Conditions: Metastatic Castration Resistant Prostate Cancer
Keywords: CRPC PARP inhibitor PARPi BRCA ATM HRD TRITON homologous recombination DNA repair DNA defect DNA anomaly BARD1 BRIP1 CDK12 CHEK2 FANCA NBN PALB2 RAD51 RAD51B RAD51C RAD51D RAD54L germline somatic mCRPC
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 277
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine how patients with metastatic castration-resistant prostate cancer, and evidence of a homologous recombination gene deficiency, respond to treatment with rucaparib.

Detailed description:

Arms:
arm 1: Oral rucaparib (monotherapy)

Interventions: intervention 1: Rucaparib
Intervention descriptions: intervention 1: Rucaparib will be administered daily

Protocol document:
Prot_000.pdf: 


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PROTOCOL APPROVAL SIGNATURE PAGE 
Protocol: 
CO-338-052 
Title: 
TRITON2: A Multicenter, Open-label Phase 2 Study of Rucaparib in 
Patients with Metastatic Castration-resistant Prostate Cancer 
Associated with Homologous Recombination Deficiency 
Date: 
24 August 2020 
Version: 
Amendment 4 
 
 
 
 
Reviewed and Approved by: 
 
DocuSign Envelope ID: 78681B12-CCF0-4042-9EC9-FD61F8D89AA7


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PROTOCOL ACCEPTANCE FORM 
Protocol: 
CO-338-052 
Title: 
TRITON2: A Multicenter, Open-label Phase 2 Study of Rucaparib in 
Patients with Metastatic Castration-resistant Prostate Cancer Associated 
with Homologous Recombination Deficiency 
 
Date: 
24 August 2020 
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 
TRITON2: A Multicenter, Open-label Phase 2 Study of Rucaparib in Patients with Metastatic 
Castration-resistant Prostate Cancer Associated with Homologous Recombination Deficiency 
Study Number 
CO-338-052  
Study Phase 
Phase 2 
Study Contact Information: 
This is a multicenter study. Information on investigators, institutions, and laboratories 
involved in the trial are maintained in the clinical study file and can be provided upon request. 
Contact information for the sponsor’s medical and other study-related personnel are available 
in the Study Reference Binder. 
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 repair (HRR) of the DNA, a complex process involving multiple proteins, 
including those encoded by breast cancer susceptibility gene 1 and 2 (BRCA1 and BRCA2), as 
well as RAD51, Fanconi anemia core complex, ataxia telangiectasia mutated serine/threonine 
kinase (ATM) 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 2nd 
leading malignancy diagnosis and 5th leading cause of death from cancer 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 metastatic 


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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.  
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 HRR 
genes eg, ATM, 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 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, but responses were observed in patients with 
mutations in these and other genes, including PALB2 and CHEK2.9 These findings provide 
compelling evidence for use of a PARPi in a selected population of CRPC patients with 
predicted loss-of-function mutations in HRR genes, including BRCA1/2 and ATM. 
Androgen deprivation therapy is the standard first-line systemic treatment for metastatic 
prostate cancer. It is highly active with clinical, radiological 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 2 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 
16-18 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. 


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Primary Objective: 
• To assess the efficacy of rucaparib based on the response rate in mCRPC patients with 
HRD who progressed on AR-targeted therapy (abiraterone acetate, enzalutamide, 
apalutamide, or investigational AR-targeted agent) and taxane-based chemotherapy in 
the castration-resistant setting  
Secondary Objectives: 
• To assess duration of response (DOR) 
• To assess radiologic PFS (rPFS) 
• To assess overall survival (OS) 
• To assess clinical benefit rate (CBR) 
• To assess PSA response ≥ 50% (all patients) 
• To assess PSA response ≥ 90% (all patients) 
• To assess time to PSA progression 
• To characterize the steady-state pharmacokinetics (PK) of rucaparib in mCRPC 
patients 
• To assess safety and tolerability 
Exploratory Objectives: 
• To evaluate Patient-reported Outcome (PRO) using the 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 changes in the molecular profile over time of matched pre and post-treatment 
tumor or plasma samples 
• To assess concordance in HRR gene mutation status in matched Pre-Screening biopsy 
tissue, archival primary and metastatic tumor tissue, and plasma circulating tumor 
DNA (ctDNA) 
• To assess ctDNA as a molecular marker of response 
• To assess time to first subsequent antineoplastic therapy 
• 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 2 multicenter study evaluating rucaparib for treatment of patients with mCRPC 
whose tumors are associated with HRD. This study will enroll mCRPC patients with 
deleterious mutations in BRCA1/2, ATM, or other HRR genes associated with sensitivity to 
PARPi (Appendix 1). All patients will be required to have progressed on prior AR-targeted 
therapy (abiraterone acetate, enzalutamide, apalutamide, or investigational AR-targeted agent) 
after receiving treatment with at least 1, but no more than 2, of these agents. Patients must also 
have progressed after 1 prior line of taxane-based chemotherapy for mCRPC. Patients who 
received prior PARPi treatment, mitoxantrone, cyclophosphamide or platinum-based 
chemotherapy will be excluded.  
This study consists of a Pre-Screening Phase, Screening Phase, Treatment Phase, and 


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Post-Treatment Phase. Patients will receive rucaparib monotherapy in the Treatment Phase, 
and will undergo procedures and assessments including regular safety and efficacy evaluations 
during the entire conduct of the study. 
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 HRR gene mutations. If a patient has an eligible 
deleterious mutation in a HRR gene 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 HRR gene mutations. All patients must have a 
deleterious mutation in BRCA1/2, ATM, or other HRR genes associated with sensitivity to 
PARPi (Appendix 1) 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.  
Treatment Phase 
Rucaparib will be administered at a starting dose of 600 mg BID. Tumor assessments by 
CT/MRI and bone scans will be performed during screening, 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 radiologic response in soft tissue 
(visceral and nodal) disease and Prostate Cancer Working Group 3 (PCWG3) criteria will be 
used to document radiologic progression in bone lesions. Any drug modifications 
(interruption, dose reduction, or discontinuation) should be documented in the 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 radiologic scans will be collected for 
central independent radiology review (IRR). 
Patients will receive rucaparib until confirmed radiologic disease progression assessed by 
investigator based on modified RECIST Version 1.1 and/or 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. PSA rise without evidence of 
confirmed radiologic 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 


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start a new systemic antineoplastic therapy throughout the study. 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 has radiologic progression, but continues to derive clinical benefit per the 
investigator, then continuation of treatment beyond progression may be requested by 
investigator. In such cases, the decision to continue will be made jointly between the 
investigator and the sponsor (or designee), and the patient must consent prior to continuing 
treatment with rucaparib. 
Safety data will be periodically reviewed by Data Monitoring Committee (DMC). The DMC 
will comprise study investigators and sponsor representatives. The DMC will meet after the 
first 20 patients received rucaparib for at least 28 days or discontinued study treatment, and 
then at least semi-annually. 
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 or unequivocal clinical disease progression and provide appropriate 
consent.  
If treatment was discontinued for reasons other than radiologic disease progression, radiologic 
tumor assessment (using the same methodology as was used at initial study screening [eg, 
CT scan]) and PRO assessments will continue until confirmed radiographic disease 
progression. 
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, 
only SAEs considered as potentially related to study drug should be reported per Clovis 
Pharmacovigilance (PV) requirements and captured in the Clovis PV database. This includes 
serious reports of pneumonitis or associated events, if considered to be related to study drug. 
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 PV 
requirements and captured in the Clovis PV database. 
• AESIs of pneumonitis or associated events should only be reported up to, but not beyond, 
the 28-Day Follow-up Visit (28-days after the last dose of rucaparib). 
 
All patients will be followed for survival and subsequent treatments every 12 weeks 
(± 14 days) relative to the last dose of rucaparib until death, loss to follow-up, withdrawal of 
consent, or study closure. 


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Number of Patients 
The total enrollment planned for this study is approximately 360 patients across 3 cohorts as 
follows: 
• Cohort A will include up to 100 patients with a deleterious BRCA1/2 mutation who 
have measurable visceral and/or nodal disease (with a maximum of 60 patients who 
have only measurable lymph node disease), and up to approximately 50 patients 
with a deleterious ATM mutation who have measurable visceral and/or nodal 
disease 
• Cohort B will include up to approximately 100 patients with a deleterious 
BRCA1/2 mutation and up to approximately 50 patients with a deleterious ATM 
mutation who do not have measurable visceral and/or nodal disease 
• Cohort C will include up to approximately 60 patients with or without measurable 
visceral and/or nodal disease who have a deleterious mutation in a HRR gene other 
than BRCA1/2 or ATM.  
 
Number of Sites 
Patients will be enrolled across approximately 150 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 (IRB)/Independent Ethics Committee 
(IEC)-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 
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). For patients currently being treated with luteinizing hormone–releasing 
hormone (LHRH) analogs (ie, patients who have not undergone an orchiectomy), 
therapy must be continued throughout the study 
5. Evidence of disease progression after prior therapy for prostate cancer: 
a. Disease progression after treatment with at least 1 but no more than 2 prior 
next-generation AR-targeted therapies (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, 
AND 
b. Disease progression after treatment with 1 prior line of taxane-based 
chemotherapy for castration-resistant disease. Prior taxane therapy 
administered for hormone-sensitive disease is permitted and is not counted 
toward this limit. 
6. Disease progression after initiation of most recent therapy is based on any of the 
following criteria: 


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a. Rise in PSA: a minimum of 2 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 RECIST 1.1 
c. Radionuclide bone scan: at least 2 new metastatic lesions  
7. Patients in Cohorts A and B must have a deleterious mutation in BRCA1/2 or ATM  
Patients in Cohort C must have a deleterious mutation in another HRR gene 
associated with sensitivity to PARPi (Appendix 1)  
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 
8. Patients in Cohort A must have measurable visceral or nodal disease per 
RECIST v1.1 criteria (Appendix 2) 
Patients in Cohorts B and C (without measurable disease) must have 
PSA ≥ 2 ng/mL on the most recent measurement  
9. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 
(Appendix 3) 
10. Have adequate organ function confirmed by the following clinical laboratory 
values obtained within 14 days prior to the first dose of rucaparib: 
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 × 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 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 be enrolled if they 
are:  
i. Documented to be surgically sterile (ie, vasectomy);  


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ii. Committed to practicing true abstinence during treatment and for 
3 months after the last rucaparib dose; or 
iii. Committed to using an effective method of contraception (refer to 
protocol) with their partner during treatment and for 3 months following 
the last dose of rucaparib 
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 
- 
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 trial 
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 PARP inhibitor, mitoxantrone, cyclophosphamide or any 
platinum-based chemotherapy 
3. 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 rucaparib) and have had appropriate scans at screening assessment 
4. Symptomatic or impending spinal cord compression unless appropriately treated, 
clinically stable, and asymptomatic 
5. Pre-existing duodenal stent and/or any gastrointestinal (GI) disorder or defect that 
would, in the opinion of the investigator, interfere with absorption of rucaparib 
6. 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 
7. Received treatment with chemotherapy, antibody therapy or other immunotherapy, 
gene therapy, vaccine therapy, angiogenesis inhibitors, or experimental drugs 
within < 2 weeks prior to first dose of rucaparib. Treatment with hormonal 
therapies (with the exception of LHRH analog) must be discontinued at least 7 days 
prior to the first dose of rucaparib  
8. 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 
9. Initiated low-dose corticosteroid, bisphosphonate, or denosumab therapy or 
adjusted low-dose corticosteroid, bisphosphonate, or denosumab dose/regimen 
within < 4 weeks prior to first dose of rucaparib. Patients on a stable low-dose 
corticosteroid, bisphosphonate, or denosumab regimen are eligible and may 
continue treatment 


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10. Non-study related minor surgical procedure within < 5 days, or major surgical 
procedure within < 21 days, prior to first dose of rucaparib; in all cases, the patient 
must be sufficiently recovered and stable before treatment administration 
11. 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 
Study Treatment 
The starting dose and schedule of rucaparib is 600 mg ingested twice a day (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 will be provided as 200, 250, and 300 mg dose strength tablets. Tablets should 
be swallowed whole. 
Dose holds or reductions are permitted in the event of unacceptable toxicity. 
Patients will receive rucaparib until confirmed radiologic disease progression as assessed by 
investigator using modified RECIST Version 1.1 and/or 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. However, if a patient receiving 
rucaparib has met criteria for confirmed radiologic 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. 
For patients who have not undergone an orchiectomy and are currently being treated with 
luteinizing hormone-releasing hormone (LHRH) analogs at the time of consent, therapy must 
be continued throughout the study. 
No other anticancer therapies (including chemotherapy, radiation, antibody or other 
immunotherapy, gene therapy, vaccine 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. 


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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. 
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, 
and CYP3A, and showed no clinically significant effect on P-gp. Caution should be exercised 
in the concomitant use of drugs that are substrates of the above CYP enzymes with narrow 
therapeutic windows. 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 MATE1 and MATE2-K, a moderate inhibitor of 
OCT1, and a weak inhibitor of OCT2. As inhibition of these transporters could increase 
metformin 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: 
• confirmed radiologic disease progression as assessed by investigator using modified 
RECIST Version 1.1 and/or 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. 
Efficacy Assessments 
Soft tissue (visceral and nodal) disease will be evaluated for evidence of radiographic response 
based on modified RECIST 1.1 criteria (Appendix 2). Bone lesions will be followed and 
evaluated for evidence of radiologic progression based on PCWG3 criteria (Appendix 2). 
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 radiologic disease progression by modified 
RECIST Version 1.1 and/or PCWG3 (for bone lesions only) criteria, as assessed by the 
investigator, loss to follow-up, withdrawal, or study closure. Tumor assessments should be 
performed at the time of treatment discontinuation, at the 28-day Follow-up visit, or during 
Long-term Follow-up if the reason was other than radiologically 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 


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progression. 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 RECIST 
Version 1.1); other studies (MRI, X-ray, 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 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 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 scans (and other imaging, as appropriate) will be collected from all patients for 
IRR. 
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, urinalysis); 
• Vital signs (blood pressure, heart rate, and body temperature); 
• 12–lead ECGs; 
• Physical examinations; and 
• ECOG performance status. 
Statistical Methods 
Sample Size Justification and Interim Analysis 
The enrollment planned for this study is approximately 360 patients, with up to approximately 
150 patients in Cohort A with measurable visceral and/or nodal disease (ie, up to 100 patients 
with a deleterious BRCA1/2 mutation [with a maximum of 60 patients who have only 
measurable lymph node disease], and up to approximately 50 patients with a deleterious ATM 
mutation), up to approximately 150 patients in Cohort B (ie, up to approximately 100 patients 
with a deleterious BRCA1/2 mutation and 50 patients with a deleterious ATM mutation), and 
up to approximately 60 patients in Cohort C.  
Cohort A 
Cohort A will be divided into 2 sub-cohorts defined by deleterious gene mutation (BRCA1/2 
vs. ATM). 
Cohort A (BRCA1/2) 
A Simon 2-stage design to evaluate confirmed ORR by modified RECIST Version 1.1 
criteria per investigator will be used. With rolling enrollment, after the first 37 patients with 
a deleterious BRCA1/2 mutation have either: a) completed 16 weeks of treatment or b) 
discontinued treatment prior to completing, an interim analysis will be performed (ie, 
Stage 1). If ≤ 8/37 patients in Stage 1 have a confirmed objective response (CR or PR per 


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investigator and without progression in bone per PCWG3), the DMC will evaluate the 
overall benefit/risk for patients with deleterious BRCA1/2 mutations in this cohort and 
make a recommendation whether further enrollment should be discontinued. If 
≥ 9/37 patients have a confirmed objective response, then enrollment will continue with 
additional patients in Stage 2. With 83 total patients with a deleterious BRCA1/2 mutation, 
characteristics of the Simon 2-stage design include: 
o 
5% probability of accepting a minimally effective drug 
o 
90% probability of accepting an effective drug 
o 
ORR of 20% for a minimally effective drug 
o 
ORR of 35% for an effective drug 
If there are at least 23 responses in 83 patients with a deleterious BRCA1/2 mutation, the 
null hypothesis (ORR = 20%) will be rejected. This design yields a type I error rate of 5% 
and power of 90% when the true response rate is 35%. 
Note: If the study is to proceed to Stage 2, additional patients with a deleterious BRCA1/2 
mutation up to 100 total patients (and a maximum of 60 patients with only measurable 
lymph node disease) will be enrolled in Cohort A (BRCA1/2) if additional clinical data is 
requested by the regulatory authorities to support regulatory filing. If sufficient evidence 
exists to support a regulatory filing prior to fully enrolling Cohort A (BRCA1/2), enrollment 
may be discontinued early. 
Cohort A (ATM) 
Patients in Cohort A (ATM), having a deleterious ATM mutation, will be enrolled 
concurrently with patients from Cohort A (BRCA1/2). It is expected that about 1/3 of the 
Cohort A patients will have deleterious ATM mutations. If 100 patients are enrolled in 
Cohort A (BRCA1/2), then approximately 50 patients would be expected to enroll into 
Cohort A (ATM). 
A Simon 2-stage type futility rule will be employed in Cohort A (ATM). An interim 
analysis (Stage 1) will be performed after the first 31 patients have either: a) completed 
16 weeks of treatment; or b) discontinued treatment prior to completing. Enrollment into the 
study will continue while this interim analysis occurs. If ≤ 6/31 patients in Stage 1 have a 
confirmed objective response (CR or PR per investigator and without progression in bone 
per PCWG3), the DMC will evaluate the overall benefit/risk for patients with deleterious 
ATM mutations in this cohort and make a recommendation whether further enrollment 
should be discontinued. If ≥ 7/31 patients have a confirmed objective response, then 
enrollment will continue in Stage 2. With 53 total patients with a deleterious ATM 
mutation, characteristics of the Simon 2-stage (minimax) design include: 
o 
5% probability of accepting a minimally effective drug 
o 
80% probability of accepting an effective drug 
o 
ORR of 20% for a minimally effective drug 
o 
ORR of 35% for an effective drug 
If there are at least 16 responses in 53 patients with a deleterious ATM mutation, the null 
hypothesis (ORR = 20%) will be rejected. This design yields a type I error rate of 5% and 
power of 80% when the true response rate is 35%. 


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Cohort B 
Cohort B will be divided into 2 sub-cohorts defined by deleterious gene mutation (BRCA1/2 
vs. ATM). Cohort B will be enrolled concurrently with Cohort A and is expected to enroll at 
approximately the same rate as Cohort A. Enrollment in Cohort B will be halted when 
Cohort A (BRCA1/2) is fully enrolled. Therefore, it is anticipated that up to approximately 
150 patients may be enrolled in Cohort B. 
Cohort B (BRCA1/2) 
A Simon 2-stage type futility rule will be employed in Cohort B (BRCA1/2). An interim 
analysis (Stage 1) will be performed after the first 19 patients have either: a) completed 
16 weeks of treatment; or b) discontinued treatment prior to completing. Enrollment into the 
study will continue while this interim analysis occurs. If ≤ 4/19 patients in Stage 1 have a 
PSA response (≥ 50% decrease), the DMC will evaluate the overall benefit/risk for patients 
with deleterious BRCA1/2 mutations in this cohort and make a recommendation whether 
further enrollment should be discontinued. If ≥ 5/19 patients have a PSA response, then 
enrollment will continue in Stage 2. With 54 total patients with a deleterious BRCA1/2 
mutation, characteristics of the Simon 2-stage design include: 
o 
5% probability of accepting a minimally effective drug 
o 
90% probability of accepting an effective drug 
o 
ORR of 20% for a minimally effective drug 
o 
ORR of 40% for an effective drug 
If there are at least 16 responses in 54 patients with a deleterious BRCA1/2 mutation, the 
null hypothesis (ORR = 20%) will be rejected. This design yields a type I error rate of 5% 
and power of 90% when the true response rate is 40%. Additionally, if the criteria for 
Stage 2 are met, additional patients, up to approximately 100 total, may be enrolled. 
Enrollment in Cohort B (BRCA1/2) will be halted when Cohort A (BRCA1/2) is fully 
enrolled. 
Cohort B (ATM) 
Patients in Cohort B (ATM), having a deleterious ATM mutation, will be enrolled 
concurrently with patients from Cohort B (BRCA1/2). It is expected that about 1/3 of the 
Cohort B patients will have deleterious ATM mutations. If 100 patients are enrolled in 
Cohort B (BRCA1/2), then approximately 50 patients would be expected to enroll into 
Cohort B (ATM). 
A Simon 2-stage type futility rule will be employed in Cohort B (ATM). An interim 
analysis (Stage 1) will be performed after the first 18 patients have either: a) completed 
16 weeks of treatment; or b) discontinued treatment prior to completing. Enrollment into the 
study will continue while this interim analysis occurs. If ≤ 4/18 patients in Stage 1 have a 
PSA response (≥ 50% decrease), the DMC will evaluate the overall benefit/risk for patients 
with deleterious ATM mutations in this cohort and make a recommendation whether further 
enrollment should be discontinued. If ≥ 5/18 patients have a PSA response, then enrollment 
will continue in Stage 2. With 33 total patients with a deleterious ATM mutation, 
characteristics of the Simon 2-stage (minimax) design include: 


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o 
5% probability of accepting a minimally effective drug 
o 
80% probability of accepting an effective drug 
o 
ORR of 20% for a minimally effective drug 
o 
ORR of 40% for an effective drug 
If there are at least 11 responses in 33 patients with a deleterious ATM mutation, the null 
hypothesis (ORR = 20%) will be rejected. This design yields a type I error rate of 5% and 
power of 80% when the true response rate is 40%. Additionally, if the criteria for Stage 2 
are met, additional patients, up to approximately 50 total, may be enrolled. Enrollment in 
Cohort B (ATM) will be halted when Cohort A (BRCA1/2) is fully enrolled.  
Cohort C 
Up to approximately 60 patients will be enrolled into Cohort C. Enrollment in Cohort C will 
be halted when Cohort A (BRCA1/2) is fully enrolled. Since this cohort will enroll patients 
that have 1 of several different deleterious HRR gene mutations, each gene will be examined 
separately. It is anticipated that < 6 patients will have a deleterious mutation in the same HRR 
gene; however, if enrollment of patients with a deleterious mutation in the same gene is higher 
than anticipated then enrollment will be held at 6 patients with any 1 deleterious gene mutation 
and a futility rule will be implemented such that if no responses are observed, then enrollment 
of patients with a deleterious mutation in that particular gene will be stopped, in consultation 
with the DMC.  
Primary Efficacy Analysis:  
Cohort A: The primary endpoint is ORR as assessed by central IRR and analyzed separately 
for patients with deleterious BRCA1/2 and ATM mutations. ORR for Cohort A 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 by IRR assessment). 
Cohort B: The primary endpoint is PSA response (≥ 50% decrease) as assessed by a local 
laboratory and analyzed separately for patients with deleterious BRCA1/2 and ATM 
mutations. The proportion of patients with ≥ 50% PSA decrease from baseline will be 
reported. 
Cohort C: The primary endpoint is ORR defined as the proportion of patients with a confirmed 
response of CR or PR using either modified RECIST Version 1.1 (if measurable visceral 
and/or nodal disease is present) or ≥ 50% PSA decrease from baseline (if visceral and/or nodal 
disease is absent). For patients with measurable disease, response will be assessed by central 
IRR. 
Secondary Efficacy Analyses: 
Duration of response is defined as the time from the date that a response (modified RECIST 
Version 1.1 or PSA ≥ 50%) is first reported to the time that progression (using modified 
RECIST Version 1.1/PCWG3 criteria or PSA-progression criteria, respectively) is 
documented. 
Radiologic PFS (rPFS) is defined as the time from first dose of rucaparib to the date of first 
objective evidence of radiographic progression (soft tissue or bone lesion) or death due to any 
cause, whichever occurs first. Radiologic disease progression includes confirmed bone disease 


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progression and soft tissue disease progression adjudicated by independent central radiological 
review using the PCWG3 guidelines for bone disease and modified RECIST Version 1.1 for 
soft tissue disease.  
OS is defined as the date from first dose of rucaparib to the date of death due to any cause. 
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. Per RECIST, 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.  
Confirmed PSA response is defined as ≥ 50% 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 1 post-
baseline assessment. PSA will be assessed by a local laboratory. 
Time to PSA progression is defined as the time from first dose of rucaparib 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. 
Safety Analyses 
Adverse events (AEs), clinical laboratory results, vital signs, ECOG performance status, body 
weight, and concomitant medications/ procedures will be tabulated and summarized. AEs will 
be summarized overall and separately for SAEs, AESIs, AEs leading to discontinuation, AEs 
leading to death, and Grade 3 or higher AEs graded using National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.03 or higher. Body weight and 
vital signs will be summarized descriptively (N, mean, standard deviation, median, minimum, 
and maximum). ECOG performance status will be summarized categorically.  
A DMC will review safety and efficacy data on a periodic basis to ensure an acceptable overall 
risk and benefit for patients participating in the study. 
Date of Protocol Amendment 4 Approval 
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TABLE OF CONTENTS 
1 SYNOPSIS .................................................................................................................................4 
LIST OF IN-TEXT TABLES ........................................................................................................23 
LIST OF IN-TEXT FIGURES.......................................................................................................23 
2 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................24 
3 INTRODUCTION ...................................................................................................................29 
3.1 
Investigational Product ................................................................................................29 
3.2 
Background and Rationale for PARP Inhibition .........................................................29 
3.3 
Metastatic Castration-resistant Prostate Cancer ...........................................................29 
3.3.1 
Treatment of Metastatic Castration-resistant Prostate Cancer ...........................30 
3.4 
Prior Experience with Rucaparib .................................................................................31 
3.4.1 
Nonclinical Experience with Rucaparib ............................................................31 
3.4.2 
Clinical Experience with Rucaparib ..................................................................32 
3.5 
Rationale for this Study of Rucaparib ..........................................................................41 
4 STUDY OBJECTIVES ............................................................................................................44 
4.1 
Primary Objective ........................................................................................................44 
4.2 
Secondary Objectives ...................................................................................................44 
4.3 
Exploratory Objectives ................................................................................................44 
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 
Treatment Phase .................................................................................................47 
5.1.4 
Post-treatment Phase ..........................................................................................48 
5.2 
Study Schema...............................................................................................................49 
5.3 
End of Study ................................................................................................................52 
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 
Patients or Partners of Patients Including Those with Reproductive Potential ...........55 
6.5 
Waivers of Inclusion/Exclusion Criteria ......................................................................56 
7 STUDY TREATMENT(S) ......................................................................................................57 
7.1 
Description of Treatment(s) and Storage .....................................................................57 
7.2 
Packaging and Labeling ...............................................................................................57 
7.2.1 
Rucaparib ...........................................................................................................57 
7.3 
Method of Assigning Patients to Treatment Groups ....................................................57 
7.4 
Preparation and Administration of Protocol-specified Treatment ...............................57 


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7.4.1 
Dietary and General Restrictions .......................................................................58 
7.4.2 
Rucaparib Dose Modification Criteria ...............................................................58 
7.4.3 
Rucaparib Dose Modification ............................................................................61 
7.4.4 
Treatment with Rucaparib beyond Disease Progression ...................................61 
7.5 
Blinding/Masking of Treatment ...................................................................................61 
7.6 
Treatment Compliance .................................................................................................62 
7.7 
Accountability of Protocol-specified Treatment ..........................................................62 
8 PRIOR AND CONCOMITANT THERAPY ..........................................................................63 
8.1 
Supportive Care ...........................................................................................................63 
8.2 
Radiotherapy ................................................................................................................63 
8.3 
Luteinizing Hormone-releasing Hormone (LHRH) analogs .......................................63 
8.4 
Anticancer or Experimental Therapy ...........................................................................63 
8.5 
CYP450 Isoenzyme Inhibitors, Inducers, and Substrates ............................................64 
8.6 
Therapies to Control Bone Loss ..................................................................................64 
8.7 
Anticoagulants .............................................................................................................64 
8.8 
Other Concomitant Medications ..................................................................................64 
9 STUDY PROCEDURES AND ACTIVITIES BY VISIT .......................................................65 
9.1 
Schedule of Assessments .............................................................................................65 
9.2 
Informed Consent.........................................................................................................69 
9.3 
Pre-Screening Phase.....................................................................................................69 
9.4 
Screening Phase ...........................................................................................................70 
9.4.1 
Screening: Up to 28 days Prior to Start of Treatment ........................................70 
9.4.2 
Screening: Up to 14 days Prior to Start of Treatment ........................................71 
9.5 
Treatment Phase ...........................................................................................................71 
9.5.1 
Study Day 1 (Week 1) ........................................................................................71 
9.5.2 
Study Day 15 (Week 3) ......................................................................................72 
9.5.3 
Study Day 29 (Week 5) ......................................................................................73 
9.5.4 
Study Day 43 (Week 7) ......................................................................................73 
9.5.5 
Study Day 57 (Week 9) and Every 28 Days Thereafter ....................................74 
9.6 
Post-treatment Phase ....................................................................................................75 
9.6.1 
Treatment Discontinuation Visit ........................................................................75 
9.6.2 
28-Day Follow-up Visit .....................................................................................76 
9.6.3 
Long-term Follow-up .........................................................................................77 
9.7 
Methods of Data Collection .........................................................................................77 
9.7.1 
Medical History and Demographic/ Baseline Characteristics ...........................77 
9.8 
Prior and Concomitant Medication Assessments ........................................................78 
9.9 
Efficacy Evaluations ....................................................................................................78 
9.10 
Safety Evaluations .......................................................................................................78 


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9.10.1 
Adverse Event Assessment ................................................................................78 
9.10.2 
Clinical Laboratory Investigations .....................................................................79 
9.10.3 
Vital Signs ..........................................................................................................80 
9.10.4 
12-Lead Electrocardiogram ...............................................................................80 
9.10.5 
Body Weight and Height ...................................................................................80 
9.10.6 
Physical Examinations .......................................................................................80 
9.10.7 
ECOG Performance Status ................................................................................80 
9.11 
Biomarker Analysis – FFPE Tumor Tissue .................................................................81 
9.12 
Biomarker Analysis – Blood ........................................................................................81 
9.13 
Pharmacokinetics Evaluation .......................................................................................81 
9.14 
Patient Reported Outcomes (Health and Quality of Life Questionnaires) ..................81 
10 ADVERSE EVENT MANAGEMENT ...................................................................................83 
10.1 
Definition of an Adverse Event ...................................................................................83 
10.2 
Definition of a Serious Adverse Event ........................................................................83 
10.3 
Definition of an Adverse Event of Special Interest .....................................................84 
10.4 
Events or Outcomes Not Qualifying as Serious Adverse Events ................................84 
10.5 
Clinical Laboratory Assessments as Adverse Events and Serious Adverse 
Events ...........................................................................................................................84 
10.6 
Pregnancy or Drug Exposure During Pregnancy .........................................................85 
10.7 
Recording of Adverse Events, Serious Adverse Events, and Adverse Events of 
Special Interest .............................................................................................................85 
10.7.1 
Onset Date of Adverse Events ...........................................................................86 
10.7.2 
Resolution Date of Adverse Events ...................................................................86 
10.7.3 
Intensity of Adverse Events ...............................................................................86 
10.7.4 
Causal Relationship of Adverse Events to Rucaparib .......................................87 
10.8 
Follow-up of Adverse Events, Serious Adverse Events, and Adverse Events of 
Special Interest .............................................................................................................87 
10.9 
Potential Drug-induced Liver Injury ............................................................................88 
10.10 Regulatory Aspects of Serious Adverse Event and Adverse Events of Special 
Interest Reporting.........................................................................................................88 
11 PLANNED STATISTICAL METHODS ................................................................................89 
11.1 
General Considerations ................................................................................................89 
11.2 
Determination of Sample Size .....................................................................................89 
11.3 
Analysis Populations ....................................................................................................92 
11.4 
Demographics and Baseline Characteristics ................................................................92 
11.5 
Efficacy Analyses ........................................................................................................92 
11.5.1 
Primary Efficacy Analyses ................................................................................92 
11.5.2 
Secondary Efficacy Analysis .............................................................................93 
11.5.3 
Exploratory Efficacy Analyses ..........................................................................94 


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11.5.4 
Exploratory Pharmacokinetic Analyses .............................................................95 
11.6 
Safety Analyses ............................................................................................................95 
11.6.1 
Adverse Events ..................................................................................................96 
11.6.2 
Clinical Laboratory Evaluations ........................................................................96 
11.6.3 
Vital Sign Measurements ...................................................................................97 
11.7 
Interim Analysis ...........................................................................................................97 
12 PATIENT DISPOSITION .....................................................................................................100 
12.1 
Removal of Patients from the Study or Study Drug ..................................................100 
13 STUDY ADMINISTRATION ..............................................................................................101 
13.1 
Regulatory and Ethical Considerations ......................................................................101 
13.1.1 
Good Clinical Practice .....................................................................................101 
13.1.2 
Regulatory Authority Approvals......................................................................101 
13.1.3 
Institutional Review Board or Independent Ethics Committee Approval .......102 
13.2 
Patient Information and Consent ...............................................................................102 
13.2.1 
General Aspects of Informed Consent .............................................................102 
13.2.2 
Informed Consent Process ...............................................................................103 
13.3 
Patient Confidentiality ...............................................................................................103 
13.4 
Study Monitoring .......................................................................................................103 
13.5 
Case Report Forms and Study Data ...........................................................................104 
13.6 
Data Monitoring Committee ......................................................................................105 
13.7 
Study Termination and Site Closure ..........................................................................105 
13.8 
Study Protocol Amendments .....................................................................................106 
13.9 
Retention of Study Documents ..................................................................................106 
13.10 Quality Control and Assurance ..................................................................................107 
13.10.1 Protocol Deviations ..........................................................................................107 
13.10.2 Study Site Training ..........................................................................................107 
13.10.3 Quality Assurance Audits and Inspections ......................................................107 
13.10.4 Direct Access to Source Data/Documents for Audits and Inspections ............108 
13.11 Clinical Study Report .................................................................................................108 
13.12 Publication and Disclosure Policy .............................................................................108 
13.13 Investigator Oversight ................................................................................................109 
14 REFERENCE LIST ...............................................................................................................110 
15 APPENDICES .......................................................................................................................114 
 
 
 


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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 ............37 
Table 2. Treatment-emergent AEs Reported in ≥ 20% of Patients (All Grades) in Any 
Treatment Group in Study CO-338-014 - Safety Population .......................................38 
Table 3. Change from Baseline in Laboratory Parameters in Patients Treated with 
600 mg BID Rucaparib (Study CO-338-014) ...............................................................40 
Table 4. Rucaparib Dose Reduction Steps ..................................................................................61 
Table 5. Schedule of Assessments ..............................................................................................66 
Table 6. Deleterious HRR Genes Associated with Sensitivity to PARPi* ...............................115 
Table 7. Examples of CYP Substrates with Narrow Therapeutic Range ..................................127 
 
LIST OF IN-TEXT FIGURES 
Figure 1. Pre-Screening Study Schema ........................................................................................50 
Figure 2. Study Schema: Screening, Treatment, and Post-treatment Phases ...............................51 
Figure 3. Controlling for Flare by Applying the 2+2 Rule using the First Post-treatment 
Scan as Baseline ..........................................................................................................123 
 
 


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2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
99m Tc MDP 
99m technecium methyl disphosphonate 
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 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
AR 
androgen receptor 
AST 
aspartate aminotransferase 
ATM 
ataxia telangiectasia mutated serine/threonine kinase 
ATR 
ataxia telangiectasia and RAD3-related 
AUC 
area under the plasma concentration-time curve 
AUC0-24 
area under the plasma concentration-time curve from 0 to 24 hours 
BCRP 
breast cancer resistance protein 
BER 
base excision repair 
BID 
twice daily 
Bp 
base-pair 
BPI-SF 
Brief Pain Inventory – Short Form 
BRCA 
breast cancer 1 or breast cancer 2 
BRCA1/2 
breast cancer gene 1 or breast cancer gene 2 
BMT 
bone marrow transplant 
CBR 
clinical benefit rate 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CL 
Clearance 
CL/F 
apparent total clearance of drug after oral administration 
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax 
maximum plasma concentration 
CNS 
central nervous system 
CR 
complete response 
CRF 
case report form 
CRM 
continual reassessment model 
CRP 
C-reactive protein 
CRPC 
castration-resistant prostate cancer 
CT 
computed tomography 


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CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating cell-free tumor DNA 
CV 
coefficient of variation 
CYP 
cytochrome P450 
DILI 
drug-induced liver injury 
DLT 
dose-limiting toxicities 
DMC 
data monitoring committee 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
DSB 
double-strand breaks 
EC 
European Commission 
EC50 
concentration producing 50% of maximum effect 
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 
F 
Bioavailability 
FACT-P 
Functional Assessment of Cancer Therapy – Prostate 
FD & C 
colorants that have been approved by the Food and Drug Administration for use in 
food, drugs and cosmetics 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
FMI 
Foundation Medicine, Inc. 
FSH 
follicle stimulating hormone 
FTC 
fallopian tube cancer 
gBRCA 
germline breast cancer gene 1 or 2 mutation 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GDPR 
General Data Protection Regulation 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practice 
H & E 
hematoxylin and eosin 
HDP 
hydroxydiphosphonate  
HDPE 
high-density polyethylene 
HIPAA 
Health Information Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HPMC 
hydroxypropyl methylcellulose 


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HGSOC 
high-grade serous ovarian cancer 
HNSTD 
highest non-severely toxic dose 
HPLC 
high-performance liquid chromatography 
HR 
hazard ratio 
Hr 
hour 
HRD 
homologous recombination deficiency 
HRR 
homologous recombination repair 
IB 
Investigator’s Brochure 
IC50 
50% inhibitory concentration 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug Application 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRR 
independent radiological review 
ITT 
intent-to-treat 
IUD 
intrauterine device 
IUS 
intrauterine system 
IWRS 
Interactive Web Response System 
IV 
Intravenous 
Ki 
inhibition constant 
Kic 
inhibition constant competitive 
LHRH 
luteinizing hormone-releasing hormone 
LOH 
loss of heterozygosity 
MATE 
multidrug and toxin extrusion transporter 
mCRPC 
metastatic castration-resistant prostate cancer 
MDP 
methylene diphosphonate 
MDR1 
multidrug resistance protein 1 
MDS 
myelodysplastic syndrome 
MRI 
magnetic resonance imagiing 
mRNA 
messenger ribonucleic acid 
MRP 
multidrug resistance associated protein 
MS 
mass spectrometry 
MTD 
maximum tolerated dose 
NAD 
nicotinamide adenine dinucleotide 
NADPH 
nicotinamide adenine dinucleotide phosphate 
NCI 
National Cancer Institute 
OAT 
organic ion transporter 
OCT 
organic cation transporter 


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ORR 
objective response rate 
OS 
overall survival 
Papp 
apparent permeability coefficient 
PARP 
poly(ADP-ribose) polymerase 
PCWG3 
Prostate Cancer Working Group 3 
PD 
progressive disease (in context of disease monitoring) 
PDX 
patient-derived xenograft 
PEG 
polyethylene glycol 
PET 
positron emission tomography 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
PLD 
pegylated liposomal doxorubicin 
PPC 
primary peritoneal cancer 
PR 
partial response 
PRO 
Patient-reported Outcome 
PSA 
prostate-specific antigen 
PV 
pharmacovigilance 
QD 
once daily 
RAD51C 
RAD51 homolog C 
RAD51D 
RAD51 homolog D 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended Phase 2 dose 
rPFS 
radiologic progression-free survival 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
sBRCA 
somatic breast cancer gene 1 or 2 mutation 
SD 
stable disease (in context of disease monitoring) 
SOC 
system organ class 
SOP 
Standard Operating Procedure 
SSB 
single-strand break 
t1/2 
terminal half-life 
tBRCA 
tumor tissue mutation in BRCA1 or BRCA2, includes gBRCA and sBRCA 
TEAE 
treatment-emergent adverse event 
Tmax  
time of occurrence of Cmax 
TMZ 
Temozolomide 
UGT 
uridine diphosphate-glucuronosyl transferase 
UK 
United Kingdom 
ULN 
upper limit of normal 


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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 
USAN 
United States Adopted Name 
USP 
US Pharmacopeia 
Vss 
volume of distribution at steady-state 
WBC 
white blood cell 
wt 
wild-type 


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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 susceptibility gene 1 or 2 (BRCA1 or BRCA2) mutation in both clinical and 
nonclinical studies. 
Clovis Oncology, Inc. (Clovis) 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 telangiecstasia 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 (UV) 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 of the 
DNA, a complex process involving multiple proteins, including those encoded by breast cancer 
susceptibility gene 1 and 2 (BRCA1 and BRCA2), as well as RAD51, Fanconi anemia core 
complex, ataxia telangiectasia mutated serine/threonine kinase (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, 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 2nd 
leading malignancy diagnosis and 5th 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 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 CDK12, a previously reported 
positive regulator of BRCA genes, and lower rates of mutation of BRCA1, FANCA, RAD51B, 
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 HRR, such as 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 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 PSA. Fourteen of the 16 responders had a mutation in a HRR gene, 
most commonly BRCA2 and ATM, but also other genes involved in DNA damage sensing and 
repair, including FANCA, PALB2, and CHEK2.9 These findings provide compelling evidence 
for use of a PARP inhibitor in a selected population of CRPC patients with predicted loss-of-
function mutations in HRR genes such as BRCA1/2 and ATM, as well as in HRR genes such as 
BARD1, BRIP1, CDK12, CHEK2, FANCA, NBN, PALB2, RAD51, RAD51B, RAD51C, 
RAD51D, or RAD54L where deleterious mutations have generally been observed at lower 
frequencies. 
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, radiological and PSA responses for most patients 
– but almost all men will eventually progress to CRPC. 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 2 agents 
that target the androgen receptor (AR) pathway, abiraterone acetate and enzalutamide.10-14, 16. 
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 16-18 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 CRPC patients 


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who progressed on ADT, but has generally been replaced by abiraterone acetate and 
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, fatigue, 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, 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 
overall survival (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 
An overview of data from nonclinical and clinical studies are provided below and described in 
detail and most currently 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-gp and BCRP substrate, rucaparib demonstrated minimal penetration of rucaparib-derived 
radioactivity through the blood-brain barrier. In vitro data suggested slow metabolism by 
cytochrome P450 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 


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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 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 (GI) 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 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 United States (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 6 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.  
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-338-063 [Phase 3 mCRPC], and CO-338-078 [hepatic impairment 
study]). 


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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 
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 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).  
o 
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 
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).  


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• 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-338-063 (TRITON3): a Phase 3 study evaluating monotherapy rucaparib versus 
physician’s choice of therapy (abiraterone acetate, enzalutamide, or docetaxel) for the 
treatment of mCRPC patients with a BRCA1/2 or ATM mutation who have received prior 
treatment with AR-directed therapy, but have not yet received taxane chemotherapy in the 
castration resistant setting (n = 400 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 QD or BID dosing, rapid absorption with 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 
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 


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not significantly impact the steady-state exposure of rucaparib at 600 mg twice daily. 
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. 
Concomitant treatment with PPIs did not show clinically significant effect on rucaparib PK. No 
dose modification is recommended based on use of 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 twice daily 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 2 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 mutation and who had 2 or more prior therapies achieve RECIST and/or GCIG 
CA-125 responses. The confirmed ORR per RECIST by investigator review was 53.8% (57/106) 
and the confirmed response by RECIST or GCIC-CA-125 was 70.8% (75/106). The confirmed 
ORR per RECIST by independent review was 41.5% (44/106).  
In addition, patients without a BRCA1/2 mutation in tumor tissue are also deriving benefit, with 
43% achieving RECIST 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 v1.1. Three patient 
populations (tBRCA, HRD, and intent-to-treat [ITT]) were evaluated in a step-down analysis.  


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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 v1.1, 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.  
Four mCRPC patients, who were tested BRCA mutation positive and had progressive disease, 
received rucaparib monotherapy in Study CO-338-010 with rucaparib or under named patient 
access. Information is available for 3 patients, all of whom experienced tumor stabilization, 
decrease of PSA levels, and/or 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 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 1-2) 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%).  
The most common treatment-related TEAEs reported were primarily mild to moderate 
(Grade 1-2) in severity and included nausea (68.3), asthenia/fatigue (67.0%), anemia/decreased 
haemoglobin (38.9%), ALT/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.  


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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 ECG parameters in cancer patients demonstrated a low risk of cardiac effects by 
rucaparib.  
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 = 545)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: AE = adverse event; 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 2017.  
c Combined MedDRA preferred terms 


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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 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 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: AE = adverse event; 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). 


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Decreased platelets, neutrophils, lymphocytes, and increased cholesterol were observed to a 
lesser extent (Table 3). 
A decrease in hemoglobin (Common Terminology Criteria for Adverse Events [CTCAE] 
Grade 1-4) 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 
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; BID = twice a day; 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 x baseline to 3.0 x baseline 
or >1.5 x ULN to 3.0 x ULN; Grade 3 is >3.0 x baseline or >3.0 x ULN to 6.0 x ULN; and Grade 4 is 
>6.0 x 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 


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AESIs of MDS/AML experienced by patients in rucaparib clinical studies is provided in the 
rucaparib IB.  
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 is seeking to 
understand whether or not there is a relationship between pneumonitis and rucaparib treatment; 
thus, Clovis 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, CHEK2, RAD51D and PALB2,30 have also been 
reported. In addition to germline mutations, somatic mutations in the HRR genes ATM, BRCA1, 
BRCA2, BRIP1, CDK12, CHEK2, FANCA, 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, such as RAD51, RAD54L, ATM, CHEK2, NBN, or FANCA.31 This 
sensitivity is the result of synthetic lethality in homologous recombination deficient cells (like 
BRCA mutant tumors) when exposed to a PARP inhibitor.  
Rucaparib, olaparib, niraparib, and talazoparib, similar agents in the growing class of PARP 
inhibitors in clinical development, have demonstrated clinical activity in several trials 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 trial of olaparib, 3 mCRPC patients 
were enrolled, of which 1 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 2 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 4 patients with germline BRCA2-mutant advanced prostate 
cancer treated with either olaparib (3 patients) or niraparib (1 patient).42 In the patients treated 
with olaparib, PSA and radiological responses lasting 34 and 26 months were noted in 2 patients, 
and SD of 10 months was noted in the 3rd. 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 trial that enrolled 
multiple tumor types, Kaufman et al. (2014) reported efficacy data for 8 BRCA mutant mCRPC 
patients who had received a median number of 2 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 ORR=50%) and 2 patients (25%) had a best response of SD. Overall duration of 
response 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 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 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 criteria, as well as durable stable disease, 
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. 
Four mCRPC patients, who were tested BRCA mutation positive and had progressive disease, 
received rucaparib monotherapy in Study CO-338-010 with rucaparib or under named patient 
access and experienced tumor reduction, decrease of PSA levels, and symptom improvement. 
Rucaparib monotherapy is well tolerated by patients and has a well-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 CRPC patients with 
predicted loss-of-function mutations in HRR genes such as BRCA1/2 and ATM, as well as in 
HRR genes such as BARD1, BRIP1, CDK12, CHEK2, FANCA, NBN, PALB2, RAD51, 


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RAD51B, RAD51C, RAD51D, or RAD54L, where deleterious mutations have generally been 
observed at lower frequencies. 
 


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4 
STUDY OBJECTIVES 
4.1 
Primary Objective  
The primary objective of this study is: 
• To assess the efficacy of rucaparib based on the response rate in mCRPC patients with HRD 
who progressed on AR-targeted therapy (abiraterone acetate, enzalutamide, apalutamide, or 
investigational AR-targeted agent) and taxane-based chemotherapy in the castration-resistant 
setting 
 
4.2 
Secondary Objectives  
The secondary objectives of this study are: 
• To assess duration of response (DOR) 
• To assess radiologic PFS (rPFS) 
• To assess OS 
• To assess clinical benefit rate (CBR) 
• To assess PSA response ≥ 50% (all patients) 
• To assess PSA response ≥ 90% (all patients) 
• To assess time to PSA progression 
• To characterize the steady-state pharmacokinetics of rucaparib in mCRPC patients 
• To assess safety and tolerability 
 
4.3 
Exploratory Objectives 
Exploratory objectives in this study are:  
• To evaluate patient reported outcomes (PRO) using the 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 changes in the molecular profile over time of matched pre- and post-treatment 
tumor or plasma samples 
• To assess concordance in HRR gene mutation status in matched Pre-Screening biopsy tissue, 
archival primary and metastatic tumor tissue, and plasma circulating tumor DNA (ctDNA) 
• To assess ctDNA as a molecular marker of response 


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• To assess time to first subsequent antineoplastic therapy 
• 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 
 


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5 
INVESTIGATIONAL PLAN 
5.1 
Overall Study Design and Plan 
This is a Phase 2 multicenter study evaluating rucaparib for treatment of patients with mCRPC 
whose tumors are associated with HRD. This study will enroll mCRPC patients with deleterious 
mutations in BRCA1/2, ATM , or other HRR genes associated with sensitivity to PARPi 
(Appendix 1). Deleterious mutations are defined as protein-truncating mutations, large protein-
truncating rearrangements, splice site mutations, deleterious missense mutations, and 
homozygous deletions. Mutations may be identified by local testing, or 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. 
All patients will be required to have progressed on prior AR-targeted therapy (abiraterone 
acetate, enzalutamide, apalutamide, or investigational AR-targeted agent) after receiving 
treatment with at least 1, but no more than 2, of these agents. Patients must also have progressed 
after 1 prior line of taxane-based chemotherapy for mCRPC. Patients who received prior PARPi 
treatment, mitoxantrone, cyclophosphamide or platinum-based chemotherapy will be excluded.  
This study consists of a Pre-Screening Phase (Section 5.1.1), Screening Phase (Section 5.1.2), 
Treatment Phase (Section 5.1.3), and Post-Treatment Phase (Section 5.1.4). Patients will receive 
rucaparib monotherapy in the Treatment Phase, and will undergo procedures and assessments 
including regular safety and efficacy evaluations during the entire conduct of the study. 
5.1.1 
Pre-Screening Phase 
The Pre-Screening Phase is to identify eligible deleterious HRR gene mutations through central 
testing of tumor tissue and plasma. Patients who have an eligible deleterious HRR 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 an eligible deleterious HRR gene mutation identified during 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, ATM, or other HRR 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 


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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, 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, ATM, or other HRR 
gene mutation will undergo Screening assessments within 28 days prior to the first dose of 
rucaparib. Patients will undergo procedures and assessments during Screening Phase as 
described in Section 9.4.  
During the Screening Phase, unless otherwise required by local regulations, serious adverse 
events (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 9.4.  
Enrollment will require prospective sponsor (or designee) review and confirmation of eligibility, 
including, but not limited to: 
• BRCA/ATM/other HRR gene test result by either local or central testing  
• details of prior therapy for prostate cancer 
• screening laboratory assessments 
 
5.1.3 
Treatment Phase 
Rucaparib will be administered at a starting dose of 600 mg BID. During the Treatment Phase, 
patients will undergo procedures and assessments including regular evaluations for safety and 
efficacy as described in Section 9.5.  
Tumor assessments by CT/MRI and bone scans will be performed during screening, 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 radiologic response 
in soft tissue (visceral and nodal) disease and PCWG3 criteria will be used to document 
radiologic 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. Any drug 
modifications (interruption, dose reduction, or discontinuation) should be documented in the 
eCRF and source documents. If study treatment is interrupted, tumor assessments will not be 
delayed and will be performed on the regular study schedule. Copies of all radiologic scans will 
be collected for central independent radiology review (IRR). 


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Patients will receive rucaparib until confirmed radiologic disease progression assessed by 
investigator based on modified RECIST Version 1.1 and/or 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. PSA rise without evidence of 
confirmed radiologic 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 
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. 
Patients who discontinue study treatment for reasons other than radiologic disease progression, 
should continue radiologic tumor assessment performed as described in Section 5.1.4. 
If a patient has radiologic progression, but continues to derive clinical benefit per the 
investigator, then continuation of treatment beyond progression may be requested by the 
investigator as per Section 7.4.4. In such cases, the decision to continue will be made jointly 
between the investigator and the sponsor (or designee), and the patient must consent prior to 
continuing treatment with rucaparib. These patients will continue to undergo all protocol 
required assessments specified in Table 5. 
Patient safety will be monitored on a regular basis using procedures and assessments described in 
Section 9 and Section 13.4. Safety data will be periodically reviewed by the Data Monitoring 
Committee (DMC) as described in Section 13.6. The DMC will comprise study investigators and 
sponsor representatives. The DMC will meet after the first 20 patients received rucaparib for at 
least 28 days or discontinued study treatment, and then at least semi-annually after sufficient data 
has been collected. 
5.1.4 
Post-treatment Phase 
The sponsor (or designee) should be notified of all treatment terminations as soon as possible. 
The date and reason for cessation of study drug must be documented in the eCRF and source 
documents. 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 Treatment Discontinuation Visit, a tumor assessment must be performed.  
If treatment was discontinued for reasons other than radiologic disease progression, radiologic 
tumor assessment (using the same methodology as was used at initial study screening [eg, CT 
scan]) and PRO assessments will continue until confirmed radiographic disease progression. For 
these patients, tumor assessments 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 and then every 12 calendar 
weeks (±7 days) thereafter, until confirmed radiologic disease progression by modified 
RECIST Version 1.1 and PCWG3 (for bone lesions only) criteria as assessed by the investigator, 
loss to follow-up, withdrawal of consent, or study closure. For patients who start subsequent 


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anticancer therapy, tumor assessments will continue until radiologic disease progression is 
confirmed.  
Ongoing SAEs, AESIs, and treatment related Grade 3/4 AEs will be followed until either 
resolution or stabilization has been determined or until loss to follow-up. After the 28-Day 
Follow-up Visit, only SAEs considered as potentially related to study drug should be reported 
per Clovis Pharmacovigilance (PV) requirements and captured in the Clovis PV database. This 
includes serious reports of pneumonitis or associated events, if considered to be related to study 
drug. 
After the 28-day Follow-up Visit, AESIs of MDS and AML, irrespective of causality, should be 
reported per Clovis PV requirements and captured in the Clovis PV database. 
• AESIs of pneumonitis or associated events should only be reported up to, but not beyond, the 
28-Day Follow-up Visit (28-days after the last dose of rucaparib). 
 
All patients will be followed for survival and subsequent treatments every 12 weeks (± 14 days) 
relative to the last dose of rucaparib until death, loss to follow-up, withdrawal of consent, or 
study closure. 
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 all enrolled patients have discontinued treatment and completed the 
28-Day Follow-up visit. Upon formal closure of the study, individual patients who are 
continuing to benefit from treatment with rucaparib at the time of study closure, and who do not 
meet any of the criteria for withdrawal, will have the option of entering an extension protocol in 
which they can continue to receive rucaparib.  
The sponsor may discontinue the study early for any reason as noted in Section 13.7. 


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6 
STUDY POPULATION SELECTION 
6.1 
Number of Patients and Sites 
The total enrollment planned for this study is approximately 360 patients.  
Cohort A will include up to 100 patients with a deleterious BRCA1/2 mutation who have 
measurable visceral and/or nodal disease (with a maximum of 60 patients who have only 
measurable lymph node disease), and up to approximately 50 patients with a deleterious ATM 
mutation who have measurable visceral and/or nodal disease.  
Cohort B will include up to approximately 100 patients with a deleterious BRCA1/2 mutation 
and up to approximately 50 patients with a deleterious ATM mutation who do not have 
measurable visceral and/or nodal disease. Patients in this cohort must have a baseline PSA of 
≥ 2 ng/mL. 
Cohort C will include up to approximately 60 patients with or without measurable visceral and/or 
nodal disease who have a deleterious mutation in a HRR gene other than BRCA1/2 or ATM 
(Appendix 1). Patients without measurable disease must have a baseline PSA of ≥ 2 ng/mL. 
Patients will be enrolled across approximately 150 sites worldwide. 
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 (IRB)/Independent Ethics Committee(IEC)-
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 
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). 
For patients currently being treated with LHRH analogs (ie, patients who have not undergone 
an orchiectomy), therapy must be continued throughout the study 
5. Evidence of disease progression after prior therapy for prostate cancer: 
a. Disease progression after treatment with at least 1 but not more than 2 prior next 
generation AR-targeted therapies (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, 
AND 
b. Disease progression after treatment with 1 prior line of taxane-based chemotherapy for 
castration-resistant disease. Prior taxane therapy administered for hormone-sensitive 
disease is permitted and is not counted toward this limit 
6. Disease progression after initiation of most recent therapy is based on any of the following 
criteria: 


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a. Rise in PSA: a minimum of 2 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 RECIST 1.144  
c. Radionuclide bone scan: at least 2 new metastatic lesions 
7. Patients in Cohorts A and B must have a deleterious mutation in BRCA1/2 or ATM  
Patients in Cohort C must have a deleterious mutation in another HRR gene associated with 
sensitivity to PARPi (Appendix 1)  
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 
8. Patients in Cohort A must have measurable visceral or nodal disease per RECIST 1.1 criteria 
(Appendix 2)  
Patients in Cohorts B and C (without measurable disease) must have PSA ≥ 2 ng/mL on the 
most recent measurement 
9. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Appendix 3) 
10. Have adequate organ function confirmed by the following laboratory values obtained within 
14 days prior to the first dose of rucaparib: 
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 × 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 (Appendix 4) 
11. 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 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 rucaparib dose; or 
iii. 
Committed to using an effective method of contraception (refer to Section 6.4) with 
their partner during treatment and for 3 months following the last dose of rucaparib 
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 trial provided all chemotherapy 
was completed > 6 months prior and/or bone marrow transplant (BMT) > 2 years prior to 
first dose of rucaparib 
2. Prior treatment with any PARP inhibitor, mitoxantrone, cyclophosphamide, or any platinum-
based chemotherapy 
3. 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 rucaparib and 
have had appropriate scans at screening assessment 
4. Symptomatic or impending spinal cord compression unless appropriately treated, clinically 
stable, and asymptomatic 
5. Pre-existing duodenal stent and/or any gastrointestinal disorder or defect that would, in the 
opinion of the Investigator, interfere with absorption of rucaparib 
6. 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 
7. Received treatment with chemotherapy, antibody therapy or other immunotherapy, gene 
therapy, vaccine therapy, angiogenesis inhibitors, or experimental drugs within < 2 weeks 
prior to first dose of rucaparib. Treatment with hormonal therapies (with the exception of 
LHRH analog) must be discontinued at least 7 days prior to the first dose of rucaparib  
8. 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 
9. Initiated low-dose corticosteroid, denosumab, or bisphosphonate therapy or adjusted low-
dose corticosteroid, denosumab, or bisphosphonate dose/regimen within < 4 weeks prior to 
first dose of rucaparib. Patients on a stable low-dose corticosteroid, denosumab, or 
bisphosphonate regimen are eligible and may continue treatment 
10. Non-study related minor surgical procedure within < 5 days, or major surgical procedure 
within < 21 days, prior to first dose of rucaparib; in all cases, the patient must be sufficiently 
recovered and stable before treatment administration 
11. 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 
 
6.4 
Patients or Partners of Patients Including Those with 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. 


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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. Male patients are considered to be of reproductive potential unless permanently 
sterile by bilateral orchidectomy or vasectomized with appropriate post-vasectomy 
documentation of absence of sperm in ejaculate. 
Female partners are considered to be of childbearing potential unless 1 of the following applies: 
• 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) 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 progesterone only injectable or implantable contraceptives (eg, Depo 
Provera, Implanon, Nexplanon); 
• Placement of an intrauterine device (IUD) or intrauterine 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. 
 
Patients will be instructed to notify the investigator if pregnancy of a female partner is 
discovered either during or within 3 months of completing treatment with study drug.  
6.5 
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. 


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7 
STUDY TREATMENT(S) 
7.1 
Description of Treatment(s) and Storage 
This study will assess the investigational drug 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. 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 high-density 
polyethylene bottles or equivalent with child-resistant caps. Patients may 
receive one or more strengths.  
Storage Conditions: 
15 to 30° C (59 to 86° F).  
 
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 1 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 dispensation visit. 
Rucaparib bottles will be labelled in accordance with local regulatory requirements.  
7.3 
Method of Assigning Patients to Treatment Groups 
All patients enrolled in the study will receive rucaparib at an initial dose of 600 mg BID. 
7.4 
 Preparation and Administration of Protocol-specified Treatment 
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.  
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 


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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 7.4.2 and Section 7.4.3. 
Patients will be provided a sufficient quantity of study drug for 28 days until the next study drug 
dispensation visit. 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.  
7.4.1 
Dietary and General Restrictions 
All patients participating in the study should be instructed to use caution with CYP2C9, 
CYP2C19, and CYP3A substrates noted in Appendix 5. 
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.  
7.4.2 
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. 


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• 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 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 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. Twice daily dosing 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 should consult with the sponsor’s medical monitor before 
reducing to 300 mg BID. If a patient continues to experience toxicity despite dose reduction 


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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. 
Drug-induced liver injury (DILI) is described in the U.S. Food and Drug Administration (FDA) 
Guidance for Industry, Drug-Induced Liver Injury: Premarketing Clinical Evaluation45 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 > 3x ULN 
and 
Bilirubin > 2x 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. 


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7.4.3 
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. 
Dose modifications (interruption, reduction, and 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 – 3* 
300 mg BID 
Abbreviation: BID = twice a day. 
*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. 
7.4.4 
Treatment with Rucaparib beyond Disease Progression 
Patients will receive rucaparib until confirmed radiologic disease progression as assessed by 
investigator using modified RECIST Version 1.1 (Appendix 2) and/or PCWG3 (for bone lesions 
only) (Appendix 2) criteria, unequivocal clinical disease progression, unacceptable toxicity or 
inability to tolerate further treatment, loss to follow-up, or withdrawal of consent. However, if a 
patient receiving rucaparib has met criteria for confirmed radiologic 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. Clinical scenarios where continuation of study drug treatment after 
radiographic progression may be considered include 1) a patient for whom radiographic 
progression develops slowly while disease-related symptoms remain well controlled, 2) 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 3) 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. Patients continuing to receive rucaparib 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. 
7.5 
Blinding/Masking of Treatment 
This is an open-label study; the investigational product will not be blinded or masked. All 
patients enrolled will receive rucaparib. 


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7.6 
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 
unopened) for accountability and bring them back at the next scheduled clinic visit. A 
compliance check and tablet count will be performed by study personnel. Study site personnel 
will record compliance information on the electronic case report form (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 
on 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 drug provided by the sponsor. An Interactive Web 
Response System (IWRS) 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, patient treatment discontinuation, 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 that is destroyed, accidentally or deliberately, must be accounted for. All 
study drug containers must be accounted for prior to their destruction at the study site, according 
to institutional procedures for disposal of cytotoxic chemotherapeutic drugs. Unused study drug 
containers should be destroyed by the site if possible. If destruction by the 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. 


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8 
PRIOR AND CONCOMITANT THERAPY 
Patients who have received prior treatment with a PARP inhibitor including IV or oral rucaparib, 
mitoxantrone, cyclophosphamide or any platinum-based chemotherapy are not eligible to 
participate in this study.  
Patients are required to have progressed after 1 prior line of taxane-based chemotherapy in the 
castration-resistant setting; patients who have progressed after 2 lines of taxane chemotherapy in 
the castration-resistant resistant setting are not eligible to participate in this study. However, an 
incomplete course of taxane chemotherapy (eg, stopping due to intolerance or stopping for 
reasons other than disease progression) will not be counted towards this limit.  
All procedures performed (eg, thoracentesis, etc.) and medications used during the study must be 
documented on 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.  
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. 
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. 
8.3 
Luteinizing Hormone-releasing Hormone (LHRH) analogs 
For patients who have not undergone an orchiectomy and are currently being treated with 
luteinizing hormone-releasing hormone (LHRH) analogs at the time of consent, therapy must be 
continued throughout the study. 
8.4 
Anticancer or Experimental Therapy 
No other anticancer therapies (including chemotherapy, radiation, antibody or other 
immunotherapy, gene therapy, vaccine therapy, angiogenesis inhibitors, or other experimental 
drugs) of any kind will be permitted while the patient is participating in the study. Prior 
treatment with anticancer therapies must have been completed at least 14 days prior to the first 


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dose of rucaparib. Prior treatment with hormonal therapies (with the exception of LHRH analog) 
must be discontinued at least 7 days prior to the first dose of rucaparib. 
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 taking concomitant medicines that are substrates of CYP1A2, 
CYP2C9, and/or CYP3A with narrow therapeutic windows (Appendix 5). 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 denosumab dose/regimen within 4 weeks prior to first dose of rucaparib. 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 clinical 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 on 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 on the eCRF.  
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 regularly via standard clinical practice.  
In vitro, rucaparib is a potent inhibitor of MATE1 and MATE2-K, a moderate inhibitor of OCT1, 
and a weak inhibitor of OCT2. As inhibition of these transporters could increase metformin renal 
elimination and decrease liver uptake of metformin, caution is advised when metformin is co-
administered with rucaparib.  


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9 
STUDY PROCEDURES AND ACTIVITIES BY VISIT 
9.1 
Schedule of Assessments 
Table 5 summarizes the procedures and assessments to be performed for all patients. 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.  


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Table 5. 
Schedule of Assessments  
 
Pre-
screening 
Phase 
Screening Phase 
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 
Study 
Day 
1b 
Study 
Day 
15 
Study 
Day 
29 
Study 
Day 
43 
Day 57 & 
every 28 days 
thereafter 
Treatment 
Discontinu
ation 
28-day 
Follow
-up 
Long-
term 
Follo
w-up 
Informed Consent 
Xc 
X 
 
 
 
 
 
 
 
 
 
BRCA, ATM or other HRR gene 
mutation assessment from ctDNA 
blood and tumor samplec, d  
Xc 
 
 
 
 
 
 
 
 
 
 
Medical/Oncology Historye 
 
X 
 
 
 
 
 
 
 
 
 
Blood samples for plasma ctDNA 
analysisf  
 
X 
 
X 
 
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 and Bone 
Scanj 
 
X 
 
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.)k 
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 
 
 
 
 
 
 
 
Study Drug Dispensation 
 
 
 
X 
 
X 
 
X 
 
 
 
Adverse Eventsr 
(X) 
(X) 
(X) 
X 
X 
X 
X 
X 
Xs 
Xs 
 
Plasma PK Sample 
 
 
 
 
 
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, BPI-SF = Brief Pain Inventory – Short Form, 
BRCA = breast cancer 1 or breast cancer 2, BUN = blood urea nitrogen, CO2 = bicarbonate, CR = complete response, ctDNA = circulating cell-free tumor DNA, 
CT = computer tomography, ECG = electrocardiogram, ECOG = Eastern Cooperative Oncology Group, EQ-5D-5L = Euro-QoL 5 dimensions 5 level questionnaire, 
FACT-P = Functional Assessment of Cancer Therapy-Prostate, Hct = hematocrit, HDL= high density lipoprotein, HDP = hydroxydiphosphonate, Hgb = hemoglobin, 
HRR = homologous recombination repair, 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, PSA = prostate-specific antigen, PV = Pharmacovigilance, 
RBC = red blood cell count, RECIST = Response Evaluation Criteria in Solid Tumors, SAE = serious adverse event, WBC = white blood cell 
a 
= The study visit window is ± 3 days, unless noted otherwise for a particular assessment. Study visits should take into account the patient’s rucaparib supply. 
b 
= First dose of rucaparib is designated as Study Day 1. Procedures required on Study Day 1 may be omitted if completed ≤ 3 days earlier during the screening 
period 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 HRR 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 of 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. 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 every 28 days thereafter 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, PR, 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.  
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 1.1/PCWG3 criteria will be used. If a CR or PR is noted, confirmatory scans should be performed at least 4 weeks after the 
initial response was first documented. 


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l 
= Radiologic assessments should continue for all patients until confirmation of radiographic progression per 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 radiologically 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.  
m 
= If archival primary or metastatic tumor tissue was not submitted during Pre-Screening, a specimen should be submitted during the Screening period 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 should 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.  
o 
= All PSA measurements are performed by the local laboratory. Serial PSA measurements that show progression at study entry must follow the protocol 
specification. 
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 on Study Day 1, it must be collected as soon as possible thereafter. 
r 
= AEs occurring after first dose of rucaparib through to 28 days after last dose of rucaparib will be recorded. In addition, SAEs 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 PV guidelines and reported in the 
Clovis 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 serious reports of 
pneumonitis or associated events, if considered to be related to study drug), and AESIs of MDS and AML irrespective of causality, will be reported. 
t 
= PK within 1 hr 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 rucaparib 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 HRR 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 Institutional Review Board (IRB)/Independent Ethics 
Committee (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 or at the time of 
radiologic disease progression/treatment discontinuation must provide additional consent for this 
procedure.  
Patients with radiologic disease progression who are still receiving benefit and are allowed to 
continue rucaparib treatment 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 HRR gene mutations. Patients with eligible deleterious HRR 
gene mutations 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 informed consent form.  
During Pre-Screening: 
• Submit patient plasma 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  
• 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  


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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 screening procedures) 
9.4 
Screening Phase 
Following written informed consent, and unless otherwise specified, the following assessments 
will be performed prior to enrollment 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 Start of Treatment 
• 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 RECIST Version 1.1); other studies (magnetic resonance imaging [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 lesions throughout the clinical study.  
- 
If a patient has known brain metastases, this disease should be evaluated at each required 
assessment time 
• 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.  
• SAE monitoring (only report if related to screening procedure) 


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9.4.2 
Screening: Up to 14 days Prior to Start of Treatment 
• PRO collected using the BPI-SF (Appendix 6), FACT-P (Appendix 7), EQ-5D-5L (Appendix 
8), and analgesic drug score instruments (Appendix 9); should be completed before other 
procedures 
• Hematology 
• Serum chemistry. Note: fasting is not required 
- 
Estimated GFR using Cockcroft-Gault formula (Appendix 4) 
• Urinalysis (performed on freshly voided clean sample) 
• ECOG performance status (Appendix 3) 
• SAE monitoring (only report if related to screening procedure) 
 
9.5 
Treatment Phase  
During the treatment period, patients 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. In each study visit, the 
first dose of rucaparib will be taken in clinic, with the remaining doses self-administered by the 
patient at home. Patients should take rucaparib at about the same time every day. Patients will 
inform the clinic staff of any changes to their dose and timing of self-administration of oral 
rucaparib.  
Unless otherwise specified, all patients will undergo the following procedures and assessments. 
9.5.1 
Study Day 1 (Week 1) 
The following procedures will be completed before rucaparib is administered, unless if 
completed ≤ 3 days earlier during the screening period in which case they may be omitted: 
• PRO collected using the BPI-SF (Appendix 6), FACT-P (Appendix 7), EQ-5D-5L (Appendix 
8), and analgesic drug score instruments (Appendix 9; should be completed before other 
procedures) 
• Physical examination 
• Weight 
• Vital signs 
• Concomitant medications and procedures 
• PSA measurement 
• ECOG performance status (Appendix 3) 
• Hematology 
• Serum chemistry (fasting is not required) 


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• 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  
• AE monitoring 
• Dispensation of rucaparib. 
 
Rucaparib tablets will be dispensed to the patient in sufficient quantity to last until the next study 
drug dispensation visit. Patients will ingest rucaparib twice daily at about the same times every 
day as close to 12 hours apart as possible. Rucaparib should be taken with at least 8 oz (240 mL) 
of water with or without food. Patients will keep all unused containers (empty, partially used, 
and/or unopened) and return with them to the study site for accountability at the next visit. In the 
event of toxicities, re-treatment or dose modification will be according to the criteria described in 
Section 7.4.2. 
Site personnel will account for all rucaparib that is administered or dispensed to the patient 
during the study visit and document appropriately. 
9.5.2 
Study Day 15 (Week 3) 
The following procedures will be completed: 
• Physical examination 
• Weight 
• Vital signs 
• Concomitant medications and procedures 
• ECOG performance status (Appendix 3) 
• Hematology 
• Serum chemistry (fasting is not required) 
• Urinalysis 
• AE (inclusive of SAE and AESI) monitoring 
 
Patients will ingest rucaparib twice daily at about the same times every day as close to 12 hours 
apart as possible. Rucaparib should be taken with at least 8 oz (240 mL) of water with or without 
food. Patients will keep all unused containers (empty, partially used, and/or unopened) and return 
with them to the study site for accountability at the next visit. In the event of toxicities, re-
treatment or dose modification will be according to the criteria described in Section 7.4.2. 


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9.5.3 
Study Day 29 (Week 5) 
Patients 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. 
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 study visit. 
The following procedures will be completed: 
• PRO collected using the BPI-SF (Appendix 6), FACT-P (Appendix 7), EQ-5D-5L (Appendix 
8), and analgesic drug score instruments (Appendix 9; should be completed before other 
procedures) 
• Physical examination 
• Weight 
• Vital signs 
• Concomitant medications and procedures 
• ECOG performance status (Appendix 3) 
• PSA measurement 
• Hematology 
• Serum chemistry (fasting is not required) 
• Urinalysis 
• Plasma sample for ctDNA  
• Plasma sample for PK analyses 
• AE (inclusive of SAE and AESI) monitoring 
• Dispensation of rucaparib 
 
Patients will ingest rucaparib twice daily at about the same times every day as close to 12 hours 
apart as possible. Rucaparib should be taken with at least 8 oz (240 mL) of water with or without 
food. Patients will keep all unused containers (empty, partially used, and/or unopened) and return 
with them to the study site for accountability at the next visit. In the event of toxicities, re-
treatment or dose modification will be according to the criteria described in Section 7.4.2. 
9.5.4 
Study Day 43 (Week 7) 
The following procedures will be completed: 
• Physical examination 
• Weight 


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• Vital signs 
• Concomitant medications and procedures 
• ECOG performance status (Appendix 3) 
• Hematology 
• Serum chemistry (fasting is not required) 
• Urinalysis 
• AE (inclusive of SAE and AESI) monitoring 
 
Patients will ingest rucaparib twice daily at about the same times every day as close to 12 hours 
apart as possible. Rucaparib should be taken with at least 8 oz (240 mL) of water with or without 
food. Patients will keep all unused containers (empty, partially used, and/or unopened) and return 
with them to the study site for accountability at the next visit. In the event of toxicities, re-
treatment or dose modification will be according to the criteria described in Section 7.4.2. 
9.5.5 
Study Day 57 (Week 9) and Every 28 Days Thereafter 
Patients will be instructed to refrain from taking their first dose of rucaparib at home on study 
visits when plasma samples are collected for PK. 
Plasma samples for PK analysis should be collected before the morning dose on Study 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 the 
delayed start of the next study visit; 
The following procedures will be completed: 
• PRO collected using the BPI-SF (Appendix 6), FACT-P (Appendix 7), EQ-5D-5L (Appendix 
8), and analgesic drug score instruments (Appendix 9; should be completed before other 
procedures) 
• Physical examination 
• 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 (Appendix 3) 
• PSA measurement 
• Hematology 


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• Serum chemistry (fasting is not required) 
• Urinalysis 
• Plasma sample for ctDNA  
• Plasma sample for PK analyses (Study Day 57, Day 85, and Day 113 only) 
• AE (inclusive of SAE and AESI) monitoring 
• Dispensation of rucaparib 
 
Patients will ingest rucaparib twice daily at about the same times every day as close to 12 hours 
apart as possible. Rucaparib should be taken with at least 8 oz (240 mL) of water with or without 
food. Patients will keep all unused containers (empty, partially used, and/or unopened) and return 
with them to the study site for accountability at the next visit. In the event of toxicities, re-
treatment or dose modification will be according to the criteria described in Section 7.4.2. 
9.6 
Post-treatment Phase 
9.6.1 
Treatment Discontinuation Visit 
Upon treatment discontinuation, regardless of the reason, patients will have a Treatment 
Discontinuation Visit. However, patients receiving rucaparib with radiologic disease progression 
by modified RECIST Version 1.1 and/or PCWG3 criteria (for bone lesions), as assessed by the 
investigator, but still receiving benefit, per the investigator, may be considered for treatment 
continuation. Continuation of rucaparib treatment beyond progression will require separate 
patient consent. If the patient does continue to receive rucaparib, then the patient will continue 
treatment with rucaparib as described starting in Section 9.5.5 and a Treatment Discontinuation 
Visit will occur at the end of all rucaparib treatment. Patients who continue treatment with 
rucaparib after radiologic 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. 
The following procedures will be performed: 
• PRO collected using the BPI-SF (Appendix 6), FACT-P (Appendix 7), EQ-5D-5L (Appendix 
8), and analgesic drug score instruments (Appendix 9; should be completed before other 
procedures) 
• Physical examination 
• Weight 
• Vital signs 
• 12-lead ECG 


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• 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 radiographically confirmed disease progression.  
• Concomitant medications and procedures 
• ECOG performance status (Appendix 3) 
• PSA measurement 
• Hematology 
• Serum chemistry (fasting is not required) 
• Urinalysis 
• Plasma sample for ctDNA 
• AE (inclusive of SAE and AESI) monitoring 
• Optional tumor tissue biopsy collection after the time of disease progression (radiologic or 
clinical) and prior to initiation of any subsequent anticancer therapy (requires additional 
consent). Tumor tissue will be processed locally as FFPE tissue. Refer to Section 9.11 for 
more information and to the Pathology Charter for detailed sample handling instructions.  
 
9.6.2 
28-Day Follow-up Visit  
The following procedures will be performed for all patients at 28 (±3) days after the last dose of 
rucaparib.  
• PRO collected using the BPI-SF (Appendix 6), FACT-P (Appendix 7), EQ-5D-5L (Appendix 
8), and analgesic drug score instruments (Appendix 9; should be completed before other 
procedures) 
• Physical examination 
• 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 confirmed by investigator assessment 
• Concomitant medications and procedures 
• ECOG performance status (Appendix 3) 
• Hematology  
• Serum chemistry (fasting is not required) 
• Urinalysis  
• AE (inclusive of SAE and AESI) monitoring 


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• 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 
Patients who complete a 28-Day Follow-up Visit after the last dose of rucaparib will continue in 
long-term follow-up as described below. 
• If applicable, tumor assessment (using the same methodology as was used at initial study 
screening [eg, CT scan]) when the reason for treatment discontinuation was other than death 
or disease progression based on radiologic 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 radiologic disease progression by modified 
RECIST Version 1.1 and/or PCWG3 (for bone lesions only) criteria, as assessed by the 
investigator, loss to follow-up, withdrawal, or study closure.  
- PRO assessments will also continue and coincide on days when tumor assessments are 
performed until confirmed radiographic disease progression. PRO using the BPI-SF 
(Appendix 6), FACT-P (Appendix 7), EQ-5D-5L (Appendix 8), and analgesic drug score 
instruments (Appendix 9) 
• All patients discontinued from treatment, regardless of reason, will be followed and 
information collected for subsequent treatments and survival every 12 weeks from last dose 
of rucaparib 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 
Methods of Data Collection 
9.7.1 
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 on the appropriate eCRF. Events that occur after signing of 
informed consent but prior to initiation of rucaparib, unless serious and due to a protocol-
mandated procedure, should be recorded on the Medical History eCRF.  
The patient’s entire oncology history will be collected on 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 BRCA/ATM/other HRR gene mutation status (if known).  


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9.8 
Prior and Concomitant Medication Assessments 
Medications being used by the patient will be recorded as prior medications during screening and 
as concomitant medications following receipt of the first dose of rucaparib through the 
completion of the 28-day Follow-up Visit after treatment discontinuation. Medication 
information will be entered in the appropriate eCRF after it is obtained at each study visit. 
9.9 
Efficacy Evaluations 
Soft tissue (visceral and nodal) disease will be evaluated for evidence of radiographic response 
based on modified RECIST 1.1 criteria (Appendix 2). Bone lesions will be followed and 
evaluated for evidence of radiologic progression based on PCWG3 criteria (Appendix 2). 
Additionally, PSA response will be evaluated using sequential PSA samples. 
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 radiologic disease progression by modified RECIST Version 1.1 
and/or PCWG3 (for bone lesions only) criteria, as assessed by the investigator, loss to follow-up, 
withdrawal, or study closure. Tumor assessments should be performed at the time of treatment 
discontinuation, at the 28-day Follow-up visit, or during Long-term Follow-up if the reason was 
other than radiologically 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. If a CR or 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 
RECIST Version 1.1); other studies (MRI, X-ray, 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 measurements. Radionuclide bone scanning (whole body) 
should be performed using 99mTc-MDP or HDP. All sites of disease should be followed and 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 time. 
Copies of CT scans (and other imaging, as appropriate) will be collected from all patients for 
IRR.  
9.10 Safety Evaluations 
9.10.1 
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, 
unless otherwise required by local regulations, SAEs which are related to protocol-mandated 


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assessments will be reported. Once enrolled and rucaparib is administered, patients will be 
monitored for all AEs/SAEs/AESIs during study participation and until 28 days after the last 
dose of rucaparib. 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 considered as 
potentially related to study drug should be reported per Clovis PV requirements and captured in 
the Clovis PV database. This includes serious reports of pneumonitis or associated events, if 
considered to be related to study drug. 
After the 28-day Follow-up Visit, AESIs of MDS and AML, irrespective of causality, should be 
reported per Clovis PV requirements and captured in the Clovis PV database. 
• AESIs of pneumonitis or associated events should only be reported up to, but not beyond, the 
28-Day Follow-up Visit (28-days after the last dose of rucaparib). 
 
AEs and laboratory abnormalities will be graded according to the National Cancer Institute 
CTCAE grading system (Version 4.03 or higher) and recorded on the eCRF. 
Complete details for monitoring AEs (inclusive of SAEs and AESIs), including the definition of 
drug-related AEs, are provided in Section 10. 
9.10.2 
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 each study visit, at 
the Treatment Discontinuation Visit, and 28-day Follow-up Visit 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 4), 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 each study visit, at the 
Treatment Discontinuation Visit, and 28-day Follow-up Visit 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 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 


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be performed at screening, during treatment at each study visit, at the Treatment Discontinuation 
Visit, and 28-day Follow-up Visit 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 on the eCRF as an AE. Refer to 
Section 10.5 for guidelines on reporting of abnormal laboratory values as AEs. 
9.10.3 
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, at the Treatment Discontinuation Visit and the 28-Day Follow-up Visit. 
9.10.4 
12-Lead Electrocardiogram 
For all patients, 12-lead ECGs will be performed at the following times: 
• Screening (within 28 days prior to enrollment) 
• Treatment Discontinuation Visit 
 
The following will be measured or calculated: heart rate, PR, 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.  
9.10.5 
Body Weight and Height 
Height will be measured during the screening visit only. Weight will be measured per 
institutional guidelines during screening, during treatment at each study visit, at the Treatment 
Discontinuation Visit, and the 28-Day Follow-up visit. 
9.10.6 
Physical Examinations 
Physical examinations will include an assessment of all the major body systems. Complete 
physical examinations will be performed during screening and at treatment discontinuation. 
Physical examinations at study visits during the Treatment Phase and 28-Day Follow-up Visit 
will be limited as appropriate.  
9.10.7 
ECOG Performance Status 
ECOG performance status (Appendix 3) will be assessed during screening, at study visits during 
the Treatment Phase, at the Treatment Discontinuation Visit and 28-Day Follow-up Visit. The 
ECOG performance status should be assessed by the same study personnel at each visit, if 


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possible. For eligibility purposes, patients with borderline ECOG performance status should be 
considered carefully to avoid enrolling patients who may have significant impairment. 
9.11 Biomarker Analysis – FFPE Tumor Tissue 
An optional tumor biopsy obtained between the time of disease progression/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 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. 
9.12 Biomarker Analysis – Blood 
Blood samples for plasma ctDNA will be collected during Pre-Screening (for deleterious BRCA, 
ATM, or other HRR gene mutation assessment), Screening, before dosing on Study Day 1, every 
28 days thereafter, and at treatment discontinuation from all patients entered in the study. Blood 
samples for pharmacogenomics analyses will be collected on Study Day 1 from all patients 
entered in the study. Genomic DNA will be extracted from the cellular portion of this blood 
sample and analyzed to determine whether the deleterious BRCA/ATM/other HRR gene 
mutation 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 finding 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. 
9.13 Pharmacokinetics Evaluation 
Plasma samples are to be collected for trough level PK analysis of rucaparib 1 hour before the 
morning dose on Study Day 29, Day 57, Day 85, and Day 113. If the start of the next dose is 
postponed or suspended, the PK sample should be collected as close to 12 hours after the 
previous dose as possible. Refer to the Laboratory Manual for sample collection details for PK 
samples. 
9.14 Patient Reported Outcomes (Health and Quality of Life 
Questionnaires) 
Patient reported outcomes utilizing the BPI-SF, (Appendix 6), FACT-P (Appendix 7), EQ-5D-5L 
(Appendix 8), and analgesic drug score instruments (Appendix 9) will be assessed during 
screening, Study Day 1 and every 28 days thereafter, at the Treatment Discontinuation Visit, at 
the 28-Day Follow-up Visit, and if applicable, during long term follow-up. The analgesic drug 
score will be recorded according to the WHO’s analgesic ladder: 0 for no analgesic, 1 for 
nonopioids, 2 for opioids for moderate pain, and 3 for opioids for severe pain.46  


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Patients should complete the instruments before any other scheduled study procedures are 
performed and dosing occurs (if applicable). For patients who discontinued treatment prior to 
radiologic disease progression, PRO assessments should be collected until subsequent radiologic 
disease progression was documented.  


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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 on 
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 on the AE eCRF, not on 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 (or, occurs 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 rucaparib through 28 days after last dose) must be treated as an SAE 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. 
 


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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 trial 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 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 either Clovis study drug or concomitant medication unless associated with an 
SAE. However, the event should still be captured as a nonserious AE on 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;  
• 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 1 of the following criteria is met: 
• an action on rucaparib treatment is made as a result of the abnormality 


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• 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 rucaparib, unless due 
to a protocol-mandated procedure, are to be recorded on 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 rucaparib through 28 days after receiving the last dose of 
rucaparib will be recorded on the AE eCRF.  
Report any AE of pneumonitis, or any of the following AEs, irrespective of causality assessment 
and severity, as an AESI within 24 hours using the study Serious Adverse Event Form: 
• Pneumonitis 
• Interstitial lung disease 
• Pulmonary fibrosis 
• Acute interstitial pneumonitis  
• Alveolitis necrotizing 
• Alveolitis 
• Hypersensitivity pneumonitis 
• Organizing pneumonia 
 
After the 28-day Follow-up Visit, only SAEs assessed as potentially related to rucaparib should 
be reported per Clovis PV requirements and captured in the Clovis PV database. This includes 
serious reports of pneumonitis or associated events, if considered to be related to study drug. 
After the 28-day Follow-up Visit, AESIs of MDS and AML, irrespective of causality, should be 
reported per Clovis PV requirements and captured in the Clovis PV database.  


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• AESIs of pneumonitis or associated events should only be reported up to, but not beyond, the 
28-day Follow-up Visit (ie, 28-days after the last dose of rucaparib). 
 
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 rucaparib, 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 
rucaparib, whether or not related to rucaparib, 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 (http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf).47 
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: 
• 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 


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• 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 Rucaparib 
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 rucaparib.  
Not Related to 
Rucaparib 
• 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 
rucaparib  
• It does not follow a known pattern of response to rucaparib  
• It does not reappear or worsen when rucaparib is restarted, or 
• An alternative explanation is likely, but not clearly identifiable. 
Related to 
Rucaparib  
• An AE that is difficult to assign to alternative causes 
• It follows a strong or reasonable temporal sequence from administration of 
rucaparib 
• 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 rucaparib, or 
• It is confirmed with a positive rechallenge or supporting laboratory data. 
 
 
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 considered as 
potentially related to rucaparib (including serious reports of pneumonitis or associated events, if 
considered to be related to rucaparib), and AESIs of MDS and AML, irrespective of causality, 
should be reported.  


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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 7.4.2),45 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 U.S. Food and Drug Administration 
(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. 


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11 PLANNED STATISTICAL METHODS 
11.1 General Considerations 
Efficacy analyses will be presented separately for each Cohort and, if applicable, cohorts may be 
combined. Safety analyses will be presented separately for each Cohort and also combined 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, 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% confidence interval will be 
summarized.  
The number of patients with events and the number of censored patients will also be presented.  
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.  
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 enrollment planned for this study is approximately 360 patients, with up to approximately 
150 patients in Cohort A with measurable visceral and/or nodal disease (ie, up to 100 patients 
with a deleterious BRCA1/2 mutation [with a maximum of 60 patients who have only 
measurable lymph node disease], and up to approximately 50 patients with a deleterious ATM 
mutation), up to approximately 150 patients in Cohort B (ie, up to approximately 100 patients 
with a deleterious BRCA1/2 mutation and 50 patients with a deleterious ATM mutation), and up 
to approximately 60 patients in Cohort C.  
Cohort A 
Cohort A will be divided into 2 sub-cohorts defined by deleterious gene mutation (BRCA1/2 vs. 
ATM). 
Cohort A (BRCA1/2) 
A Simon 2-stage design to evaluate confirmed ORR by modified RECIST Version 1.1 criteria 
per investigator will be used. Characteristics of the Simon 2-stage design include: 


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• 5% probability of accepting a minimally effective drug 
• 90% probability of accepting an effective drug 
• ORR of 20% for a minimally effective drug 
• ORR of 35% for an effective drug 
 
In the first stage, 37 patients with a deleterious BRCA1/2 mutation will be evaluated. If the study 
is to proceed to the second stage, additional patients with a deleterious BRCA1/2 mutation will 
be accrued for a total of 83.  
Note: If the study is to proceed to Stage 2, additional patients with a deleterious BRCA1/2 
mutation up to 100 total patients (and a maximum of 60 patients with only measurable lymph 
node disease) will be enrolled in Cohort A (BRCA1/2) if additional clinical data is requested by 
the regulatory authorities to support regulatory filing. If sufficient evidence exists to support a 
regulatory filing prior to fully enrolling Cohort A (BRCA1/2), enrollment may be discontinued 
early. 
Cohort A (ATM) 
Patients in Cohort A (ATM), having a deleterious ATM mutation, will be enrolled concurrently 
with patients from Cohort A (BRCA1/2). It is expected that about 1/3 of the Cohort A patients 
will have deleterious ATM mutations. If 100 patients are enrolled in Cohort A (BRCA1/2), then 
approximately 50 patients would be expected to enroll into Cohort A (ATM). 
A Simon 2-stage design to evaluate confirmed ORR by modified RECIST Version 1.1 criteria 
per investigator will be used. Characteristics of the Simon 2-stage (minimax) design include: 
• 5% probability of accepting a minimally effective drug 
• 80% probability of accepting an effective drug 
• ORR of 20% for a minimally effective drug 
• ORR of 35% for an effective drug 
 
In the first stage, 31 patients with a deleterious ATM mutation will be evaluated. If the study is 
to proceed to the second stage, additional patients with a deleterious ATM mutation will be 
accrued for a total of 53.  
Cohort B 
Cohort B will be divided into 2 sub-cohorts defined by deleterious gene mutation (BRCA1/2 vs. 
ATM). Cohort B will be enrolled concurrently with Cohort A and is expected to enroll at 
approximately the same rate as Cohort A. Enrollment in Cohort B will be halted when Cohort A 
(BRCA1/2) is fully enrolled.  


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Cohort B (BRCA1/2) 
A Simon 2-stage type futility rule will be employed in Cohort B (BRCA1/2). Characteristics of 
the Simon 2-stage design include: 
• 5% probability of accepting a minimally effective drug 
• 90% probability of accepting an effective drug 
• ORR of 20% for a minimally effective drug 
• ORR of 40% for an effective drug 
 
In the first stage, 19 patients with a deleterious BRCA1/2 mutation will be evaluated. If the study 
is to proceed to the second stage, additional patients with a deleterious BRCA1/2 mutation will 
be accrued for a total of 54. Additionally, if the criteria for Stage 2 are met, additional patients, 
up to approximately 100 total, may be enrolled. Enrollment in Cohort B (BRCA1/2) will be 
halted when Cohort A (BRCA1/2) is fully enrolled. 
Cohort B (ATM) 
Patients in Cohort B (ATM), having a deleterious ATM mutation, will be enrolled concurrently 
with patients from Cohort B (BRCA1/2). It is expected that about 1/3 of the Cohort B patients 
will have deleterious ATM mutations. If 100 patients are enrolled in Cohort B (BRCA1/2), then 
approximately 50 patients would be expected to enroll into Cohort B (ATM). 
A Simon 2-stage type futility rule will be employed. Characteristics of the Simon 2-stage 
(minimax) design include: 
• 5% probability of accepting a minimally effective drug 
• 80% probability of accepting an effective drug 
• ORR of 20% for a minimally effective drug 
• ORR of 40% for an effective drug 
 
In the first stage, 18 patients with a deleterious ATM mutation will be evaluated. If the study is 
to proceed to the second stage, additional patients with a deleterious ATM mutation will be 
accrued for a total of 33. Additionally, if the criteria for Stage 2 are met, additional patients, up 
to approximately 50 total, may be enrolled. Enrollment in Cohort B (ATM) will be halted when 
Cohort A (BRCA1/2) is fully enrolled. 
Cohort C 
Up to approximately 60 patients will be enrolled into Cohort C. Enrollment in Cohort C will be 
halted when Cohort A (BRCA1/2) is fully enrolled. Since this cohort will enroll patients that 
have 1 of several different deleterious HRR gene mutations, each gene will be examined 
separately.  


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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 
1 dose of protocol-specified treatment. 
IRR Efficacy Population – The IRR efficacy population will consist of all patients evaluable for 
response by RECIST Version 1.1/PCWG3 criteria (Appendix 2) per independent radiology 
review or, for Cohort B, PSA response.  
Investigator Efficacy Population – The investigator efficacy population will consist of all 
patients evaluable for response by RECIST Version 1.1/PCWG3 criteria (Appendix 2) per 
investigator or, for Cohort B, PSA response.  
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. 
11.4 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 baseline variables will be summarized with frequency tabulations: 
• Time since diagnosis of primary tumor (months): 0 to 12, > 12 to 24, > 24; 
• The following BRCA/ATM/other HRR gene mutation characteristics will also be 
summarized:  
- 
BRCA/ATM/other HRR gene mutation status (germline or somatic)  
 
Descriptive statistics may also be used to summarize the continuous variables.  
11.5 Efficacy Analyses 
11.5.1 
Primary Efficacy Analyses 
For Cohort A, the primary efficacy endpoint for the study is confirmed radiologic ORR (CR or 
PR per modified RECIST Version 1.1 criteria and no bone progression per PCWG3 prior to a 
CR or PR) by central independent radiology review (IRR) in patients with measurable visceral 
and/or nodal disease at baseline per IRR (Cohort A). This endpoint will be summarized along 
with a 95% confidence interval and will be analyzed separately for patients with deleterious 
BRCA1/2 and ATM mutations. 
An analysis of confirmed radiologic ORR by the investigator will also be conducted as 
supportive to the primary endpoint. 


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For Cohort B, the primary efficacy endpoint is confirmed PSA response (≥ 50% decrease) as 
assessed by a local laboratory in patients with non-measurable disease and will be summarized 
along with a 95% confidence interval and will be analyzed separately for patients with 
deleterious BRCA1/2 and ATM mutations. 
For Cohort C, the primary endpoint is confirmed radiologic ORR if measurable visceral and/or 
nodal disease is present at baseline or ≥ 50% PSA decrease from baseline if visceral and/or nodal 
disease is absent. For patients with measurable disease, response will be assessed by central IRR. 
11.5.2 
Secondary Efficacy Analysis 
Duration of confirmed response is defined as the time from the date that a response (modified 
RECIST 1.1 or PSA ≥ 50%) is first reported to the time that progression is first documented: 
• For responses per RECIST 1.1, duration of confirmed response is defined as the time from 
the date that a response (modified RECIST 1.1) is first reported to the time that progression 
(per modified RECIST Version 1.1 criteria or bone progression per PCWG3) is first 
documented 
• For PSA-response, duration of confirmed response is defined as the time from the date that a 
response (PSA decrease ≥ 50%) is first reported to the time that PSA progression is first 
documented 
 
Radiologic PFS (rPFS) is defined as the time from first dose of rucaparib to the date of first 
objective evidence of radiographic progression (soft tissue or bone lesion) or death due to any 
cause, whichever occurs first. Radiographic disease progression includes confirmed bone disease 
progression and soft tissue disease progression adjudicated by independent central radiological 
review using the PCWG3 guidelines for bone disease and modified RECIST Version 1.1 for soft 
tissue disease.  
OS is defined as the date from first dose of rucaparib to the date of death due to any cause. 
Clinical benefit rate (CBR) is defined as the combination of CR, PR, and SD as defined by 
modified RECIST Version 1.1 and no progression in bone by PCWG3 criteria. Per RECIST, 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. 
Confirmed PSA response is defined as ≥ 50% 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 1 post-
baseline assessment. PSA will be assessed by a local laboratory. 
Similarly, PSA response will also be define as ≥ 90% reduction in PSA from baseline to lowest 
post-baseline PSA result, with a consecutive assessment conducted at least 3 weeks later. 


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Time to PSA progression is defined as the time from first dose of rucaparib 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. 
11.5.3 
Exploratory Efficacy Analyses 
The endpoints for exploratory analyses are: 
• To evaluate PRO using the 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 changes in the molecular profile over time of matched pre- and post-treatment 
tumor or plasma samples 
• To assess concordance in HRR gene mutation status in matched Pre-Screening biopsy tissue, 
archival primary and metastatic tumor tissue and plasma ctDNA 
• To assess ctDNA as a molecular marker of response 
• To assess time to first subsequent antineoplastic therapy 
• 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. 
 
11.5.3.1 
Patient-reported Outcome  
Patient reported outcome endpoints by FACT-P and BPI-SF will be summarized according to 
their respective scoring manuals. Analgesic drug score will be recorded according to the World 
Health Organization (WHO) scale (0 for no medication, 1 for non-opioid pain medication, 2 for 
opioids for moderate pain, and 3 for opioids for severe pain). 
Analyses of change and/or percent change 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 VAS. Patients 
who do not have both a baseline measurement and at least one post-baseline measurement will 
not be included. 
11.5.3.2 
Concordance of HRR Gene 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. In particular, the concordance of genotyping results between 
archival primary or metastatic tissue and Pre-Screening biopsy tissue will be assessed to explore 
whether the HRR gene status of the archival primary or metastatic specimen accurately reflects 


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that found in a Pre-Screening tissue biopsy. Additionally, the sensitivity and specificity of 
plasma HRR gene assessment relative to the tissue results will be explored.  
11.5.3.3 
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 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. The analysis will include but not be limited to reversions in HRR genes that restore 
wild-type function and mutations in other components of DNA repair and oncogenic signaling 
pathways.  
Plasma and tumor samples may be used for the development of a blood or tissue-based 
diagnostic test. 
Analyses may be performed on a subset of patients if it becomes clear that the analysis will have 
limited scientific value in some patients (eg, because of very low titer of ctDNA from plasma or 
low tumor cellularity in tumor samples), or if there are not enough serially collected blood 
samples from individual patients to allow for adequate biomarker evaluation. 
11.5.3.4 
Time to First Subsequent Antineoplastic Therapy 
Time to first subsequent antineoplastic therapy will be summarized using a Kaplan-Meier plot 
and descriptive statistics. 
11.5.3.5 
Loss of Heterozygosity (LOH) 
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 
11.5.4 
Exploratory Pharmacokinetic Analyses 
In all patients with at least one PK sample collected, the trough plasma rucaparib PK data (Cmin) 
and summary statistics (N, mean, SD, 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 analyses, and the results will be reported separately. 
11.6 Safety Analyses 
Safety endpoints include incidence of AEs, clinical laboratory abnormalities, and dose 
modifications. 


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Data from all patients who receive at least 1 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. 
11.6.1 
Adverse Events 
AEs will be classified using the Medical Dictionary for Regulatory Activities (MedDRA) 
classification system. The severity of the toxicities will be graded according to the NCI 
CTCAE Version 4.03 or later. Only treatment-emergent adverse events (TEAEs) will be 
collected: 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 preferred term will be presented. Multiple instances of the TEAE in each SOC and 
multiple occurrences of the same preferred term are counted only once per patient. The number 
and percentage of patients with at least 1 TEAE will also be summarized.  
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 1 TEAE of the given 
grade will be summarized.  
11.6.2 
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 


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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). 
11.6.3 
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.  
The summary of vital sign data will include descriptive statistics (N, mean, SD, minimum, 
median, third quartile, and maximum) of the maximum, minimum and last value during the on-
treatment period. Summaries using descriptive statistics (N, mean, SD, 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.  
11.7 Interim Analysis 
Cohort A 
As described in Section 11.2, up to approximately 150 patients will be enrolled in Cohort A, 
which will be divided into 2 sub-cohorts defined by deleterious gene mutation (BRCA1/2 vs. 
ATM).  
Cohort A (BRCA1/2) 
A Simon 2-stage design to evaluate confirmed ORR by modified RECIST Version 1.1 criteria 
per investigator will be used. With rolling enrollment, after the first 37 patients with a deleterious 
BRCA1/2 mutation have either: a) completed 16 weeks of treatment, or b) discontinued 
treatment prior to completing, an interim analysis will be performed (ie, Stage 1). If ≤ 8/37 
patients in Stage 1 have a confirmed objective response (CR or PR per investigator and without 
progression in bone per PCWG3), the DMC will evaluate the overall benefit/risk for patients 
with deleterious BRCA1/2 mutations in this cohort and make a recommendation whether further 
enrollment should be discontinued. If ≥ 9/37 patients have a confirmed objective response, then 
enrollment will continue with additional patients in Stage 2. With 83 total patients with a 
deleterious BRCA1/2 mutation, characteristics of the Simon 2-stage design include: 
• 5% probability of accepting a minimally effective drug 
• 90% probability of accepting an effective drug 


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• ORR of 20% for a minimally effective drug 
• ORR of 35% for an effective drug 
 
Cohort A (ATM) 
A Simon 2-stage type futility rule will be employed in Cohort A (ATM). An interim analysis 
(Stage 1) will be performed after the first 31 patients have either: a) completed 16 weeks of 
treatment; or b) discontinued treatment prior to completing. Enrollment into the study will 
continue while this interim analysis occurs. If ≤ 6/31 patients in Stage 1 have a confirmed 
objective response (CR or PR per investigator and without progression in bone per PCWG3), the 
DMC will evaluate the overall benefit/risk for patients with deleterious ATM mutations in this 
cohort and make a recommendation whether further enrollment should be discontinued. If ≥ 7/31 
patients have a confirmed objective response, then enrollment will continue in Stage 2. With 
53 total patients with a deleterious ATM mutation, characteristics of the Simon 2-stage 
(minimax) design include: 
• 5% probability of accepting a minimally effective drug 
• 80% probability of accepting an effective drug 
• ORR of 20% for a minimally effective drug 
• ORR of 35% for an effective drug 
 
Cohort B 
As described in Section 11.2, up to approximately 150 patients will be enrolled into Cohort B 
which will be divided into 2 sub-cohorts defined by deleterious gene mutation (BRCA1/2 vs. 
ATM).  
Cohort B (BRCA1/2) 
A Simon 2-stage type futility rule will be employed in Cohort B (BRCA1/2). An interim analysis 
(Stage 1) will be performed after the first 19 patients have either: a) completed 16 weeks of 
treatment; or b) discontinued treatment prior to completing. Enrollment into the study will 
continue while this interim analysis occurs. If ≤ 4/19 patients in Stage 1 have a PSA response 
(≥ 50% decrease), the DMC will evaluate the overall benefit/risk for patients with deleterious 
BRCA1/2 mutations in this cohort and make a recommendation whether further enrollment 
should be discontinued. If ≥ 5/19 patients have a PSA response, then enrollment will continue in 
Stage 2. With 54 total patients with a deleterious BRCA1/2 mutation, characteristics of the 
Simon 2-stage design include: 
• 5% probability of accepting a minimally effective drug 
• 90% probability of accepting an effective drug 
• ORR of 20% for a minimally effective drug 
• ORR of 40% for an effective drug 


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If there are at least 16 responses in 54 patients with a deleterious BRCA1/2 mutation, the null 
hypothesis (ORR = 20%) will be rejected. Additionally, if the criteria for Stage 2 are met, 
additional patients, up to approximately 100 total, may be enrolled. Enrollment in Cohort B 
(BRCA1/2) will be halted when Cohort A (BRCA1/2) is fully enrolled. 
Cohort B (ATM) 
A Simon 2-stage type futility rule will be employed in Cohort B (ATM). An interim analysis 
(Stage 1) will be performed after the first 18 patients have either: a) completed 16 weeks of 
treatment; or b) discontinued treatment prior to completing. Enrollment into the study will 
continue while this interim analysis occurs. If ≤ 4/18 patients in Stage 1 have a PSA response 
(≥ 50% decrease), the DMC will evaluate the overall benefit/risk for patients with deleterious 
ATM mutations in this cohort and make a recommendation whether further enrollment should be 
discontinued. If ≥ 5/18 patients have a PSA response, then enrollment will continue in Stage 2. 
With 33 total patients with a deleterious ATM mutation, characteristics of the Simon 2-stage 
(minimax) design include: 
• 5% probability of accepting a minimally effective drug 
• 80% probability of accepting an effective drug 
• ORR of 20% for a minimally effective drug 
• ORR of 40% for an effective drug 
 
If there are at least 11 responses in 33 patients with a deleterious ATM mutation, the null 
hypothesis (ORR = 20%) will be rejected. Additionally, if the criteria for Stage 2 are met, 
additional patients, up to approximately 50 total, may be enrolled. Enrollment in Cohort B 
(ATM) will be halted when Cohort A (BRCA1/2) is fully enrolled 
Cohort C 
Up to approximately 60 patients will be enrolled into Cohort C. Enrollment in Cohort C will be 
halted when Cohort A (BRCA1/2) is fully enrolled. Since this cohort will enroll patients that 
have 1 of several different deleterious HRR gene mutations, each gene will be examined 
separately. It is anticipated that < 6 patients will have a deleterious mutation in the same HRR 
gene; however, if enrollment of patients with a deleterious mutation in the same gene is higher 
than anticipated then enrollment will be held at 6 patients with any 1 deleterious gene mutation 
and a futility rule will be implemented such that if no responses are observed, then enrollment of 
patients with a deleterious mutation in that particular gene will be stopped, in consultation with 
the DMC.  


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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; treatment beyond progression is permitted with additional consent); 
• 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 
• 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;  
• 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 on the appropriate eCRF. A patient may withdraw 
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 trial early for any of the reasons noted in Section 13.7. 


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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) Directive 2001/20/EC, 2003/94/EC, 2005/28/EC, 536/2014 and 
• All applicable local requirements, and in accordance with the ethical 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 (eg, debarment).  
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 prescreening or screening until appropriate regulatory approval of the study 
protocol has been received. 


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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 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 its 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 submitted, 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 IEC/IRB. 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 informed consent 
form 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 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.  
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. 


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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 a 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 patient will have the option to provide additional consent to allow the sponsor to retain 
residual samples for future unspecified research.  
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.  
13.4 Study Monitoring 
The sponsor, or a contract research organization (CRO) or contract monitor acting on the 
sponsor’s behalf, will contact and 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 


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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 predetermined appropriate intervals during the study until after the last patient is 
completed. The monitor will also perform a study closure visit.  
In accordance with ICH GCP guidelines, and local regulations, the clinical monitor will 
periodically review, via direct access, all eCRFs, study documents, medical records (office, 
clinic, or hospital) for patients in this study (anonymity is to be preserved), research facilities, 
and clinical laboratory facilities associated with the study 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. 
The investigator must ensure provision of sufficient time, reasonable space, and adequate 
qualified personnel for the monitoring visits. The visits are for the purpose of verifying 
adherence to the study protocol and the completeness, consistency, and accuracy of data entered 
on the eCRF and other documents; however, the investigator retains ultimate responsibility for 
the quality and integrity of data generated by the site. Aspects of the study that are essential for 
human patient protection and safety and the reliability of study data shall be confirmed. 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 the relevant site records 
of the patients with the entries on the eCRF (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.  
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. 


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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. 
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 screened.  
13.6 Data Monitoring Committee 
A DMC will be established to review safety data in compliance with a prospective charter. For 
Cohort A and B, DMC may be requested to evaluate the overall risk/benefit of rucaparib therapy 
in this patient population based on the outcome of Stage 1 interim analysis. The DMC will be 
comprised of study investigators and of sponsor representatives. The DMC responsibilities, 
authorities, and procedures for this study will be documented in the DMC charter, which will be 
endorsed by the DMC members and signed by the DMC chair prior to the first data review 
meeting. The DMC will also ensure the study is beneficial to patients (see Section 11.7). 
The DMC will meet after the first 20 patients received rucaparib for at least 28 days or 
discontinued study treatment, and then at least semi-annually after sufficient data has been 
collected. The DMC chairperson or sponsor may convene an unscheduled DMC meeting if there 
are newly identified significant safety concerns. Following data review, the DMC will 
recommend continuation, revision, or termination of the study and/ or continuing or halting 
enrollment into a particular subgroup. Details regarding the DMC 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).  


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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. 
 
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.  


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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 trial-related records are no longer needed. 
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 and rendering that patient’s data nonevaluable. Any deviation must be documented in the 
source documents and reported to the sponsor and to the IEC/IRB according to institutional and 
sponsor requirements. 
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 


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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 
investigator(s) and their staff cooperate with the quality assurance auditor or regulatory authority 
inspector during this 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 
clinical study report. The clinical study report 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 by any employee or agent of the study center to any third 
party or otherwise 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]).48 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 


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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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ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer 
correlating with platinum-free interval. J Clin Oncol. 2010;28(15):2512-9. 
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 
mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet. 
2010;376(9737):245-51. 
34. Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, et al. Oral 
poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 
mutations and advanced breast cancer: a proof-of-concept trial. Lancet. 
2010;376(9737):235-44. 
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 
carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-
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-
Label, Randomized, Multicenter Study Comparing the Efficacy and Safety of Olaparib, a 
Poly (ADP-Ribose) Polymerase Inhibitor, and Pegylated Liposomal Doxorubicin in Patients 
With BRCA1 or BRCA2 Mutations and Recurrent Ovarian Cancer. J Clin Oncol. 
2012;30(4):372-9. 
37. Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al. Olaparib 
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-
92. 
39. De Bono JS, Mina LA, Gonzalez M, Curtin NJ, Wang E, Henshaw JW, et al. First-in-human 
trial of novel oral PARP inhibitor BMN 673 in patients with solid tumors. J Clin Oncol. 
2013;31 (suppl; abstr 2580). 
40. Kristeleit RS, Shapiro G, LoRusso P, Infante JR, Flynn M, Patel MR. A phase I dose-
escalation and PK study of continuous oral rucaparib in patients with advanced solid tumors. 
J Clin Oncol. 2013;31(suppl):2585. 
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 
patients with sporadic cancer: a phase 1 dose-escalation trial. Lancet Oncol. 2013;14(9):882-
92. 
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 
mutation. J Clin Oncol. 2015;33(3):244-50. 


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44. 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. 
45. US Department of Health and Human Services, Food and Drug Administration, CDER, 
CBER. Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation 
2009 [Available from: 
http://www.fda.gov/downloads/Drugs/.../Guidances/UCM174090.pdf. 
46. Sandblom G, Carlsson P, Sennfält K, Varenhorst E. A population-based study of pain and 
quality of life during the year before death in men with prostate cancer. Br J Cancer. 
2004;90(6):1163-8. 
47. National Cancer Institute. Common Terminology Criteria for Adverse Events, Version 4.03 
14 June 2010 [Available from: http://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-
06-14_QuickReference_5x7.pdf. 
48. 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/. 
49. US Department of Health andHuman Services, Food and Drug Administration, CDER. 
Draft Guidance for Industry: Drug Interaction Studies - Study Design, Data Analysis, 
Implications for Dosing, and Labeling Recommendations February 2012 [Available from: 
https://www.xenotech.com/regulatory-documents/2012/2012_guidance.aspx. 
 
 


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15 APPENDICES 
Appendix 1 
Deleterious HRR Genes Associated with Sensitivity to PARPi 
Appendix 2 
Modified Response Evaluation Criteria in Solid Tumors Criteria (Version 1.1) 
and Prostate Cancer Working Group 3 Criteria 
Appendix 3 
Eastern Cooperative Oncology Group (ECOG) Performance Status Scale 
Appendix 4 
Cockcroft-Gault Formula 
Appendix 5 
Examples of CYP Substrates with Narrow Therapeutic Range 
Appendix 6 
Brief Pain Inventory - Short Form (BPI-SF) 
Appendix 7 
Functional Assessment of Cancer Therapy - Prostate (FACT-P) 
Appendix 8 
Euro-Quality of Life 5D 5L (EQ-5D-5L) Patient Reported Outcome 
Appendix 9 
Analgesic Use Questionnaire 
 




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* “deleterious mutation” defined as protein truncating mutations, large protein-truncating rearrangements, splice site mutations, 
deleterious missense mutations, and homozygous deletions 
A total of 15 HRR genes were chosen for evaluation in cohorts A, B and C of this study. Deleterious mutations have been previously reported in 
mCRPC for most. For those genes where deleterious mutations have not been previously reported or have been reported at low frequency (<1%) in 
mCRPC, compelling clinical or pre-clinical data referenced here suggests sensitivity to rucaparib, and that patients with these deleterious 
mutations should not be excluded from the study. 
 
Abbreviations: HRR, homologous recombination repair; mCRPC, metastatic castration-resistance prostate cancer; PARPi, poly ADP ribose polymerase inhibitor; 
NR, not reported; NS, not seen (this gene was evaluated, but a deleterious mutation or associated clinical activity was not observed); NE, not evaluated  
 
a Robinson, Cell 2015 
b Mateo, N Engl J Med 2015 
c Pritchard, N Engl J Med 2016 
d Norquist, JAMA Oncol 2016 
e Clovis ARIEL2 study data (unpublished) 
f Lheureux, ASCO Annual Meeting 2016 
g as reported in Mateo, N Engl J Med 2016; clinical activity is defined as a response by RECIST v1.1; a reduction in prostate-specific antigen (PSA) level of 
≥50%; or a conversion in the circulating tumor-cell count from ≥5 per 7.5 ml of blood at baseline to <5 per 7.5 ml during treatment, with a confirmatory 
assessment ≥4 weeks later 
h clinical activity is defined as a response by RECIST v1.1 or a reduction in serum CA-125 level of ≥50% 
i as of 15 February 2018, sufficient CDK12 patients have been enrolled and recruitment has been halted by the DMC, until further notice 
 
 
 
 


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Appendix 2 
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. 200944 and at 
http://www.eortc.be/Recist/Default.htm. and PCWG3 criteria as described by Scher, et al. 201625 
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 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 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 (US), 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 1 or more nontarget lesion(s). 
Progressive Disease 
Appearance of 1 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 NonTarget- 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 trials 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.  
 
 


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Duration of Response 
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 
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. 
 
 
  
  
 


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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. 201625 
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 trial. 
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, positron emission tomography 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 
 
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 
trial 
Following for bone progression during the study 
• Exclude pseudoprogression in the absence of symptoms or other signs of progression 


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• 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 
Figure 3. 
Controlling for Flare by Applying the 2+2 Rule using the First Post-
treatment Scan as Baseline 
 
 


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PCWG3 Criteria for Confirmation of Radiographic Progression in Bone by Investigator 
Assessment (to be used in conjunction with modified RECIST 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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Appendix 3 
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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Appendix 5 
Examples of CYP Substrates with Narrow Therapeutic 
Range 
Table 7. 
Examples of CYP Substrates with Narrow 
Therapeutic Range 
CYP Enzyme 
Substrates with Narrow Therapeutic Rangea 
CYP1A2 
Tizanidine, theophylline 
CYP2C9 
Warfarin, phenytoin  
CYP3A 
Alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, 
ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, 
terfenadine 
a CYP substrates with narrow therapeutic range refers to drugs whose exposure-response 
relationship indicates that small increases in their exposure levels by the concomitant use of 
CYP inhibitors may lead to serious safety concerns (eg, Torsades de Pointes). 
Online reference tool: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInter
actionsLabeling/ucm093664 htm 
Source: Draft FDA Guidance on Drug Interaction Studies — Study Design, Data Analysis, 
Implications for Dosing, and Labeling Recommendations, 2012.49  
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 6 
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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Appendix 7 
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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Appendix 8 
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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Appendix 9 
Analgesic Use Questionnaire 
A sample form for the Analgesic Use Questionnaire is included on the next page.  
 


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SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN 
TRITON2: A Multicenter, Open-label Phase 2 Study of Rucaparib in 
Patients with Metastatic Castration-resistant Prostate Cancer Associated 
with Homologous Recombination Deficiency 
 
 
 
 
PROTOCOL NUMBER: 
 CO-338-052 
VERSION: 
 1.0 
DATE FINAL: 
 2 July 2019  
SPONSOR: 
 Clovis Oncology 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential 
and, except to the extent necessary to obtain informed consent, may not be 
disclosed to another party unless such disclosure is required by law or 
regulations.  Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further 
disclosed by them. 




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TABLE OF CONENTS 
ABBREVIATIONS AND SPECIALIST TERMS ....................................................................5 
1 
INTRODUCTION ...........................................................................................................6 
2 
OVERALL STUDY DESIGN, OBJECTIVES, AND ENDPOINTS .............................6 
2.1 
Study Objectives and Endpoints ..............................................................................6 
2.2 
Trial Design .............................................................................................................8 
2.3 
Sample Size Justification .......................................................................................10 
3 
GENERAL ANALYSIS CONVENTIONS ..................................................................13 
4 
ANALYSIS POPULATIONS .......................................................................................14 
5 
PATIENT DISPOSITION .............................................................................................15 
6 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ....................................15 
6.1 
Demographics ........................................................................................................15 
6.2 
Baseline Clinical Characteristics ...........................................................................16 
6.3 
Medical History .....................................................................................................16 
7 
PRIOR AND CONCOMITANT MEDICATIONS ......................................................16 
8 
STUDY DRUG EXPOSURE AND COMPLIANCE ...................................................17 
9 
EFFICACY VARIABLES ............................................................................................17 
9.1 
Primary Efficacy Variables ....................................................................................17 
9.2 
Secondary Efficacy Variables ................................................................................17 
9.3 
Exploratory Efficacy Variables ..............................................................................17 
10 
EFFICACY ANALYSIS ...............................................................................................18 
10.1 
Primary Efficacy Analysis .....................................................................................18 
10.2 
Secondary Efficacy Analyses ................................................................................19 
10.2.1 
Duration of Confirmed Response ................................................................19 
10.2.2 
Radiographic PFS ........................................................................................20 
10.2.3 
Overall Survival ...........................................................................................20 
10.2.4 
Clinical Benefit Rate ....................................................................................21 
10.2.5 
Confirmed PSA Response............................................................................21 
10.2.6 
Time to PSA progression .............................................................................21 
10.3 
Exploratory Efficacy Analyses ..............................................................................21 
10.3.1 
Patient-reported Outcome ............................................................................21 
10.3.2 
Changes in Tumor Samples and Changes in Circulating Tumor DNA .......22 
10.3.3 
Concordance of HRR gene status between Metastatic Disease Site 
Biopsy, Archival Primary Tissue and Plasma ctDNA .................................23 
10.3.4 
ORR and/or PSA Response in Relation to Germline/Somatic Status..........23 
10.3.5 
Time to First Subsequent Antineoplastic Therapy .......................................23 
10.3.6 
Genomic Loss of Heterozygosity (%LOH) .................................................23 
10.3.7 
Change from Baseline in PSA .....................................................................23 


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10.4 
Exploratory Pharmacokinetic Analyses .................................................................23 
11 
STATISTICAL / ANALYTICAL ISSUES ..................................................................24 
11.1 
Handling of Dropouts or Missing Data ..................................................................24 
11.2 
Pooling of Centers in Multi-Center Studies ...........................................................24 
11.3 
Multiple Comparison / Multiplicity .......................................................................24 
11.4 
Interim Analysis and Data Monitoring ..................................................................24 
12 
SAFETY ANALYSIS ...................................................................................................27 
12.1 
Adverse Events ......................................................................................................27 
12.2 
Clinical Laboratory Evaluations ............................................................................28 
12.3 
Vital Signs ..............................................................................................................29 
12.4 
ECGs ......................................................................................................................29 
13 
CHANGES IN THE PLANNED ANALYSES.............................................................30 
14 
REFERENCES ..............................................................................................................32 
 
LIST OF IN-TEXT TABLES 
Table 1. Primary, Secondary, and Exploratory Objectives and Endpoints .............................6 
 
LIST OF FIGURES 
Figure 1: Pre-Screening Study Schema. ....................................................................................9 
Figure 2: Study Schema - Screening, Treatment, and Post-treatment Phases. ........................10 
 
 


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ABBREVIATIONS AND SPECIALIST TERMS 
AE 
adverse event 
ATC 
Anatomical Therapeutical Chemical (coding) 
ATM 
ataxia telangiectasia mutated serine/threonine kinase 
BRCA 
breast cancer genes 
CI 
confidence interval  
Cmin 
minimum concentration 
CR 
complete response 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating tumor DNA 
DMC 
data monitoring committee 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
HRD 
homologous recombination deficiency 
HRR 
homologous recombination repair 
ICH 
International Conference on Harmonisation 
IRR 
independent radiology review 
mCRPC 
MedDRA 
metastatic castration-resistant prostate cancer 
Medical Dictionary for Regulatory Activities 
ORR 
objective response rate 
OS 
overall survival 
PCWG3 
Prostate Cancer Working Group 3 
PD 
progressive disease 
PFS 
progression-free survival  
PR 
partial response 
PRO 
patient reported outcomes 
rPFS 
radiographic progression-free survival 
RECIST 
Response Evaluation Criteria In Solid Tumors 
SAE 
serious adverse event 
SAP  
statistical analysis plan 
SD 
standard deviation 
TEAE 
treatment-emergent adverse event 


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1 
INTRODUCTION 
This document describes the statistical analyses and data presentations to be performed for 
Clovis Oncology’s protocol CO-338-052 “TRITON2: A Multicenter, Open-label Phase 2 
Study of Rucaparib in Patients with Metastatic Castration-resistant Prostate Cancer 
Associated with Homologous Recombination Deficiency”.  
This statistical analysis plan (SAP) provides a comprehensive and detailed description of the 
strategy, rationale, and statistical techniques to be used to assess the efficacy and safety of 
rucaparib (CO-338) in patients with metastatic castration-resistant prostate cancer (mCRPC) 
associated with homologous recombination deficiency (HRD). 
The purpose of the SAP is to ensure the credibility of the study findings by providing a 
detailed outline of the statistical analyses that will be presented. All statistical analyses 
detailed in this SAP will be conducted using SAS® Version 9.3 or higher. 
 
2 
OVERALL STUDY DESIGN, OBJECTIVES, AND ENDPOINTS 
2.1 
Study Objectives and Endpoints 
Table 1. 
Primary, Secondary, and Exploratory Objectives and Endpoints 
Primary Objectives 
Primary Endpoints 
To assess the efficacy of rucaparib based on 
the response rate in mCRPC patients with 
HRD who progressed on AR-targeted therapy 
(abiraterone acetate, enzalutamide, 
apalutamide, or investigational AR-targeted 
agent) and taxane-based chemotherapy in the 
castration-resistant setting 
A. Cohort A: Confirmed radiographic 
ORR (as assessed by central 
independent radiology review [IRR]) 
using modified RECIST Version 1.1 
(ie, CR or PR by IRR assessment and 
no confirmed progression in bone per 
PCWG3 by IRR assessment). 
Analyzed separately for patients with 
deleterious BRCA1/2 and ATM 
mutations. 
B. Cohort B: Confirmed PSA response 
(≥ 50% decrease from baseline) as 
assessed by a local laboratory. 
Analyzed separately for patients with 
deleterious BRCA1/2 and ATM 
mutations. 
C. Cohort C: Confirmed radiographic 
ORR (as assessed by central IRR) 
using either modified RECIST 
Version 1.1 (if measurable visceral 
and/or nodal disease is present) or 
confirmed PSA response (≥ 50% PSA 


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decrease from baseline) (if measurable 
visceral and/or nodal disease is 
absent). 
Secondary Objectives 
Secondary Endpoints 
To assess duration of response (DOR) 
Time from the date that a response 
(modified RECIST Version 1.1/PCWG3 
criteria or PSA ≥ 50%, respectively) is 
first reported to the time that progression 
(using modified RECIST Version 
1.1/PCWG3 criteria or PSA-progression 
criteria, respectively) is first documented. 
To assess radiographic progression-free 
survival (rPFS) 
Time from first dose of rucaparib to the 
date of first objective evidence of 
radiographic progression (soft tissue or 
bone lesion, using modified RECIST 
Version 1.1/PCWG3 criteria, 
respectively) or death due to any cause, 
whichever comes first  
To assess overall survival (OS) 
Time from first dose of rucaparib to date 
of death due to any cause. 
To assess clinical benefit rate (CBR) 
Proportion of patients with CR, PR, or 
SD as defined by modified RECIST 
Version 1.1 and no progression in bone 
by PCWG3 criteria  
To assess PSA response 
Confirmed PSA response, 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.  
Similarly, a cut off of at least a 90% 
reduction will be assessed. 
To assess time to PSA progression 
Time from first dose of rucaparib to the 
date that a ≥ 25% increase and absolute 
increase of ≥ 2 ng/mL above the nadir is 
observed, confirmed by a consecutive 
measure at least 3 weeks later  
To assess the safety and tolerability of 
rucaparib 
The incidence of adverse events (AEs), 
clinical laboratory abnormalities, dose 
modifications, vital signs, ECGs, 
physical examinations, and ECOG 
performance status 
To characterize the steady-state 
pharmacokinetics (PK) of rucaparib 
Trough level plasma rucaparib 
concentrations (Cmin) 


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Exploratory Objectives 
Exploratory Endpoints 
To evaluate patient reported outcomes (PRO) 
using the EuroQol 5 dimensions questionnaire 
(EQ-5D-5L), Functional Assessment of 
Cancer Therapy – Prostate (FACT-P), 
analgesic drug score, and Brief Pain Inventory 
– Short Form (BPI-SF) instruments 
Change and/or percent change from 
baseline for the EQ-5D-5L 
instrument. FACT-P and BPI-SF 
summarized according to their respective 
scoring manuals. Analgesic drug score 
recorded according to the World Health 
Organization (WHO) scale.  
To assess changes in the molecular profile 
over time of matched pre- and post-treatment 
tumor and plasma samples 
Changes in cancer-related mutations 
detected in plasma and tissue samples. 
To assess concordance in HRR gene mutation 
status in matched screening biopsy tumor 
tissue, archival primary and metastatic tumor 
tissue and plasma ctDNA 
Pairwise comparisons of available tissue 
and plasma HRR testing results.  
To assess ctDNA as a molecular marker of 
response 
Target lesion and/or PSA dynamics in 
relation to available longitudinal ctDNA 
test results.  
To assess time to first subsequent 
antineoplastic therapy 
Kaplan-Meier plot and/or descriptive 
statistics. 
To evaluate loss of heterozygosity (LOH) in 
metastatic disease site biopsy and archival 
primary and metastatic tumor tissue samples 
Concordance between percentage 
genomic loss of heterozygosity (%LOH) 
in available archival primary and 
metastatic tumor tissue samples. 
To evaluate mechanisms of response and 
resistance in ctDNA and progression tumor 
tissue samples 
Target lesion and/or PSA dynamics in 
relation to available plasma and tissue 
test results. 
 
2.2 
Trial Design 
This is a Phase 2 multicenter study evaluating rucaparib for treatment of patients with 
mCRPC whose tumors are associated with HRD. This study will enroll mCRPC patients with 
mutations in BRCA1/2, ATM, or other HRR genes (BARD1, BRIP1, CDK12, CHEK2, 
FANCA, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D, or RAD54L). Patients will 
be enrolled in 1 of 3 cohorts based on whether or not they had measurable disease at baseline 
per investigator, and based on gene mutation. All patients will be required to have progressed 
following treatment with at least 1, but no more than 2, prior AR-targeted therapy 
(abiraterone acetate, enzalutamide, apalutamide, or investigational AR-targeted agent). 
Patients must also have progressed after 1 prior taxane-based chemotherapy for mCRPC. 
Patients who received prior PARPi treatment, mitoxantrone, cyclophosphamide or platinum-
based chemotherapy will be excluded.  






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deleterious BRCA1/2 mutation have either: a) completed 16 weeks of treatment or b) 
discontinued treatment prior to completing, an analysis will be performed (ie, Stage 1). If ≤ 
8/37 patients in Stage 1 have a confirmed objective response (CR or PR per investigator and 
without progression in bone per PCWG3), the data monitoring committee (DMC) will 
evaluate the overall benefit/risk for patients with deleterious BRCA1/2 mutations in this 
cohort and make a recommendation whether further enrollment should be discontinued. If ≥ 
9/37 patients have a confirmed objective response, then enrollment will continue with 
additional patients in Stage 2. With 83 total patients with a deleterious BRCA1/2 mutation, 
characteristics of the Simon 2-stage design include: 
• 5% probability of accepting a minimally effective drug 
• 90% probability of accepting an effective drug 
• ORR of 20% for a minimally effective drug 
• ORR of 35% for an effective drug 
 
If there are at least 23 responses in 83 patients with a deleterious BRCA1/2 mutation, the null 
hypothesis (ORR = 20%) will be rejected. This design yields a type I error rate of 5% and 
power of 90% when the true response rate is 35%. 
Note: If the study is to proceed to Stage 2, additional patients with a deleterious BRCA1/2 
mutation up to 100 total patients will be enrolled in Cohort A (BRCA1/2) if additional 
clinical data are requested by any Health Authority to support a regulatory filing. If sufficient 
evidence exists to support a regulatory filing prior to fully enrolling Cohort A (BRCA1/2), 
enrollment may be discontinued early. 
Cohort A (ATM) 
Patients in Cohort A (ATM), having a deleterious ATM mutation, will be enrolled 
concurrently with patients from Cohort A (BRCA1/2). It is expected that about 1/3 of the 
Cohort A patients will have a deleterious ATM mutation. If 100 patients are enrolled in 
Cohort A (BRCA1/2), then approximately 50 patients would be expected to enroll into 
Cohort A (ATM). 
A Simon 2-stage design to evaluate confirmed ORR by modified RECIST Version 1.1 
criteria per investigator will be used. Characteristics of the Simon 2-stage (minimax) design 
include: 
• 5% probability of accepting a minimally effective drug 
• 80% probability of accepting an effective drug 
• ORR of 20% for a minimally effective drug 
• ORR of 35% for an effective drug 
 
In the first stage, 31 patients with a deleterious ATM mutation will be evaluated. If there are 
6 or fewer responses, the DMC will consider stopping the sub-cohort for futility. If the sub-
cohort proceeds to the second stage (≥ 7/31 responders), additional patients will be accrued 
for a total of approximately 50. According to the Simon 2-stage parameters, if there are at 


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least 16 responses in a total of 53 patients, the null hypothesis (ORR = 20%) would be 
rejected.  
Cohort B 
Cohort B will be divided into 2 sub-cohorts defined by deleterious gene mutation (BRCA1/2 
vs. ATM). Cohort B will be enrolled concurrently with Cohort A and is expected to enroll at 
approximately the same rate as Cohort A. Enrollment in Cohort B (both sub-cohorts) will be 
halted when Cohort A (BRCA1/2) is fully enrolled.  
Cohort B (BRCA1/2) 
A Simon 2-stage type futility rule will be employed in Cohort B (BRCA1/2). The Stage 1 
analysis will be performed after the first 19 patients have either: a) completed 16 weeks of 
treatment; or b) discontinued treatment prior to completing. Enrollment into the study will 
continue while this analysis occurs. If ≤ 4/19 patients in Stage 1 have a PSA response (≥ 50% 
decrease from baseline), the DMC will evaluate the overall benefit/risk for patients with a 
deleterious BRCA1/2 mutation in this sub-cohort and make a recommendation whether 
further enrollment should be discontinued. If ≥ 5/19 patients have a PSA response, then 
enrollment will continue in Stage 2. With 54 total patients with a deleterious BRCA1/2 
mutation, characteristics of the Simon 2-stage design include: 
• 5% probability of accepting a minimally effective drug 
• 90% probability of accepting an effective drug 
• ORR of 20% for a minimally effective drug 
• ORR of 40% for an effective drug 
 
If there are at least 16 responses in 54 patients with a deleterious BRCA1/2 mutation, the null 
hypothesis (ORR = 20%) will be rejected. This design yields a type I error rate of 5% and 
power of 90% when the true response rate is 40%. Additionally, if the criteria for Stage 2 are 
met, additional patients, up to approximately 100 total, may be enrolled. Enrollment in 
Cohort B (BRCA1/2) will be halted when Cohort A (BRCA1/2) is fully enrolled. 
Cohort B (ATM) 
Patients in Cohort B (ATM), having a deleterious ATM mutation, will be enrolled 
concurrently with patients from Cohort B (BRCA1/2). It is expected that about 1/3 of the 
Cohort B patients will have a deleterious ATM mutation. If 100 patients are enrolled in 
Cohort B (BRCA1/2), then approximately 50 patients would be expected to enroll in Cohort 
B (ATM). 
A Simon 2-stage type futility rule will be employed. The Stage 1 analysis will be performed 
after the first 18 patients have either: a) completed 16 weeks of treatment; or b) discontinued 
treatment prior to completing. Enrollment into the study will continue while this analysis 
occurs. If ≤ 4/18 patients in Stage 1 have a PSA response (≥ 50% decrease from baseline), 
the DMC will evaluate the overall benefit/risk for patients with a deleterious ATM mutation 
in this cohort and make a recommendation whether further enrollment should be 


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discontinued. If ≥ 5/18 patients have a PSA response, then enrollment will continue in Stage 
2. With 33 total patients with a deleterious ATM mutation, characteristics of the Simon 2-
stage (minimax) design include: 
• 5% probability of accepting a minimally effective drug 
• 80% probability of accepting an effective drug 
• ORR of 20% for a minimally effective drug 
• ORR of 40% for an effective drug 
 
If there are at least 11 responses in 33 patients with a deleterious ATM mutation, the null 
hypothesis (ORR = 20%) will be rejected. This design yields a type I error rate of 5% and 
power of 80% when the true response rate is 40%. Additionally, if the criteria for Stage 2 are 
met, additional patients, up to approximately 50 total, may be enrolled. Enrollment in 
Cohort B (ATM) will be halted when Cohort A (BRCA1/2) is fully enrolled. 
Cohort C 
Up to approximately 60 patients will be enrolled in Cohort C. Enrollment in Cohort C will be 
halted when Cohort A (BRCA1/2) is fully enrolled. Since this cohort will enroll patients that 
have a deleterious mutation in 1 of several different deleterious HRR genes, each gene will 
be examined separately. It is anticipated that < 6 patients will have a deleterious mutation in 
the same HRR gene; however, if enrollment of patients with a deleterious mutation in the 
same gene is higher than anticipated, then enrollment will be held at 6 patients with a 
deleterious mutation in the same HRR gene and a futility rule will be implemented such that 
if no responses are observed, then enrollment of patients with a deleterious mutation in that 
particular gene will be stopped, in consultation with the DMC. 
3 
GENERAL ANALYSIS CONVENTIONS 
The safety analyses will be performed using the safety population. In general, safety analyses 
will be presented by gene mutation (e.g., BRCA1/2, ATM, CDK12, CHEK2, and Other) and 
Overall. Safety data may also be presented by subgroups (e.g., measurable disease status at 
baseline or germline/somatic status for BRCA patients). 
In general, efficacy analyses will be presented by gene mutation based on study entry test 
results (e.g., BRCA1/2, ATM, CDK12, CHEK2, and Other) and Overall. The CRF has 
several questions regarding gene mutations. The first asks “Does the patient have a 
deleterious mutation of either BRCA1, BRCA2 or ATM?” and only 1 can be selected. A 
second question asks “Does the patient have a deleterious mutation of another gene 
associated with HRD?” and 12 other gene mutations are listed, and more than 1 can be 
selected. Patients will be categorized into 1 of several gene mutation groups defined as 
follows: 
• BRCA: if BRCA1 or BRCA2 is selected in the first question (regardless of any others 
being selected in the second question) 


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• ATM: if ATM is selected in the first question (regardless of any others being selected 
in the second question)  
• CDK12: if the answer to the first question is “No” and only CDK12 is selected in the 
second question 
• CHEK2: if the answer to the first question is “No” and only CHEK2 is selected in the 
second question 
• Other: all others.  
Note: Other gene mutation groups may be added depending on the number of patients with a 
specific gene mutation. 
As mentioned in Section 2.2, patients are enrolled in 1 of 3 cohorts based on measurable 
disease status at baseline per investigator and based on gene mutation. However, patients 
could be classified in a different cohort based on IRR assessment of measurable disease at 
baseline. For example, a patient with a deleterious BRCA1/2 mutation who is assessed to 
have measurable disease by the investigator would be categorized into Cohort A for analysis 
of endpoints dependent upon measurable disease status per investigator. However, if this 
patient was determined to not have measurable disease per IRR, he would not be categorized 
into Cohort A for analysis of endpoints dependent upon measurable disease status per IRR. 
As a convention in this SAP, cohort labels (i.e., Cohort A, Cohort B, and Cohort C) will refer 
to the group of patients associated with the specified analysis (i.e., per investigator or per 
IRR). 
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.  
The Kaplan-Meier methodology will be used to summarize time-to-event endpoints. If 
estimable, the 50th percentile (median) with the 95% confidence interval and range 
(minimum, maximum) will be summarized. The number of patients with events and the 
number of censored patients will also be presented.   
All data will be used to their maximum possible extent but without any imputations for 
missing data. Unless otherwise specified, baseline is defined as the last measurement on or 
prior to the first day of study drug administration.  
4 
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 
1 dose of protocol-specified treatment. 


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IRR Efficacy Population – The IRR efficacy population will be defined by measurable 
disease status at baseline using modified RECIST Version 1.1 criteria per independent 
radiology review.  
• For endpoints using radiographic data, all treated patients with measurable disease 
(per IRR) at baseline will be included.  
• For PSA endpoints, all treated patients without measurable disease (per IRR) at 
baseline and with a baseline PSA value ≥ 2ng/ml will be included.  
Investigator Efficacy Population – The Investigator efficacy population will be defined by 
measurable disease status at baseline using modified RECIST Version 1.1 criteria per the 
investigator (Inv).  
• For endpoints using radiographic data, all treated patients with measurable disease 
(per Inv) at baseline will be included.  
• For PSA endpoints, all treated patients without measurable disease (per Inv) at 
baseline and with a baseline PSA value ≥ 2ng/ml will be included. 
5 
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. 
A protocol deviation review process/committee will determine the importance of various 
protocol deviations. The number of patients with important protocol deviations (e.g., those 
considered to potentially impact the integrity of the analysis or thought to be relevant) will be 
determined prior to data base lock and will be summarized with frequencies and percentages 
or provided in a patient listing. Patients will not be excluded from efficacy or safety analyses 
due to protocol violations.  
6 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
All demographic and baseline characteristics will be summarized for the safety population. 
6.1 
Demographics 
The demographic variables will be summarized with frequency tabulations and descriptive 
statistics. The demographic variables presented will include the following categorizations: 
• Age (years): <65, 65-74, ≥75 and separately ≤ 50, 51-60, 61-70, 71-80, 81-90, > 90; 
• Height (cm): ≤ 75, > 75-100, > 100-125, > 125-150, > 150-175, > 175; 
• Weight (kg): ≤ 50, > 50-75, > 75-100, > 100-125, > 125-150, > 150; 


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• Race: American Indian or Alaska Native, Asian, Black, Native Hawaiian or 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; 
• Region: North America, Europe, and Other 
6.2 
Baseline Clinical Characteristics 
Baseline characteristics, including the following variables, will be summarized with 
frequency tabulations: 
• Time since diagnosis of primary tumor (years): 0-3, >3-6, >6-9, >9;  
• ECOG Performance Status: 0, 1, ≥2; 
• Gleason score (< 7, 7, 8, 9, 10, not reported); 
• HRR gene mutation; 
• Germline status for patients with a BRCA mutation (Germline, Somatic, Unknown); 
• 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 the continuous variables.   
6.3 
Medical History 
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 and preferred term. 
7 
PRIOR AND CONCOMITANT MEDICATIONS 
All concomitant treatments documented during the study period will be summarized in 
frequency tabulations. Prior/concomitant medication coding will utilize World Health 
Organization (WHO) Drug version 2017MAR (Enhanced) or higher. 
Separate data summaries of prior medications will be provided. 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. 


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8 
STUDY DRUG EXPOSURE AND COMPLIANCE 
Duration of treatment will be calculated as 1+ the number of days from study drug start date 
to date of discontinuation. Descriptive statistics and frequencies/percentages for appropriate 
categorizations will be used to summarize treatment duration. 
9 
EFFICACY VARIABLES 
9.1 
Primary Efficacy Variables 
For Cohort A, the primary efficacy endpoint for the study is confirmed radiographic ORR 
(CR or PR per modified RECIST Version 1.1 criteria and no confirmed bone progression per 
PCWG3 prior to a CR or PR) by central IRR in patients with measurable visceral and/or 
nodal disease at baseline per IRR. 
For Cohort B, the primary efficacy endpoint is confirmed PSA response (≥ 50% decrease) as 
assessed by a local laboratory in patients without measurable disease at baseline per IRR. 
For Cohort C, the primary endpoint is confirmed radiographic ORR if measurable visceral 
and/or nodal disease (per IRR) is present at baseline or confirmed PSA response (≥ 50% 
decrease) if measurable visceral and nodal disease (per IRR) is absent at baseline. 
Supportive analyses will also be conducted using measurable disease status at baseline per 
the Investigator. 
9.2 
Secondary Efficacy Variables 
Secondary variables include: 
• Duration of response (DOR) (modified RECIST 1.1 or PSA ≥ 50%, separately)  
• Radiographic progression-free survival (rPFS) 
• Overall survival (OS) 
• Clinical benefit rate (CBR) 
• PSA response ≥ 50% (all patients) 
• PSA response ≥ 90% (all patients) 
• Time to PSA progression 
• AEs, clinical lab abnormalities, and dose modifications 
• Trough (Cmin) level plasma rucaparib concentrations 
9.3 
Exploratory Efficacy Variables 
Exploratory variables include: 
• Patient reported outcomes (PROs) including 
• EQ-5D-5L instrument and the EQ VAS 


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• FACT-P 
• BPI-SF 
• Analgesic drug score 
• Plasma and tissue genomic profiling results  
• ORR and/or PSA response in relation to germline/somatic status (patients with a 
BRCA1/2 alteration) 
• Time to first subsequent antineoplastic therapy 
• Percentage genomic loss of heterozygosity (%LOH)  
• Best change from baseline in PSA at any time 
 
10 EFFICACY ANALYSIS 
In general, efficacy analyses will be presented by gene mutation (e.g., BRCA1/2, ATM, 
CDK12, CHEK2, and Other) and Overall. 
Efficacy analyses for the endpoints using radiographic data for the Cohort A sub-cohorts 
(i.e., BRCA1/2 and ATM) will be conducted using the IRR Efficacy Population (patients 
evaluable for response by modified RECIST/PCWG3 criteria per IRR). Supportive analyses 
will also be conducted using the Investigator Efficacy Population. 
PSA-related efficacy analyses for Cohort B (patients without measurable disease at Baseline) 
will be conducted using patients evaluable for PSA response.  
Cohort C will consist of some patients with measurable disease at Baseline and some patients 
without measurable disease at Baseline. Efficacy analyses for Cohort C will be conducted 
similarly to Cohorts A and B, dependent upon measurable disease status. Generally, 
Cohort C will be divided up by gene mutation (e.g., CDK12, CHEK2, and Other), when 
warranted by the numbers of patients with a specific mutation. These categories will typically 
appear on the outputs in columns along with the BRCA and ATM columns. 
Some efficacy endpoints can be assessed regardless of measurable disease status (e.g., PSA 
response, CBR, rPFS). These endpoints may also be summarized for all patients, regardless 
of measurable disease status at Baseline. Additionally, the primary efficacy endpoint will 
also be presented by age group (< 65, 65-74, ≥ 75) and race (White, Other). 
10.1 Primary Efficacy Analysis 
For Cohort A, the primary efficacy endpoint is confirmed radiographic ORR by central IRR 
(as described in Section 9.1) in patients with measurable visceral and/or nodal disease at 
baseline. 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 a 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/PCWG3 progression event.  


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Confirmed radiographic ORR will be summarized with frequencies and percentages along 
with 95% confidence intervals. The frequency and percentages of patients with a best overall 
response of complete response (CR), partial response (PR), stable disease (SD), or 
progressive disease (PD) will also be summarized. 
An analysis of confirmed radiographic ORR by the investigator will also be conducted as 
supportive to the primary endpoint and will use the Investigator Efficacy Population (patients 
evaluable for response by modified RECIST/PCWG3 criteria per investigator). 
For Cohort B, the primary efficacy endpoint is confirmed PSA response as assessed by a 
local laboratory in patients without measurable disease at baseline (by central IRR). 
Confirmed PSA response 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 10.2.6). 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 patients with PSA values at baseline. 
Confirmed PSA response will be summarized separately, with frequencies and percentages 
along with 95% confidence intervals, for patients without measurable disease per IRR 
(primary endpoint) and without measurable disease per Investigator (supportive analysis). 
PSA response will also be summarized for patients with measurable disease (both IRR and 
Investigator, separately) and for all patients. 
For Cohort C, the primary endpoint is confirmed radiographic ORR (by central IRR) if 
measurable visceral and/or nodal disease is present at baseline [as described for Cohort A] or 
confirmed PSA response (≥ 50% decrease from baseline) if visceral and nodal disease is 
absent at baseline [as described for Cohort B]. This endpoint will be summarized with 
frequencies and percentages along with 95% confidence intervals. 
10.2 Secondary Efficacy Analyses 
10.2.1 
Duration of Confirmed Response  
The duration of confirmed response is defined as the time from the date that a response is 
first reported (which is subsequently confirmed) to the time that progression is first 
documented plus 1 day. 
• For radiographic response, duration of confirmed response is defined as the time from 
the date that a response (per modified RECIST Version 1.1/PCWG3) is first reported 
to the time that progression (per modified RECIST Version 1.1 criteria 
or confirmed bone progression per PCWG3) is first documented. DOR will be 
summarized separately for patients with confirmed responses per IRR and 
Investigator. 
• For PSA-response, duration of confirmed response (PSA-DOR) is defined as the time 
from the date that a response (PSA decrease ≥ 50%) is first reported to the time that 
PSA progression (as defined in Section 10.2.6) is first documented. PSA-DOR will be 


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summarized separately for patients without measurable disease per IRR and patients 
without measurable disease per Investigator. PSA-DOR may also by summarized for 
patients with measurable disease per IRR, patients with measurable disease per 
Investigator, and for all patients. 
Patients without a progression event will be censored at the time of their last assessment 
(radiographic or PSA, as applicable). The duration of confirmed response will be 
summarized using Kaplan-Meier methodology. In the case of a low censoring rate, the 
duration of response may be summarized with descriptive statistics.   
10.2.2 
Radiographic PFS 
rPFS is defined as the time from first dose of rucaparib to the date of first objective evidence 
of radiographic progression (soft tissue or bone lesion) or death due to any cause, whichever 
occurs first, plus 1 day. Radiographic disease progression includes confirmed bone disease 
progression and soft tissue disease progression adjudicated by IRR using the PCWG3 
guidelines for bone disease and modified RECIST Version 1.1 for soft tissue disease. 
Patients without a documented event of progression will be censored on the date of their last 
adequate tumor assessment (i.e., radiographic assessment) or date of first dose of study drug 
if no post-baseline tumor assessments have been performed.  
Patients who withdraw from treatment prior to radiographic progression will be followed for 
disease status and survival whenever possible. Only tumor scans (and deaths, for PFS 
analyses) prior to start of any subsequent anticancer treatment will be included. If a patient 
discontinues study drug due to a reason other than radiographic PD and subsequently begins 
another anticancer therapy (ACT) prior to a PFS event, that patient will be censored at the 
last scan prior to the start of ACT. However, scans/PFS events occurring more than 24 weeks 
after DC/stop of study drug and more than 24 weeks after their last previous scan but prior to 
start of subsequent ACT will not be included in the analysis and such patients will be 
censored at their last scan prior to the end of the 24-week window.  
rPFS will be presented by gene mutation for all patients (separately, using IRR and 
Investigator assessments) and may also be presented by measurable disease status at 
Baseline.  
A sensitivity analysis will be performed in which patients who have discontinued without 
radiographic progression, but who have had PSA progression, will be treated as having an 
event at the time of PSA progression. 
rPFS will be summarized using Kaplan-Meier methodology and in the case of a low 
censoring rate it may be summarized with descriptive statistics. 
10.2.3 
Overall Survival 
OS is defined as the date from first dose of rucaparib to the date of death due to any cause, 
plus 1 day. OS will be summarized using the Safety Population, by gene mutation and 
Overall, using Kaplan-Meier methodology. OS may also be summarized for the subgroups of 


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patients defined by measurable disease status at baseline. In the case of a low censoring rate 
OS may be summarized with descriptive statistics.  
10.2.4 
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: e.g., 4-, 6-, 9-, and 12-months, with frequencies and percentages along 
with 95% confidence intervals. 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.  
CBR will be summarized for all patients (separately, using IRR and Investigator 
assessments) and may also be summarized for the subgroups of patients defined by 
measurable disease status at baseline. 
10.2.5 
Confirmed PSA Response 
Confirmed PSA response (≥ 50% reduction) will be analyzed for all patients who had PSA 
values at baseline as described in Section 10.1. Similarly, PSA response will also be analyzed 
using a ≥ 90% reduction. 
10.2.6 
Time to PSA progression 
Time to PSA progression is defined as the time from first dose of rucaparib to the date that a 
≥ 25% increase and absolute increase of ≥ 2 ng/mL above the nadir (or baseline if there was 
no PSA decline after baseline) in PSA was measured, plus 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. 
Time to PSA progression will be summarized for all patients and may also be summarized 
for the subgroups of patients defined by measurable disease status at baseline. 
10.3 Exploratory Efficacy Analyses 
10.3.1 
Patient-reported Outcome 
Patient reported outcome endpoints by FACT-P and BPI-SF will be summarized according to 
their respective scoring manuals.  
Analgesic drug score will be recorded according to the World Health Organization (WHO) 
scale (0 for no medication, 1 for non-opioid pain medication, 2 for opioids for moderate pain, 
and 3 for opioids for severe pain). 


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Analyses of change and/or percent change 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.  
PRO endpoints will be summarized for all patients and may also be summarized for the 
subgroups of patients defined by measurable disease status at baseline. 
BPI-SF 
The primary analysis of change in pain intensity over time will be assessed using BPI-SF 
Item #3 (pain symptoms at their worst over the last 24 hours). A composite assessment of 
change in pain intensity (Item #3-6, worst pain, least pain, average pain, and current pain, 
respectively) will also be analyzed.  
BPI item scores, change from baseline, and percentage change from baseline in daily pain 
intensity will be summarized at each visit and at the final visit using descriptive statistics (N, 
mean, SD, minimum, median, and maximum). 
Longitudinal plots of the mean changes from baseline to each scheduled visit may also be 
presented. These plots may exclude visits for which only a small percentage (e.g., ≤ 30%) of 
patients have data. 
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, SD, 
minimum, median, and maximum). 
Longitudinal plots of the mean changes from baseline to each scheduled visit may also be 
presented. These plots may exclude visits for which only a small percentage (e.g., ≤ 30%) of 
patients have data. 
EQ-5D-5L 
Change and percent change from baseline will be analyzed at each visit and at the final visit 
for EQ-5D-5L VAS. Patients who do not have both a baseline measurement and at least one 
post-baseline measurement will not be included. 
10.3.2 
Changes in Tumor Samples and Changes in Circulating Tumor DNA 
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 will be described using graphical plots and 
descriptive statistics.  


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10.3.3 
Concordance of HRR gene status between Metastatic Disease Site Biopsy, 
Archival Primary Tissue and Plasma ctDNA   
Pairwise comparisons will be performed using available plasma and tissue (including 
archival and metastatic) test results to explore the concordance in HRR gene alterations.  
10.3.4 
ORR and/or PSA Response in Relation to Germline/Somatic Status 
The ORR and/or PSA response rate will be analyzed for the subgroups of patients with a 
germline or a somatic BRCA1/2 alteration. 
10.3.5 
Time to First Subsequent Antineoplastic Therapy 
Time from date of last dose of study drug to first subsequent antineoplastic therapy will be 
summarized using a Kaplan-Meier plot and descriptive statistics. 
10.3.6 
Genomic Loss of Heterozygosity (%LOH) 
The percentage 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. 
10.3.7 
Change from Baseline in PSA 
Best change from baseline in PSA at any time will be presented using a waterfall plot. 
10.4 Exploratory Pharmacokinetic Analyses 
In all patients with at least one PK sample collected, the trough plasma rucaparib PK data 
(Cmin) and summary statistics (N, mean, SD, 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 analyses, and the results will be reported 
separately. 
 
 


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11 STATISTICAL / ANALYTICAL ISSUES 
11.1 Handling of Dropouts or Missing Data 
All data will be used to their maximum possible extent but without any imputations for 
missing data. All time to event analyses include censoring and the rules for deriving the 
censoring value are described in more detail under each one of the time to event endpoints.   
11.2 Pooling of Centers in Multi-Center Studies 
The centers within a given region (e.g., United States versus Rest of World) will be pooled, if 
applicable. 
11.3 Multiple Comparison / Multiplicity 
No adjustments for multiple comparisons will be made. 
11.4 Interim Analysis and Data Monitoring 
A DMC has been incorporated into the Study conduct to provide review and assessment of 
the safety and efficacy data, in a systematic manner and to safeguard the interest and the 
safety of the participating patients in the Study. The DMC is tasked with regularly reviewing 
the safety and efficacy of the Study to ensure a favorable risk-benefit ratio for the patients. A 
separate DMC charter contains the details regarding the membership and activities of the 
DMC. 
Simon 2-stage designs have been employed in each sub-cohort to allow futility analyses to be 
conducted to help assess whether each sub-cohort should proceed to full enrollment. The 
Sample Size Justification section (Section 2.3) contains additional detail regarding the Simon 
2-stage assumptions and parameters. 
Cohort A 
Cohort A will be divided into 2 sub-cohorts defined by deleterious gene mutation (BRCA1/2 
vs. ATM). 
Cohort A (BRCA1/2) 
A Simon 2-stage design to evaluate confirmed ORR by modified RECIST Version 1.1 
criteria per investigator will be used. With rolling enrollment, after the first 37 patients have 
either: a) completed 16 weeks of treatment, or b) discontinued treatment prior to completing, 
an analysis will be performed (i.e., Stage 1). If ≤ 8/37 patients in Stage 1 have a confirmed 
objective response (CR or PR per investigator and without progression in bone per PCWG3), 
the DMC will evaluate the overall risk benefit for study treatment and make a 
recommendation whether further enrollment should be discontinued. If ≥ 9/37 patients have a 
confirmed objective response, then enrollment will continue with additional patients in Stage 
2. The parameters of the Simon 2-stage design would accrue a total of 83 patients in this sub-


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cohort. If there were at least 23 responses in 83 patients, the null hypothesis (ORR = 20%) 
would be rejected.  
Note: If the study is to proceed to Stage 2, additional patients with a deleterious BRCA1/2 
mutation up to 100 total patients may be enrolled in Cohort A (BRCA1/2) if additional 
clinical data is requested by the regulatory authorities to support regulatory filing. If 
sufficient evidence exists to support a regulatory filing prior to fully enrolling Cohort A 
(BRCA1/2), enrollment may be discontinued early. 
Cohort A (ATM) 
Patients in Cohort A (ATM), having a deleterious ATM mutation, will be enrolled 
concurrently with patients from Cohort A (BRCA1/2). It is expected that about 1/3 of the 
Cohort A patients will have deleterious ATM mutations. If 100 patients are enrolled in 
Cohort A (BRCA1/2), then approximately 50 patients would be expected to enroll into 
Cohort A (ATM). 
A Simon 2-stage type futility rule will be employed in Cohort A (ATM). The Stage 1 
analysis will be performed after the first 31 patients have either: a) completed 16 weeks of 
treatment; or b) discontinued treatment prior to completing. Enrollment into the study will 
continue while this analysis occurs. If ≤ 6/31 patients in Stage 1 have a confirmed objective 
response (CR or PR per investigator and without progression in bone per PCWG3), the DMC 
will evaluate the overall benefit/risk for patients with deleterious ATM mutations in this 
cohort and make a recommendation whether further enrollment should be discontinued. If 
≥ 7/31 patients have a confirmed objective response, then enrollment will continue in Stage 
2. If the study is to proceed to the second stage, additional patients with a deleterious ATM 
mutation may be accrued for a total of approximately 50, dependent upon the enrollment of 
Cohort A (BRCA1/2). If there are at least 16 responses in 53 patients with a deleterious ATM 
mutation, the null hypothesis (ORR = 20%) would be rejected. 
Cohort B 
Cohort B will be divided into 2 sub-cohorts defined by deleterious gene mutation (BRCA1/2 
vs. ATM). Cohort B will be enrolled concurrently with Cohort A and is expected to enroll at 
approximately the same rate as Cohort A. Enrollment in Cohort B will be halted when 
Cohort A (BRCA1/2) is fully enrolled.  
Cohort B (BRCA1/2) 
Up to approximately 100 patients may be enrolled into Cohort B (BRCA1/2), dependent 
upon enrollment in Cohort A (BRCA1/2). As in Cohort A, a Simon 2-stage type futility rule 
will be employed. The Stage 1 analysis will be performed after the first 19 patients have 
either: a) completed 16 weeks of treatment; or b) discontinued treatment prior to completing. 
Enrollment into the study will continue while this analysis occurs. If ≤ 4/19 patients in Stage 
1 have a PSA response (≥ 50% decrease), the DMC will evaluate the overall risk benefit for 
study treatment. If ≥ 5/19 patients have a PSA response, then enrollment will continue in 
Stage 2.  


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If the study/cohort proceeds to the second stage, additional patients with a deleterious 
BRCA1/2 mutation will be accrued for a total of 54. If there are at least 16 responses in 54 
patients, the null hypothesis (ORR = 20%) will be rejected. Additionally, if the criteria for 
Stage 2 are met, additional patients, up to approximately 100 total, may be enrolled. 
Enrollment in Cohort B (BRCA1/2) will be halted when Cohort A (BRCA1/2) is fully 
enrolled. 
Cohort B (ATM) 
Patients in Cohort B (ATM), having a deleterious ATM mutation, will be enrolled 
concurrently with patients from Cohort B (BRCA1/2). It is expected that about 1/3 of the 
Cohort B patients will have deleterious ATM mutations. If 100 patients are enrolled in 
Cohort B (BRCA1/2), then approximately 50 patients would be expected to enroll into 
Cohort B (ATM). 
A Simon 2-stage type futility rule will be employed in Cohort B (ATM). The Stage 1 
analysis will be performed after the first 18 patients have either: a) completed 16 weeks of 
treatment; or b) discontinued treatment prior to completing. Enrollment into the study will 
continue while this analysis occurs. If ≤ 4/18 patients in Stage 1 have a PSA response (≥ 50% 
decrease), the DMC will evaluate the overall benefit/risk for patients with deleterious ATM 
mutations in this cohort and make a recommendation whether further enrollment should be 
discontinued. If ≥ 5/18 patients have a PSA response, then enrollment will continue in Stage 
2. If there are at least 11 responses in 33 patients with a deleterious ATM mutation, the null 
hypothesis (ORR = 20%) will be rejected. Additionally, if the criteria for Stage 2 are met, 
additional patients, up to approximately 50 total, may be enrolled. Enrollment in Cohort B 
(ATM) will be halted when Cohort A (BRCA1/2) is fully enrolled. 
Cohort C 
Up to approximately 60 patients will be enrolled into Cohort C. Enrollment in Cohort C will 
be halted when Cohort A (BRCA1/2) is fully enrolled. Since this cohort will enroll patients 
that have 1 of several different deleterious HRR gene mutations, each gene will be examined 
separately. It is anticipated that < 6 patients will have a deleterious mutation in the same 
HRR gene; however, if enrollment of patients with a deleterious mutation in the same gene is 
higher than anticipated then enrollment will be held at 6 patients with any 1 deleterious gene 
mutation and a futility rule will be implemented such that if no responses are observed, then 
enrollment of patients with a deleterious mutation in that particular gene will be stopped, in 
consultation with the DMC. 
 
 


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12 SAFETY ANALYSIS 
The safety analyses will be performed using the safety population. In general, safety analyses 
will be presented by gene mutation (e.g., BRCA1/2, ATM, CDK12, CHEK2, and Other) and 
Overall. Safety data may also be presented by measurable disease status at baseline to 
explore the safety profile between patients with and without measurable disease at baseline. 
Additionally, safety data will be further explored by age group (< 65, 65-74, ≥ 75) and race 
(White, Other). 
12.1 Adverse Events 
Adverse events will be classified using the Medical Dictionary for Regulatory Activities 
(MedDRA) classification system. The severity of the toxicities will be graded according to 
the NCI CTCAE version 4.03 or higher whenever possible. Treatment-emergent adverse 
events (TEAEs) are defined as AEs with onset date on or after the date of first dose of study 
medication until the date of the last study medication dose plus 28 days. Adverse events 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 adverse event meets the definition for treatment-
emergent. 
The number and percentage of patients who experienced TEAEs for each system organ class 
and preferred term will be presented. Multiple instances of the TEAE in each system organ 
class and multiple occurrences of the same preferred term are counted only once per patient. 
The number and percentage of patients with at least one TEAE will also be summarized.  
MedDRA preferred terms will also be combined and presented in summaries for the 
following similar terms: 
• Asthenia/Fatigue; 
• ALT/AST Increased; 
• Anemia and/or Decreased Hemoglobin; 
• Thrombocytopenia and/or Decreased Platelets; and 
• Neutropenia and/or Decreased ANC. 
 
Separate tables will be presented as follows: 
• TEAE Overview; 
• All TEAEs; 
• Treatment-related TEAEs; 
• Grade 3 or higher TEAEs; 
• Grade 3 or higher treatment-related TEAEs; 
• Serious TEAEs; 
• Serious treatment-related TEAEs; 
• TEAEs by CTCAE grade; 


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• 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 medication; 
• Treatment-related TEAEs leading to discontinuation of study medication; 
• TEAEs leading to reduction of study medication; 
• Treatment-related TEAEs leading to reduction of study medication; 
• TEAEs resulting in interruption of study medication; 
• Treatment-related TEAEs resulting in interruption of study medication; 
• TEAEs resulting in reduction or interruption of study medication; 
• Treatment-related TEAEs resulting in reduction or interruption of study medication; 
• TEAEs resulting in reduction or interruption or discontinuation of study medication; and 
• Treatment-related TEAEs resulting in reduction or interruption or discontinuation 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.  
Time to the first treatment-related TEAE that resulted in a dose reduction, interruption, or 
discontinuation of study drug is defined as 1+ the number of days from the first dose of study 
drug to the start of the first respective AE. The cumulative incidence will be presented in a 
Kaplan-Meier plot for just the patients with an event, and the median time to onset will be 
calculated along with the 95% CI. Additionally, the analysis of combined terms for anemia 
will be presented as a time to first event analysis, as described above. 
Non-TEAEs (pre-treatment and post-treatment) will be presented in the by-patient data 
listings for the safety population.  
12.2 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 first dose 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.   


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The summary of laboratory data will include tables based on CTCAE grades generally using 
CTCAE version 5.0. A few assessments (e.g., 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, SD, 
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 given. 
Longitudinal plots of the mean (and/or percent) changes from baseline to each scheduled 
visit may also be presented for select laboratory parameters. These plots may exclude visits 
for which only a small percentage (e.g., ≤ 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. 
12.3 Vital Signs 
The on-treatment period will be defined as the time from first dose 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.   
The summary of vital sign data will include descriptive statistics (N, mean, SD, 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 given. The data will be 
presented separately for each sub-cohort and overall.   
12.4 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, SD, minimum, median, and maximum) will be used to summarize ECG 
parameters at Screening and at Treatment Discontinuation.   
 
 


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13 CHANGES IN THE PLANNED ANALYSES 
The definition of confirmed PSA responder (primary endpoint for Cohort B) in the protocol 
has been described in more detail in the SAP. The protocol stated: 
 
Confirmed PSA response is defined as ≥ 50% 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 1 
post-baseline assessment. 
 
This has been updated in the SAP to the following: 
 
Confirmed PSA response 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 10.2.6). 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 patients with PSA values at baseline. 
 
The definition of time to PSA progression in the protocol did not contain all the details 
outlined in the PCWG3 guidelines. The protocol stated: 
Time to PSA progression is defined as the time from first dose of rucaparib 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 has been updated in the SAP to the following: 
 
Time to PSA progression is defined as the time from first dose of rucaparib to the date 
that a ≥ 25% increase and absolute increase of ≥ 2 ng/mL above the nadir (or baseline if 
there was no PSA decline after baseline) in PSA was measured, plus 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. 
The clinical benefit rate analysis in the protocol has been described in more detail in the 
SAP. The protocol stated: 
Clinical benefit rate (CBR) is defined as the combination of CR, PR, and SD as defined 
by modified RECIST Version 1.1 and no progression in bone by PCWG3 criteria. Per 
RECIST, 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. 
 


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This has been updated in the SAP to the following: 
 
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: e.g., 4-, 6-, 9-, and 12-months, with frequencies and 
percentages along with 95% confidence intervals. 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 PCWG3 paper suggests analyzing best percent change from baseline in PSA (using a 
waterfall plot). This analysis has been added in the SAP. 
At the time the protocol was initiated, version 4.03 was the current version of CTCAE. It has 
since been updated to version 5.0 so this more current version will be used to grade the 
laboratory data.  
 


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14 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.