assessed, PSA 
and radiology reports. 
f 
Blood samples for plasma ctDNA analysis during Screening, before dosing on Study Day 1, and at Treatment Discontinuation are for pharmacodynamic assessments and 
companion diagnostic development. Plasma ctDNA is required on Study Day 1 even when it was previously collected.  
g 
Height at screening only. 
h 
Vital signs (blood pressure, pulse, and temperature) to be taken on drug administration days, after the patient has been resting for at least 5 minutes. 
i 
Heart rate, pule rate, QRS, QT, QTc, and rhythm. Investigator to review results and assess as normal or abnormal (clinically significant or not clinically significant). ECGs 
to be repeated as clinically indicated. 
j 
Tumor assessments to consist of clinical examination and appropriate imaging techniques (CT scans of the chest, abdomen and pelvis, with appropriate slice thickness); CT 
with contrast is preferred, non-contrast may be used where clinically indicated. MRI may be used in place of CT scan if requested by local authorities. Where indicated for 
neurological symptoms, MRI of spine and skull to be conducted. Radionuclide bone scanning (whole body) using 99mTc-MDP or HDP. Other studies, such as PET/CT, 
may also be performed. The same methods used to detect lesions at baseline are to be used to follow the same lesions throughout the clinical study. If a patient has known 
brain metastases, this disease should be evaluated at each required assessment.  


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Clinical Study Protocol: CO-338-063 Amendment 4 
 
18 February 2022 
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k 
Disease assessment by CT/MRI and bone scans will be performed during screening, during the treatment phase, and Treatment Discontinuation, and if applicable, during 
follow up. Modified RECIST Version 1.1/PCWG3 criteria will be used. End of every 8 weeks from Study Day 1, up to 24 weeks (Study Weeks 9, 17, 25) and then every 
12 weeks thereafter (Study weeks 37, 49, 61, etc.). If a CR or PR is noted, confirmatory scans should be performed at least 4 weeks after the initial response was first 
documented. 
l 
Radiographic assessments should continue for all patients until central confirmation of radiographic progression, including any patient who discontinued from study 
treatment for reason other than disease progression or death. Tumor assessments should be performed during the Treatment Discontinuation Visit, 28-day Follow-up, or 
during Long-term Follow-up if the reason was other than radiographically confirmed disease progression and it has been ≥ 8 weeks (≥ 12 weeks if previous scan was after 
24 weeks on study) since the last assessment. Tumor assessments should continue on schedule (ie, every 8 or 12 weeks) during Long-term Follow-up until central 
radiographically confirmed disease progression. After the primary endpoint analysis is performed central confirmation of radiographic progression will no longer occur; 
radiographic progression and confirmation of disease progression will be performed by the investigator. 
m 
If archival primary or metastatic tumor tissue is not submitted during Pre-Screening, a specimen should be submitted during the Screening Phase or after enrollment for 
retrospective testing by the central laboratory. Archival tissue submitted during Screening for retrospective testing can be > 3 years old. Refer to the Pathology Charter for 
detailed sample handling instructions.  
n 
The BPI-SF, analgesic drug score, FACT-P, and EQ-5D-5L instruments must be completed every 4 weeks (±7 days) prior to other scheduled study procedures and dosing 
(if applicable). During long-term follow up, if possible, PROs to be collected to coincide on days when tumor assessments are performed. Collection of PROs at any other 
study visit within 7 days of the scheduled time point is permitted. PRO assessments should continue to be collected until confirmed radiologic disease progression. 
o 
All PSA measurements are performed by the local laboratory. 
p 
Clinical laboratory assessments will be done locally. Hematology should include RBC and parameters (Hgb, Hct, MCV, MCH, MCHC) and reticulocyte count, WBC and 
differential (with ANC), and platelet count. Serum chemistry should include total protein, albumin, creatinine for estimating GFR using the Cockcroft Gault formula, BUN 
or urea, total bilirubin, ALP, ALT, AST, LDH, lipid panel (total cholesterol, LDL, HDL, and triglycerides), glucose, sodium, potassium, chloride, CO2, calcium, and 
phosphorus. Fasting is not required. Urinalysis should include protein, glucose, blood, pH, and ketones. Microscopic evaluation to assess abnormal findings, if clinically 
warranted by investigator. 
q 
If pharmacogenomic sample is not collected prior to Study Day 1, it must be collected as soon as possible thereafter.  
r 
AEs (inclusive of SAEs and AESIs) occurring after first dose of study drug through to 28 days after last dose of study drug will be recorded. In addition, SAEs occurring 
after signing of ICF that were related to a Pre-Screening or Screening procedure will also be reported. 
s 
Ongoing SAEs, AESIs and Grade 3/4 AEs will be followed to resolution or stabilization. SAEs/AESIs are collected per Clovis Oncology PV guidelines and reported in 
the Clovis Oncology PV database through the 28-day Follow-up Visit after the last dose of rucaparib. Ongoing SAEs and AESIs at the time of the 28-day Follow-up Visit 
will be followed to resolution, stabilization, or lost to follow-up. After this visit, only SAEs considered as potentially related to study drug (including pneumonitis or 
similar events meeting the criteria for an SAE and assessed as potentially related to study drug), and AESIs of MDS and AML irrespective of causality, should be 
reported. 
t 
Optional tumor biopsy should be collected from patients at time of disease progression. Refer to the Pathology Charter for detailed sample handling instructions. 
u 
All patients discontinued from treatment, regardless of reason, should be followed for subsequent treatments and survival every 12 weeks relative to the last dose of study 
drug until death, loss to follow-up, withdrawal of consent from study, or closure of the study. Follow-up can be performed via the telephone and can be completed to 
coincide with scheduled tumor assessments and/or PRO during this period.  
v 
Patients eligible for cross-over to rucaparib will have a Treatment Discontinuation Visit after discontinuation of comparator therapy, but are not required to complete the 
28-day follow-up visit on their original study treatment. 


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Clinical Study Protocol: CO-338-063 Amendment 4 
 
18 February 2022 
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Table 7. 
Schedule of Assessments for Patients Who Cross over to Rucaparib after Physician’s Choice 
Comparator 
 
XO-Screening Phase 
Treatment Phase 
Post-Treatment Phase 
 
XO-Week 
1 
XO-Week 
3 
XO-Week 
5 
XO-Week 7 
XO-Week 
9 & every 
4 weeks 
thereafter 
Procedurea 
Day -28 to 
Day -1 
Day -14 
to 
Day -1 
XO-Study 
Day 1b 
XO-Study 
Day 15 
XO-Study 
Day  
29 
XO-Study 
Day 43 
XO-Day 57 
& every 
28 days 
thereafter 
Treatment 
Discontinuation 
28-day 
Follow
-up 
Long-
term 
Follow-up 
Cross-over Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Blood samples for plasma 
ctDNA analysis 
 
 
X 
 
 
 
 
X 
 
 
Physical Examination, 
Weight, Heightc 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signsd 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECGe 
X 
 
 
 
 
 
 
X 
 
 
Prior/Concomitant 
Medications/Procedures  
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Tumor 
Assessment/CT/MRI/Bone 
Scanf 
X 
 
 
 
 
 
Xg 
Xh 
Xh 
Xh 
Patient-reported outcome 
(BPI-SF, analgesic drug 
score, FACT-P, EQ-5D-5L)i 
 
X 
X 
 
X 
 
X 
X 
X 
X 
ECOG Performance Status 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum Testosterone 
X 
 
 
 
 
 
 
 
 
 
PSA Measurementj 
X 
 
X 
 
X 
 
X 
X 
 
 
Clinical Laboratory 
Assessmentsk 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study Drug Dispensation 
 
 
X 
 
X 
 
X 
 
 
 
Adverse Eventsl 
(X) 
(X) 
X 
X 
X 
X 
X 
Xm 
Xm 
 
Post-progression Tumor 
Biopsy (Optional) 
 
 
 
 
 
 
Xn 
 
Subsequent Treatments, 
AESIs, & Survivalo 
 
 
 
 
 
 
 
X 
X 


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Clinical Study Protocol: CO-338-063 Amendment 4 
 
18 February 2022 
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Abbreviations: AESI = adverse event of special interest, ALP = alkaline phosphatase, ALT = alanine transaminase, AML = acute myeloid leukemia, ANC = absolute 
neutrophil count, AST = aspartate transaminase, BPI-SF = Brief Pain Inventory – Short Form, BUN = blood urea nitrogen, CO2 = bicarbonate, CR = complete response, 
CT = computer tomography, ctDNA = circulating cell-free tumor DNA, DNA = deoxyribonucleic acid, ECG = electrocardiogram, ECOG = Eastern Cooperative Oncology 
Group, EQ-5D-5L = EuroQol 5 dimensions 5 level questionnaire, FACT-P = Functional Assessment of Cancer Therapy-Prostate, Hct = hematocrit, HDL= high density 
lipoprotein, HDP = hydroxydiphosphonate, Hgb = hemoglobin, INR = international normalized ratio, LDL= low density lipoprotein, MCH = mean corpuscular hemoglobin, 
MCHC = mean corpuscular hemoglobin concentration, MCV = mean corpuscular volume, MDP = methylene diphosphonate, MDS = myelodysplastic syndrome, 
MRI = magnetic resonance imaging, PET = positron emission tomography, PK = pharmacokinetic, PR = partial response, PV = Pharmacovigilance, RBC = red blood cell count, 
RECIST = Response Evaluation Criteria in Solid Tumors, SAE = serious adverse event, WBC = white blood cells 
a 
The study visit window is ±3 days, unless noted otherwise for a particular assessment. Study visits should take into account the patient’s study drug supply. 
b 
First dose of study drug is designated as XO-Study Day 1. Procedures required on XO-Study Day 1 may be omitted if completed ≤ 3 days earlier during the Screening 
Phase. 
c 
Height at screening only. 
d 
Vital signs (blood pressure, pulse, and temperature) to be taken on drug administration days, after the patient has been resting for at least 5 minutes. 
e 
Heart rate, pulse rate, QRS, QT, QTc, and rhythm. Investigator to review results and assess as normal or abnormal (clinically significant or not clinically significant). 
ECGs to be repeated as clinically indicated. 
f 
Tumor assessments to consist of clinical examination and appropriate imaging techniques (CT scans of the chest, abdomen and pelvis, with appropriate slice thickness); CT 
with contrast is preferred, non-contrast may be used where clinically indicated. MRI may be used in place of CT scan if requested by local authorities. Where indicated for 
neurological symptoms, MRI of spine and skull to be conducted. Radionuclide bone scanning (whole body) using 99mTc-MDP or HDP. Other studies, such as PET/CT, 
may also be performed. The same methods used to detect lesions at baseline are to be used to follow the same lesions throughout the clinical study. If a patient has known 
brain metastases, this disease should be evaluated at each required assessment.  
g 
Disease assessment by CT/MRI and bone scans will be performed during screening, during the treatment phase, and Treatment Discontinuation, and if applicable, during 
follow up. Modified RECIST Version 1.1/PCWG3 criteria will be used. Tumor assessments will occur at the end of every 8 weeks from XO-Study Day 1, up to 24 weeks 
(XO-Study Weeks 9, 17, 25) and then every 12 weeks thereafter (XO-Study weeks 37, 49, 61, etc.). If a CR or PR is noted, confirmatory scans should be performed at least 
4 weeks after the initial response was first documented. 
h 
Radiographic assessments should continue for all patients until confirmation of radiographic progression by investigator assessment, including any patient who 
discontinued from study treatment for reason other than disease progression or death. Tumor assessments should be performed during the Treatment Discontinuation Visit, 
28-day Follow-up, or during Long-term Follow-up if the reason was other than radiographically confirmed disease progression and it has been ≥ 8 weeks (≥ 12 weeks if 
previous scan was after 24 weeks on study) since the last assessment. Tumor assessments should continue on schedule (ie, every 8 or 12 weeks) during Long-term Follow-
up until radiographically confirmed disease progression by investigator assessment. 
i 
The BPI-SF, analgesic drug score, FACT-P, and EQ-5D-5L instruments must be completed prior to other scheduled study procedures and dosing (if applicable). During 
long-term follow up, if possible, PROs to be collected to coincide on days when tumor assessments are performed. PRO assessments should continue to be collected until 
radiologic disease progression is confirmed by investigator assessment. 
j 
All PSA measurements are performed by the local laboratory.  
k 
Clinical laboratory assessments will be done locally. Hematology should include RBC and parameters (Hgb, Hct, MCV, MCH, MCHC) and reticulocyte count, WBC and 
differential (with ANC), and platelet count. Serum chemistry should include total protein, albumin, creatinine for estimating GFR using the Cockcroft Gault formula, BUN 
or urea, total bilirubin, ALP, ALT, AST, LDH, lipid panel (total cholesterol, LDL, HDL, and triglycerides), glucose, sodium, potassium, chloride, CO2, calcium, and 
phosphorus. Fasting is not required. Urinalysis should include protein, glucose, blood, pH, and ketones. Microscopic evaluation to assess abnormal findings, if clinically 
warranted by investigator. 
l 
AEs (inclusive of SAEs and AESIs) occurring after first dose of study drug through to 28 days after last dose of study drug will be recorded. In addition, SAEs occurring 
after signing of ICF that were related to a Pre-Screening or Screening procedure will also be reported. 


Rucaparib 
Clovis Oncology, Inc. 
Clinical Study Protocol: CO-338-063 Amendment 4 
 
18 February 2022 
Confidential 
Page 78 
m 
Ongoing SAEs, AESIs and Grade 3/4 AEs will be followed to resolution or stabilization. SAEs/AESIs are collected per Clovis Oncology PV guidelines and reported in 
the Clovis Oncology PV database through the 28-day Follow-up Visit after the last dose of rucaparib. Ongoing SAEs and AESIs at the time of the 28-day Follow-up Visit 
will be followed to resolution, stabilization, or lost to follow-up. After this visit, only SAEs considered as potentially related to study drug (including pneumonitis or 
similar events meeting the criteria for an SAE and assessed as potentially related to study drug), and AESIs of MDS and AML irrespective of causality, should be 
reported. 
n 
Optional tumor biopsy should be collected from patients at time of disease progression. Refer to the Pathology Charter for detailed sample handling instructions. 
o 
All patients discontinued from treatment, regardless of reason, should be followed for subsequent treatments and survival every 12 weeks relative to the last dose of study 
drug until death, loss to follow-up, withdrawal of consent from study, or closure of the study. Follow-up can be performed via the telephone and can be completed to 
coincide with scheduled tumor assessments and/or PRO during this period.  


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9.2 
Informed Consent 
Patients are required to sign the Pre-Screening ICF prior to undergoing any Pre-Screening 
activities (ie, deleterious BRCA1/2 or ATM gene mutation testing), and are required to sign the 
Screening ICF prior to undergoing any other Screening assessments. Obtaining written informed 
consent does not signify the start of the Screening Phase as it begins when the first study-specific 
screening activity is performed. 
The investigator or their designee shall discuss with each patient the nature of the study and its 
requirements. The information on the IRB/IEC approved consent form should be translated and 
communicated in the language the patient (or legally authorized representative) can understand.  
Additionally, patients undergoing tumor tissue biopsy during Pre-Screening at the time of 
radiographic disease progression/randomized treatment discontinuation must provide additional 
consent for this procedure.  
Patients who cross-over to treatment with rucaparib after confirmed radiographic disease 
progression must provide additional consent to continue treatment, as well as sponsor (or 
designee) approval of the radiology report confirming disease progression and eligibility. Details 
regarding cross-over to rucaparib are described in Section 9.7. 
Patients with radiographic disease progression who are still receiving benefit and are allowed to 
continue study drug must also provide consent for continued treatment. 
9.3 
Pre-Screening Phase 
Following written informed consent, and unless otherwise specified, the following assessments 
will be performed prior to Screening. Pre-Screening procedures may be repeated in the event of 
test failure. 
Pre-screening is for central testing of plasma ctDNA and tumor tissue samples to identify 
patients with qualifying deleterious BRCA1/2 and ATM gene mutations. Patients with 
deleterious BRCA1/2 or ATM gene mutation identified through local testing need not enter 
Pre-Screening. To enter Pre-Screening, patients should have evidence of radiographic or 
biochemical disease progression, and be eligible for this study as their immediate next therapy. 
Patients must sign the Pre-Screening ICF.  
During Pre-Screening: 
• Submit patient plasma sample for ctDNA analysis and tissue samples simultaneously 
• Tissue should be from a newly obtained metastatic biopsy, if there is a lesion suitable for 
biopsy. A biopsy or resection of a visceral or nodal site of metastasis is preferred; however, a 
biopsy of primary tumor or of a site of bony metastasis is also acceptable.  
• If a metastatic biopsy is not feasible, archival tissue samples can be submitted. Archival 
tissue should be < 3 years old. The most recently collected tumor tissue sample available that 
is of adequate quality (at least 30% tumor content with a minimum of 80% nucleated cellular 
content) should be provided. 


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Clinical Study Protocol: CO-338-063 Amendment 4 
 
18 February 2022 
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• If plasma or tissue samples result in test failure, sites are encouraged to submit additional 
samples, as available, in order to obtain a successful test result  
 
A central laboratory test result or a local laboratory test result is required for subsequent 
Screening of these patients 
Refer to the Pathology Charter for detailed tissue sample handling instructions.  
SAE monitoring is ongoing during Pre-Screening (only report if related to Pre-Screening 
procedures). 
9.4 
Screening Phase 
Following written informed consent, and unless otherwise specified, the following assessments 
will be performed prior to randomization within the allowable windows of time as indicated 
below. Assessments performed within the specified windows, but prior to patient signing 
informed consent, are acceptable only if confirmed to have been standard of care. Screening 
procedures may be repeated if the findings/results are considered invalid or not representative of 
the patient’s baseline medical status. When screening procedures are repeated, the rationale 
should be documented in the source file.  
9.4.1 
Screening: Up to 28 Days Prior to Randomization: 
• Serum testosterone level measurement 
• PSA measurement 
• Medical/oncology history, including demographic information 
• Plasma sample for ctDNA 
• Physical examination by body system, including height and weight 
• Vital signs (blood pressure, pulse, and body temperature) 
• 12-lead ECG 
• Prior and concomitant medications, any surgical/ medical procedures 
• Tumor assessment: assessments should consist of clinical examination and appropriate 
imaging techniques (preferably CT scans of the chest, abdomen, and pelvis with appropriate 
slice thickness per modified RECIST Version 1.1); other studies (MRI, X-ray, positron 
emission tomography [PET]/CT, and ultrasound) may be performed if required. Radionuclide 
bone scanning (whole body) should be performed using 99mTc-methylene diphosphonate 
(MDP) or hydroxydiphosphonate (HDP). The same methods used to detect lesions at 
baseline are to be used to follow the same lesions throughout the clinical study.  
- 
If a patient has known brain metastases, this disease should be evaluated at each required 
assessment 
• Archival primary and metastatic tumor tissue (if available, and not already submitted to the 
central laboratory) for retrospective testing by the central laboratory. Archival tissue samples 
> 3 years old are allowed for retrospective testing purposes. Samples may be submitted after 
enrollment. Refer to the Pathology Charter for detailed tissue sample handling instructions.  


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Clinical Study Protocol: CO-338-063 Amendment 4 
 
18 February 2022 
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• SAE monitoring (only report if related to screening procedures) 
 
9.4.2 
Screening: Up to 14 Days Prior to Randomization: 
• PRO collected using the BPI-SF (Appendix 5), FACT-P (Appendix 6), EQ-5D-5L (Appendix 7), 
and analgesic drug score instruments (Appendix 8); complete before other procedures 
• Clinical laboratory assessments (hematology, serum chemistry [fasting is not required], 
urinalysis; see Section 9.12.2) 
• ECOG performance status (Appendix 2);  
• SAE monitoring (only report if related to screening procedures) 
9.5 
Treatment Phase  
Patients are to be randomized to receive either rucaparib or the physician's choice of comparator 
therapy (Section 5.1.3) through IXRS after meeting eligibility criteria (Sections 6.2 and 6.3) and 
having completed screening assessments (Section 9.3).  
The first dose of study drug must be administered ≤ 3 days after randomization and the day of 
first dose is Study Day 1.  
During the treatment period, patients randomized to rucaparib will receive oral rucaparib tablets 
which should be taken BID at 600 mg/dose with 8 oz (240 mL) of water with or without food. At 
each study visit, the first dose of rucaparib will be taken in the clinic, with the remaining doses 
self-administered by the patient at home. Patients should take rucaparib at about the same time 
every day and should inform the clinic staff of any changes to their dose and timing of 
self-administration of oral rucaparib.  
The choice of comparator therapy is at the discretion of the investigator from the regimens 
described in this protocol and must be specified prior to randomization. Refer to 
Sections 7.5.2 to 7.5.4 for dosing details. 
Patients initially randomized and treated with comparator who have crossed over to rucaparib 
following radiographic progression will be required to sign a cross-over ICF as described in 
Section 9.7, meet eligibility criteria for the cross-over described in Section 6.4, and have sponsor 
(or designee) approval prior to crossing over to rucaparib treatment. Patients who cross-over to 
rucaparib will follow the procedures/assessments described in Section 9.8, Sections 9.5.1.1 to 
9.5.1.5 , Section 9.6.1, and Section 9.6.2.  
9.5.1 
Patients Randomized to Rucaparib, Physician’s Choice of Abiraterone Acetate 
or Enzalutamide or Cross-over to Rucaparib 
9.5.1.1 
Study Day 1 (Week 1) and Cross-over Study Day 1 (XO Week 1) 
The following procedures/assessments will be completed for all patients randomized to rucaparib 
or physician’s choice of abiraterone acetate or enzalutamide (whichever the patient has not yet 
received) or cross-over to rucaparib before initiation of treatment on Study Day 1. Procedures 


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required on Study Day 1/ Cross-over Study Day 1 may be omitted if completed ≤ 3 days earlier 
during the Screening Phase. 
• PRO collected using the BPI-SF, analgesic drug score, FACT-P, and EQ-5D-5L instruments; 
complete before other procedures 
• Physical examination, including weight 
• Vital Signs 
• Concomitant medications and procedures 
• PSA measurement 
• ECOG performance status  
• Clinical laboratory assessments (hematology, serum chemistry [fasting is not required], 
urinalysis)  
• Plasma sample for ctDNA (required on Study Day 1 even if collected at any time during the 
Pre-Screening or Screening Phase) 
• Blood sample for pharmacogenomic analysis (not required for patients crossing over to 
rucaparib) 
• AE (inclusive of SAE and AESI) monitoring 
• Study drug dispensation (rucaparib, abiraterone acetate, enzalutamide). Enough study drug 
will be dispensed to patient in sufficient quantity to last until the next study drug dispensation 
visit. 
 
Site personnel will account for study drug that is administered or dispensed to the patient during 
the study visit and document appropriately. 
9.5.1.2 
Study Day 15 (Week 3) and Cross-over Day 15 (XO-Week 3) 
The following procedures will be completed: 
• Physical examination, including weight 
• Vital signs 
• Concomitant medications and procedures 
• ECOG performance status  
• Clinical laboratory assessments (hematology, serum chemistry [fasting is not required], 
urinalysis)  
• AE (inclusive of SAE and AESI) monitoring 
 
Patients will keep all unused containers (empty, partially used, and/or unopened) and return with 
them to the study site for accountability/compliance review at the next visit. In the event of 
toxicities, re-treatment or dose modification will be according to the criteria described in 
Sections 7.5.1.1 and 7.5.5. 


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9.5.1.3 
Study Day 29 (Week 5) and Cross-over Day 29 (XO-Week 5) 
Patients randomized to rucaparib will be instructed to refrain from taking their first dose of 
rucaparib at home on the day of their visit to collect plasma samples for PK. Cross-over patients 
will not have plasma samples for PK collected. 
Plasma samples for PK analysis should be collected before the morning dose as close to 12 hours 
after the previous dose as possible. If the start of the next dose is delayed, the PK sample should 
still be collected during this visit instead of the delayed start of the next treatment cycle. 
The following procedures will be completed: 
• PRO collected using the BPI-SF, analgesic drug score, FACT-P, EQ-5D-5L instruments; 
complete before other procedures 
• Physical examination, including weight 
• Vital signs 
• Concomitant medications and procedures 
• ECOG performance status  
• PSA measurement 
• Clinical laboratory assessments (hematology, serum chemistry [fasting is not required], 
urinalysis)  
• Plasma sample for PK analyses (patients initially randomized to rucaparib only, PK is not 
required for patients who cross-over to rucaparib) 
• AE (inclusive of SAE and AESI) monitoring 
• Study drug dispensation (rucaparib, abiraterone acetate, enzalutamide). Enough study drug 
will be dispensed to patient in sufficient quantity to last until the next study drug dispensation 
visit. 
 
Patients will keep all unused containers (empty, partially used, and/or unopened) and return with 
them to the study site for accountability/compliance review at the next visit. In the event of 
toxicities, re-treatment or dose modification will be according to the criteria described in 
Sections 7.5.1.1 and 7.5.5. 
9.5.1.4 
Study Day 43 (Week 7) and Cross-over Study Day 43 (XO-Week 7) 
The following procedures will be completed: 
• Physical examination, including weight 
• Vital signs 
• Concomitant medications and procedures 
• ECOG performance status  
• Clinical laboratory assessments (hematology, serum chemistry [fasting is not required], 
urinalysis)  


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• AE (inclusive of SAE and AESI) monitoring 
 
9.5.1.5 
Study Day 57 (Week 9) and Cross-over Day 57 (XO-Week 9), and Every 28 Days 
Thereafter 
Patients randomized to rucaparib will be instructed to refrain from taking their first dose of 
rucaparib at home on the day of their visit to collect plasma samples for PK. Cross-over 
rucaparib patients will not collect PK samples. 
Plasma samples for PK analysis should be collected before the morning dose on Study Day 57, 
Study Day 85, and Study Day 113 as close to 12 hours after the previous dose as possible. If the 
start of the next dose is delayed, the PK sample should still be collected during this visit instead 
of the delayed start of the next dose. 
The following procedures will be completed: 
• PRO collected using the BPI-SF, analgesic drug score, FACT-P, EQ-5D-5L instruments; 
complete before other procedures 
• Physical examination, including weight 
• Vital signs 
• Tumor assessment scans at the end of every 8 calendar weeks (± 7 days) for the first 
24 weeks (Weeks 9, 17, 25), and then every 12 calendar weeks (± 7 days) thereafter 
(Weeks 37, 49, 61, etc.) 
• Concomitant medications and procedures 
• ECOG performance status  
• PSA measurement 
• Clinical laboratory assessments (hematology, serum chemistry [fasting is not required], 
urinalysis)  
• Plasma sample for PK analyses (patients initially randomized to rucaparib only, PK is not 
required for patients who cross-over to rucaparib) 
• AE (inclusive of SAE and AESI) monitoring 
• Study drug dispensation (rucaparib, abiraterone acetate, enzalutamide). Enough study drug 
will be dispensed to patient in sufficient quantity to last until the next study drug dispensation 
visit. 
 
Patients will keep all unused containers (empty, partially used, and/or unopened) and return with 
them to the study site for accountability/compliance review at the next visit. In the event of 
toxicities, re-treatment or dose modification will be according to the criteria described in 
Sections 7.5.1.1 and 7.5.5. 


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9.5.2 
Patients Randomized to Physician’s Choice of Docetaxel 
9.5.2.1 
Study Day 1 (Week 1) and Every 21 Days Thereafter 
The following procedures/assessments will be completed for patients randomized to physician’s 
choice of docetaxel before initiation of treatment on Study Day 1. Procedures required on 
Study Day 1 may be omitted if completed ≤ 3 days earlier during the Screening Phase. 
• Physical examination, including weight 
• Vital Signs 
• Concomitant medications and procedures 
• PSA measurement 
• ECOG performance status  
• Clinical laboratory assessments (hematology, serum chemistry [fasting is not required], 
urinalysis)  
• AE (inclusive of SAE and AESI) monitoring 
• Docetaxel administration  
- 
Docetaxel administration will continue up to a maximum of 10 cycles (whereupon no 
study treatment shall be given, but assessments continue). 
 
9.5.2.2 
Study Day 1 (Week 1) 
• Plasma sample for ctDNA (required on Study Day 1 even if collected at any time during the 
Pre-Screening or Screening Phase) 
• Blood sample for pharmacogenomic analysis 
 
9.5.2.3 
Study Day 1 (Week 1) and Every 28 Days Thereafter 
• PRO collected using the BPI-SF, analgesic drug score, FACT-P, and EQ-5D-5L instruments; 
complete before other procedures (every 28 days ±7 days)  
• AE (inclusive of SAE, and AESI) monitoring 
 
9.5.2.4 
Study Day 57 (Week 9) and Every 56 Days Thereafter  
• Tumor assessment scans at the end of every 8 calendar weeks (± 7 days) for the first 
24 weeks (Weeks 9, 17, 25), and then every 12 calendar weeks (± 7 days) thereafter 
(Weeks 37, 49, 61, etc.) 
 


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9.6 
Post-treatment Phase (Randomized Treatment/ Cross-over to 
Rucaparib) 
9.6.1 
Treatment Discontinuation Visit 
Upon randomized treatment discontinuation, regardless of the reason, patients will have a 
Treatment Discontinuation Visit.  
However, patients with radiographic disease progression by modified RECIST Version 1.1 
and/or PCWG3 criteria (for bone lesions), as assessed by IRR, but still receiving benefit per the 
investigator, may be considered for treatment continuation. Once the analysis of the primary 
endpoint has been performed, radiographic scans will continue to be performed by the 
investigator as per the protocol schedule of assessments until radiographic disease progression is 
determined by the investigator, including to assess for consideration to continue treatment; scans 
will no longer be submitted to or read by IRR. The sponsor will inform investigators when 
submission of scans for IRR should discontinue. These patients will continue cycles of study 
drug as described starting in Sections 9.5.1.5 and 9.5.2.3, and a Treatment Discontinuation Visit 
as described below will occur at the end of all study treatment. In such cases, the patient must 
consent prior to continuing treatment with study drug.  
Patients who continue treatment on study drug after radiographic disease progression will have 
the option of tumor tissue biopsy collection at time of first disease progression on study (requires 
additional consent). Tumor tissue will be processed locally as formalin-fixed paraffin-embedded 
(FFPE) tissue. Refer to the Pathology Charter for detailed sample handling instructions. Patients 
on comparator arms may be evaluated for eligibility to cross-over to treatment as described in 
Sections 6.4 and 9.8.  
Patients who cross-over to rucaparib will complete a Treatment Discontinuation Visit after 
discontinuation of comparator therapy, and will then complete a second Treatment 
Discontinuation Visit after discontinuation of rucaparib. 
The following procedures will be performed when treatment to which the patient is randomized 
and/or cross-over to rucaparib has been completed or is discontinued: 
• PRO collected using the BPI-SF, analgesic drug score, FACT-P, and EQ-5D-5L instruments; 
complete before other procedures 
• Physical examination, including weight 
• Vital Signs 
• 12-lead ECG 
• Tumor assessment if it has been ≥ 8 weeks (≥ 12 weeks if previous scan was after 24 weeks 
on study) since the last assessment and the reason for treatment discontinuation was other 
than disease progression confirmed by IRR for the randomized Treatment Phase and by 
investigator assessment for the Cross-over Phase. Once the analysis of the primary endpoint 
has been performed, radiographic scans will continue to be performed by the investigator as 
per the protocol schedule of assessments until radiographic disease progression is determined 
by the investigator; scans will no longer be submitted to or read by IRR. 


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• Concomitant medications and procedures 
• ECOG performance status 
• PSA measurement 
• Clinical laboratory assessments (hematology, serum chemistry [fasting is not required], 
urinalysis)  
• Plasma sample for ctDNA 
• AE (inclusive of SAE, and AESI) monitoring 
• Optional tumor tissue biopsy collection from the time of disease progression (radiographic or 
clinical) / randomized treatment discontinuation and prior to the initiation of any subsequent 
anticancer therapy (requires additional consent). Tumor tissue will be processed locally as 
FFPE tissue. Refer to Section 9.13 for more information and to the Pathology Charter for 
detailed sample handling instructions.  
 
9.6.2 
28-day Safety Follow-up Visit (Randomized Treatment/ Cross-over to 
Rucaparib) 
The following procedures will be performed for all patients at 28 (± 3) days after the last dose of 
randomized study drug and/or cross-over to rucaparib.  
Patients initially randomized to rucaparib and patients who cross-over to receive rucaparib after 
comparator therapy will have a safety follow-up visit 28 (±3) days after the last dose of rucaparib 
and continue with long-term follow-up. (Section 9.6.3). 
Patients randomized to comparator therapy who do not cross-over to receive rucaparib will have 
a safety follow up visit 28 (±3) days after the last dose of comparator and continue with 
long-term follow-up (Section 9.6.3). 
• PRO collected using the BPI-SF, analgesic pain score, FACT-P, and EQ-5D-5L instruments; 
complete before other procedures 
• Physical examination, including weight 
• Vital Signs 
• Tumor assessment only if it has been ≥ 8 weeks (≥ 12 weeks if previous scan was after 
24 weeks on study) since the last assessment for those patients that have not had radiographic 
progression (by central assessment for the randomized Treatment Phase and by investigator 
assessment for the Cross-over Phase). Once the analysis of the primary endpoint has been 
performed, radiographic scans will continue to be performed by the investigator as per the 
protocol schedule of assessments until radiographic disease progression is determined by the 
investigator; scans will no longer be submitted to or read by IRR. 
• Concomitant medications and procedures 
• ECOG performance status 
• Clinical laboratory assessments (hematology, serum chemistry [fasting is not required], 
urinalysis)  


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•
AE monitoring (Note: all SAEs, AESIs, and treatment-related Grade 3/4 AEs are to be
followed to outcome [Section 10.8] if longer than the 28-day follow-up period); and
•
Information collected for subsequent treatments
Patients who do not withdraw from the study at this visit will continue with long-term follow-up 
as described in Section 9.6.3.  
9.6.3 
Long-term Follow-up (Randomized Treatment/ Cross-over to Rucaparib) 
Patients randomized to rucaparib who complete a safety follow-up visit 28 (±3) days after the 
last dose of rucaparib will continue in long-term follow-up as described below. 
Patients randomized to comparator therapy who discontinue treatment due to radiographic 
disease progression and are ineligible or do not consent to cross-over to rucaparib treatment will 
continue in long-term follow-up as described below, after a safety follow-up visit.  
Patients randomized to comparator therapy who discontinue treatment before radiographic 
disease progression and complete a safety follow-up visit 28 (± 3) days after the last dose of 
randomized chemotherapy will continue in long-term follow-up as described below. At the time 
of radiographic disease progression, the patient may be eligible and consent to cross-over to 
treatment with rucaparib. The patient may also be ineligible or not consent to cross-over to 
rucaparib treatment and will continue in long-term follow-up. 
Patients who cross-over to rucaparib treatment will follow the procedures beginning in 
Section 9.7. These patients will have appropriate follow-up visits after discontinuation of 
cross-over rucaparib treatment. 
Patients in long-term follow-up will undergo the following assessments: 
•
If applicable, tumor assessment (using the same methodology as was used at initial study
screening [eg, CT and bone scan]) when the reason for treatment discontinuation was other
than death or disease progression based on radiographic assessment and it has been
≥ 8 weeks (≥ 12 weeks if previous scan was after 24 weeks on study) since last scan or
disease progression was noted on the last scan. Tumor assessment should continue to be
performed at the end of every 8 calendar weeks (±7 days) relative to Study Day 1 (Week 1)
up to 24 weeks, then every 12 calendar weeks (±7 days), until confirmed radiographic
disease progression by modified RECIST Version 1.1 and/or PCWG3 (for bone lesions only)
criteria, as assessed by IRR for the randomized Treatment Phase, until analysis of the
primary endpoint has been performed, and by investigator assessment for the Cross-over
Phase, loss to follow-up, withdrawal, or study closure. Once the analysis of the primary
endpoint has been performed, radiographic scans will continue to be performed by the
investigator as per the protocol schedule of assessments until radiographic disease
progression is determined by the investigator; scans will no longer be submitted to or read by
IRR.
- 
PRO assessments will also continue and coincide on days when tumor assessments are
performed until confirmed radiographic disease progression for the randomized 
Treatment Phase or the Cross-over Phase. PRO using the BPI-SF (Appendix 5), FACT-P 


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(Appendix 6), EQ-5D-5L instruments (Appendix 7), and analgesic drug score 
(Appendix 8). 
• All patients discontinued from treatment, regardless of reason, will be followed and 
information collected for subsequent treatments and survival every 12 weeks (± 14 days) 
from last dose of study drug until death, loss to follow-up, withdrawal of consent from study, 
or closure of the study. Follow-up can be performed via the telephone and can be completed 
to coincide with scheduled tumor assessments and/or PRO during this period. 
• SAEs related to study drug and AESIs are to be reported as specified in Section 10.7.  
 
9.7 
Informed Consent for Patients Who Cross-over to Rucaparib after 
Disease Progression on Comparator Treatment 
Patients who initially received comparator treatment and then cross-over to treatment with 
rucaparib after radiographic disease progression is confirmed by IRR (after the analysis of the 
primary endpoint is performed, this will change to investigator-assessed radiographic 
progression, as IRR will be discontinued) must provide additional consent to receive rucaparib 
treatment, as well as sponsor (or designee) approval. Patients who are eligible to cross-over as 
described in Section 6.4 and receive approval should receive the first dose of rucaparib within 
28-days following the scan date resulting in confirmation of radiographic progression. Ineligible 
patients will continue with a 28-day Safety Follow-up Visit and long-term follow-up as in 
Sections 9.6.2 and 9.6.3. 
Additionally, patients participating in the optional tumor tissue biopsy at the time of radiographic 
disease progression/treatment discontinuation after cross-over to rucaparib must provide 
additional consent for this procedure.  
9.8 
Screening Prior to Cross-over to Rucaparib 
Following written informed consent, and unless otherwise specified, the screening assessments 
equivalent to 28 days before study start through 14 days before study start (Section 9.4.1) will be 
performed prior to initiating treatment with rucaparib within the allowable windows of time as 
indicated. Assessments performed within the specified windows, but prior to patient signing 
informed consent, are acceptable only if confirmed to have been standard of care. Assessments 
performed at treatment discontinuation and/or at the 28-day Safety Follow-up Visit following 
discontinuation of comparator therapy may be utilized, provided they were within the allowable 
windows of time as indicated. 
Screening procedures may be repeated if the findings/results are considered invalid or not 
representative of the patient’s baseline medical status. When screening procedures are repeated, 
the rationale should be documented in the source file. 
9.8.1 
Ongoing Assessments for Cross-over Patients: 
Patients will continue with all assessments required from and including XO-Study Day 1 of the 
first dose of rucaparib through to 28-day follow-up after study drug is stopped per schedule of 
assessments, as described in Sections 9.5.1.1 to 9.5.1.5 and Sections 9.6.1 and 9.6.2 of this 
protocol. Radiographic assessments performed during the Cross-over Phase will not be submitted 


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for IRR. As described in Section 9.6.3, these patients will have appropriate follow-up visits after 
discontinuation of cross-over rucaparib treatment. 
9.9 
Methods of Data Collection 
9.9.1 
Medical History and Demographic/ Baseline Characteristics 
Basic demographic and baseline characteristics will be collected during screening. In addition to 
the evaluation of a patient’s medical history in terms of study eligibility, all relevant medical 
conditions will be documented in the appropriate eCRF. Events that occur after signing of 
informed consent but prior to initiation of study drug, unless an SAE and due to a 
protocol-mandated procedure, should be recorded in the Medical History eCRF.  
The patient’s entire oncology history will be collected in the appropriate eCRF including date of 
diagnosis for mCRPC (and other malignancy, if applicable), prior surgeries/ treatments received 
for cancer, dates of treatment administration, best response achieved, date of progression and 
how assessed, and BRCA1/BRCA2/ATM/other HRR gene mutation status (if known). 
9.10 Prior and Concomitant Medication/ Procedure Assessments 
Medications being used by the patient and surgical/ medical procedures experienced by the 
patient will be recorded as prior/ concomitant medications/ procedures during screening and as 
concomitant medications/ procedures following receipt of the first dose of study drug through the 
completion of the 28-day Safety Follow-up Visit after discontinuation of randomized treatment 
or cross-over treatment discontinuation if the patient crosses over. Medication information will 
be entered in the appropriate eCRF after it is obtained at each study visit. 
9.11 Efficacy Evaluations 
9.11.1 
Disease/ Tumor Assessments 
Radiographic tumor assessments including CT scans of the chest, abdomen & pelvis (and other 
anatomical regions as indicated) that are contrast-enhanced and have ≤ 5 mm slice thickness, as 
well as skeletal scintigraphy (whole body) using 99mTc-MDP or HDP. MRI or non-contrast CT 
may be utilized for patients intolerant to contrast. Where indicated for neurological symptoms, 
MRI of the spine and skull should be performed. Other studies, such as PET, may also be 
performed. If a site can document that the CT performed as part of a PET/CT is of identical 
diagnostic quality to a diagnostic CT (with IV and oral contrast) then the CT portion of the 
PET/CT can be used for RECIST Version 1.1 measurements. Disease assessment by CT/MRI 
and bone scans will be performed during screening, every 8 calendar weeks (± 7 days) from 
Study Day 1 up to 24 weeks and then every 12 calendar weeks (± 7 days) thereafter. If study 
drug was discontinued for reasons other than radiographic disease progression confirmed by 
IRR, tumor assessments (using the same methodology as was used at initial study screening [eg, 
CT scan]) will continue until radiographic disease progression is confirmed by IRR. Once the 
analysis of the primary endpoint has been performed, radiographic scans will continue to be 
performed by the investigator as per the protocol schedule of assessments until radiographic 
disease progression is determined by the investigator; scans will no longer be submitted to or 


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read by IRR. The sponsor will inform investigators when submission of scans for IRR should 
discontinue. If a CR or PR is noted, confirmatory scans should be performed at least 4 weeks 
after the initial response was first documented. Modified RECIST Version 1.1/PCWG3 criteria 
will be used (Appendix 1); up to five lesions in any metastatic site shall be recorded for 
extra-skeletal disease according to PCWG3. Criteria for progressive disease (PD) and 
confirmation thereof are summarized in Table 8. 
Copies of all radiographic scans during the Treatment Phase, including baseline scans and any 
scans collected in follow-up after the Treatment Phase, must be submitted for IRR. After the 
primary endpoint analysis is performed, confirmation of radiographic progression by IRR will no 
longer occur; radiographic progression and confirmation of disease progression will be 
performed by the investigator, including to assess eligibility for cross-over or consideration to 
continue treatment. Scans collected during the Cross-over Phase will not be submitted for IRR.  
Table 8. 
Requirements for Confirmation of Radiographic Disease Progression 
in Bone per Investigator’s Assessment 
Date Progression 
Detected (Visit) 
Criteria for Initial 
Progression 
Timing for Confirmation 
of Progression 
Criteria for 
Documentation of 
Disease Progression on 
Confirmatory Scan 
Week 9 
(1st on-treatment 
scan) 
Bone lesions: Two or more 
new lesions compared to 
baseline bone scan by 
PCWG3 
At least 6 weeks after 
progression identified or at 
Week 17 Visit 
Two or more new 
lesions identified at 
Week 9 must persist at 
Week 17 and two or 
more additional new 
lesions must be 
identified on Week 17 
bone scan (compared to 
Week 9 scan). 
Week 17 
(2nd on-treatment 
scan) 
Bone lesions: Two or more 
new lesions on bone scan 
compared to Week 9 bone 
scan 
At least 6 weeks after 
progression identified 
or at Week 25 Visit  
Two or more new 
lesions identified at 
Week 17 must persist at 
Week 25 bone scan.  
Week 25 or later 
(3rd on-treatment 
scan and after) 
Bone lesions: Two or more 
new lesions compared to 
Week 9 bone scan 
At least 6 weeks after 
progression identified or at 
next regularly scheduled 
radiographic assessment  
Two or more new 
lesions identified at 
Week 25 (or later) bone 
scan must persist at scan 
obtained 6 weeks later.  
Abbreviation: PCWG3 = Prostate Cancer Working Group Guidelines Version 3. 
 
9.12 Safety Evaluations 
9.12.1 
Adverse Event Assessment 
The investigator has the responsibility for assessing the safety of the patients and for compliance 
with the protocol to ensure study integrity. During the Pre-Screening Phase and Screening Phase, 


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unless otherwise required by local regulations, SAEs which are related to protocol-mandated 
assessments will be reported. Once enrolled to study drug, patients will be monitored for all 
AEs/SAEs/AESIs during study participation and until 28 days after the last dose of study drug. 
Any ongoing SAEs, AESIs, or treatment-related Grade 3/4 AEs will be followed until resolution 
or stabilization. After the 28-day window, only SAEs assessed as potentially related to study 
drug should be reported per Clovis Oncology PV requirements and captured in the Clovis 
Oncology PV database. 
After the 28-day Follow-up Visit, AESIs of MDS and AML, irrespective of causality, should 
be reported per Clovis Oncology PV requirements and captured in the Clovis Oncology PV 
database. 
• AESIs of pneumonitis or similar events (ie, interstitial lung disease, pulmonary fibrosis, 
acute interstitial pneumonitis, alveolitis necrotizing, alveolitis, hypersensitivity pneumonitis, 
and organizing pneumonia) should be reported up to, but not beyond, the 28-Day Follow-up 
Visit (28-days after the last dose of rucaparib). After the 28-day Follow-up Visit, only 
pneumonitis or similar events meeting the criteria for an SAE and assessed as potentially 
related to study drug should be reported per Clovis Oncology PV requirements. 
 
AEs and laboratory abnormalities will be graded according to the NCI CTCAE grading system 
(Version 4.03 or higher) and recorded in the eCRF. 
Complete details for monitoring AEs (inclusive of SAEs and AESIs), including the definition of 
drug-related AEs, are provided in Section 10. 
9.12.2 
Clinical Laboratory Investigations 
Samples for hematology, serum chemistry, and urinalysis will be analyzed by a local laboratory. 
The panels of laboratory tests to be performed are shown below: 
Hematology: red blood cells (RBC) and parameters (hemoglobin, hematocrit, mean corpuscular 
volume [MCV], mean corpuscular hemoglobin [MCH], and mean corpuscular hemoglobin 
concentration [MCHC]) and reticulocyte count, white blood cells (WBC) and differential (with 
ANC), and platelet count will be assessed at screening, during treatment at study visits, and at 
the Treatment Discontinuation and 28-day Follow-up Visits (including those for cross-over) for 
all patients. Hematology results must be reviewed by the investigator before the start of 
treatment with study drug and ongoing at times testing occurs. Additional and more frequent 
tests may be performed at the investigator’s discretion. 
Serum Chemistry: total protein, albumin, creatinine for estimating GFR using the 
Cockcroft-Gault formula (Appendix 3), BUN or urea, total bilirubin, alkaline phosphatase 
(ALP), ALT, AST, lactate dehydrogenase (LDH), glucose, sodium, potassium, chloride, CO2, 
calcium, phosphorus, and lipid panel (total cholesterol, low density lipoprotein [LDL], high 
density lipoprotein [HDL], and triglycerides), at screening, during treatment at study visits, and 
at the Treatment Discontinuation and 28-day Follow-up Visits (including those for cross-over) 
for all patients. Fasting is not required before blood sampling. Serum chemistry results must be 
reviewed by the investigator before the start of treatment with study drug and ongoing at times 


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testing occurs. Additional and more frequent tests may be performed at the investigator’s 
discretion. 
Urinalysis: performed locally on a freshly voided clean sample by dipstick for protein, glucose, 
blood, pH, and ketones. If dipstick findings are abnormal based on the investigator’s judgment, 
then a microscopic evaluation will be performed to assess the abnormal findings. Urinalysis will 
be performed at screening, during treatment at study visits, and at the Treatment Discontinuation 
and 28-day Follow-up Visits (including those for cross-over) for all patients, but may be 
conducted at other times as clinically indicated.  
Laboratory reports will be reviewed by the investigator or delegated physician who will then 
comment on out-of-range parameters and assess clinical significance. Clinically significant 
abnormalities and associated panel results will be documented in the eCRF as an AE; any results 
of unscheduled tests will also be recorded in the eCRF. Refer to Section 10.5 for guidelines on 
reporting of abnormal laboratory values as AEs. 
9.12.3 
Vital Signs 
Vital signs will include blood pressure, pulse, and body temperature and will be taken after the 
patient has been resting for at least 5 minutes during screening, at study visits during the 
Treatment Phase, and at the Treatment Discontinuation and 28-day Follow-up Visits (including 
those for cross-over). 
9.12.4 
12-lead Electrocardiogram 
For all patients, 12-lead ECGs will be performed at the following times: 
• Screening (within 28 days prior to randomization) 
• Treatment Discontinuation Visit 
 
The following will be measured or calculated: heart rate, pulse rate, QRS, QT, QTc, and rhythm. 
The investigator or qualified designee will review the ECGs locally and assess the results as 
normal or abnormal (clinically significant or not clinically significant). 
If it is clinically indicated, ECGs can be performed at other times during the study.  
9.12.5 
Physical Examinations, Body Weight and Height 
Physical examinations will include an assessment of all the major body systems. Complete 
physical examinations will be performed during screening and at the Treatment Discontinuation 
Visit. Physical examinations at study visits during the Treatment Phase and 28-day Follow-up 
Visit (including cross-over) will be limited as appropriate.  
Height will be measured during the screening visit only. Weight will be measured per 
institutional guidelines during screening, at study visits prior to therapy administration, and at the 
Treatment Discontinuation and 28-day Follow-up Visits (including those for cross-over). 


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9.12.6 
ECOG Performance Status 
ECOG performance status (Appendix 2) will be assessed during screening, at study visits during 
the Treatment Phase, and at the Treatment Discontinuation and 28-day Follow-up Visits 
(including cross-over). The ECOG performance status should be assessed by the same study 
personnel at each visit, if possible. For eligibility purposes, patients with borderline ECOG 
performance status should be considered carefully to avoid enrolling patients who may have 
significant impairment. 
9.13 Biomarker Analysis – FFPE Tumor Tissue 
An optional tumor biopsy obtained between the time of disease progression/randomized 
treatment discontinuation and the start of the next treatment will be obtained from consenting 
patients. The molecular profile of the progression biopsy will be compared with that from 
matched pretreatment primary or metastatic tumor tissue to identify mechanisms of resistance to 
rucaparib. Patients must provide additional consent for the optional tumor tissue biopsy sample. 
New lesions or lesions that are growing should be prioritized for the optional biopsy. If possible, 
collect the lesion responsible for progression. Detailed sample handling instructions are located 
in the Pathology Charter.  
9.14 Biomarker Analysis – ctDNA/genomic DNA from Blood 
Blood samples will be collected during Pre-Screening (for deleterious BRCA1/2 or ATM gene 
mutation assessment), Screening, before dosing on Study Day 1 and at treatment discontinuation 
from all patients entered in the study for plasma ctDNA analysis.  
Blood will be collected for pharmacogenomics analyses on Study Day 1 from all patients; this 
sample is not collected on Cross-over Study Day 1. Genomic DNA will be extracted from the 
cellular portion of this blood sample and may be analyzed to determine whether the deleterious 
BRCA1, BRCA2 or ATM gene mutation identified is germline or somatic prior to final data 
analysis. Because the germline analysis will be done near the end of the study, there are no plans 
to share these results with the investigator. However, if an actionable mutation, as defined by the 
American College of Medical Genetics and Genomics 
(https://www.ncbi.nlm.nih.gov/clinvar/docs/acmg/), is revealed that was not detected in tumor or 
plasma, these incidental findings will be made available to the investigator provided the results 
are generated from a Clinical Laboratory Improvement Amendments (CLIA)-certified 
laboratory. Sample collection details will be provided in a Laboratory Manual. 
9.15 Pharmacokinetics Evaluation 
For patients receiving rucaparib (except those in the Cross-over Phase), plasma samples are to be 
collected for trough level PK analysis of rucaparib before the morning dose on Study Day 29, 
Day 57, Day 85, and Day 113 as close to 12 hours after the previous dose as possible. If the start 
of the next dose is delayed, the PK sample should still be collected during this visit instead of on 
the delayed start of the next dose. Samples are not to be collected in patients receiving 
comparator therapy or crossing over to rucaparib. Refer to the Laboratory Manual for sample 
collection details for PK samples. 


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9.16 Patient-reported Outcomes (Health and Quality of Life 
Questionnaires) 
Patient-reported outcomes utilizing the BPI-SF (Appendix 5), FACT-P (Appendix 6), EQ-5D-5L 
(Appendix 7), and analgesic drug score (Appendix 8) instruments will be assessed during 
screening, at study treatment visits during the Treatment Phase, the Treatment Discontinuation 
Visit, and at the 28-day Safety Follow-up Visit. The analgesic drug score will be recorded 
according to the World Health Organization's (WHO’s) analgesic ladder: 0 for no analgesic, 
1 for non-opioids, 2 for opioids for moderate pain, and 3 for opioids for severe pain.47 Patients 
must complete the instruments before any other scheduled study procedures are performed and 
dosing occurs (if applicable).  
PRO assessments should be collected at every study visit for all patients through disease 
progression in association with the radiographic assessments for disease progression. For patients 
who discontinue treatment prior to radiologic disease progression, PRO assessments should be 
collected until confirmed radiologic disease progression is documented.  
10 ADVERSE EVENT MANAGEMENT 
10.1 Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a patient administered a medicinal 
product that does not necessarily have a causal relationship with this treatment. An AE can, 
therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, whether or 
not related to the investigational medicinal product. This includes an exacerbation of pre-existing 
conditions or events, intercurrent illnesses, or drug interaction that is not recorded elsewhere in 
the eCRF under specific efficacy assessments. Anticipated fluctuations of pre-existing 
conditions, including the disease under study, that do not represent a clinically significant 
exacerbation or worsening are not considered AEs.  
It is the responsibility of the investigator to monitor all AEs that occur during the study. AEs 
should be elicited by asking the patient a non-leading question (eg, “Have you experienced any 
new or changed symptoms since we last asked/since your last visit?”). The existence of an AE 
may be concluded from a spontaneous report of the patient; from the physical examination; or 
from special tests such as the ECG, laboratory assessments, or other study-specified procedure 
(source of AE). Symptoms reported spontaneously by the patient during the physical 
examination would also qualify as an AE (and hence documented in the AE eCRF, not in the 
physical examination eCRF, which is reserved for physical signs or findings). 
10.2 Definition of a Serious Adverse Event 
An SAE is any untoward medical occurrence that occurs at any dose (including after informed 
consent is given and prior to dosing if the SAE is related to a study procedure) that: 
• Results in death. Any event resulting in death during the reporting period (from date of first 
dose of investigational product through 28 days after last dose) must be treated as an SAE 


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and reported as such. An event related to a study procedure that occurs after informed 
consent, but prior to dosing, that results in death must also be reported as an SAE. This 
excludes death due to progression of patient’s underlying cancer. (refer Section 10.4) 
• Is life-threatening (patient is at immediate risk of death from the event as it occurred) 
• Requires in-patient hospitalization (formal admission to a hospital for medical reasons) or 
prolongation of existing hospitalization 
• Results in persistent or significant disability/ incapacity 
• Results in a congenital anomaly or birth defect 
• Important medical events that may not result in death, are not life-threatening, or do not 
require hospitalization may be considered SAEs when, based on appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition. Examples of such events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home or the 
development of drug dependency or drug abuse. 
 
10.3 Definition of an Adverse Event of Special Interest 
AESIs (serious or nonserious) are defined as AEs of scientific and medical concern specific to 
the sponsor’s product or program, for which ongoing monitoring and rapid communication by 
the investigator to the sponsor can be appropriate. Such an event might warrant further 
investigation in order to characterize and understand it. Depending on the nature of the event, 
rapid communication by the study sponsor to other parties (eg, regulators) might also be 
warranted. 
Details on the sponsor’s currently agreed list of AESIs for rucaparib can be found in the current 
rucaparib IB. These AESIs are to be reported to the sponsor within 24 hours of knowledge of the 
event (see Section 10.7 for reporting instructions).  
10.4 Events or Outcomes Not Qualifying as Serious Adverse Events 
The following are not considered SAEs for the purposes of this protocol, and therefore do not 
need to be reported as such: 
• Preplanned or elective hospitalization including social and/ or convenience situations 
(eg, respite care) 
• Hospital visits of less than 24 hours duration (eg, patient presents to the emergency room, but 
is not admitted to a ward)  
• Overdose of study drug or concomitant medication unless associated with an SAE. However, 
the event should still be captured as a nonserious AE in the appropriate eCRF page 
• Events of progression of the patient’s underlying cancer as well as events clearly related to 
progression of the patient’s cancer (signs and symptoms of progression) and progression of 
disease leading to death should not be reported as an AE or SAE. This section excludes other 
SAEs with fatal outcome  


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• Events that meet the SAE criteria (as outlined in Section 10.2) and occur after informed 
consent but before the first dose of study drug, which are considered unrelated to protocol-
mandated procedures 
 
10.5 Clinical Laboratory Assessments as Adverse Events and Serious 
Adverse Events 
It is the responsibility of the investigator to assess the clinical significance of all abnormal values 
as defined by the list of reference ranges from the local laboratory. In some cases, significant 
changes in lab values within the normal range will require similar judgment. 
An abnormal laboratory value that is not already associated with an AE is to be recorded as an 
AE only if any one of the following criteria is met: 
• an action on the study drug is made as a result of the abnormality 
• intervention for management of the abnormality is required 
• at the discretion of the investigator should the abnormality be deemed clinically significant 
 
10.6 Pregnancy or Drug Exposure During Pregnancy 
A pregnancy is not considered to be an AE or SAE; however, any pregnancy occurring in a 
partner of a study patient during study participation or within 3 months of last dosing must be 
reported to the sponsor using the Pregnancy Report Form within the same timelines as an SAE. 
A pregnancy will be followed through to outcome. Once the outcome of the pregnancy is known, 
the Pregnancy Outcome Report Form is to be completed and reported to the Sponsor. 
AEs, SAEs, or AESIs that occur during pregnancy will be assessed and processed according to 
the AE or SAE/AESI processes using the appropriate AE or SAE/AESI forms.  
10.7 Recording of Adverse Events, Serious Adverse Events, and Adverse 
Events of Special Interest 
Events that occur after signing of informed consent but prior to initiation of study drug, unless 
due to a protocol-mandated procedure, are to be recorded in the Medical History eCRF; however, 
events are to be reported as SAEs if serious and related to a protocol-mandated procedure during 
the Pre-Screening Phase or Screening Phase.  
Any AE that occurs after first dose of study drug through 28 days after receiving the last dose of 
study drug will be recorded in the AE eCRF.  
After the 28-day Follow-up Visit, only SAEs assessed as potentially related to study drug should 
be reported per Clovis Oncology PV requirements and captured in the Clovis Oncology PV 
database.  


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After the 28-day Follow-up Visit, AESIs of MDS and AML, irrespective of causality, should 
be reported per Clovis Oncology PV requirements and captured in the Clovis Oncology PV 
database.  
• AESIs of pneumonitis or similar events (ie, interstitial lung disease, pulmonary fibrosis, 
acute interstitial pneumonitis, alveolitis necrotizing, alveolitis, hypersensitivity pneumonitis, 
and organizing pneumonia) should be reported up to, but not beyond, the 28-day Follow-up 
Visit (ie, 28-days after the last dose of rucaparib). After the 28-day Follow-up Visit, only 
pneumonitis or similar events meeting the criteria for an SAE and assessed as potentially 
related to study drug should be reported per Clovis Oncology PV requirements. 
 
Information on the follow-up of AEs, SAEs, and AESIs is provided in Section 10.8. 
In order to avoid vague, ambiguous, or colloquial expressions, the AE should be recorded in 
standard medical terminology rather than the patient’s own words. Whenever possible, the 
investigator should combine signs and symptoms that constitute a single disease entity or 
syndrome into a final diagnosis, if appropriate. For example, fever, cough, and shortness of 
breath may be reported as pneumonia, if that is a reasonable diagnosis. 
Each AE is to be evaluated for causal relationship to the investigational drug, severity, and 
seriousness. The action taken and the outcome must also be recorded. 
SAEs and AESIs that occur during the study or within 28 days after receiving the last dose of 
study drug, whether or not related to study drug, must be reported immediately (ie, within 
24 hours of knowledge of the event or additional information for a previously-reported event) to 
the sponsor/ SAE designee. The contact information for reporting of SAEs/ AESIs can be found 
on the SAE/ AESI Reporting Form.  
10.7.1 
Onset Date of Adverse Events 
The onset date is the date that the event or the signs/symptoms attributed to the event started. 
10.7.2 
Resolution Date of Adverse Events 
The resolution date is the date that the event or the signs/symptoms attributed to the event 
resolved or resolved with sequelae or it is the date when the patient has reached a new baseline if 
the event is not expected to resolve.  
10.7.3 
Intensity of Adverse Events 
The severity of each AE will be graded using the NCI CTCAE, Version 4.03 or higher grading 
scale.48  
Severity is not the same as Serious. 
For AEs not covered by NCI CTCAE, the severity will be characterized as mild, moderate, 
severe, life-threatening, or fatal according to the following definitions: 


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• Mild events are usually asymptomatic or have mild symptoms with clinical or diagnostic 
observations only; intervention is not indicated 
• Moderate events introduce a low level of inconvenience or concern to the patient, local or 
noninvasive intervention may be indicated, and may interfere with age-appropriate daily 
activities 
• Severe events are medically significant, but not immediately life-threatening; interrupt the 
patient’s usual self-care daily activities, disabling, and hospitalization (or prolongation of 
hospitalization) is indicated 
• Life-threatening events require urgent intervention to prevent death; or 
• Fatal events are those events that lead to the patient’s death  
 
10.7.4 
Causal Relationship of Adverse Events to Study Drug 
Medical judgment should be used to determine the cause of the AE considering all relevant 
factors such as, but not limited to, the underlying study indication, coexisting disease, 
concomitant medication, relevant history, pattern of the AE, temporal relationship to the study 
medication, and dechallenge or rechallenge with the study drug.  
Not Related to 
Study Drug 
• An AE that is clearly due to extraneous causes (eg, concurrent disease, 
concomitant medications, disease under study, etc.) 
• It does not follow a reasonable temporal sequence from administration of the 
study drug 
• It does not follow a known pattern of response to study drug 
• It does not reappear or worsen when study drug is restarted, or 
• An alternative explanation is likely, but not clearly identifiable. 
 
Related to 
Study Drug 
• An AE that is difficult to assign to alternative causes. 
• It follows a strong or reasonable temporal sequence from administration of study 
drug 
• It could not be reasonably explained by the patient’s clinical state, concurrent 
disease, or other concomitant therapy administered to the patient  
• It follows a known response pattern to study drug, or 
• It is confirmed with a positive rechallenge or supporting laboratory data. 
 
 
10.7.5 
Outcome and Action Taken 
The investigator will record the action taken and outcome for each AE according to the 
following criteria: 


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Action Taken With Study Drug (check all that apply) 
• Dose not changed 
• Dose reduced 
• Study drug interrupted 
• Study drug withdrawn 
• Not applicable 
• Other action taken (check all that apply) 
- 
None 
- 
Procedure intervention 
- 
Concomitant medication taken 
- 
Transfusion given 
- 
Hospitalization 
- 
Other, (specify) 
 
Outcome 
• Recovered/Resolved 
• Recovered/Resolved with sequelae 
• Recovering/Resolving 
• Not Recovered/Resolved 
• Fatal 
• Unknown 
 
10.8 Follow-up of Adverse Events, Serious Adverse Events, and Adverse 
Events of Special Interest 
All AEs (including SAEs and AESIs) occurring during the study are to be followed up in 
accordance with good medical practice until resolved; judged no longer clinically significant; or, 
if a chronic condition, until fully characterized through 28 days after the last dose of study drug. 
Any SAEs, AESIs, and treatment-related Grade 3/4 AEs must be followed until resolution or 
stabilization, death, or until lost to follow-up. After the 28-day window, only SAEs assessed as 
potentially related to study drug, and AESIs of MDS and AML, irrespective of causality, 
should be reported.  
• AESIs of pneumonitis or similar events (ie, interstitial lung disease, pulmonary fibrosis, 
acute interstitial pneumonitis, alveolitis necrotizing, alveolitis, hypersensitivity pneumonitis, 
and organizing pneumonia) should be reported up to, but not beyond, the 28-day Follow-up 
Visit (ie, 28-days after the last dose of rucaparib). After the 28-day Follow-up Visit, only 
pneumonitis or similar events meeting the criteria for an SAE and assessed as potentially 
related to study drug should be reported per Clovis Oncology PV requirements. 
 


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10.9 Potential Drug-induced Liver Injury 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, 
meeting the defined criteria (see Section 7.5.1.1),46 must be reported as SAEs (see Section 10.7 
for reporting details). 
10.10 Regulatory Aspects of Serious Adverse Event and Adverse Events of 
Special Interest Reporting 
It is important that the investigator provide an assessment of relationship of the SAE or AESI to 
study treatment at the time of the initial report. For reporting SAEs/AESIs or pregnancies, use 
the applicable report forms. The contact information for reporting of SAEs/AESIs or pregnancies 
can be found on each of the forms.  
The sponsor or its designee is responsible for submitting reports of AEs associated with the use 
of the drug that are both serious and unexpected to the US FDA, according to 21 Code of Federal 
Regulations (CFR) 312.32; to the European regulatory authorities according to the European 
Commission Clinical Trials Directive (2001/20/EC); and to other applicable regulatory 
authorities, according to national law and/or local regulations. All investigators participating in 
ongoing clinical studies with the study medication will receive copies of these reports for prompt 
submission to their IRB or IEC. In accordance with the European Commission Clinical Trials 
Directive (2001/20/EC), the sponsor or its designee will notify the relevant ethics committees in 
concerned member states of applicable suspected unexpected serious adverse reactions 
(SUSARs) as individual notifications or through periodic line listings. 
The sponsor or its designee will submit all safety updates and periodic reports to the regulatory 
authorities as required by applicable regulatory requirements. 
11 PLANNED STATISTICAL METHODS 
11.1 General Considerations 
All efficacy analyses will be done at a two-sided 0.05 significance level, including all data from 
the randomized portion of the study.  
All safety analyses will be summarized for all patients who received at least one dose of 
protocol-specified treatment.  
Quantitative variables will typically be summarized using frequencies and percentages for 
appropriate categorizations and may also be summarized using descriptive statistics. For 
variables summarized with descriptive statistics, the following will be presented: N, mean, 
standard deviation (StD), median, minimum, and maximum. Categorical variables will be 
presented using frequencies and percentages.  
The Kaplan-Meier methodology will be used to summarize time-to-event variables. If estimable, 
the 25th, 50th (median), and 75th percentiles with the 95% CI will be summarized for each 


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randomized treatment group. The stratified HR from the Cox proportional hazards model will be 
used to estimate the HR between the randomized treatment groups for the primary endpoint.  
The number of patients with events and the number of censored patients will also be presented. 
For stratified analyses, if one or more of the strata contain few patients (eg, < 5 patients) or only 
patients from a single treatment group, or if the convergence criteria in SAS are not met, strata 
will be combined to ensure a sufficient number of patients in each stratum by first removing the 
hepatic metastases variable (which is equivalent to combining the 2 categories) and then 
combining the BRCA1/2 categories, if necessary.  
For secondary, exploratory, and subgroup analyses, statistical testing will not be stratified. 
Stratified analyses may be performed as sensitivity analyses. For time-to-event analyses the 
log-rank test will be used for treatment group comparisons. 
The primary and key secondary endpoints will be tested among the patients with a deleterious 
BRCA1/2 mutation and the ITT Population, using an ordered step-down multiple comparisons 
procedure. The primary endpoint of rPFSirr in the subgroup of patients with a deleterious 
BRCA1/2 mutation will be tested first at a two-sided 0.05 significance level. If rPFSirr in the 
subgroup of patients with a deleterious BRCA1/2 mutation is statistically significant, then 
rPFSirr will be tested in the ITT Population (see Section 11.3). Continuing in an ordered 
step-down manner, the key secondary endpoints of OS and ORR (by IRR) will be tested at the 
two-sided 0.05 significance level. Once statistical significance is not achieved for one test, 
statistical significance will not be declared for all subsequent analyses in the ordered step-down 
procedure. See Section 11.6 for details about the ordered step-down procedure. 
As a secondary endpoint of the study, trough concentrations (Cmin) of rucaparib will be 
summarized with descriptive statistics overall and by cycle in all patients with at least one PK 
sample collected. 
Further details to describe handling of missing, unused, and spurious data will be in the 
Statistical Analysis Plan (SAP). Unless otherwise specified, baseline is defined as the last 
measurement on or prior to the first day of study drug administration or randomization date, if 
the patient was never treated.  
All statistical analyses will be conducted with the SAS® System, Version 9.3 or higher. Further 
details around the statistical analyses planned in this study will be outlined in the SAP. Changes 
to or deviations from the SAP will be described in the clinical study report (CSR).  
11.2 Determination of Sample Size 
The total enrollment planned for this study is approximately 400 patients. A total of 
approximately 300 patients with a deleterious BRCA1/2 gene mutation will be randomized and 
approximately 100 patients with a deleterious ATM gene mutation may be randomized. This is a 
multicenter, multinational study. Patients will be enrolled across approximately 150 study sites 
worldwide. 
The total enrollment planned is approximately 400 patients, with approximately 300 patients in 
the subgroup with a deleterious BRCA1/2 mutation and approximately 100 patients in the 


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subgroup with a deleterious ATM mutation. The median rPFS is assumed to be 6 months for the 
control arm and 10 months for rucaparib in the subgroup of patients with a deleterious BRCA1/2 
mutation and 9 months for rucaparib in the total population. A sample size of approximately 
300 patients in the subgroup with a deleterious BRCA1/2 mutation should result in 
approximately 200 events of rPFS, which will provide approximately 90% power to detect a HR 
of 0.6 at a one-sided 0.025 significance level. A sample size of approximately 400 total patients 
should result in approximately 270 events of rPFS, which will provide approximately 90% power 
to detect a HR of 0.67 at a one-sided 0.025 significance level. 
11.3 Analysis Populations  
The following analysis populations are defined for the study: 
Safety Population – The safety population will consist of all patients who received at least one 
dose of protocol-specified treatment. 
Intent-to-Treat Population – The ITT population will consist of all randomized patients 
(ie, patients with BRCA-mutated mCRPC and patients with ATM-mutated mCRPC). 
BRCA Subgroup – The BRCA Subgroup will consist of patients in the ITT population with 
BRCA-mutated mCRPC.  
IRR Efficacy Population – The IRR efficacy population will consist of all patients evaluable for 
response by RECIST Version 1.1/PCWG3 criteria (Appendix 1) per independent radiology 
review.  
Investigator Efficacy Population – The investigator efficacy population will consist of all 
patients evaluable for response by RECIST Version 1.1/PCWG3 criteria (Appendix 1) per 
investigator.  
11.4 Patient Disposition 
Patient disposition will be summarized using frequency counts and the corresponding 
percentages. The number of patients in each analysis population, number of patients 
discontinued, and the primary reason for discontinuation will be summarized. 
11.5 Demographics and Baseline Characteristics 
All demographic (eg, age, race, and ethnicity as allowed by local regulations) and baseline 
characteristics will be summarized for the safety population. 
The following BRCA/ATM gene mutation characteristics will also be summarized:  
• BRCA1/2 or ATM gene mutation status (germline or somatic)  
• HRR gene mutation (BRCA1, BRCA2, or ATM) 
Descriptive statistics may also be used to summarize the continuous variables.  


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11.6 Step-down Procedure of Primary and Secondary Endpoints 
The primary and key secondary endpoints will first be tested in the BRCA subgroup and then in 
the ITT Population (ie, BRCA + ATM) using an ordered step-down multiple comparisons 
procedure. The primary endpoint of rPFSirr in the BRCA subgroup will be tested first at a 
two-sided 0.05 significance level. If rPFSirr in the BRCA subgroup is statistically significant, 
then rPFSirr will be tested in the ITT Population. Continuing in an ordered step-down manner, 
the key secondary endpoints will be tested at the two-sided 0.05 significance level. To preserve 
the overall Type 1 error rate, statistical significance will only be declared for a secondary 
endpoint if the primary endpoints and previous secondary endpoints are also statistically 
significant. The ordered step-down procedure is illustrated in Figure 3. 
 
 




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11.7 Efficacy Analyses 
11.7.1 
Primary Efficacy Analysis 
The primary efficacy endpoint for the study is rPFSirr, defined as the time from randomization to 
the first objective evidence of radiographic progression, or death due to any cause (whichever 
occurs first). Radiographic disease progression includes confirmed soft tissue disease 
progression and confirmed bone disease progression as per modified 
RECIST Version 1.1/PCWG3 criteria.  
The primary endpoint of rPFSirr will be analyzed using Cox proportional hazard methodology. 
The stratified HR from the Cox proportional hazards model will be used to estimate the HR 
between the randomized treatment groups.  
Assessment of rPFS by the investigator (rPFSinv) will also be conducted as a supportive analysis 
for rPFSirr. 
11.7.2 
Secondary Efficacy Analyses 
Overall survival time will be calculated as the time from randomization to death (by any cause) 
+1 day. Patients who have not died will be censored on the date the patient was last known to be 
alive. OS will be analyzed using Cox proportional hazard methodology and a log-rank test. The 
HR from the Cox proportional hazards model will be used to estimate the HR between the 
randomized treatment groups. The log-rank test will be the official test used for the hierarchical 
testing outlined in Section 11.6. OS will be analyzed at the time of the primary analysis (interim 
OS analysis) and again for a final OS analysis when maturity is reached (see Section 11.9). 
ORR is defined as the percentage of patients with a confirmed best response of CR or PR in 
patients with measurable disease at study entry. Modified RECIST Version 1.1 criteria will be 
used to determine ORR (ie, CR or PR by IRR assessment and no progression in bone per 
PCWG3 by IRR assessment). Per RECIST Version 1.1, to be assigned a best overall response of 
CR or PR, changes in tumor measurements must be confirmed by repeat assessments that should 
be performed no less than 4 weeks after the criteria for response are first met. The proportion of 
responders will be analyzed using a Cochran-Mantel-Haenszel (CMH) test. ORR will be 
analyzed separately for both IRR and investigator assessments. Only tumor scans included for 
the evaluation of the primary endpoint are considered for the ORR endpoint.  
DOR is defined as the time from the first response (modified RECIST Version 1.1 in patients 
with visceral/nodal disease) until the first date that PD (using the same criteria) is documented. 
DOR will be summarized and analyzed for the responders using the same methodology as 
described for the primary endpoint. DOR will be analyzed separately for both IRR and 
investigator assessments. 
Time to PSA progression is defined as the time from randomization to the date that a ≥ 25% 
increase and absolute increase of ≥ 2 ng/mL above the nadir (or baseline value for patients who 
did not have a decline in PSA) in PSA was measured. The increase must be confirmed by a 
second consecutive assessment conducted at least 3 weeks later. This endpoint will be analyzed 
in patients with both baseline and at least 1 post-baseline value using Cox proportional hazard 


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methodology. The HR from the Cox proportional hazards model will be used to estimate the HR 
between the randomized treatment groups. 
Confirmed PSA response is defined as ≥ 50% (or ≥ 90%) reduction in PSA from baseline on at 
least two assessments conducted at least 3 weeks apart. PSA response will be calculated for all 
patients with PSA values at baseline and at least one post-baseline assessment. PSA will be 
assessed by a local laboratory. 
Patient-reported outcome endpoints by FACT-P and BPI-SF will be scored according to their 
respective scoring manuals.  
Patient-reported Outcome EQ-5D-5L: Analyses of changes and/ or percent changes from 
baseline will be analyzed for each scheduled post-baseline visit and for the final visit for the 
EQ-5D-5L instrument and the EQ visual analog scale (VAS). Patients who do not have both a 
baseline measurement and at least one post-baseline measurement will not be included. At a 
given visit, the change and/or percent change from baseline will be compared between the 
randomized treatment groups using an analysis of covariance (ANCOVA) using the treatment as 
a categorical factor and baseline measurement for the parameter as a continuous covariate. 
CBR is defined as the combination of CR, PR, and SD as defined by modified 
RECIST Version 1.1 with no progression in bone per PCWG3 criteria. 
In all patients with at least one PK sample collected, the trough plasma rucaparib PK data (Cmin) 
and summary statistics (N, mean, StD, minimum, median, max, CV%) will be reported. 
11.7.3 
Exploratory Efficacy Analyses 
The endpoints for exploratory analyses are: 
• To assess concordance in BRCA1/BRCA2/ATM gene mutation status in matched 
Pre-Screening biopsy tissue, archival primary and metastatic tumor tissue and plasma ctDNA 
• To assess changes in the molecular profile over time of matched pre and post-treatment 
tumor or plasma samples 
• To evaluate LOH in metastatic disease site biopsy and archival primary and metastatic tumor 
tissue samples 
• To evaluate mechanisms of response and resistance in ctDNA and progression tumor tissue 
samples 
 
11.7.3.1 
Concordance of HRR Gene Mutation Status between Metastatic Disease 
Site Biopsy, Archival Primary and Metastatic Tumor Tissue, and Plasma 
ctDNA 
Pairwise comparisons will be performed for HRR genotyping results between centrally-assessed 
Pre-Screening biopsy tissue, archival primary and metastatic tumor tissue (where available), and 
plasma ctDNA in all combinations. 


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11.7.3.2 
 Changes in Tumor Samples and Changes in Circulating Tumor DNA 
Changes in the molecular profile over time of matched pairs of pre and post-treatment tumor 
tissue (if available) and plasma will be evaluated. Additionally, analysis of plasma ctDNA from 
serially collected blood will be performed to assess early changes in ctDNA that may associate 
with response to rucaparib, and to identify and characterize the emergence of mechanisms of 
resistance. 
11.7.3.3 
Loss of Heterozygosity 
Metastatic disease site biopsy and archival primary and metastatic tumor tissue samples, where 
available, will be analyzed and assigned a percentage loss of heterozygosity (% LOH) score. The 
concordance between % LOH in archival primary and metastatic tumor tissue and screening 
biopsy tissue will be evaluated, and the relationship between % LOH (treated as a binary 
variable) and response to rucaparib will be explored. 
11.7.3.4 
Circulating Tumor DNA in Plasma as a Molecular Marker of Efficacy 
Analysis of ctDNA from serially collected blood will be performed to assess early changes in 
plasma ctDNA that may associate with response to rucaparib, to compare longitudinal ctDNA 
profiles between rucaparib and comparator arms, and to identify and characterize the emergence 
of mechanisms of resistance to rucaparib.  
11.8 Safety Analyses 
All safety analyses will be summarized by randomization treatment group. Data form the 
cross-over period will be summarized separately. 
Safety endpoints are incidence of AEs, clinical laboratory abnormalities, and dose modifications. 
Data from all patients who receive at least one dose of study drug will be included in the safety 
analyses. AEs, clinical laboratory results, vital signs, ECG results, ECOG performance status, 
body weight, and concomitant medications/ procedures will be tabulated and summarized. 
11.8.1 
Adverse Events 
AEs will be classified using the Medical Dictionary for Drug Regulatory Activities (MedDRA) 
classification system. The severity of the toxicities will be graded according to the NCI 
CTCAE v4.03 or later. Only TEAEs will be summarized: TEAEs are defined as AEs with onset 
date on or after the date of first dose of study drug until the date of the last study drug dose plus 
28 days.  
The number and percentage of patients who experienced TEAEs for each system organ class 
(SOC) and PT will be presented. Multiple instances of the TEAE in each SOC and multiple 
occurrences of the same PT are counted only once per patient. The number and percentage of 
patients with at least one TEAE will also be summarized.  


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Separate tables will be presented as follows: 
• All TEAEs; 
• TEAEs by CTCAE grade; 
• Grade 3 or greater TEAEs; 
• Treatment-related TEAEs; 
• Serious TEAEs; 
• TEAEs with an outcome of death; 
• TEAEs leading to discontinuation of study medication; 
• TEAEs resulting in interruption/delay of study medication; and 
• TEAEs resulting in dose reduction of study medication. 
 
The incidence of TEAEs will be summarized by relationship to study drug according to the 
following categories: “treatment-related,” or “not treatment-related”. If a patient experiences 
multiple occurrences of the same AE with different relationship categories, the patient will be 
counted once, as a relationship category of treatment-related.  
If a patient experiences multiple occurrences of the same AE with different toxicity grades, the 
patient will be counted once for the maximum (most severe) toxicity grade. AEs with a missing 
toxicity grade will be presented in the summary table with a toxicity grade of “Missing.” For 
each toxicity grade, the number and percentage of patients with at least one TEAE of the given 
grade will be summarized.  
11.8.2 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations include the continuous variables for hematology, serum 
chemistry, and urinalysis. The laboratory values will generally be presented in SI units. The 
on-treatment period will be defined as the time from the first dose of study drug to 28 days after 
the last dose of study drug. Laboratory values collected during the on-treatment period will be 
included in the summary tables. The laboratory values collected after the on-treatment period 
will only be presented in the data listings.  
The summary of laboratory data will include shift tables based on CTCAE for shifts in grade 
from baseline to maximum, minimum and last value during the on-treatment period.  
Supporting laboratory data including normal ranges and abnormal laboratory flags will be 
provided using by-patient listings. Separate listings will be produced for clinically significant 
laboratory abnormalities (ie, those that meet Grade 3 or 4 criteria according to CTCAE). 
11.8.3 
Vital Sign Measurements 
The on-treatment period will be defined as the time from the first dose of study drug to 28 days 
after the last dose of study drug. Vital sign measurements collected during the on-treatment 
period will be included in the summary tables. The vital sign measurements collected after the 
on-treatment period will only be presented in the data listings.  


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The summary of vital sign data will include descriptive statistics (N, mean, StD, minimum, 
median, third quartile, and maximum) of the maximum, minimum and last value during the 
on-treatment period. Summaries using descriptive statistics (N, mean, StD, minimum, median 
and maximum) of the change from baseline to the maximum, minimum, and last value during the 
on-treatment period will also be given.  
11.9 Interim Analysis 
Other than the analysis of OS described below, no formal interim efficacy analyses are planned; 
however, ongoing review of data by the IDMC will occur. 
OS will be analyzed at the time of the primary analysis (interim OS analysis) and again for a 
final analysis when maturity is reached. It is anticipated that the data for OS will be heavily 
censored at the time of the primary endpoint analysis. To adjust for multiple analyses of OS at a 
later stage, a stopping rule will be applied. The Haybittle-Peto49, 50 stopping rule will be applied 
where any interim (early) OS with a p-value < 0.001 can be used to claim superiority. This 
means that a two-sided p-value very close to 0.05 can still be utilized at the final analysis which 
is projected to be once approximately 70% of the death events has been collected. 
12 PATIENT DISPOSITION 
12.1 Removal of Patients from the Study or Study Drug 
A patient must be discontinued from protocol-prescribed therapy if any of the following apply: 
• Consent withdrawal for any reason at the patient’s own request or at the request of their 
legally authorized representative; 
• Radiographic progression of patient’s underlying cancer per modified 
RECIST Version 1.1/PCWG3 (unless, in the opinion of the investigator, the patient continues 
to derive clinical benefit); 
• Unequivocal clinical progression of the patient’s underlying cancer that in the opinion of the 
investigator requires immediate change in systemic anticancer therapy, or results in marked 
deterioration in ECOG performance status to Grade 3 or higher (adapted from Ryan et al, 
2017);51 
• Any event, adverse or otherwise, that, in the opinion of the investigator, would pose an 
unacceptable safety risk to the patient; 
• An intercurrent illness that, in the opinion of the investigator, would affect assessments of the 
clinical status to a significant degree and requires discontinuation of therapy; or  
• Noncompliance by the patient with protocol-mandated procedures 
 
Discontinuation of treatment does not necessarily indicate study discontinuation for a patient. 
Samples collected for research will continue to be used unless the patient explicitly withdraws 
consent for their use. If the patient withdraws consent to continue in the study or discontinues the 
study for another reason it will be documented in the appropriate eCRF. A patient may withdraw 


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consent to participate in an additional part of a study that has an additional consent (ie, optional 
tumor biopsy) yet continue to participate and be treated/ followed in the main part of the study.  
The sponsor may discontinue the study early for any of the reasons noted in Section 13.7. 
13 STUDY ADMINISTRATION 
13.1 Regulatory and Ethical Considerations 
13.1.1 
Good Clinical Practice 
This study will be conducted in accordance with the protocol and applicable standard operating 
procedures (SOPs); and in compliance with applicable regulations and guidelines including: 
• International Council for Harmonisation (ICH) E6 (R2);  
• The Code of Federal Regulations (21 CFR Parts 11, 50, 54, 56, and 312);  
• European Union (EU) Directives 2001/20/EC, 2003/94/EC, 2005/28/EC, 536/2014 and 
• All applicable local requirements, including the principles of the Declaration of Helsinki. 
 
The investigator will assure that no amendments to the protocol will take place without prior 
agreement from the sponsor and documented approval from the IRB/IEC, and local health 
authority (where applicable), except where necessary to eliminate an immediate hazard(s) to the 
study participants. 
Significant noncompliance with the protocol, SOPs, Good Clinical Practice (GCP), and/or 
applicable regulatory requirement(s) by an investigator/institution, or by member(s) of the 
sponsor staff or its representatives will lead to prompt action by the sponsor to secure 
compliance. If monitoring and/or auditing identifies serious noncompliance on the part of an 
investigator/institution, the sponsor will take steps to secure compliance or terminate the 
investigator's/institution’s participation in the study. When an investigator's/institution’s 
participation is terminated because of significant noncompliance, the sponsor will promptly 
notify the regulatory authority(ies) and other appropriate parties (eg, IEC/IRB). 
All potential serious breaches of GCP must be reported to the sponsor or designee within 
24 hours. A serious breach is a breach of the conditions and principles of GCP in connection 
with the study or the protocol, which is likely to affect, to a significant degree, the safety or 
physical or mental integrity of the participants of the study or the scientific value of the study. 
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks. 
This study will not use the services of study site personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (eg, loss of medical licensure or debarment).  


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13.1.2 
Regulatory Authority Approvals 
The sponsor or designee will submit the study protocol plus all relevant study documents to 
applicable regulatory agencies for approval prior to the study start. No patient will begin the 
study-specific pre-screening or screening until appropriate regulatory approval of the study 
protocol has been received. 
Each investigator must complete a Form FDA 1572 (or equivalent, when participating in a US 
Investigational New Drug Application [IND] study). In addition, local statement of investigator 
documents must be provided where required. Each investigator must submit to the sponsor (or 
designee) financial disclosure information for studies under a US IND or if required by national 
law and/or local regulations. 
The study will be registered on regionally-relevant registries, including www.clinicaltrials.gov, 
EudraCT, and other applicable clinical study registry systems as appropriate. Data generated 
from this study must be handled in accordance with any laws, rules, and regulations related to the 
privacy of personal data or personal health information applicable in the jurisdiction where the 
data are processed, including without limitation, the US Health Information Portability and 
Accountability Act of 1996 (HIPAA), and it implementing regulations, and the EU General Data 
Protection Regulation 2016/679 (GDPR). 
13.1.3 
Institutional Review Board or Independent Ethics Committee Approval 
This protocol, all protocol amendments, and any material to be provided to the patient (such as 
the ICF, advertisements, patient information sheets (PIS), or descriptions of the study used to 
obtain informed consent) must be reviewed and approved by the IEC/ IRB before study start, 
according to national law and/or local regulations. There must be proof of submission of the IB 
to the IRB/IEC. The sponsor will supply relevant information to the investigator to submit the 
study protocol and additional study documents to the IEC/ IRB.  
Verification of the IEC’s/ IRB’s approval of the study protocol and the written ICF will be 
transmitted to the sponsor by the investigator or by other means as determined between the 
investigator and the sponsor.  
No patient will begin the study-specific prescreening or screening until appropriate IEC/ IRB 
approval of the study protocol and ICF/PIS have been received and the investigator has obtained 
the patient’s legally-effective ICF/PIS.  
The investigator will submit appropriate reports on the progress of the study to the IEC/ IRB at 
least annually in accordance with applicable national law and/ or local regulations and in 
agreement with the policy established by the IEC/ IRB.  
The IEC/ IRB must be informed by the investigator of all subsequent protocol amendments and 
of all SAEs or SUSARs occurring during the study that are likely to affect the safety of the 
patients or the conduct of the study, according to institutional policies.  


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13.2 Patient Information and Consent 
13.2.1 
General Aspects of Informed Consent 
All information about the clinical study, including the patient information and the ICF, is 
prepared and used for the protection of the human rights of the patient according to ICH GCP 
guidelines, the Declaration of Helsinki, and local requirements. 
The ICF(s), prepared by the investigator with the assistance of the sponsor, must comply with all 
applicable regulations, be approved along with the study protocol by the IEC/IRB and be 
acceptable to the sponsor.  
It is the responsibility of the investigator to obtain legally-effective informed consent from each 
patient participating in this study after adequate explanation of the aims, methods, objectives, 
and potential hazards of the study, answering all questions from the patients regarding the study, 
and prior to undertaking any study-related procedures.  
13.2.2 
Informed Consent Process 
The patient must be provided with the patient information, if applicable, and the most current 
IEC/IRB-approved ICF. The investigator or their designee shall discuss with each patient the 
nature of the study, its requirements, and that participation is voluntary and may be terminated at 
any time by the investigator or participant. To participate in the study, informed consent must be 
obtained from each prospective patient prior to any protocol-specific activities.  
The ICF must be in language fully comprehensible to the prospective patient. Patients or 
legally-authorized representatives (where acceptable according to national law and/or local 
regulations) must be given sufficient time and opportunity to inquire about the details of the 
study and to discuss and decide on their participation in the study with the investigator. The 
patient and the person conducting the informed consent discussion for the study will personally 
sign and date the ICF in addition to any other required signature (if applicable). A copy of the 
signed ICF will be retained by the patient or legally-authorized representative and the original 
ICF will be filed in the investigator file. The process of obtaining informed consent will be 
documented in the patient’s source documents. The date when a patient’s informed consent was 
obtained will be captured in the patient’s source documents and eCRF. The patient will need to 
re-consent if the ICF is updated during the study, such as after an amendment to the protocol, if 
mandated by the IEC/IRB.  
The ICF will contain a separate section that addresses the use of remaining mandatory or 
optional samples for optional exploratory research. The investigator or authorized designee will 
explain to each study patient the objectives of the exploratory research. Patients will be told that 
they are free to refuse to participate and may withdraw their consent at any time and for any 
reason during the storage period. A separate consent will be required to document a patient's 
agreement to allow any remaining specimens to be used for exploratory research. 


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13.3 Patient Confidentiality 
The investigator must assure that patients’ anonymity is strictly maintained and that their 
identities are protected from unauthorized parties. Only identification codes (ie, no names or, in 
some regions, initials or date of birth) according to country regulations will be recorded on any 
form submitted to the sponsor and the IEC/IRB. The investigator must maintain a list with the 
identity of all study participants, but not intended for use by the sponsor.  
The investigator further agrees to take all reasonable precautions to prevent the disclosure of 
confidential patient information to any unauthorized party or into the public domain. The 
investigator will notify Clovis Oncology 
 within 24 hours of a 
security event that impacts or has the potential to impact the confidentiality, integrity, or 
availability of patient study data. 
13.4 Study Monitoring 
The sponsor, or contract research organization (CRO) or contract monitor acting on the sponsor’s 
behalf, will contact or visit the investigator at the study center prior to the entry of the first 
patient (unless the sponsor or the CRO has worked with the center recently in the same or 
comparable indication, the site location and facilities have not changed significantly since after 
the last visit by the sponsor or CRO, and the potential investigator/site are currently in good 
standing with respect to regulatory compliance, in which case this initial visit maybe waived) 
and at appropriate intervals during the study until after the last patient is completed.  
In accordance with ICH GCP guidelines, and local regulations, the clinical monitor will 
periodically review, via direct access, eCRFs, study documents, and medical records (office, 
clinic, or hospital) for patients enrolled in this study. Monitors will not share patient identifiers 
with the sponsor. Additionally, the clinical monitor will review and assess research facilities, and 
clinical laboratory facilities associated with the study. Clinical monitoring will be scheduled to 
occur at mutually convenient times until completion of the study. If these requirements are in 
conflict with local regulatory restrictions or institutional requirements, the investigator must 
inform the sponsor of these restrictions before initiation of the study. 
Where applicable, if the sponsor or their representatives are not able to come to the study center, 
patient study data may be reviewed by them remotely, in conformity with the applicable 
institutional guidance and local regulations. The site staff may place relevant medical records, 
with personal identifiers removed, into a secure computer system for the sponsor or their 
representative to view, allow them to view these records during a video conference, and/or 
provide them direct access to patient’s electronic medical records. This review would occur in a 
manner that protects the confidentiality of study patient data. Whether a patient’s medical 
records are reviewed at the study center or remotely, their identity and medical records will be 
kept secure during this process. Remote review of patient study data should not be carried out if 
adequate data protection, including data security and protection of personal data even if 
pseudonymized, is not ensured. Further details will be provided in the study training materials 
and/or the clinical monitoring plan. 


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The investigator must ensure provision of sufficient time, reasonable space, and adequate 
qualified personnel for the monitoring visits. The purpose of these visits is to allow the clinical 
monitor an opportunity to verify adherence to the study protocol and assess the completeness, 
consistency, and accuracy of data entered in the eCRFs and other documents; however, the 
investigator retains ultimate responsibility for the quality and integrity of data generated by the 
site. The clinical monitor will confirm all aspects of the study that are essential for human patient 
protection and safety as well as those related to the validity and the reliability of study data.  
The investigator will make all source data (ie, the various study records, laboratory test reports, 
other patient records, drug accountability forms, and other pertinent data) and eCRFs for the 
entire study period available for the monitor. Monitoring is done by comparing study patients’ 
relevant source data that is maintained in site records with the information entered on the eCRFs 
(ie, source data verification and review).  
By agreeing to participate in the study, the investigator agrees to cooperate with the monitor to 
ensure that any problems detected in the course of the monitoring visits are resolved. Contact 
information for the study monitor is located in the investigator file. Representatives from the 
sponsor may also contact and visit the investigators and monitor data during the study. 
13.5 Case Report Forms and Study Data 
The data will be collected using an electronic data capture (EDC) system by remote data entry on 
eCRFs. Sites will receive training on the EDC system. All users will be supplied with unique 
login credentials.  
Data collection is the responsibility of the clinical study staff at the site under the supervision of 
the site investigator. The investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. All source documents will be completed in a neat, 
legible manner, according to the principles of Attributable, Legible, Contemporaneous, Original 
or Certified Copy, Accurate, and ‘Plus’ (+) Complete, Consistent, Enduring, and Available 
(ALCOA+), to ensure accurate interpretation of data. Data recorded in the eCRF should be 
consistent with the data recorded on the source documents.  
Prior to study start, the investigator will prepare a list showing the signature, handwritten initials, 
delegated tasks, and dates of delegations for all individuals delegated responsibility on this study. 
This “study site personnel and delegation list” must be kept current throughout the study. 
Clinical data and clinical laboratory data will be entered into a 21 CFR Part 11-compliant 
EDC system. The data system includes password protection and internal quality checks, such as 
automatic range checks, to identify data that appear inconsistent, incomplete, or inaccurate. If a 
patient withdraws from the study, the reason must be noted in the source documents and eCRF. 
If a patient is withdrawn from the study because of a treatment-limiting AE, thorough efforts will 
be made to clearly document the outcome.  
Laboratory data and investigator observations on the results and any other clinically significant 
test results are to be documented in the source documents and entered into applicable eCRFs. 


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Full information regarding EDC and completing eCRFs is included in the investigator files. All 
questions or comments related to EDC should be directed to the assigned monitor. 
Clinical data will be entered directly into the eCRFs from the source documents for all 
participants who are enrolled. 
13.6 Independent Data Monitoring Committee 
An IDMC will be established to review safety and efficacy data in compliance with a prospective 
charter. The IDMC will be comprised of medical oncologists with experience in treating patients 
with the cancer being studied and a statistician, all of whom are not otherwise involved in the 
study as investigators. The IDMC responsibilities, authorities, and procedures for this study will 
be documented in the IDMC charter, which will be endorsed and signed by the IDMC members 
prior to the first data review meeting. 
The IDMC will meet at least semi-annually after sufficient data has been collected. The IDMC 
chairperson may convene a formal IDMC meeting if there are safety concerns. The sponsor can 
also request an IDMC review of safety data. Details regarding the IDMC will be in the 
committee charter.  
13.7 Study Termination and Site Closure 
The sponsor, the investigator/institution, or IEC/IRB reserve the right to terminate the study at 
any time. Should this be necessary, the sponsor and investigator will arrange discontinuation 
procedures. In terminating the study, the sponsor and the investigator will assure that adequate 
consideration is given to the protection of the patients’ interests. If the trial is terminated 
prematurely, the sponsor will promptly inform the investigators/institutions, and the regulatory 
authority(ies) of the termination or suspension and the reason(s) for the termination or 
suspension. The investigators will promptly inform their IRB/IEC, providing the reason(s) for 
the termination or suspension by the sponsor or by the investigator/institution, as specified by the 
applicable regulatory requirement(s).  
The sponsor reserves the right to terminate the study at any time for medical or administrative 
reasons. When feasible, a 30-day written notification will be given. 
The entire study will be stopped if: 
• The protocol-specified treatment is considered too toxic to continue the study; 
• Evidence has emerged that, in the opinion of the sponsor or the investigator(s), makes the 
continuation of the study unnecessary or unethical; 
• The stated objectives of the study are achieved; or 
• The sponsor discontinues the development of rucaparib. 
 


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Regardless of the reason for termination, all data available for the patient at the time of 
discontinuation of follow-up must be recorded in the source documents and on the eCRF. All 
reasons for discontinuation of treatment must be documented.  
13.8 Study Protocol Amendments 
Protocol amendments must be made only with the prior approval of the sponsor. Agreement 
from the investigator must be obtained for all protocol modifications and changes to the 
informed consent document. The IEC/ IRB must be informed of all amendments and give 
approval prior to their implementation. The sponsor will submit any study protocol amendments 
to the concerned regulatory authorities (as required) for approval and keep the investigator(s) 
updated as detailed in the ICH GCP guidelines. Managing protocol deviations is described in 
Section 13.10.1.  
13.9 Retention of Study Documents 
The study site will maintain a study file, which will contain all documents defined in the 
ICH E6(R2) Guideline for Good Clinical Practice. The investigator will have control of all 
essential documents generated by the site. Source documents must be maintained and ALCOA+ 
documentation practice used. Any changes to source data will be traceable, will not obscure the 
original entry, and will be explained if necessary (via an audit trail). The investigator must 
implement procedures to ensure the integrity of any data generated.  
The sponsor and investigator will maintain a record of the location(s) of their respective essential 
documents including source documents. The storage systems used during the study and for 
archiving (irrespective of media used) must provide for documentation identification, version, 
history, search, and retrieval. The investigator agrees to keep records and those documents that 
include (but are not limited to) the identification of all participating patients, medical records, 
study-specific source documents, source worksheets, all original signed and dated informed 
consent forms, copies of all eCRFs, query responses, and detailed records of drug disposition to 
enable inspections or audits from regulatory authorities, the IEC/IRB, and the sponsor or its 
designees.  
The investigator shall retain records and documents, including signed ICFs, pertaining to the 
conduct of the study for a period of 25 years after study completion or, if no application is to be 
filed or if the application is not approved for such indication, until at least 5 years after the 
investigation is discontinued. However, these documents will be retained for a longer period of 
time if required by the applicable regulatory requirement(s), institutional policies, or if needed by 
the sponsor. In addition, the investigator must make provision for the patients’ medical records to 
be kept for the same period of time. 
No data shall be destroyed without the agreement of the sponsor. Copies of original documents 
will fulfill the requirements for certified copies. Should the investigator wish to assign the study 
records to another party or move them to another location, the sponsor must be notified in 
writing of the new responsible person and/or the new location. The sponsor will inform the 
investigator, in writing, when the study-related records are no longer needed. 


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All clinical study information will be recorded, handled, and stored in a way that allows accurate 
reporting, interpretation, and verification, irrespective of the media used.  
Patients’ medical records and other original data will be archived in accordance with the 
archiving regulations or facilities of the investigational site; but at a minimum, for the period 
defined by the applicable regulatory requirements. 
13.10 Quality Control and Assurance 
The sponsor will implement and maintain quality control and quality assurance procedures with 
written SOPs to ensure that the study is conducted, and data are generated, documented, and 
reported in compliance with the protocol, GCP, and applicable regulatory requirements.  
13.10.1 Protocol Deviations 
The investigator may not deviate from the protocol unless necessary to eliminate immediate 
hazards to the patient. A deviation may result in the subject having to be withdrawn from the 
study which could potentially render that patient’s data nonevaluable. Any deviation must be 
documented in the source documents and reported to the sponsor.  
13.10.2 Study Site Training 
Each investigator and the site personnel for this study will be trained by the sponsor and/ or a 
designee (ie, a CRO) on GCP and on the design, conduct, procedures, and administrative aspects 
of this study. This training may include, but is not limited to, on-site training, Investigator 
Meeting(s), and/ or tele/ videoconferencing. Training may be ongoing as refresher, to address 
specific items, or to introduce changes in the study. When site staff join after study training has 
been conducted, the investigator is responsible for ensuring that the new staff member is trained. 
13.10.3 Quality Assurance Audits and Inspections 
An audit of a clinical center may be conducted by a quality assurance auditor appointed by the 
sponsor. The purpose of an audit, which is independent of and separate from routine monitoring 
or quality control functions, is to evaluate study conduct and compliance with the protocol, 
SOPs, ICH GCPs, and the applicable regulatory requirements. The investigator will be informed 
if an audit is to take place and advised as to the scope of the audit. IRB/IEC representatives may 
also conduct an audit of the study at any time. 
Representatives of the FDA, European Medicines Agency (EMA), or other regulatory agencies 
may conduct an inspection of the study at any time. If informed of such an inspection, the 
investigator will notify the sponsor immediately. 
13.10.4 Direct Access to Source Data/ Documents for Audits and Inspections 
The investigator will ensure that the auditors or inspectors have access to the clinical supplies, 
study site facilities, and laboratory, and that all data (including original source documentation) 
and all study files and audit trails are available, if requested. It is important that the 


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investigator(s) and their staff cooperate with the quality assurance auditor or regulatory authority 
inspector during an audit or inspection. 
13.11 Clinical Study Report 
A clinical study report will be prepared under the responsibility and supervision of the sponsor 
and signed by the sponsor’s Chief Medical Officer, Head of Biostatistics, and Head of 
Regulatory Affairs; thereby indicating their agreement with the analyses, results, and conclusions 
of the CSR. The CSR will be provided to the clinical investigator(s) and regulatory agency(ies) 
as required by the applicable regulatory requirements.  
13.12 Publication and Disclosure Policy 
All information for the study provided by the sponsor or designee to the investigator, including, 
but not limited to, the IB, this protocol, eCRFs, the protocol-specified treatment, and any other 
study information, will remain the sole and exclusive property of the sponsor during the conduct 
of the study and thereafter. This information is not to be disclosed to any third party (except 
employees or agents directly involved in the conduct of the study or as required by law) without 
the prior written consent of the sponsor. The investigator further agrees to take all reasonable 
precautions to prevent the disclosure of this information by any employee or agent of the study 
center to any third party or into the public domain. 
All data generated from this study will be maintained by the sponsor. All data generated from 
this study, and all information furnished by the sponsor, the investigators, and other participating 
study groups shall be held in strict confidence. Independent analysis and/or publication of study 
data by the investigator(s) or any member of their staff are not permitted without the prior 
written consent of the sponsor. Any collaborative publications will be authored in accordance 
with the applicable guidelines (eg, International Committee of Medical Journal Editors 
[ICMJE]).52 Written permission to the investigator will be contingent on the review of the 
statistical analysis and manuscript/abstract by the sponsor and participating cooperative groups, 
and will provide for nondisclosure of the confidential or proprietary information. 
In all cases, the parties agree to provide all manuscripts or abstracts to all other parties 60 days 
prior to submission. This will enable all parties to protect proprietary information and to provide 
comments based on information that may not yet be available to other parties.  
13.13 Investigator Oversight 
The investigator has full responsibility for supervising any individual or party to whom they 
delegate study-related duties and functions conducted at the study site, including satellite 
locations. The responsibility for supervision includes the services of any party or individual 
retained by the investigator for this purpose, regardless of location. All staff delegated study 
responsibilities must be documented on an approved Delegation of Authority log for the study 
and this filed with the essential documents. In addition, the investigator must ensure that 
delegated staff are qualified by training, experience and licensure (as applicable). The 
investigator should implement procedures to ensure integrity of the study and data generated.  


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33. Audeh MW, Carmichael J, Penson RT, Friedlander M, Powell B, Bell-McGuinn KM, et al. 
Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 
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35. Gelmon KA, Tischkowitz M, Mackay H, Swenerton K, Robidoux A, Tonkin K, et al. 
Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian 
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randomised study. Lancet Oncol. 2011;12(9):852-61. 
36. Kaye SB, Lubinski J, Matulonis U, Ang JE, Gourley C, Karlan BY, et al. Phase II, Open-
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Maintenance Therapy in Platinum-Sensitive Relapsed Ovarian Cancer. N Engl J Med. 2012. 
38. Sandhu SK, Schelman WR, Wilding G, Moreno V, Baird RD, Miranda S, et al. The 
poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and 
patients with sporadic cancer: a phase 1 dose-escalation trial. Lancet Oncol. 2013;14(9):882-
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39. De Bono JS, Mina LA, Gonzalez M, Curtin NJ, Wang E, Henshaw JW, et al. First-in-human 
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41. Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, et al. Inhibition of 
poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 
2009;361(2):123-34. 
42. Sandhu SK, Schelman WR, Wilding G, Moreno V, Baird RD, Miranda S, et al. The 
poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and 
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43. Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, et 
al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 
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44. Halabi S, Lin CY, Kelly WK, Fizazi KS, Moul JW, Kaplan EB, et al. Updated prognostic 
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45. Halabi S, Kelly WK, Ma H, Zhou H, Solomon NC, Fizazi K, et al. Meta-Analysis Evaluating 
the Impact of Site of Metastasis on Overall Survival in Men With Castration-Resistant 
Prostate Cancer. J Clin Oncol. 2016;34(14):1652-9. 
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51. Ryan CJ, Kheoh T, Scher HI, De Porre P, Yu MK, Morris MJ. Clinical versus radiographic 
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52. International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing, and Publication of Scholarly Work in Medical Journals December 2017 
[Available from: http://www.icmje.org/recommendations/. 
53. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J 
Cancer. 2009;45(2):228-47. 
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15 APPENDICES 
Appendix 1 Modified Response Evaluation Criteria in Solid Tumors Criteria (Version 1.1) and 
Prostate Cancer Working Group 3 Criteria 
Appendix 2 Eastern Cooperative Oncology Group (ECOG) Performance Status Scale 
Appendix 3 Cockcroft-Gault Formula 
Appendix 4 Examples of CYP Substrates with Narrow Therapeutic Range 
Appendix 5 Brief Pain Inventory – Short Form (BPI-SF) 
Appendix 6 Functional Assessment of Cancer Therapy – Prostate (FACT P) 
Appendix 7 Euro-Quality of Life 5D 5L (EQ-5D-5L) Patient Reported Outcome 
Appendix 8 Analgesic Use Questionnaire 


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15.1 Appendix 1 - Modified Response Evaluation Criteria in Solid Tumors 
Criteria (Version 1.1) and Prostate Cancer Working Group 3 Criteria 
The RECIST guidelines (Version 1.1) are described in Eisenhauer et al. 200953 at 
http://www.eortc.be/Recist/Default.htm and PCWG3 criteria as described by Scher, et al. 2016.25 
A short summary is given below. 
Measurable Disease: 
Tumor lesions: measurable lesions are defined as those that can be accurately measured in at 
least one dimension (longest diameter to be recorded) with the following: 
− A minimum size of 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
− A minimum size of 10 mm caliper measurement by clinical exam (lesions that cannot be 
accurately measured with calipers should be recorded as nonmeasurable) 
− A minimum size of 20 mm by chest X-ray 
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be not greater than 5 mm). At baseline and in follow-up, only the short axis will 
be measured and followed.  
Nonmeasurable Disease: 
All other lesions (or sites of disease), including small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥ 10 to < 15 mm short axis), as well as truly nonmeasurable 
lesions, are considered nonmeasurable disease. Lesions considered truly nonmeasurable include 
leptomeningeal disease, ascites, pleural/pericardial effusions, inflammatory breast disease, 
lymphangitic involvement of skin and lung, and abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques.  
Bone Lesions 
For the purposes of this study, bone metastatic lesions should be recorded at baseline and 
followed during treatment using PCWG3 criteria. Bone lesions should not be recorded as target 
or nontarget lesions to be followed by RECIST Version 1.1 criteria; this includes bone lesions 
with a soft tissue component and soft tissue lesions extending from a bone lesion.  
Lesions with Prior Local Treatment 
Tumor lesions situated in a previous irradiated area or in an area subjected to other locoregional 
therapy are usually not considered measurable unless there has been demonstrated progression in 
the lesion. 


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Target Lesions 
All measurable lesions up to a maximum of 5 lesions per organ (per PCWG3), representative of 
all involved organs, should be identified as target lesions and recorded and measured at baseline. 
A maximum of 10 target lesions total should be selected on the basis of their size (lesions with 
the longest diameter) and their suitability for accurate repeated measurements (either by imaging 
techniques or clinically). A sum of the longest diameter (LD) for all target lesions will be 
calculated and reported as the baseline sum LD. The baseline sum LD will be used as reference 
by which to characterize the objective tumor response.  
Prostate and prostatic bed lesions should NOT be selected as target lesions, according to PCWG3 
criteria. 
Nontarget Lesions 
RECIST Version 1.1 criteria require unequivocal quantification of the changes in tumor size for 
adequate interpretation of the sum of target lesions. Consequently, when the boundaries of the 
primary are difficult to delineate, this tumor should not be considered a target lesion. A 
maximum of 10 target lesions total should be selected. 
Guidelines for Evaluation of Measurable Disease 
CT and MRI are the best currently available and reproducible methods to measure target lesions 
selected for response assessment. Conventional CT and MRI should be performed with cuts of 
5 mm or less in slice thickness contiguously. Spiral CT should be performed using a ≤ 5 mm 
contiguous reconstruction algorithm. If a site can document that the CT performed as part of a 
PET/CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast) then the 
CT portion of the PET/CT can be used for RECIST Version 1.1 measurements. 
Lesions on chest X-ray are acceptable as measurable lesions when they are clearly defined and 
surrounded by aerated lung. However, CT is preferable.  
Ultrasound, endoscopy and laparoscopy should not be used to measure tumor lesions. 
Cytology and histology can be used to differentiate between PR and CR in rare cases (eg, after 
treatment to differentiate between residual benign lesions and residual malignant lesions. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess the 
antitumor effect of a treatment. 


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Evaluation of Target Lesions 
Complete Response 
Disappearance of all target lesions. Any pathological lymph nodes (whether 
target or nontarget) must have reduction in short axis to < 10 mm. 
Partial Response 
At least a 30% decrease in the sum of the LD of target lesions, taking as 
reference the baseline sum LD. 
Stable Disease 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum LD since the treatment started. 
Progressive Disease 
At least a 20% increase in the sum of the LD of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm. The appearance of one 
or more new extra-skeletal lesions is also considered progression. For bone 
lesions, refer to PCWG3 criteria for determining progressive disease. 
 
Evaluation of Nontarget Lesions 
Complete Response 
Disappearance of all nontarget lesions. 
Stable 
Disease/Incomplete 
Response 
Persistence of one or more nontarget lesion(s). 
Progressive Disease 
Appearance of one or more new extra-skeletal lesions and/or unequivocal 
progression of existing nontarget lesions. For bone lesions, refer to PCWG3 
criteria for determining progressive disease. 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started). The patient’s best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 


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Evaluation of Best Overall Response: Patients with Target (+/- Non-Target) Disease 
 
Target Lesions 
Nontarget Lesions 
New Lesionsa 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not evaluated 
No 
PR 
SD 
Non-PD or not evaluated 
No 
SD 
Not Evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
a 
New bone metastatic lesions should not be considered as a ‘Yes’ response; only new extra-skeletal lesions. 
 
Evaluation of Best Overall Response: Patients with Non-Target Disease Only 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PDa 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
a 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as 
endpoint for assessment of efﬁcacy in some studies so to assign this category when no lesions can be 
measured is not advised. 
 
Patients with global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be classified as having symptomatic 
deterioration. Every effort should be made to document the objective progression, even after 
discontinuation of treatment. 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When evaluation of CR depends on this determination, it is recommended that the residual lesion 
be investigated (fine needle aspiration/biopsy) prior to confirming the complete response status.  
Confirmation 
If an initial CR or PR is noted, confirmatory scans must be performed at least 4 weeks later.  
Duration of Response (DOR) 
CT scans are required for this study at screening and every 8 calendar weeks (within 7 days 
before or after is permitted) thereafter. Patients who have been on study at least 24 weeks, may 


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decrease the frequency of disease/ tumor assessments to every 12 calendar weeks (within 7 days 
before or after is permitted).  
Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are met for CR 
or PR (whichever is first recorded) until the first date that recurrent or PD is objectively 
documented (taking as reference for PD the smallest measurements recorded since the treatment 
started), including progression in bone per PCWG3 criteria. 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 
Duration of Stable Disease 
SD is measured from the start of the treatment until the criteria for progression are met, taking as 
reference the smallest measurements recorded since the treatment started. 
PCWG3 Criteria for Assessment of Bone Disease  
PCWG3 criteria will be used to document evidence of disease progression in bone lesions as 
described by Scher, et al. 2016.25 
Imaging of Baseline Bone Disease 
The use of bone scan as the standard for bone imaging is retained in PCWG3, with the presence 
or absence of metastasis recorded first. A quantitative measure of disease burden, such as lesion 
number, the bone scan index, or lesion area, is also suggested, recognizing that these measures 
require further analytical and prospective clinical validation. Changes in lesions considered 
metastatic on bone scintigraphy should be followed and assessed serially using a bone scan 
assessment form. Areas/lesions on bone scintigraphy that are suggestive can be assessed further 
with CT or MRI and followed separately, but such supplemental imaging should not be used to 
establish indicator lesions for the purposes of a study. 
Different modalities for imaging bone metastases can provide different information for the same 
patient. However, because of the lack of standards for reporting disease presence or changes after 
treatment, PET imaging with sodium fluoride, fluorodeoxyglucose, choline, or prostate-specific 
membrane antigen, bone marrow MRI (body MRI), and other modalities that are in use to image 
bone, should be approached as new biomarkers subject to independent validation. 
Criteria for progression in bone at study entry 
• Two new lesions observed on 99mTc-MDP or HDP radionuclide bone scintigraphy 
• Confirm ambiguous results by other imaging modalities (eg, CT or MRI) however only 
positivity on the bone scan defines metastatic disease to bone 
 


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Documentation of baseline bone disease 
• Presence or absence of metastasis recorded first 
• A quantitative measure of disease burden, such as lesional number, the bone scan index, or 
lesion area, is required 
• Changes in lesions considered metastatic on bone scintigraphy should be followed and 
assessed serially using a bone scan assessment form. Areas/lesions on bone scintigraphy that 
are suggestive can be assessed further with CT or MRI and followed separately, but such 
supplemental imaging should not be used to establish indicator lesions for the purposes of a 
study 
 
Following for bone progression during the study 
• Exclude pseudoprogression in the absence of symptoms or other signs of progression 
• At least two new lesions on scans during the 12-week flare window (ie, the first post-
treatment scan), which are persistent and appear with at least two additional lesions on the 
next scan after the 12-week flare window (2+2 rule) 
• If at least two additional new lesions are seen on the next (confirmatory) scan performed 
after the 12-week flare window, the date of progression is the date of the first post-treatment 
scan, when the first two new lesions were documented 
• For scans after the 12-week flare window (ie, after the first post-treatment scan), at least two 
new lesions relative to the first post-treatment scan confirmed on a subsequent scan 
• Date of progression is the date of the scan that first documents the second lesion 
• Changes in intensity of uptake alone do not constitute either progression or regression 
 


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Controlling for Flare by Applying the 2+2 Rule using the First Post-treatment Scan as Baseline 
 
 
PCWG3 Criteria for Confirmation of Radiographic Progression in Bone by Investigator 
Assessment (to be used in conjunction with modified RECIST Version 1.1 criteria for visceral and 
nodal disease) 
Date 
Progression 
Detected  
(Visit) 
Criteria for Progression 
in Bone 
Criteria for Confirmation of Progression in 
Bone 
Week 9 
(1st on-treatment 
scan) 
Two or more new lesions on 
bone scan compared to 
baseline bone scan by 
PCWG3 
Two or more new bone lesions identified at 
Week 9 must persist at Week 17 and 2 or more 
additional new lesions must be identified on Week 
17 bone scan (compared to Week 9 scan) 
Week 17  
(2nd on-treatment 
scan) 
Two or more new 
lesions on bone scan 
compared to Week 9 
bone scan. 
Two or more new lesions identified at Week 17 
must persist at Week 25 bone scan  
Week 25 and 
after  
(3rd on-
treatment scan 
and after) 
Two or more new 
lesions bone scan 
compared to Week 9 
bone scan 
Two or more new lesions identified at Week 25 
(or later) bone scan must persist at scan obtained 
6 weeks later 
 


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15.2 Appendix 2 - Eastern Cooperative Oncology Group (ECOG) 
Performance Status Scale 
ECOG Performance Status 
0 
Fully active, able to carry on all predisease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature (eg, light house work or office work). 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours. 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 
Dead. 
 
In the event performance status is assessed by the Karnofsky Performance Status scale, the 
following conversion chart applies. 
Karnofsky Performance Status 
ECOG 
Performance 
Status 
General Description 
Score 
Specific Description 
Score 
Able to carry on 
normal activity and to 
work; no special care 
needed 
100 
Normal; no complaints; no evidence of 
disease 
0 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease 
1 
80 
Normal activity with effort; some signs or 
symptoms of disease 
Unable to work; able 
to live at home and 
care for most personal 
needs; varying amount 
of assistance needed 
70 
Cares for self, unable to carry on normal 
activity or to do active work 
2 
60 
Requires occasional assistance, but is able 
to care for most of personal needs 
50 
Requires considerable assistance and 
frequent medical care 
3 
Unable to care for self; 
requires equivalent of 
institutional or 
hospital care; disease 
may be progressing 
rapidly 
40 
Disabled; requires special care and 
assistance 
30 
Severely disabled; hospital admission is 
indicated although death not imminent 
4 
20 
Very sick; hospital admission necessary; 
active supportive treatment necessary 
10 
Moribund; fatal processes progressing 
rapidly 
0 
Dead 
5 
 
 




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15.4 Appendix 4 - Examples of Sensitive CYP Substrates (not an inclusive 
list) 
Examples of CYP Sensitive Substrates Drugsa 
Enzyme or 
Transporter 
Sensitive Substrate Drugs 
CYP1A2 
Tizanidine, theophylline, alosetron, caffeine, duloxetine, melatonin, ramelteon, 
tasimelteon 
CYP2C9 
Celecoxib  
CYP2C19 
S-mephenytoin, omeprazole  
CYP3A 
Alfentanil, sirolimus, tacrolimus, avanafil, buspirone, conivaptan, darifenacin, 
darunavir, ebastine, everolimus, ibrutinib, lomitapide, lovastatin, midazolam, 
naloxegol, nisoldipine, saquinavir, simvastatin, tipranavir, triazolam, vardenafil, 
budesonide, dasatinib, dronedarone, eletriptan, eplerenone, felodipine, indinavir, 
lurasidone, maraviroc, quetiapine, sildenafil, ticagrelor, tolvaptan 
Source: FDA Guidance on Clinical Drug Interaction Studies — Cytochrome P450 Enzyme- and 
Transporter-mediated Drug Interactions, January 202054 
Abbreviations: AUC = area under the concentration-time curve; CYP = cytochrome P450; FDA = Food and Drug 
Administration. 
a 
Sensitive substrates are drugs that demonstrate an increase in AUC of ≥ 5-fold with strong index inhibitors of 
a given metabolic pathway in clinical Drug-drug interaction studies. This table is prepared to provide 
examples of clinical sensitive or moderate sensitive index substrates and is not intended to be an exhaustive 
list. 
 
 


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15.5 Appendix 5 - Brief Pain Inventory – Short Form (BPI-SF) 
A sample form for the BPI-SF is below and background for the questionnaire is available at 
https://www.mdanderson.org/research/departments-labs-institutes/departments-
divisions/symptom-research/symptom-assessment-tools/brief-pain-inventory.html. 
 


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15.6 Appendix 6 - Functional Assessment of Cancer Therapy – Prostate 
(FACT-P) 
A sample form for the FACT-P is below and background for the questionnaire is available at 
http://www.facit.org/facitorg/questionnaires. 
 


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Below is a list of statements that other people with your illness have said are important. Please circle 
or mark one number per line to indicate your response as it applies to the past 7 days. 
 
 
 
 
PHYSICAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GP1 
I have a lack of energy........................................................
0 
1 
2 
3 
4 
GP2 
I have nausea ......................................................................
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have trouble 
meeting the needs of my family .........................................
 
0 
 
1 
 
2 
 
3 
 
4 
GP4 
I have pain ..........................................................................
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment .........................
0 
1 
2 
3 
4 
GP6 
I feel ill ...............................................................................
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in bed ........................................
0 
1 
2 
3 
4 
 
 
SOCIAL/FAMILY WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GS1 
I feel close to my friends ....................................................
0 
1 
2 
3 
4 
GS2 
I get emotional support from my family ............................
0 
1 
2 
3 
4 
GS3 
I get support from my friends .............................................
0 
1 
2 
3 
4 
GS4 
My family has accepted my illness ....................................
0 
1 
2 
3 
4 
GS5 
I am satisfied with family communication about my 
illness ..................................................................................
 
0 
 
1 
 
2 
 
3 
 
4 
GS6 
I feel close to my partner (or the person who is my main 
support) ...............................................................................
 
0 
 
1 
 
2 
 
3 
 
4 
Q1 
Regardless of your current level of sexual activity, please 
answer the following question. If you prefer not to answer it, 
please mark this box           and go to the next section. 
 
 
 
 
 
GS7 
I am satisfied with my sex life.............................................
0 
1 
2 
3 
4 


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Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
 
 
 
EMOTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GE1 
I feel sad ..............................................................................
0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am coping with my illness ..........
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my illness ..................
0 
1 
2 
3 
4 
GE4 
I feel nervous .......................................................................
0 
1 
2 
3 
4 
GE5 
I worry about dying .............................................................
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get worse ............................
0 
1 
2 
3 
4 
 
 
 
 
FUNCTIONAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GF1 
I am able to work (include work at home) ..........................
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is fulfilling .....................
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life ..........................................................
0 
1 
2 
3 
4 
GF4 
I have accepted my illness ...................................................
0 
1 
2 
3 
4 
GF5 
I am sleeping well ................................................................
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for fun ......................
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right now ..............
0 
1 
2 
3 
4 
 


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Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
 
 
 
ADDITIONAL CONCERNS 
 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
 
C2 
I am losing weight ...............................................................
0 
1 
2 
3 
4 
C6 
I have a good appetite ..........................................................
0 
1 
2 
3 
4 
P1 
I have aches and pains that bother me .................................
0 
1 
2 
3 
4 
P2 
I have certain parts of my body where I experience pain ....
0 
1 
2 
3 
4 
P3 
My pain keeps me from doing things I want to do ..............
0 
1 
2 
3 
4 
P4 
I am satisfied with my present comfort level ......................
0 
1 
2 
3 
4 
P5 
I am able to feel like a man .................................................
0 
1 
2 
3 
4 
P6 
I have trouble moving my bowels .......................................
0 
1 
2 
3 
4 
P7 
I have difficulty urinating ....................................................
0 
1 
2 
3 
4 
BL2 
I urinate more frequently than usual ....................................
0 
1 
2 
3 
4 
P8 
My problems with urinating limit my activities ..................
0 
1 
2 
3 
4 
BL5 
I am able to have and maintain an erection .........................
0 
1 
2 
3 
4 
 


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15.7 Appendix 7 - Euro-Quality of Life 5D 5L (EQ-5D-5L) Patient-reported 
Outcome 
A sample form for the EQ-5D-5L is included on the next page. Background information for the 
questionnaire is available at http://www.euroqol.org/home.html. 
 
 


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15.8 Appendix 8 - Analgesic Use Questionnaire 
A sample form for the Analgesic Use Questionnaire is included on the next page.  
 


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SAP_001.pdf: 
 
 
ClinicalTrials.gov Oﬃcial Title: A Study of Rucaparib Versus 
Physician's Choice of Therapy in PaƟents With MetastaƟc 
CastraƟon-resistant Prostate Cancer and Homologous 
RecombinaƟon Gene Deﬁciency (TRITON3) 
 
 
ClinicalTrials.gov IdenƟﬁer Number: NCT02975934    
 
 
 
Document Date: 01 July 2022 
 
 
 
Document: StaƟsƟcal Analysis Plan (SAP) for Study CO-338-063 
 
 
Study Title: TRITON3: A MulƟcenter, Randomized, Open-label 
Phase 3 Study of Rucaparib versus Physician’s Choice of 
Therapy for PaƟents with MetastaƟc CastraƟon-resistant 
Prostate Cancer Associated with Homologous RecombinaƟon 
Deﬁciency 




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Approval Page


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ABBREVIATIONS AND SPECIALIST TERMS ....................................................................5 
1 
INTRODUCTION...........................................................................................................7 
2 
OVERALL STUDY DESIGN, OBJECTIVES, AND ENDPOINTS.............................8 
2.1 
Study Objectives Outlined in Protocol ....................................................................8 
2.2 
Trial Design .............................................................................................................9 
2.3 
Sample Size Determination....................................................................................10 
2.4 
Independent Data Monitoring Committee (IDMC) ...............................................11 
3 
GENERAL ANALYSIS CONVENTIONS ..................................................................12 
3.1 
Analysis Populations..............................................................................................12 
3.2 
Statistical Hypothesis.............................................................................................13 
3.3 
Step-down Procedure of Primary and Secondary Endpoints.................................13 
4 
PATIENT DISPOSITION.............................................................................................15 
5 
PROTOCOL DEVIATIONS.........................................................................................15 
6 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS....................................15 
6.1 
Demographics ........................................................................................................15 
6.2 
Baseline Clinical Characteristics ...........................................................................16 
6.3 
Medical History .....................................................................................................16 
7 
STUDY DRUG EXPOSURE AND COMPLIANCE...................................................17 
8 
PRIOR AND CONCOMITANT MEDICATIONS ......................................................17 
9 
EFFICACY VARIABLES ............................................................................................17 
9.1 
Primary Efficacy Variables....................................................................................17 
9.2 
Secondary Efficacy Variables Included in the Step-down Testing .......................17 
9.3 
Exploratory Efficacy Variables..............................................................................18 
10 
EFFICACY ANALYSIS...............................................................................................18 
10.1 
Primary Efficacy Analysis .....................................................................................18 
10.1.1 
Censoring Distribution.................................................................................19 
10.2 
Secondary Efficacy Analyses ................................................................................20 
10.2.1 
Overall Survival...........................................................................................20 
10.2.2 
Objective Response Rate by Modified RECIST v1.1/PCWG3...................21 
10.2.3 
Duration of Response...................................................................................21 
10.2.4 
Time to PSA Progression.............................................................................22 
10.2.5 
......................................................22 
10.2.6 
......................................................22 
10.2.7 
Patient-Reported Outcomes .........................................................................23 
10.2.7.1 
Functional Assessment of Cancer Therapy Prostate (FACT-P) .....23 
10.2.7.2 
Brief Pain Index Short Form (BPI-SF)...........................................24 
10.2.7.3 
EQ-5D-5L ..........................................................................................24 


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10.2.7.4 
Analgesic Use Questionnaire.............................................................24 
10.2.7.5 
PRO Patient Disposition and Completion Rate .................................24 
10.2.7.6 
PRO Correlation With Adverse Events .............................................25 
10.2.8 
Clinical Benefit Rate....................................................................................25 
10.2.9 
Sparse Pharmacokinetics .............................................................................25 
10.3 
Exploratory Efficacy Analyses ..............................................................................26 
10.3.1 
Concordance in BRCA1/BRCA2/ATM Gene Mutation Status...................26 
10.3.2 
Molecular Profile Over Time.......................................................................26 
10.3.3 
Loss of Heterozygosity (LOH) ....................................................................26 
10.3.4 
Mechanisms of Response and Resistance....................................................26 
10.4 
Examination of Efficacy in Subgroups..................................................................26 
11 
SAFETY ANALYSIS ...................................................................................................27 
11.1 
Adverse Events ......................................................................................................27 
11.2 
Clinical Laboratory Evaluations ............................................................................29 
11.3 
Vital Signs..............................................................................................................30 
11.4 
ECGs......................................................................................................................30 
11.5 
Examination of Safety in Subgroups .....................................................................31 
12 
REFERENCES..............................................................................................................32 
LIST OF IN-TEXT TABLES
Table 1.  Primary, Secondary and Exploratory Objectives......................................................8 
LIST OF IN-TEXT FIGURES
Figure 1. Schema of Study Design.........................................................................................10 
Figure 2.  Ordered Step-down Procedure................................................................................14 
LIST OF APPENDICES
Appendix 1 
FACT-P (Version 4) ....................................................................................33 
Appendix 2 
Brief Pain Inventory Short Form ..............................................................37 
Appendix 3 
Euro-Quality of Life 5 Dimension 5 Level (EQ-5D-5L).............................40 
Appendix 4 
Analgesic Use Questionnaire.......................................................................43 
Appendix 5 
Amendment History.....................................................................................44 


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ABBREVIATIONS AND SPECIALIST TERMS
AE(s)
adverse event(s)
ANCOVA
analysis of covariance
AR
androgen receptor
ATM
ataxia telangiectasia mutated serine/threonine kinase
BID
twice daily
BPI-SF 
Brief Pain Inventory Short Form 
BRCA
breast cancer gene
CBR
clinical benefit rate
CI
confidence interval 
CMH
Cochran-Mantel-Haenszel
CR
complete response
CRF
case report form
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating cell-free tumor DNA
DOR
duration of response
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
ER
exposure-response
EQ-5D-5L
EuroQol five-dimension scale (five levels of severity)
FACT-P
Functional Assessment of Cancer Therapy - Prostate
HR
hazard ratio
HRD
homologous recombination deficiency
IDMC
Independent Data Monitoring Committee 
IRR
independent radiology review
ITT
intent-to-treat
KM
Kaplan-Meier
LOH
loss of heterozygosity
mCRPC
metastatic castrate-resistant prostate cancer
MedDRA
Medical Dictionary for Regulatory Activities
ORR
overall response rate
OS
overall survival
PARP
poly(ADP-ribose) polymerase
PARPi
PARP inhibitor
PCWG3
Prostate Cancer Working Group 3
PD
progressive disease




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1
INTRODUCTION
This document describes the statistical analyses and data presentations to be performed for 
the clinical study report (CSR) for Clovis Oncology protocol CO-338-063 TRITON3: A 
Multicenter, Randomized, Open-
of Therapy for Patients with Metastatic Castration-resistant Prostate Cancer Associated with 
Homologous Recombination Deficiency .
The purpose of the statistical analysis plan (SAP) is to ensure the credibility of the study 
findings by prespecifying the statistical approaches to the analysis of study data prior to the
snapshot for the primary endpoint in this study. This SAP provides additional details 
concerning the statistical analyses that are already outlined in the original protocol dated 
12 October 2016, protocol amendment 1 (dated 7 December 2017), protocol amendment 2
(dated 19 June 2018), protocol amendment 3 (dated 27 August 2020), and protocol 
amendment 4 (dated 18 February 2022). TRITON3 SAP Version 3.0 (1 July 2022) replaces 
Version 2.0 (28 Feb 2022) and Version 1.0 (23 Oct 2019). A brief summary of the key 
changes is provided in Appendix 5.
All statistical analyses detailed in this SAP will be conducted using SAS® Version 9.3 or
higher.




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2.2
Trial Design
This is an ongoing
choice of second-line AR-directed therapy (abiraterone acetate or enzalutamide) or docetaxel 
as treatment for mCRPC patients who have progressed on one prior AR-directed therapy 
(abiraterone acetate, enzalutamide, apalutamide, or investigational AR-targeted agent) and 
have not yet received chemotherapy in the castration resistant setting. Patients who received 
prior PARPi treatment will be excluded. This study will enroll mCRPC patients with a
deleterious mutation in BRCA (BRCA1 or BRCA2) or ATM.
This study consists of a Pre-screening and Screening Phase (denoted as Screening Phase in 
this document), Randomization, Treatment Phase, Post Treatment Phase, and Cross-over 
comparator therapy (pre-designated prior to randomization) in the Treatment Phase, and will 
undergo procedures and assessments including regular safety and efficacy evaluations during 
the entire conduct of the study. Patients randomized to the control arm in the Treatment 
Phase will have the opportunity to receive treatment with rucaparib in the Cross-over Phase.
Eligible patients will be randomized 2:1 to receive rucaparib (600 mg twice daily [BID]) or 
-directed therapy (abiraterone acetate or 
oice of agent in 
the control arm must be prespecified prior to randomization. The randomization assignments 
are stratified by
ECOG performance status (0 vs 1), presence vs absence of 
hepatic metastases, and gene (BRCA1 vs BRCA2 vs ATM) to maintain balance between 
treatment groups. 
Patients must have a deleterious mutation in BRCA or ATM in order to be eligible for the 
study. Mutations may be identified by local testing, or through central testing provided by the 
sponsor. Patients will be randomized after confirmation that all eligibility criteria in the 
screening phase have been met.
Patients will receive study drug until radiographic disease progression is confirmed by 
independent radiology review (IRR) based on modified RECIST Version 1.11 (for 
nodal/visceral lesions only) and PCWG32 (for bone lesions only) criteria, unequivocal 
clinical disease progression, unacceptable toxicity or inability to tolerate further treatment, 
loss to follow up, or withdrawal of consent. If a patient demonstrates radiographic 
progression per investigator assessment while receiving treatment with study drug, but 
continues to derive clinical benefit, then continuation of treatment beyond progression is 
permitted. In such cases, the patient must consent prior to continuing treatment with study 
drug. Figure 1 shows the schedule of the study design with the Screening Phase followed by 
the randomized Treatment Phase and lastly the Post-treatment Phase with an option to cross 
over for patients randomized to 
.




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approximately 400 total patients should result in approximately 270 events of rPFS, which 
will provide approximately 90% power to detect a hazard ratio (HR) of 0.67 at a one sided
0.025 significance level (and equivalently at a two-sided 0.05 significance level).
April 2022 Update on Sample Size per IDMC: Based on discussions with the TRITON3 
IDMC, Clovis was informed that the planned number of 200 events in the BRCA subgroup 
would not be reached in a timely manner congruent with study objectives or may not be 
reached at all. The IDMC and Clovis further discussed and agreed that it was important to 
maintain at least 80% power for the rPFSirr analysis in the BRCA subgroup, and thus at least 
160 rPFSirr events must be observed, under the original HR assumptions above. 
Additionally, both Clovis and the IDMC felt that an appropriate amount of follow-up of 
approximately 6 months should be considered such that all patients would have the 
opportunity to have at least 3 post baseline scans. The last patient in TRITON3 was 
randomized on February 28, 2022 allowing for 6 months of follow-up in August 2022. Using 
prospective IDMC projections and observed monthly rates of events, it was estimated that 
160 to 170 events in the BRCA subgroup would be observed by August 2022, after which 
event accumulation would start to decrease. Therefore, the primary analysis of TRITON3 
will occur after at least 160 rPFSirr events in the BRCA Subgroup have occurred and after at 
least 6 months of follow-up for the last patient has been accrued.
2.4
Independent Data Monitoring Committee (IDMC)
The IDMC will be responsible for safeguarding the interests of trial participants, assessing 
the safety and efficacy of the interventions during the trial, and for monitoring the overall 
conduct of the clinical trial. The IDMC will provide recommendations about the 
continuation, revision, or termination of the study. Details regarding the IDMC will be 
documented in a separate committee charter.


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3
GENERAL ANALYSIS CONVENTIONS
All efficacy analyses will be done at a two-sided 0.05 significance level including all data 
from the randomized portion of the study.
The efficacy data for the patients crossing over from 
to rucaparib will 
generally be presented separately.
The summary tables will be presented by randomized treatment group (rucaparib vs
ce) and may also present each comparator treatment (abiraterone acetate, 
enzalutamide, or docetaxel) separately. Generally, summary outputs will be presented 
separately for the BRCA subgroup and for the ITT Population.
Quantitative variables will typically be summarized using frequencies and percentages for 
appropriate categorizations and may also be summarized using descriptive statistics. For 
variables summarized with descriptive statistics, the following will be presented: N, mean, 
standard deviation, median, minimum, and maximum. Categorical variables will be presented 
using frequencies and percentages. Months will be calculated as number of days divided by 
30.4375.
The Kaplan-Meier (KM) methodology will be used to summarize time-to-event variables. If 
estimable, 50th percentile (median) with 95% confidence intervals will be presented. The 
stratified hazard ratio from the Cox proportional hazards model will be used to estimate the 
HR between the randomized treatment groups for the primary endpoint. The number of 
patients with events and the number of censored patients will also be presented. For stratified 
analyses, if one or more of the strata contain few patients (eg, < 5 patients) or only patients 
from a single treatment group, or if the convergence criteria in SAS are not met, strata will be 
combined to ensure a sufficient number of patients in each stratum by first removing the
hepatic metastases variable (which is equivalent to combining the 2 categories) and then
combining the BRCA1/BRCA2 categories, if necessary.
For secondary (other than OS), exploratory, and subgroup analyses, statistical testing will not 
be stratified. Stratified analyses may be performed as sensitivity analyses. For time-to event 
analyses the log-rank test will be used for treatment group comparisons.
All data will be used to their maximum possible extent without any imputations for missing 
data.
Unless otherwise indicated, baseline is defined as the last measurement on or prior to the first 
day of study drug administration or randomization date, if the patient was never treated.
3.1
Analysis Populations
Safety Population
The Safety Population will consist of all patients who received at least 
one dose of protocol-specified treatment.


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Intent-to-Treat Population
The Intent-to-Treat (ITT) Population will consist of all 
randomized patients (ie, patients with BRCA-mutated mCRPC and patients with ATM-
mutated mCRPC) .
BRCA Subgroup
The BRCA subgroup will consist of patients in the ITT Population with
BRCA-mutated mCRPC.
IRR Efficacy Population
The IRR Efficacy Population will consist of all patients 
evaluable for response by modified RECIST Version 1.1/PCWG3 criteria per independent 
radiology review. 
Investigator Efficacy Population
The Investigator Efficacy Population will consist of all 
patients evaluable for response by modified RECIST Version 1.1/PCWG3 criteria per 
investigator.
3.2
Statistical Hypothesis 
The primary statistical hypothesis for this study is to test for differences in rPFSirr using a 
stratified log-rank test.
H0: HR (rucaparib/
)
1
Ha: HR (rucaparib/
) < 1
The stratification factors used for randomization are ECOG performance status (0 vs 1), 
presence vs absence of hepatic metastases, and gene (BRCA1 vs BRCA2 vs ATM). The first 
test in the step-down procedure is in the subgroup of BRCA patients (thus the stratification 
for gene will be only 2 levels). The second test is in the ITT Population.
All efficacy analyses will be based on the randomization strata given at randomization, 
however, a sensitivity analysis of rPFSirr may be performed using the actual strata if patients 
have been allocated incorrectly. 
3.3
Step-down Procedure of Primary and Secondary Endpoints
The primary and key secondary endpoints will first be tested among the BRCA subgroup and 
then in the ITT Population (ie, BRCA + ATM) using an ordered step-down multiple 
comparisons procedure. The primary endpoint of rPFSirr (radiographic progression-free 
survival by independent radiology review) in the BRCA subgroup will be tested first at a 
two-sided 0.05 significance level. If rPFSirr in the BRCA subgroup is statistically significant,
then rPFSirr will be tested in the ITT Population. Continuing in an ordered step-down
manner, the key secondary endpoints will be tested at the two-sided 0.05 significance level.
To preserve the overall Type 1 error rate, statistical significance will only be declared for a
secondary endpoint if the primary endpoints and previous secondary endpoints are also 
statistically significant. The ordered step-down procedure is illustrated in Figure 2.




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4
PATIENT DISPOSITION
Patient disposition (analysis population allocation, randomized, discontinued, and primary 
reason for discontinuation) will be summarized using frequency counts, and the 
corresponding percentages, by treatment group and overall. Patient disposition will be 
summarized for the ITT Population and may also be summarized for the prespecified 
Analysis Populations and/or gene subgroups.
5
PROTOCOL DEVIATIONS
Important protocol deviations will be identified prior to releasing the treatment codes for 
primary efficacy analysis in accordance with Clovis SOP CR019 (Identification, 
Documentation, Management and Review of Protocol Deviations). A listing with the 
important protocol deviations will be presented. No patients will be excluded from the
Efficacy Populations due to protocol deviations.
6
DEMOGRAPHICS AND BASELINE CHARACTERISTICS
Demographic and baseline characteristics will be summarized, by treatment group and 
overall, for the ITT Population and may also be summarized for the prespecified Analysis 
Populations and/or gene subgroups.
6.1
Demographics
The demographic variables will be summarized with frequency tabulations that will focus on 
identifying differences between treatment groups in the extreme values of the distributions.
Descriptive statistics may also be used to summarize the quantitative variables. The 
demographic variables presented will include age, height, weight, race, ethnicity, smoking 
status, and geographic region using the following categorizations:
Age (years): <65, 65-
5 and separately 
50, 51-60, 61-70, 71-80, 81-90, > 90;
75, > 75-100, > 100-125, > 125-150, > 150-175, > 175;
50, > 50-75, > 75-100, > 100-125, > 125-150, > 150;
Race: American Indian or Alaska Native, Asian, Black, Native Hawaiian or Other Pacific 
Islander, White, Other, Not Reported;
Ethnicity: Hispanic or Latino, Not Hispanic or Latino, Not Reported, Unknown;
Smoking status: Current Smoker, Former Smoker, Never Smoked;
Geographic Regions: North America, Europe, Other and separately US, Non-US.
These categorizations may be adjusted if the majority of the data lies in only 2 or 3 of the 
categories.


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6.2
Baseline Clinical Characteristics
The following variables will be summarized with frequency tabulations
Time since diagnosis, years (0 to 3, > 3 to 6, > 6 to 9, > 9);
Clinical tumor stage at initial prostate cancer diagnosis (Stage I, IIA, IIB, III, IV);
Clinical regional lymph node stage at initial prostate cancer diagnosis (N0, N1, NX);
Distant metastasis (M status) at initial prostate cancer diagnosis (M0, M1, MX);
Gleason score (<7, 7, 8, 9, not reported);
ECOG performance status (
);
Presence or absence of hepatic metastases;
Presence or absence of lung metastases; 
HRR gene (BRCA1, BRCA2, or ATM);
BRCA germline/somatic status;
ATM germline/somatic status;
Measurable disease status;
Type of measurable disease (nodal only, visceral ± nodal);
Prior anticancer therapies for prostate cancer;
Number of prior anticancer therapies for CRPC.
Descriptive statistics may also be used to summarize these variables, where appropriate.
6.3
Medical History
The medical history will be summarized for the safety population. Medical history events 
will be classified using the Medical Dictionary for Regulatory Activities (MedDRA) 
classification system version 20.1 or higher. Medical history data will be summarized using 
frequency tabulations by System Organ Class (SOC) and Preferred Term (PT).


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7
STUDY DRUG EXPOSURE AND COMPLIANCE
Study drug exposure will be summarized for all patients in the Safety Population. The 
duration of treatment will be calculated as the number of days from the first dose of study 
drug to the day of the last dose of study drug +1. Descriptive statistics and 
frequencies/percentages for appropriate categorizations will be used to summarize treatment 
duration for each treatment arm and also for each of the 
hoice therapies 
separately.
The number of patients with at least one dose reduction or interruption based on the dosing 
log will be summarized with frequencies and percentages. In addition, for the patients 
randomized to rucaparib, the number of patients on each dose level will be summarized (ie,
600 mg BID, 500 mg BID, 400 mg BID, etc.) in order to assess patients with multiple levels 
of dose reductions. 
8
PRIOR AND CONCOMITANT MEDICATIONS
Prior and concomitant medications will be summarized for all patients in the Safety 
Population. All concomitant treatments documented during the study period will be 
summarized in frequency tabulations for each randomized treatment group and overall.
Prior/concomitant medication coding will utilize the World Health Organization (WHO) 
Drug Dictionary version Global-B3 202003 or later.
Prior medications will only be presented in listings. Prior medications will be defined as 
those medications with both a start and a stop date that is before the day of the first dose of 
study drug administration. If either the start date and/or the stop date of the medication is 
missing so that it is unclear whether the medication was stopped prior to first dose of study 
drug administration then the medication will be included in the summary of the concomitant 
medications.
9
EFFICACY VARIABLES
9.1
Primary Efficacy Variables
The primary efficacy variable is radiographic PFS by independent radiology review (rPFSirr)
in the BRCA subgroup of patients. Following the test in the BRCA subgroup, rPFS by IRR
for the ITT Population will be tested in the step-down procedure. Radiographic PFS, as 
assessed by the investigator (rPFSinv), is defined similarly and will be supportive of the 
primary endpoint.
9.2
Secondary Efficacy Variables Included in the Step-down Testing 
Secondary variables included in the step-down testing procedure:
1. Overall survival (OS), BRCA subgroup
ITT Population
2. Objective response rate (ORR) by IRR, BRCA subgroup
ITT Population


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Additional secondary variables:
Duration of response (DOR) by IRR
Time to PSA progression
PSA respo
PSA response (
90% reduction)
Patient-reported outcome endpoints 
-
FACT-P
-
BPI-SF
-
EQ-5D-5L
Clinical benefit rate (CBR)
9.3
Exploratory Efficacy Variables  
To assess concordance in BRCA/ATM gene mutation status in matched screening biopsy 
tissue, archival primary and metastatic tumor tissue and plasma ctDNA
To assess changes in the molecular profile over time of matched pre and post-treatment 
tumor or plasma samples
To evaluate LOH in metastatic disease site biopsy and archival primary and metastatic 
tumor tissue samples;
To evaluate mechanisms of response and resistance in ctDNA and progression tumor 
tissue samples
10 EFFICACY ANALYSIS
10.1
Primary Efficacy Analysis
The primary efficacy endpoint for the study is rPFSirr, defined as the time from 
randomization to the first objective evidence of radiographic progression, or death due to any 
cause (whichever occurs first), +1 day. Radiographic disease progression includes confirmed 
soft tissue disease progression per modified RECIST Version 1.1 and confirmed bone disease 
progression per PCWG3 criteria. 
Patients who withdraw from treatment prior to progression will be followed for disease status 
and survival whenever possible.
Scans and deaths occurring after the start of subsequent anticancer treatment (SACT) 
disallowed per protocol will be excluded from the primary PFS analysis. However, if bone 
progression started prior to SACT, scans following SACT may be used for the confirmation 
of bone progression (as the progression date will precede the start of SACT).
A gap in evaluable scans may affect how subsequent scans and events (progression or death) 
are counted or censored. This gap is defined as two or more missed expected scans resulting 


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in a duration of greater than 25 weeks (ie, 2 times the 12-week scan interval plus 1 week for 
protocol visit window allowance) between scans. Any event (death or progression) occurring 
before the end of this gap may be included in the PFS analysis. If a patient has an event 
(progression or death) immediately following the gap, the patient will be censored at the last 
scan date prior to the gap. If a patient has an evaluable non-PD scan immediately following 
the gap, the gap-clock will reset and subsequent scans and events (progression or death) may 
be used in the primary PFS assessment (barring intervening SACT, as above).
Patients without a documented event per the rules above will be censored on the date of their 
last tumor assessment (ie, radiologic assessment), or the date of randomization if no 
post-baseline tumor assessments have been performed. 
cycles of study drug. Patients completing their docetaxel treatment without documented 
disease progression by IRR should continue to be assessed periodically until radiographic 
progression by IRR is determined. There should not be intervals > 25 weeks between scans 
for these patients.
The primary endpoint of rPFSirr will be analyzed using Cox proportional hazard 
methodology. The stratified hazard ratio from the Cox proportional hazards model will be 
used to estimate the HR between the randomized treatment groups. The stratified log-rank 
test will be the official test used for the hierarchical testing outlined in Section 3.3.
Employing a step-down procedure, a test for significance between the 2 treatment groups will 
be performed for rPFSirr in the BRCA subgroup of patients. If the result is significant 
(2-
the ITT Population.
Assessment of rPFS by the investigator (rPFSinv) will also be conducted as a supportive 
analysis for rPFSirr.
10.1.1
Censoring Distribution
Sensitivity analyses for rPFS will be performed to evaluate the impact of censored patients.
The following analyses will be performed:
Patients without radiographic progression who discontinued the study due to clinical 
progression will be considered to have an event of rPFS on the date of the last dose of 
study drug.
Patients who discontinued the study without radiographic progression, but who had 
confirmed PSA progression, will be treated as having an event of rPFS on the date of 
PSA progression.
Patients who initiate subsequent anti-cancer therapy (SACT) prior to an event of rPFS,
but who have an event of rPFS at a subsequent radiographic assessment following 
initiation of SACT, will have this rPFS event counted.


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Additional sensitivity analyses may also be performed to evaluate the robustness of the study 
results. These analyses will be considered exploratory and will likely be motivated by the 
observed results.
10.2
Secondary Efficacy Analyses
If the primary endpoint is statistically significant, for both the BRCA subgroup and the ITT 
Population, then key secondary efficacy endpoints will be tested in a step-down order. To
preserve the overall Type-1 error rate, statistical significance will only be declared for a
secondary endpoint if the primary endpoints and any previous secondary endpoints are also 
statistically significant. All tests will be performed at the 2-sided 0.05 significance level.
10.2.1
Overall Survival
Overall survival time will be calculated in months as the time from randomization to death 
(by any cause) +1 day. Patients who have not died will be censored on the date the patient 
was last known to be alive. 
Overall survival will be analyzed using the Cox proportional hazard methodology and a 
log-rank test. The stratified hazard ratio from the Cox proportional hazards model will be 
used to estimate the HR between the randomized treatment groups. The stratified log-rank
test will be the official test used for the hierarchical testing outlined in Section 3.3.
It is anticipated that the data for overall survival will be heavily censored at the time of the 
primary endpoint analysis. To adjust for multiple analyses of OS at a later stage, a stopping 
rule will be applied. The Haybittle-Peto3, 4 stopping rule will be applied where any interim 
(early) overall survival with a p-value < 0.001 can be used to claim superiority. This means 
that a two-sided p-value very close to 0.05 can still be utilized at the final analysis which is 
projected to be once approximately 70% of the death events has been collected.
For both the interim and final overall survival analyses, the duration of follow-up will be 
summarized using medians for both the BRCA subgroup and the ITT Population in the 
following groups of patients:
In censored patients: Time from randomization date to date of censoring (ie, date last 
known to be alive) + 1 day
In all patients (ie, both censored patients and those who have died):
-
For censored patients, treat censored dates as OS event dates and then calculate 
follow up as time from randomization date to OS event date + 1 day or
-
For patients with OS events, treat OS event dates as censored dates and then calculate 
follow up as time from randomization date to censoring date + 1 day
Kaplan-Meier methodology will be used to estimate the median duration of follow up for the 
above patient groups.


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To explore the impact of cross over to rucaparib treatment on OS, the following sensitivity 
analyses may be conducted:
Censoring the data at time of cross over (ie, patients who crossed over from 
choice to rucaparib)
Time-varying covariate for starting rucaparib5
Two-stage estimation6
10.2.2
Objective Response Rate by Modified RECIST v1.1/PCWG3
The ORR as assessed by IRR will be analyzed for the IRR Efficacy Population. The 
confirmed response rate will be summarized. To be considered a responder at a specific time
point, a patient must have a CR or PR assessment per modified RECIST and no confirmed 
bone progression per PCWG3 on or prior to the CR or PR. To be considered a confirmed 
responder, a patient must have at least 2 responses at least 4 weeks apart prior to a modified 
RECIST/confirmed PCWG3 progression event. Only tumor scans included for evaluation of 
the primary endpoint are considered for the ORR endpoint.
ORR will be summarized with frequencies and percentages together with 95% confidence 
intervals (CI) and compared between treatments by using a Cochran-Mantel-Haenszel 
(CMH) test. Per the step-down procedure, the BRCA subgroup will be tested followed by the
ITT Population.
In addition, the frequency and proportion of patients will be summarized for each of the 
following best confirmed response categories:
CR
PR
Stable disease (SD)
Progressive disease (PD)
Not evaluable (for example discontinuations or deaths before first tumor assessment)
Similar analyses will be performed for ORR as assessed by the investigator for the
Investigator Efficacy Population.
10.2.3
Duration of Response
The DOR as assessed by IRR will be analyzed in the IRR Efficacy Population for the
subgroup of patients who have a confirmed response. DOR for confirmed response will be 
measured from the date of the first response (which is subsequently confirmed) until the first 
date that radiographic progressive disease is documented. DOR will be calculated in months 
as the time from the first date of the scan showing a response to the first scan with disease 
progression +1 day. Any patients with an ongoing response will be censored at the date of the 
last post-baseline scan. 


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DOR will be analyzed using Cox proportional hazard methodology and a log-rank test. The 
hazard ratio from the Cox proportional hazards model will be used to estimate the HR 
between the randomized treatment groups. The BRCA subgroup will be tested followed by 
the ITT Population.
Similar analyses will be performed for DOR as assessed by the investigator for the 
Investigator Efficacy Population.
10.2.4
Time to PSA Progression
25% 
who did not have a decline in PSA) in PSA was measured + 1 day. The increase must be 
confirmed by a second consecutive assessment conducted at least 3 weeks later (unless the 
PSA progression occurred at the last recorded PSA assessment). If confirmed, the date used 
for time of PSA progression is the earlier of the 2 PSA dates. Additionally, early rises (before 
12 weeks following first dose of study drug) are not considered in determining PSA 
progression.
This endpoint will be analyzed in patients with both Baseline and at least 1 post-baseline 
value using Cox proportional hazards methodology. The hazard ratio from the Cox 
proportional hazards model will be used to estimate the HR between the randomized 
treatment groups. The BRCA subgroup will be tested followed by the ITT Population.
10.2.5
PSA Response Rate
Confirmed PSA response (PSA50) is defined as having 2 consecutive PSA values (at least 
3 weeks apart) that are at least 50% lower than baseline and that occur prior to PSA 
progression (as defined in Section 10.2.4). Per PCWG3, early rises (before 12 weeks
following first dose of study drug) in PSA should be ignored when determining PSA 
response. Confirmed PSA response will be calculated for all patients with PSA values at 
baseline.
PSA response in patients with both Baseline and at least 1 post-Baseline value will be 
summarized with frequencies and proportion together with 95% CI and compared between
treatment groups using a CMH test. The BRCA subgroup will be tested followed by the ITT 
Population.
10.2.6
Confirmed PSA response (PSA90) is defined as having 2 consecutive PSA values (at least 
3 weeks apart) that are at least 90% lower than baseline and that occur prior to PSA 
progression (as defined in Section 10.2.4). Per PCWG3, early rises (before 12 weeks
following first dose of study drug) in PSA should be ignored when determining PSA 
response. Confirmed PSA response will be calculated for all patients with PSA values at 
baseline.


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PSA90 response in patients with both Baseline and at least 1 post-Baseline value will be 
summarized with frequencies and proportion together with 95% CI and compared between
treatment groups using a CMH test. The BRCA subgroup will be tested followed by the ITT 
Population.
10.2.7
Patient-Reported Outcomes
The patient reported outcome data will be scored and summarized in accordance with the 
scoring manuals for the respective questionnaires. Appendix 1 through Appendix 4 include
the English version of the questionnaires used. Analysis tables for PROs may be limited to 
time points with a meaningful amount of patient data. Additionally, patient experience data 
which includes aspects of healthcare utilization and clinical outcome assessments will be 
assessed.
For the protocol-specified Treatment Discontinuation visit (which could occur at any time),
the PRO assessment will be assigned to the scheduled Cycle to which the assessment date is 
closest. If multiple assessments are then present at a given Cycle, the scheduled visit 
assessment will be used.
10.2.7.1
Functional Assessment of Cancer Therapy 
Prostate (FACT-P)
Scores and post-baseline score changes for the FACT-P global, physical, functional, and 
prostate-cancer scale scores as well as scores for the FACT-P trial outcome index (TOI) will 
be summarized at each visit and at the final visit using descriptive statistics (N, mean, StD,
minimum, median, and maximum). Patients who do not have both a baseline measurement 
and at least 1 post-baseline measurement will not be included.
At a given visit, the change and/or percent change from baseline will be compared between
the randomized treatment groups using analysis of covariance (ANCOVA) with treatment 
group and baseline measurement for the parameter as a continuous covariate. 
Distribution of item level responses and change from baseline in these item levels for the 
following 5 questions will be summarized by Cycle over the first year of participation in the
randomized portion of the study:
From the Physical Well-being questions:
GP1: I have a lack of energy
GP2: I have nausea
GP5: I am bothered by side effects of treatment
GP7: I am forced to spend time in bed
From the Functional Well-being questions:
GF1: I am able to work


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Change from baseline will be categorized as: Improved, Stable, Worsening 1 category, 
Worsening 2 categories, Worsening 3 categories, or Worsening 4 categories. This will be 
summarized in a table and may be displayed graphically.
10.2.7.2
Brief Pain Index 
Short Form (BPI-SF)
The primary assessment of pain from the BPI-SF questionnaire will be taken from item #3 
(pain at its worst in the last 24 hours). The other pain severity measures (least, average, and 
current pain) will be analyzed separately and as a composite (along with item #3, as a mean 
severity measure) score. BPI pain interference will be scored using the mean of the 
7 interference items. For the mean to be calculated, at least 4 of the 7 total interference items 
must have been completed on a given administration.
Descriptive statistics will be presented for each score, change from baseline, and percent 
change from baseline at each post-baseline time point for the pain intensity measures and the 
mean pain interference score.
At a given visit, the change and/or percent change from baseline will be compared between 
the randomized treatment groups using ANCOVA with treatment group and baseline 
measurement for the parameter as a continuous covariate.
10.2.7.3
EQ-5D-5L
Analyses of changes and/or percent changes from baseline will be analyzed for each 
scheduled post-baseline visit and for the final visit for the EQ-5D-5L VAS. Patients who do 
not have both a baseline measurement and at least one post-baseline measurement will not be 
included. 
At a given visit, the change and/or percent change from baseline will be compared between 
the randomized treatment groups using an ANCOVA with the treatment group and baseline 
measurement for the parameter as a continuous covariate.
10.2.7.4
Analgesic Use Questionnaire
The analgesic use questionnaire rates the strength (from 0-3) of pain medication used within 
the last 24 hours and is completed at the same time points as the other PROs. This
questionnaire is designed to be used in conjunction with assessment of pain, so will not be 
summarized in a stand alone analysis.
10.2.7.5
PRO Patient Disposition and Completion Rate
The following analyses will be summarized to characterize PRO data (eg, FACT-P and 
EQ-5D) completeness over the first year of participation in the randomized portion of the 
study.
PRO patient disposition will be displayed in a table (and possibly graphically) with the 
cumulative patient disposition by treatment per PRO assessment window for each scheduled 


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post-baseline visit (eg, Cycle 1 Day 1, Cycle 2 Day 1, etc.). The following categories will be 
summarized: 
PRO assessment expected;
PRO assessment not expected due to disease progression;
PRO assessment not expected due to other reasons; and
Patient ongoing in study, PRO assessment time point not yet reached.
Overall PRO completion rates will be summarized for each PRO assessment window. 
Overall completion rate is defined as the number of patients having at least 1 response in the 
PRO instrument, divided by the number of patients expected to have completed a PRO 
assessment at a given visit.
10.2.7.6
PRO Correlation With Adverse Events
The correlation between EQ-5D and FACT-P will be summarized by tabulating the mean 
EQ-5D-5L subscale score for the a) mobility, b) self-care, and c) usual activities dimensions 
at each cycle, within the first 6 months of participation in the randomized portion of the 
study, broken down by response to FACT-P item GP1 (I have lack of energy) as well as by 
Grade 1, 2, or 3 CTCAE maximum grade of asthenia/fatigue. 
The mean EQ-5D-5L subscale scores of a) self-care and b) usual activities dimensions at 
each cycle, within the first 6 months of participation in the randomized portion of the study, 
will be broken down by response to FACT-P item GP2 (I have nausea) as well as by Grade 1,
2, or 3 CTCAE maximum grade of nausea.
10.2.8
Clinical Benefit Rate
Clinical benefit rate (CBR) is defined as the number of patients without radiographic 
progression (defined by modified RECIST Version 1.1/ PCWG3 criteria) who were 
continuing with study drug treatment through the given time interval divided by the number 
of patients who had the given amount of follow-up. Clinical benefit rates will be summarized 
at several intervals: eg, 4-, 6-, 9-, and 12-months, with frequencies and percentages along 
with 95% CIs. For example, the 6-month CBR would be the number of patients who neither 
discontinued nor had radiographic PD through 6 months divided by the number of patients 
who were enrolled at least 6 months prior to the visit cut-off.
The CBR will be summarized with frequencies and proportions together with 95% CI and 
compared between treatment groups by using CMH test. The BRCA subgroup will be tested 
followed by the ITT Population.
10.2.9
Sparse Pharmacokinetics
For patients receiving rucaparib (except those in the Cross-over Phase), plasma samples are 
to be collected for trough level PK analysis of rucaparib before the morning dose on 
Study Day 29, Day 57, Day 85, and Day 113 as close as posssible to 12 hours after the 


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previous dose. Samples are not to be collected in patients receiving comparator therapy or 
crossing over to rucaparib. 
In all patients with at least one PK sample collected, the trough plasma rucaparib PK data 
(Cmin) and summary statistics (N, mean, StD, minimum, median, max, CV%) will be 
reported. The PK data and selected safety and efficacy endpoints will be included in 
exploratory population PK and exposure-response (ER) analyses, and the results will be 
reported separately.
10.3
Exploratory Efficacy Analyses
10.3.1
Concordance in BRCA1/BRCA2/ATM Gene Mutation Status
Pairwise comparisons will be performed using available plasma and tissue (including 
archival and contemporaneous samples) test results to explore the concordance in BRCA1, 
BRCA2, and ATM gene alterations.
10.3.2
Molecular Profile Over Time
The relationship between rucaparib activity and gene mutations identified from testing the 
available tissue and plasma samples will be evaluated. Additional genomic or transcriptional 
signatures may also be evaluated. Analyses may be described using graphical plots and/or 
descriptive statistics.
10.3.3
Loss of Heterozygosity (LOH)
The percentage of genomic loss of heterozygosity (% LOH) will be determined from all 
tissue samples with adequate sequencing data. The concordance between % LOH in archival 
and metastatic samples will be evaluated. The relationship between % LOH and response to 
rucaparib may also be explored.
10.3.4
Mechanisms of Response and Resistance
Genomic test results from plasma and tissue samples will be used to evaluate mechanisms of 
innate and acquired resistance to rucaparib. Due to the exploratory and complex nature of 
these analyses, analyses are likely to be reported using graphical plots and/or descriptive 
statistics (or other methods as appropriate).
10.4
Examination of Efficacy in Subgroups
Subgroup analyses of the primary endpoint (rPFSirr) will be presented for the following: 
The stratification factors used for randomization
-
ECOG performance status (0, 1)
-
Presence, absence of hepatic metastases 
-
Gene (BRCA1, BRCA2, ATM) 
Age groups (< 65, 65-


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Race (White, Other, Unknown)
Region (US, non-US)
Germline status (germline, somatic) in the BRCA subgroup
Type of p
choice of therapy
-
AR-directed therapy (enzalutamide + abiraterone) vs rucaparib
-
Docetaxel vs rucaparib
11 SAFETY ANALYSIS
The safety analyses will be presented for the Safety Population presenting the data for each 
treatment group separately and overall. All safety data which is considered 
treatment-emergent will be summarized. Treatment-emergent is defined as safety data with 
an onset date on or after the date of first dose of study drug until the date of the last study 
drug plus 28 days, or up to the date of first dose of rucaparib for those patients who cross 
over from p
choice.
Safety data will be presented for the Cross-over phase separately, using the safety assessment 
before or on the date of first dose of rucaparib as the baseline value for the Cross-over phase 
for the patients who cross over.
11.1
Adverse Events
AEs will be classified using the MedDRA version 23.0 or higher classification system. The 
severity of the toxicities will be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) whenever possible. 
Treatment--emergent adverse events (TEAEs) are defined as events with an onset date on or 
after the date of first dose of study drug until the date of the last study drug plus 28 days, or 
up to the date of first dose of rucaparib for those patients who cross over from p
choice of therapy. Also AEs will be considered treatment-emergent if all or part of the date 
of onset of the adverse event is missing and it cannot be determined if the AE meets the 
definition for treatment-emergent.
The number and percentage of patients who experienced TEAEs for each SOC and PT will 
be presented. Multiple instances of the TEAE in each SOC and multiple occurrences of the 
same PT are counted only once per patient. The number and percentage of patients with at 
least one TEAE will also be summarized.
MedDRA PTs will be combined for the following similar terms:
Asthenia/Fatigue;
Alanine Aminotransferase (ALT)/ Aspartate Aminotransferase (AST) Increased;
Anaemia and/or Decreased Haemoglobin;
Thromobocytopenia and/or Decreased Platelets;
Neutropenia and/or Decreased Absolute Neutrophil Count (ANC);


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Rash (PTs below):
Blister
Blood blister
Dermatitis
Dermatitis 
acneiform
Dermatitis 
allergic
Dermatitis 
bullous
Dermatitis 
contact
Eczema
Palmar-plantar 
erythrodysaesthesia 
syndrome
Photosensitivity 
reaction
Pruritus
Pruritus 
allergic
Pruritus genital
Psoriasis
Rash
Rash 
erythematous
Rash 
maculo-
papular
Rash papular
Rash pruritic
Scrotal 
dermatitis
Seborrhoeic 
keratosis
Skin burning 
sensation
Skin candida
Skin discolouration
Skin disorder
Skin 
exfoliation
Skin 
haemorrhage
Skin 
hyperpigmentation
Skin induration
Skin lesion
Skin oedema
Skin toxicity
Skin ulcer
Solar dermatitis
Urticaria
Separate tables will be presented as follows:
TEAE Overview;
All TEAEs;
Treatment-related TEAEs;
Grade 3 or greater TEAEs;
Grade 3 or greater treatment-related TEAEs;
Serious TEAEs;
Serious treatment-related TEAEs;
TEAEs by PT;
Treatment-related TEAEs by PT;
TEAEs by CTCAE grade;
Treatment-related TEAEs by CTCAE grade;
TEAEs with an outcome of death;
Treatment-related TEAEs with an outcome of death;
TEAEs leading to discontinuation of study drug;
Treatment-related TEAEs leading to discontinuation of study drug;
TEAEs resulting in reduction of study drug;
Treatment-related TEAEs resulting in reduction of study drug;
TEAEs resulting in interruption of study drug;
Treatment-related TEAEs resulting in interruption of study drug;
TEAEs resulting in reduction or interruption of study drug;


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Treatment-related TEAEs resulting in reduction or interruption of study drug;
TEAEs resulting in reduction or interruption or discontinuation of study drug;
Treatment-related TEAEs resulting in reduction or interruption or discontinuation of 
study drug.
The incidence of TEAEs will be summarized by relationship to study drug according to the 
following categories:
-
-
If a patient experiences 
multiple occurrences of the same AE with different relationship categories, the patient will be 
counted once, as a relationship category of treatment related.
If a patient experiences multiple occurrences of the same AE with different toxicity grades, 
the patient will be counted once for the maximum (most severe) toxicity grade. AEs with a 
missing toxicity grade will be presented in the summary table with a toxicity grade of 
For each toxicity grade, the number and percentage of patients with at least one 
TEAE of the given maximum grade will be summarized.
The time to certain adverse events will also be explored using KM methodology. The time to 
event will be defined as 1+ the number of days from the first dose of study drug to the start of 
the first applicable adverse event. The cumulative incidence will be presented in a 1-KM
graph for just the patients with an event and the median time to onset will be calculated 
together with the 95% CI for the following:
First TEAE and that led to dose reduction;
First treatment-related TEAE that led to dose reduction;
First TEAE and that led to dose interruption;
First treatment-related TEAE that led to dose interruption;
First TEAE and that led to discontinuation of study drug;
First treatment-related TEAE that led to discontinuation of study drug;
First TEAE of combined terms for anemia;
First treatment-related TEAE of combined terms for anemia.
Non-TEAEs (pre-treatment and post-treatment) will be presented in the by patient data 
listings for the safety population. 
Transfusions (blood or plasma) and concomitant medications / growth factor support will be
provided in patient listings and the number of transfusions will be summarized. 
11.2
Clinical Laboratory Evaluations
Clinical laboratory evaluations include the continuous variables for hematology, serum 
chemistry, and urinalysis. The laboratory values will generally be presented in SI units. The 
on-treatment period will be defined as the date of the first dose of study drug until the date of 
the last dose of study drug plus 28 days, or up to the date of first dose of rucaparib for those 
patients who cross over from p
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treatment period will be included in the summary tables. The laboratory values collected 
outside of the on-treatment period will only be presented in the data listings. 
The summary of laboratory data will include tables based on CTCAE grades generally using 
CTCAE version 5.0. A few assessments (eg, hyperglycemia, hypophosphatemia, and 
hyponatremia) may use version 4.03 as quantitative grading is not available in version 5.0.
Where available, baseline, worst post-baseline, and shift to worst post-baseline grade during 
the on-treatment period will be summarized. The baseline value will be defined as the value 
closest to, but not subsequent to, the date of first dose.
The summary of laboratory data will also include descriptive statistics (N, mean, StD,
minimum, median, and maximum) of the maximum, minimum, and last value during the 
on-treatment period. Summaries using descriptive statistics of the change from baseline to 
the maximum, minimum, and last value during the on-treatment period will also be 
presented. 
Summary tables and longitudinal plots of the mean (and/or percent) changes from baseline to 
each scheduled visit may also be presented for select laboratory parameters. These outputs 
30%) of patients have data.
Supporting laboratory data including normal ranges and abnormal laboratory flags may be 
provided using by-patient listings. Separate listings may be produced for laboratory 
abnormalities that meet Grade 3 or 4 criteria according to CTCAE.
11.3
Vital Signs
The on-treatment period will be defined as the time from first dose of study drug to 28 days 
after the last dose of study drug, or start of first dose of rucaparib for those patients who cross 
over from 
hoice. Vital sign measurements collected during the on-treatment 
period will be included in the summary tables. The vital sign measurements collected outside 
of the on-treatment period will only be presented in the data listings.
The summary of vital sign data will include descriptive statistics (N, mean, StD, minimum, 
median, and maximum) of the maximum, minimum and last value during the on-treatment 
period. Summaries using descriptive statistics (N, mean, StD, minimum, median, and 
maximum) of the change from baseline to the maximum, minimum, and last value during the 
on-treatment period will also be presented. The data will be presented separately for each 
randomized treatment group, and overall.
11.4
ECGs
ECGs are collected at Screening (within 28 days prior to enrollment), at the Treatment 
Discontinuation Visit, and if clinically indicated, at other times during the study. The 
following are measured or calculated: heart rate, PR, QRS, QT, and QTc. Descriptive 
statistics (N, mean, StD, minimum, median, and maximum) will be used to summarize ECG 
parameters at Screening and at Treatment Discontinuation.


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11.5
Examination of Safety in Subgroups
Safety will be further explored in the following subgroups: 
HRR gene (BRCA1, BRCA2, ATM)
Germline status (germline, somatic) in the BRCA subgroup
Age groups (< 65, 65-74, 75)
Race (White, Other, Unknown)
Region (US, non-US)
Type of 
s choice therapy
-
AR-directed therapy (enzalutamide + abiraterone) vs rucaparib
-
Docetaxel vs rucaparib


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12 REFERENCES
1. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
Eur J Cancer. 2009;45(2):228-47.
2. Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, et al. Trial Design and 
Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From 
the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol. 2016.
3. Haybittle JL. Repeated assessment of results in clinical trials of cancer treatment. Br J 
Radiol. 1971;44(526):793-7.
4. Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, et al. Design and 
analysis of randomized clinical trials requiring prolonged observation of each patient. I. 
Introduction and design. Br J Cancer. 1976;34(6):585-612.
5. Watkins C, Huang X, Latimer N, Tang Y, Wright EJ. Adjusting overall survival for 
treatment switches: commonly used methods and practical application. Pharm Stat. 
2013;12(6):348-57.
6. Latimer NR, Abrams KR, Lambert PC, Morden JP, Crowther MJ. Assessing methods for 
dealing with treatment switching in clinical trials: A follow-up simulation study. Stat 
Methods Med Res. 2018;27(3):765-84.


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Appendix 1
FACT-P (Version 4)
A sample form for the FACT-P is below and background for the questionnaire is available at
http://www.facit.org/facitorg/questionnaires.








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Appendix 2
Brief Pain Inventory 
Short Form
A sample form for the BPI-SF is below and background for the questionnaire is available at 
https://www.mdanderson.org/research/departments-labs-institutes/departments-
divisions/symptom-research/symptom-assessment-tools/brief-pain-inventory.html.


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Appendix 3
Euro-Quality of Life 5 Dimension 5 Level (EQ-5D-5L)
A sample form for the EQ-5D-5L is included on the next page. Background information for 
the questionnaire is available at https://euroqol.org/.


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Appendix 4
Analgesic Use Questionnaire
A sample form for the Analgesic Use Questionnaire is below: 


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Appendix 5
Amendment History
Brief Description of Notable Changes from SAP version 1.0 (23 Oct 2019) to version 2.0
(28 Feb 2022)
Overall Survival was elevated to the first secondary endpoint analysis included in the 
step-down procedure [Section 3.3]
Added a stopping rule (Haybittle-Peto) to adjust for multiple OS analyses (one at time of 
primary analysis and a final OS analysis when OS data is more mature) [Section 10.2.1]
Clarified that the log-rank statistic will be used for the PFS and OS analyses in the step-
down procedure [Section 3.3, Section 10.1, Section 10.2.1]
Removed Duration of Response and PSA-based endpoints from the step-down procedure 
[Section 3.3]
Pooling strategy to deal with potential small cell sizes among the stratification variables 
and/or SAS convergence issues was added [Section 3]
Specified the use of unstratified analyses for all but the primary endpoints [Section 3]
Clarified censoring rules for PFS analyses [Section 10.1]
Clarified that after the analysis of the primary endpoint is completed, for patients 
treatment, the eligibility to cross over (to rucaparib) will 
be determined by radiographic progression as assessed by the investigator and scans will 
no longer be read by IRR [Section 2.2]
PRO analyses for patient experience data which includes aspects of healthcare utilization 
and clinical outcome assessments were added [Section 10.2.7]
Specified a combined term for Rash for use in AE tables [Section 11.1]
Brief Description of Notable Changes from SAP version 2.0 (28 Feb 2022) to version 3.0
(1 July 2022)
Updated the timing of the primary endpoint analysis [Section 2.3]
Specified the use of stratified analyses for OS in the step-down procedure [Section 3] and 
[Section 10.2.1]
Added potential sensitivity analyses to explore the effect of cross over to rucaparib 
treatment on OS [Section 10.2.1]
Minor editorial corrections and format changes for consistency with the Clovis style 
guide