Clinical trial NCT04179396
Conditions: Metastatic Castration Resistant Prostate Cancer
Keywords: CRPC PARP inhibitor RAMP homologous recombination DNA repair DNA defect DNA anomaly mCRPC enzalutamide abiraterone Zytiga Xtandi ADT AR ARi
Sponsor: pharmaand GmbH
Start date: 2019-12-05; Completion date: 2023-01-18
Enrollment: 8 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Assess the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of Oral Rucaparib in Combination with Other Anticancer Agents in Patients with Metastatic Castration Resistant Prostate Cancer

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Rucaparib intervention 2: Enzalutamide intervention 3: Abiraterone
Intervention descriptions: intervention 1: Oral rucaparib will be administered twice daily intervention 2: Enzalutamide will be administered once daily.

Enrollment into Arm A will be prioritized over Arm B until the objectives for Arm A have been achieved. intervention 3: Abiraterone will be administered once daily with prednisone

Protocol documents:
Prot_000.pdf: 
ClinicalTrials.gov Official Title: Study of Oral Rucaparib with 
Other Anticancer Agents in Metastatic Castration Resistant 
Prostate Cancer Patients (RAMP) 
 
ClinicalTrials.gov Identifier Number: NCT04179396 
 
Document Date: 19 January 2022 
 
Document: Clinical Study Protocol CO-338-107 
 
Study Title: RAMP: A Phase 1b, Open-label, Parallel Arm Study 
to Assess the Safety, Tolerability, Pharmacokinetics, and 
Preliminary Efficacy of Oral Rucaparib in Combination with 
Other  
 






[Rucaparib (CO-338)] 
 
Clovis Oncology, Inc. 
Clinical Study Protocol: CO-338-107 Amendment 2 
 
19 January 2022 
Confidential 
Page 3 of 106 
PROTOCOL ACCEPTANCE FORM 
Protocol: 
CO-338-107  
Title: 
RAMP: A Phase 1b, Open-label, Parallel Arm Study to Assess the 
Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of Oral 
Rucaparib in Combination with Other Anticancer Agents in Patients 
with Metastatic Castration Resistant Prostate Cancer 
Date: 
19 January 2022 
Version: 
Amendment 2 
 
 
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 MMM YYYY) 
 
 
 
Name (printed) 
 
 
 
 


[Rucaparib (CO-338)] 
 
Clovis Oncology, Inc. 
Clinical Study Protocol: CO-338-107 Amendment 2 
 
19 January 2022 
Confidential 
Page 4 of 106 
SPONSOR’S MEDICAL EXPERT FOR THE STUDY 
Medical Expert:  
 
 
 
 
 
 
 
 
 
 
 
 
 


[Rucaparib (CO-338)] 
 
Clovis Oncology, Inc. 
Clinical Study Protocol: CO-338-107 Amendment 2 
 
19 January 2022 
Confidential 
Page 5 of 106 
PROTOCOL SYNOPSIS 
Sponsor: 
Clovis Oncology, Inc. 
Name of Finished Product: 
Rucaparib tablets 
Enzalutamide capsules 
Abiraterone tablets 
Name of Active Ingredient: 
Rucaparib camsylate (CO-338) 
Enzalutamide  
Abiraterone acetate 
Study Title: 
RAMP: A Phase 1b, Open-label, Parallel Arm Study to Assess the Safety, Tolerability, 
Pharmacokinetics, and Preliminary Efficacy of Oral Rucaparib in Combination with Other 
Anticancer Agents in Patients with Metastatic Castration Resistant Prostate Cancer 
Study Number: 
CO-338-107 
Study Phase: 
Phase 1b 
Study Duration: 
Q4 2019-Q4 2022 
Background and Study Rationale: 
Prostate cancer is the most common malignancy among men in the United States (US), and 
the second-most common cause of cancer-related mortality, with approximately 30,000 
men dying of the disease each year.1 Based upon GLOBOCAN 2018 estimates, prostate 
cancer is the second leading malignancy diagnosed and the fifth leading cause of death 
from cancer in men worldwide, with almost 359,000 deaths estimated in 2018.2 The course 
of prostate cancer from diagnosis to death is often a series of clinical states progressing 
from localized disease to metastatic castration-resistant prostate cancer (mCRPC), a 
disease state characterized by resistance to standard androgen deprivation therapy 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 breast cancer gene 2 (BRCA2) 
are at increased risk for developing prostate cancer, estimated at 2.5 to 8.6-fold compared 
with non-carriers.3 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 breast cancer 
gene 1 (BRCA1) are also associated with more aggressive disease.4 In addition to germline 
mutations in breast cancer gene 1 or 2 (BRCA1/2), somatic mutations in BRCA1/2 and 


[Rucaparib (CO-338)] 
 
Clovis Oncology, Inc. 
Clinical Study Protocol: CO-338-107 Amendment 2 
 
19 January 2022 
Confidential 
Page 6 of 106 
other homologous recombination deoxyribonucleic acid (DNA)-repair 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 homologous recombination repair (HRR), such as a poly(adenosine 
diphosphate [ADP]-ribose) polymerase (PARP) inhibitor (PARPi).5  
The TRITON2 study (CO-338-052) is evaluating rucaparib in patients with DNA-damage 
repair (DDR) gene alterations who progressed on 1 to 2 lines of androgen 
receptor (AR)-directed therapy and 1 prior line of taxane-based chemotherapy for mCRPC. 
Interim efficacy results from the TRITON2 study in breast cancer gene (BRCA)-mutated 
mCRPC patients administered rucaparib 600 mg twice a day (BID) demonstrated a 44% 
overall response rate (ORR) by independent radiology review (IRR) in 62 patients 
evaluable by Response Evaluation Criteria in Solid Tumors (RECIST Version [v]1.1) 
modified according to Prostate Cancer Working Group Guidelines Version 3 (PCWG3), 
combined with evaluation of bone disease according to PCWG3 (mRECIST/PCWG3).6 
Clinical activity was also observed in patients with other DDR gene alterations. In 
addition, the PARPi olaparib and niraparib have shown evidence of clinical activity in 
mCRPC patients with a DDR alteration.7, 8 These findings provide compelling evidence for 
use of a PARPi in a selected population of mCRPC patients with predicted loss-of-function 
alterations in a DDR gene, including BRCA1/2. 
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 AR 
pathway, abiraterone acetate and enzalutamide.9-13 Based on their tolerability and proven 
efficacy in the prechemotherapy setting, abiraterone acetate and enzalutamide are often 
used as first-line therapies for mCRPC; however, patients progress on these AR-directed 
therapies after a median duration of 16 to 18 months on treatment.  
Recent studies have demonstrated complex cross-talk between ARs and the DDR pathway. 
The bulk of evidence suggests regulation of double-strand break (DSB) repair by the 
AR;14-17 therefore, AR antagonists used in prostate cancer treatment cause irreparable 
DSBs and point to a viable synergy between AR-directed therapies and PARP inhibitors, 
independent of homologous recombination gene mutations.14 This hypothesis has been 
clinically tested in a randomized study where the combination of olaparib and abiraterone 
in unselected mCRPC patients was found to be superior to the abiraterone alone arm with a 
hazard ratio (HR) of 0.65 (median radiographic progression-free survival [rPFS] 13.8 vs. 
8.2 months).18 
Novel therapies that provide robust clinical benefit and have a manageable safety profile 
are still needed for patients with advanced mCRPC. Therefore, evaluation of rucaparib in 
combination with other anticancer therapies, such as an AR antagonist or other therapeutic 
option, represents a viable treatment option for patients with and without evidence of 
HRD. 
The study will evaluate the combinations of rucaparib with 2 widely used AR-directed 
therapies, enzalutamide and abiraterone. Enzalutamide is a next-generation anti-androgen 


[Rucaparib (CO-338)] 
 
Clovis Oncology, Inc. 
Clinical Study Protocol: CO-338-107 Amendment 2 
 
19 January 2022 
Confidential 
Page 7 of 106 
that acts on multiple steps of AR signaling within prostate cancer tumor cells and is 
indicated for the treatment of patients with castration-resistant prostate cancer (CRPC).19, 20 
Abiraterone is an inhibitor of 17α-hydroxylase/C17,20-lyase (CYP17), an enzyme 
expressed in testicular, adrenal and prostatic tumor tissues, which is required for androgen 
biosynthesis. The blockade of nongonadal androgen production is a key factor in treating 
CRPC, since prostate cancer cells are dependent on androgens. Abiraterone is indicated in 
combination with prednisone for the treatment of patients with mCRPC and metastatic 
high-risk castration-sensitive prostate cancer (CSPC).21 The addition of prednisone is to 
prevent mineralocorticoid excess-related adverse events (AEs; such as hypertension, 
hypokalemia and fluid retention), resulting from CYP17 inhibition.22 
Subsequent arms of the study may include other combination partners (eg, other 
AR-directed therapy in development or immune modulators such as checkpoint inhibitors). 
Study Arms 
Treatment Arm A: Rucaparib and enzalutamide  
Treatment Arm B: Rucaparib and abiraterone  
Primary Objective:  
• To evaluate the pharmacokinetics (PK), safety and tolerability of rucaparib in 
combination with other anticancer agents for mCRPC. 
Secondary Objectives: 
• To evaluate the preliminary efficacy of rucaparib in combination with other anticancer 
agents for mCRPC.  
Exploratory Objectives: 
• To evaluate the PK of mCRPC anticancer agents when administered in combination 
with rucaparib. 
• To assess the relationship between genomic alterations detected in tissue or blood with 
clinical outcomes to treatment. 
• To assess the relationship between changes in circulating tumor DNA (ctDNA) profiles 
over time and clinical outcomes to treatment. 
Study Design: 
This is a Phase 1b, open-label study with multiple treatment arms evaluating the PK, 
safety, tolerability and preliminary efficacy of rucaparib in combination with other 
anticancer therapies in patients with mCRPC. The study is designed to test the combination 
of rucaparib with AR-directed therapy (enzalutamide [Arm A] and abiraterone [Arm B]). 
Each arm consists of an initial PK, safety and tolerability assessment. Once completed, 
additional patients may be evaluated to better characterize the PK, safety/tolerability and 
preliminary efficacy of the combination in an expansion phase. 
Patients participating in this study will enroll into one of the study arms (in either the PK 
assessment phase or the expansion phase). If a patient appears to be eligible for more than 
one treatment arm that is open to enrollment, the investigator will be responsible for 
selecting the most appropriate treatment arm for the patient. However, enrollment into 
Arm A will be prioritized over Arm B until the objectives for Arm A have been achieved. 


[Rucaparib (CO-338)] 
 
Clovis Oncology, Inc. 
Clinical Study Protocol: CO-338-107 Amendment 2 
 
19 January 2022 
Confidential 
Page 8 of 106 
A run-in period of 1 week of rucaparib monotherapy has been included in the study design, 
following which, the combination of drugs will be administered. The run-in period is 
designed to assess the PK of rucaparib administered as monotherapy, prior to any 
administration of the combination drug, as this may impact the PK of rucaparib. This 
run-in period will occur both in the initial PK phase as well as the expansion phase of the 
study.  
All dose levels of Arm A (enzalutamide combination) will use the approved dose of 
160 mg once a day (QD) enzalutamide; similarly, all dose levels of Arm B (abiraterone 
combination) will use the approved dose of 1,000 mg QD abiraterone along with 5 mg BID 
prednisone. 
• In Arm A, based on the individual safety profiles of both rucaparib and enzalutamide, 
no significant overlap in toxicity is expected. Therefore, the approved monotherapy 
dose of each agent will be the starting dose for the initial combination evaluation. 
Patients will be closely monitored for safety and tolerability and the dose of rucaparib 
may be reduced, if appropriate, based on emerging safety data. Preliminary assessment 
of the metabolic profile of rucaparib and enzalutamide indicates that rucaparib 
exposure may be diminished due to cytochrome P450 (CYP)3A4 induction by 
enzalutamide. Therefore, depending on the PK profile of rucaparib, and taking into 
account the emerging safety/tolerability data, the rucaparib dose may be escalated 
beyond the starting dose of 600 mg BID. Rucaparib escalation, up to a maximum dose 
of 1,000 mg BID rucaparib, may be explored based on emerging PK, safety and 
tolerability data. The increase in rucaparib dose will be determined by exposure 
observed in the prior cohort of patients. 
• In Arm B, the target combination doses will be the approved monotherapy doses for 
abiraterone and rucaparib. It is not anticipated that abiraterone will reduce rucaparib 
exposure. However, the dose of rucaparib may also be increased beyond 600 mg BID if 
there is unexpected lower exposure with co-administration of abiraterone, similar to the 
approach outlined for Arm A. However, as there is potential for overlapping toxicities 
with this combination, the initial starting dose for rucaparib will be 400 mg BID, with 
escalation planned to 600 mg BID if the initial dose level is deemed safe and tolerable. 
If a dose of 600 mg BID rucaparib in combination with the standard dose of 
abiraterone is not tolerated, a dose of 500 mg BID rucaparib in combination with the 
standard dose of abiraterone may be explored.  
 
Up to 3 dose levels may be tested in the initial PK and safety/tolerability assessment phase, 
with a maximum of 6 patients in each dose level. Further assessment of PK, 
safety/tolerability and preliminary efficacy of the combination may be made in an 
expansion phase, enrolling up to 12 patients per arm. 
Screening assessments will include demographics and medical history, prior treatments, 
prior and current medications and procedures, 12-lead electrocardiogram (ECG), Eastern 
Cooperative Oncology Group (ECOG) performance status, hematology, laboratory 
chemistry, urinalysis, a baseline disease/tumor assessment by computed tomography 
(CT)/magnetic resonance imaging (MRI)/bone scan, PSA measurement, physical 
examination, height, weight, and vital signs measurements and AE assessment. Archival 
tumor tissue, and preferably optional screening biopsies, will be collected, if available. 


[Rucaparib (CO-338)] 
 
Clovis Oncology, Inc. 
Clinical Study Protocol: CO-338-107 Amendment 2 
 
19 January 2022 
Confidential 
Page 9 of 106 
Samples for ctDNA and germline testing will be collected for exploratory assessments 
during the PK run-in period. PK collection for both arms is performed following a 1-week 
run-in period with rucaparib alone. PK of rucaparib in combination with enzalutamide in 
Arm A will be assessed over 2 cycles (one cycle is 28 days) due to the longer half-life of 
enzalutamide and its metabolites, while PK of rucaparib in combination with abiraterone 
will be assessed over a single cycle (also 28 days) in Arm B. Samples collected for 
longitudinal ctDNA profiling and pharmacogenomics will be analyzed to evaluate gene 
variants associated with the clinical activity and PK of the study drugs. 
As of the implementation of Protocol Amendment 2, during and at the end of treatment, 
patients will undergo a more limited number of assessments; however, an appropriate level 
of safety monitoring will remain in place. Patients will be monitored for AEs, but only 
serious adverse events (SAEs) and adverse events of special interest (AESIs) will be 
reported through 28 days after last dose of study drug. Hematology assessments are 
advised on a monthly basis, and vital signs, clinical chemistry, and urinalysis assessments 
will be performed according to local standard of care per investigator. 
Disease/tumor assessments and PSA measurements will be performed according to local 
standard of care per investigator.  
The End-of-Treatment (EOT) Visit and the 28-day safety Follow-up Visit will include an 
assessment of AEs. Any ongoing SAEs, AESIs, or treatment-related Grade 3/4 AEs will be 
followed until resolution or stabilization. After the 28-day Follow-up Visit, only SAEs 
assessed as potentially related to study drug should be reported per Clovis 
Pharmacovigilance (PV) requirements and captured in the Clovis PV database. 
After the 28-day Follow-up Visit, AESIs of myelodysplastic syndrome (MDS) and acute 
myeloid leukemia (AML), irrespective of causality, should be reported per Clovis PV 
requirements and captured in the Clovis PV database.  
• AESIs of pneumonitis or similar events (ie, interstitial lung disease, pulmonary 
fibrosis, acute interstitial pneumonitis, alveolitis necrotizing, alveolitis, 
hypersensitivity pneumonitis, and organizing pneumonia) should be reported up to, but 
not beyond, the 28-day Follow-up Visit (ie, 28 days after the last dose of study drug). 
After the 28-day Follow-up Visit, only serious pneumonitis or similar events assessed 
as potentially related to study drug should be reported per Clovis Oncology PV 
requirements. 
Any drug modifications (treatment interruption, dose modifications, and/or treatment 
discontinuation) will be documented in the electronic Case Report Form (eCRF) and 
source documents, until the implementation of Protocol Amendment 2, after which it is no 
longer required to collect data in the eCRF. If a patient has radiologic progression, but 
continues to derive clinical benefit per the investigator, then continuation of treatment with 
the combination 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.  


[Rucaparib (CO-338)] 
 
Clovis Oncology, Inc. 
Clinical Study Protocol: CO-338-107 Amendment 2 
 
19 January 2022 
Confidential 
Page 10 of 106 
Number of Patients: 
The total enrollment planned for this study is approximately 12 to 60 patients. Each arm of 
the study will enroll as follows: 
PK assessment phase: 6 to 18 patients  
Expansion phase: Up to 12 patients 
Number of Sites: 
Patients will be enrolled across up to 10 sites in the US. 
Inclusion Criteria: 
Eligible patients must meet the following inclusion criteria. Unless otherwise specified, the 
criterial apply to patients enrolling into all parts of the study:  
1. Have signed an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
approved informed consent form prior to any study-specific evaluation.  
2. Be ≥ 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). 
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) agonists (ie, patients who have not undergone an orchiectomy), 
therapy must be continued throughout the study. 
5. Be either AR-directed therapy naïve or have received 1-2 lines of AR-directed therapy 
in the castration-resistant setting. If most recently treated with enzalutamide in the 
castrate-resistant setting, patients must have had no enzalutamide treatment for at least 
6 weeks prior to prior to the first planned dose of rucaparib. If most recently treated 
with an AR-directed therapy other than enzalutamide, patients must have ceased 
AR-directed therapy treatment for at least 4 weeks prior to prior to the first planned 
dose of rucaparib.  
6. Have disease progression after initiation of most recent therapy based on any of the 
following criteria:  
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 mRECIST. 
c.  Radionuclide bone scan: at least 2 new metastatic lesions.  
7. Have adequate organ function confirmed by the following laboratory values obtained 
within 14 days prior to enrollment: 
a. Bone Marrow Function 
i. 
Absolute neutrophil count (ANC) ≥ 1.5 × 109/L; 
ii. 
Platelets ≥ 100 × 109/L; 


[Rucaparib (CO-338)] 
 
Clovis Oncology, Inc. 
Clinical Study Protocol: CO-338-107 Amendment 2 
 
19 January 2022 
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iii. 
Hemoglobin ≥ 10 g/dL independent of transfusion ≤ 14 days prior to screening 
hemoglobin assessment. Transfusions are not permitted between the screening 
hemoglobin assessment and the first dose of rucaparib. 
b. Hepatic Function 
i. 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
≤ 3 × upper limit of normal (ULN); if liver metastases, then ≤ 5 × ULN; 
ii. 
Bilirubin ≤ 1.5 × ULN; < 2 × ULN if hyperbilirubinemia is due to Gilbert’s 
syndrome; 
iii. 
Serum albumin ≥ 30 g/L (3.0 g/dL). 
c. Renal function 
i. 
Serum creatinine ≤ 1.5 × ULN; OR  
ii. 
Estimated glomerular filtration rate (GFR) ≥ 45 mL/min using the 
Cockcroft-Gault formula. 
8. Have an ECOG performance status of 0 to 1 within 14 days prior to the first dose of 
rucaparib. 
9. Have a life expectancy of at least 6 months. 
10. Patients with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or 
hepatitis C virus (HCV) infection may be enrolled if they have undetectable viral load 
with antiviral medication and if the antiviral medications do not interfere with any of 
the study drugs. 
Exclusion Criteria: 
Patients will be excluded from participation if any of the following apply: 
1. Active second malignancy, ie, patient known to have potentially fatal cancer present 
for which he may be (but not necessarily) currently receiving treatment. Exceptions are 
patients with history of malignancy that has been successfully treated, with no 
evidence of active cancer for 3 years prior to enrollment, or surgically cured and/or low 
risk tumors, such as non-melanoma skin cancers. 
2. Have received greater than 2 previous lines of chemotherapy for mCRPC, including 
taxanes.  
3. Prior treatment with any PARP inhibitor. 
4. Spinal cord compression, symptomatic and/or untreated central nervous system (CNS) 
metastases or leptomeningeal disease. Patients with asymptomatic previously treated 
CNS metastases are eligible provided they have been clinically stable for at least 
4 weeks.  
5. Severe concurrent disease, infection, comorbidities. 
6. Known hepatic disorder that would affect drug metabolism or gastrointestinal disorders 
that would potentially alter absorption. 
7. Any clinically significant cardiovascular disease.  
8. Pre-existing duodenal stent and/or any gastrointestinal disorder or defect that would, in 
the opinion of the investigator, interfere with ingestion or absorption of rucaparib or 
the combination treatment. 


[Rucaparib (CO-338)] 
 
Clovis Oncology, Inc. 
Clinical Study Protocol: CO-338-107 Amendment 2 
 
19 January 2022 
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Page 12 of 106 
9. Received anticancer treatment with chemotherapy, radiation, antibody therapy or other 
immunotherapy, gene therapy, vaccine therapy, angiogenesis inhibitors, or 
experimental drugs (other than gonadotropin releasing hormone [GnRH] therapy or 
approved bone-targeting agents) ≤ 14 days prior to first dose of rucaparib and/or 
ongoing adverse effects from such treatment > National Cancer Institute (NCI) 
Common Terminology of Criteria for Adverse Events (CTCAE) Version 5.0 (v5) 
Grade 1, with the exception for alopecia and Grade 2 peripheral neuropathy.  
10. Nonstudy related minor surgical procedure ≤ 5 days, or major surgical procedure 
≤ 21 days, prior to first dose of rucaparib; in all cases, the patient must be sufficiently 
recovered and stable before treatment administration. 
11. Taking any concomitant medications or herbs that could confound PK assessment. 
12. Presence of any other condition that may increase the risk associated with study 
participation or may interfere with the interpretation of study results, and, in the 
opinion of the investigator, would make the patient ineligible for entry into the study. 
13. Refusal to undertake the following measures for the duration of the study and after the 
last dose of study drug for the time period specified: 
a. Using a condom during sex while being treated and for 3 months after the last dose 
of study drug, 
b. Abstaining from semen donations during treatment and for 3 months after the last 
dose of rucaparib. 
14. Those with female partners of childbearing potential will be excluded if they are not: 
a. Documented to be surgically sterile (ie, vasectomy); or 
b. Committed to practicing true abstinence during treatment and for 3 months after the 
last dose of study drug; or 
c. Committed to using a highly effective method of contraception with their partner 
during treatment and for 3 months following the last dose of study drug. 
15. Cohort-specific exclusion criteria: 
a. Arm A: Patients with  
i. 
A history of seizures or traumatic brain or head injury, and/or receiving 
concomitant medication that lowers seizure thresholds; or  
ii. 
Uncontrolled or suboptimally controlled ischemic heart disease, history of 
myocardial infarction/unstable angina, coronary vascular intervention such as 
percutaneous coronary intervention (PCI), stent placement or coronary artery 
bypass graft (CABG) within past 1 year, stable angina or New York Heart 
Association (NYHA) Class 2 to 4 heart failure. 
b. Arm B: Patients with: 
i. 
Mean resting QTc > 470 msec obtained from 3 consecutive ECGs; 
ii. 
Any clinically significant abnormalities in rhythm, conduction or morphology 
of resting ECG, eg, complete left bundle branch block, third degree heart block, 
etc.; 


[Rucaparib (CO-338)] 
 
Clovis Oncology, Inc. 
Clinical Study Protocol: CO-338-107 Amendment 2 
 
19 January 2022 
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Page 13 of 106 
iii. 
Any history of syncope of suspected/confirmed cardiovascular etiology, 
ventricular arrhythmia of pathologic origin, uncontrolled atrial fibrillation, or 
sudden cardiac arrest within the past 1 year; 
iv. 
Any factors that increase the risk of QTc prolongation or risk of arrhythmic 
events, such as heart failure, congenital long QT syndrome, family history of 
long QT syndrome or unexplained sudden death under 40 years of age, or any 
concomitant medication known to prolong the QT interval; 
v. 
History of hypokalemia < 3 mmol/L, uncontrolled hypertension (defined as 
median BP ≥ 160/90 mm Hg on three serial measurements performed at the 
time of screening despite maximal medical management) or presence of 
symptoms due to elevated blood pressure at the time of screening; 
vi. 
Grade 2 edema of any kind (generalized, pitting, or peripheral); or  
vii. 
Diagnosis of Addison’s disease. 
Randomization:  
No randomization or blinding will be performed in the study. 
Study Treatment:  
Patients will take the dose of rucaparib they are assigned, orally BID, as close to 12 hours 
apart as possible and preferably at the same times every day, with approximately 8 oz 
(240 mL) of water starting on Day 1. Rucaparib tablets must be swallowed whole and may 
be taken with or without food. Rucaparib will be provided as 200 mg, 250 mg, and/or 
300 mg dose strength tablets. 
Patients will take rucaparib BID for continuous 28-day cycles until disease progression as 
assessed by the investigator, or other reason for discontinuation. Dose modification is 
permitted in the event of unacceptable toxicity. 
In Arm A (enzalutamide), patients will take 160 mg once daily, with or without food. 
Patients who have not had a bilateral orchiectomy should continue the GnRH analog they 
were taking prior to enrolling into this study. 
In Arm B (abiraterone), patients will take 1,000 mg orally QD with prednisone 
5 mg orally BID. Abiraterone must be taken on an empty stomach with water at least 
1 hour before or 2 hours after a meal, without crushing or chewing tablets. Patients who 
have not had a bilateral orchiectomy should continue the GnRH analog they were taking 
prior to enrolling into this study. 
Dose reductions will not be permitted for enzalutamide, abiraterone or prednisone during 
the PK assessment phase, unless the patient experiences a dose-limiting toxicity (DLT). 
Dose reduction of enzalutamide, abiraterone or prednisone will be allowed for patients 
who were enrolled in the PK assessment phase portion of the study and have completed the 
required treatment period for assessment of DLT or who are enrolled in the dose expansion 
phase, as per the relevant prescribing information. 


[Rucaparib (CO-338)] 
 
Clovis Oncology, Inc. 
Clinical Study Protocol: CO-338-107 Amendment 2 
 
19 January 2022 
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Withdrawal Criteria: 
A patient must be discontinued from treatment with study drug if any of the following 
apply: 
• Consent withdrawal at the patient's own request or at the request of their legally 
authorized representative (where acceptable according to national law and/or local 
regulations). 
• Progression of patient's underlying disease by mRECIST/PCWG3 criteria as assessed 
by the investigator (unless, in the opinion of the investigator, the patient continues to 
receive clinical benefit). 
• Any event, adverse or otherwise, that, in the opinion of the investigator, would pose an 
unacceptable safety risk to the patient. If it is determined that 1 of the study drugs in 
the combination is posing a safety risk and that study drug is permanently 
discontinued, administration of the other study drug may continue if none of the other 
withdrawal criteria have been met and the investigator believes that the patient may 
continue to receive benefit. 
• Any concomitant 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; or  
• The study is terminated. 
Efficacy Assessments: 
Soft tissue (visceral and nodal) disease will be evaluated for evidence of radiographic 
response based on modified RECIST (mRECIST) criteria. Bone lesions will be followed 
and evaluated for evidence of radiologic progression based on PCWG3 criteria.  
Disease/tumor assessments will be performed according to local standard of care per 
investigator, until confirmed radiologic disease progression by mRECIST criteria, as 
assessed by the investigator, loss to follow-up, withdrawal, or study closure.  
Prostate-specific antigen (PSA) levels will be collected according to local standard of care 
per investigator, and as clinically indicated.  


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Safety Assessments: 
Safety and tolerability will be assessed based on the following: 
• Incidence, type, seriousness, severity, and causality of AEs reported (CTCAE v5.0 
or later); 
• 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.  
As of the implementation of Protocol Amendment 2, during and at the end of treatment, 
patients will undergo a more limited number of assessments. Adverse events will be 
monitored, but only SAEs/AESIs will be reported through 28 days after the last dose of 
study drug. 
Hematology assessments (complete blood count) are advised on a monthly basis. Clinical 
chemistry, urinalysis, and vital sign assessments will be performed according to local 
standard of care per investigator. 
Pharmacokinetic Assessments: 
Sparse predose PK sampling for rucaparib and/or its combination partner will be 
performed on Run-In Days 6 and 7 of the 7-day rucaparib run-in treatment, and predose on 
Days 1, 8, 15 and 22 of Cycle 1 and Day 1 of subsequent cycles in all patients. In addition, 
in Arm A, sparse predose PK samples will be collected on Days 8, 15 and 22 of Cycle 2. 
Potential drug-drug interactions (DDIs; effect of combination partner on rucaparib PK) 
will be assessed based on PK data in Cycles 1 and 2 for Arm A and Cycle 1 for Arm B.  
The PK and DDI assessments have been completed and no additional samples will be 
collected for analysis.  
Statistical Methods:  
Sample Size  
In each study arm, 6 to 18 patients (up to 3 dose cohorts) will be enrolled in the PK 
assessment phase; and up to 12 patients will be enrolled in the expansion phase. 
Safety Analyses 
All safety analyses will be summarized for the Safety Population separately for each 
treatment arm. Within a treatment arm, safety analyses will be summarized by dose cohort 
(if applicable) and pooled for all patients in the PK/dose-finding cohort and in the 
expansion cohort.  
Adverse events, 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 
NCI CTCAE v5.0 or later. Body weight and vital signs will be summarized descriptively 
(N, mean, standard deviation, median, minimum, and maximum). ECOG performance 
status will be summarized categorically. 


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Efficacy Analysis: 
Confirmed ORR is defined as the proportion of patients with a documented and confirmed 
best overall response of complete response (CR) or partial response (PR) as assessed by 
the investigator using mRECIST/PCWG3 criteria. A confirmed CR or PR is a response 
that is maintained and documented on a subsequent tumor assessment no less than 4 weeks 
after initial response. ORR (confirmed CR + PR) will also be summarized with frequencies 
and percentages. Changes in PSA levels will also be summarized. The frequency and 
percentages of patients with a best overall response of CR, PR, stable disease (SD), or 
progressive disease (PD) will be summarized. All summaries of response rate will be 
accompanied by 95% confidence intervals (CIs). 
Pharmacokinetic Analyses 
Sparse blood sampling for PK analyses of both rucaparib and the combination drug partner 
will be conducted in all patients. The PK parameters will be determined using 
non-compartmental methods and will be reported. Predose concentrations (ie, minimum 
concentration during a dose interval [Cmin]) of rucaparib, combination drug partners, and 
metabolites of interest (if any) will be reported. The effect of combination drug on the PK 
of rucaparib and its metabolite, M324, will be assessed by comparing their steady-state 
Cmin with and without treatment of the combination drug in each arm. The 
M324-to-rucaparib steady-state Cmin ratio with and without treatment of the combination 
drug in each arm will also be determined. 
Dose Cohort Review Committee: 
This committee will include study investigators, the sponsor’s medical monitor, and may 
include other representatives or designees of the sponsor and the study sites. Prior to 
initiating treatment at each new dose level or prior to expanding a dose level, the 
committee will review patient data, including, but not limited to, demographics, PK 
results, study drug dosing, concomitant medications, hematology and serum chemistry, and 
AEs. The discussion and agreement to escalate or reduce the rucaparib dose and/or expand 
an existing dose level will be documented. 
Date of Protocol Approval (Amendment 2): 
19 January 2022 
 


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TABLE OF CONTENTS 
PROTOCOL APPROVAL SIGNATURE PAGE .....................................................................2 
PROTOCOL ACCEPTANCE FORM .......................................................................................3 
SPONSOR’S MEDICAL EXPERT FOR THE STUDY ...........................................................4 
PROTOCOL SYNOPSIS...........................................................................................................5 
LIST OF IN-TEXT TABLES ..................................................................................................21 
LIST OF IN-TEXT FIGURES.................................................................................................21 
LIST OF APPENDICES ..........................................................................................................21 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................22 
1 
INTRODUCTION ...........................................................................................................27 
1.1 
Background ............................................................................................................27 
1.1.1 
Rucaparib .....................................................................................................28 
1.1.1.1 
Nonclinical Experience ......................................................................29 
1.1.1.2 
Clinical Experience ............................................................................30 
1.1.2 
Enzalutamide................................................................................................33 
1.1.2.1 
Overview of Pharmacokinetics ..........................................................33 
1.1.2.2 
Overview of Efficacy .........................................................................34 
1.1.2.3 
Overview of Safety ............................................................................34 
1.1.3 
Abiraterone ..................................................................................................34 
1.1.3.1 
Overview of Pharmacokinetics ..........................................................35 
1.1.3.2 
Overview of Efficacy .........................................................................36 
1.1.3.3 
Overview of Safety ............................................................................36 
1.2 
Study Rationale ......................................................................................................36 
1.2.1 
Known and Potential Risks and Benefits to Patients ...................................37 
1.2.2 
Rationale for the Study Design ....................................................................37 
1.2.3 
Dose Rationale .............................................................................................38 
1.2.4 
Rationale for Duration of Treatment ............................................................39 
2 
STUDY OBJECTIVES ....................................................................................................40 
3 
STUDY DESIGN .............................................................................................................41 
3.1 
Screening Period ....................................................................................................41 
3.2 
Enrollment..............................................................................................................41 
3.3 
Treatment Period ....................................................................................................41 
3.4 
End of Treatment and Follow-up ...........................................................................43 
3.5 
Treatment Beyond Disease Progression ................................................................44 
3.6 
Dose Cohort Review Committee ...........................................................................44 
3.7 
Removal of Patients From Therapy or Assessment ...............................................44 
3.8 
Study Schema.........................................................................................................45 
3.9 
End of Study ..........................................................................................................48 
4 
STUDY POPULATION ..................................................................................................48 


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4.1 
Number of Patients and Sites .................................................................................48 
4.2 
Inclusion Criteria ...................................................................................................48 
4.3 
Exclusion Criteria ..................................................................................................49 
4.4 
Patients or Partners of Patients of Reproductive Potential ....................................51 
4.5 
Compliance with Inclusion/Exclusion Criteria ......................................................52 
5 
STUDY TREATMENT(S) ..............................................................................................52 
5.1 
Description of Investigational Product(s) and Storage ..........................................52 
5.1.1 
Rucaparib .....................................................................................................52 
5.1.2 
Enzalutamide................................................................................................53 
5.1.3 
Abiraterone Acetate .....................................................................................53 
5.2 
Packaging and Labeling .........................................................................................54 
5.2.1 
Rucaparib .....................................................................................................54 
5.2.2 
Enzalutamide................................................................................................54 
5.2.3 
Abiraterone Acetate .....................................................................................54 
5.3 
Measures to Minimize Bias: Randomization and Blinding ...................................54 
5.4 
Method of Assigning Patients to Treatment Groups ..............................................54 
5.5 
Preparation and Administration of Protocol-specified Treatment .........................55 
5.5.1 
Rucaparib .....................................................................................................55 
5.5.2 
Enzalutamide................................................................................................55 
5.5.3 
Abiraterone Acetate .....................................................................................56 
5.6 
Dose-Limiting Toxicities .......................................................................................56 
5.7 
Definition of DLT-evaluable Patient .....................................................................57 
5.8 
Dose Modifications of Protocol-specified Treatment ............................................57 
5.8.1 
Rucaparib Dose Modification Criteria .........................................................57 
5.8.1.1 
Management of New or Worsening Pulmonary Symptoms ..............59 
5.8.2 
Rucaparib Dose Modification Steps ............................................................59 
5.8.3 
Enzalutamide or Abiraterone Dose Modification ........................................60 
5.9 
Treatment Compliance ...........................................................................................60 
5.10 
Accountability of Protocol-specified Treatment ....................................................61 
5.11 
Investigational Treatment Beyond Disease Progression ........................................61 
6 
PRIOR AND CONCOMITANT THERAPY ..................................................................62 
6.1 
Supportive Care .....................................................................................................62 
6.2 
Anticancer or Experimental Therapy .....................................................................62 
6.3 
Radiotherapy ..........................................................................................................62 
6.4 
CYP450 Isoenzyme Inhibitors, Inducers, and Substrates ......................................62 
6.5 
Anticoagulants .......................................................................................................63 
6.6 
Imaging Restrictions and Precautions ....................................................................63 
6.7 
Other Concomitant Medications ............................................................................64 


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6.8 
General Restrictions ...............................................................................................64 
7 
STUDY PROCEDURES AND METHODS ...................................................................64 
7.1 
Schedule of Assessments .......................................................................................64 
7.2 
Informed Consent Process .....................................................................................67 
7.3 
Methods of Data Collection ...................................................................................67 
7.3.1 
Medical History and Demographic/Baseline Characteristics ......................67 
7.3.2 
Prior and Concomitant Medication Assessments ........................................68 
7.3.3 
Efficacy Evaluations ....................................................................................68 
7.3.3.1 
Disease/Tumor Assessments ..............................................................68 
7.3.3.2 
Tumor Markers ..................................................................................68 
7.3.4 
Safety Evaluations .......................................................................................68 
7.3.4.1 
Adverse Event Assessment ................................................................68 
7.3.4.2 
Clinical Laboratory Investigations .....................................................69 
7.3.4.3 
Vital Signs ..........................................................................................69 
7.3.4.4 
12-Lead Electrocardiograms ..............................................................69 
7.3.4.5 
Physical Examinations, Body Weight and Height .............................69 
7.3.4.6 
ECOG Performance Status ................................................................69 
7.3.5 
Pharmacokinetic Assessments .....................................................................69 
7.3.6 
Biomarker Analyses .....................................................................................70 
7.3.6.1 
Formalin-fixed Paraffin-embedded Tumor Tissue or Fresh 
Tumor Biopsy ....................................................................................70 
7.3.6.2 
Optional Tumor Biopsy .....................................................................70 
7.3.6.3 
Blood Sample for Plasma ctDNA Analyses ......................................71 
7.3.6.4 
Blood Sample for Pharmacogenomics Analyses ...............................71 
7.3.6.5 
Additional Research ...........................................................................71 
8 
ADVERSE EVENT MANAGEMENT ...........................................................................71 
8.1 
Definition of an Adverse Event .............................................................................71 
8.2 
Definition of a Serious Adverse Event ..................................................................72 
8.3 
Definition of an Adverse Event of Special Interest ...............................................72 
8.4 
Events or Outcomes Not Qualifying as Serious Adverse Events ..........................73 
8.5 
Clinical Laboratory Assessments as Adverse Events and Serious Adverse 
Events .....................................................................................................................73 
8.6 
Pregnancy or Drug Exposure During Pregnancy ...................................................74 
8.7 
Reporting of Adverse Events, Serious Adverse Events, and Adverse Events 
of Special Interest ..................................................................................................74 
8.7.1 
Onset Date of Adverse Events .....................................................................75 
8.7.2 
Resolution Date of Adverse Events .............................................................75 
8.7.3 
Intensity of Adverse Events .........................................................................75 
8.7.4 
Causal Relationship of Adverse Events to Study Drug ...............................75 
8.7.5 
Outcome and Action Taken .........................................................................76 


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8.8 
Follow-up of Adverse Events, Serious Adverse Events, and Adverse Events 
of Special Interest ..................................................................................................77 
8.9 
Potential Drug-induced Liver Injury ......................................................................77 
8.10 
Regulatory Aspects of Serious Adverse Event and Adverse Events of Special 
Interest Reporting...................................................................................................78 
9 
STATISTICAL METHODS ............................................................................................78 
9.1 
Determination of Sample Size ...............................................................................78 
9.2 
Analysis Populations ..............................................................................................79 
9.3 
Patient Disposition .................................................................................................79 
9.4 
Demographics and Baseline Characteristics ..........................................................79 
9.5 
Efficacy Analysis ...................................................................................................80 
9.6 
Safety Analyses ......................................................................................................80 
9.6.1 
Extent of Exposure .......................................................................................80 
9.6.2 
Adverse Events ............................................................................................80 
9.6.3 
Clinical Laboratory Evaluations ..................................................................81 
9.6.4 
Vital Sign Measurements .............................................................................82 
9.6.5 
Other Safety Measurements .........................................................................82 
9.7 
Pharmacokinetic Analysis ......................................................................................82 
9.8 
Exploratory Analysis .............................................................................................82 
9.9 
Interim Analysis .....................................................................................................82 
10 STUDY ADMINISTRATION .........................................................................................83 
10.1 
Regulatory and Ethical Considerations ..................................................................83 
10.1.1 
Good Clinical Practice .................................................................................83 
10.1.2 
Regulatory Authority Approvals..................................................................84 
10.1.3 
Institutional Review Board or Independent Ethics Committee Approval ...84 
10.2 
Patient Information and Consent ...........................................................................85 
10.3 
Patient Confidentiality ...........................................................................................85 
10.4 
Study Monitoring ...................................................................................................86 
10.5 
Case Report Forms and Study Data .......................................................................87 
10.6 
Study Termination and Site Closure ......................................................................88 
10.7 
Modification of the Study Protocol........................................................................88 
10.8 
Retention of Study Documents ..............................................................................88 
10.9 
Quality Control and Assurance ..............................................................................89 
10.9.1 
Protocol Deviations ......................................................................................89 
10.9.2 
Study Site Training and Ongoing Monitoring .............................................89 
10.9.3 
Quality Assurance Audits ............................................................................90 
10.9.4 
Direct Access to Source Data/Documents for Audits and Inspections ........90 
10.10 Clinical Study Report .............................................................................................90 
10.11 Publication and Disclosure Policy .........................................................................90 


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10.12 Investigator Oversight ............................................................................................91 
11 REFERENCE LIST .........................................................................................................92 
12 APPENDICES .................................................................................................................96 
 
LIST OF IN-TEXT TABLES 
Table 2-1. 
Study Objectives and Endpoints ........................................................................40 
Table 5-1. 
Description of Rucaparib ...................................................................................53 
Table 5-2. 
Description of Enzalutamide ..............................................................................53 
Table 5-3. 
Description of Abiraterone Acetate ....................................................................53 
Table 5-4. 
Dose Modification Criteria for Rucaparib .........................................................58 
Table 5-5. 
Rucaparib Dose Reduction Steps .......................................................................60 
Table 7-1. 
Revised Schedule of Assessments as of the Implementation of Protocol 
Amendment 2 .....................................................................................................66 
Table 7-2. 
Pharmacokinetic Sample Collections in Treatment Arm A and Arm B 
(PK Assessment and Expansion) ........................................................................67 
Table 8-1. 
Causal Relationship of Adverse Events to Study Drug ......................................76 
 
LIST OF IN-TEXT FIGURES 
Figure 3-1. Study Schema .....................................................................................................46 
Appendix 1, Figure A: Controlling for Flare by Applying the 2+2 Rule using the First 
Post-treatment Scan as Baseline .......................................................................102 
 
LIST OF APPENDICES 
Appendix 1 Modified Response Evaluation Criteria In Solid Tumors v1.1 and 
Prostate Cancer Working Group 3 Criteria ........................................................96 
Appendix 2 Eastern Cooperative Oncology Group (ECOG) Performance Status 
Scale .................................................................................................................104 
Appendix 3 Example Sensitive Clinical CYP Substrates (not an inclusive list) .................105 
Appendix 4 Example Inhibitors and Inducers of CYP2C8 and CYP3A4 (not an 
inclusive list) ....................................................................................................106 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ACTH 
adrenocorticotropic hormone 
ADME 
absorption, distribution, metabolism and excretion 
ADP 
adenosine diphosphate 
ADR 
adverse drug reaction 
AE 
adverse event 
AESI 
adverse events of special interest 
ALCOA+ 
attributable, legible, contemporaneous, original or certified copy, accurate, and 
plus (+) complete, consistent, enduring, and available 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
AR 
androgen receptor 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0-24 
area under the concentration-time curve from 0 to 24 hours 
AUC0-inf 
area under the concentration-time curve from 0 to infinity 
BCRP 
breast cancer resistance protein 
BER 
base excision repair 
BID 
twice a day 
BRCA 
breast cancer gene 
BRCA1 
breast cancer gene 1 
BRCA2 
breast cancer gene 2 
BRCA1/2 
breast cancer gene 1 or 2 
BUN 
blood urea nitrogen 
Cmax 
maximum concentration 
Cmin 
minimum concentration during a dose interval 
Ctrough 
concentration before the next dose is administered  
CABG 
coronary artery bypass graft 
CFR 
Code of Federal Regulations 
CI 
confidence interval 


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CL/F 
apparent clearance 
CLIA 
Clinical Laboratory Improvement Amendments 
CNS 
central nervous system 
CR 
complete response 
CrCL 
creatinine clearance 
CRO 
contract research organization 
CRPC 
castration-resistant prostate cancer 
CSPC 
castration-sensitive prostate cancer 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating tumor DNA 
CYP 
cytochrome P450 
CYP17 
17α hydroxylase/C17,20-lyase 
DDI 
drug-drug interaction 
DDR 
DNA damage repair 
DILI 
drug-induced liver injury 
DLT 
dose-limiting toxicities 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
DSB 
double-strand break 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ECOG PS 
Eastern Cooperative Oncology Group performance status 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EOC 
epithelial ovarian cancer 
EOT 
End-of-Treatment 
EU 
European Union 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
FSH 
follicle-stimulating hormone 


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FTC 
fallopian tube cancer 
GCP 
Good Clinical Practice 
GCSF 
granulocyte-colony stimulating factor 
GDPR 
General Data Protection Regulation 
GFR 
glomerular filtration rate 
GnRH 
gonadotropin releasing hormone 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HDL 
high-density lipoprotein 
HDPE 
high-density polyethylene 
HIV 
human immunodeficiency virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HPLC 
high-performance liquid chromatography 
HR 
hazard ratio 
HRD 
homologous recombination deficiency 
HRR 
homologous recombination repair 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug Application 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRR 
independent radiology review 
IUD 
intrauterine device 
IUS 
intrauterine system 
IV 
intravenous 
IWRS 
Interactive Web Response System 
LD 
longest diameter 
LDH 
lactate dehydrogenase 
LDL 
low-density lipoprotein 


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LFT 
liver function test 
LHRH 
luteinizing hormone-releasing hormone 
LOH 
loss of heterozygosity 
MATE 
multidrug and toxin extrusion transporter 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
mCRPC 
metastatic castration-resistant prostate cancer 
MCV 
mean corpuscular volume 
MDS 
myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
mRECIST 
Modified RECIST version 1.1 
mRECIST/ 
PCWG3 
Response Evaluation Criteria in Solid Tumors modified according to PCWG3 
guidelines, combined with evaluation of bone disease according to PCWG3 
MRI 
magnetic resonance imaging 
MS 
mass spectrometry 
N/A 
not applicable 
NCI 
National Cancer Institute 
NGS 
next-generation sequencing 
NYHA 
New York Heart Association 
OAT 
organic anion transporter 
OCT 
organic cation transporter 
ORR 
overall response rate 
PARP 
poly(ADP-ribose) polymerase 
PARPi 
poly(ADP-ribose) polymerase inhibitor 
PCI 
percutaneous coronary intervention 
PCWG3 
Prostate Cancer Working Group Guidelines Version 3 
PD 
progressive disease  
PET 
positron emission tomography 
P-gp 
P-glycoprotein 
PIS 
Patient Information Sheet 
PK 
pharmacokinetic 
PPC 
primary peritoneal cancer 


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PPI 
proton pump inhibitor 
PPK 
population pharmacokinetics 
PR 
partial response 
PRES 
posterior reversible encephalopathy syndrome 
PSA 
prostate-specific antigen 
PT 
Preferred Term 
PV 
pharmacovigilance 
QD 
once a day 
QTc 
QT interval corrected for heart rate  
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
rPFS 
radiographic progression-free survival 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SI 
International System of Units 
StD 
standard deviation 
SOA 
schedule of assessments 
SOC 
system organ class 
SOP 
standard operating procedure 
SmPC 
Summary of Product Characteristics 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
half-life 
tmax 
time to maximum concentration 
TEAE 
treatment-emergent adverse events 
UGT 
uridine diphosphate-glucuronosyl transferase 
ULN 
upper limit of normal 
US 
United States 
V 
version 
WBC 
white blood cell 
 
 


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1 
INTRODUCTION 
1.1 
Background 
Prostate cancer is the most common malignancy among men in the United States (US), and 
the second-most common cause of cancer-related mortality, with approximately 30,000 men 
dying of the disease each year.1 Based upon GLOBOCAN 2018 estimates, prostate cancer is 
the second leading malignancy diagnosed and the fifth leading cause of death from cancer in 
men worldwide, with almost 359,000 deaths estimated in 2018.2 The course of prostate 
cancer from diagnosis to death is often a series of clinical states progressing from localized 
disease to metastatic castration-resistant prostate cancer (mCRPC), a disease state 
characterized by resistance to standard androgen deprivation therapy 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 breast cancer gene 2 (BRCA21) 
are at increased risk for developing prostate cancer, estimated at 2.5 to 8.6-fold compared 
with non-carriers.3 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 breast cancer gene 1 (BRCA1) 
are also associated with more aggressive disease.4 In addition to germline mutations in 
BRCA1/2, somatic mutations in breast cancer gene 1 or 2 (BRCA1/2) and other homologous 
recombination deoxyribonucleic (DNA)-repair 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 homologous recombination 
repair (HRR), such as a poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) 
inhibitor (PARPi)5  
The TRITON2 study (CO-338-052) is evaluating rucaparib in patients with DNA damage 
repair (DDR) gene alterations who progressed on 1 to 2 lines of androgen 
receptor (AR)-directed therapy and 1 prior line of taxane-based chemotherapy for mCRPC. 
Interim efficacy results from the TRITON2 study in breast cancer gene (BRCA)-mutated 
mCRPC patients administered rucaparib 600 mg twice a day (BID) demonstrated a 44% 
(95% confidence interval [CI]: 31 to 57) overall response rate (ORR) by independent 
radiology review (IRR) in 62 patients evaluable by Response Evaluation Criteria in Solid 
Tumors (RECIST Version [v] 1.1) modified according to Prostate Cancer Working Group 
Guidelines Version 3 (PCWG3), combined with evaluation of bone disease according to 
PCWG3 (mRECIST/PCWG3); ORR by IRR was similar in patients with germline versus 
somatic BRCA mutation.6 Activity was also observed in patients with other DDR gene 
alterations. In addition, the PARP inhibitors olaparib and niraparib have shown evidence of 
clinical activity in mCRPC patients with DDR alterations.7, 8 These findings provide 
 
1 Gene and protein names should typically 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. 


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compelling evidence for use of a PARPi in a selected population of mCRPC patients with 
predicted loss-of-function alterations in DDR genes, including BRCA1/2. 
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 
AR pathway, abiraterone acetate and enzalutamide.9-13 Based on their tolerability and proven 
efficacy in the prechemotherapy setting, abiraterone acetate and enzalutamide are often used 
as first-line therapies for mCRPC; however, patients progress on these agents after a median 
duration of 16 to 18 months on treatment.  
Recent studies have demonstrated complex cross-talk between ARs and the DDR pathway. 
The bulk of evidence suggests regulation of double strand break (DSB) repair by the AR;14-17 
therefore, AR antagonists used in prostate cancer treatment cause irreparable DSBs and point 
to a viable synergy between AR-directed therapy and PARP inhibitors, independent of 
homologous recombination gene mutations.14 This hypothesis has been clinically tested in a 
randomized study where the combination of olaparib and abiraterone in unselected mCRPC 
patients was found to be superior to the abiraterone alone arm with a hazard ratio (HR) of 
0.65 (median radiographic progression-free survival [rPFS] 13.8 vs. 8.2 months).18 
Novel therapies that provide robust clinical benefit and have a manageable safety profile are 
still needed for patients with advanced mCRPC. Therefore, evaluation of rucaparib in 
combination other anticancer therapies, such as an AR antagonist or other therapeutic option, 
represents a viable treatment option, including for patients with and without evidence of 
HRD. 
1.1.1 
Rucaparib 
Rucaparib is a potent, oral small molecule inhibitor of PARP enzymes, including PARP-1, 
PARP-2, and PARP-3, that play a critical role in base excision repair (BER).23  
Rucaparib (Rubraca®) is approved in the US for the treatment of adult patients with 
deleterious BRCA mutation (germline and/or somatic)-associated epithelial ovarian (EOC), 
fallopian tube (FTC), or primary peritoneal (PPC) cancer who have been treated with 2 or 
more prior chemotherapies; for the treatment of adult patients with a deleterious BRCA 
mutation (germline and/or somatic)-associated mCRPC who have been treated with 
AR-directed therapy and a taxane-based chemotherapy; and for the maintenance treatment of 
adult patients with recurrent EOC, FTC, or PPC who are in a complete or partial response 
(PR) to platinum-based chemotherapy.6 Rucaparib is also approved in the European Union 
(EU) 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, and for maintenance treatment of 
adult patients with platinum-sensitive recurrent EOC, FTC, or PPC who are in response 


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(complete or partial) to platinum-based chemotherapy.24 In addition, rucaparib is being 
developed for the treatment of cancer associated with HRD, defined by the presence of a 
deleterious mutation in BRCA1, BRCA2, or other HRR genes, and/or high percentage of 
tumor genome with loss of heterozygosity (LOH), which is a phenotypic consequence of 
HRD. 
A brief overview of data from nonclinical and clinical studies are provided below and 
described in detail in the rucaparib Investigator’s Brochure (IB).  
1.1.1.1 
Nonclinical Experience 
The results from nonclinical studies are consistent with the 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 models, 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.  
In pharmacokinetic (PK) studies, rucaparib demonstrated species-dependent oral 
bioavailability, moderate plasma protein binding, and large volumes of distribution in 
nonclinical species. As a P-glycoprotein (P-gp) and breast cancer resistant protein (BCRP) 
substrate, rucaparib demonstrated minimal penetration of rucaparib-derived radioactivity 
through the blood-brain barrier. In vitro data suggested slow metabolism by cytochrome 
P450 (CYP) enzymes, with CYP2D6 and to a lesser extent CYP1A2 and CYP3A4 
contributing to the metabolism of rucaparib. Rucaparib was mainly excreted in feces in rats 
and dogs. Rucaparib reversibly inhibited CYP1A2, CYP2C9, CYP2C19, and CYP3A, and to 
a lesser extent CYP2C8, CYP2D6, and uridine diphosphate-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) and may inhibit P-gp and BCRP in the gut. 
Oral dosing of rucaparib in single and repeat dose toxicity studies in rats and dogs resulted in 
toxicity to the hematopoietic, lymphopoietic, and gastrointestinal systems. These toxicities 
were generally both reversible upon recovery and predictive of toxicities observed in 
patients. Rucaparib was shown to be clastogenic in an in vitro chromosomal aberration assay 
suggesting potential genotoxicity in humans. Reproductive and development toxicity studies 
in rat showed that rucaparib caused maternal toxicity and was embryotoxic. 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.25-28  


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1.1.1.2 
Clinical Experience 
Rucaparib is being evaluated in Phase 1, 2, and 3 clinical studies in patients with advanced 
cancer with and without evidence of HRD. Rucaparib clinical studies have evaluated (and 
continue to evaluate) patients with relapsed, high-grade ovarian, fallopian tube, or primary 
peritoneal cancer in both the treatment and maintenance settings.  
Rucaparib is being evaluated as treatment for patients with mCRPC, both as monotherapy 
and in combination with nivolumab. 
Clinical pharmacology studies in patients with advanced solid tumors have evaluated 
rucaparib drug-drug interactions (DDIs) and mass balance and drug metabolism. Additional 
clinical pharmacology studies continue to characterize rucaparib DDIs, as well as rucaparib 
PK in special populations. 
Additional studies of rucaparib as monotherapy and in combination with other anticancer 
therapies are planned in ovarian, prostate, and bladder cancers, as well as other tumors. 
Information regarding clinical studies with rucaparib is available in the IB. 
1.1.1.2.1 
Overview of Pharmacokinetics and Drug-drug Interactions 
Assessment of rucaparib PK in cancer patients showed an approximate dose proportional 
exposure after once a day (QD) or BID dosing, rapid absorption with maximum 
concentration (Cmax) achieved within 1.5 to 6 hours. The oral bioavailability was 36% and 
half-life (t1/2) was approximately 24 hours. Rucaparib was moderately bound to human 
plasma proteins in vitro (70%).  
At a dose of 600 mg BID rucaparib, steady state was achieved after approximately 1 week 
with approximately 4-fold accumulation. A high-fat meal increased the Cmax and area under 
the concentration-time curve from 0 to 24 hours (AUC0-24) of rucaparib by 20% and 38%, 
respectively, as compared with that under fasted conditions. The effect of food on rucaparib 
PK is not considered to be clinically significant, thus rucaparib can be taken with or without 
food. 
In vitro, rucaparib showed slow enzymatic turnover in human liver microsomes and 
hepatocytes. Recombinant CYP2D6, and to a lesser extent CYP1A2 and CYP3A4, were able 
to metabolize rucaparib. In cancer patients, M324, a carboxylic acid, was a major inactive 
metabolite of rucaparib. 
Drug interactions with rucaparib as a substrate were assessed in a population PK (PPK) 
analysis. CYP2D6 phenotypes (poor metabolizers, intermediate metabolizers, normal 
metabolizers, and ultrarapid metabolizers) and CYP1A2 phenotypes (normal metabolizers 
and hyper-inducers) did not significantly impact the steady-state exposure of rucaparib at 
600 mg BID. Concomitant administration of strong CYP1A2 or CYP2D6 inhibitors did not 
significantly impact rucaparib PK. Current smokers had overlapping rucaparib exposures as 
compared to nonsmokers and former smokers. Collectively, the results suggest that CYP1A2 
and CYP2D6 play limited role in rucaparib metabolism. Although in vitro rucaparib 


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metabolism mediated by CYP3A4 was slow, a significant contribution of CYP3A4 in vivo 
cannot be excluded. No rucaparib dose adjustment is recommended when concomitantly 
administered with CYP inhibitors or inducers. 
Concomitant treatment with proton pump inhibitors (PPIs) showed no clinically significant 
effect on rucaparib PK. No dose modification of rucaparib is required for patients who are 
receiving concomitant treatment with a PPI. 
Results from Study CO-338-044 evaluating potential DDI with rucaparib, indicated that 
rucaparib, at 600 mg BID, moderately inhibited CYP1A2, weakly inhibited CYP2C9, 
CYP2C19, and CYP3A, and showed no clinically significant effect on the PK of oral digoxin 
(a P-gp substrate). Caution should be exercised in the concomitant use of drugs that are 
sensitive clinical substrates of the above CYP enzymes (Section 6.4). 
In another DDI study (Study CO-338-095) in cancer patients, effects of rucaparib on oral 
rosuvastatin as BCRP substrate and oral contraceptives were determined following 14 days 
of dosing at 600 mg BID. Rucaparib weakly inhibited BCRP and caused mild increases in 
plasma exposures to ethinylestradiol and levonorgestrel. 
In Study CO-338-078, PK of a single dose of rucaparib was compared between cancer 
patients with normal hepatic function and moderate hepatic impairment. Patients with 
moderate hepatic impairment showed approximately 46% increase in area under the 
concentration-time curve from 0 to infinity (AUC0-inf) without apparent change in Cmax. 
Details of these clinical DDI studies are provided in the rucaparib IB. 
1.1.1.2.2 
Overview of Efficacy 
Rucaparib was originally approved by the US Food and Drug Administration (FDA) in 
December 2016 as monotherapy treatment of patients with deleterious BRCA mutation 
(germline and/or somatic) associated advanced ovarian cancer who have been treated with 
≥ 2 chemotherapies. As of May 2018, rucaparib was approved by the European Commission 
for the same indication with the exception that patients must be intolerant to subsequent 
platinum-based chemotherapy.29 The recommended dose of rucaparib is 600 mg BID.  
The primary outcome measure on which approval by FDA for the treatment indication was 
based is investigator-assessed ORR per RECIST v1.1, with ORR by central independent 
radiological review conducted as a supportive analysis. ORR by investigator was 53.8%, 
while ORR by independent review was 41.5%, confirming the results of investigator 
assessment for this endpoint.30 Responses were durable, indicated by a duration of response 
(DOR) by investigator assessment of approximately 9.2 months.  
In April 2018, rucaparib was approved by the US FDA for the maintenance treatment of 
adult patients with recurrent EOC, FTC, or PPC who are in a complete or partial response to 
platinum-based chemotherapy.31 This approval was based on Study CO-338-014 (ARIEL3), 
a randomized, placebo-controlled Phase 3 study.  


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In May 2020, rucaparib was approved by the US FDA for the treatment of adult patients with 
a deleterious BRCA mutation (germline and/or somatic)-associated mCRPC who have been 
treated with AR-directed therapy and a taxane-based chemotherapy. The approval was based 
on Study CO-338-052 (TRITON2), for which the primary outcome measure was ORR by 
IRR evaluable by mRECIST/PCWG3; ORR by IRR was 44% at the recommended dose of 
rucaparib 600 mg BID.6  
1.1.1.2.3 
Overview of Safety 
Results of a recent integrated safety analysis in over 1,000 patients with ovarian or prostate 
cancer who received 600 mg BID rucaparib in the treatment or maintenance setting showed 
that the most common treatment-emergent adverse events (TEAEs) reported were primarily 
mild to moderate (Grade 1-2) in severity and included gastrointestinal disorders (nausea, 
vomiting, diarrhea, constipation, and abdominal pain), asthenia/fatigue, anemia/decreased 
hemoglobin, alanine aminotransferase (ALT)/ aspartate aminotransferase (AST) increased, 
decreased appetite, and dysgeusia. The most common TEAE ≥ Grade 3 include 
anemia/decreased hemoglobin, ALT/AST increased, neutropenia/decreased absolute 
neutrophil count (ANC), and asthenia/fatigue. Section 6.6 of the rucaparib IB serves as 
guidance to the investigator on adverse drug reactions (ADRs) for rucaparib, based on 
incidence of TEAEs by all National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) grades and by ≥ Grade 3. 
The laboratory abnormalities were consistent with the TEAEs, with decreased hemoglobin 
(and associated increase in mean corpuscular volume [MCV] and mean corpuscular 
hemoglobin [MCH]), increased ALT, increased AST, and increased serum creatinine, most 
commonly occurring. Decreased platelets, neutrophils, leukocytes, lymphocytes and 
increased cholesterol were observed to a lesser extent. The transient elevations in ALT/AST 
with rucaparib treatment were not associated with abnormal increases in bilirubin or other 
criteria for drug-induced hepatotoxicity and generally resolved over time. Furthermore, no 
cases met Hy’s law criteria for drug-induced liver injury (DILI),32, 33 and few patients 
discontinued rucaparib due to ALT/AST elevations.34, 35 Similarly, elevations in creatinine 
were self-limiting and generally stabilized over time. The majority of creatinine elevations 
were Grade 1 or Grade 2. Elevated serum creatinine levels resolved upon interruption or 
discontinuation of rucaparib were not accompanied by changes in blood urea nitrogen (BUN) 
and did not lead to discontinuation of rucaparib treatment. Increased creatinine with 
rucaparib treatment is likely due to the potent inhibition by rucaparib of MATE1 and 
MATE2-K renal transporters (Section 1.1.1.1). 
An updated analysis of safety presented in the US prescribing information6 and the 
EU Summary of Product Characteristics (SmPC)24 demonstrate that safety results in ovarian 
cancer patients treated with rucaparib have remained consistent with those previously 
reported, and that the safety profile is consistent across both the treatment and maintenance 
indications for rucaparib in ovarian cancer and in the treatment of mCRPC.  
Effects on cardiac channel activity in vitro and a comprehensive assessment of the effects of 
rucaparib on electrocardiogram (ECG) parameters in cancer patients demonstrated a low risk 
of cardiac effects by rucaparib. 


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Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are considered 
adverse events of special interest (AESI), as these events have been observed in patients 
exposed to cytotoxic chemotherapy (eg, platinum and anthracyclines) used for treatment of 
ovarian cancer as well as with PARP inhibitors, including rucaparib. Patients in rucaparib 
clinical studies diagnosed with MDS or AML had significant confounding risk factors 
including prior cytotoxic chemotherapy, and in some cases a deleterious BRCA mutation, 
which increases the risk of developing cancer(s). Based on these confounding factors, there is 
insufficient scientific evidence to conclude that MDS and AML are causally related to 
rucaparib. More information on AESIs 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 8.7. Also, refer to the rucaparib IB for information regarding the AESI of 
pneumonitis.  
1.1.2 
Enzalutamide 
Enzalutamide is a next-generation anti-androgen that acts on multiple steps of AR signaling 
within prostate cancer tumor cells.20 It is indicated for the treatment of patients with 
castration-resistant prostate cancer (CRPC), that develops after patients are treated with 
luteinizing hormone-releasing hormone (LHRH) therapy. Further details about enzalutamide, 
including clinical efficacy, are available in the prescribing information.19 
1.1.2.1 
Overview of Pharmacokinetics 
Following oral administration of enzalutamide in patients with mCRPC, the time to 
maximum concentration (tmax) was 1 hour. The steady-state of enzalutamide was reached 
after 28 days dosing with 8.3-fold accumulation. Enzalutamide showed approximately dose 
proportional steady-state PK over the daily dose range of 30 to 360 mg.  
Enzalutamide is primarily eliminated by hepatic metabolism. N-desmethyl enzalutamide is a 
major active metabolite. The Cmax values of enzalutamide and N-desmethyl enzalutamide 
were 16.6 µg/mL and 12.7 µg/mL, respectively. The terminal half-lives were approximately 
5.8 days for enzalutamide and 7.8 to 8.6 days for N-desmethyl enzalutamide. A high-fat meal 
did not alter the area under the concentration-time curve (AUC) of enzalutamide or 
N-desmethyl enzalutamide. Enzalutamide can be dosed with or without food. 
Based on clinical DDI studies, co-administration of strong CYP2C8 inhibitor gemfibrozil 
increased the AUC of enzalutamide plus its active metabolite N-desmethyl enzalutamide by 


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2.2-fold. Co-administration of rifampin, a strong CYP3A4 inducer and a moderate CYP2C8 
inducer, decreased the AUC of enzalutamide and N-desmethyl enzalutamide by 37%. Strong 
CYP2C8 inhibitors and strong CYP3A4 inducers should be avoided. Enzalutamide is a 
strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer. Concomitant use 
of enzalutamide with narrow therapeutic index drugs that are metabolized by CYP3A4, 
CYP2C9, and CYP2C19 should be avoided. 
Effect of organ dysfunction on PK was evaluated in a population PK analysis. The apparent 
clearance (CL/F) of enzalutamide was similar in subjects with pre-existing mild and 
moderate renal impairment (creatinine clearance [CrCL] 30 to < 90 mL/min) compared to 
subjects with normal renal function (CrCL ≥ 90 mL/min). The composite AUC of 
enzalutamide plus N-desmethyl enzalutamide was similar in subjects with mild, moderate, or 
severe baseline hepatic impairment compared to subjects with normal hepatic function.  
No clinically significant PK covariates have been identified. 
The effect of enzalutamide 160 mg QD on the QT interval corrected for heart rate (QTc) was 
evaluated in patients with mCRPC. No large QTc prolongation was observed (ie, greater than 
20 ms), but small increases (ie, < 10 ms) due to enzalutamide cannot be excluded. 
1.1.2.2 
Overview of Efficacy 
The efficacy and safety of enzalutamide in 4,692 patients with CRPC were demonstrated in 
4 randomized, multicenter clinical studies: AFFIRM, PREVAIL, TERRAIN and PROSPER. 
All patients continued on gonadotropin releasing hormone (GnRH) therapy or had prior 
bilateral orchiectomy. Patients were allowed, but not required, to continue or initiate 
glucocorticoids. Further details are available in the prescribing information.19  
1.1.2.3 
Overview of Safety 
Seizure occurred in 0.4% of patients receiving enzalutamide. In patients with predisposing 
factors, seizures were reported in 2.2% of patients. There have been reports of posterior 
reversible encephalopathy syndrome (PRES) in patients receiving enzalutamide. PRES is a 
neurological disorder which can present with rapidly evolving symptoms including seizure, 
headache, lethargy, confusion, blindness, and other visual and neurological disturbances, 
with or without associated hypertension. Hypersensitivity reactions, including edema of the 
face (0.5%), tongue (0.1%), or lip (0.1%) have been observed in the clinical studies with 
pharyngeal edema seen in postmarketing cases. Patients receiving enzalutamide also had a 
higher rate of ischemic heart disease as well as falls and fractures. The most common adverse 
reactions are asthenia/fatigue, decreased appetite, hot flush, arthralgia, dizziness/vertigo, 
hypertension, headache, and weight decrease. Further details including management of these 
adverse effects are available in the prescribing information.19  
1.1.3 
Abiraterone 
Abiraterone is an inhibitor of 17α-hydroxylase/C17,20-lyase (CYP17), an enzyme expressed 
in testicular, adrenal, and prostatic tumor tissues, which is required for androgen 
biosynthesis. The blockade of nongonadal androgen production is a key factor in treating 


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CRPC, since prostate cancer cells are dependent on androgens. Abiraterone is indicated in 
combination with prednisone for the treatment of patients with mCRPC and metastatic 
high-risk castration-sensitive prostate cancer (CSPC).21 The addition of prednisone is to 
prevent mineralocorticoid excess-related AEs (such as hypertension, hypokalemia and fluid 
retention), resulting from CYP17 inhibition.22 Further details about abiraterone, including 
clinical efficacy, are available in the prescribing information.21 
1.1.3.1 
Overview of Pharmacokinetics 
Following oral administration of abiraterone acetate at 1,000 mg QD to patients with 
mCRPC, the steady-state Cmax was 226 ng/mL and the AUC was 993 ng hr/mL with a 2-fold 
accumulation. Further increase of dose to 2,000 mg resulted in minimal increase (8%) in 
AUC.  
Significant food effect on PK was observed. In healthy subjects, a low-fat meal (7% fat, 
300 calories) increased abiraterone Cmax and AUC by 7- and 5-fold, respectively; while a 
high-fat meal (25% fat, 491 calories) increased Cmax and AUC by 17- and 5-fold, 
respectively. When abiraterone acetate was dosed 2 hours after or 1 hour before a medium fat 
meal, abiraterone AUC increased by approximately 7- or 1.6-fold, respectively. In patients 
with mCRPC, systemic exposures of abiraterone at steady state were similar when 
abiraterone acetate was taken with low-fat meals and increased by approximately 2-fold 
when taken with high-fat meals compared to when taken at least 2 hours after a meal and at 
least 1 hour before a meal. As a result, abiraterone acetate must be taken on an empty 
stomach with water at least 1 hour before or 2 hours after a meal.  
Abiraterone has high plasma protein binding (> 99%) and large apparent steady-state volume 
of distribution. At clinical exposures, abiraterone acetate and abiraterone are not P-gp 
substrates; abiraterone acetate is a P-gp inhibitor. 
After oral administration, abiraterone acetate is hydrolyzed to the active metabolite 
abiraterone, which is further metabolized to 2 inactive metabolites abiraterone sulphate and 
N-oxide abiraterone sulphate. The formation of abiraterone is likely mediated by esterases, 
and CYP3A4 and SULT2A1 are responsible for the subsequent N-oxidation and formation of 
sulphate metabolites. 
In patients with mCRPC, the t1/2 of abiraterone in plasma is approximately 12 hours. 
Following an oral dose of 14C-abraterone acetate, approximately 88% of the radioactive dose 
was recovered in feces and approximately 5% in urine. 
Subjects with mild (Child-Pugh A), moderate (Child-Pugh B), and severe (Child-Pugh C) 
hepatic impairment showed 1.1, 3.6, and 7-fold increases in systemic exposure to 
abiraterone, respectively, compared to subjects with normal hepatic function following a 
single oral dose of 1,000 mg abiraterone acetate. Patients with end-stage renal disease on 
hemodialysis showed no apparent PK difference than patients with normal renal function. 
In vitro studies showed that abiraterone has the potential to inhibit CYP1A2, CYP2D6 
CYP2C8, and to a lesser extent CYP2C9 CYP2C19, and CYP3A4/5. Clinically, the Cmax and 
AUC of dextromethorphan, a CYP2D6 substrate, increased by 2.8- and 2.9-fold, 


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respectively, when co-administered with 1,000 mg abiraterone acetate daily. However, no 
clinical inhibition of CYP1A2 was observed when theophylline was used as a CYP1A2 DDI 
probe. Abiraterone is a CYP3A4 substrate. While co-administration of ketoconazole (a 
strong CYP3A4 inhibitor) showed no effect on abiraterone PK, a 55% decrease in mean 
abiraterone AUC was observed when abiraterone acetate was co-administered with rifampin 
(a strong CYP3A4 inducer). Abiraterone was a weak CYP2C8 inhibitor and increased the 
AUC of pioglitazone by 46%. 
The QT prolongation potential was assessed following abiraterone 1,000 mg QD in patients 
with mCRPC. No large change in the QTc interval from baseline (ie, > 20 ms), however, 
small increases in the QTc interval (ie, < 10 ms) due to abiraterone acetate cannot be 
excluded. 
1.1.3.2 
Overview of Efficacy 
Abiraterone was tested in a Phase 3 randomized, placebo-controlled study with a total of 
1,195 mCRPC patients to demonstrate its superiority over placebo with a 57% reduction in 
the risk of radiographic progression or death (HR 0.43; 95% CI: 0.35 to 0.52; p < 0.001) and 
an estimated 25% decrease in the risk of death (HR 0.75; 95% CI: 0.61 to 0.93; p = 0.009).12, 
36 Additional details are provided in the prescribing information.21, 37  
1.1.3.3 
Overview of Safety 
Abiraterone may cause hypertension, hypokalemia, and fluid retention as a consequence of 
increased mineralocorticoid levels resulting from CYP17 inhibition, and therefore should be 
used with caution in patients with a history of cardiovascular disease. Co-administration of a 
corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a 
reduction in the incidence and severity of these adverse reactions. Adrenocortical 
insufficiency has been reported in clinical studies in patients receiving abiraterone in 
combination with prednisone, following interruption of daily steroids and/or with concurrent 
infection or stress. Marked increases in liver enzymes leading to drug discontinuation or 
dosage modification have occurred in clinical studies with abiraterone. Aside from these, the 
most common side effects were joint swelling or discomfort, hypokalemia, edema, muscle 
discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, 
urinary frequency, nocturia, dyspepsia, and upper respiratory tract infection. Additional 
details are provided in the prescribing information.21  
1.2 
Study Rationale 
The study will initially evaluate the combinations of rucaparib with 2 widely used 
AR-directed therapies, enzalutamide and abiraterone. Subsequent arms of the study may 
include other combination partners (eg, AR inhibitors in development or immune modulators 
such as checkpoint inhibitors). The primary goal of this study is to investigate potential DDI 
and safety/tolerability in the 2 combinations, and also preliminary efficacy. The outcome of 
these studies will be used to support larger studies to investigate these combinations in 
mCRPC.  


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1.2.1 
Known and Potential Risks and Benefits to Patients 
While there is scientific rationale and clinical precedence of benefit for the combination of 
PARPi and AR-directed therapy, as elucidated above, the combination of rucaparib with 
either enzalutamide or abiraterone has not been previously tested and thus clinical benefit of 
these combinations has not been established. In this trial, both enzalutamide and abiraterone 
will be administered at their approved monotherapy doses. The starting dose of rucaparib 
(further detailed in Section 1.2.3) in each arm has been chosen based on review of the 
individual agent safety profiles, with an aim towards minimizing overlapping toxicities. 
Escalation of rucaparib dose will take into account safety and tolerability observed at prior 
dose levels. 
1.2.2 
Rationale for the Study Design 
The primary objectives for this study are to evaluate the PK, safety and tolerability of 
rucaparib in combination with other anticancer therapies for the treatment of mCRPC.  
The study is therefore divided into an initial PK assessment phase, which also evaluates 
safety/tolerability in addition to PK, and a dose expansion phase to further characterize PK 
and safety/tolerability if needed. The PK assessment will incorporate a run-in phase of 
rucaparib alone in the first week, in order to assess the impact on rucaparib PK once the 
combination partner is also introduced. 
In Arm A, based on the individual safety profiles of both rucaparib and enzalutamide, no 
significant overlap in toxicity is expected. Therefore, the approved monotherapy dose of each 
agent will be the starting dose for the initial combination evaluation. Patients will be closely 
monitored for safety and tolerability and the dose of rucaparib may be reduced, if 
appropriate, based on emerging safety data. Preliminary assessment of the metabolic profile 
of rucaparib and enzalutamide indicates that rucaparib exposure may be diminished due to 
CYP3A4 induction by enzalutamide (detailed in Section 1.2.3). Therefore, depending on the 
PK profile of rucaparib, and taking into account the emerging safety/tolerability data, 
rucaparib dose may be escalated beyond the starting dose of 600 mg BID. Rucaparib 
escalation, up to a maximum dose of 1,000 mg BID rucaparib, may be explored based on 
emerging PK, safety and tolerability data. The potential increase in rucaparib dose will be 
proportional to the decrease in exposure (relative to expected exposure for monotherapy) 
seen at the previous dose level.  
In Arm B, the target combination doses will be the approved monotherapy doses for 
abiraterone and rucaparib. However, as there is potential for overlapping toxicities with this 
combination (detailed in Section 1.2.3), the initial starting dose for rucaparib will be 
400 mg BID, with escalation planned to 600 mg BID if the initial dose level is deemed safe 
and tolerable. If a dose of 600 mg BID rucaparib in combination with the standard dose of 
abiraterone is not tolerated, a dose of 500 mg BID rucaparib in combination with the standard 
dose of abiraterone may be explored. In the event that there is unexpected lower exposure of 
rucaparib with co-administration of abiraterone, the dose of rucaparib may be increased 
beyond 600 mg BID, similar to the approach outlined for Arm A. 


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Dose escalation or de-escalation strategy for both Arms A and B is further detailed in 
Section 3.3.  
Once a safe and tolerable dose combination is established, for both Arm A and Arm B, PK 
and safety/tolerability characterization may be conducted with up to 12 additional patients in 
the dose expansion phase, particularly if PK in the initial PK assessment phase is variable or 
additional safety information is required.  
1.2.3 
Dose Rationale 
Dose determination in each arm of the study will be performed as described in Section 3.3. 
All patients in Arm A will receive enzalutamide at 160 mg QD and all patients in Arm B will 
receive abiraterone at 1,000 mg QD with 5 mg prednisone BID. Starting dose of rucaparib is 
600 mg BID in Arm A and 400 mg BID in Arm B.  
Arm A:  
In vitro, rucaparib is metabolized by CYP2D6, and to a lesser extent by CYP1A2 and 
CYP3A4. Enzalutamide is a strong clinical inducer of CYP3A4,38 thus enzalutamide may 
result in reduced rucaparib exposure when administered in combination.  
Based on clinical safety data, significant overlapping toxicities between enzalutamide and 
rucaparib are not expected. Based on the available data, a combination of approved dose 
levels of enzalutamide 160 mg QD and rucaparib 600 mg BID administered with or without 
food is anticipated to be a safe starting dose.  
Another justification for starting the first dose cohort at the full doses of rucaparib and 
enzalutamide is the long t1/2 of enzalutamide (5.8 days) and its active metabolite N-desmethyl 
enzalutamide (7.8 to 8.6 days). The plasma exposure of enzalutamide and N-desmethyl 
enzalutamide increase slowly following enzalutamide treatment, and it takes approximately 
40 days to reach the steady state. Therefore, any exacerbation of overlapping toxicities is 
likely to be gradual.  
Enzalutamide starting dose will be fixed at the approved dose of 160 mg QD. No dose 
adjustment is planned for the starting dose of enzalutamide. 
Arm B: 
Abiraterone administration is not expected to have any impact on rucaparib exposure. 
However, anemia, hypercholesterolemia, increased alkaline phosphatase (ALP), nausea, 
vomiting, fatigue, diarrhea and upper respiratory tract infections have been reported in 
patients receiving abiraterone, as well as for patients receiving rucaparib. A conservative 
starting dose of rucaparib 400 mg BID (~ 67% of approved starting dose) and the approved 
starting dose of abiraterone 1,000 mg QD are selected for initiation of Arm B in the dose 
escalation phase.  
Abiraterone acetate starting dose will be fixed at the approved dose of 1,000 mg QD. No 
adjustment is planned for the starting dose of abiraterone acetate. 


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1.2.4 
Rationale for Duration of Treatment 
Patients will be on study as long as they benefit from the study treatment or unless they 
withdraw from study. 
A 1-week run-in period with rucaparib alone prior to the start of combination therapy allows 
for the assessment of rucaparib PK in the absence of either enzalutamide or abiraterone in 
Arms A and B respectively. 
In Arm A, the dose-limiting toxicity (DLT) window is 8 weeks (Cycles 1 and 2). This is 
justified as enzalutamide and its major active metabolite N-desmethyl enzalutamide have 
long half-lives. Evaluation and assessment over an 8-week period will allow for adequate PK 
and DLT assessments.  
In Arm B, due to the shorter t1/2 of abiraterone, a 4-week period is expected to suffice for 
assessment of PK and DLTs. 


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2 
STUDY OBJECTIVES 
Primary, secondary, and exploratory objectives and endpoints are shown in Table 2-1. 
Table 2-1. 
Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary Objective 
Primary Endpoint 
• To evaluate the PK, safety and 
tolerability of rucaparib in combination 
with other anticancer agents for 
mCRPC. 
 
• Minimum concentration (Cmin) of 
rucaparib and its metabolite M324 
• Safe and tolerable dose of rucaparib in 
combination with other anticancer agents 
for mCRPC 
Secondary Objectives 
Secondary Endpoints 
• To evaluate the preliminary efficacy of 
rucaparib with each of its combination 
partners.  
• Best overall response as assessed by 
investigator summarized by ORR (as 
measured by modified RECIST v1.1 
(mRECIST)/PCWG3 criteria; Appendix 
1) at the optimal combination dose in 
each arm 
• Change from baseline PSA levels 
Exploratory Objectives 
Exploratory Endpoints 
• To evaluate the PK of anticancer drugs 
in combination with rucaparib. 
• Cmin of combination drugs (and 
metabolites if applicable) 
• To assess the relationship between 
genomic alterations detected in tissue or 
blood with clinical outcomes to 
treatment 
• Association between genomic alterations 
and ORR and PSA responses 
• To assess the relationship between 
changes in circulating tumor DNA 
(ctDNA) profiles over time and clinical 
outcomes to treatment 
• Changes in genomic alterations as 
assessed by ctDNA over time 
 
 


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3 
STUDY DESIGN 
This is a Phase 1b, open-label, platform study with multiple treatment arms evaluating the 
PK, DDIs, safety, tolerability and preliminary efficacy of rucaparib in combination with a 
second anticancer therapy in patients with mCRPC. Each arm consists of a preliminary phase 
designed to assess PK and safety and tolerability of rucaparib in combination with other 
anticancer agents, followed by an expansion phase (if needed) to further evaluate PK, safety, 
tolerability and preliminary efficacy of the combination. 
3.1 
Screening Period 
All mCRPC patients will undergo screening assessments between Day -28 and Day -1 after 
they sign an Informed Consent Form (ICF) and prior to any study-specific procedures being 
performed.  
Refer to the inclusion/exclusion criteria (Section 4.2 and Section 4.3) for details. 
3.2 
Enrollment 
Eligible patients will be enrolled into the PK assessment phase or the dose expansion phase 
(after a combination dose is established) across the treatment arms. If a patient appears to be 
eligible for more than one treatment arm that is open to enrollment, the investigator will be 
responsible for selecting the treatment arm for the patient. However, enrollment into Arm A 
will be prioritized over Arm B until the objectives for Arm A have been achieved. No patient 
randomization is planned.  
3.3 
Treatment Period 
As of the implementation of Protocol Amendment 2, during and at the end of treatment, a 
more limited number of assessments will be performed compared to previously; however, an 
appropriate level of safety monitoring will remain in place. A revised Schedule of 
Assessments (SOA) is provided in Section 7.1; this replaces all prior SOAs and should be 
followed for all patients who remain on treatment. 
During the treatment phase (continuous 28-day treatment cycles), patients will be monitored 
for safety and efficacy. Assessments during the treatment phase will include AEs, complete 
blood count (monthly assessment advised), and study drug administration/accountability; in 
addition, disease assessments (imaging/PSA), clinical chemistry, urinalysis, and vital signs 
will be performed per local standard of care practices. Disease/tumor assessments per 
mRECIST/PCWG3 criteria will be performed according to local standard of care per 
investigator. 
Patients starting on the study in either the PK assessment phase or the dose expansion phase 
will be administered rucaparib alone for 1 week. After completing this run-in period, they 
will immediately begin continuous 28-day treatment cycles of rucaparib and the combination 
drug.  


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PK Assessment Phase:  
Doses of rucaparib may be modified in this phase from the starting dose; however, the dose 
of its combination partner (either enzalutamide in Arm A or abiraterone co-administered with 
prednisone in Arm B) will remain fixed.  
Arm A: Six patients will be enrolled at the standard monotherapy dose of enzalutamide and 
starting dose of rucaparib of 600 mg BID. If no significant PK interaction is observed and 
safety and tolerability is within acceptable guidelines (Section 5.6), no further dose titration 
will be done. However, if PK interactions indicate the concentration of rucaparib is 
25% to 50% of the expected rucaparib exposure in monotherapy, then a higher dose of 
rucaparib will be considered, to a maximum dose of 1,000 mg BID, also taking safety and 
tolerability into account. The increase in dose will be scaled to be proportional to the 
decrease in expected exposure. In the event ≥ 1 of 6 patients experiences a DLT (as defined 
in Section 5.6), a lower dose of rucaparib may be explored, with subsequent dose cohorts 
enrolling a minimum of 3 patients and a maximum of 6 patients, unless the rucaparib dose is 
at the minimal dose of 300 mg BID. 
Arm B: Three patients will be enrolled at the starting dose of 400 mg BID rucaparib in 
combination with the standard monotherapy dose of abiraterone. If there is no DLT (as 
defined in Section 5.6) observed in any of these 3 patients, the next higher dose of 
600 mg BID rucaparib will be explored. If one patient develops a DLT, the cohort will be 
expanded to 6 patients. If DLTs are observed in ≥ 1 of 3 to 6 patients in a given dose cohort, 
no further dose escalation will be performed. If a dose of 600 mg BID rucaparib in 
combination with the standard dose of abiraterone is not tolerated, a dose of 500 mg BID 
rucaparib in combination with the standard dose of abiraterone may be explored. The dose of 
rucaparib may also be increased beyond 600 mg BID if there is unexpected lower exposure 
with co-administration of abiraterone, similar to the approach outlined for Arm A. Each dose 
cohort in this arm will enroll a minimum of 3 patients and a maximum of 6 patients.  
Prior to initiating treatment at each new combined dose level or prior to expanding an 
existing dose level, a teleconference with the Dose Cohort Review Committee (Section 3.6) 
will be held to review patient data.  
The combination dose for evaluation in the expansion phase will be selected based on overall 
safety and tolerability, PK, as well as any efficacy observed.  
Disease/tumor assessments and PSA measurements will be performed according to local 
standard of care per investigator. Any drug modifications (interruption, dose reduction, or 
discontinuation) should be documented in the electronic Case Report Form (eCRF, see 
Section 10.5) and source documents.  
Patients will receive rucaparib and the combination drug until confirmed radiologic disease 
progression assessed by investigator based on mRECIST/PCWG3 (Appendix 1), 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 


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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. 
Sparse PK samples will be collected from all patients for assessments of PK and DDIs 
(Table 7-2). 
Expansion Phase: 
Once the optimal combination dose has been provisionally determined, up to 12 additional 
patients may be enrolled and treated at that dose combination to further characterize PK, 
safety and tolerability, in order to establish that this is the optimal dose combination for 
future clinical studies. 
Pharmacokinetics and Drug-Drug Interaction Assessment: 
In both the initial PK assessment phase as well as the expansion phase, PK assessment will 
start with a 1-week run-in period, during which patients will receive rucaparib treatment 
only. Predose rucaparib PK samples at selected timepoints will be collected. This will be 
followed by continuous treatment of rucaparib and the combination drug in 28-day treatment 
cycles, with predose PK samples collected for rucaparib and the combination drug at selected 
timepoints. 
3.4 
End of Treatment and Follow-up 
As of the implementation of Protocol Amendment 2, more limited post-treatment 
assessments will be performed while maintaining appropriate safety monitoring. A revised 
SOA is provided in Section 7.1; this replaces prior SOAs. 
Patients experiencing disease progression by mRECIST/PCWG3, as assessed by the 
investigator, will be discontinued from study treatment and enter into follow-up with the 
exception defined in Section 3.5.  
Upon treatment discontinuation, patients will have an End-of-Treatment (EOT) Visit and a 
28-day Follow-up Visit. Ongoing serious adverse events (SAEs), AESIs, and 
treatment-related Grade 3/4 AEs will be followed until either resolution or stabilization has 
been determined or until lost to follow-up. 
After the 28-day Follow-up Visit, only SAEs assessed as potentially related to study drug 
should be reported per Clovis Pharmacovigilance (PV) requirements and captured in the 
Clovis PV database.  
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 similar events (ie, interstitial lung disease, pulmonary fibrosis, 
acute interstitial pneumonitis, alveolitis necrotizing, alveolitis, hypersensitivity 
pneumonitis, and organizing pneumonia) should be reported up to, but not beyond, the 
28-day Follow-up Visit (ie, 28 days after the last dose of study drug). After the 28-day 
Follow-up Visit, only serious pneumonitis or similar events assessed as potentially 
related to study drug should be reported per Clovis Oncology PV requirements. 
 
3.5 
Treatment Beyond Disease Progression 
If the patient has met criteria for radiologic progression by mRECIST/PCWG3, but the 
patient is still receiving benefit from the study drugs according to the investigator (eg, patient 
has mixed radiologic response or is continuing to have symptomatic benefit), then 
continuation of treatment will be considered upon discussion with the medical monitor 
(see Section 5.11). The patient must consent prior to continuing treatment with the study 
drugs.  
3.6 
Dose Cohort Review Committee 
This committee will include study investigators, the sponsor’s medical monitor, and may 
include other representatives or designees of the sponsor and the study sites. It will be 
responsible for reviewing safety, PK, and preliminary efficacy data at regular intervals 
throughout the study. Prior to initiating treatment at a new dose level or expanding a dose 
level, a safety teleconference will be held to review patient data, including, but not limited to, 
demographics, PK results, study drug dosing, concomitant medications, hematology and 
serum chemistry, and AEs. The discussion and agreement to escalate or reduce the rucaparib 
dose and/or expand an existing dose level will be documented. 
3.7 
Removal of Patients From Therapy or Assessment 
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, where acceptable 
according to national law and/or local regulations, at the request of their legally 
authorized representative; 
• Progression of patient’s underlying cancer per mRECIST and/or PCWG3 criteria as 
assessed by the investigator, unless the patient continues to derive clinical benefit from 
the study drug(s) according to the investigator, the investigator has consulted with the 
sponsor’s medical officer or designee, and the patient has provided additional consent for 
treatment beyond progression at the next study visit; 
• Any event, adverse or otherwise, that, in the opinion of the investigator, would pose an 
unacceptable safety risk to the patient. If it is determined that one of the study drugs in 
the combination is posing a safety risk and that study drug is permanently discontinued, 
administration of the other study drug may continue if none of the other withdrawal 


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criteria have been met and the investigator believes that the patient may continue to 
receive benefit; 
• Any concomitant 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; or  
• The study is terminated. 
 
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. The sponsor will store samples for up to 7 years after the 
study is over and any remaining samples will be destroyed at that time. Information that is 
collected while the patient has consented to be in the study cannot be withdrawn. Details are 
provided in the ICF.  
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 (see Section 10.5). A patient may 
withdraw consent to participate in an additional or optional part of a study that has a 
corresponding consent (ie, optional tumor biopsy) yet continue to participate and be 
treated/followed in the main part of the study.  
The sponsor may discontinue the study early for any of the reasons noted in Section 10.6.  
3.8 
Study Schema 
The study schema in Figure 3-1 summarizes the treatment design of the study. 
 


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Figure 3-1. Study Schema 
 
NOTE: For patients remaining on treatment as of the implementation of Protocol Amendment 2, during and at the end of treatment, a more limited 
number of assessments will be performed compared to previously; however, an appropriate level of safety monitoring will remain in place. A revised 
SOA is provided in Section 7.1; this replaces all prior SOAs and should be followed for all patients who remain on treatment. 
Abbreviations: AR = androgen receptor; BID = twice a day; CRPC = castration-resistant prostate cancer; DLT = dose-limiting toxicity; ECOG PS = Eastern Cooperative 
Oncology Group performance status; LHRH = luteinizing hormone–releasing hormone; mCRPC = metastatic castration-resistant prostate cancer; PK = pharmacokinetic; 
QD = once a day; SOA = Schedule of Assessments. 


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a 
Rucaparib dose may be reduced to < 600 mg BID if more than one patient experiences a DLT. If rucaparib exposure is lower than expected with co-administration of 
enzalutamide, rucaparib dose may be increased proportional to the decrease in exposure, to a maximum of 1,000 mg BID. 
b 
Rucaparib dose will be escalated from 400 mg BID to 600 mg BID, with a possible de-escalation to 500 mg BID. The dose of rucaparib may also be increased if 
there is unexpected lower exposure with co-administration of abiraterone, similar to the approach described for Arm A.  


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3.9 
End of Study 
The study will close when all enrolled patients have discontinued treatment and completed 
the 28-day Safety Follow-up Visit, or have withdrawn consent for the study (Section 3.7), or 
the sponsor terminates the study for any reason as noted in Section 10.6.  
4 
STUDY POPULATION  
4.1 
Number of Patients and Sites 
For each combination arm, the PK assessment cohort will include 6 to 18 patients (1 to 
3 dose cohorts), and the expansion phase will include up to 12 patients. The number of 
patients in each cohort may increase if some patients are not DLT-evaluable, thereby 
requiring additional patients to be enrolled into the study. The total enrollment planned for 
Arm A and Arm B will be up to 60 patients. There will be approximately 10 investigative 
sites in the US. 
4.2 
Inclusion Criteria 
Eligible patients must meet the following inclusion criteria. Unless otherwise specified, the 
criteria below apply to patients enrolling into all parts of the study. 
1. Have signed an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
approved ICF prior to any study-specific evaluation.  
2. Be ≥ 18 yrs 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). 
4. Surgically or medically castrated, with serum testosterone levels of ≤ 50 ng/dL 
(1.73 nM). For patients currently being treated with LHRH agonists (ie, patients who 
have not undergone an orchiectomy), therapy must be continued throughout the study. 
5. Be either AR-directed therapy naïve or have received 1-2 lines of AR-directed therapy in 
the castration-resistant setting. If most recently treated with enzalutamide in the 
castrate-resistant setting, they must have been had no enzalutamide treatment for at least 
6 weeks prior to the first planned dose of rucaparib. If most recently treated with an 
AR-directed therapy other than enzalutamide, patients must have ceased AR-directed 
therapy treatment for at least 4 weeks prior to the first planned dose of rucaparib.  
6. Have disease progression after initiation of most recent therapy based on any of the 
following criteria:  
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 mRECIST 
c. Radionuclide bone scan: at least 2 new metastatic lesions 


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7. Have adequate organ function confirmed by the following laboratory values obtained 
within 14 days prior to enrollment: 
a. Bone Marrow Function 
i. 
ANC ≥ 1.5 × 109/L; 
ii. 
Platelets ≥ 100 × 109/L; 
iii. 
Hemoglobin ≥ 10 g/dL independent of transfusion ≤ 14 days prior to screening 
hemoglobin assessment. Transfusions are not permitted between the screening 
hemoglobin assessment and the first dose of rucaparib. 
b. Hepatic Function 
i. 
AST and ALT ≤ 3 × upper limit of normal (ULN); if liver metastases, then 
≤ 5 × ULN; 
ii. 
Bilirubin ≤ 1.5 × ULN; < 2 × ULN if hyperbilirubinemia is due to Gilbert’s 
syndrome; 
iii. 
Serum albumin ≥ 30 g/L (3.0 g/dL). 
c. Renal function 
i. 
Serum creatinine ≤ 1.5 × ULN; OR  
ii. 
Estimated glomerular filtration rate (GFR) ≥ 45 mL/min using the 
Cockcroft-Gault formula 
8. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 
within 14 days prior to the first dose of rucaparib (Appendix 2). 
9. Have a life expectancy of at least 6 months. 
10. Patients with human immunodeficiency virus (HIV), hepatitis B (HBV) or hepatitis C 
(HCV) infection may be enrolled if they have undetectable viral load with antiviral 
medication and if the antiviral medications do not interfere with any of the study drugs. 
 
4.3 
Exclusion Criteria 
Patients will be excluded from participation if any of the following criteria apply: 
1. Active second malignancy, ie, patient known to have potentially fatal cancer present for 
which he may be (but not necessarily) currently receiving treatment. Exceptions are 
patients with history of malignancy that has been successfully treated, with no evidence 
of active cancer for 3 years prior to enrollment, or surgically cured and/or low risk 
tumors, such as non-melanoma skin cancers. 
2. Have received greater than 2 previous lines of chemotherapy for mCRPC, including 
taxanes.  
3. Prior treatment with any PARP inhibitor. 
4. Spinal cord compression, symptomatic and/or untreated central nervous system (CNS) 
metastases or leptomeningeal disease. Patients with asymptomatic previously treated 
CNS metastases are eligible provided they have been clinically stable for at least 
4 weeks.  
5. Severe concurrent disease, infection, comorbidities. 


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6. Known hepatic disorder that would affect drug metabolism or gastrointestinal disorders 
that would potentially alter absorption. 
7. Any clinically significant cardiovascular disease.  
8. Pre-existing duodenal stent and/or any gastrointestinal disorder or defect that would, in 
the opinion of the investigator, interfere with ingestion or absorption of rucaparib. 
9. Received anticancer treatment with chemotherapy, radiation, antibody therapy or other 
immunotherapy, gene therapy, vaccine therapy, angiogenesis inhibitors, or experimental 
drugs (other than GnRH therapy or approved bone-targeting agents) ≤ 14 days prior to 
first dose of rucaparib and/or ongoing adverse effects from such treatment 
> NCI CTCAE v5.0 Grade 1, with the exception for alopecia and Grade 2 peripheral 
neuropathy.  
10. Nonstudy related minor surgical procedure ≤ 5 days, or major surgical procedure 
≤ 21 days, prior to first dose of rucaparib; in all cases, the patient must be sufficiently 
recovered and stable before treatment administration. 
11. Taking any concomitant medications or herbs that could confound PK assessment. 
12. Presence of any other condition that may increase the risk associated with study 
participation or may interfere with the interpretation of study results, and, in the opinion 
of the investigator, would make the patient ineligible for entry into the study. 
13. Refusal to undertake the following measures for the duration of the study and after the 
last dose of study drug for the time period specified: 
a. Using a condom during sex while being treated and for 3 months after the last dose of 
study drug, 
b. Abstaining from semen donations during treatment and for 3 months after the last 
dose of rucaparib, 
14. Those with female partners of childbearing potential may be enrolled if they are: 
a. Documented to be surgically sterile (ie, vasectomy); or 
b. Committed to practicing true abstinence during treatment and for 3 months after the 
last dose of study drug; or 
c. Committed to using a highly effective method of contraception (Section 4.4) with 
their partner during treatment and for 3 months following the last dose of study drug. 
15. Cohort-specific exclusion criteria: 
a. Arm A: Patients with  
i. 
A history of seizures or traumatic brain or head injury, and/or receiving 
concomitant medication that lowers seizure thresholds; or  
ii. 
Uncontrolled or suboptimally controlled ischemic heart disease, history of 
myocardial infarction/unstable angina, coronary vascular intervention such as 
percutaneous coronary intervention (PCI), stent placement or coronary artery 
bypass graft (CABG) within past 1 year, stable angina or New York Heart 
Association (NYHA) Class 2 to 4 heart failure. 
b. Arm B: Patients with: 
i. 
Mean resting QTc > 470 msec obtained from 3 consecutive ECGs; 


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ii. 
Any clinically significant abnormalities in rhythm, conduction or morphology of 
resting ECG, eg, complete left bundle branch block, third degree heart block, etc.; 
iii. 
Any history of syncope of suspected/confirmed cardiovascular etiology, 
ventricular arrhythmia of pathologic origin, uncontrolled atrial fibrillation, or 
sudden cardiac arrest within the past 1 year; 
iv. 
Any factors that increase the risk of QTc prolongation or risk of arrhythmic 
events, such as heart failure, congenital long QT syndrome, family history of long 
QT syndrome or unexplained sudden death under 40 years of age, or any 
concomitant medication known to prolong the QT interval; 
v. 
History of hypokalemia < 3 mmol/L, uncontrolled hypertension (defined as 
median BP ≥ 160/90 mm Hg on three serial measurements performed at the time 
of screening despite maximal medical management) or presence of symptoms due 
to elevated blood pressure at the time of screening; 
vi. 
Grade 2 edema of any kind (generalized, pitting, or peripheral); or  
vii. 
Diagnosis of Addison’s disease 
 
4.4 
Patients or Partners of Patients of Reproductive Potential 
Male patients are required to use a condom during sex with a partner to avoid the possibility 
of exposure of the partner to rucaparib. 
Male patients must not make semen donations for 3 months after the last dose of rucaparib 
and its combination partner. 
Male patients of reproductive potential must avoid pregnancy in partners who are women of 
childbearing potential, and such partners should not be considering getting pregnant during 
the study and for at least 3 months after treatment is discontinued or longer if requested by 
local authorities. Patients will be instructed to notify the investigator if pregnancy of female 
partner is discovered either during or within 3 months of completing treatment with study 
drug.  
Male patients are considered to be of reproductive potential unless permanently sterile by 
bilateral orchiectomy, or with appropriate post-vasectomy documentation of absence of 
sperm in ejaculate. 
Female partners are considered to be of childbearing potential unless one of the following 
applies: 
• 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  


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• 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; or 
• 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. 
 
4.5 
Compliance with Inclusion/Exclusion Criteria 
All inclusion/exclusion criteria must be met for the prospective participant to enroll. Neither 
the investigator nor the sponsor/designee, may allow a prospective participant who has not 
met the inclusion/exclusion criteria to enter the study. 
5 
STUDY TREATMENT(S) 
This section describes the treatments of rucaparib and combination drugs across all treatment 
arms. 
5.1 
Description of Investigational Product(s) and Storage 
5.1.1 
Rucaparib 
Rucaparib camsylate (also known as CO-338) is an oral formulation. A brief description of 
rucaparib is provided below with details in the Pharmacy Manual. 


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Table 5-1. 
Description of Rucaparib 
Drug Name: 
RUBRACA 
INN: 
Rucaparib 
Formulation: 
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: 
15–30°C (59-86°F) 
 
5.1.2 
Enzalutamide  
Enzalutamide is an oral formulation. A brief description of enzalutamide is provided below 
with details in the Pharmacy Manual. 
Table 5-2. 
Description of Enzalutamide 
Drug Name: 
XTANDI 
INN: 
Enzalutamide 
Formulation: 
40 mg enzalutamide as white to off-white oblong soft gelatin capsules 
imprinted with “ENZ” in black ink on one side. 
How Supplied: 
Bottles of 120 capsules  
Cartons of 112 capsules 
Storage Conditions: 
20-25°C (68-77°F) 
< 25°C (< 77°F) 
 
5.1.3 
Abiraterone Acetate  
Abiraterone acetate is an oral formulation. A brief description of abiraterone is provided 
below with details in the Pharmacy Manual. 
Table 5-3. 
Description of Abiraterone Acetate 
Drug Name: 
Abiraterone 
INN: 
Abiraterone acetate 
Formulation: 
500 mg film-coated tablets, 250 mg uncoated tablets 
How Supplied: 
Abiraterone 500 mg film-coated tablets are supplied in high-density 
polyethylene bottles of 60 tablets  
Abiraterone 250 mg tablets are supplied in high-density polyethylene 
bottles of 120 tablets 
Storage Conditions: 
20-25°C (68-77°F) 
 


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5.2 
Packaging and Labeling 
Study drug containers will be labeled according to national regulations for investigational 
products. Where accepted, the expiry date will not appear on the labels, but will be controlled 
by the use of an Interactive Web Response System (IWRS). 
Details with respect to packaging and labeling of all study drugs are described in the 
Pharmacy Manual. 
5.2.1 
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° and 30°C 
(59° and 86°F). Patients will be dispensed one or more strengths depending on their current 
dose of rucaparib. The number of bottles of each strength dispensed will be sufficient to 
supply 28 days treatment per cycle in all treatment arms, including a small overage. One 
exception is for the 1-week PK run-in period of each arm (both dose escalation and 
expansion phases) wherein patients will receive enough rucaparib for that time period.  
5.2.2 
Enzalutamide 
Enzalutamide is provided in bottles of 120 capsules or cartons of 112 capsules of 40 mg 
each. The number of containers dispensed to patients will be sufficient to supply 28 days of 
treatment per cycle, including a small overage.  
5.2.3 
Abiraterone Acetate 
Abiraterone acetate are provided in HDPE bottles of 60 × 500 mg tablets or 120 × 250 mg 
tablets. Abiraterone acetate tablets should be stored in the provided containers between 
15° and 30°C (59° and 86°F). Patients will be dispensed one or more strengths depending on 
their current dose of abiraterone. The number of bottles of each strength dispensed will be 
sufficient to supply 28 days of treatment per cycle in Arm B, including a small overage.  
5.3 
Measures to Minimize Bias: Randomization and Blinding 
This is an open-label study; the investigational products will not be blinded or masked. 
Patients enrolled will receive rucaparib with the combination drug in a specified treatment 
arm. 
5.4 
Method of Assigning Patients to Treatment Groups 
No randomization is planned for this study. After confirming that a patient fulfills eligibility 
criteria, the investigator or his/her delegate will enroll the patient into one of the study arms 
(in either the PK assessment phase or the expansion phase). If a patient appears to be eligible 
for more than one treatment arm that is open to enrollment, the investigator will be 
responsible for selecting the most appropriate treatment arm for the patient. However, 
enrollment into Arm A will be prioritized over Arm B until the objectives for Arm A have 
been achieved.  


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5.5 
Preparation and Administration of Protocol-specified Treatment 
Treatment will begin on Day 1 of the run-in period with rucaparib prior to Cycle 1. Patients 
will be provided a sufficient quantity of rucaparib to last until Day 1 of the next treatment 
cycle. The assigned combination drug will be dispensed on Cycle 1 Day 1, to last until Day 1 
of the next treatment cycle. Patients will be instructed to bring their study drug 
tablets/capsules and all containers (empty, partially used, and/or unopened) to the next 
scheduled visit for reconciliation by site personnel. 
If a patient vomits after dosing, the dose will not be made up; the patient will take their next 
dose at the regularly scheduled interval. 
Refer to the Pharmacy Manual for additional information.  
5.5.1 
Rucaparib 
For the PK assessment phase of each treatment arm, rucaparib will be administered orally 
BID at the dose level specified by the dose cohort to which the patient is enrolled.  
For the expansion phase of each treatment arm, rucaparib will be administered orally at the 
combination dose chosen for further exploration. As rucaparib is administered BID, the dose 
should be administered as close to 12 hours apart as possible, preferably at the same times 
every day with at least 8 ounces (240 mL) of water starting on Study Day 1 (start of the 
run-in period). Rucaparib tablets should be swallowed whole without crushing or chewing.  
Food has no clinically meaningful effect on rucaparib PK, thus rucaparib tablets may be 
taken with or without food. In Arm A, there is no food restriction for study drug 
administration. However, in Arm B, abiraterone acetate and rucaparib should be taken at the 
same time in the morning on an empty stomach (ie, at least 1 hour before or 2 hours after a 
meal) to avoid food effect on abiraterone PK. 
Rucaparib will be provided as 200, 250, and 300 mg [as free base] dose strength tablets 
(Section 5.1.1).  
5.5.2 
Enzalutamide 
Enzalutamide starting dose will be the full approved dose for mCRPC patients: 160 mg 
(4 × 40 mg capsules) QD in both the PK assessment phase and the expansion phase in 
Arm A. Patients receiving enzalutamide should also take GnRH analog concurrently or 
should have had bilateral orchiectomy. Patients who have not had a bilateral orchiectomy 
should continue the GnRH analog they were taking prior to enrolling into this study. 
Enzalutamide should be dosed together with the rucaparib morning dose and at 
approximately the same time every day starting on Cycle 1 Day 1. Enzalutamide and 
rucaparib may be taken with or without food. The enzalutamide capsules should be 
swallowed whole without crushing or chewing.  
Enzalutamide will be provided as 40 mg dose strength capsules (Section 5.1.2). 


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5.5.3 
Abiraterone Acetate 
Abiraterone acetate starting dose will be the full approved dose for mCRPC patients: 
1,000 mg (2 × 500 mg tablets) QD in both the PK assessment phase and the expansion phase 
in Arm B. Abiraterone acetate must be taken together with prednisone 5 mg orally BID. 
Patients receiving abiraterone should also take GnRH analog concurrently or should have had 
bilateral orchiectomy. Patients who have not had a bilateral orchiectomy should continue the 
GnRH analog they were taking prior to enrolling into this study. 
Abiraterone acetate should be dosed together with the rucaparib morning dose and at 
approximately the same time every day starting on Cycle 1 Day 1. Abiraterone acetate and 
rucaparib must be taken on an empty stomach (at least 1 hour before or 2 hours after a meal). 
The abiraterone acetate tablets should be swallowed whole without crushing or chewing.  
Abiraterone acetate will be provided as 250 and 500 mg dose strength tablets (Section 5.1.3). 
5.6 
Dose-Limiting Toxicities 
A DLT is defined according to criteria specified below and assessed by the investigator, 
based on toxicity grade (according to the NCI CTCAE v5.0), clinical significance, and 
possible relationship to the study drug combination (refer to Section 8.7.4 for consideration 
of causal relationship). The toxicity should not be a recognized adverse effect of 
enzalutamide, abiraterone or prednisone/prednisolone and/or attributable to mCRPC or 
mCRPC-related processes under investigation. 
The DLT-evaluation period for the determination of dose escalation is the first 2 cycles of 
rucaparib combination treatment (56 days) for Arm A and the first cycle of rucaparib 
combination treatment (28 days) for Arm B. 
DLTs are defined as: 
• Grade 3 or greater febrile neutropenia (ie, fever > 38.3°C with ANC < 1.0 × 109/L) of any 
duration or Grade 4 neutropenia lasting more than 7 days despite granulocyte-colony 
stimulating factor (GCSF) administration; 
• Grade 3 thrombocytopenia (platelets < 50 × 109/L) with significant bleeding or Grade 4 
thrombocytopenia (platelets < 25 × 109/L) ≥ 5 days duration; 
• Grade 4 anemia (ie, life-threatening consequences; urgent intervention indicated); 
• Any nonhematological AE ≥ Grade 3, with the exception of: 
- 
Nausea, vomiting, and diarrhea well controlled by systemic medication and with 
duration ≤ 72 hours; 
- 
Fatigue; 
- 
Grade 3 ALT or AST not accompanied by concomitant increase in total bilirubin 
above the ULN. Note: any Grade 4 ALT/AST is a DLT; 
- 
Grade 3 arthralgia treated with non-steroidal anti-inflammatory drug(s) (or 
equivalent) that resolves to ≤ Grade 2 within 14 days;  


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- 
Alopecia of any grade. 
• Grade 3 QTc prolongation (average QTc ≥ 501 ms; > 60 ms change from baseline, over 
3 consecutive assessments) or Grade 4 QTc prolongation (Torsade de pointes, 
polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia) (Specific 
to Arm B). 
 
5.7 
Definition of DLT-evaluable Patient 
For Arm A of the study, in order to be considered evaluable for dose escalation/de-escalation 
decisions, a patient must have received at least 70% of the scheduled doses of both rucaparib 
and enzalutamide and completed 2 cycles of treatment or have experienced a DLT in either 
Cycle 1 or Cycle 2. If a patient withdraws from the study without having met either of these 
criteria, then an additional patient will be enrolled in that cohort; however, safety data, 
including AEs for that patient will also be considered in dose escalation decisions. 
For Arm B of the study, in order to be considered evaluable for dose escalation/de-escalation 
decisions, a patient must have received at least 80% of the scheduled doses of both rucaparib 
and abiraterone and completed Cycle 1 of treatment or have experienced a DLT in Cycle 1. If 
a patient withdraws from the study without having met either of these criteria, then an 
additional patient will be enrolled in that cohort; however, safety data, including AEs for that 
patient will also be considered in dose escalation decisions. 
5.8 
Dose Modifications of Protocol-specified Treatment 
5.8.1 
Rucaparib Dose Modification Criteria 
Doses of rucaparib may be interrupted or delayed for toxicity and other protocol-specified 
criteria. Dose reductions are permitted for rucaparib. The assessment for delay or 
discontinuation should be made separately for rucaparib and its combination partner; 
however, if toxicity is considered related to all study drugs or if the investigator is unable to 
determine which study drug is the cause of the AE, then all study drugs in the combination 
should be delayed and/or discontinued. Treatment may be discontinued due to withdrawal of 
consent, unacceptable toxicity, disease progression or termination of the study, whichever 
occurs first. 
Dose modification and retreatment of rucaparib are to be based on the criteria presented in 
Table 5-4. 


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Table 5-4. 
Dose Modification Criteria for Rucaparib 
Adverse Event 
including Laboratory 
Abnormalities 
Severity 
(CTCAE 
Grade) 
Rucaparib 
Treatment 
Interruption 
Retreatment 
Dose Modification 
Adverse event or 
laboratory abnormality 
1 or 2 
Nonea 
N/A 
None 
Adverse eventb  
3 or 4 
Hold dose 
≤ Grade 2 
1st occurrence: 
Same dose 
 
2nd or 3rd 
occurrence of same 
AE: 
Reduce dosec 
ALT/AST elevation (in 
the absence of other 
signs of liver 
dysfunction) 
3 
Continuation of dosing 
permitted provided total 
bilirubin is < ULN and 
ALP is < 3 × ULN; 
monitor LFTs weekly; 
Hold if levels do not 
decline within 2 weeks 
or if levels increase 
≤ Grade 2 
1st occurrence: 
Same dose 
 
2nd occurrence or 
more of same AE: 
Reduce dosec 
ALT/AST elevation 
4 
Hold 
≤ Grade 2 
Reduce dose; 
monitor LFTs weekly 
for 3 weeks 
(Section 5.8.2) 
ALT or AST elevations 
(> 3 × ULN)  
AND total bilirubin (> 2 
× ULN) - suspected 
DILI (Section 8.9) 
N/A 
Holdd; 
Monitor LFTs weekly 
≤ Grade 1 
(or baseline) 
Subject to 
investigation: reduce 
dosec 
If DILI is confirmed, 
treatment should be 
permanently 
discontinued 
Anemia 
≥ 3  
Hold dosee 
≤ Grade 2  
Same or reduced 
dosea, c 
Abbreviations: AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; 
AST = aspartate aminotransferase; CTCAE = Common Terminology Criteria for Adverse Events; 
DILI = drug-induced liver injury; INR = international normalized ratio; LFT = liver functions test; N/A = not 
applicable; ULN = upper limit of normal. 
a 
At the discretion of the investigator, the dose of rucaparib may be held and/or reduced for Grade 2 
toxicity that is attributed to rucaparib and not adequately controlled by concomitant medications and/or 
supportive care. 
b 
Exceptions include Grade 3 or 4 nausea, vomiting, or diarrhea adequately controlled with systemic 
anti-emetic/antidiarrheal medication administered in standard doses according to institutional guidelines. 
c 
For dose reductions, see Section 5.8.2. 


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d 
Evaluate patient for the presence of confounding factors, including malignant disease in the liver, co-
administration 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 INR should 
be implemented as indicated. If no alternative cause is identified, study drugs must be permanently 
discontinued. Patients should be followed until all abnormalities have returned to normal, returned to 
baseline levels, or an alternative cause is found to explain the combination of the increased transaminases 
and total bilirubin. 
e 
If anemia CTCAE Grade ≥ 3 persists for > 14 consecutive days, or a dependence upon blood transfusions 
occurs, then weekly complete blood counts should be performed until resolution of the event. If after 
42 days of interruption and anemia has not improved to CTCAE Grade ≤ 1, the patient should be referred 
to hematologist and analysis of the bone marrow with cytogenetic studies and recommended according to 
standard practice. 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). 
 
5.8.1.1 
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 computed 
tomography [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 judgment 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 8.3 and 8.7 of the protocol for additional information regarding 
classification and reporting of pneumonitis (and similar events) as an AESI.  
5.8.2 
Rucaparib Dose Modification Steps 
Dose reduction steps are presented in Table 5-5. Dose reduction steps from a starting dose of 
greater than 600 mg BID will be determined and agreed upon by the Dose Review 
Committee, based on the starting dose, exposure of rucaparib achieved and toxicities 
observed in prior dose level cohort(s). 
Dose escalation upon resolution of toxicity to ≤ CTCAE Grade 1 is permitted at the 
discretion of the investigator.  
If rucaparib PK is decreased by 25-50% due to interactions with its combination partner, 
(particularly in Arm A), it may be necessary to escalate the dose of rucaparib from 
600 mg BID to a maximum of 1,000 mg BID. The increase in rucaparib dose will be 
determined by exposure observed in the prior cohort of patients.  


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Dose modifications (ie, interruption, reduction, and/or re-escalation) must be recorded for 
each patient in the appropriate section of the eCRF (see Section 10.5). 
Table 5-5. 
Rucaparib Dose Reduction Steps 
Starting Dose 
600 mg BID 
Dose Level – 1 
500 mg BID 
Dose Level – 2 
400 mg BID 
Dose Level – 3a 
300 mg BID 
Abbreviation: BID = twice a day. 
a 
Consult with sponsor’s medical monitor before reducing the dose to this level.  
 
5.8.3 
Enzalutamide or Abiraterone Dose Modification 
Dose reductions will not be permitted for enzalutamide, abiraterone or prednisone in the PK 
assessment phase, unless the patient experiences a DLT. For treatment interruptions or dose 
modifications necessary for either enzalutamide or abiraterone for patients enrolled and 
treated in the PK assessment portion of the study and who have completed the DLT 
assessment period or for patients enrolled into the expansion phase, refer to the applicable 
prescribing information for further details and for any additional restrictions or cautions 
required due to the administration of enzalutamide, abiraterone or prednisone. 
Arm A: Discontinuation of enzalutamide may be warranted (refer to prescribing information) 
if the patient exhibits the following symptoms/syndromes: seizure, posterior reverse 
encephalopathy syndrome, hypersensitivity or ischemic heart disease. 
Arm B: Discontinuation of abiraterone and/or modification of abiraterone may be warranted 
(refer to the prescribing information) if the patient exhibits symptoms of mineralocorticoid 
excess, adrenocortical insufficiency or hepatotoxicity. 
5.9 
Treatment Compliance 
As of the implementation of Protocol Amendment 2, the requirement to use drug dosing 
diaries will be discontinued, and compliance and dosing data are no longer required to be 
entered in the eCRF (see Section 10.5). 
Study site personnel will review dosing information with the patient (or legally authorized 
representative, where acceptable) 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, where acceptable according to local regulations) will be 
instructed to keep all unused containers (empty, partially used, and/or unopened) for 
accountability at scheduled clinic visits. Documentation of dosing will be recorded in a 
study-specific dosing diary provided by the sponsor (or designee). Dosing noncompliance is 
defined as a patient missing > 14 days of study drug within a cycle for 2 consecutive cycles 
for reasons other than toxicity. The sponsor may require patients meeting noncompliance 
criteria to discontinue study treatment. 


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A compliance check and tablet count will be performed by study site personnel during clinic 
visits. Study site personnel will record compliance information on the eCRF 
(see Section 10.5). Additional details regarding study drug dispensation and return can be 
found in the Pharmacy Manual.  
Every effort should be made to ensure patients return all study drug containers/unused study 
drugs at the end of each cycle of treatment. Study site personnel should conduct a verbal 
review of dosing with the patient and document the discussion in the patient’s medical 
record. This documentation may serve as source documentation for entering dosing data on 
the appropriate eCRF (see Section 10.5). 
5.10 Accountability of Protocol-specified Treatment 
Study site personnel will maintain accurate records of study drug receipt, dispensation, use, 
return, destruction, and reconciliation for study drugs provided by the sponsor. The IWRS 
will be used to manage study drug inventory at all sites. To function properly, the system will 
require real-time entry of study drug receipt, dispensation, destruction, etc. by study site 
personnel. 
The site is responsible for the return or destruction of study drug supplied by the sponsor, as 
required. Authorization for on-site destruction of study drug that has not been dispensed to a 
patient (eg, expired study drug), must be requested from the sponsor prior to destruction. All 
study drug containers must be accounted for prior to their destruction at the study site, 
according to institutional procedures for disposal of hazardous materials. Unused and 
returned study drug product and containers should be destroyed on-site if possible. If on-site 
destruction is not possible, supply should be returned to the drug depot, following the 
sponsor’s instructions. 
During the study and at completion of the study, the number of study drug units and 
containers received, dispensed, returned, and destroyed must be recorded and reconciled. 
Additional details regarding study drug accountability can be found in the Pharmacy Manual.  
5.11 Investigational Treatment Beyond Disease Progression 
Patients will receive study drugs until confirmed radiologic disease progression as assessed 
by investigator using mRECIST/PCWG3 criteria, unacceptable toxicity, patient or physician 
request to discontinue, death, initiation of any other anticancer therapy, or termination of the 
study (refer to Section 10.6). 
If a patient receiving study drugs has met criteria for confirmed radiologic disease 
progression by mRECIST/PCWG3, but the patient continues to derive clinical benefit per the 
investigator, then continuation of study drug(s) may be permitted upon discussion with the 
medical monitor. In such cases, the documented decision to continue will be made jointly 
between the investigator and the sponsor (or designee), it must be documented in the 
patient’s chart, and the patient must provide consent within a reasonable timeframe of the 
documented decision to continue study treatment. Clinical scenarios where continuation of 
study drugs after radiographic progression may be considered include, but are not limited to: 


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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 study drug(s) will continue to have all protocol-required assessments as described in 
Section 7.  
6 
PRIOR AND CONCOMITANT THERAPY 
As of the implementation of Protocol Amendment 2, it is no longer required to document 
procedures and medications used during the study in the eCRF (see Section 10.5). 
6.1 
Supportive Care 
During the study, supportive care (eg, anti-emetics; analgesics for pain control) may be used 
at the investigator’s discretion and in accordance with institutional procedures. 
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. 
6.2 
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, with the exception of palliative radiotherapy and hormonal treatment, such as GnRH 
therapy. Prior treatment with such excluded anticancer therapies must have been completed 
> 14 days prior to the first dose of study drug or as specified in the treatment arm-specific 
inclusion/exclusion criteria (Section 4.2 and Section 4.3, respectively). 
Any botanical preparations (eg, herbal supplements or traditional Chinese medicines) 
intended to treat the disease under study or provide supportive care are prohibited (except 
those prescribed as supportive care by a health care professional as per Section 6.1). 
6.3 
Radiotherapy 
Palliative radiotherapy on lesions not considered target lesions for tumor evaluation is 
permitted during the study. Treatment with study drug should be held prior to initiation of 
radiation therapy and until the patient has recovered from any radiation related toxicity. 
6.4 
CYP450 Isoenzyme Inhibitors, Inducers, and Substrates 
At the steady state following treatment with 600 mg rucaparib BID, rucaparib is a moderate 
inhibitor of CYP1A2, and a weak inhibitor of CYP2C9, CYP2C19, and CYP3A. Refer to the 


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rucaparib IB, Contraindications and Precautions, for caution when co-administering 
medicinal products that are CYP substrates.  
Although in vitro rucaparib metabolism mediated by CYP3A4 was slow, a significant 
contribution of CYP3A4 in vivo cannot be excluded. To assess the effect of enzalutamide on 
rucaparib PK, no other strong or moderate CYP3A inhibitors or inducers are allowed.  
In addition, the following rules should be followed in specific study arms: 
• Arm A: Enzalutamide is a substrate of CYP2C8 and CYP3A4. Concomitant strong 
CYP2C8 inhibitors, strong CYP3A4 inducers are prohibited. Enzalutamide is a strong 
CYP3A4 inducer, and a moderate inducer of CYP2C9 and CYP2C19. Concomitant use 
with drugs that are sensitive substrates of CYP3A4, CYP2C9, or CYP2C19 should be 
avoided. 
• Arm B: Concomitant strong CYP3A4 inducers and sensitive CYP2D6 substrates are 
prohibited. 
 
Refer to Appendix 3 for examples of sensitive CYP substrates and refer to Appendix 4 for 
examples of CYP inhibitors and inducers. 
6.5 
Anticoagulants 
Rucaparib is a weak inhibitor of CYP2C9 and enzalutamide is a moderate CYP2C9 inducer. 
Caution should be exercised particularly in Arm A, for patients receiving rucaparib or 
enzalutamide with concomitant warfarin (Coumadin). Patients taking warfarin should have 
international normalized ratio (INR) monitored regularly per standard clinical practice. 
Direct oral anticoagulants (eg, apixaban, rivaroxaban, and dabigatran) have elimination 
mediated by CYP3A4 and/or P-gp. As enzalutamide is a strong CYP3A4 inducer in vivo, and 
enzalutamide and N-desmethyl enzalutamide are P-gp inhibitors in vitro, concomitant 
administration with enzalutamide may result in altered exposures of these anticoagulants. If 
such anticoagulants have to be used, monitor INR regularly per standard clinical practice. 
6.6 
Imaging Restrictions and Precautions 
It is the local imaging facility’s responsibility to determine, based on patient attributes 
(eg, allergy history, diabetic history, and renal status), the appropriate imaging modality and 
contrast regimen for each patient. Oral and/or intravenous (IV) contrast should be used 
whenever possible and appropriate, and rectal contrast should only be considered in patients 
with peritoneal disease. Imaging contraindications and contrast risks should be considered in 
this assessment. Patients with renal insufficiency should be assessed as to whether or not they 
should receive contrast and if so, what type and dose of contrast is appropriate. Specific to 
magnetic resonance imaging (MRI), patients with severe renal insufficiency (ie, estimated 
GFR < 30 mL/min) are at increased risk of nephrogenic systemic fibrosis. MRI contrast 
should not be given to this patient population. In addition, patients should not get MRI if they 
have tattoos, metallic implants, pacemakers, etc. 


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The ultimate decision to perform MRI in an individual patient in this study rests with the site 
radiologist, the investigator and the standard set by the local IRB. 
6.7 
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 (see Section 10.5). 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 (see Section 10.5).  
Rucaparib marginally increased digoxin AUC by 20%. Caution should be exercised for 
patients receiving rucaparib and requiring concomitant medication with digoxin. Patients 
taking digoxin should have their digoxin levels monitored after starting rucaparib and then 
regularly per standard clinical practice.  
In vitro, rucaparib is a potent inhibitor of MATE-1 and MATE-2-K, a moderate inhibitor of 
OCT1, and a weak inhibitor of OCT2. As inhibition of these transporters could decrease 
renal elimination and liver uptake of metformin, caution is advised when metformin is 
co-administered with rucaparib. 
Abiraterone is a weak CYP2C8 inhibitor in vivo. In vitro, abiraterone and its metabolites 
inhibit organic anion transporter (OAT) OATP1B1. Use caution if sensitive CYP2C8 
substrate drugs or OATP1B1 substrate drugs need to be used concomitantly with study drugs. 
Refer to the rucaparib IB and to the enzalutamide or abiraterone prescribing information for 
additional information. 
6.8 
General Restrictions 
Photosensitivity has been observed in patients treated with rucaparib. Patients should avoid 
spending time in direct sunlight because they burn more easily during treatment with 
rucaparib. When outdoors, patients should use typical precautions such as applying sunscreen 
(sun protection factor 50 or greater) and/or covering exposed skin with clothing and wearing 
a hat and sunglasses. 
7 
STUDY PROCEDURES AND METHODS 
7.1 
Schedule of Assessments 
Table 7-1 summarizes the procedures and assessments to be performed for all patients 
remaining on study drug or in follow-up as of the implementation of Protocol 
Amendment 2. The revised evaluations should commence immediately after the patient 
has provided appropriate informed consent, maintaining previous treatment cycle and 
day sequence.  


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The purpose of the revised SOA is to allow patients who continue to benefit from treatment 
with the combination to continue receiving study drugs, but to reduce the number of 
assessments required at study visits (including at the end of treatment and follow-up 
assessments), while maintaining an appropriate level of safety monitoring. 
Study procedures and assessments should be performed as close as possible to the scheduled 
time, but within ± 3 days of the scheduled time unless otherwise stated.  
Both arms will start with a 1-week run-in period with rucaparib alone, followed by 
continuous 28-days treatment cycles of rucaparib and the combination drug. The DLT period 
in Arm A will be across Cycles 1 and 2, and for Arm B will be across Cycle 1. 
Food restriction must be followed for the morning doses of abiraterone acetate and rucaparib. 
The doses must be taken on an empty stomach at least 1 hour before or 2 hours after a meal. 
There is no food restriction in Arm A and evening doses of rucaparib in Arm B. 
Table 7-2 summarizes the PK sample collection schedule for all patients in Arm A and 
Arm B. Predose PK samples will be collected at the specified timepoints. 


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Table 7-1. 
Revised Schedule of Assessments as of the Implementation of Protocol Amendment 2 
Procedurea 
Treatment Phase 
(± 3 days) 
Cycle X Day 1 
Post-Treatment Phase 
End of Treatment 
(± 3 days after last dose) 
28-Day Follow-up 
 
Adverse Eventsb 
The investigator should monitor and educate patients 
on possible AEs observed with the treatment 
combination 
X 
Complete Blood Count 
Monthly assessments advised 
 
Clinical Chemistry, Urinalysis, Vital Signs 
Local standard of care practices per investigator 
 
Disease Assessments (Imaging/PSA) 
Local standard of care practices per investigator 
 
Arm A: Rucaparib 
Dispensation/Administration/Accountability 
X 
X 
 
Arm A: Enzalutamide 
Dispensation/Administration/Accountability 
X 
X 
 
Abbreviations: AE = adverse event, AESI = adverse event of special interest, AML = acute myeloid leukemia, MDS = myelodysplastic syndrome, 
PSA = prostate-specific antigen, PV = pharmacovigilance, SAE = serious adverse event. 
a 
Treatment cycles are 28 days. Unless otherwise specified, all assessments are to be completed within ± 3 days of scheduled time point. 
b 
AEs will be monitored, but only SAEs/AESIs will be reported through 28 days after the last dose of study drug. Ongoing SAEs, AESIs and Grade 3/4 
treatment-related AEs will be followed until resolution, stabilization, or lost to follow-up. SAEs/AESIs will be collected per Clovis PV guidelines and 
reported in the Clovis PV database through the 28-day Follow-up Visit after the last dose of study drug. 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 assessed as potentially related to study 
drug, and AESIs of MDS and AML irrespective of causality, will be reported.  
Note: Treatment Arm B was not activated. 
 


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Table 7-2. 
Pharmacokinetic Sample Collections in Treatment Arm A and 
Arm B (PK Assessment and Expansion) 
Cycle 
Study Visit 
Rucaparib PK 
Combination Druga PK 
Rucaparib Run-In 
D6, D7 
Predoseb 
N/A 
Cycle 1  
D1, D8, D15, 
D22 
Predoseb 
Predoseb 
Cycle 2  
D1 
Predoseb 
Predoseb 
Cycle 2 (Arm A only) 
D8, D15, D22 
Predoseb 
Predoseb 
Cycles 3, 4, 6, and 8 
 
D1 
Predoseb 
Predoseb 
Abbreviations: D = day; N/A = not applicable; PK = pharmacokinetics. 
a 
Arm A, enzalutamide and N-desmethyl enzalutamide; Arm B, abiraterone 
b 
Predose refers to collection prior to the morning dose of both rucaparib and the combination drug. The 
predose PK sample should be collected within 30 minutes before taking the morning dose of study drugs. 
Special attention is required for Arm B where rucaparib and abiraterone acetate should be taken on an 
empty stomach (at least 1 hour before or 2 hours after a meal); the predose PK samples should be 
collected at a time in the morning with assurance that the drugs can be administered within 30 minutes 
after PK sampling.  
Notes: Collection of the actual time(s) of dose administration and PK sampling is essential for PK analysis. 
Refer to the Laboratory Manual for details on sample handling and processing. 
 
7.2 
Informed Consent Process 
The investigator or their designee shall discuss with each patient the nature of the study and 
its requirements. To participate in the study, informed consent must be obtained from each 
potential patient (or legally authorized representative) prior to any study activities. The 
information on the IRB-approved consent form should be translated and communicated in the 
language the patient (or legally authorized representative) can understand. A separate consent 
form may be used for tissue testing.  
Patients with radiologic disease progression who are still receiving benefit and are permitted 
to continue treatment following disease progression must provide consent for continued 
treatment.  
7.3 
Methods of Data Collection 
As of the implementation of Protocol Amendment 2, it is no longer required to record data in 
the eCRF (see Section 10.5); however, SAEs and AESIs will be reported to Clovis PV as 
described in Section 8.7. 
7.3.1 
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 


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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 due to a 
protocol-mandated procedure, should be recorded on the Medical History eCRF.  
The patient’s entire relevant oncology history will be collected on the appropriate eCRF 
including date of diagnosis for prostate cancer, prior surgeries/treatments received for cancer, 
dates of treatment administration, best response achieved, date of progression and how 
assessed, progression-free interval after last platinum regimen (if applicable), radiology 
reports, and status (germline or somatic – if known) of deleterious mutation in BRCA1/2 or 
other HRR gene.  
7.3.2 
Prior and Concomitant Medication Assessments 
Medications being used by the patient will be recorded as prior/concomitant medications 
during screening. 
As of Protocol Amendment 2, information on concomitant medications will no longer be 
collected. 
7.3.3 
Efficacy Evaluations 
7.3.3.1 
Disease/Tumor Assessments 
Disease/tumor assessments will be performed according to local standard of care per 
investigator.  
Tumor response will be interpreted using mRECIST/PCWG3 criteria (Appendix 1).  
7.3.3.2 
Tumor Markers 
Blood samples to assess PSA will be collected according to local standard of care per 
investigator, and as clinically indicated. PSA will be measured by a local laboratory.  
7.3.4 
Safety Evaluations 
7.3.4.1 
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 screening period, unless 
otherwise required by local regulations, AEs/SAEs related to protocol-mandated procedures 
will be reported. As of the implementation of Protocol Amendment 2, during and at the end 
of treatment, AEs will be monitored but only SAEs/AESIs will be reported through 28 days 
after the last dose of study drug. Any ongoing SAEs, AESIs, or treatment-related Grade 3/4 
AEs will be followed until resolution, stabilization, or lost to follow-up. After the 28-day 
window, only SAEs assessed as potentially related to study drug should be reported per 
Clovis PV requirements and captured in the Clovis PV database. 
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 similar events (ie, interstitial lung disease, pulmonary fibrosis, 
acute interstitial pneumonitis, alveolitis necrotizing, alveolitis, hypersensitivity 
pneumonitis, and organizing pneumonia) should be reported up to, but not beyond, the 
28-day Follow-up Visit (ie, 28 days after the last dose of study drug). After the 28-day 
Follow-up Visit, only serious pneumonitis or similar events assessed as potentially 
related to study drug should be reported per Clovis Oncology PV requirements. 
 
In the time after informed consent is provided but before rucaparib is administered, 
AEs/SAEs are to be recorded if they are the result of a study-related procedure. Any ongoing 
SAEs, AESIs, or treatment-related Grade 3/4 AEs will be followed until resolution or 
stabilization. AEs and laboratory abnormalities will be graded according to the NCI CTCAE 
grading system (v5) and recorded on the eCRF (see Section 10.5). 
Complete details for monitoring AEs (inclusive of SAEs and AESIs), including the definition 
of drug-related AEs, are provided in Section 8. 
7.3.4.2 
Clinical Laboratory Investigations 
As of the implementation of Protocol Amendment 2, monthly hematology assessment, 
consisting of a complete blood count, is advised. Clinical chemistry assessments will be 
performed according to local standard of care per investigator. 
As of the implementation of Protocol Amendment 2, urinalysis will be performed according 
to local standard of care per investigator. 
7.3.4.3 
Vital Signs 
As of the implementation of Protocol Amendment 2, vital signs will be performed according 
to local standard of care per investigator. 
7.3.4.4 
12-Lead Electrocardiograms  
As of the implementation of Protocol Amendment 2, ECGs will no longer be required. 
7.3.4.5 
Physical Examinations, Body Weight and Height 
As of the implementation of Protocol Amendment 2, physical examinations, body height and 
weight assessments will no longer be required. 
7.3.4.6 
ECOG Performance Status 
As of the implementation of Protocol Amendment 2, ECOG performance status assessments 
will no longer be required. 
7.3.5 
Pharmacokinetic Assessments 
As of the implementation of Protocol Amendment 2, the PK assessment phase is complete 
and PK samples are no longer being collected. 


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PK samples will be collected according to Table 7-2. 
In Arm A, patients will receive treatment of rucaparib for 1 week (Run-In Days 1-7), 
followed by treatments of enzalutamide and rucaparib in 28-day cycles. Plasma PK samples 
will be collected prior to the morning doses in on Run-In Days 6 and 7 during the run-in 
period, and on Days 1, 8, 15 and 22 of Cycles 1 and 2, and on Day 1 of Cycles 3, 4, 6 and 8. 
The morning dose should be approximately 24 hours after the previous morning doses of 
enzalutamide and rucaparib, and approximately 12 hours before the previous evening dose of 
rucaparib. If the start of the next treatment cycle is delayed, the PK sample should still be 
collected during this visit instead of on Day 1 of the delayed start of the next treatment cycle. 
Concentrations of enzalutamide, its metabolite N-desmethyl enzalutamide, rucaparib, and its 
metabolite M324 will be determined using validated assays. 
In Arm B, patients will receive treatment of rucaparib for 1 week (Run-In Days 1-7), 
followed by treatments of abiraterone and rucaparib in 28-day cycles. Plasma PK samples 
will be collected prior to the morning doses on Run-In Days 6 and 7 during the run-in period, 
on Days 1, 8, 15 and 22 of Cycle 1, as well as on Day 1 of Cycles 2, 3, 4, 6, and 8. The 
morning dose should be approximately 24 hours after the previous morning doses of 
abiraterone acetate and rucaparib, and approximately 12 hours before the previous evening 
dose of rucaparib. If the start of the next treatment cycle is delayed, the PK sample should 
still be collected during this visit instead of on Day 1 of the delayed start of the next 
treatment cycle. Concentrations of abiraterone, rucaparib and its metabolite M324 will be 
determined using validated assays. 
Refer to the Laboratory Manual for sample collection, handling, and storage details for PK 
samples.  
7.3.6 
Biomarker Analyses 
The biomarker samples and analyses are described below. The Laboratory Manual will 
include details of the sampling methods, number of samples to be collected, processing, 
handling, and storage. 
As of the implementation of Protocol Amendment 2, the collection of blood samples for 
biomarker analysis has been completed and no additional samples will be collected. 
7.3.6.1 
Formalin-fixed Paraffin-embedded Tumor Tissue or Fresh Tumor Biopsy 
Optional archival formalin-fixed paraffin-embedded (FFPE) tumor tissue or metastatic 
biopsy sample (preferred) will be collected from patients. Next-generation sequencing (NGS) 
will be performed on these samples, and the relationship between genomic alterations and 
signatures to clinical outcomes from treatment will be assessed. 
7.3.6.2 
Optional Tumor Biopsy 
As of the implementation of Protocol Amendment 2, post-treatment tumor biopsies will no 
longer be collected. 


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7.3.6.3 
Blood Sample for Plasma ctDNA Analyses 
Blood samples for plasma ctDNA analyses will be collected during screening, before dosing 
with rucaparib on the first run-in day, and on Day 1 of Cycle 2 during combination treatment. 
These samples will be used for genomic profiling to assess alterations in genes that may be 
associated with response and resistance to rucaparib in combination with AR-directed 
therapy. 
7.3.6.4 
Blood Sample for Pharmacogenomics Analyses 
Blood samples for pharmacogenomics analyses will be collected at Study Day 1 of the run-in 
period from all patients. If the pharmacogenomics sample is missed, it may be collected 
during a later cycle (ie, Cycle 2 or later). Genomic DNA will be extracted from the cellular 
portion of these blood samples analyzed to determine whether the BRCA1/2 mutation or 
other HRR gene mutation is germline or somatic prior to final data analysis. Additionally, 
polymorphisms of absorption, distribution, metabolism and excretion (ADME)-related genes 
relevant to the DDI analysis may be explored per sponsor’s request.  
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 may be made available to the investigator provided 
the results are generated from a Clinical Laboratory Improvement 
Amendments (CLIA)-certified laboratory.  
7.3.6.5 
Additional Research 
Patients will have the option to provide additional consent to allow the sponsor to retain 
residual samples for future unspecified research.  
8 
ADVERSE EVENT MANAGEMENT 
As of the implementation of Protocol Amendment 2, it is no longer required to record AEs in 
the eCRF (see Section 10.5); however, SAEs and AESIs will be reported to Clovis PV as 
described in Section 8.7. 
8.1 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, drug interaction, or 
the significant worsening of the indication under investigation that is not recorded elsewhere 
on the eCRF (see Section 10.5) under specific efficacy assessments. Anticipated fluctuations 


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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, instead of the physical examination eCRF [see Section 10.5], which is reserved 
for physical signs or findings). 
8.2 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 study drug 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 
• 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 
• Is an important medical event – Important medical events may not result in death, are not 
life-threatening, or do not require hospitalization but 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. 
 
8.3 Definition of an Adverse Event of Special Interest 
Adverse events of special interest (AESIs, serious or nonserious) are defined as AEs of 
scientific and medical concern specific to the sponsor’s product or program, for which 
ongoing monitoring and rapid communication by the investigator to the sponsor can be 
appropriate. Such an event might warrant further investigation in order to characterize and 
understand it. Depending on the nature of the event, rapid communication by the study 
sponsor to other parties (eg, regulators) might also be warranted. 


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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 8.7 for reporting instructions). Details on the AESIs for 
either enzalutamide or abiraterone can be found in the prescribing instructions. 
8.4 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 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 (see Section 10.5). The accompanying SAE should be reported and overdose should 
be described in the report; 
• 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) should not be 
reported as an AE or SAE; or 
• Events that meet the SAE criteria (as outlined in Section 8.2) and occur after informed 
consent but before the first dose of study drug, which are considered unrelated to 
protocol-mandated screening procedures.  
 
8.5 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 laboratory values within the normal range will require similar 
judgment. 
An abnormal laboratory value that is not already associated with an AE is to be recorded as 
an AE only if any one of the following criteria is met: 
• an action on the study drug is made as a result of the abnormality 
• intervention for management of the abnormality is required 
• at the discretion of the investigator should the abnormality be deemed clinically 
significant. 
 


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8.6 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. 
All pregnancies 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.  
8.7 Reporting of Adverse Events, Serious Adverse Events, and Adverse 
Events of Special Interest 
Events that occur after signing of informed consent but prior to initiation of study drug, 
unless due to a protocol-mandated procedure, are to be recorded on the Medical History 
eCRF (see Section 10.5); however, during this time if the event is serious and related to a 
protocol-mandated procedure it is to be reported as an SAE. As of the implementation of 
Protocol Amendment 2, during and at the end of treatment, AEs will be monitored but only 
SAEs/AESIs will be reported through 28 days after the last dose of study drug. 
After the 28-day Follow-up Visit, only SAEs assessed as potentially related to study drug 
should be reported per Clovis PV requirements and captured in the Clovis PV database.  
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 similar events (ie, interstitial lung disease, pulmonary fibrosis, 
acute interstitial pneumonitis, alveolitis necrotizing, alveolitis, hypersensitivity 
pneumonitis, and organizing pneumonia) should be reported up to, but not beyond, the 
28-day Follow-up Visit (ie, 28 days after the last dose of study drug). After the 28-day 
Follow-up Visit, only serious pneumonitis or similar events assessed as potentially 
related to study drug should be reported per Clovis Oncology PV requirements. 
 
Information on the follow-up of AEs, SAEs and AESIs is provided in Section 8.8. 
In order to avoid vague, ambiguous, or colloquial expressions, the AE should be recorded in 
standard medical terminology rather than the patient’s own words. Whenever possible, the 
investigator should combine signs and symptoms that constitute a single disease entity or 
syndrome into a final diagnosis, if appropriate. For example, fever, cough, and shortness of 
breath may be reported as pneumonia, if that is a reasonable diagnosis. 
Each AE is to be evaluated for causal relationship to the investigational drug, severity, and 
seriousness. The action taken and the outcome must also be recorded. 


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SAEs and AESIs that occur during the study or within 28 days after receiving the last dose of 
study drug, whether or not related to study drug, must be reported immediately (ie, within 
24 hours of knowledge of the event or additional information for a previously-reported 
event) to the sponsor/SAE designee. The contact information for reporting of SAEs/AESIs 
can be found on the SAE/AESI Reporting Form.  
8.7.1 Onset Date of Adverse Events 
The onset date is the date that the event or the signs/symptoms attributed to the event started. 
8.7.2 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.  
8.7.3 Intensity of Adverse Events 
The severity of each AE will be graded using the NCI CTCAE, v5 grading scale.39 
“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 transient and do not interfere with the patient’s daily activities, 
• Moderate events introduce a low level of inconvenience or concern to the patient and 
may interfere with daily activities, 
• Severe events interrupt the patient’s usual daily activities and hospitalization (or 
prolongation of hospitalization) may be required, 
• Life-threatening events require urgent intervention to prevent death, or  
• Fatal events are those events that lead to the patient’s death. 
 
8.7.4 
Causal Relationship of Adverse Events to Study Drug 
Medical judgment should be used to determine the cause of the AE considering all relevant 
factors such as, but not limited to, the underlying study indication, co-existing disease, 
concomitant medication, relevant history, pattern of the AE, temporal relationship to the 
study medication, and dechallenge or rechallenge with the study drug (Table 8-1).  


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Table 8-1. 
Causal Relationship of Adverse Events to Study Drug 
Not Related 
to Study 
Drug 
• An AE that is clearly due to extraneous causes (eg, concurrent disease, 
concomitant medications, disease under study, etc.). 
• It does not follow a reasonable temporal sequence from administration 
of the study drug. 
• It does not follow a known pattern of response to study drug. 
• It does not reappear or worsen when study drug is restarted. 
• An alternative explanation is likely, but not clearly identifiable. 
Related to 
Study Drug 
• An AE that is difficult to assign to alternative causes. 
• It follows a strong or reasonable temporal sequence from 
administration of study drug. 
• It could not be reasonably explained by the patient’s clinical state, 
concurrent disease, or other concomitant therapy administered to the 
patient.  
• It follows a known response pattern to study drug. 
• It is confirmed with a positive rechallenge or supporting laboratory 
data. 
 
8.7.5 Outcome and Action Taken 
The investigator will record the action taken and outcome for each AE according to the 
following criteria: 
Action Taken with Study Drug (note all that apply) 
• None 
• Dose reduced/delayed 
• Study drug temporarily interrupted 
• Study drug permanently discontinued 
• Other (specify) 
 
Outcome 
• Recovered 
• Recovered with sequelae 
• Recovering/ Resolving/ Improving 


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• Ongoing 
• Death 
• Lost to follow-up 
 
8.8 
Follow-up of Adverse Events, Serious Adverse Events, and 
Adverse Events of Special Interest 
All AEs (including SAEs and AESIs) occurring during the study are to be followed up in 
accordance with good medical practice until resolved; judged no longer clinically significant; 
or, if a chronic condition, until fully characterized through 28 days after the last dose of study 
drug. Any SAEs, AESIs, and treatment-related Grade 3/4 AEs must be followed until 
resolution or stabilization, death, or until lost to follow-up. After the 28-day window, only 
SAEs assessed as potentially related to study drug and all AESIs of MDS and AML, 
irrespective of causality, should be reported.  
• AESIs of pneumonitis or similar events (ie, interstitial lung disease, pulmonary fibrosis, 
acute interstitial pneumonitis, alveolitis necrotizing, alveolitis, hypersensitivity 
pneumonitis, and organizing pneumonia) should be reported up to, but not beyond, the 
28-day Follow-up Visit (ie, 28 days after the last dose of study drug). After the 28-day 
Follow-up Visit, only serious pneumonitis or similar events assessed as potentially 
related to study drug should be reported per Clovis Oncology PV requirements. 
 
8.9 
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,32 must be reported as SAEs (see Section 8.7 for reporting 
details). 
Potential drug-induced liver injury is defined as: 
1. ALT or AST elevation > 3 × ULN 
AND 
2. Total bilirubin > 2 × ULN, without initial findings of cholestasis (elevated serum ALP), 
AND 
3. No other immediately apparent possible causes of ALT/AST elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or 
acute liver disease, or the administration of other drug(s) known to be hepatotoxic. 
 


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8.10 Regulatory Aspects of Serious Adverse Event and Adverse Events 
of Special Interest Reporting 
It is important that the investigator provide an assessment of relationship of the SAE or AESI 
to study treatment at the time of the initial report. For reporting SAEs/AESIs or pregnancies, 
use the applicable report forms. The contact information for reporting of SAEs/AESIs or 
pregnancies can be found on each of the forms. 
The sponsor or its designee is responsible for submitting reports of AEs associated with the 
use of the drug that are both serious and unexpected to the US FDA, according to 21 Code of 
Federal Regulations (CFR) 312.32. 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.  
The sponsor or its designee will submit all safety updates and periodic reports to the 
regulatory authorities as required by applicable regulatory requirements. 
9 
STATISTICAL METHODS 
General Considerations 
Quantitative variables will be summarized using frequencies and percentages for appropriate 
categorizations and may also be summarized using descriptive statistics. For variables 
summarized with descriptive statistics, the following will be presented: N, mean, standard 
deviation (StD), median, minimum, and maximum. Categorical variables will be presented 
using frequencies and percentages.  
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.  
All statistical analyses will be conducted with the SAS® System, v 9.3 or higher. Further 
details around the statistical analyses planned in this study will be outlined in the statistical 
analysis plan (SAP). Changes to or deviations from the SAP will be described in the clinical 
study report (CSR).  
9.1 
Determination of Sample Size 
The total enrollment planned is up to 60 evaluable patients (30 in Arm A and 30 in Arm B). 
The overall sample size in the PK assessment phase of each arm depends on the occurrence 
of safety findings, specifically DLTs, observed at the different dose regimens. It is 
anticipated that a minimum of 6 and maximum of 18 patients will be enrolled, unless 
additional patients are required to be enrolled, due to some patients not being evaluable for 
DLT assessment.  
The Dose Expansion phase of each arm will enroll up to 12 additional patients to evaluate the 
optimal dose combination for each treatment arm.  


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A total of 18 patients at the recommended combination dose in each treatment arm is 
anticipated to provide adequate PK information (in addition to safety and tolerability) for 
each combination. Assuming an intra-subject PK variability of 40%, N = 18 patients would 
be sufficient for the point estimate of the geometric ratio of trough concentration 
(ie, concentration before the next dose is administered [Ctrough]) of rucaparib with and without 
co-administration of one of the combination drugs to fall within 80% and 125% of the true 
value with 90% confidence. Fewer patients may be enrolled if the PK variability is less than 
anticipated.  
If a patient drops off the study or becomes unevaluable for safety (DLTs), an additional 
patient may be enrolled. 
9.2 
Analysis Populations 
The following analysis populations are defined for the study: 
• Dose-limiting toxicity (DLT)-evaluable Population – For Arm A, the DLT-evaluable 
population will consist of all patients who completed at least 70% of the scheduled doses 
of both rucaparib and enzalutamide and completed Cycles 1 and 2 of treatment, or who 
experienced a DLT in Cycles 1 or 2. For Arm B, the DLT-evaluable population will 
consist of all patients who completed at least 80% of the scheduled doses of both 
rucaparib and enzalutamide and completed Cycle 1 of treatment, or who experienced a 
DLT in Cycle 1. 
• Safety Population – The safety population will consist of all patients who received at 
least 1 dose of any study drug.  
• Efficacy Population – The efficacy population will consist of all patients evaluable for 
response by mRECIST/PCWG3 criteria (ie, PSA response) and could be subdivided into 
the RECIST-evaluable population and the PSA-evaluable population. 
• Pharmacokinetic (PK) Population – The PK population will consist of all patients who 
received at least 1 dose of study drug and had at least 1 measurable concentration.  
 
9.3 
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. 
9.4 
Demographics and Baseline Characteristics 
All demographic and baseline characteristics will be summarized for the safety population. 
In addition to basic demographic characteristics, the following baseline variables will be 
summarized with frequency tabulations: 
• Time since diagnosis of primary tumor (months): 0 to 12, > 12 to 24, > 24; 


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• The following characteristics of a deleterious mutation in BRCA1/2 or other HRR gene 
will also be summarized for patients with these mutations:  
- 
Status (germline or somatic) of mutation in BRCA1/2 or other HRR gene 
 
Descriptive statistics may also be used to summarize the continuous variables.  
9.5 
Efficacy Analysis 
The secondary efficacy endpoints will be analyzed by calculating response rates. The ORR is 
defined as the proportion of patients with a documented and confirmed best overall response 
of complete response (CR) or partial response (PR) per mRECIST v1.1 as assessed by the 
investigator. A confirmed CR or PR is a response that is maintained and documented on a 
subsequent tumor assessment at least 4 weeks after initial response. 
ORR (confirmed CR+PR) will be summarized with frequencies and percentages, Similar 
summaries of patients with a best overall response of CR, PR, stable disease (SD), or 
progressive disease (PD) will be presented. All summaries of response rates will be 
accompanied by 95% CIs. 
PSA response per PCWG3 criteria is a confirmed PSA response (≥ 50% decrease from 
baseline) as reflected local laboratory measurements. PSA response rate will be summarized 
along with a 95% CI. 
9.6 
Safety Analyses 
All safety analyses will be summarized for the Safety Population. 
Safety endpoints are incidence of AEs, clinical laboratory abnormalities, and dose 
modifications. 
AEs, clinical laboratory results, vital signs, ECG results, ECOG PS, body weight, and 
concomitant medications/ procedures will be tabulated and summarized. 
9.6.1 
Extent of Exposure 
Duration of exposure will be summarized descriptively and categorically. The number and 
percentage of patients with dose reductions and dose interruptions will be provided.  
9.6.2 
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 v5.0. TEAEs are defined as AEs with onset date ranging from on or after 
the date of first dose of study drug until 28 days after the last dose of study drug.  
The number and percentage of patients who experienced TEAEs for each System Organ 
Class (SOC) and Preferred Term (PT) will be presented. Multiple instances of the TEAE in 


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each SOC and multiple occurrences of the same PT are counted only once per patient. The 
number and percentage of patients with at least one TEAE will also be summarized. 
Separate tables will be presented as follows: 
• All TEAEs; 
• TEAEs by CTCAE grade; 
• Grade 3 or greater TEAEs; 
• Treatment-related TEAEs;  
• Serious TEAEs; 
• Treatment-related serious TEAEs; 
• TEAEs with an outcome of death; 
• TEAEs leading to discontinuation of study; 
• TEAEs resulting in interruption/delay of study drug; and TEAEs resulting in dose 
reduction of study drug. 
 
The incidence of TEAEs will be summarized by relationship to study drug (rucaparib and/or 
enzalutamide/abiraterone) 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 for the study drug, 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. 
9.6.3 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations include the continuous variables for hematology and 
chemistry. The laboratory values will generally be presented in International System of Units 
(SI). The treatment period will be defined as the time from the first dose of rucaparib to 
28 days after the last dose of rucaparib or the last Safety Follow-up Visit, whichever is later. 
Laboratory values collected during the treatment period will be included in the summary 
tables. The laboratory values collected after the 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 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 


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laboratory abnormalities (ie, those that meet Grade 3 or Grade 4 criteria according to 
CTCAE). 
9.6.4 
Vital Sign Measurements 
The treatment period will be defined as the time from the first dose of study drug to 28 days 
after the last dose of drug or the last Safety Follow-up Visit, whichever is later. Vital sign 
measurements collected during the treatment period will be included in the summary tables. 
The vital sign measurements collected after the treatment period will only be presented in the 
data listings.  
The summary of vital sign data will include descriptive statistics (N, mean, StD, minimum, 
median, and maximum) of the maximum, minimum, and last value during the treatment 
period. Summaries using descriptive statistics (N, mean, StD, minimum, median and 
maximum) of the change from baseline to the maximum, minimum, and last value during the 
treatment period will also be given.  
9.6.5 
Other Safety Measurements 
Body weight will be summarized descriptively (N, mean, StD, median, minimum, and 
maximum). 12-lead electrocardiogram findings and ECOG status will be summarized 
categorically. 
9.7 
Pharmacokinetic Analysis 
Plasma concentrations of rucaparib, its combination drug partner and their metabolite of 
interest will be determined using validated high-performance liquid chromatography tandem 
mass spectrometry (HPLC-MS/MS) methods. The Cmin data of rucaparib, the combination 
drugs, and metabolites will be reported, and summary statistics be provided. 
The effect of combination drug on the PK of rucaparib and M324 will be assessed by 
comparing their steady-state Cmin with and without treatment of the combination drug in each 
arm. The M324-to-rucaparib steady-state Cmin ratio with and without treatment of the 
combination drug in each arm will also be determined. 
9.8 
Exploratory Analysis 
Genomic alterations detected in blood or tissue samples will be correlated to clinical efficacy 
of the rucaparib combination treatments. 
9.9 
Interim Analysis 
No formal interim analysis is planned. 


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10 STUDY ADMINISTRATION 
10.1 Regulatory and Ethical Considerations 
10.1.1 
Good Clinical Practice 
The study will be conducted in accordance with the protocol and applicable Standard 
Operating Procedures (SOP); 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) 
• EU Directives 2001/20/EC, 2003/94/EC, 2005/28/EC, 536/2014, and  
• All applicable local requirements, including 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, 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 noncompliance, the sponsor will promptly notify the 
regulatory authority. 
All potential serious breaches of GCP must be reported to 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 patients in the study or the scientific value of the study. 
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks. 
This study will not use the services of study site personnel where sanctions have been 
invoked or where there has been scientific misconduct or fraud (eg, loss of medical licensure, 
debarment).  


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10.1.2 
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 
study-specific screening until appropriate regulatory approval of the study protocol has been 
received. 
Each investigator must complete a Form FDA 1572 (or equivalent, when participating in a 
US Investigational New Drug Application [IND] study). In addition, local statement of 
investigator documents must be provided where required. Each investigator must submit to 
the sponsor (or designee) financial disclosure information for studies under a US IND or if 
required by national law and/or local regulations. 
The study will be registered on regionally relevant registries, including 
www.clinicaltrials.gov, EudraCT, and other applicable clinical study registry systems as 
appropriate. Data generated from this study must be handled in accordance with any laws, 
rules, and regulations related to the privacy of personal data or medical 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).  
10.1.3 
Institutional Review Board or Independent Ethics Committee Approval 
This protocol, the IB, and any material to be provided to the patient (such as the ICF, 
advertisements, Patient Information Sheets (PIS), drug dosing diaries, or descriptions of the 
study used to obtain informed consent) will be submitted by the investigator to an IRB/IEC. 
This also applies to protocol amendments.  
The sponsor will supply relevant data for the investigator to submit the study protocol and 
additional study documents to the IRB/IEC. The investigator will submit the study protocol 
for review and approval by an IRB/IEC, according to national law and/or local regulations, 
and will provide the IRB/IEC with all appropriate materials.  
Verification of the IRBs/IECs unconditional approval of the study protocol and the written 
ICF will be transmitted to the sponsor. This approval must refer to the study by exact study 
protocol title and number, identify the documents reviewed, and state the date of the review 
and approval. 
No patient will be admitted to the study until appropriate IRB/IEC approval of the study 
protocol and ICF/PIS have been received, the investigator has obtained the patient’s signed 
and dated ICF/PIS, and the eligibility criteria have been satisfied and confirmed.  
The investigator will submit appropriate reports on the progress of the study to the IRB/IEC 
at least annually in accordance with applicable national law and/or local regulations and in 
agreement with the policy established by the IRB/IEC and sponsor.  


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The IRB/IEC must be informed by the investigator of all subsequent study protocol 
amendments and of SAEs or suspected unexpected serious adverse reactions (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. 
10.2 Patient Information and 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 and the Declaration of Helsinki. 
It is the responsibility of the investigator to obtain signed ICFs from each patient 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and prior to undertaking any study-related procedures.  
The ICF, prepared by the investigator with the assistance of the sponsor, must be approved 
along with the study protocol by the IRB/IEC and be acceptable to the sponsor. 
The patient must be provided with the patient information and ICF consistent with the study 
protocol version used and approved by the relevant IRB/IEC. The ICF must be in a language 
fully comprehensible to the prospective patient. Patients (and/or relatives, guardians, or 
legally authorized representatives [where acceptable according to national law and/or local 
regulations], if necessary) 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 concerned. Both the patient and the person who explains the study and ICF to the 
patient will sign and date the ICF. A copy of the signed ICF will be retained by the patient 
and the original will be filed in the investigator file unless otherwise agreed. 
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research. The investigator or authorized designee will 
explain to each study patient the objectives of the exploratory research. Patients will be told 
that they are free to refuse to participate and may withdraw their consent at any time and for 
any reason during the storage period. A separate signature will be required to document a 
patient's agreement to allow any remaining specimens to be used for exploratory research. 
Patients who decline to participate in this optional research will not provide this separate 
signature. 
10.3 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, not names 
or, in some regions, initials) according to country regulations should be recorded on any form 
submitted to the sponsor and the IRB/IEC. The investigator must record all screened and 
enrolled patients in the eCRF. The investigator must maintain a list where the identity of all 
study participants can be found, but not intended for use by the sponsor. 


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The investigator further agrees to take all reasonable precautions to prevent the disclosure of 
confidential patient information to any unauthorized party or into the public domain. The 
investigator will notify Clovis Oncology (ithelpdesk@clovisoncology.com) within 24 hours 
of a security event that impacts or has the potential to impact the confidentiality, integrity, or 
availability of patient study data. 
10.4 Study Monitoring 
On behalf of the sponsor, a contract research organization (CRO) or contract monitor will 
contact or visit the investigator at the study center prior to the entry of the first patient (unless 
the sponsor or the CRO has worked with the center recently in the same or comparable 
indication, the site location and facilities have not changed significantly, and the potential 
investigator/site are in good standing with respect to previous regulatory compliance, in 
which case this initial visit maybe waived) and at appropriate intervals during the study until 
after the last patient is completed.  
In accordance with ICH GCP and local regulations, the clinical monitor will periodically 
review, via direct access, eCRFs, study documents, and medical records (office, clinic, or 
hospital) for patients enrolled in this study. Monitors will not share patient identifiers with 
the sponsor. Additionally, the clinical monitor will review and assess research facilities and 
clinical laboratory facilities associated with the study. Clinical monitoring will be scheduled 
to occur at mutually convenient times until completion of the study. If these requirements are 
in conflict with local regulatory restrictions or institutional requirements, the investigator 
must inform the sponsor of these restrictions before initiation of the study. 
Where applicable, if the sponsor or their representatives are not able to come to the study 
center, patient study data may be reviewed by them remotely, in conformity with the 
applicable institutional guidance and local regulations. The site staff may place relevant 
medical records, with personal identifiers removed, into a secure computer system for the 
sponsor or their representative to view, allow them to view these records during a video 
conference, and/or provide them direct access to patients’ electronic medical records. This 
review would occur in a manner that protects the confidentiality of study patient data. 
Whether a patient’s medical records are reviewed at the study center or remotely, their 
identity and medical records will be kept secure during this process. Remote review of 
patient study data should not be carried out if adequate data protection, including data 
security and protection of personal data even if pseudonymized, is not ensured. Further 
details will be provided in the study training materials and/or the clinical monitoring plan. 
The investigator must ensure provision of sufficient time, reasonable space, and adequate 
qualified personnel for the monitoring visits. The purpose of these visits is to allow the 
clinical monitor an opportunity to verify adherence to the study protocol and assess the 
completeness, consistency, and accuracy of data entered on the eCRFs and other documents; 
however, the investigator retains ultimate responsibility for the quality and integrity of data 
generated by the site. The clinical monitor will confirm all aspects of the study that are 
essential for human patient protection and safety as well as those related to the validity and 
reliability of study data. 


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The investigator will make all source data (ie, the various study records, the eCRFs, 
laboratory test reports, other patient records, drug accountability forms, and other pertinent 
data) available for the monitor and allow access to them throughout the entire study period. 
Monitoring is done by comparing study patients’ relevant source data that are maintained in 
site records with the information entered on the eCRF (ie, source data verification). It is the 
monitor’s responsibility to verify the adherence to the study protocol and the completeness, 
consistency, and accuracy of the data recorded on the eCRFs; however, the investigator 
retains ultimate responsibility for the quality and integrity of data generated by the site.  
By agreeing to participate in the study, the investigator agrees to cooperate with the monitor 
to ensure that any problems detected in the course of the monitoring visits are resolved. 
Contact information for the study monitor is located in the investigator file. Representatives 
from the sponsor may also contact and visit the investigators and monitor data during the 
study. 
10.5 Case Report Forms and Study Data 
Upon approval of Protocol Amendment 2, collection of data in eCRFs is no longer 
required as the study database will be locked.  
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 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 and handwritten 
initials of all individuals delegated responsibility on this study. This “study site personnel and 
delegation list” must be kept current throughout the study. 
Clinical data (including AEs, concomitant medications, and expected adverse reactions 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. 
This also applies to records for those patients who fail to complete the study. If a patient 
withdraws from the study, the reason must be noted in the eCRF. If a patient is withdrawn 
from the study because of a treatment-limiting AE, thorough efforts should 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 and input into applicable eCRFs. 


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Full information regarding EDC and completing eCRFs is included in the investigator files. 
All questions or comments related to EDC should be directed to the assigned monitor. 
Clinical data will be entered directly from the source documents.  
10.6 Study Termination and Site Closure 
The sponsor, the investigator/institution, or IRB/IEC 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. 
The sponsor reserves the right to discontinue 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 the study treatment. 
 
If the study 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).  
10.7 Modification of the Study Protocol 
Protocol modifications (ie, 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 IRB/IEC 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 for approval and keep the 
investigator(s) updated as detailed in the ICH GCP guidelines. Protocol deviations are 
described in Section 10.9.1. 
10.8 Retention of Study Documents 
The study site will maintain a study file, which should contain all documents defined in the 
ICH E6(R2) Guideline for Good Clinical Practice. The investigator should have control of all 
essential documents generated by the site. Source documents must be maintained, ALCOA+ 
documentation practice used. Any changes to source data should be traceable, should not 


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obscure the original entry, and should 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 ICFs, copies of all eCRFs, query responses, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities and the sponsor or its designees. 
The investigator shall retain records and documents, including signed ICFs, pertaining to the 
conduct of the study for a period of 25 years after study completion; or, if no application is to 
be filed or if the application is not approved for such indication, until at least 10 years after 
the investigation is discontinued and FDA is notified. No data should be destroyed without 
the agreement of the sponsor. Copies of original documents should fulfill the requirements 
for certified copies. Should the investigator wish to assign the study records to another party 
or move them to another location, the sponsor must be notified in writing of the new 
responsible person and/or the new location. The sponsor will inform the investigator, in 
writing, when the study-related records are no longer needed. 
All clinical study information should 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. 
10.9 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. 
Patient protection and safety and the reliability of study results are major areas of focus for 
the procedures.  
10.9.1 
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 patient having to be withdrawn from the 
study which could potentially render that patient nonevaluable. Any deviation must be 
documented in the source documents and reported to the sponsor.  
10.9.2 
Study Site Training and Ongoing Monitoring 
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 


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aspects of this study. This 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. 
10.9.3 
Quality Assurance Audits 
An audit visit to clinical centers may be conducted by an auditor appointed by the sponsor. 
The purpose of an audit, which is independent of and separate from routine monitoring or 
quality control functions, is to evaluate study conduct and compliance with the protocol, 
SOPs, ICH GCPs, and the applicable regulatory requirements.  
10.9.4 
Direct Access to Source Data/Documents for Audits and Inspections 
Each investigator site is to maintain a record of locations of essential documents and study 
source documents. Members of the sponsor’s GCP Quality Assurance Department or 
designees may conduct an audit of a clinical site at any time during or after completion of the 
study. The investigator will be informed if an audit is to take place and advised as to the 
scope of the audit. Inspections and audits are typically carried out during the clinical and 
reporting phases of this study to ensure that the study is conducted, and data are generated, 
documented, and reported in compliance with the protocol, GCP, written SOPs and 
applicable laws, rules, and regulations. 
Representatives of the FDA, European Medicines Agency, or other regulatory agencies, as 
well as IRB representatives may also conduct an inspection of the study. If informed of such 
an inspection, the investigator should notify the sponsor immediately. 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 
are available, if requested.  
10.10 Clinical Study Report 
A CSR will be prepared and provided to regulatory agency(ies), regardless of whether the 
study is completed, 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 CSR will be provided to the regulatory agency(ies) as required by the 
applicable regulatory requirements.  
10.11 Publication and Disclosure Policy 
The investigator agrees that all information received from the sponsor or designee, including, 
but not limited to, the IB, this protocol, eCRFs, the protocol-specified treatment, and any 
other study information, 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 


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law) without prior written consent from the sponsor. The investigator further agrees to take 
all reasonable precautions to prevent the disclosure of this information by any employee or 
agent of the study center to any third party or 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 these 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]).40 Written permission to the investigator will be 
contingent on the review of the statistical analysis and manuscript/abstract by the sponsor 
and participating cooperative groups, and will provide for nondisclosure of the confidential 
or proprietary information. In all cases, the parties agree to provide all manuscripts or 
abstracts to all other parties 60 days prior to submission. This will enable all parties to protect 
proprietary information and to provide comments based on information that may not yet be 
available to other parties.  
10.12 Investigator Oversight 
The investigator has a responsibility for supervising any individual or party to whom they 
delegate study-related duties and functions conducted at the study site. This includes the 
services of any party or individual retained by the investigator for this purpose. All staff 
delegated study responsibilities must be documented on a 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-related duties, 
functions performed, and any data generated.  


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29. Clovis Oncology UK Ltd. RUBRACA (rucaparib) SmPC May 2018. Available from: 
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41. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
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12 APPENDICES 
Appendix 1 
Modified Response Evaluation Criteria In Solid Tumors 
v1.1 and Prostate Cancer Working Group 3 Criteria 
The RECIST guidelines (Version 1.1) are described in Eisenhauer et al. 200941 and at 
http://www.eortc.be/Recist/Default.htm. and PCWG3 criteria as described by Scher, et al. 
201642 
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 [LD] 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 (LD < 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 according to mRECIST criteria.  


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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. 
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. Target lesions should be selected on the basis of their size (lesions with the LD) and 
their suitability for accurate repeated measurements (either by imaging techniques or 
clinically). A sum of the 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.  
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. 
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 positron emission tomography (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, 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 and normalization of tumor marker 
level. 
Stable 
Disease/Incomplete 
Response 
Persistence of 1 or more nontarget lesion(s) or/and maintenance of tumor 
marker level above the normal limits. 
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. 
If tumor markers are initially above the institutional ULN, they must normalize for a patient 
to be considered a complete responder.  
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements 
recorded since the treatment started). The patient’s best response assignment will depend on 
the achievement of both measurement and confirmation criteria. 


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Evaluation of Best Overall Response: Patients with Target (± Non-Target) Disease 
 
Target Lesions 
Nontarget Lesions 
New Lesionsa 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not evaluated 
No 
PR 
SD 
Non-PD or not evaluated 
No 
SD 
Not Evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
a 
New bone metastatic lesions should not be considered as a ‘Yes’ response; only new extra-skeletal 
lesions. 
 
Evaluation of Best Overall Response: Patients with Non-Target Disease Only 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PDa 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
a 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used 
as endpoint for assessment of efﬁcacy in some 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. 
 
 


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Confirmation 
If an initial CR or PR is noted, confirmatory scans must be performed at least 4 weeks later. 
Duration of Response 
Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are met for 
CR or PR (whichever is first recorded) until the first date that recurrent or PD is objectively 
documented (taking as reference for PD the smallest measurements recorded since the 
treatment started), including progression in bone per PCWG3 criteria. 
The duration of overall CR is measured from the time measurement criteria are first met for 
CR until the first date that recurrent disease is objectively documented. 
Duration of Stable Disease 
SD is measured from the start of the treatment until the criteria for progression are met, 
taking as reference the smallest measurements recorded since the treatment started. 
PCWG3 Criteria for Assessment of Bone Disease  
PCWG3 criteria will be used to document evidence of disease progression in bone lesions as 
described by Scher, et al. 201642 
Imaging of Baseline Bone Disease 
The use of bone scan as the standard for bone imaging is retained in PCWG3, with the 
presence or absence of metastasis recorded first. A quantitative measure of disease burden, 
such as lesion number, the bone scan index, or lesion area, is also suggested, recognizing that 
these measures require further analytical and prospective clinical validation. Changes in 
lesions considered metastatic on bone scintigraphy should be followed and assessed serially 
using a bone scan assessment form. Areas/lesions on bone scintigraphy that are suggestive 
can be assessed further with CT or MRI and followed separately, but such supplemental 
imaging should not be used to establish indicator lesions for the purposes of a study. 
Different modalities for imaging bone metastases can provide different information for the 
same patient. However, because of the lack of standards for reporting disease presence or 
changes after treatment, PET imaging with sodium fluoride, fluorodeoxyglucose, choline, or 
prostate-specific membrane antigen, bone marrow MRI (body MRI), and other modalities 
that are in use to image bone, should be approached as new biomarkers subject to 
independent validation. 
Criteria for progression in bone at study entry 
• Two new lesions observed on 99mTc-methylene diphosphonate radionuclide bone 
scintigraphy 


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• 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 
• At least two new lesions on first post-treatment scan, with at least two additional lesions 
on the next scan (2 + 2 rule) 
• If at least two additional new lesions are seen on the next (confirmatory) scan, the date of 
progression is the date of the first post-treatment scan, when the first two new lesions 
were documented 
• For scans after the first post-treatment scan, at least two new lesions relative to the first 
post-treatment scan confirmed on a subsequent scan 
• Date of progression is the date of the scan that first documents the second lesion 
• Changes in intensity of uptake alone do not constitute either progression or regression 
 


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Clinical Study Protocol: CO-338-107 Amendment 2 
 
19 January 2022 
 
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Appendix 1, Figure A: Controlling for Flare by Applying the 2+2 Rule using the 
First Post-treatment Scan as Baseline 
 
 


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Clinical Study Protocol: CO-338-107 Amendment 2 
 
19 January 2022 
 
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PCWG3 Criteria For Confirmation of Radiographic Progression in Bone by Investigator 
Assessment (to be used in conjunction with mRECIST v1.1 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 compared to 
Week 9 on bone scan obtained at least 
6 weeks after progression identified (or at 
Week 17 assessment) 
Week 17  
(2nd on-treatment 
scan) 
Two or more new lesions on 
bone scan compared to 
Week 9 bone scan. 
Persistent or increase in number of bone 
lesions compared to Week 17 assessment on 
bone scan obtained at least 6 weeks after 
progression identified (or at Week 25 
assessment) 
Week 25 and after  
(3rd on-treatment 
scan and after) 
Two or more new lesions 
bone scan compared to 
Week 9 bone scan 
Persistent or increase in number of bone 
lesions compared to prior assessment on 
bone scan obtained at least 6 weeks after 
progression identified (or at next scheduled 
assessment) 
 
 
 


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Clinical Study Protocol: CO-338-107 Amendment 2 
 
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Appendix 2 
Eastern Cooperative Oncology Group (ECOG) 
Performance Status Scale 
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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19 January 2022 
 
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Appendix 3 
Example Sensitive Clinical CYP Substrates (not an 
inclusive list) 
Examples of Sensitive Clinical CYP Substrate Drugsa 
Enzyme or 
Transporter 
Sensitive Substrate Drugs  
CYP1A2 
Tizanidine, theophylline, alosetron, caffeine, duloxetine, melatonin, 
ramelteon, tasimelteon 
CYP2C9 
Celecoxib 
CYP2C19 
S-mephenytoin, omeprazole  
CYP3A 
Alfentanil, sirolimus, tacrolimus, avanafil, buspirone, conivaptan, 
darifenacin, darunavir, ebastine, everolimus, ibrutinib, lomitapide, 
lovastatin, midazolam, naloxegol, nisoldipine, saquinavir, simvastatin, 
tipranavir, triazolam, vardenafil, budesonide, dasatinib, dronedarone, 
eletriptan, eplerenone, felodipine, indinavir, lurasidone, maraviroc, 
quetiapine, sildenafil, ticagrelor, tolvaptan 
Source: FDA Guidance on Clinical Drug Interaction Studies — Cytochrome P450 Enzyme- and Transporter-
mediated Drug Interactions, January 2020.43  
a 
This table is prepared to provide examples of clinical sensitive or moderate sensitive index substrates 
and is not intended to be an exhaustive list.  
 
 


[Rucaparib (CO-338)] 
 
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Clinical Study Protocol: CO-338-107 Amendment 2 
 
19 January 2022 
 
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Appendix 4 
Example Inhibitors and Inducers of CYP2C8 and 
CYP3A4 (not an inclusive list) 
CYP 
Enzyme 
Strong Inhibitor 
(Prohibited) 
Moderate Inhibitor 
(Use with Caution) 
CYP2C8 
clopidogrel 
gemfibrozil 
deferasirox 
teriflunomide 
CYP3A 
boceprevir 
clarithromycin 
cobicistat 
conivaptan 
danoprevir and ritonavir 
diltiazem 
grapefruit juicea 
idelalisib 
indinavir and ritonavir 
itraconazole 
ketoconazole 
lopinavir and ritonavir 
paritaprevir and ritonavir and (ombitasvir 
and/or dasabuvir) 
nefazodone 
nelfinavir 
posaconazole 
ritonavir 
saquinavir and ritonavir 
telaprevir 
tipranavir and ritonavir 
troleandomycin 
voriconazole 
aprepitant 
cimetidine 
ciprofloxacin 
clotrimazole 
crizotinib  
cyclosporine 
dronedarone 
erythromycin 
fluconazole 
erythromycin 
imatinib 
tofisopam 
verapamil 
CYP 
Enzyme 
Strong Inducer (Contraindicated) 
Moderate Inducer (Contraindicated) 
CYP3A 
carbamazepine 
mitotane 
phenytoin 
rifampin 
St. John’s Wort 
bosentan 
efavirenz 
etravirine 
modafinil 
Source: FDA Guidance on Clinical Drug Interaction Studies — Cytochrome P450 Enzyme- and Transporter-
mediated Drug Interactions, January 2020.43  
a 
The effects of grapefruit juice vary widely among brands, thus can be classified as both a strong and 
moderate inhibitor depending on concentration, quantity consumed, and preparation. Patients should be 
advised to avoid. 
 

SAP_001.pdf: 
ClinicalTrials.gov Official Title: Study of Oral Rucaparib with 
Other Anticancer Agents in Metastatic Castration Resistant 
Prostate Cancer Patients (RAMP) 
 
ClinicalTrials.gov Identifier Number: NCT04179396 
 
Document Date: 2 September 2021 
 
Document: Statistical Analysis Plan (SAP) for Study CO-338-107 
 
Study Title: RAMP: A Phase 1b, Open-label, Parallel Arm Study 
to Assess the Safety, Tolerability, Pharmacokinetics, and 
Preliminary Efficacy of Oral Rucaparib in Combination with 
Other  
 


 
STATISTICAL ANALYSIS PLAN 
RAMP: A Phase 1b, Open-label, Parallel Arm Study to Assess the Safety, 
Tolerability, Pharmacokinetics, and Preliminary Efficacy of Oral Rucaparib in 
Combination with Other Anticancer Agents in Patients with Metastatic 
Castration-Resistant Prostate Cancer 
 
 
 
 
PROTOCOL NUMBER: 
 CO-338-107 
VERSION: 
 1.0 
DATE FINAL: 
  02 September 2021  
SPONSOR: 
 Clovis Oncology, Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
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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APPROVAL PAGE
 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ...........................................................................................................3 
ABBREVIATIONS AND SPECIALIST TERMS ....................................................................5 
1 
INTRODUCTION .............................................................................................................7 
2 
OVERALL STUDY DESIGN, OBJECTIVES, AND ENDPOINTS ...............................7 
2.1 
Study Design ............................................................................................................7 
2.2 
Study Schema...........................................................................................................7 
2.3 
Study Objectives and Endpoints ..............................................................................9 
2.4 
Sample Size Justification .........................................................................................9 
3 
GENERAL ANALYSIS CONVENTIONS .......................................................................9 
3.1 
Analysis Populations ..............................................................................................10 
4 
PATIENT DISPOSITION ...............................................................................................10 
5 
PROTOCOL DEVIATIONS ...........................................................................................10 
6 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ......................................10 
6.1 
Demographics ........................................................................................................10 
6.2 
Baseline Clinical Characteristics ...........................................................................11 
6.3 
Medical History .....................................................................................................11 
7 
DOSE-LIMITING TOXICITIES.....................................................................................11 
8 
STUDY DRUG EXPOSURE AND COMPLIANCE .....................................................12 
9 
PRIOR AND CONCOMITANT MEDICATIONS .........................................................12 
10 EFFICACY ANALYSIS .................................................................................................12 
11 EXPLORATORY ANALYSIS .......................................................................................13 
12 PHARMACOKINETIC ANALYSIS ..............................................................................13 
13 SAFETY ANALYSIS ......................................................................................................13 
13.1 
Adverse Events ......................................................................................................13 
13.2 
Clinical Laboratory Evaluations ............................................................................14 
13.3 
Vital Signs ..............................................................................................................14 
14 STATISTICAL / ANALYTICAL ISSUES .....................................................................15 
14.1 
Handling of Dropouts or Missing Data ..................................................................15 
14.2 
Pooling of Centers in Multi-Center Studies ...........................................................15 
14.3 
Multiple Comparison / Multiplicity .......................................................................15 
14.4 
Examination of Subgroups .....................................................................................15 
14.5 
Interim Analyses and Data Monitoring..................................................................15 
14.6 
Analysis Included on ClinicalTrials.gov................................................................15 
15 REFERENCES ................................................................................................................16 
16 APPENDICES .................................................................................................................17 
 
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LIST OF TABLES 
Table 1 
Primary, Secondary, and Exploratory Objectives and Endpoints ................9 
 
LIST OF FIGURES 
Figure 1 
Study Schema...............................................................................................8 
 
LIST OF APPENDICES 
Appendix 1 
Modified Response Evaluation Criteria In Solid Tumors v1.1 and 
Prostate Cancer Working Group 3 Criteria ................................................17 
 
 
 
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ABBREVIATIONS AND SPECIALIST TERMS 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AR 
androgen receptor 
AST 
aspartate aminotransferase 
BRCA1 
breast cancer gene 1 
BRCA2 
breast cancer gene 2 
BRCA1/2 
breast cancer gene 1 or 2 
Clovis Oncology, Inc. 
Clovis Oncology 
Cmin 
minimum concentration 
CR 
complete response 
CRM 
cohort review meeting 
CRPC 
castration-resistant prostate cancer 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating cell-free tumor DNA 
DDI 
drug-drug interaction 
DLT 
dose-limiting toxicity 
ECOG 
Eastern Cooperative Oncology Group 
GCSF 
granulocyte colony-stimulating factor 
HRR 
homologous recombination repair 
IV 
intravenous 
LD 
longest diameter 
mCRPC 
metastatic castration-resistant prostate cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
NCI 
National Cancer Institute 
NE 
not evaluable 
ORR 
objective response rate 
PCWG3 
Prostate Cancer Working Group 3 
PD 
progressive disease 
PET 
positron emission tomography 
PK 
pharmacokinetics 
PR 
partial response 
PSA 
prostate-specific antigen 
PT 
Preferred Term 
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RECIST 
Response Evaluation Criteria in Solid Tumors 
SAP  
statistical analysis plan 
SD 
stable disease 
SI 
International System of Units 
SOC 
System Organ Class 
StD 
standard deviation 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
US 
United States 
v 
version 
vs 
versus 
WHO 
World Health Organization 
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1 
INTRODUCTION 
This SAP describes the statistical analyses and data summaries to be performed to assess the 
safety, efficacy, and PK of rucaparib (CO-338) for Clovis Oncology sponsored clinical study 
CO-338-107, entitled “RAMP: A Phase 1b, Open-label, Parallel Arm Study to Assess the 
Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of Oral Rucaparib in 
Combination with Other Anticancer Agents in Patients with Metastatic Castration-Resistant 
Prostate Cancer.”  
2 
OVERALL STUDY DESIGN, OBJECTIVES, AND ENDPOINTS 
2.1 
Study Design 
The most recent version of the protocol (Amendment 1, dated 14 December 2020) indicates 
that this is a Phase 1b, open-label study with multiple treatment arms evaluating the PK, 
safety, tolerability, and preliminary efficacy of rucaparib in combination with androgen 
receptor (AR)-directed therapy (enzalutamide [Arm A] and abiraterone [Arm B]) in patients 
with mCRPC. Each arm consists of an initial PK, safety and tolerability assessment. Once 
completed, additional patients were to be evaluated to better characterize the PK, 
safety/tolerability and preliminary efficacy of the combination in an expansion phase.  
This study consists of a Screening Phase, a 1-week run-in period, a PK/DLT assessment 
phase, a Treatment Extension Phase (if applicable), and a Post-treatment Phase. Subjects start 
with a 1-week run-in period with rucaparib alone, followed by continuous 28-day treatment 
cycles of rucaparib and enzalutamide in combination. The PK/DLT assessment period in 
Arm A is across Cycles 1 and 2. 
Prior to enrollment of patients, the decision was made to prioritize Arm A and not enroll into 
Arm B, so this SAP will only address Arm A. Furthermore, as this is an uncontrolled study 
not designed to establish efficacy, an abbreviated CSR will be provided to summarize results 
from Arm A. 
2.2 
Study Schema 
The study schema in Figure 1 summarizes the treatment design of the study. 
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Figure 1 
Study Schema 
 
Abbreviations: AR = androgen receptor; BID = twice a day; CRPC = castration-resistant prostate cancer; DLT = dose-limiting toxicity; ECOG PS = Eastern 
Cooperative Oncology Group performance status; LHRH = luteinizing hormone–releasing hormone; mCRPC = metastatic castration-resistant prostate cancer; 
PK = pharmacokinetic; QD = once a day. 
a 
Rucaparib dose may be reduced to < 600 mg BID if more than one patient experiences a DLT. If rucaparib exposure is lower than expected with 
co-administration of enzalutamide, rucaparib dose may be increased proportional to the decrease in exposure, to a maximum of 1,000 mg BID. 
b 
Rucaparib dose will be escalated from 400 mg BID to 600 mg BID, with a possible de-escalation to 500 mg BID. The dose of rucaparib may also be 
increased if there is unexpected lower exposure with coadministration of abiraterone, similar to the approach described for Arm A  
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2.3 
Study Objectives and Endpoints 
Table 1 
Primary, Secondary, and Exploratory Objectives and Endpoints 
Primary Objectives 
Primary Endpoints 
To evaluate the PK, safety and tolerability of 
rucaparib in combination with enzalutamide 
for mCRPC.  
• Minimum concentration (Cmin) of 
rucaparib and its metabolite M324.  
• Safe and tolerable dose of rucaparib in 
combination with enzalutamide for 
mCRPC  
Secondary Objectives 
Secondary Endpoints 
To evaluate the preliminary efficacy of 
rucaparib with enzalutamide  
• Best overall response as assessed by 
investigator summarized by ORR (as 
measured by mRECIST v1.1/ PCWG3 
criteria; Appendix 1) at the optimal 
combination dose in each arm.  
• Change from baseline PSA levels  
Exploratory Objectives 
Exploratory Endpoints 
To evaluate the PK of enzalutamide in 
combination with rucaparib.  
Cmin of enzalutamide (and metabolites 
N-desmethyl enzalutamide)  
To assess the relationship between genomic 
alterations detected in tissue or blood with 
clinical outcomes to treatment  
Association between genomic alterations 
and ORR and PSA responses  
To assess the relationship between changes in 
circulating tumor DNA (ctDNA) profiles over 
time and clinical outcomes to treatment 
Changes in genomic alterations as 
assessed by ctDNA over time  
 
2.4 
Sample Size Justification 
The total enrollment planned for the PK/DLT portion of the study was between 6 and 
18 patients for Arm A (rucaparib & enzalutamide combination) to allow evaluation of PK 
and safety parameters.  
3 
GENERAL ANALYSIS CONVENTIONS 
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, 
StD, median, minimum, and maximum. Categorical variables will be presented using 
frequencies and percentages.  
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Baseline is defined as the last measurement on or prior to the first dose of rucaparib 
administration, unless otherwise specified.  
PK analysis will be conducted using R (version 1.2.5033 or above). All other statistical 
analyses will be conducted with the SAS® System, Version 9.4 or higher.  
3.1 
Analysis Populations 
The following analysis populations are defined for the study: 
PK-evaluable Population: The PK Population will consist of all patients who received at 
least 1 dose of either rucaparib or enzalumatide and had at least 1 measurable concentration. 
Safety Population – The Safety Population will include all patients who received at least 
1 dose of rucaparib or 1 dose of enzalutamide. 
DLT-evaluable Population: – The DLT-evaluable Population will consist of all patients 
who completed at least 70% of the scheduled doses of both rucaparib and enzalutamide and 
completed Cycles 1 and 2 of treatment, or who experienced a DLT in Cycles 1 or 2. 
Efficacy Population: The Efficacy Population will consist of all patients evaluable for 
response by mRECIST/ PCWG3 criteria, or for PSA response, and could be subdivided into 
the RECIST-evaluable Efficacy Population and the PSA-evaluable Efficacy Population. 
4 
PATIENT DISPOSITION 
Patient disposition will be summarized using frequency counts and the corresponding 
percentages. The number of patients in each analysis population, number of patients 
discontinued, and the primary reason for treatment discontinuation will be summarized. 
5 
PROTOCOL DEVIATIONS 
The number of patients with major protocol deviations (eg, inclusion or exclusion criteria) 
will be determined prior to data base lock and will be summarized with frequencies and 
percentages or provided in a patient listing. 
Protocol deviations will not be used to exclude any patients from the efficacy analyses. 
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 but not be limited to the 
following variables: 
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• Age (years): ≤ 50, 51-60, 61-70, 71-80, 81-90, > 90; 
• Race: American Indian or Alaska Native, Asian, Black, Native Hawaiian or Pacific 
Islander, White, Other, Not Reported; 
• Ethnicity: Hispanic, Not Hispanic;  
• Height (cm): ≤ 75, > 75-100, > 100-125, > 125-150, > 150-175, > 175; 
• Weight (kg): ≤ 50, > 50-75, > 75-100, > 100-125, > 125-150, > 150; 
• BMI (kg/m2); 
• Baseline ECOG performance status score: 0, 1 
 
6.2 
Baseline Clinical Characteristics 
The following variables will be summarized:  
• Time since diagnosis of primary tumor (months): 0 to 12, 13 to 24, > 24; 
• Number of prior lines of AR-directed therapy in a CRPC setting; 
• Number of prior lines of chemotherapy in a mCRPC setting; 
• Deleterious mutations in BRCA1/2 or other HRR genes; 
• Status (germline or somatic) of mutation in BRCA1/2 or other HRR gene  
 
Frequency tabulations and descriptive statistics will be presented as appropriate. Other 
baseline characteristic variables of interest may also be summarized if deemed appropriate. 
6.3 
Medical History 
Medical history events will be classified using the MedDRA classification system version 
20.1 or more recent. Medical history data will be listed. 
7 
DOSE-LIMITING TOXICITIES 
A patient listing of all DLTs will be provided for the patients in the DLT-evaluable 
Population. A DLT is defined at any of the following events occurring in Cycle 1 or 2, 
according to CTCAE v5.0: 
• Grade 3 or greater febrile neutropenia (ie, fever > 38.3°C with ANC < 1.0 × 109/L) of any 
duration or Grade 4 neutropenia lasting more than 7 days despite GCSF administration 
• Grade 3 thrombocytopenia (platelets < 50 × 109/L) with significant bleeding or Grade 4 
thrombocytopenia (platelets < 25 × 109/L) ≥ 5 days duration;  
• Grade 4 anemia (ie, life-threatening consequences; urgent intervention indicated); 
• Any nonhematological AE ≥ Grade 3, with the exception of:  
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- 
Nausea, vomiting, and diarrhea well controlled by systemic medication and with 
duration ≤ 72 hours;  
- 
Fatigue; 
- 
Grade 3 ALT or AST not accompanied by concomitant increase in total bilirubin 
above the ULN. Note: any Grade 4 ALT/AST is a DLT;  
- 
Grade 3 arthralgia treated with non-steroidal anti-inflammatory drug(s) (or 
equivalent) that resolves to ≤ Grade 2 within 14 days  
- 
Alopecia of any grade. 
 
8 
STUDY DRUG EXPOSURE AND COMPLIANCE 
The following variables will be summarized: 
• Duration of treatment (days, months) 
• Number of dose reductions 
• Number of treatment interruptions 
 
Duration of treatment will be calculated as 1+ the number of days from study drug start date 
to date of study drug discontinuation. It will also be converted to months (#days/30.4375) 
and presented. Descriptive statistics and frequencies/percentages for appropriate 
categorizations will be used to summarize study drug exposure variables. 
9 
PRIOR AND CONCOMITANT MEDICATIONS 
All concomitant treatments documented during the study period will be listed. 
Prior/concomitant medication coding will utilize WHO Drug version WHODrug Global B3 
202003 or more recent. 
A separate data listing 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 concomitant 
medications listing. 
10  EFFICACY ANALYSIS 
Efficacy analyses will be performed using the Efficacy Population. 
Response to treatment according to mRECIST/ PCWG3 and best overall response as 
assessed by the investigator will be listed. 
PSA response will be listed and presented in a spider plot. 
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11  EXPLORATORY ANALYSIS 
Exploratory analyses will not be included. 
12 PHARMACOKINETIC ANALYSIS 
The PK analysis will be performed on the PK-evaluable Population. 
Rucaparib and M324 concentrations, as well as M324/rucaparib concentration ratio vs time 
profiles will be plotted for each patient. Effect of enzalutamide on rucaparib and/or M324 PK 
will be evaluated by comparing the trough PK data and the M324/rucaparib concentration 
ratio during the 7-day run-in period and the trough PK data in combination with 
enzalutamide. A drug-drug interaction (DDI) due to CYP3A4 induction by enzalutamide can 
be suggested if there is a decrease in rucaparib PK, and/or an increase in M324 PK or an 
increase in the M324/rucaparib concentration ratio. Mean PK plots may be provided if there 
are limited dose modifications.  
Due to the limited data (ie, trough concentrations only, dose modifications), formal 
noncompartmental PK analysis is not planned. 
13 SAFETY ANALYSIS 
The safety analyses will be performed using the Safety Population. Tabulated AEs will at a 
minimum be presented as ‘Rucaparib Only’ (first 7 days on study) or ‘Rucaparib and 
Enzalutamide’. 
13.1  Adverse Events 
AEs will be classified using the MedDRA classification system. The severity of the toxicities 
will be graded according to the NCI-CTCAE v5.0 or higher whenever possible. 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. AEs will be considered treatment-
emergent if all or part of the date of onset of the AE is missing and it cannot be determined if 
the AE meets the definition for treatment-emergent. 
The number and percentage of patients who experienced TEAEs for each SOC and PT will 
be presented. Multiple instances of the TEAE in each SOC and multiple occurrences of the 
same PT are counted only once per patient. The number and percentage of patients with at 
least 1 TEAE will also be summarized.   
The incidence of TEAEs will also 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 
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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.    
Separate tables including but not limited to the following, will be presented: 
• All TEAEs; 
• TEAEs by CTCAE grade; 
• Grade 3 or greater TEAEs; 
• Treatment-related TEAEs will be included in the following 3 categories of relatedness: 
related to rucaparib, related to enzalutamide, and related to either study drug. Relatedness 
will be analyzed overall and by categories: CTCAE grade, Grade 3 or greater, resulting in 
dose reduction, resulting in treatment interruption, resulting in treatment discontinuation, 
outcome of death; 
• Serious TEAEs, overall and by categories: age, sex, and treatment-relatedness (as defined 
above); 
• TEAEs with an outcome of death; 
• TEAEs leading to discontinuation of study medication of either study drug; 
• TEAEs resulting in interruption of study medication of either study drug; and 
• TEAEs resulting in reduction, delay, or interruption of study medication of either study 
drug. 
 
Non-TEAEs (pre-treatment and post-treatment) will be presented in the by-patient data 
listings for the safety population.  
13.2  Clinical Laboratory Evaluations 
Clinical laboratory evaluations include the continuous variables for hematology, serum 
chemistry, and urinalysis. The laboratory values will generally be presented in International 
System (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.   
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. 
Additional listings will be presented as listing. 
13.3  Vital Signs 
Vital signs, including change from baseline calculations, will be listed.  
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14 STATISTICAL / ANALYTICAL ISSUES 
14.1  Handling of Dropouts or Missing Data 
All data will be used to their maximum possible extent, but without any imputations for 
missing data.  
14.2  Pooling of Centers in Multi-Center Studies 
All centers will be pooled for analysis. 
14.3  Multiple Comparison / Multiplicity 
No statistical comparisons will be performed. 
14.4  Examination of Subgroups 
Analyses of primary, secondary, and exploratory endpoints may be analyzed by baseline 
demographics and clinical characteristics listed in Section 6.1and Section 6.2 or for other 
subgroups of interest as appropriate. 
14.5  Interim Analyses and Data Monitoring 
No formal interim analysis occurred. Cohort Review Meetings (CRMs) were held throughout 
the study, and appropriate safety and PK analyses were provided prior to the meetings as 
applicable. Data were monitored and reviewed on an ongoing basis by the sponsor and 
investigators.  
14.6 Analysis Included on ClinicalTrials.gov 
Because enrollment was halted early with fewer than 20 subjects enrolled, only the primary 
endpoint will be included in ClinicalTrials.gov analyses.  
 
 
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15 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). 
European journal of 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. 
 
 
 
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16 APPENDICES 
Appendix 1 
Modified Response Evaluation Criteria In Solid Tumors 
v1.1 and Prostate Cancer Working Group 3 Criteria 
The RECIST guidelines (Version 1.1) are described in Eisenhauer et al. 20091 and at 
http://www.eortc.be/Recist/Default.htm. and PCWG3 criteria as described by Scher, et al. 
20162 
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 [LD] 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 t 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 (LD < 10 mm or pathological 
lymph nodes with t 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 according to mRECIST criteria.  
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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. 
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. Target lesions should be selected on the basis of their size (lesions with the LD) and 
their suitability for accurate repeated measurements (either by imaging techniques or 
clinically). A sum of the 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.  
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. 
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 positron emission tomography (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, 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 and normalization of tumor 
marker level. 
Stable 
Disease/Incomplete 
Response 
Persistence of 1 or more nontarget lesion(s) or/and maintenance of 
tumor marker level above the normal limits. 
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. 
If tumor markers are initially above the institutional ULN, they must normalize for a patient 
to be considered a complete responder.  
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements 
recorded since the treatment started). The patient’s best response assignment will depend on 
the achievement of both measurement and confirmation criteria. 
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Evaluation of Best Overall Response: Patients with Target (± Non-Target) Disease 
 
Target Lesions 
Nontarget Lesions 
New Lesionsa 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not 
evaluated 
No 
PR 
SD 
Non-PD or not 
evaluated 
No 
SD 
Not Evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
a 
New bone metastatic lesions should not be considered as a ‘Yes’ response; only new extra-skeletal 
lesions. 
 
Evaluation of Best Overall Response: Patients with Non-Target Disease Only 
Nontarget Lesions 
New Lesions 
Overall 
Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PDa 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
a 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used 
as endpoint for assessment of efﬁcacy in some 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 
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lesion be investigated (fine-needle aspiration/biopsy) prior to confirming the complete 
response status. 
Confirmation 
If an initial CR or PR is noted, confirmatory scans must be performed at least 4 weeks later. 
Duration of Response 
Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are met for 
CR or PR (whichever is first recorded) until the first date that recurrent or PD is objectively 
documented (taking as reference for PD the smallest measurements recorded since the 
treatment started), including progression in bone per PCWG3 criteria. 
The duration of overall CR is measured from the time measurement criteria are first met for 
CR until the first date that recurrent disease is objectively documented. 
Duration of Stable Disease 
SD is measured from the start of the treatment until the criteria for progression are met, 
taking as reference the smallest measurements recorded since the treatment started. 
PCWG3 Criteria for Assessment of Bone Disease  
PCWG3 criteria will be used to document evidence of disease progression in bone lesions as 
described by Scher, et al. 20162 
Imaging of Baseline Bone Disease 
The use of bone scan as the standard for bone imaging is retained in PCWG3, with the 
presence or absence of metastasis recorded first. A quantitative measure of disease burden, 
such as lesion number, the bone scan index, or lesion area, is also suggested, recognizing that 
these measures require further analytical and prospective clinical validation. Changes in 
lesions considered metastatic on bone scintigraphy should be followed and assessed serially 
using a bone scan assessment form. Areas/lesions on bone scintigraphy that are suggestive 
can be assessed further with CT or MRI and followed separately, but such supplemental 
imaging should not be used to establish indicator lesions for the purposes of a study. 
Different modalities for imaging bone metastases can provide different information for the 
same patient. However, because of the lack of standards for reporting disease presence or 
changes after treatment, PET imaging with sodium fluoride, fluorodeoxyglucose, choline, or 
prostate-specific membrane antigen, bone marrow MRI (body MRI), and other modalities 
that are in use to image bone, should be approached as new biomarkers subject to 
independent validation. 
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Criteria for progression in bone at study entry 
• Two new lesions observed on 99mTc-methylene diphosphonate 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 
• At least two new lesions on first post-treatment scan, with at least two additional lesions 
on the next scan (2 + 2 rule) 
• If at least two additional new lesions are seen on the next (confirmatory) scan, the date of 
progression is the date of the first post-treatment scan, when the first two new lesions 
were documented 
• For scans after the first post-treatment scan, at least two new lesions relative to the first 
post-treatment scan confirmed on a subsequent scan 
• Date of progression is the date of the scan that first documents the second lesion 
• Changes in intensity of uptake alone do not constitute either progression or regression 
 
 
 
 
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