A Phase 3, Randomized, Open-Label, Controlled Study of Cabozantinib (XL184) in Combination With Atezolizumab vs Second Novel Hormonal Therapy (NHT) in Subjects With Metastatic Castration-Resistant Prostate Cancer
Phase: PHASE3
Conditions: Metastatic Prostate Cancer, Prostate Adenocarcinoma
Sponsor: Exelixis

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CLINICAL STUDY PROTOCOL
A Phase 3, Randomized, Open-Label, Controlled Study of 
Cabozantinib (XL184) in Combination with 
Atezolizumab vs Second Novel Hormonal Therapy (NHT)
in Subjects with Metastatic Castration-Resistant Prostate
Cancer 
PROTOCOL NUMBER:
XL184-315
STUDY TREATMENT:
Cabozantinib (XL184) in Combination with Atezolizumab vs 
Second NHT
IND NUMBER:
144,735
EudraCT NUMBER:
2020-000348-77
SPONSOR:
Exelixis, Inc.
1851 Harbor Bay Parkway 
Alameda, CA 94502
MEDICAL MONITOR:
DATE FINAL (Version 0.0): 
20 December 2019
DATE AMENDED:
24 April 2020     PROTOCOL AMENDMENT 1.0
13 May 2021      PROTOCOL AMENDMENT 2.0
02 June 2022     PROTOCOL AMENDMENT 3.0
10 Nov 2022     PROTOCOL AMENDMENT 4.0
24 Jan 2023       PROTOCOL AMENDMENT 5.0
NCT # NCT04446117
PPD

PPD
PPD
PPD
PPD

XL184-315 Protocol Amendment 5.0
Page 3 of 232
PROTOCOL ACCEPTANCE FORM
PROTOCOL TITLE:
A Phase 3, Randomized, Open-Label, Controlled Study of 
Cabozantinib (XL184) in Combination with Atezolizumab vs Second 
Novel Hormonal Therapy (NHT) in Subjects with Metastatic 
Castration-Resistant Prostate Cancer  
PROTOCOL NUMBER:
XL184-315
STUDY TREATMENT:
Cabozantinib (XL184) in Combination with Atezolizumab vs Second 
Novel Hormonal Therapy 
IND NUMBER:
144,735
EudraCT NUMBER:
2020-000348-77
SPONSOR:
Exelixis, Inc.
1851 Harbor Bay Parkway 
Alameda, CA 94502
MEDICAL MONITOR:
DATE FINAL (Version 0.0):
20 December 2019
DATE AMENDED:
24 April 2020    PROTOCOL AMENDMENT 1.0
13 May 2021      PROTOCOL AMENDMENT 2.0
02 June 2022      PROTOCOL AMENDMENT 3.0
10 Nov 2022     PROTOCOL AMENDMENT 4.0
24 Jan 2023      PROTOCOL AMENDMENT 5.0
By my signature below, I hereby state that I have read, and agree to abide by, the instructions, 
conditions, and restrictions of the protocol or protocol amendment referenced above. 
________________________________________________________________ 
Name of Investigator (print)
________________________________________________________________ 
Name of Investigator (signature) 
 
 
 
 
 
Date
PPD

 
XL184-315 Protocol Amendment 5.0 
Page 4 of 232 
PROTOCOL SYNOPSIS 
TITLE 
A Phase 3, Randomized, Open-Label, Controlled Study of Cabozantinib (XL184) in Combination 
with Atezolizumab vs Second Novel Hormonal Therapy (NHT) in Subjects with Metastatic 
Castration-Resistant Prostate Cancer  
PROTOCOL NUMBER 
XL184-315 
CLINICAL PHASE 
Phase 3 
RATIONALE  
In 2018, prostate cancer was the fourth most commonly diagnosed malignancy worldwide behind 
cancers of the lung, breast, and colorectum (GLOBOCAN 2018). Incident prostate cancer was 
reported in 1.3 million men and accounted for 7.1% of all new cancer diagnoses that year. It is the 
most common cancer among men worldwide and the second leading cause of cancer deaths in the 
US (Bashir 2015), where its incidence in 2018 exceeded that of cancers of the bladder, kidney, 
and testis combined (NIH NCI SEER 2018). 
There are multiple histologic types of prostate cancer, but adenocarcinoma accounts for the vast 
majority of cases. Prostate adenocarcinoma typically is associated with elevation in the serum 
prostate-specific antigen (PSA) and often responds to testosterone-lowering (castration) and other 
hormonal manipulations targeting signaling through the androgen receptor (AR) axis.  
Prostate adenocarcinoma is radiographically localized at diagnosis in the majority of cases where 
PSA testing is widely implemented. Approximately two-thirds of men with radiographically 
localized disease are cured with definitive localized therapy (radical prostatectomy or 
radiotherapy), but the remainder will experience recurrence heralded by a rising PSA, local 
radiographic occurrence, and/or metastases. Androgen deprivation therapy (ADT) is the mainstay 
of treatment for advanced or metastatic prostate cancer due to the androgen dependency of this 
disease. A rising PSA without radiographically evident metastases despite initiation of ADT 
castration signifies a non-metastatic castration-resistant state (non-metastatic castration-resistant 
prostate cancer [M0 CRPC]). De novo metastatic disease (metastatic castration-sensitive prostate 
cancer [mCSPC]) accounts for 3-7% of new cases of prostate cancer in developed nations and its 
incidence in the US may be rising due to recent declines in population-based PSA surveillance 
(Weiner et al 2016). Furthermore, de novo metastatic disease is commonly diagnosed in countries 
where PSA testing is not part of standard clinical practice. M0 CRPC and mCSPC are the primary 
pathways to metastatic castration-resistant prostate cancer (mCRPC), which all subjects enrolling 
in this Phase 3 study are required to have. 
Systemic treatment alternatives for patients with mCRPC now include chemotherapy, 
immunotherapy, androgen signaling pathway receptor inhibitors, radionuclide therapy, and PARP 
inhibitors (Tannock et al 2004, de Bono et al 2010, de Bono et al 2011, Kantoff et al 2010, Parker 

 
XL184-315 Protocol Amendment 5.0 
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et al 2013, Ryan et al 2015, Scher et al 2012, Beer et al 2014, Beer et al 2017, de Bono et al 2020, 
Abida et al 2020; Sartor et al 2021).  
ADT has historically been used to treat mCSPC preceded by radiographically localized disease. 
However, docetaxel/prednisone and NHTs, including abiraterone, apalutamide, and enzalutamide 
have been shown to improve outcomes when combined with ADT initiation (Sweeney et al 2015, 
Kyriakopolous et al 2018, James et al 2016, Fizazi et al 2017, Fizazi et al [Lancet Oncol] 2019, 
Armstrong et al 2019, Chi et al 2019). 
For M0 CRPC patients, three AR antagonists (apalutamide, enzalutamide, and darolutamide) 
have demonstrated improvements in metastasis-free survival (MFS) and overall survival (OS) 
compared with placebo in men with a PSA doubling time less than 10 months (Smith et al 2018, 
Hussain et al 2018, Fizazi et al [NEJM] 2019, Sternberg et al 2020, Fizazi et al 2020, Smith et al 
2021).  
Potentially linked to the recent introduction of new treatments earlier in disease, the incidence of 
visceral metastases in men with mCRPC may be increasing and is associated with a particularly 
poor prognosis, particularly in the setting of liver disease (Nafissi et al 2019, Iwamoto et al 2018, 
Pezaro et al 2014, Whitney et al 2017).  
Standard-of-care therapies used for patients with visceral disease include taxane-based 
chemotherapy and NHTs (NCCN [Prostate Cancer v2.2019] 2019). However, none of these 
treatments is likely curative, and, upon progression, many patients with mCRPC will likely have 
already been treated with an NHT either as their first treatment for mCRPC or earlier disease 
(mCSPC or M0 CRPC), respectively.  
Cabozantinib (XL184) is a potent, orally bioavailable inhibitor of multiple receptor tyrosine 
kinases (RTKs) known to play important roles in tumor cell proliferation and/or tumor 
neovascularization, including the vascular endothelial growth factor receptor (VEGFR2), MET, 
RET, and KIT. Somatic KIT mutations have been associated with aggressive forms of prostate 
cancer (Martinez-Gonzalez et al 2018). Increased expression of MET, HGF (the ligand for MET), 
and VEGF have been observed in prostate carcinomas and are associated with poorer prognosis 
(Knudsen et al 2002, Zhang et al 2010, Humphrey et al 2006, Bok et al 2001, George et al 2001). 
Cabozantinib targets also include TYRO3, AXL, and MER (TAM family kinases) and are 
implicated in promoting suppression of an antitumor immune response.  
Cabozantinib tablets (60 mg) are approved in the United States, Europe, and other regions for 
advanced renal cell carcinoma (RCC; different patient populations depending on region; 
Cabometyx® US Prescribing Information [PI] and European Medicines Agency [EMA] 
Summary of Product Characteristics [SmPC]). Cabozantinib tablets have also been approved in 
the US and other regions for the treatment of hepatocellular carcinoma (HCC) in patients who 
have previously been treated with sorafenib and in the US for the treatment of adult and pediatric 
patients 12 years of age and older with locally advanced or metastatic differentiated thyroid 
cancer (DTC) that has progressed following prior VEGFR-targeted therapy and who are 
radioactive iodine-refractory or ineligible (HCC: 60 mg; DTC: 40 mg [in pediatric patients 
≥ 12 years with body surface area (BSA) < 1.2 m2] and 60 mg [in adult and pediatric patients 
≥ 12 years with BSA ≥ 1.2 m2]; Cabometyx US PI and EMA SmPC). The EU has also approved 
cabozantinib for similar use in adults but not in pediatric patients. Cabozantinib tablets (40 mg) 
are also approved for advanced RCC as a first-line treatment in combination with nivolumab. 

 
XL184-315 Protocol Amendment 5.0 
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Cabozantinib capsules (140 mg) are approved in the United States for the treatment of patients 
with progressive, metastatic medullary thyroid cancer (MTC) and in the European Union for the 
treatment of patients with progressive, unresectable locally advanced or metastatic MTC 
(Cometriq® US PI and EMA SmPC). The capsule and tablet formulations are not bioequivalent 
or interchangeable.  
COMET-1 was a randomized, double-blind, controlled Phase 3 study of cabozantinib 
(60 mg orally [po] once daily [qd]) vs prednisone (5 mg po twice a day [bid]) in 1028 men with 
bone-metastatic CRPC who had previously been treated with docetaxel and at least one NHT 
(abiraterone acetate [“abiraterone”] with prednisone, and/or enzalutamide; Smith et al 2016). This 
trial enrolled subjects in third- or later-line mCRPC where no therapy has yet proved efficacious. 
Cabozantinib did not demonstrate a statistically significantly improvement in the primary 
endpoint, OS, although there was a positive trend. Median radiographic progression-free survival 
(PFS) per Investigator (including bone scan progression) was improved in the cabozantinib group 
(5.6 vs 2.8 months; hazard ratio [HR] 0.48 [95% confidence interval {CI}: 0.40, 0.57; stratified 
logrank p-value < 0.0001]), and improvements were also observed in circulating tumor cell 
(CTC) conversion (which has been associated with OS; Scher et al 2012), bone biomarkers, and 
time to symptomatic skeletal event (SSE) incidence. Notably, OS and PFS (based on 
computerized tomography [CT]/ magnetic resonance imaging [MRI] with or without bone scan 
assessments) benefits among those who received cabozantinib were observed in a post hoc 
subgroup analysis of those with visceral disease, which suggests a potential role for cabozantinib 
in the treatment of such mCRPC. 
Immune checkpoint inhibitor (ICI) monotherapy with the PD-1 inhibitor, pembrolizumab; the 
PD-L1 inhibitor, atezolizumab; and the CTLA-4 inhibitor, ipilimumab; as well as the 
combination of the PD-1 inhibitor, nivolumab, with ipilimumab have been studied in mCRPC. 
Prostate cancer is often a slow-growing tumor that may allow enough time for ICI therapy to 
activate the immune system with higher percentages of regulatory T-cells (Tregs) being found in 
higher stages of prostate cancer and tumor-infiltrating cytotoxic lymphocytes expressing high 
levels of PD-1 (an indicator of T-cell exhaustion), among other observations (Schepisi et al 2017, 
Ebelt et al 2009, Sfanos et al 2009). However, the limited data available from ICI monotherapy 
trials in patients with mCRPC suggest that single-agent immunotherapy may only benefit a 
modest subset of patients with mCPRC (Kim et al 2018, Kwon et al 2014, Sharma et al 2019).  
Preclinical studies (Kwilas et al 2014, Lu et al 2017, Wang et al 2019) and clinical observations 
on circulating immune suppressive cells and immune effector cells in cancer patients (Apolo et al 
2014) suggest that cabozantinib promotes an immune-permissive environment, which might lead 
to synergistic effects from combination treatment with ICIs, independent of PD-L1 expression.  
COSMIC-021 is an ongoing Phase 1b study that evaluates the efficacy of cabozantinib in 
combination with atezolizumab in multiple tumor types including subjects with metastatic CRPC 
without small-cell features who have radiographically progressed in soft tissue on or after NHT 
(enzalutamide and/or abiraterone) initiated for treatment of metastatic disease. Subjects are 
required to have measurable soft tissue (visceral or adenopathic) disease per Response Evaluation 
Criteria in Solid Tumors version 1.1 (RECIST 1.1). Prior treatment with docetaxel is only 
permitted when given in combination with ADT for metastatic castration-sensitive prostate 
cancer prior to treatment with NHT. Subjects receive cabozantinib 40 mg po qd and atezolizumab 
1200 mg intravenously [IV] every 3 weeks [q3W]. As of 21 October 2019, 61 CRPC subjects had 

 
XL184-315 Protocol Amendment 5.0 
Page 7 of 232 
been enrolled in this study and 44 of these subjects with at least 12 weeks of follow-up were 
evaluable for response. Fourteen of the 44 evaluable subjects (31.8%) had a confirmed tumor 
response per RECIST 1.1 by Investigator assessment, including 2 subjects with a complete 
response and 12 with partial response. Disease control rate was 80%. An additional subject, not 
included as responder above, with initial PD per RECIST 1.1 exhibited a durable irPR per 
irRECIST criteria. An objective tumor response rate was also observed (33%) in 36 patients with 
features of disease associated with poor prognosis: measurable visceral disease and/or measurable 
extrapelvic lymph node metastasis. The observed clinical activity of the combination therapy in 
COSMIC-021 is especially encouraging given the more limited single-agent activity of either 
cabozantinib or atezolizumab in subjects with metastatic CRPC and is suggestive of cooperative 
effects of these agents (Schoffski et al 2017, Kim et al 2018). For further information on 
COSMIC-021, refer to the current cabozantinib Investigator’s Brochure. 
There is a significant unmet medical need for treatment options for men with mCRPC who have 
previously received an NHT for mCRPC and/or earlier lines of disease (mCSPC, M0 CRPC) and 
who have measurable visceral disease or measurable extrapelvic adenopathy. Based on the 
encouraging data from Cohort 6 of Study XL184-021 (COSMIC-021), this Phase 3 study will 
evaluate the safety and efficacy of cabozantinib in combination with atezolizumab versus a 
second NHT in subjects with such mCRPC. This study is particularly suited to men with a good 
performance status who wish to avoid chemotherapy or to men deemed unable to tolerate side 
effects from chemotherapy.  
OBJECTIVES and ENDPOINTS 
The primary objective of this study is to evaluate the efficacy of cabozantinib in combination 
with atezolizumab versus second NHT (abiraterone or enzalutamide) in subjects with mCRPC 
who have previously received one and only one NHT (eg, abiraterone, apalutamide, 
darolutamide, or enzalutamide) to treat mCSPC, M0 CRPC, and/or mCRPC, and who have 
measurable visceral disease or measurable extrapelvic adenopathy.  
The multiple-primary efficacy endpoints comparing the experimental and control arms are: 
• 
Duration of PFS per RECIST 1.1 with radiographic assessments by Blinded Independent 
Radiology Committee (BIRC)  
• 
Duration of OS 
The secondary efficacy endpoint is:  
• 
ORR per RECIST 1.1 per BIRC  
Additional endpoints are:  
• 
PSA response rate 
• 
Duration of radiographic response per RECIST 1.1 (per Investigator and BIRC) 
• 
Duration of PFS as determined per Prostate Cancer Working Group 3 (PCWG3) criteria 
(Scher et al 2016) by BIRC 
• 
Time to PSA progression 
• 
Time to SSE 

 
XL184-315 Protocol Amendment 5.0 
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• 
Time to pain progression 
• 
Time to chemotherapy 
• 
Health care resource utilization 
• 
Change in mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, and 
global health as assessed by the EuroQol Health questionnaire EQ-5D-5L and European 
Organization for Research and Treatment of Cancer (EORTC) questionnaire QLQ-C30 
• 
Safety as assessed through the evaluation of adverse events (AEs), including immune-related 
adverse events (irAEs)  
• 
Pharmacokinetics (PK) of cabozantinib given in combination with atezolizumab 
• 
Immunogenicity of atezolizumab given in combination with cabozantinib 
• 
Correlation of immune cell, tumor cell, and plasma biomarker analyses with clinical 
outcomes 
STUDY DESIGN 
This is a Phase 3, multicenter, randomized, parallel group, open-label, controlled trial of the 
combination of cabozantinib (40 mg po qd) with atezolizumab (1200 mg IV q3W) versus second 
NHT (abiraterone or enzalutamide) in subjects with mCRPC (adenocarcinoma) who previously 
received one and only one NHT (eg, abiraterone, apalutamide, darolutamide, or enzalutamide) to 
treat mCSPC, M0 CRPC, and/or mCRPC and whose disease biochemically (PSA progression) or 
radiographically progressed on that NHT. PFS and OS are the multiple-primary endpoints. The 
primary analysis of PFS per RECIST 1.1 will be based upon radiographic assessments by BIRC. 
Approximately 580 eligible subjects who have mCRPC with measurable visceral metastasis or 
measurable extrapelvic lymphadenopathy, and whose disease is deemed to be worsening based on 
PSA or radiographic soft tissue progression in the opinion of the Investigator, will be randomized 
at approximately 280 sites in this trial. 
The sample size may be increased up to an additional 25% if a review of the accumulating data 
suggests that the COVID-19 pandemic has caused the rate of study dropout or non-compliance to 
increase to a degree that the ability to adequately evaluate study endpoints may be undermined.   
Special accommodations during the global COVID-19 pandemic are described in Appendix N. 
Each subject’s course of trial participation will consist of the following periods: 
Pre-Treatment Period:  
Potential subjects will be screened to determine whether they meet the required eligibility criteria. 
Qualifying screening assessments must be performed within 21 days before randomization unless 
otherwise specified. If there is a change in clinical status after screening and prior to 
randomization, these assessments are to be repeated as clinically indicated. Prior to 
randomization, the Investigator will designate in the interactive response technology (IRT) 
system the NHT (abiraterone, apalutamide, darolutamide, or enzalutamide) the patient previously 
received and progressed on. If eligible and randomized to the control group (second NHT), the 
IRT system will then dispense enzalutamide if the prior NHT was abiraterone; abiraterone if the 

 
XL184-315 Protocol Amendment 5.0 
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prior NHT was enzalutamide; and Investigator’s choice of abiraterone or enzalutamide if the prior 
NHT was apalutamide or darolutamide.  
Treatment Period: Subjects who meet all study eligibility criteria will be randomly assigned in a 
1:1 fashion to receive cabozantinib plus atezolizumab or second NHT, respectively. Based on 
treatment assignment, subjects will begin treatment on one of the following regimens: 
Experimental Arm (290 subjects): 
Cabozantinib (40 mg po qd) + atezolizumab (1200 mg IV q3w)  
Control Arm (290 subjects): 
Abiraterone (1000 mg po qd) + prednisone (5 mg po bid), OR enzalutamide (160 mg po qd) 
Randomization will be stratified by the following factors: 
• 
Liver metastasis (yes/no) 
• 
Prior docetaxel for locally advanced or metastatic castration-sensitive prostate cancer 
(yes/no) 
• 
Response is “no” if subject previously had M0 CRPC  
• 
First NHT given for mCRPC vs M0 CRPC vs metastatic castration-sensitive prostate 
cancer. Note: For subjects who have received the same NHT for both mCRPC and 
either mCSPC (including locally advanced M0 CSPC) or M0 CRPC, subjects should 
be stratified by the disease state for which they received their first NHT even if they 
did not progress on it then. 
Subjects may receive study treatment, even after protocol-defined progression, until they are no 
longer clinically benefitting in the opinion of the Investigator, unless they 1) need subsequent 
systemic anticancer treatment or urgent tumor-directed alternative medical intervention (eg, to 
central nervous system [CNS] metastases), 2) experience unacceptable toxicity, or 3) have any 
other reason for treatment discontinuation as listed in the protocol. In the absence of such, 
continued treatment after radiographic progression may occur in subjects who meet both of the 
following criteria: 
• 
Clinical benefit per Investigator judgment 
• 
ECOG performance status 0 or 1 
Crossover among treatment arms will not be allowed.  
Post-Treatment Period:  
A first Post-Treatment Follow-up Visit (FU-1) for safety assessment is to occur at least 30 (+14) 
days after the date of the decision to permanently discontinue study treatment (defined as the later 
of the date of the decision to permanently discontinue study treatment or the date of the last dose 
of study treatment). A second follow-up visit (FU-2) for safety evaluation will be conducted 
approximately 100 days (±14 days) after the date of the decision to permanently discontinue 
study treatment. Radiographic tumor, PSA, health-related quality of life (HRQOL), and pain 
assessments are to continue, regardless of whether study treatment is given, reduced, held or 

 
XL184-315 Protocol Amendment 5.0 
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discontinued until a criterion for ending radiographic assessments is met (defined below in Tumor 
Assessments). Consequently, these assessments may be required in the Post-Treatment Period for 
some subjects.  
In addition, subjects are to be contacted every 8 weeks (± 7 days) after FU-2 to assess survival 
status and document receipt of nonprotocol anticancer therapy (NPACT). This will continue until 
the subject expires or the Sponsor decides to discontinue collection of these data in the study. 
Every effort must be made to collect these protocol-specified evaluations unless consent to 
provide these data is withdrawn.  
Study Completion:  
The study will be considered complete if the null hypothesis is rejected for the primary endpoint 
of OS in any of the planned interim analyses or if the final planned analysis for OS has been 
conducted (irrespective of the results).  
Maintenance Phase/Treatment after Study Completion: 
The purpose of the Maintenance Phase is to continue to provide long-term access to study drug(s) 
to subjects who are deriving clinical benefit even after the study objectives have been completed 
(Study Completion, see above). When sufficient data have been collected to adequately evaluate 
all study endpoints, the Sponsor may initiate a Maintenance Phase. Upon initiation of the 
Maintenance Phase, the Sponsor considers the safety and efficacy profile of the experimental 
treatment regimen within this study to have been sufficiently established, and data analyses 
required for regulatory purposes to have been completed. The Sponsor is to notify the sites if or 
when the study will enter the Maintenance Phase or if an alternative post-Study Completion 
option will be implemented.  
In the Maintenance Phase, subjects on study treatment will continue to receive the study 
treatment(s) to which they were randomized until they meet a protocol-defined criterion for 
treatment discontinuation. Subjects in the Maintenance Phase are to undergo periodic safety 
assessments (including local laboratory tests, ECGs, symptom-directed physical examination and 
vital signs) and tumor assessments every 12 weeks (or more frequently as clinically indicated) for 
as long as they are in this phase.  
In order to continue to collect important safety information for subjects enrolled in the study 
during the Maintenance Phase, reporting of serious adverse events (SAEs), certain AEs (including 
AEs of special interest [AESIs, Table 8-1; whether serious or not] and AEs leading to dose 
modifications or treatment discontinuation), and other reportable events (pregnancy and 
medication errors with sequelae) is to continue per protocol requirements specific to the 
Maintenance Phase. 
End of Trial: 
End of trial is defined as the last scheduled visit or scheduled procedure for the last subject 
(including Maintenance Phase assessments).  
NUMBER OF SUBJECTS 
Approximately 580 subjects will be randomized in a 1:1 fashion to the cabozantinib and 
atezolizumab combination (290) and second NHT (290) treatment arms, respectively, at 

 
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approximately 280 global sites. The sample size may be increased up to an additional 25% if a 
review of the accumulating data suggests that the COVID-19 pandemic has caused the rate of 
study dropout or non-compliance to increase to a degree that the ability to adequately evaluate 
study endpoints may be undermined. 
TARGET POPULATION 
To be eligible for the study the subject must meet all inclusion criteria and no exclusion criteria. 
The Sponsor will not grant exceptions to these eligibility criteria.  
Inclusion Criteria: 
1. Men with histologically or cytologically confirmed adenocarcinoma of the prostate. 
Note: Neuroendocrine differentiation and other histological features are permitted if 
adenocarcinoma is the primary histology.  
2. Subjects must have had a rising PSA or radiographically progressed on their prior treatment 
with one, and only one, NHT (eg, abiraterone, apalutamide, darolutamide, or enzalutamide) 
for castration-sensitive locally advanced (T3 or T4) or metastatic castration-sensitive prostate 
cancer, M0 CRPC, and/or mCRPC.  
Note: Subjects may have previously received taxane-based chemotherapy for locally 
advanced or metastatic castration-sensitive prostate cancer but no other approved or 
experimental nonhormonal systemic therapies for mCRPC.  
3. Bilateral orchiectomy or ongoing ADT with a gonadotropin-releasing hormone (GnRH) 
agonist/antagonist (surgical or medical castration), with serum testosterone ≤ 50 ng/dL 
(≤ 1.73 nmol/L) at screening. 
4. Measurable (extrapelvic soft tissue) metastatic disease per Investigator assessment as defined 
by at least one of the following: 
a. Measurable visceral (eg, adrenal, kidney, liver, lung, pancreas, spleen) disease per 
RECIST 1.1, OR 
b. Measurable extrapelvic adenopathy (ie, adenopathy above the aortic bifurcation).  
5. Progressive disease at study entry as defined by at least one of the following two criteria: 
a. Prostate specific antigen (PSA) progression defined by a minimum of 2 rising PSA 
values from 3 or 4 most recent consecutive assessments with an interval of at least 7 days 
between assessments.  
Note: If qualifying solely by PSA progression, the screening PSA value must be at least 
2 ng/mL (2 μg/L), and the oldest qualifying value must have been based on a blood 
sample drawn no longer than one year prior to signing of the informed consent form 
(ICF); up to one PSA decrease is permitted as long as it is not the most recent value. If 
the study lab is the local lab at which the subject’s previous PSA blood samples were 
drawn, then the screening local lab PSA must be the highest, OR 
b. Soft tissue disease progression (PD) in the opinion of the Investigator. 
Note: Subjects with bone disease progression alone are not eligible.  
6. Age ≥ 18 years old or meeting country definition of adult, whichever is older, on the day of 
consent. 
7. ECOG performance status score of 0 or 1. 

 
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8. Recovery to baseline or ≤ Grade 1 per Common Terminology Criteria for Adverse Events 
(CTCAE) v5 from toxicities related to any prior treatments, unless AE(s) are clinically 
nonsignificant and/or stable on supportive therapy in the opinion of the Investigator.  
9. Adequate organ and marrow function, based upon all of the following laboratory assessments 
from samples obtained within 21 days before randomization: 
a. Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥ 1.5 × 109/L) without granulocyte 
colony-stimulating factor support within 2 weeks before screening laboratory sample 
collection.  
b. Platelets ≥ 100,000/mm3 (≥ 100 × 109/L) without transfusion within 2 weeks before 
screening laboratory sample collection.  
c. Hemoglobin ≥ 9 g/dL (≥ 90 g/L) without transfusion within 1 week before screening 
laboratory sample collection.  
d. Serum bilirubin ≤ 1.5 × upper limit of normal (ULN)  
Note: Subjects with known Gilbert’s disease or unconjugated hyperbilirubinemia who 
have serum bilirubin level ≤ 3 × ULN may be enrolled. 
e. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) both 
≤ 3 × ULN. Subjects with known hepatic metastasis may enroll with serum ALT and 
AST both ≤ 5 × ULN.  
f. Serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance ≥ 40 mL/min using the 
Cockcroft-Gault equation: (140 – age) × weight (kg)/(serum creatinine [mg/dL] × 72).  
g. Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.1 mg/mmol) or 24-hour urine 
protein < 1 g. 
h. Negative hepatitis B surface antigen (HBsAg) test  
i. 
Negative hepatitis C virus (HCV) antibody test, or positive HCV antibody test followed 
by a negative HCV RNA test and no ongoing anti-HCV therapy.  
Note: The HCV RNA test will be performed only for patients who have a positive HCV 
antibody test. 
10. Understanding and ability to comply with the protocol requirements, including scheduled 
visits, treatment plan, laboratory tests, and all other study procedures. Evidence of a signed 
and dated ICF, indicating that the subject has been informed of all pertinent aspects of the 
study, prior to any screening assessments except those procedures performed as standard of 
care within the screening window. 
11. Sexually active fertile subjects and their female partners must agree to use highly effective 
methods of contraception during the course of the study and for 4 months (16 weeks) after the 
last dose of cabozantinib in the experimental arm (cabozantinib + atezolizumab), 3 weeks 
after the last dose of abiraterone (control arm), or 3 months (12 weeks) after the last dose of 
enzalutamide (control arm). A barrier contraceptive method (eg, condom) is also required. In 
addition, men must agree not to donate sperm during these same periods. 
 

 
XL184-315 Protocol Amendment 5.0 
Page 13 of 232 
 
Exclusion Criteria:  
1. Only evidence of metastasis is adenopathy below the aortic bifurcation, non-measurable soft 
tissue (visceral or adenopathic) disease per RECIST 1.1, or bone-only disease. 
2. Any prior systemic nonhormonal therapy initiated for the treatment of mCRPC. 
3. Receipt of abiraterone within 1 week; cyproterone within 10 days; or receipt of flutamide, 
nilutamide, bicalutamide, enzalutamide, or other androgen-receptor inhibitors within 2 weeks 
before randomization.  
Note: Subjects receiving prior enzalutamide, bicalutamide, flutamide, or nilutamide 
monotherapy without ADT at the time of screening are not eligible, unless bilateral 
orchiectomy has already been performed. 
4. Radiation therapy within 4 weeks (2 weeks for bone metastases) prior to randomization. 
Subjects with clinically relevant ongoing complications from prior radiation therapy are not 
eligible.  
5. Known brain metastases (symptomatic or non-symptomatic) or cranial epidural disease 
unless adequately treated with radiotherapy, radiosurgery, or major surgery (eg, removal or 
biopsy of brain metastasis) and clinically stable for at least 4 weeks prior to randomization.  
Note: Subjects who are neurologically symptomatic as a result of their CNS disease or 
receiving systemic corticosteroid treatment for their CNS disease are not eligible. 
6. Symptomatic or impending spinal cord compression or cauda equina syndrome. 
7. Concomitant anticoagulation with oral anticoagulants including, but not limited to, platelet 
inhibitors (eg, clopidogrel or ticagrelor), warfarin, dabigatran, and betrixaban, except for 
those specified below.  
a. Allowed anticoagulants are: 
i. 
Prophylactic use of low-dose aspirin for cardioprotection (per local applicable 
guidelines) and low-dose low molecular weight heparins (LMWH)  
ii. Therapeutic doses of LMWH or the direct factor Xa inhibitors rivaroxaban, 
edoxaban, or apixaban in subjects without known brain metastases who are on a 
stable dose of the anticoagulant for at least 1 week before randomization and without 
clinically significant hemorrhagic complications from the anticoagulation regimen or 
the tumor.  
8. Administration of a live, attenuated vaccine within 30 days prior to randomization. The use of 
inactivated (killed) vaccines for the prevention of infectious disease is permitted. 
9. Systemic treatment with, or any condition requiring, either corticosteroids (> 10 mg daily 
prednisone equivalent) or other immunosuppressive medications within 14 days prior to 
randomization. Subjects with brain metastases requiring systemic corticosteroid at any dose 
are not eligible.  
Note: Prednisone (5 mg po bid) should be used with abiraterone. Inhaled, intranasal, intra-
articular, and topical steroids are permitted. Adrenal replacement steroid doses > 10 mg 
daily prednisone equivalent are permitted in the absence of active autoimmune disease (eg, in 
presence of adrenal metastasis). Transient short-term use of systemic corticosteroids for 
allergic conditions (eg, contrast allergy) is also allowed. 

 
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10. Uncontrolled, significant intercurrent or recent illness that may impede interpretation of 
safety data, including, but not limited to, the following conditions: 
a. Cardiovascular and cardiac disorders: 
i. 
Congestive heart failure (CHF) class III or IV as defined by the New York Heart 
Association, unstable angina pectoris, serious cardiac arrhythmias (eg, ventricular 
flutter, ventricular fibrillation, torsades de pointes) within 6 months before 
randomization. 
ii. Uncontrolled hypertension defined as systolic blood pressure (BP) > 150 mm Hg or 
diastolic BP > 90 mm Hg despite optimal antihypertensive treatment 
iii. Stroke, transient ischemic attack [TIA], myocardial infarction, or other symptomatic 
ischemic event or thromboembolic event (eg, deep venous thrombosis, pulmonary 
embolism [DVT/PE]) within 6 months before randomization.  
Notes:  
Upon Sponsor approval, subjects with a diagnosis of incidental, subsegmental PE or 
DVT within 6 months are allowed if asymptomatic and stable at screening and 
treated with LMWH or the direct factor Xa inhibitors rivaroxaban, edoxaban, or 
apixaban for at least 1 week before randomization.  
Non-symptomatic white matter disease in the brain is acceptable. 
iv. History of additional significant risk factors for torsades de pointes (eg, long QT 
syndrome) 
b. Neuropsychiatric disorder (including active suicidal ideation) likely to interfere with 
ability to give informed consent or comply with protocol requirements.  
c. Gastrointestinal (GI) disorders, including those affecting absorption or associated with a 
high risk of perforation or fistula formation: 
i. 
Tumors invading the GI tract, active peptic ulcer disease, acute pancreatitis, acute 
obstruction of the pancreatic or biliary duct, appendicitis, cholangitis, cholecystitis, 
diverticulitis, gastric outlet obstruction, or inflammatory bowel disease (eg, Crohn’s 
disease, ulcerative colitis)  
ii. Abdominal fistula, bowel obstruction, GI perforation, or intra-abdominal abscess 
within 6 months before randomization  
Note: Subjects with intra-abdominal abscesses are eligible if complete healing has 
been confirmed before randomization. 
d. Hemoptysis of > 0.5 teaspoon (2.5 ml) of red blood, clinically significant hematuria, 
hematemesis, coagulopathy, or other history of significant bleeding (eg, pulmonary 
hemorrhage) within 3 months before randomization. 
e. Known cavitating pulmonary lesion(s) or known endobronchial disease manifestation. 
f. Lesions invading major pulmonary blood vessels. 
g. Other clinically significant disorders, such as: 

 
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i. 
Any active, known or suspected autoimmune disease (see Appendix F for a 
comprehensive list of autoimmune diseases and immune deficiencies). 
Note: Subjects with type I diabetes mellitus, skin disorders (such as vitiligo, 
psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected 
to recur in the absence of an external trigger are permitted to enroll. 
ii. Any active infection requiring systemic treatment.  
Note: Subjects receiving oral (including prophylactic) antibiotics with no symptoms 
of infection at randomization or oral valacyclovir (valaciclovir) are eligible. 
iii. Known human immunodeficiency virus (HIV) or acquired immunodeficiency 
syndrome (AIDS)-related illness.  
Note: HIV testing will be performed at screening if and as required by local 
regulation. 
iv. Active tuberculosis. 
v. Known history of COVID-19 unless the subject has demonstrated recovery from the 
disease at least 30 days prior to randomization. 
vi. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced 
pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening 
chest CT scan 
vii. Serious non-healing wound/ulcer/bone fracture per Investigator judgment.  
viii. Clinically significant malabsorption syndrome per Investigator judgment. 
ix. Pharmacologically uncompensated, symptomatic hypothyroidism. 
Note: Asymptomatic hypothyroidism only requiring hormone replacement is allowed. 
x. Moderate to severe hepatic impairment (Child-Pugh B or C) or known cirrhosis. 
xi. Requirement for hemodialysis or peritoneal dialysis. 
xii. History of solid organ transplantation 
xiii. 
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (once monthly or more frequently) 
-Patients with indwelling cathethers (e.g. PleurX® ) are allowed 
11. Major surgery (eg, prostatectomy, GI surgery, removal or biopsy of brain metastasis) within 
4 weeks prior to randomization. Minor surgeries (eg, fine-needle biopsy) within 10 days prior 
to randomization. Subjects must have complete wound healing from major surgery or minor 
surgery before randomization. Subjects with clinically relevant ongoing complications from 
prior surgery are not eligible. 
12. Corrected QT interval calculated by the Fridericia formula (QTcF) > 480 ms per 
electrocardiogram (ECG) within 21 days before randomization.  
Note: If a single ECG shows a QTcF with an absolute value > 480 ms, two additional ECGs 
at intervals of approximately 3 minutes must be performed within 30 minutes after the initial 
ECG, and the average of the three consecutive results for QTcF must be ≤ 480 ms for the 
subject to be eligible. 
Note: This requirement does not apply if the subject has a permanent cardiac pacemaker in 
place or a history of asymptomatic bundle branch block in the absence of cardiac ischemia.  

 
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13. Inability or unwillingness to swallow tablets or receive IV administration. 
14. Previously identified allergy or hypersensitivity to components of the study treatment 
formulations or history of severe infusion-related reactions to monoclonal antibodies. 
Subjects with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency 
or glucose-galactose malabsorption are also excluded. 
15. Any other active malignancy at time of randomization or diagnosis of another malignancy 
within 2 years prior to randomization that requires active treatment, except for locally curable 
cancers that have been apparently cured, such as basal or squamous cell skin cancer, or 
carcinoma in situ of the breast. 
ESTIMATED LENGTH OF SUBJECT PARTICIPATION 
It is estimated that subjects will participate for an average of 6 months on study treatment. 
Subjects will be followed until death, withdrawal of consent for non-interventional study 
assessments, or Sponsor decision to no longer collect survival data. 
ESTIMATED STUDY DATES  
It is estimated that approximately 24 months will be required to randomize 580 subjects. The 
numbers of events required for the primary analyses of PFS (202 events among the first 
324 randomized subjects) and OS (340 events among all 580 randomized subjects) are expected 
to be observed approximately 21 months and 37 months (final OS analysis), respectively, after 
the first subject is randomized. The true intervals required to meet these milestones may be longer 
or shorter due to divergence from assumptions or due to the impact of the global COVID-19 
pandemic on subject enrollment and other aspects of study conduct. These estimates for the 
timing of event-driven analyses do not include the additional months required for event 
ascertainment, data quality review, data analysis and interpretation. 
STUDY TREATMENT REGIMEN DOSE/ ROUTE/ DURATION 
Subjects in the experimental arm will take oral study medication (40 mg of cabozantinib: 2 tablets 
containing 20 mg each of cabozantinib) qd, and atezolizumab will be administered at a standard 
dosing regimen of 1200 mg as an IV infusion q3w. Two dose reduction levels of cabozantinib 
will be allowed in the experimental arm (20 mg qd and 20 mg every other day [qod]). Dose 
reductions for atezolizumab will not be allowed, but AEs may be managed by dose delays. 
Subjects in the control arm will receive abiraterone 1000 mg po qd with prednisone 5 mg po bid, 
or enzalutamide 160 mg po qd as designated by the Investigator prior to randomization and as per 
local prescribing information. Dose interruptions and reductions will be allowed as per local 
prescribing information. 
Subjects will continue study treatment until they no longer clinically benefit in the opinion of the 
Investigator or until unacceptable toxicity, the need for alternative systemic anticancer treatment, 
or another reason for treatment discontinuation (Section 5.6.6.2).  
EFFICACY ASSESSMENTS 
Subjects will be monitored for radiographic response and progression per RECIST 1.1. 
Determination of the multiple-primary endpoint, PFS, and of the secondary endpoint, ORR, will 

 
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be per radiographic assessments performed by BIRC. The additional endpoint of PFS per 
PCWG3 will be determined by soft tissue progression based on CT/MRI per RECIST 1.1 or bone 
disease progression based on bone scan per PCWG3 and will be assessed by BIRC.  
Subjects will be assessed for survival through the FU-2 visit and every 8 weeks (± 7 days) after 
that.  
TUMOR ASSESSMENTS 
Chest / Abdomen / Pelvis (CAP): CT of CAP or chest CT and abdomen/pelvis MRI will be 
performed in all subjects at screening prior to randomization. Tumor assessments after 
randomization are to be performed every 9 weeks ± 7 days through Week 28 (ie, the first three 
on-study tumor assessments), and then every 12 weeks ± 7 days as per PCWG3 guidelines. 
Additional imaging of potential disease sites should be performed whenever radiographic disease 
progression is suspected. 
Brain: MRI (or CT) of the brain will be performed only if clinically indicated at screening. After 
randomization, MRI (or CT) scans of the brain are only required in subjects with known brain 
metastasis or if clinically indicated following the same post-baseline frequency as the imaging for 
CAP. MRI is the preferred method for brain scans. If CT of the brain is performed instead of 
MRI, ambiguous results must be confirmed by MRI unless contraindicated. Note: For eligibility 
requirements regarding prior treatment of brain metastasis, refer to Section 4.3. 
Bone: Technetium-99m bone scans (TBS) are to be performed at screening for all subjects. 
Evidence of or suspicion for soft tissue masses extending from bone must be corroborated with 
CT at screening. If a screening CT scan shows measurable soft tissue disease extending from 
bone, that soft tissue disease must be followed by on-study CT when CAP imaging (not capturing 
the lesion) is done. After randomization, TBS are to be performed on all subjects on the same 
schedule as for CAP. Subjects who report new symptoms associated with new or worsening bone 
scan lesions must have bone-directed CT performed (unless already captured by routine CT), 
which are to continue on the same schedule as for CAP.  
Subjects who are treated beyond radiographic disease progression will continue to undergo tumor 
assessments at the frequency described above until study treatment is discontinued. 
The same imaging modalities used at screening must be used for subsequent tumor assessments 
after randomization. If there is clinical concern regarding the administration of contrast at 
screening, then a non-contrast CAP imaging study is acceptable as a screening assessment if it 
clearly demonstrates measurable soft tissue disease that can be followed without the need for 
contrast. If, at a follow-up imaging time point, the use of contrast is prohibited (eg, due to 
acquired renal impairment or contrast allergy), then the same modality should be used without 
contrast. 
Tumor assessments should continue on the protocol-defined schedule relative to the date of 
randomization, regardless of whether study treatment is given, reduced, held or discontinued.  
Radiographic response and PD will be determined centrally using RECIST 1.1 (by Investigator 
and BIRC) and PCWG3 guidelines (by BIRC only). Investigators are encouraged to continue 
study treatment and imaging until the subject is no longer clinically benefitting. 

 
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Radiographic tumor assessments are to continue under the following guidelines: 
Subject Status  
Action with Radiographic Assessments 
Study 
Treatment 
Discontinued? 
Investigator-Assessed rPD 
per RECIST 1.1 Reached? 
No 
No 
Continue radiographic assessments 
No 
Yes 
Continue radiographic assessments (ie, 
Investigator-assessed clinical benefit after 
radiographic progression) 
Yes 
No 
Continue radiographic assessments unless 
receipt of new systemic therapy has been 
documented 
Yes 
Yes 
Radiographic assessments discontinued 
rPD, radiographic progressive disease; RECIST 1.1, Response Evaluation Criteria for Solid Tumors 
version 1.1. 
For the purpose of determining radiographic study endpoints, central review of radiographic 
images will be conducted by a BIRC. All radiographic tumor assessments will be promptly sent 
to the BIRC until the primary analysis for the primary endpoint of PFS is completed. The BIRC 
will also review prior radiation history data for the purpose of selection of target lesions. 
PROSTATE-SPECIFIC ANTIGEN ASSESSMENTS 
Serum PSA levels will be assessed in all subjects at screening. Subsequent assessments will occur 
with scheduled imaging. PSA assessments should not be used to make study treatment decisions 
in this study. 
OVERALL SURVIVAL FOLLOW-UP ASSESSMENTS 
Overall survival will be assessed every 8 weeks (± 7 days) after the FU-2 visit. Subjects will be 
followed until death, withdrawal of consent for non-interventional study assessments, or Sponsor 
decision to no longer collect these data. 
SAFETY ASSESSMENTS  
Safety will be assessed on a schedule based on the date of first dose. Routine safety assessments 
will be done at least every 3 weeks (± 3 days). All serious adverse events (SAEs) occurring any 
time after informed consent must be reported to the Sponsor or designee within 24 hours. The 
safety follow-up visit (FU-1) will be performed 30 (+14) days after the date of the decision to 
permanently discontinue study treatment.  
Monitoring will continue for SAEs and AESIs (whether serious or not) through 100 (± 14) days 
after the date of the decision to permanently discontinue study treatment (FU-2 visit). Related 
AEs leading to study treatment discontinuation, AESIs, and related SAEs will continue to be 
followed until resolution (event is fully resolved, ≤ Grade 2 severity, or is deemed stable or 
irreversible by the Investigator). 

 
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Safety assessments include AE review, directed physical examination, vital signs, performance 
status, 12-lead ECG, hematology, serum chemistry, coagulation tests, urine tests (including 
UPCR and components), and thyroid function tests. AE seriousness, severity grade, relationship 
to study treatment, and relationship to immune effects (ie, irAEs) will be assessed by the 
Investigator. Severity grade will be defined by the National Cancer Institute (NCI) CTCAE v5.  
An Independent Data Monitoring Committee (IDMC) will be established to monitor safety of the 
study on a regular basis. The IDMC will operate independently from the Sponsor and the clinical 
investigators. In addition, the Sponsor has an established internal safety governance structure, 
which oversees the monitoring of the safety and benefit-risk profile for all investigational 
products on an ongoing basis across all ongoing company-sponsored clinical studies. 
HEALTH-RELATED QUALITY OF LIFE (HRQoL) 
Health-related quality of life assessments will be performed using the EuroQol Health 
questionnaire EQ-5D-5L and EORTC questionnaire QLQ-C30. Subjects will be requested to 
complete the assessment at baseline (prior to first dose of study treatment on RSV1) and with 
scheduled imaging (prior to image acquisition) thereafter. Subjects will continue completing 
questionnaires regardless of whether study treatment is given, reduced, held, or discontinued until 
the date of the last tumor imaging assessment or study completion. Consequently these 
assessments may be required in the Post-Treatment Period for some subjects. Subjects themselves 
should complete the questionnaire on the day of the visit prior to seeing study site personnel. 
HRQOL assessments will no longer be collected for subjects who transition to the Maintenance 
Phase. 
PAIN ASSESSMENTS 
Assessment of pain will be self-reported by each subject using an 11-point (from 0 to 10) numeric 
rating scale (NRS) measuring worst pain in the last week, with 0 representing “No Pain” and 10 
representing “Pain as Bad as You Can Imagine”.  
Assessments of baseline pain will be performed prior to first dose of study treatment on RSV1, 
and subsequent pain assessments will be performed with scheduled imaging (prior to image 
acquisition). In addition, for analgesics taken for at least seven consecutive days, the Investigator 
will continuously assess new or increased use relative to baseline.  
These assessments are to continue regardless of whether study treatment is given, reduced, held, 
or discontinued until the date of the last tumor imaging assessment or study completion. 
Consequently these assessments may be required in the Post-Treatment Period for some subjects. 
Pain assessments will no longer be collected for subjects who transition to the Maintenance 
Phase. 
SYMPTOMATIC SKELETAL EVENTS 
Symptomatic skeletal events (SSEs) will be continuously assessed from RSV1 through the FU-2 
visit. The definition of an SSE is an instance of any one of the following: radiation therapy to 
bone, surgery to bone, spinal cord compression, or symptomatic fracture. 

 
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HEALTHCARE RESOURCE UTILIZATION 
Healthcare resource utilization parameters will be collected from randomization through the FU-2 
visit. These include hospital admissions, emergency room visits, intensive care unit admissions, 
length of stay, surgeries, and transfusions. These data will not be collected in the Maintenance 
Phase.  
BIOMARKERS 
The schedule of biomarker assessments is specified in Appendix A and Appendix B. The samples 
include: 
• 
Tumor samples (archival or fresh tumor biopsy; recommended but not required)  
o If archival tumor tissue is not available, a fresh tumor biopsy may be obtained prior to first 
dose of study treatment. 
o A fresh tumor tissue biopsy may also be performed at disease progression. 
• 
Peripheral blood 
Exploratory analyses may include but are not limited to the following: 
• 
Targets of the study drugs (eg, PD-L1, MET) and relevant biomarker expression levels  
• 
Tumor characteristics (eg, immune cell infiltration, tumor mutational burden [TMB]) in 
tumor specimens  
• 
Plasma biomarkers (eg, cytokines/chemokines) 
• 
Circulating tumor cells (CTCs) 
• 
Circulating tumor DNA (ctDNA) 
A pharmacogenetic blood sample will be collected predose on the first day of treatment (RSV1) 
and may be used for genotyping/single nucleotide polymorphism/copy number variation analysis 
to correlate genetic variation with the pharmacokinetics, safety, tolerability, and/or response to 
the study drug combination. This sample may also be used for assay development to facilitate 
identification of novel predictive biomarker profiles and improve treatment strategies. 
Collection of biomarker samples may be halted early or sampling frequency may be modified at 
the discretion of the Sponsor. These samples will no longer be collected if the study transitions to 
the Maintenance Phase. 
PHARMACOKINETICS  
Blood samples will be obtained from all subjects in the cabozantinib plus atezolizumab 
combination arm. Samples will be collected for plasma cabozantinib concentration measurement 
predose on RSV1, RSV2, RSV3, RSV4, and RSV5. The results will be used to confirm exposure 
to cabozantinib and to further characterize the population PK and exposure-response relationships 
for cabozantinib taken in combination with atezolizumab in this population.  
Serum concentrations of atezolizumab will be measured in the cabozantinib plus atezolizumab 
combination arm. Samples will be collected for serum atezolizumab concentration measurement 
predose on RSV1, RSV3, RSV5, RSV9, RSV16, RSV19, and FU-1 and FU-2 visits. The results 
will be used to confirm exposure to atezolizumab.  

 
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Collection of PK samples may be halted early or sampling frequency may be modified at the 
discretion of the Sponsor. 
IMMUNOGENICITY ASSESSMENTS 
Blood samples will be obtained from all subjects in the cabozantinib plus atezolizumab 
combination arm for immunogenicity assessment (anti-drug antibodies [ADA]) predose on 
RSV1, RSV3, RSV5, RSV9, RSV16, RSV19, and FU-1 and FU-2 visits. Samples may be 
analyzed for neutralizing ADA response to atezolizumab if ADA testing is positive, as applicable. 
STATISTICAL METHODS 
The multiple primary efficacy analyses in this study are comparisons of duration of PFS per 
RECIST 1.1 per BIRC and duration of OS in subjects treated with cabozantinib in combination 
with atezolizumab (the experimental arm) versus second NHT (the control arm). Treatment with 
cabozantinib in combination with atezolizumab will be inferred to be superior to treatment with 
second NHT if the null hypothesis of no difference between arms is rejected for either OS or PFS 
in favor of the combination arm. Inflation of Type 1 error associated with multiple primary 
endpoints and a single secondary efficacy endpoint will be controlled by a closed testing 
procedure that employs modified Bonferroni, gatekeeping, and fallback methods. The study-wise 
2-sided alpha of 0.05 will be nominally divided between multiple primary endpoints PFS (0.002) 
and OS (0.048) with alpha allocations passed from significant endpoints to those to be tested next 
per the pre-specified testing strategy. 
For the primary analyses, PFS is defined as time from randomization to PD per RECIST 1.1 as 
determined by the BIRC or death from any cause and OS is defined as time from randomization 
to death due to any cause.  
PFS and OS will be summarized descriptively using the Kaplan-Meier method. Inferential 
comparisons between treatment arms will use the stratified log-rank test. The HR will be 
estimated using a stratified Cox proportional hazards model. Stratification will be based on the 
stratification factors used for randomization.  
The study is designed to provide adequate power for both PFS and OS endpoints. Compared with 
OS, a smaller sample size is needed to provide reasonable power for PFS. As a result, the number 
of events necessary to trigger the primary analysis of PFS could be reached before the study is 
fully accrued, and PFS events could be biased toward shorter progression times were PFS 
evaluated in the larger sample size required for OS. Thus, to reduce bias toward shorter 
progression times, this study employs a “trial within a trial” design (Hessel et al 2016) to allow 
longer, more robust PFS follow-up among fewer subjects than the total required for OS. Futility 
and interim analyses of PFS are not planned. 
For PFS, a total of 202 events in the first 324 subjects randomized in the combination and second 
NHT control arms provide the study with 90% power for a 2-sided log-rank test with a 0.002 
level of significance to detect a hypothesized true HR of 0.54. Assuming an exponential 
distribution of PFS, this corresponds to an 85% increase in median PFS from 4 months to 
7.4 months. In the current design, the minimum observed effect that would result in statistical 
significance for PFS is a HR of 0.65, a 55% improvement in median PFS from 4 to 6.2 months. 
For OS, a total of 340 deaths among all 580 subjects randomized in the combination and second 

 
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NHT arms are required to provide 90% power to detect an HR of 0.70 using the log-rank test and 
a 2-sided significance level of 0.048. Assuming an exponential distribution for OS, this 
corresponds to a 43% increase in median survival from 14 months to 20 months. Under this 
design, the minimum observed effect that would result in statistical significance for the primary 
analysis of OS is an HR of 0.80, a 25% improvement in median from 14 to 17.5 months. 
Two interim analyses of OS are planned and will include all subjects randomized to combination 
and second NHT control arms at the time of each analysis. The first interim analysis of OS will 
be conducted at the time of primary analysis of PFS. This is expected to occur at approximately 
the 32% information fraction for OS. The second interim analysis of OS is planned at 
approximately the 76% information fraction. Inflation of Type 1 error associated with these 
interim analyses will be controlled using Lan-DeMets O’Brien-Fleming (LD-OF) alpha-spending 
functions based upon a total alpha allocation for OS that depends upon whether the PFS result is 
significant. If the null hypothesis of no difference in OS is rejected at a planned interim OS 
analysis in favor of the experimental arm, no subsequent testing of OS is planned.  
With an average accrual rate of ~24 subjects per month and using a 1:1 treatment allocation ratio 
between the combination and control arms, a total of 580 subjects (290 subjects in each arm) are 
required to observe the required number of events within the planned study duration 
(approximately 24 months accrual; approximately 21 months to observe the required PFS events 
and approximately 37 months to observe the required deaths for OS). The true intervals required 
to meet these milestones may be longer or shorter due to divergence from assumptions, or due to 
the impact of the global COVID-19 pandemic on subject enrollment and other aspects of study 
conduct. The estimates for the timing of event-driven analyses do not include the additional 
months required for event ascertainment, data quality review, data analysis and interpretation. 
The sample size may be increased up to an additional 25% if a review of the accumulating data 
suggests that the COVID-19 pandemic has caused the rate of study dropout or non-compliance to 
increase to a degree that the ability to adequately evaluate study endpoints may be undermined. 

 
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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS.....................................................................................................4 
LIST OF ABBREVIATIONS ............................................................................................30 
1 
BACKGROUND ......................................................................................................35 
1.1 
Prostate Cancer ................................................................................................35 
1.2 
Cabozantinib ....................................................................................................38 
1.3 
Atezolizumab and Other Immune Checkpoint Inhibitors ................................41 
1.4 
Combination Therapy with Cabozantinib and Atezolizumab ..........................43 
1.5 
Rationale ..........................................................................................................46 
1.5.1 
Rationale for Evaluating Cabozantinib in Combination with 
Atezolizumab in Metastatic Castration-Resistant Prostate Cancer ......46 
1.5.2 
Rationale for Study Design ..................................................................46 
1.5.3 
Rationale for Study Treatment Dose Selection and Treatment 
Schedule………………………………………………………..…….49 
1.6 
Overall Risk Benefit Assessment .....................................................................51 
1.7 
Study Conduct ..................................................................................................52 
2 
STUDY OBJECTIVES AND ENDPOINTS ............................................................52 
2.1 
Objective ..........................................................................................................52 
2.2 
Endpoints .........................................................................................................53 
3 
STUDY DESIGN......................................................................................................53 
3.1 
Study Sites .......................................................................................................53 
3.2 
Estimated Study Dates and Duration of Subject Participation ........................53 
3.3 
Overview of Study Design ...............................................................................54 
3.4 
Treatment Groups and Randomization ............................................................57 
3.5 
Treatment Discontinuation and Withdrawals ..................................................58 
3.5.1 
Treatment Discontinuation ...................................................................58 
3.5.2 
Study Withdrawal ................................................................................60 
3.5.3 
Study Completion ................................................................................60 
3.5.4 
End of Trial ..........................................................................................60 
4 
STUDY POPULATION ...........................................................................................61 
4.1 
Target Population .............................................................................................61 
4.2 
Inclusion Criteria .............................................................................................61 
4.3 
Exclusion Criteria ............................................................................................63 
5 
STUDY ASSESSMENTS AND PROCEDURES ....................................................66 
5.1 
Pre-Treatment Period .......................................................................................67 

 
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5.2 
Treatment Period ..............................................................................................68 
5.3 
Post-Treatment Period .....................................................................................70 
5.4 
Maintenance Phase/Treatment after Study Completion ..................................71 
5.5 
Unscheduled Visits or Assessments .................................................................72 
5.6 
Procedure Details .............................................................................................72 
5.6.1 
Demographics, Baseline Characteristics, Medical and Cancer History72 
5.6.2 
Physical Examination...........................................................................72 
5.6.3 
Vital Signs ............................................................................................73 
5.6.4 
Electrocardiogram (ECG) Assessments ...............................................73 
5.6.5 
Laboratory Assessments ......................................................................74 
5.6.6 
Tumor Assessments .............................................................................77 
5.6.7 
Prostate-Specific Antigen Assessments ...............................................80 
5.6.8 
Health-related Quality of Life Assessments ........................................80 
5.6.9 
Pain Assessments .................................................................................81 
5.6.10 
Symptomatic Skeletal Events ..............................................................82 
5.6.11 
Health Care Resource Utilization ........................................................82 
5.6.12 
Pharmacokinetic Assessments .............................................................83 
5.6.13 
Immunogenicity Assessments ..............................................................83 
5.6.14 
Biomarker Assessments .......................................................................83 
5.6.15 
Overall Survival ...................................................................................84 
5.7 
Protocol Deviations ..........................................................................................84 
6 
TREATMENTS ........................................................................................................85 
6.1 
Composition, Formulation, and Storage ..........................................................85 
6.1.1 
Study Treatment ...................................................................................85 
6.2 
Treatment Schedule of Administration ............................................................86 
6.2.1 
Experimental Arm: Cabozantinib in Combination with Atezolizumab86 
6.2.2 
Control Arm: NHT (Abiraterone with Prednisone, or Enzalutamide) .86 
6.2.3 
Study Drug Administration in the Clinic .............................................87 
6.2.4 
Experimental Arm: Cabozantinib Administration Outside the Clinic .89 
6.2.5 
Control Arm: Abiraterone with Prednisone, or Enzalutamide 
Administration outside the Clinic ........................................................90 
6.3 
Treatment after Study Completion...................................................................91 
6.4 
Compliance ......................................................................................................91 
6.5 
Study Treatment Accountability ......................................................................91 
6.6 
Safety Considerations ......................................................................................92 
6.6.1 
Management of AEs Associated with Cabozantinib ...........................93 
6.6.2 
Management of AEs Associated with Atezolizumab ........................109 
6.6.3 
Warnings, Precautions, and Management Guidelines for Adverse 
Events Associated with Abiraterone Plus Prednisone .......................135 

 
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6.6.4 
Warnings, Precautions, and Management Guidelines for Adverse 
Events Associated with Enzalutamide ...............................................136 
7 
CONCOMITANT MEDICATION AND THERAPY ............................................137 
7.1 
Allowed Therapies .........................................................................................138 
7.2 
Prohibited or Restricted Therapies .................................................................140 
7.2.1 
Prohibited or Restricted Therapies in Both Arms ..............................140 
7.2.2 
Prohibited or Restricted Therapies in the Experimental Arm ............141 
7.2.3 
Prohibited or Restricted Therapies in the Control Arm (NHT) .........142 
7.3 
Potential Drug Interactions ............................................................................143 
7.3.1 
Potential Drug Interactions with Cabozantinib ..................................143 
7.3.2 
Potential Drug Interactions with Atezolizumab .................................145 
7.3.3 
Potential Drug Interactions with Abiraterone and Prednisone ..........145 
7.3.4 
Potential Drug Interactions with Enzalutamide .................................145 
8 
SAFETY .................................................................................................................146 
8.1 
Adverse Events and Laboratory Abnormalities .............................................146 
8.1.1 
Adverse Events Definition .................................................................146 
8.1.2 
Adverse Events Causality Assessment ..............................................147 
8.1.3 
Adverse Events Grading ....................................................................147 
8.1.4 
Laboratory Abnormalities and Other Clinical Investigations ............148 
8.2 
Serious Adverse Events .................................................................................148 
8.2.1 
Serious Adverse Events Definitions ..................................................148 
8.2.2 
Serious Adverse Events Reporting Rules ..........................................149 
8.2.3 
Regulatory Reporting .........................................................................151 
8.3 
Adverse Events of Special Interest for Atezolizumab ...................................151 
8.3.1 
General Information on Immune-Related Adverse Events ................152 
8.4 
Follow-Up of Adverse Events .......................................................................153 
8.5 
Other Safety Considerations ..........................................................................154 
8.5.1 
Pregnancy ...........................................................................................154 
8.5.2 
Special Situation Reporting ...............................................................154 
9 
STATISTICAL CONSIDERATIONS....................................................................155 
9.1 
Analysis Populations ......................................................................................155 
9.1.1 
Intent-to-Treat Population ..................................................................155 
9.1.2 
PFS Intent-to-Treat Population ..........................................................155 
9.1.3 
Safety Population ...............................................................................155 
9.2 
Primary Efficacy Endpoints ...........................................................................155 
9.2.1 
Definitions..........................................................................................156 
9.2.2 
Primary Analysis ................................................................................156 
9.3 
Secondary Efficacy Endpoint ........................................................................158 

 
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9.3.1 
Definitions..........................................................................................158 
9.3.2 
Objective Response Rate ...................................................................158 
9.4 
Additional Endpoints .....................................................................................158 
9.5 
Control of Type I Error ..................................................................................159 
9.6 
Safety Analyses ..............................................................................................160 
9.6.1 
Adverse Events ..................................................................................160 
9.6.2 
Laboratory Test Results .....................................................................161 
9.6.3 
Other Safety Endpoints ......................................................................161 
9.7 
Power and Sample Size ..................................................................................161 
9.8 
Interim Analyses ............................................................................................163 
10 
OTHER ANALYSES .............................................................................................164 
10.1 
Pharmacokinetic Analysis ..............................................................................164 
10.2 
Immunogenicity Analyses .............................................................................165 
10.3 
Biomarker Analyses .......................................................................................165 
11 
DATA QUALITY ASSURANCE ..........................................................................165 
12 
STUDY COMMITTEES ........................................................................................165 
12.1 
Independent Data Monitoring Committee (IDMC) .......................................165 
12.2 
Blinded Independent Radiology Committee (BIRC) .....................................166 
12.3 
Clinical Steering Committee (CSC) ...............................................................166 
12.4 
Corporate Safety Governance ........................................................................166 
13 
ETHICAL ASPECTS .............................................................................................166 
13.1 
Local Regulations ..........................................................................................166 
13.2 
Informed Consent...........................................................................................167 
13.3 
Institutional Review Board/Ethics Committee (IRB/EC) ..............................167 
13.4 
Disposition of Subject Samples .....................................................................167 
14 
CONDITIONS FOR MODIFYING THE PROTOCOL.........................................168 
15 
CONDITIONS FOR TERMINATING THE STUDY ...........................................168 
16 
STUDY DOCUMENTATION, CASE REPORT FORMS, AND RECORD 
KEEPING ...............................................................................................................168 
16.1 
Investigator’s Files and Retention of Documents ..........................................168 
16.2 
Source Documents and Background Data .....................................................169 
16.3 
Audits and Inspections ...................................................................................169 
16.4 
Case Report Forms .........................................................................................169 

 
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17 
MONITORING THE STUDY ................................................................................170 
18 
CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT RECORDS .171 
19 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS..........172 
20 
COMPLIANCE WITH DATA PROTECTION LAWS .........................................172 
21 
REFERENCES .......................................................................................................174 
APPENDICES .................................................................................................................188 
 
 
 

 
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LIST OF TABLES 
Table 1-1: 
COMET-1 Posthoc Subgroup Analysis .................................................... 41 
Table 5-1: 
Local Laboratory Panels ........................................................................... 76 
Table 5-2: 
Estimation of the Creatinine Clearance by Cockcroft and Gault .............. 77 
Table 5-3: 
Criteria for Discontinuing Radiographic Assessments ............................. 79 
Table 6-1: 
Cabozantinib Tablet Components and Composition ................................ 85 
Table 6-2: 
Atezolizumab Infusion Requirements and Guidance ............................... 88 
Table 6-3: 
Dose Levels of Cabozantinib (Oral Dosing) ............................................. 95 
Table 6-4: 
General Dose Modification Guidelines for Cabozantinib-Related AEs ... 95 
Table 6-5: 
Management of Diarrhea Associated with Cabozantinib ......................... 98 
Table 6-6: 
Management of Hypertension Associated with Cabozantinib ................ 101 
Table 6-7: 
Management of Palmar-plantar Erythrodysesthesia (PPE) Associated with 
Cabozantinib ........................................................................................... 103 
Table 6-8: 
Management of Proteinuria Associated with Cabozantinib .................... 104 
Table 6-9: 
Management of Hepatotoxicity Associated with Cabozantinib .............. 106 
Table 6-10: 
Dose Interruptions of Atezolizumab ....................................................... 110 
Table 6-11: 
Guidance Overview for Atezolizumab Treatment Modifications .......... 110 
Table 6-12: 
Management Guidelines for Immune-Related Pulmonary Events, 
Including Pneumonitis ............................................................................ 114 
Table 6-13: 
Management Guidelines for Immune-Related Diarrhea or Colitis ......... 116 
Table 6-14: 
Management Guidelines for Endocrine Events ...................................... 117 
Table 6-15: 
Atezolizumab Management Guidance of Immune-Related Dermatologic 
Events ...................................................................................................... 120 
Table 6-16: 
Atezolizumab Management Guidance of Immune-Related Ocular 
Events… .................................................................................................. 121 
Table 6-17: 
Management Guidelines for Immune-Related Meningoencephalitis ..... 122 
Table 6-18: 
Management Guidelines for Immune-Related Neurologic Disorders .... 123 
Table 6-19: 
Management Guidelines for Immune-Mediated Myelitis ....................... 124 
Table 6-20: 
Management Guidelines for Pancreatic Events, Including Pancreatitis . 125 
Table 6-21: 
Management Guidelines for Immune-Related Cardiac Events .............. 127 
Table 6-22: 
Management Guidelines for Immune-Related Nephritis ........................ 128 
Table 6-23: 
Management Guidelines for Immune-Related Myositis ......................... 130 
Table 6-24: 
Management Guidelines for Hepatic Events .......................................... 132 
Table 6-25: 
Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome .................. 134 
Table 8-1: 
Adverse Events of Special Interest for Atezolizumab ............................ 152 
Table 9-1: 
Summary of Endpoint Analysis .............................................................. 163 
Table 9-2: 
Boundaries for Interim and Final Analyses of Overall Survival ............ 164 
 

 
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LIST OF FIGURES 
Figure 1: 
Prostate Cancer Treatment Algorithm ...................................................... 37 
 
LIST OF APPENDICES 
Appendix A: Screening Assessments ........................................................................... 188 
Appendix B: Schedule of Assessments from Randomization Onwards ...................... 190 
Appendix C: Maintenance Phase .................................................................................. 199 
Appendix D: Performance Status Criteria .................................................................... 202 
Appendix E: Highly Effective Methods of Contraception ........................................... 203 
Appendix F: Preexisting Autoimmune Diseases and Immune Deficiencies ............... 207 
Appendix G: Infusion-Related Reaction and Cytokine-Release Syndrome 
Guidelines………………………………………………………………208 
Appendix H: Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 
1.1)……………………………………………………………………...211 
Appendix I: 
List of Substrates, Inducers, and Inhibitors of Selected CYP450 
Isozymes….…………………………………………………………….220 
Appendix J: 
Collection, Follow-Up, and Documentation Requirements for AEs, AESIs, 
and SAEs ................................................................................................. 222 
Appendix K: EuroQoL Questionnaire EQ-5D-5L, USA (English) Sample Version ... 224 
Appendix L: EORTC QLQ-C30 Questionnaire, English Sample Version 3 ............... 226 
Appendix M: 11-point Numeric Rating Scale (NRS) for Pain Assessments ................ 228 
Appendix N: COVID-19 Instructions ........................................................................... 229 
 
 

 
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LIST OF ABBREVIATIONS 
ACTH 
Adrenocorticotropic hormone 
ADA 
Anti-drug antibodies, also called anti-therapeutic antibodies 
ADT 
Androgen deprivation therapy 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AIDS 
Acquired immunodeficiency syndrome 
ALK 
Anaplastic lymphoma kinase 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AR 
Androgen receptor 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma drug concentration time curve 
Bid 
Twice daily 
BIRC 
Blinded Independent Radiology Committee 
BP 
Blood pressure 
BRCA1(2) 
Breast cancer 1(2) 
BUN 
Blood urea nitrogen 
CAP 
Chest / Abdomen / Pelvis 
CAR 
Chimeric antigen receptor 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CHF 
Congestive heart failure 
Cmax 
Maximum plasma concentration 
CI 
Confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CNS 
Central nervous system 
COPD 
Chronic Obstructive Pulmonary Disease 
CR 
Complete response 
CrCl 
Creatinine clearance 
(e)CRF 
(electronic) Case report form 
CRO 
Contract research organization 
CRP 
C-reactive protein 
CRS 
Cytokine-release syndrome 
CSC 
Clinical Steering Committee 
CT 
Computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTCs 
Circulating tumor cells 
ctDNA 
Circulating tumor DNA 
CTLA-4 
Cytotoxic T-lymphocyte associated protein 4 
CYP 
Cytochrome P450 
DICOM 
Digital Imaging and Communications in Medicine 

 
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DILI 
Drug-induced liver injury 
dMMR 
deficient mismatch repair 
DNA 
Deoxyribonucleic acid 
DTC 
Differentiated thyroid cancer 
DVT 
Deep vein thrombosis 
EC 
Ethics committees 
ECG 
Electrocardiogram 
ECMO 
Extracorporeal membrane oxygenation 
ECOG 
Eastern Cooperative Oncology Group  
EDC 
Electronic data capture 
EGFR 
Epidermal growth factor receptor 
EMA 
European Medicines Agency 
EORTC 
European Organization for Research and Treatment of Cancer 
EOT 
End of treatment 
ERBT 
External beam radiotherapy 
ESMO 
European Society for Medical Oncology 
ES-SCLC 
Extensive-stage small cell lung cancer 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
FTP 
File Transfer Protocol 
FU-1(2) 
Follow-up visit 1(2) 
FXa 
Factor Xa 
GCP 
Good clinical practice 
G(M)-CSF 
Granulocyte colony-stimulating factors 
GGT 
γ-glutamyltranspeptidase 
GLP 
Good Laboratory Practice 
GI 
Gastrointestinal 
GnRH 
Gonadotropin-releasing hormone 
H0 
Null hypothesis 
HBV 
Hepatitis B virus 
HCC 
Hepatocellular carcinoma 
HCV 
Hepatitis C virus 
HGF 
Hepatocyte growth factor 
HIV 
Human immunodeficiency virus 
HLH 
Hemophagocytic lymphohistiocytosis 
HPMC 
Hydroxypropyl methylcellulose 
HR 
Hazard ratio 
HRD 
Homologous recombination deficiency 
HRQOL 
Health-related quality of life 
HTTP 
HyperText Transfer Protocol 
IC50 
Concentration required for 50% target inhibition 
IC(F) 
Informed consent (form) 
ICH 
International Council on Harmonization 
ICI 
Immune checkpoint inhibitor 

 
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IDMC 
Independent Data Monitoring Committee 
Ig 
Immunoglobulin 
irAE 
Immune-related adverse event 
IRB 
Institutional Review Boards 
irPR 
Immune-related partial response 
IRR 
Infusion-related reaction 
irRC 
Immune-related response criteria 
irRECIST 
Immune-related RECIST 
ITT 
Intent to treat  
IV 
Intravenous 
IRT 
Interactive Response Technology 
LDH 
Lactate dehydrogenase 
LD-OF 
Lan-DeMets O’Brien-Fleming 
LFT 
Liver function test 
LH 
Luteinizing hormone 
LMWH 
Low molecular weight heparin 
M0 
Non-metastatic 
(m)CRPC 
(metastatic) Castration-resistant prostate cancer 
(m)CSPC 
(metastatic) Castration-sensitive prostate cancer 
MAS 
Macrophage activation syndrome 
MDSC 
Myeloid-derived suppressor cells 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFS 
Metastasis-free survival 
MI 
Myocardial infarction 
MRI 
Magnetic resonance imaging 
MSI-H 
Microsatellite instability-high 
MTC 
Medullary thyroid cancer 
NA 
Not applicable 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NHT 
Novel hormonal therapy 
NIH 
National Institutes of Health 
NK 
Natural killer 
NPACT 
Nonprotocol anticancer therapy 
NR 
Not reached 
NRS 
Numeric Rating Scale 
NSAID 
Non-steroidal anti-inflammatory drug 
NSCLC 
Non-small cell lung cancer 
ONJ 
Osteonecrosis of the jaw 
ORR 
Objective response rate 
OS 
Overall survival 
PARP 
Poly ADP ribose polymerase 
PCWG3 
Prostate Cancer Working Group 3 
PD 
Progressive disease 

 
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PD-1 
Programmed cell death protein 1 
PD-L1 
Programmed death-ligand 1 
PE 
Pulmonary embolism 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PITT 
PFS Intent-to-Treat 
PK 
Pharmacokinetic 
po 
Per os (orally administered) 
PPE 
Palmar-plantar erythrodysesthesia  
PPI 
Proton pump inhibitor 
PR 
Partial response 
PRES 
Posterior reversible encephalopathy syndrome 
PSA 
Prostate specific antigen 
PSADT 
PSA doubling time 
PT/INR 
Prothrombin time/international normalized ratio 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
Q3W 
Every 3 weeks 
QD 
Once daily 
QOD 
Every other day 
QTcF 
Corrected QT interval by Fridericia 
RBC 
Red blood cell 
RCC 
Renal cell carcinoma 
RF 
Radiofrequency 
RLPS 
Reversible posterior leukoencephalopathy syndrome 
RNA 
Ribonucleic acid 
RSV 
Routine safety visit 
PFS 
Radiographic progression-free survival 
rPD 
Radiographic progressive disease 
RSI 
Reference safety information 
RTK 
Receptor tyrosine kinase 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable disease 
SEER 
Surveillance, Epidemiology, and End Results 
SmPC 
Summary of product characteristics 
SOC 
Standard of care 
SoD 
Sum of the diameters 
SSE 
Symptomatic skeletal events 
T3 
Triiodothyronine 
T4 
Thyroxine 
t1/2 
Terminal half-life 
TBS 
Technetium-99m bone scans 

 
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TEAE 
Treatment-emergent adverse event 
TIA 
Transient ischemic attack 
tmax 
Observed time to reach peak plasma concentration 
TMB 
Tumor mutational burden 
TNBC 
Triple negative breast cancer 
TPR 
Target lesion time point response 
TSH 
Thyroid-stimulating hormone 
UA 
Urinary analysis 
UC 
Urothelial cancer 
UE 
Unable to evaluate 
ULN 
Upper limit of normal 
UPCR 
Urine protein/creatinine ratio 
uPR 
Unconfirmed partial response 
US PI 
United States prescribing information 
VAD 
Ventricular assist device 
VAS 
Visual analog rating scale 
VEGF(R) 
Vascular endothelial growth factor (receptor) 
WBC 
White blood cell 
 

 
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1 
BACKGROUND  
1.1 
Prostate Cancer 
In 2018, prostate cancer was the fourth most commonly diagnosed malignancy worldwide 
behind cancers of the lung, breast, and colorectum (GLOBOCAN 2018). Incident prostate cancer 
was reported in 1.3 million men and accounted for 7.1% of all new cancer diagnoses that year. It 
is the most common cancer among men worldwide and the second leading cause of cancer 
deaths in the US (Bashir 2015), where its incidence in 2018 exceeded that of cancers of the 
bladder, kidney and testis combined (NIH NCI SEER 2018). 
There are multiple histologic types of prostate cancer but adenocarcinoma accounts for the vast 
majority of cases. Prostate adenocarcinoma typically is associated with elevation in the serum 
prostate-specific antigen (PSA) and often responds to testosterone-lowering (castration) and 
other hormonal manipulations targeting signaling through the androgen receptor (AR) axis.  
Prostate adenocarcinoma is radiographically localized at diagnosis in the majority of cases where 
PSA testing is widely implemented. Approximately two-thirds of men with radiographically 
localized disease are cured with definitive localized therapy (radical prostatectomy or 
radiotherapy) but the remainder will experience recurrence heralded by a rising PSA, local 
radiographic occurrence and/or metastases. Androgen deprivation therapy (ADT) is the mainstay 
of treatment for advanced or metastatic prostate cancer due to the androgen dependency of this 
disease. A rising PSA without radiographically evident metastases despite initiation of ADT 
castration signifies a non-metastatic castration-resistant state (non-metastatic castration-resistant 
prostate cancer [M0 CRPC]). De novo metastatic disease (metastatic castration-sensitive prostate 
cancer [mCSPC]) accounts for 3-7% of new cases of prostate cancer in developed nations and its 
incidence in the US may be rising due to recent declines in population-based PSA surveillance 
(Weiner et al 2016). Furthermore, de novo metastatic disease is commonly diagnosed in 
countries where PSA testing is not part of standard clinical practice. M0 CRPC and mCSPC 
(including locally advanced M0 CSPC) are the primary pathways to metastatic castration-
resistant prostate cancer (mCRPC), which all subjects enrolling in this Phase 3 study are required 
to have. 
Treatment of mCRPC  
Systemic treatment alternatives for patients with metastatic castration-resistant prostate cancer 
(mCRPC) now include chemotherapy, immunotherapy, androgen signaling pathway receptor 
inhibitors, radionuclide therapy, and PARP inhibitors (Tannock et al 2004, de Bono et al 2010, 
de Bono et al 2011, Kantoff et al 2010, Parker et al 2013, Ryan et al 2015, Scher et al 2012, Beer 
et al 2014, Beer et al 2017, de Bono et al 2020, Abida et al 2020; Sartor et al 2021). 

 
XL184-315 Protocol Amendment 5.0 
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Treatment of locally advanced or metastatic CSPC 
ADT has historically been used to treat de novo metastatic disease or metastatic castration-
sensitive disease preceded by radiographically localized disease. However, docetaxel/prednisone 
and novel hormonal therapies (NHTs), including abiraterone, apalutamide and enzalutamide 
have been shown to improve outcomes when combined with ADT initiation (Sweeney et al 
2015, Kyriakopolous et al 2018, James et al 2016, Fizazi et al 2017, Fizazi et al [Lancet Oncol] 
2019, Armstrong et al 2019, Chi et al 2019).  
Treatment of M0 CRPC 
ADT (potentially with salvage radiotherapy) may be initiated for a rising PSA detected after 
failure of definitive localized therapy with curative intent for radiographically localized disease. 
Patients who develop PSA progression while receiving ADT without evident metastasis are 
defined as having M0 CRPC, an alternative path to mCRPC distinct from mCSPC (including 
locally advanced M0 CSPC). For these M0 CRPC patients, three AR antagonists (apalutamide, 
enzalutamide, and darolutamide) have demonstrated improvements in metastasis-free survival 
(MFS) and overall survival (OS) compared with placebo in men with a PSA doubling time less 
than 10 months (Smith et al 2018, Hussain et al 2018, Fizazi et al [NEJM] 2019, Sternberg et al 
2020, Fizazi et al 2020, Smith et al 2021).  
Clinically useful molecular and genomic characterization enabling confident prediction of the 
aggressiveness of incident prostate cancer is still largely lacking, although variables such as the 
Gleason score, time to castration resistance, PSA doubling time (PSADT), presence or absence 
of visceral disease, extent of osseous metastases, and genomic status regarding DNA damage 
response gene (eg, BRCA1, BRCA2) mutations and microsatellite instability or mismatch repair 
deficient status may assist the clinician in counseling the patient with advanced disease as to the 
need for aggressive or targeted therapy.  
Potentially linked to the recent introduction of new treatments earlier in disease, the incidence of 
visceral metastases in men with mCRPC may be increasing and is associated with a particularly 
poor prognosis, particularly in the setting of liver disease (Nafissi et al 2019, Iwamoto et al 2018, 
Pezaro et al 2014, Whitney et al 2017). While patients with visceral disease were permitted to 
participate in the PREVAIL trial of enzalutamide in pre-chemotherapy mCRPC (Beer et al 2014) 
and the LATITUDE trial of abiraterone plus prednisone with ADT in high risk mCSPC (Fizazi et 
al 2017), these patients have a particularly dire unmet need upon progression on their first NHT 
(enzalutamide and abiraterone, respectively), which this Phase 3 study proposes to meet prior to 

 
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adequately fit patients having to resort to taxane-based chemotherapy with its attendant 
toxicities, and irrespective of when the first NHT was taken.  
Standard-of-care therapies used for patients with visceral disease include taxane-based 
chemotherapy and NHTs (NCCN [Prostate Cancer v2.2019] 2019). Apart from their approvals in 
pre- and post-chemotherapy mCRPC, NHTs abiraterone, apalutamide, and enzalutamide have 
prolonged OS and PFS in combination with ADT in mCSPC while apalutamide, enzalutamide, 
and darolutamide have prolonged MFS and OS in M0 CRPC. However, none of these treatments 
is likely curative, and, upon progression, many patients with mCRPC will likely have already 
been treated with an NHT either as their first treatment for mCRPC or earlier disease (mCSPC 
[including locally advanced M0 CSPC] or M0 CRPC), respectively (Figure 1).  
Figure 1: 
Prostate Cancer Treatment Algorithm 
 
Despite recent progress in the systemic therapy of mCSPC (including locally advanced M0 
CSPC), M0 CRPC and mCRPC, patients with visceral metastases or extrapelvic adenopathy 
have limited treatment options if they have already been treated with an NHT given the 
restriction of radium-223 use to patients with no known visceral disease; sipuleucel-T’s 
relatively better efficacy in patients with indolent, low volume disease; pembrolizumab’s 
restriction to men with microsatellite instability-high (MSI-H) or deficient mismatch repair 
(dMMR) tumors; PARP inhibitors’ current restriction to men with homologous recombination 
deficiency (HRD)-positive (eg, BRCA) disease; and 177-lutetium-617-PSMA’s current 
restriction to men with PSMA-positive disease who have been treated with androgen receptor 
(AR) pathway inhibition and taxane-based chemotherapy. As such, the proposed study design 

 
XL184-315 Protocol Amendment 5.0 
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defines a patient population with high unmet need and is further supported by the encouraging 
data from the ongoing Phase 1b XL184-021 study (Section 1.4).  
1.2 
Cabozantinib 
Cabozantinib (XL184) is a potent, orally bioavailable inhibitor of multiple receptor tyrosine 
kinases (RTKs) known to play important roles in tumor cell proliferation and/or tumor 
neovascularization, including the vascular endothelial growth factor receptor (VEGFR2), MET, 
RET, and KIT. Somatic KIT mutations have been associated with aggressive forms of prostate 
cancer (Martinez-Gonzalez et al 2018). Cabozantinib targets also include TYRO3, AXL, and 
MER (TAM family kinases) and are implicated in promoting suppression of an antitumor 
immune response. 
AXL and MER participate in the innate immune response where they function as regulators of 
inflammation by inhibiting activities mediated by dendritic cells and support maturation of NK 
cells. Their activation is part of a negative feedback loop that reduces the inflammatory process 
and tissue damage through engagement of inflammatory cytokine receptors (Rothlin et al 2015). 
Activation of the TAM receptors in macrophages mediates the transition from the M1 to M2 
phenotype and the latter results in reduction of CD8+ T cells in tumors (Cook et al 2013, Myers 
et al 2019). 
The receptor tyrosine kinase MET plays important roles in cell motility, proliferation, and 
survival, and has been shown to be a key factor in tumor angiogenesis, invasiveness, and 
metastasis. The effect of MET on immune cell activity was observed in preclinical solid tumors 
models, where blocking MET impeded neutrophil recruitment to tumors and lymph nodes and 
this activity potentiates T cell anti-tumor immunity (Glodde et al 2017). Prominent expression of 
MET has been observed in primary and metastatic prostate carcinomas (Pisters et al 1995, 
Humphrey et al 1995) with evidence for higher levels of expression in bone metastases compared 
to lymph node metastases or primary tumors (Knudsen et al 2002, Zhang et al 2010). 
Overexpression of HGF, the ligand for MET, has also been observed in prostate carcinoma (Zhu 
et al 2000), and increased plasma levels of HGF in CRPC are associated with decreased overall 
survival (Humphrey et al 2006).  
Data from preclinical studies suggest that both HGF and MET are regulated by the androgen 
signaling pathway in prostatic tissue. Both proteins are expressed at low levels in xenograft 
models of androgen-sensitive prostate cancer but are upregulated in CRPC models (Humphrey 
et al 1995, Verras et al 2007). MET expression increases substantially in androgen-sensitive 
tumor cells after androgen withdrawal (Humphrey et al 1995, Verras et al 2007). Administration 
of a MET kinase inhibitor after castration reduced tumor cell proliferation in a preclinical model 

 
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of CRPC (Tu et al 2010). These observations indicate that upregulation of MET signaling may 
be associated with and contribute to the emergence of resistance to androgen suppression in 
prostate cancer.  
VEGF and its receptors are key mediators in the process of tumor neoangiogenesis, invasion, and 
dissemination (Carmeliet and Jain 2011). In prostate cancer, elevated VEGF in either plasma or 
urine is associated with shorter overall survival (Bok et al 2001, George et al 2001). VEGF may 
also play a role in activating the MET pathway in tumor cells by binding to neuropilin-1, which 
is frequently upregulated in prostate cancer and appears to activate MET in a co-receptor 
complex (Zhang et al 2010). 
Cabozantinib tablets (60 mg) are approved in the United States, Europe, and other regions for 
advanced renal cell carcinoma (RCC; different patient populations depending on region; 
Cabometyx® US Prescribing Information [PI] and European Medicines Agency [EMA] 
Summary of Product Characteristics [SmPC]). Cabozantinib tablets have also been approved in 
the US and other regions for the treatment of hepatocellular carcinoma (HCC) in patients who 
have previously been treated with sorafenib and in the US for the treatment of adult and pediatric 
patients 12 years of age and older with locally advanced or metastatic differentiated thyroid 
cancer (DTC) that has progressed following prior VEGFR-targeted therapy and who are 
radioactive iodine-refractory or ineligible (HCC: 60 mg; DTC: 40 mg [in pediatric patients 
≥ 12 years with body surface area (BSA) < 1.2 m2] and 60 mg [in adult and pediatric patients 
≥ 12 years with BSA ≥ 1.2 m2]; Cabometyx US PI). The EU has also approved cabozantinib for 
similar use in adults but not in pediatric patients (Cabometyx EMA SmPC). Cabozantinib tablets 
(40 mg) are also approved for advanced RCC as a first-line treatment in combination with 
nivolumab. Cabozantinib capsules (140 mg) are approved in the United States for the treatment 
of patients with progressive, metastatic medullary thyroid cancer (MTC) and in the European 
Union for the treatment of patients with progressive, unresectable locally advanced or metastatic 
MTC (Cometriq® US PI and EMA SmPC). The capsule and tablet formulations are not 
bioequivalent or interchangeable.  
Following encouraging preliminary results for cabozantinib-treated CRPC subjects in a Phase 2 
study (Smith et al 2013, Smith et al 2014, Basch et al 2015; NCT00940225), a randomized, 
double-blind, active-controlled Phase 3 study (COMET-1) was conducted to evaluate 
cabozantinib (60 mg po qd) vs prednisone (5 mg po bid) in 1028 men with bone-metastatic 
mCRPC who had previously been treated with docetaxel and at least one NHT (abiraterone 
acetate/prednisone and/or enzalutamide [Smith et al 2016; NCT01605227]). Subjects may have 
also received cabazitaxel at study entry, and there was no limit to the number of prior treatments 
allowed. In this study, cabozantinib significantly improved neither the primary endpoint OS 

 
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(11.0 vs 9.8 months; hazard ratio [HR] = 0.90 [95% confidence interval {CI}: 0.76, 1.06; 
stratified log-rank p = 0.21]) nor PSA outcomes compared with prednisone. Improvement in 
median radiographic progression-free survival (PFS) per Investigator was observed in the 
cabozantinib group (5.6 vs 2.8 months; HR = 0.48 [95% CI: 0.40, 0.57; p < 0.001]), as were 
improvements in circulating tumor cell (CTC) conversion, bone biomarkers, and symptomatic 
skeletal event (SSE) incidence. The improvement noted in CTC conversion from 
≥ 5 CTCs/7.5 mL blood at baseline to < 5 CTCs/7.5 mL blood (cabozantinib 33% vs 
prednisone 6%) is notable given the association between CTC counts and OS (Heller et al 2018). 
The discordance in results comparing OS with PFS observed in COMET-1 may be related to the 
inclusion of late (third, fourth, or fifth) lines of disease when dramatic improvements in 
outcomes may be difficult to obtain and demonstrate, and to differences in post-progression 
therapies (eg, cabazitaxel). Grade 3 to 4 adverse events (AEs) and treatment discontinuations due 
to AEs were higher with cabozantinib than with prednisone (71% vs 56% and 33% vs 12%, 
respectively), which may also partly be explained by the inclusion of subjects with late line 
disease. It is worth noting that this trial enrolled subjects in third- or later-line mCRPC where no 
therapy had yet proved efficacious; nevertheless, there was a trend (albeit statistically non-
significant) in OS favoring cabozantinib in addition to positive findings on PFS favoring 
cabozantinib. Furthermore, an OS benefit among subjects who received cabozantinib was 
observed in a posthoc subgroup analysis of those with visceral disease enrolled in COMET-1. Of 
191 subjects (133 cabozantinib, 58 placebo) with visceral metastases, the median OS was 
7.1 months for those randomized to cabozantinib as compared with 4.8 months for those on 
prednisone (stratified HR = 0.63 [95% CI: 0.44, 0.92; p = 0.018]). In addition, a PFS benefit was 
also observed in this analysis of those with visceral disease; the median PFS per Investigator 
(including bone scan data) was 3.0 months for those randomized to cabozantinib as compared to 
2.6 months for those on prednisone (HR 0.38 [95% CI: 0.25, 0.58]). The PFS benefit associated 
with cabozantinib treatment was noted regardless of whether bone scan data (showing two or 
more new lesions not consistent with tumor flare) informed the PFS endpoint (see Table 1-1), 
which suggests that PFS per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 is a 
suitable multiple primary endpoint. 

 
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Table 1-1: 
COMET-1 Posthoc Subgroup Analysis 
Population 
ITT 
Visceral Mets at 
Baseline Subgroup 
No Visceral Mets at 
Baseline Subgroup 
All durations in 
months 
Cabo 
(N=682) 
Pred 
(N=346) 
Cabo 
(n=133) 
Pred 
(n=58) 
Cabo 
(n=549) 
Pred 
(n=288) 
OS Median 
(95% CI) 
11.0 
(10.1, 
11.6) 
9.8 
(9.0, 11.5) 
7.1 
(5.7, 8.6) 
4.8 
(3.5, 7.5) 
11.8 
(11.1, 
12.9) 
11.5 
(9.8, 12.7) 
HR (95% CI) 
0.90 (0.76, 1.06) 
0.63 (0.44, 0.92) 
0.92 (0.76, 1.12) 
PFS per INV  
(incl TBS PD) 
Median (95% CI) 
5.6 
(5.5, 5.6) 
2.8 
(2.8, 2.9) 
3.0 
(2.8, 5.2) 
2.6 
(2.0, 2.6) 
5.7 
(5.6, 7.1) 
2.8 
(2.8, 3.0) 
HR (95% CI) 
0.48 (0.40, 0.57) 
0.38 (0.25, 0.58) 
0.46 (0.38, 0.56) 
PFS per INV  
(w/o TBS PD) 
Median (95% CI) 
7.4 
(5.8, 8.3) 
5.1  
(3.1, 5.5) 
3.1 
(2.8, 5.3) 
2.6 
(2.3, 2.7) 
8.3 
(8.1, 9.9) 
5.5 
(4.6, 5.8) 
HR (95% CI) 
0.59 (0.48, 0.73) 
0.44 (0.28, 0.68) 
0.56 (0.44, 0.72) 
cabo, cabozantinib; CI, confidence interval; HR, hazard ratio; INV, investigator; ITT, intent-to-treat; mets, 
metastases; OS, overall survival; PD, progressive disease; PFS, progression free survival; pred, prednisone; TBS, 
technetium bone scan; w/o, without 
1.3 
Atezolizumab and Other Immune Checkpoint Inhibitors 
Atezolizumab 
Atezolizumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody which potently and 
selectively inhibits binding of programmed death receptor 1 ligand (PD-L1) on tumor cells and 
tumor infiltrating immune cells in the tumor microenvironment (McDermott et al 2016). 
Through this interaction, atezolizumab interrupts the negative regulatory effects of PD-L1 on 
T-cell proliferation and function that result from PD-L1 binding to programmed death 
receptor 1 (PD-1) and B7.1 (CD80) expressed on T lymphocytes and other immune cells. The 
result is an increase in the susceptibility of tumor cells to T-cell-meditated immune response, an 
effect that has been demonstrated clinically across several tumor types.  
Atezolizumab injection for intravenous (IV) use (1200 mg once every 3 weeks [q3w]) has been 
approved in the US and the EU for the treatment of adult patients with advanced urothelial 
carcinoma (UC) after prior platinum-containing chemotherapy or in a subset of patients who are 
considered cisplatin-ineligible (different patient populations are indicated depending on region; 

 
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Rosenberg et al 2016, Balar et al 2017). Atezolizumab in combination with bevacizumab, 
paclitaxel, and carboplatin has been approved in US for the first-line treatment of adult patients 
with metastatic non-squamous non-small cell lung cancer (NSCLC) with no epidermal growth 
factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. 
Atezolizumab is also approved for adult patients with locally advanced or metastatic NSCLC 
after prior chemotherapy (Fehrenbacher et al 2016; Tecentriq™ US PI and EMA SmPC). 
Atezolizumab was also approved for first-line treatment in combination with carboplatin and 
etoposide in adult patients with extensive-stage small cell lung cancer (ES-SCLC; Horn et al 
2018, Tecentriq US PI). In these tumor indications, atezolizumab has prolonged OS and/or 
induced durable disease responses. Notably, similar to other ICIs, the effects of single-agent 
atezolizumab on PFS were modest, suggesting the possibility of delayed anticancer immune 
effects contributing to the observed survival benefit (Fehrenbacher et al 2016). Like other ICIs, 
treatment with atezolizumab is generally well-tolerated but can be associated with immune-
related adverse events (irAEs) including pneumonitis, hepatitis, colitis, endocrinopathies 
including hypophysitis, ocular toxicity, myocarditis, myositis, pancreatitis, and severe cutaneous 
adverse reactions (Michot et al 2016; Tecentriq US PI and EMA SmPC). 
Immune Checkpoint Inhibitors in mCRPC 
Immune checkpoint inhibitor (ICI) monotherapy with atezolizumab; the PD-1 inhibitor, 
pembrolizumab; the CTLA-4 inhibitor, ipilimumab; as well as the combination of the PD-1 
inhibitor, nivolumab, with ipilimumab have been studied in mCRPC. Prostate cancer is often a 
slow-growing tumor that may allow enough time for ICI therapy to activate the immune system 
with higher percentages of regulatory T-cells (Tregs) being found in higher stages of prostate 
cancer and tumor-infiltrating cytotoxic lymphocytes expressing high levels of PD-1 (an indicator 
of T-cell exhaustion), among other observations (Schepisi et al 2017, Ebelt et al 2009, Sfanos et 
al 2009).  
However, there are limited data available from ICI monotherapy trials in subjects with mCRPC. 
With the exception of unresectable or metastatic MSI-H or dMMR prostate cancer, single-agent 
pembrolizumab has failed to generate impressive RECIST responses although it has 
demonstrated encouraging immune responses. For example, the KEYNOTE-199 study in 
docetaxel-refractory mCRPC enrolled PD-L1-positive, PD-L1-negative, and bone-predominant 
with no measurable disease (irrespective of PD-L1 status) cohorts. Overall, 19% of 193 subjects 

 
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had any PSA reduction, while the objective response rate (ORR) was 6% and 3% for the PD-L1-
positive and PD-L1-negative cohorts, respectively.  
In a Phase 1 study of 15 men not preselected for PD-L1 status and with post-enzalutamide and/or 
post-sipuleucel-T mCRPC, atezolizumab monotherapy was associated with a median PFS of 3.4 
months (95% CI: 2.3, 5.7); the 6-month PFS rate was 26.7% (95% CI: 4.3, 49.1); only one 
subject (9%) had a partial response (PR) per immune-related response criteria (irRC [irPR]); and 
only 2 subjects (13%) had an at least 50% decrease in PSA from baseline (Kim et al 2018).  
Monotherapy with the CTLA-4 inhibitor, ipilimumab (10 mg/kg IV q3W for four doses and then 
q12W), was studied in two randomized, double-blind, placebo-controlled trials of men with 
mCRPC, one in men previously treated with docetaxel and the other in chemotherapy-naïve men. 
The primary endpoint in both studies was OS with key secondary endpoints of radiographic PFS 
and pain response. Neither study met its primary endpoint (Kwon et al 2014, Beer et al [J Clin 
Oncol] 2017). In the post-docetaxel study, median OS was numerically longer for ipilimumab 
compared with placebo but the HR did not reach statistical significance (11.2 vs 10.0 months, 
HR 0.85 [95% CI: 0.72, 1.00; p=0.053]) with subgroup analyses generally suggesting greatest 
benefit from ipilimumab in those subjects with good prognostic features. Median PFS was longer 
for ipilimumab compared with placebo (4.0 vs 3.1 months, HR 0.70 [95% CI: 0.61, 0.82]). The 
number of subjects meeting the prespecified criteria for a pain response was too small to allow 
meaningful assessment, while more ipilimumab subjects achieved a PSA reduction of at least 
50% compared with placebo (13.1% vs 5.3%). In the pre-docetaxel study, the HR for OS was 
1.11 (95% CI: 0.88, 1.39; p=0.37). However, median PFS was longer in the ipilimumab group 
compared with placebo (5.6 vs 3.8 months, HR 0.67 [95% CI: 0.55, 0.81]), as was time to 
nonhormonal cytotoxic chemotherapy (18.0 vs 10.9 months, HR 0.65 [95% CI: 0.52, 0.83]), 
which suggested activity with ipilimumab.  
In the CheckMate-650 study among post-NHT mCRPC subjects, 25% (8 of 32) responded to 
the combination of nivolumab and ipilimumab at a median follow-up of 11.9 months. Among 
post-chemotherapy, post-NHT mCRPC subjects, 10% (3 of 30) had a response at a median 
follow-up of 13.5 months (Sharma et al 2019).  
Overall, currently available data suggest that single-agent ICIs may only benefit a subset of 
patients with mCPRC. 
1.4 
Combination Therapy with Cabozantinib and Atezolizumab 
Preclinical studies (Kwilas et al 2014, Lu et al 2017, Wang et al 2019) and clinical observations 
on circulating immune suppressive cells and immune effector cells in cancer patients (Apolo et al 

 
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2014) suggest that cabozantinib promotes an immune-permissive environment, which might lead 
to synergistic effects from combination treatment with ICIs, independent of PD-L1 expression.  
High levels of circulating myeloid-derived suppressor cells (MDSCs), which are involved in 
tumor immune evasion (Gabrilovich and Nagaraj 2009), have been associated with increased 
PSA levels and tumor metastasis (Vuk-Pavlović et al 2010, Brusa et al 2013, Hossain et al 2015, 
Idorn et al 2014). In addition, high levels of immunosuppressive peripheral blood regulatory 
T cells (Tregs) have been identified in patients with prostate cancer and may hamper the anti-
tumor response (Miller et al 2006). Preclinical studies in PTEN/p53 deficient mice treated with 
cabozantinib showed rapid elimination of invasive prostate cancer through a neutrophil-mediated 
anticancer innate immune response (Patnaik et al 2017).  
In a chimeric murine model of mCRPC, anti-CTLA-4 or anti-PD-1 antibodies had a modest 
effect on tumor mass, but in combination with cabozantinib, a strong synergistic response 
mediated by neutralization of MDSCs (CD11b+, Gr1+) was observed (Lu et al 2017). 
Cabozantinib inhibited PI3K signaling, which impaired the release of cytokines by prostate 
cancer cells; the cytokines in turn induced expression of MDSC genes responsible for tumor 
suppressive activity. Inhibitory modulation of Gr1+ MDSCs was associated with an increase in 
CD8+ T cell tumor infiltration in prostate tumors, which supports the antagonistic activity of 
Gr1+ MDSCs on the CD8+ population of T cells. The collective preclinical evidence supports 
the combination of cabozantinib with atezolizumab as a therapeutic strategy for CRPC.  
COSMIC-021 is an ongoing Phase 1b study that evaluates the efficacy of cabozantinib in 
combination with atezolizumab in multiple tumor types including subjects with metastatic CRPC 
without small-cell features who have radiographically progressed in soft tissue on or after NHT 
(enzalutamide and/or abiraterone) initiated for treatment of metastatic disease. Subjects are 
required to have measurable soft tissue (visceral or adenopathic) disease per RECIST 1.1. Prior 
treatment with docetaxel is only permitted when given in combination with ADT for metastatic 
castration-sensitive prostate cancer prior to treatment with NHT. Subjects receive cabozantinib 
40 mg po qd and atezolizumab 1200 mg intravenously IV q3w. As of 21 October 2019, 
61 CRPC subjects had been enrolled in this study and 44 of these subjects with at least 12 weeks 
of follow-up were evaluable for response. Fourteen of the 44 evaluable subjects (31.8%) had a 
confirmed tumor response per RECIST 1.1 by Investigator assessment, including 2 subjects with 
a complete response and 12 with partial response. Disease control rate was 80%. An additional 
subject, not included as responder above, with initial PD per RECIST 1.1 exhibited a durable 
irPR per irRECIST criteria. An objective tumor response rate was also observed (33%) in 36 
patients with features of disease associated with poor prognosis: measurable visceral disease 
and/or measurable extrapelvic lymph node metastasis. The observed clinical activity of the 

 
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combination therapy in COSMIC-021 is especially encouraging given the more limited single-
agent activity of either cabozantinib or atezolizumab in subjects with metastatic CRPC and is 
suggestive of cooperative effects of these agents (Schoffski et al 2017, Kim et al 2018). 
To date, AEs observed within XL184-021 mCRPC Cohort 6 have been consistent with the safety 
profile of cabozantinib and atezolizumab. As of 21 October 2019, of the 44 subjects described 
above, 42 (95%) experienced at least one AE. Forty-one (93%) subjects experienced at least one 
related AE, 28 (64%) at least one Grade 3 or 4 AE, 28 (64%) at least one related Grade 3 AE, 
two (4.5%) a Grade 4 AE (pulmonary embolism [not related], diverticular perforation [related), 
and one (2%) a related Grade 5 AE (dehydration).  
Among these 44 subjects, the most frequent AEs (reported in ≥ 10% of subjects) observed as of 
the 21 October 2019 data cutoff, regardless of causality, were fatigue (57%), nausea (48%), 
decreased appetite (45%), diarrhea (39%), palmar-plantar erythrodysesthesia syndrome (32%), 
vomiting (32%), aspartate aminotransferase increased (30%), dysgeusia (30%), headache (30%), 
alanine aminotransferase increased (25%), hyponatremia (25%), cough (23%), weight decreased 
(20%), abdominal pain (18%), anemia (18%), arthralgia (18%), constipation (18%), dizziness 
(18%), platelet count decreased (18%), pulmonary embolism (18%), dysphonia (16%), 
hypertension (16%), hypophosphatemia (16%), blood alkaline phosphatase increased (14%), dry 
mouth (14%), hyperglycemia (14%), peripheral edema (14%), rash maculo-papular (14%), 
stomatitis (14%), white blood cell count decreased (14%), dehydration (11%), fall (11%), 
gamma-glutamyltransferase increased (11%), lymphocyte count decreased (11%), neutrophil 
count decreased (11%), oral pain (11%), and sinusitis (11%). Of note, the majority of pulmonary 
embolism events with accompanying narratives (ie, serious events) were discovered incidentally 
on restaging CT scans: 6 of 7 (85.7%) described asymptomatic clinical courses. All 6 subjects 
experiencing an incidental event continued on cabozantinib after a brief interruption and 
initiation of anticoagulation. Immune-related AEs (irAEs) were also observed. 
Seven (16%) subjects discontinued all study treatment (both cabozantinib and atezolizumab) due 
to an AE or serious adverse event (SAE) unrelated to disease progression. Four (9.1%) subjects 
discontinued all study treatment due to an AE or SAE related to disease progression. 
Adverse events were managed with dose modifications and supportive care. The overall safety 
profile is consistent with what has been observed with each agent individually. The lower dose of 
cabozantinib (40 mg), even in combination with atezolizumab, appears to be better tolerated than 
the 60 mg single agent cabozantinib dosing regimen used in the earlier COMET-1 trial in 
mCRPC. In that study, 33% of subjects discontinued cabozantinib due to an AE, and 88% had a 
dose modification. Median duration of treatment was 20 weeks.  

 
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Overall, the combination of cabozantinib and atezolizumab showed acceptable tolerability and 
encouraging clinical activity in this patient population, particularly given the poor prognosis and 
limited treatment options. For further information on COSMIC-021, refer to the current 
cabozantinib Investigator’s Brochure. 
1.5 
Rationale 
1.5.1 
Rationale for Evaluating Cabozantinib in Combination with Atezolizumab in 
Metastatic Castration-Resistant Prostate Cancer 
Preclinical studies and clinical observations suggest that cabozantinib promotes an immune-
permissive environment, which might lead to synergistic effects from combination treatment 
with ICIs (Section 1.4). In Cohort 6 of the ongoing Phase 1b study XL184-021, the combination 
of cabozantinib and atezolizumab showed encouraging clinical activity and acceptable 
tolerability in mCRPC subjects who had radiographically progressed in soft tissue on or after 
NHT (enzalutamide and/or abiraterone) treatment (Section 1.4).  
There is a significant unmet medical need for treatment options for men with mCRPC who have 
previously received an NHT for mCRPC and/or earlier lines of disease (mCSPC [including 
locally advanced M0 CSPC], M0 CRPC) and who have measurable visceral disease or 
measurable extrapelvic adenopathy. Based on the encouraging data from Cohort 6 of Study 
XL184-021, the current Phase 3 study will evaluate the safety and efficacy of cabozantinib in 
combination with atezolizumab versus a second NHT in subjects with such mCRPC who 
biochemically or radiographically progressed on that NHT. Furthermore, this study is 
particularly suited to men with a good performance status who wish to avoid chemotherapy or to 
men deemed unable to tolerate side effects from chemotherapy. 
1.5.2 
Rationale for Study Design 
1.5.2.1 
Rationale for Patient Population 
This is a randomized, open-label, controlled Phase 3 study of cabozantinib in combination with 
atezolizumab versus a second NHT in subjects with mCRPC who have previously received one, 
and only one, NHT for mCRPC and/or earlier lines of disease (mCSPC [including locally 
advanced M0 CSPC] or M0 CRPC), who biochemically or radiographically progressed on that 
NHT, and who have measurable visceral disease or measurable extrapelvic adenopathy. The 
selection of subjects with measurable visceral disease or measurable extrapelvic adenopathy is 
based on review of data from Cohort 6 in the XL184-021 study (Section 1.4). 
A meta-analysis of the impact of metastatic site on overall survival in nearly 9000 men enrolled 
in nine Phase 3 trials of docetaxel in previously chemotherapy-naïve men with mCRPC showed 

 
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that visceral disease is associated with a poor prognosis, with liver disease associated with a 
median OS of 13.5 months and lung disease with 19.5 months (Halabi et al 2016). In the post-
chemotherapy AFFIRM (enzalutamide) and COUGAR-301 (abiraterone) mCRPC NHT trials, 
23.2% (278/1199) and 29.5% (352/1195) of subjects had visceral (ie, liver, lung) disease at 
baseline, respectively (Goodman et al 2014, Loriot et al 2017). Visceral disease (12%; 204/1717) 
was also documented in the pre-chemotherapy mCRPC PREVAIL trial of enzalutamide 
(Alumkal et al 2017; visceral disease was not permitted in the sister COUGAR-302 study of 
abiraterone). Thus, visceral disease is common in mCRPC. Furthermore, the proportion of men 
with mCRPC with measurable disease may be increasing due to the increased sensitivity of 
currently available imaging modalities and, possibly, the increasing use of docetaxel and novel 
hormonal therapies in subjects before they even reach the mCRPC state.  
Subjects will be stratified by presence or absence of liver metastasis, a particularly adverse 
prognostic factor for survival in patients with visceral disease enrolled in mCRPC trials (Pond et 
al 2014). In addition, they will be stratified by whether they had previously received docetaxel 
for locally advanced or metastatic castration-sensitive prostate cancer (yes/no) had their mCRPC 
been preceded by documented locally advanced or metastatic CSPC (response is “no” if subject 
previously had M0 CRPC). As docetaxel treatment is now thought to be used in approximately 
25% of newly diagnosed mCSPC patients with primarily high-volume disease (CHAARTED; 
Sweeney et al 2015), this stratification may decrease bias in efficacy analyses given high-volume 
disease’s representing another adverse prognostic factor. Furthermore, stratification on use of 
docetaxel for locally advanced or metastatic CSPC (including locally advanced M0 CSPC) may 
reduce bias in OS assessment across the study arms, as taxane treatment prior to mCRPC could 
reduce the efficacy of taxane treatment initiated after subjects progress on study drug(s) and 
could be used following discontinuation of study treatment. Finally, subjects will be stratified on 
whether their first NHT was given for first-line treatment of mCRPC, M0 CRPC or mCSPC 
(including locally advanced M0 CSPC), as the survival experience for subjects meeting entry 
criteria could differ by disease state when the first NHT was given. 
1.5.2.2 
Rationale for Multiple-Primary Endpoints 
The multiple-primary endpoints in this study are PFS per RECIST 1.1 evaluated by a Blinded 
Independent Radiology Committee (BIRC), and OS. OS has long served as a primary endpoint in 
multiple mCRPC trials, but PFS is also a clinically relevant primary endpoint supported by 
regulatory precedent in advanced prostate cancer trials (eg, PREVAIL, COUGAR-302, 
TALAPRO-2, LATITUDE, ARCHES, TITAN).  
Inclusion of PFS in soft tissue per RECIST 1.1 criteria as a multiple primary endpoint is 
supported by the observation that RECIST changes are associated with survival in men who 

 
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participated in the docetaxel control arm of Phase 3 mCRPC trials. For instance, in the VENICE 
trial, the OS HR was 0.64 (95% CI: 0.42, 0.99) for those who had a PR compared with those 
without such a response, and 1.78 (95% CI: 1.07, 2.95) for those with progressive disease (PD) 
compared to those without PD. Similarly, in the MAINSAIL trial, the corresponding OS HRs 
were 0.51 (95% CI: 0.22, 1.18) and 3.51 (95% CI: 1.92, 6.43), respectively (Sonpavde et al 
2016). Furthermore, in SWOG study S0421, the median OS was 7.1 (95% CI: 3.5, 8.8), 13.4 
(95% CI: 11.4 15.6), and 16.3 (95% CI: 10.0, 19.6) months for men with PD, stable disease 
(SD), and unconfirmed partial response (uPR), respectively; in a multivariate model, the OS HR 
was 2.47 (95% CI: 1.42, 4.29) for those with PD compared with those with uPR (Sonpavde et al 
2017). Interestingly, in a review of 31 Phase 3 mCRPC trials that included men with measurable 
disease, preceding objective tumor responses in Phase 2 studies best correlated with positive OS 
data in Phase 3 in the pre-chemotherapy setting, but less so in 1) post-chemotherapy studies, 
where response rates were lower and OS shorter, and 2) studies that combined docetaxel with 
another agent, where there have been no successful trials (Brown et al 2018). Therefore, it is 
reasonable to employ PFS per RECIST 1.1 as a multiple primary endpoint in mCRPC, with the 
expectation that, at the time of the primary PFS analysis, no detriment to OS should be 
demonstrated.  
Additionally, the inclusion of PFS per RECIST 1.1 rather than per Prostate Cancer Working 
Group 3 (PCWG3) as a multiple primary endpoint is supported by the objective of isolating the 
primary radiographic evaluation to soft tissue given the key requirement for measurable soft 
tissue disease at screening as a driver of high risk. Of note, in a posthoc subgroup analysis of 
subjects with visceral disease enrolled in COMET-1, a PFS benefit associated with cabozantinib 
treatment was observed regardless of whether bone scan data (showing two or more new lesions 
not consistent with tumor flare) informed the PFS endpoint (Table 1-1), adding further support 
for using PFS per RECIST 1.1 as a multiple primary endpoint. It is generally recognized that 
bone scans are not highly sensitive means of detecting bone metastases and bone disease 
progression. The significantly higher likelihood that radiographic progression may be seen in 
visceral disease (per RECIST 1.1) compared with contemporaneous bone disease (per PCWG) 
further justifies PFS per RECIST 1.1 as a multiple primary endpoint.  
Finally, the current trial landscape for men with mCRPC now includes combination of ICIs with 
each of chemotherapy, NHTs (eg, atezolizumab plus enzalutamide, pembrolizumab plus 
enzalutamide), or PARP inhibitors; lutetium-177 PSMA617; and other novel research treatments, 
which may render the ability to demonstrate an effect on OS challenging as patients switch to 
new systemic therapies upon radiographic progression. 

 
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The proposed trial is therefore designed to provide statistically robust evaluations of PFS and OS 
as multiple primary endpoints. PFS will be assessed by a BIRC to reduce potential bias in this 
open-label study.  
1.5.2.3 
Rationale for Control Arm 
Treatment with a second NHT (as approved standard of care) after failure of a first NHT initiated 
to treat mCRPC leads to a PSA response in approximately 20% of patients (Azad et al 2015, 
Suzman et al 2014, Matsubara et al 2018, Maughan et al 2017, Khalaf et al 2018). Given that 
subjects may, among others, receive either abiraterone or enzalutamide as the first NHT, the 
proposed control arm includes both agents to afford subjects the opportunity to receive the other. 
Subjects who have received another NHT, such as apalutamide or darolutamide, could receive 
either abiraterone with prednisone, or enzalutamide (Investigator’s choice). Given an assumed 
median OS of 14 months for the control group, a projected median PFS of 4 months affords the 
opportunity for subjects in the control group to initiate taxane-based or new investigational 
therapy should progression occur under trial treatment. 
Given that many men with mCRPC may wish to avoid chemotherapy or may be deemed unable 
to tolerate side effects from chemotherapy, alternative therapies are preferred in this disease 
stage setting. This is supported by the absence of any published evidence in the population to be 
enrolled in this study that taxane-based therapy (eg, docetaxel or cabazitaxel) is more efficacious 
than a second NHT after prior treatment with a first NHT (Suzman et al 2014, Schweizer et al 
2014, Aggarwal et al 2014, Azad et al 2014, Mezynski et al 2012). This observation is consistent 
with the hypothesis that docetaxel’s effect is mediated, at least in part, by disruption of 
microtubule function relevant to proper AR function. Review of this literature, which included 
studies in which the percentage of patients with visceral disease ranged from 6% to 48%, showed 
that the median OS was approximately 12 months, and the median PFS approximately 4 months, 
similar to what was seen in studies of chemotherapy-naïve patients who received a second NHT 
after a first NHT. Restricting the control treatment to second NHT also avoids the potential for 
serious chemotherapy-related toxicity (eg, myelosuppression, febrile neutropenia, neuropathy, 
alopecia, etc). 
1.5.3 
Rationale for Study Treatment Dose Selection and Treatment Schedule 
In accordance with the standard approved dose, atezolizumab 1200 mg will be administered as 
an IV infusion over 60 min (± 15 min) every 3 weeks (-2 days) on Day 1 of each 21-day cycle. If 
the first infusion is tolerated, all subsequent infusions may be delivered over 30 minutes 
(Tecentriq US PI, SmPC). 

 
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In the Phase Ib study, a total of 12 subjects with advanced RCC were evaluated in the 
dose-escalation stage at the 40-mg or 60-mg cabozantinib dose levels (six subjects each) plus the 
standard dose of atezolizumab. After reviewing all available safety and efficacy data of the 
dose-escalation stage, the Cohort Review Committee determined that cabozantinib 40 mg qd 
orally in combination with 1200 mg atezolizumab q3w IV is the recommended dose for the 
expansion-stage combination-therapy cohorts. The Cohort Review Committee decision was 
based on the favorable safety profile of the 40-mg cabozantinib dose level over a prolonged time 
on study treatment with less frequent dose reductions and encouraging preliminary efficacy, 
which was deemed to optimize the benefit/risk of the combination therapy in multiple solid 
tumor expansion cohorts including CRPC cohorts. 
Encouraging and durable responses were observed in the XL184-021 CRPC Expansion Stage 
Cohort 6, and data from which informed the definition of the population for this proposed study 
(Section 1.4). Furthermore, the combination of cabozantinib and atezolizumab has been 
tolerable, and the safety profile has been consistent with that of each agent individually.  
The lower 40-mg dose of cabozantinib in combination with atezolizumab is further supported by 
an exposure-response analysis of safety and efficacy endpoints from cabozantinib monotherapy 
data in the METEOR trial in second-line RCC evaluating 60-mg cabozantinib versus everolimus 
(Lacy et al 2018). Dose reductions to 40 mg and then 20 mg were allowed and occurred in 62% 
of patients in the cabozantinib group. The 60-mg exposure was associated with a higher risk for 
selected adverse events PPE (≥ Grade 1), fatigue/asthenia (≥ Grade 3), hypertension (systolic 
blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg) and diarrhea (≥ Grade 3) 
with predicted HRs of 1.49, 1.42, 1.36, and 1.33, respectively, relative to the predicted average 
steady-state cabozantinib concentration for a 40-mg starting dose. While the efficacy was 
predicted to be somewhat lower with a 40-mg monotherapy dose compared to the 60-mg dose 
(higher risk of disease progression/death (HR = 1.1), lower maximal median reduction in tumor 
size (-9.1% vs. −11.9%) and lower ORR (15.6 % vs. 19.1%), the benefit/risk in combination with 
atezolizumab based on the dose-escalation stage of the COSMIC-021 Phase Ib study favored the 
lower 40-mg cabozantinib dose, considering the potential overlapping adverse events of the two 
agents. 
The dosing regimens for abiraterone with prednisone and enzalutamide are based on their 
respective labeling in the US, Europe, and other regions.  

 
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An open-label design takes into consideration the impracticality of blinding given the desire to 
avoid dummy infusions in the control arm, in addition to the complications related to abiraterone 
administration with twice daily prednisone, a requirement that does not exist for enzalutamide.  
1.6 
Overall Risk Benefit Assessment 
Prostate cancer is the most common cancer among men worldwide and the second leading cause 
of cancer deaths in the US (Bashir 2015), where its incidence in 2018 exceeded that of cancers of 
the bladder, kidney and testis combined (NIH NCI SEER 2018). 
The incidence of visceral metastases in men with mCRPC may be increasing and is associated 
with a particularly poor prognosis, particularly in the setting of liver disease (Nafissi et al 2019, 
Iwamoto et al 2018, Pezaro et al 2014, Whitney et al 2017).  
In Cohort 6 of the ongoing Phase 1b Study XL184-021, the combination of cabozantinib with 
atezolizumab has demonstrated encouraging clinical activity, indicating possible cooperative 
effects, based on previous data on the contribution of single components (Sections 1.2 and 1.3), 
of these agents in subjects with mCRPC who have previously received an NHT for metastatic 
disease and who have measurable visceral disease or measurable extrapelvic adenopathy. 
Furthermore, the combination of cabozantinib and atezolizumab has been well-tolerated, and the 
safety profile has been consistent with that of each agent individually. 
Study inclusion/exclusion criteria were designed to prevent subjects at a heightened safety risk 
from entering the study (Section 4.2 and Section 4.3). The protocol provides guidance to 
Investigators for the management of important AEs that are associated with cabozantinib 
(Section 6.6.1), atezolizumab (Section 6.6.2), abiraterone with prednisone (Section 6.6.3), and 
enzalutamide (Section 6.6.4). Frequent safety assessments including laboratory assessments will 
allow identification and early intervention of potential AEs due to study treatment. 
An Independent Data Monitoring Committee (IDMC) will be established to monitor the safety of 
the study on a regular basis. The committee will operate independently from the Sponsor and the 
clinical investigators. To minimize the potential introduction of bias, IDMC members will not 
have any direct contact with the study site personnel or subjects. IDMC members will be selected 
for their expertise in conducting studies in oncology. Additionally, the Sponsor’s executive 
safety committee will monitor the safety of the study on a regular basis. 
The safety profile of each agent is well defined, and dose modification guidelines have been 
established and used in previous clinical studies to effectively manage side effects. Therefore, 

 
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potential benefits of evaluating the combination of these agents in this patient population 
outweigh the potential risks.  
1.7 
Study Conduct 
This study will be conducted in compliance with Good Clinical Practice (GCP), including 
International Council on Harmonization (ICH) Guidelines and also consistent with the most 
recent accepted version of the Declaration of Helsinki. In addition, all applicable local laws and 
regulatory requirements relevant to the use of new therapeutic agents in the countries involved 
will be adhered to. 
The study will be conducted in compliance with the protocol. The appropriate Institutional 
Review Boards (IRBs) or Ethics Committees (ECs) must approve the protocol, any amendments, 
and the subject informed consent form (ICF) prior to implementation.  
Freely given written informed consent must be obtained from every subject prior to his 
participation in this clinical trial. The rights, safety, and well-being of participating subjects are 
the most important considerations and should prevail over interests of science and society. 
Study personnel involved in conducting this trial will be qualified by education, training, and 
experience to perform their respective task(s). This trial will not use the services of study 
personnel for whom sanctions have been invoked or who have engaged in scientific misconduct 
or fraud (eg, loss of medical licensure, debarment, etc). 
2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Objective 
The primary objective of this study is to evaluate the efficacy of cabozantinib in combination 
with atezolizumab versus second NHT (abiraterone or enzalutamide) in subjects with mCRPC 
who have previously received one and only one NHT (eg, abiraterone, apalutamide, 
darolutamide, or enzalutamide) to treat mCSPC (including locally advanced M0 CSPC), M0 
CRPC, and/or mCRPC where biochemical progression (PSA progression) or radiographic 
progression has occurred on that NHT, and who have measurable visceral disease or measurable 
extrapelvic adenopathy. 

 
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2.2 
Endpoints  
Multiple-primary efficacy endpoints: 
• Duration of PFS per RECIST 1.1 per BIRC  
• Duration of OS 
Secondary efficacy endpoint: 
• ORR per RECIST 1.1 per BIRC 
Additional endpoints: 
• PSA response rate 
• Duration of radiographic response per RECIST 1.1 (per Investigator and BIRC) 
• Duration of PFS per PCWG3 per BIRC 
• Time to PSA progression 
• Time to SSE 
• Time to pain progression  
• Time to chemotherapy 
• Health care resource utilization 
• Change in mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, and 
global health as assessed by the EuroQol Health questionnaire EQ-5D-5L and European 
Organization for Research and Treatment of Cancer (EORTC) questionnaire QLQ-C30 
• Safety as assessed through the evaluation of adverse events (AEs), including immune-
related adverse events (irAEs)  
• Pharmacokinetics (PK) of cabozantinib given in combination with atezolizumab 
• Immunogenicity of atezolizumab given in combination with cabozantinib 
• Correlation of immune cell, tumor cell, and plasma biomarker analyses with clinical 
outcomes 
 
3 
STUDY DESIGN 
3.1 
Study Sites 
This study will be conducted at approximately 280 sites. 
3.2 
Estimated Study Dates and Duration of Subject Participation 
It is estimated that approximately 24 months will be required to randomize 580 subjects. The 
number of events required for the primary analyses of PFS (202 events among the first 
324 randomized subjects) and OS (340 events among all 580 randomized subjects) is expected to 

 
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be observed approximately 21 months and 37 months (final OS analysis), respectively, after the 
first subject is randomized. The true intervals required to meet these milestones may be longer or 
shorter due to divergence from assumptions, or due to the impact of the global COVID-19 
pandemic on subject enrollment and other aspects of study conduct. These estimates for the 
timing of event-driven analyses do not include the additional months required for event 
ascertainment, data quality review, data analysis and interpretation. 
It is estimated that subjects will participate for an average of 6 months on study treatment. 
Subjects will be followed until death, withdrawal of consent for non-interventional study 
assessments, or Sponsor decision to no longer collect survival data. 
3.3 
Overview of Study Design 
This is a Phase 3, multicenter, randomized, parallel group, open-label, controlled trial of the 
combination of cabozantinib (40 mg qd) with atezolizumab (1200 mg IV q3W) versus second 
NHT (abiraterone or enzalutamide) in subjects with mCRPC (adenocarcinoma) who previously 
received one and only one NHT (eg, abiraterone, apalutamide, darolutamide, or enzalutamide) to 
treat mCSPC (including locally advanced M0 CSPC), M0 CRPC, and/or mCRPC. PFS and OS 
are the multiple-primary endpoints. The primary analysis of PFS will be based upon RECIST 1.1 
per BIRC assessment. Approximately 580 eligible subjects who have mCRPC with measurable 
visceral metastasis or measurable extrapelvic lymphadenopathy, and whose disease is deemed to 
be worsening based on PSA or radiographic soft tissue progression in the opinion of the 
Investigator, will be randomized at approximately 280 sites in this trial. 
The sample size may be increased up to an additional 25% if a review of the accumulating data 
suggests that the COVID-19 pandemic has caused the rate of study dropout or non-compliance to 
increase to a degree that the ability to adequately evaluate study endpoints may be undermined. 
Special accommodations during the global COVID-19 pandemic are described in Appendix N. 
Each subject’s course of trial participation will consist of the following periods: 
Pre-Treatment Period: Potential subjects will be screened to determine whether they meet the 
required eligibility criteria. Qualifying screening assessments must be performed within 21 days 
before randomization unless otherwise specified. If there is a change in clinical status after 
screening and prior to randomization, these assessments are to be repeated as clinically indicated. 
Prior to randomization, the Investigator will designate in the interactive response technology 
(IRT) system the NHT (abiraterone, apalutamide, darolutamide, or enzalutamide) the patient 
previously received and progressed on. If eligible and randomized to the control group (second 

 
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NHT), the IRT system will then dispense enzalutamide if the prior NHT was abiraterone; 
abiraterone if the prior NHT was enzalutamide; and Investigator’s choice of abiraterone or 
enzalutamide if the prior NHT was apalutamide or darolutamide.   
Treatment Period: Subjects who meet all study eligibility criteria will be randomly assigned in 
a 1:1 fashion to cabozantinib plus atezolizumab or second NHT, respectively. Based on 
treatment assignment, subjects will begin treatment on one of the following regimens: 
Experimental Arm (290 subjects): 
Cabozantinib (40 mg po qd) plus atezolizumab (1200 mg IV q3w)  
Control Arm (290 subjects): 
Abiraterone (1000 mg po qd) + prednisone (5 mg po bid), OR enzalutamide (160 mg po qd) 
Details about the study treatment regimens are provided in Section 6. 
Subjects may receive study treatment, even after protocol-defined progression, until they are no 
longer clinically benefitting in the opinion of the Investigator, unless they 1) need subsequent 
systemic anticancer treatment or urgent tumor-directed alternative medical intervention (eg, to 
central nervous system [CNS] metastases), 2) experience unacceptable toxicity, or 3) have any 
other reason for treatment discontinuation as listed in the protocol (Section 3.5). In the absence 
of such, continued treatment after radiographic progression may occur in subjects who meet both 
of the following criteria: 
• Clinical benefit per Investigator judgment 
• ECOG performance status 0 or 1 
Crossover among treatment arms will not be allowed.  
Post-Treatment Period: A first Post-Treatment Follow-up Visit (FU-1) for safety assessment is 
to occur at least 30 (+14) days after the date of the decision to permanently discontinue study 
treatment (defined as the later of the date of the decision to permanently discontinue study 
treatment or the date of the last dose of study treatment). A second follow-up visit (FU-2) for 
safety evaluation will be conducted approximately 100 days (±14 days) after the date of the 
decision to permanently discontinue study treatment. Radiographic tumor, PSA, pain, and health-
related quality of life (HRQOL) assessments are to continue, regardless of whether study 
treatment is given, reduced, held, or discontinued until a criterion for ending radiographic 

 
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assessments is met (Section 5.6.6). Consequently, these assessments may be required in the Post-
Treatment Period for some subjects.  
In addition, subjects are to be contacted every 8 weeks (± 7 days) after FU-2 to assess survival 
status and document receipt of nonprotocol anticancer therapy (NPACT). This will continue until 
the subject expires or the Sponsor decides to discontinue collection of these data in the study. 
Every effort must be made to collect these protocol-specified evaluations unless consent to 
provide these data is withdrawn.  
Study Completion: The study will be considered complete if the null hypothesis is rejected for 
the primary endpoint of OS in any of the planned interim analyses or if the final planned analysis 
for OS has been conducted (irrespective of the results).  
Maintenance Phase/Treatment After Study Completion: The purpose of the Maintenance 
Phase is to continue to provide long-term access to study drug(s) to subjects who are deriving 
clinical benefit even after the study objectives have been completed (Study Completion, see 
above). When sufficient data have been collected to adequately evaluate all study endpoints, the 
Sponsor may initiate a Maintenance Phase. Upon initiation of the Maintenance Phase, the 
Sponsor considers the safety and efficacy profile of the experimental treatment regimen within 
this study to have been sufficiently established, and data analyses required for regulatory 
purposes to have been completed. The Sponsor is to notify the sites if or when the study will 
enter the Maintenance Phase or if an alternative post-Study Completion option will be 
implemented.  
In the Maintenance Phase, subjects on study treatment will continue to receive the study 
treatment(s) to which they were randomized until they meet a protocol-defined criterion for 
treatment discontinuation. Subjects in the Maintenance Phase are to undergo periodic safety 
assessments (including local laboratory tests, ECGs, symptom-directed physical examination and 
vital signs) and tumor assessments every 12 weeks (or more frequently as clinically indicated) 
for as long as they are in this phase.  
In order to continue to collect important safety information for subjects enrolled in the study 
during the Maintenance Phase, reporting of serious adverse events (SAEs), certain AEs 
(including AEs of special interest [AESIs, Table 8-1; whether serious or not] and AEs leading to 
dose modifications or treatment discontinuation), and other reportable events (pregnancy and 
medication errors with sequelae) is to continue per protocol requirements specific to the 
Maintenance Phase. 

 
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End of Trial: End of trial is defined as the last scheduled visit or scheduled procedure for the 
last subject (including Maintenance Phase assessments).  
3.4 
Treatment Groups and Randomization 
After obtaining informed consent, the site representative will use the designated web-based IRT 
system to register a subject. The IRT will assign a unique subject number. When a subject has 
been deemed eligible at the study site, the site representative will use the IRT to randomize and 
enroll the subject into the study. 
Eligible subjects will be randomly assigned in a 1:1 ratio to the following treatment arms: 
• Experimental Arm (290 subjects): 
Cabozantinib (40 mg po qd) plus atezolizumab (1200 mg IV q3w)  
• Control Arm (290 subjects): 
Abiraterone (1000 mg po qd) + prednisone (5 mg po bid), OR enzalutamide (160 mg po qd) 
Details about treatment regimens are provided in Section 6. 
Randomization will be stratified by the following factors established at screening: 
• Liver metastasis (yes/no) 
• Prior docetaxel for locally advanced or metastatic castration-sensitive prostate 
cancer (yes/no) 
• Response is “no” if subject previously had M0 CRPC  
• First NHT given for mCRPC vs M0 CRPC vs metastatic castration-sensitive 
prostate cancer. Note: For subjects who have received the same NHT for both 
mCRPC and either mCSPC (including locally advanced M0 CSPC) or M0 CRPC, 
subjects should be stratified by the disease state for which they received their first 
NHT even if they did not progress on it then. 
Randomization should occur as close as possible to the planned start of treatment (ie, within 
3 days). Subjects are defined as enrolled in the study if randomized. Changes to stratification 
values entered in the IRT will not be performed after randomization. Randomization will not be 
voided except under very rare circumstances and with Sponsor approval. Subjects who sign 
consent, are assigned a subject identifier, and are screened (to any degree, including rescreening) 
but never randomized are deemed permanent screen failures. 

 
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3.5 
Treatment Discontinuation and Withdrawals 
Details for handling treatment discontinuation and study withdrawal are discussed in 
Sections 3.5.1 and 3.5.2, respectively.  
If a subject requests to discontinue study treatment and/or withdraws study consent, the 
Investigator must establish the specific nature of the subject’s request. 
The subject’s decisions (there may be more than one over time) must be recorded in source 
documents and transcribed to study case report forms (CRFs). 
3.5.1 
Treatment Discontinuation 
Subjects will receive study treatment until treatment discontinuation for any of the reasons listed 
below. Subjects may discontinue study treatment and assessments or withdraw their consent to 
participate in the study at any time without prejudice. If a subject discontinues all study 
treatment, the reason will be documented in source documents and all study treatment will be 
stopped. The Investigator may also discontinue a subject from all study treatment if in his or her 
clinical judgment it is in the best interest of the subject or if the subject cannot comply with the 
protocol. In addition, the Investigator will also discontinue a subject from study treatment upon 
the Sponsor’s request or if the Sponsor chooses to terminate the study.  

 
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Furthermore, any of the following conditions require discontinuation of study treatment:  
• Subject no longer experiences clinical benefit as determined by the Investigator  
• Unacceptable side effects the Investigator feels may be due to study treatment  
• Subject participation in another clinical study using an investigational agent, 
investigational medical device, or other intervention 
• Necessity for treatment with non-protocol systemic anticancer therapy or urgent tumor-
directed alternative medical intervention (eg, to CNS metastases) 
• Necessity for interrupting all study treatment for greater than 12 weeks for 
study-treatment related AEs unless approved by the Sponsor. (Note: temporary 
interruptions of study treatment for greater than 12 weeks due to the effects of COVID-19 
and unrelated to AEs are described in Appendix N) 
• Refusal of sexually active fertile subjects to use highly effective methods of 
contraception (defined in Appendix E) 
• Significant noncompliance with the protocol schedule in the opinion of the Investigator 
or the Sponsor 
In addition, specific criteria for discontinuation are provided for cabozantinib and atezolizumab 
(Sections 6.6.1 and 6.6.2, respectively), abiraterone plus prednisone (Section 6.6.3), and 
enzalutamide (Section 6.6.4).  
To ensure timely Sponsor notification of study treatment discontinuations, site personnel are to 
promptly record treatment discontinuations in the study IRT. The reason for study treatment 
discontinuation must be recorded in source documents and CRFs. If a subject fails to return for 
the protocol-defined visits, an effort must be made to determine the reason. If the subject cannot 
be reached by telephone, at the minimum a registered letter requesting contact with the clinic 
should be sent to the subject. 
For subjects who discontinue study treatment, every effort must be made to undertake 
protocol-specified follow up procedures including end of treatment assessments, survival 
follow-up, and documentation of subsequent anticancer treatment(s) unless consent for 
non-interventional study assessments is also withdrawn. 

 
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If a subject is discontinued from study treatment because of an AE (including AESI; Table 8-1) 
considered to be related to study treatment, the event must be followed until resolution or 
determination by the Investigator that the event has become stable or irreversible. 
3.5.2 
Study Withdrawal  
Upon discontinuation of study treatment, at any time without prejudice, subjects may:  
• Continue study interventions (eg, examination, blood and tissue sampling, radiographic 
assessments, questionnaires) and non-interventional study assessments (eg, medical 
record review, survival contacts), or 
• Withdraw their consent for study interventions but continue non-interventional study 
assessments, or  
• Withdraw their consent for both study interventions and non-interventional study 
assessments.  
Reasons for study withdrawal will be recorded in the source documents and CRFs. As 
applicable, no further study procedures or assessments will be performed or study data collected. 
For subjects who withdraw consent, determination of survival status from public records such as 
government vital statistics or obituaries will be performed as allowed by local regulations. 
Subjects who withdraw from the study will not be replaced. 
3.5.3 
Study Completion 
The study will be complete if the null hypothesis is rejected for the primary endpoint of OS in 
any of the planned interim analyses or if the final planned analysis for OS has been conducted 
(irrespective of the results).  
3.5.4 
End of Trial 
End of trial is defined as the last scheduled visit or scheduled procedure for the last subject 
remaining (including Maintenance Phase assessments). 

 
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4 
STUDY POPULATION 
4.1 
Target Population 
This study will enroll subjects with mCRPC who have previously received one, and only one, 
NHT (eg, abiraterone, apalutamide, darolutamide, or enzalutamide) to treat mCSPC (including 
locally advanced M0 CSPC), M0 CRPC, and/or mCRPC, and who have measurable visceral 
disease (eg, adrenal, kidney, liver, lung, pancreas, spleen; but not bladder or other pelvic 
structures) or measurable extrapelvic adenopathy. Eligibility criteria for this study have been 
carefully considered to ensure the safety of the study subjects and to safeguard the integrity of 
the study results. It is imperative that subjects fully meet all inclusion criteria and none of the 
exclusion criteria. The Sponsor will not grant waivers to study eligibility criteria. 
4.2 
Inclusion Criteria 
1. Men with histologically or cytologically confirmed adenocarcinoma of the prostate. 
Note: Neuroendocrine differentiation and other histological features are permitted if 
adenocarcinoma is the primary histology.  
2. Subjects must have had a rising PSA or radiographically progressed on their prior treatment 
with one, and only one, NHT (eg, abiraterone, apalutamide, darolutamide, or enzalutamide) 
for castration-sensitive locally advanced (T3 or T4) or metastatic castration-sensitive prostate 
cancer, M0 CRPC, and/or mCRPC.  
Note: Subjects may have previously received taxane-based chemotherapy for locally 
advanced or metastatic castration-sensitive prostate cancer but no other approved or 
experimental nonhormonal systemic therapies for mCRPC.  
3. Bilateral orchiectomy or ongoing ADT with a gonadotropin-releasing hormone (GnRH) 
agonist/antagonist (surgical or medical castration), with serum testosterone ≤ 50 ng/dL 
(≤ 1.73 nmol/L) at screening. 
4. Measurable (extrapelvic soft tissue) metastatic disease per Investigator assessment as defined 
by at least one of the following: 
a. Measurable visceral (eg, adrenal, kidney, liver, lung, pancreas, spleen) disease per 
RECIST 1.1, OR 
b. Measurable extrapelvic adenopathy (ie, adenopathy above the aortic bifurcation). 
5. Progressive disease at study entry as defined by at least one of the following two criteria: 
a. Prostate specific antigen (PSA) progression defined by a minimum of 2 rising PSA 
values from 3 or 4 most recent consecutive assessments with an interval of at least 
7 days between assessments.  
Note: If qualifying solely by PSA progression, the screening PSA value must be at 
least 2 ng/mL (2 μg/L), and the oldest qualifying value must have been based on a 
blood sample drawn no longer than one year prior to signing of the informed consent 
form (ICF); up to one PSA decrease is permitted as long as it is not the most recent 

 
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value. If the study lab is the local lab at which the subject’s previous PSA blood 
samples were drawn, then the screening local lab PSA must be the highest, OR 
b. Soft tissue disease progression (PD) in the opinion of the Investigator. 
Note: Subjects with bone disease progression alone are not eligible.  
6. Age ≥ 18 years old or meeting country definition of adult, whichever is older, on the day of 
consent. 
7. ECOG performance status score of 0 or 1. 
8. Recovery to baseline or ≤ Grade 1 per Common Terminology Criteria for Adverse Events 
(CTCAE) v5 from toxicities related to any prior treatments, unless AE(s) are clinically 
nonsignificant and/or stable on supportive therapy in the opinion of the Investigator.  
9. Adequate organ and marrow function, based upon all of the following laboratory assessments 
from samples obtained within 21 days before randomization: 
a. Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥ 1.5 × 109/L) without granulocyte 
colony-stimulating factor support within 2 weeks before screening laboratory sample 
collection.  
b. Platelets ≥ 100,000/mm3 (≥ 100 × 109/L) without transfusion within 2 weeks before 
screening laboratory sample collection.  
c. Hemoglobin ≥ 9 g/dL (≥ 90 g/L) without transfusion within 1 week before screening 
laboratory sample collection.  
d. Serum bilirubin ≤ 1.5 × upper limit of normal (ULN)  
Note: Subjects with known Gilbert’s disease or unconjugated hyperbilirubinemia who 
have serum bilirubin level ≤ 3 × ULN may be enrolled. 
e. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) both 
≤ 3 × ULN. Subjects with known hepatic metastasis may enroll with serum ALT and 
AST both ≤ 5 × ULN.  
f. Serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance ≥ 40 mL/min using 
the Cockcroft-Gault equation: (140 – age) × weight (kg)/(serum creatinine [mg/dL] × 
72).  
g. Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.1 mg/mmol) or 24-hour 
urine protein < 1 g. 
h. Negative hepatitis B surface antigen (HBsAg) test  
i. Negative hepatitis C virus (HCV) antibody test, or positive HCV antibody test 
followed by a negative HCV RNA test and no ongoing anti-HCV therapy.  
Note: The HCV RNA test will be performed only for patients who have a positive 
HCV antibody test. 
10. Understanding and ability to comply with the protocol requirements, including scheduled 
visits, treatment plan, laboratory tests, and all other study procedures. Evidence of a signed 
and dated ICF, indicating that the subject has been informed of all pertinent aspects of the 

 
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study, prior to any screening assessments except those procedures performed as standard of 
care within the screening window. 
11. Sexually active fertile subjects and their female partners must agree to use highly effective 
methods of contraception during the course of the study and for 4 months (16 weeks) after 
the last dose of cabozantinib in the experimental arm (cabozantinib + atezolizumab), 3 weeks 
after the last dose of abiraterone (control arm), or 3 months (12 weeks) after the last dose of 
enzalutamide (control arm). A barrier contraceptive method (eg, condom) is also required. In 
addition, men must agree not to donate sperm during these same periods. 
 
4.3 
Exclusion Criteria 
1. Only evidence of metastasis is adenopathy below the aortic bifurcation, non-measurable soft 
tissue (visceral or adenopathic) disease per RECIST 1.1, or bone-only disease.  
2. Any prior systemic nonhormonal therapy initiated for the treatment of mCRPC.  
3. Receipt of abiraterone within 1 week; cyproterone within 10 days; or receipt of flutamide, 
nilutamide, bicalutamide, enzalutamide, or other androgen-receptor inhibitors within 2 weeks 
before randomization.  
Note: Subjects receiving prior enzalutamide, bicalutamide, flutamide, or nilutamide 
monotherapy without ADT at the time of screening are not eligible, unless bilateral 
orchiectomy has already been performed. 
4. Radiation therapy within 4 weeks (2 weeks for bone metastases) prior to randomization. 
Subjects with clinically relevant ongoing complications from prior radiation therapy are not 
eligible.  
5. Known brain metastases (symptomatic or non-symptomatic) or cranial epidural disease 
unless adequately treated with radiotherapy, radiosurgery, or major surgery (eg, removal or 
biopsy of brain metastasis) and clinically stable for at least 4 weeks prior to randomization.  
Note: Subjects who are neurologically symptomatic as a result of their CNS disease or 
receiving systemic corticosteroid treatment for their CNS disease are not eligible. 
6. Symptomatic or impending spinal cord compression or cauda equina syndrome. 
7. Concomitant anticoagulation with oral anticoagulants including, but not limited to, platelet 
inhibitors (eg, clopidogrel or ticagrelor), warfarin, dabigatran, and betrixaban, except for 
those specified below.  
a. Allowed anticoagulants are: 
i. Prophylactic use of low-dose aspirin for cardioprotection (per local applicable 
guidelines) and low-dose low molecular weight heparins (LMWH)  
ii. Therapeutic doses of LMWH or the direct factor Xa inhibitors rivaroxaban, 
edoxaban, or apixaban in subjects without known brain metastases who are on a 
stable dose of the anticoagulant for at least 1 week before randomization and 
without clinically significant hemorrhagic complications from the anticoagulation 
regimen or the tumor.  

 
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8. Administration of a live, attenuated vaccine within 30 days prior to randomization. The use 
of inactivated (killed) vaccines for the prevention of infectious disease is permitted. 
9. Systemic treatment with, or any condition requiring, either corticosteroids (> 10 mg daily 
prednisone equivalent) or other immunosuppressive medications within 14 days prior to 
randomization. Subjects with brain metastases requiring systemic corticosteroid at any dose 
are not eligible.  
Note: Prednisone (5 mg po bid) should be used with abiraterone. Inhaled, intranasal, intra-
articular, and topical steroids are permitted. Adrenal replacement steroid doses > 10 mg 
daily prednisone equivalent are permitted in the absence of active autoimmune disease (eg, 
in presence of adrenal metastasis). Transient short-term use of systemic corticosteroids for 
allergic conditions (eg, contrast allergy) is also allowed. 
10. Uncontrolled, significant intercurrent or recent illness that may impede interpretation of 
safety data, including, but not limited to, the following conditions: 
a. Cardiovascular and cardiac disorders: 
i. Congestive heart failure (CHF) class III or IV as defined by the New York Heart 
Association, unstable angina pectoris, serious cardiac arrhythmias (eg, ventricular 
flutter, ventricular fibrillation, torsades de pointes) within 6 months before 
randomization 
ii. Uncontrolled hypertension defined as systolic blood pressure (BP) > 150 mm Hg 
or diastolic BP > 90 mm Hg despite optimal antihypertensive treatment 
iii. Stroke, transient ischemic attack [TIA], myocardial infarction, or other 
symptomatic ischemic event or thromboembolic event (eg, deep venous 
thrombosis, pulmonary embolism [DVT/PE]) within 6 months before 
randomization.  
Notes:  
Upon Sponsor approval, subjects with a diagnosis of incidental, subsegmental PE 
or DVT within 6 months are allowed if asymptomatic and stable at screening and 
treated with LMWH or the direct factor Xa inhibitors rivaroxaban, edoxaban, or 
apixaban for at least 1 week before randomization.  
Non-symptomatic white matter disease in the brain is acceptable. 
iv. History of additional significant risk factors for torsades de pointes (eg, long QT 
syndrome) 
b. Neuropsychiatric disorder (including active suicidal ideation) likely to interfere with 
ability to give informed consent or comply with protocol requirements.  
c. Gastrointestinal (GI) disorders, including those affecting absorption or associated 
with a high risk of perforation or fistula formation: 
i. Tumors invading the GI tract, active peptic ulcer disease, acute pancreatitis, acute 
obstruction of the pancreatic or biliary duct, appendicitis, cholangitis, 
cholecystitis, diverticulitis, gastric outlet obstruction, or inflammatory bowel 
disease (eg, Crohn’s disease, ulcerative colitis)  

 
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ii. Abdominal fistula, bowel obstruction, GI perforation, or intra-abdominal abscess 
within 6 months before randomization  
Note: Subjects with intra-abdominal abscesses are eligible if complete healing 
has been confirmed before randomization. 
d. Hemoptysis of > 0.5 teaspoon (2.5 ml) of red blood, clinically significant hematuria, 
hematemesis, coagulopathy, or other history of significant bleeding (eg, pulmonary 
hemorrhage) within 3 months before randomization. 
e. Known cavitating pulmonary lesion(s) or known endobronchial disease 
manifestation. 
f. Lesions invading major pulmonary blood vessels. 
g. Other clinically significant disorders, such as: 
i. Any active, known or suspected autoimmune disease (see Appendix F for a 
comprehensive list of autoimmune diseases and immune deficiencies). 
Note: Subjects with type I diabetes mellitus, skin disorders (such as vitiligo, 
psoriasis, or alopecia) not requiring systemic treatment, or conditions not 
expected to recur in the absence of an external trigger are permitted to enroll. 
ii. Any active infection requiring systemic treatment. 
Note: Subjects receiving oral (including prophylactic) antibiotics with no 
symptoms of infection at randomization or oral valacyclovir (valaciclovir) are 
eligible. 
iii. Known human immunodeficiency virus (HIV) or acquired immunodeficiency 
syndrome (AIDS)-related illness.  
Note: HIV testing will be performed at screening if and as required by local 
regulation. 
iv. Active tuberculosis. 
v. Known history of COVID-19 unless the subject has demonstrated recovery from 
the disease at least 30 days prior to randomization. 
vi. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced 
pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on 
screening chest CT scan 
vii. Serious non-healing wound/ulcer/bone fracture per Investigator judgment.  
viii. 
Clinically significant malabsorption syndrome per Investigator judgment. 
ix. Pharmacologically uncompensated, symptomatic hypothyroidism. 
Note: Asymptomatic hypothyroidism only requiring hormone replacement is 
allowed. 
x. Moderate to severe hepatic impairment (Child-Pugh B or C) or known cirrhosis. 
xi. Requirement for hemodialysis or peritoneal dialysis. 

 
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xii. History of solid organ transplantation 
xiii. 
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring 
recurrent drainage procedures (once monthly or more frequently) 
-Patients with indwelling cathethers (e.g. PleurX®) are allowed 
11. Major surgery (eg, prostatectomy, GI surgery, removal or biopsy of brain metastasis) within 
4 weeks prior to randomization. Minor surgeries (eg, fine-needle biopsy) within 10 days prior 
to randomization. Subjects must have complete wound healing from major surgery or minor 
surgery before randomization. Subjects with clinically relevant ongoing complications from 
prior surgery are not eligible. 
12. Corrected QT interval calculated by the Fridericia formula (QTcF) > 480 ms per 
electrocardiogram (ECG) within 21 days before randomization.  
Note: If a single ECG shows a QTcF with an absolute value > 480 ms, two additional ECGs 
at intervals of approximately 3 minutes must be performed within 30 minutes after the initial 
ECG, and the average of the three consecutive results for QTcF must be ≤ 480 ms for the 
subject to be eligible. 
Note: This requirement does not apply if the subject has a permanent cardiac pacemaker in 
place or a history of asymptomatic bundle branch block in the absence of cardiac ischemia. 
13. Inability or unwillingness to swallow tablets or receive IV administration. 
14. Previously identified allergy or hypersensitivity to components of the study treatment 
formulations or history of severe infusion-related reactions to monoclonal antibodies. 
Subjects with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency 
or glucose-galactose malabsorption are also excluded. 
15. Any other active malignancy at time of randomization or diagnosis of another malignancy 
within 2 years prior to randomization that requires active treatment, except for locally curable 
cancers that have been apparently cured, such as basal or squamous cell skin cancer, or 
carcinoma in situ of the breast. 
 
5 
STUDY ASSESSMENTS AND PROCEDURES 
This protocol generally presents scheduled timelines for study procedures that will be performed 
based on routine safety visits (RSVs). Routine Safety Visit 1 (RSV1) is to occur no more than 
72 hours prior to the first dose of any study treatment. First dose of study treatment(s) is to occur 
within 3 days after the date of randomization.  
After RSV1, subsequent RSVs are required at least every 3 weeks (± 3 days) (ie, no more than 3 
weeks [± 3 days] apart). If there is a dose delay for any study treatment, subjects must return to 
the site for an RSV at least every 3 weeks (± 3 days) during the dose delay and follow up with 
additional unscheduled visits or telephone calls weekly (or more frequently) as clinically 

 
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indicated to monitor subject safety and appropriateness for resumption of study treatment. See 
Appendix B for the schedule of safety assessments performed at each RSV. 
In the experimental arm, an RSV is required within 72 hours prior to each planned infusion of 
atezolizumab (vital signs must be assessed within 60 min prior to initiation of the infusion), even 
if fewer than 3 weeks have elapsed since the last RSV. Once atezolizumab is restarted after a 
treatment delay, RSVs are to occur at least every 3 weeks (± 3 days) thereafter (ie, RSV schedule 
resets on date of infusion). 
Radiographic tumor, PSA, HRQOL, and pain assessments are to be performed at protocol-
defined intervals based on the date of randomization; all subsequent time points for these 
assessments will occur at a defined time interval and will not be modified as a result of 
modifications or discontinuations of treatment administration. Tumor assessments after 
randomization are to be performed every 9 weeks (± 7 days) through Week 28 (ie, the first three 
on-study tumor assessments) and then every 12 weeks (± 7 days; see Section 5.6.6.1). After 
RSV1, PSA, HRQOL, and pain assessments will occur with scheduled radiographic tumor 
assessments. See Sections 5.6.7, 5.6.8, and 5.6.9, respectively, for details. 
Special accommodations during the global COVID-19 pandemic are described in Appendix N. 
Unscheduled visits for safety evaluations are allowed at any time (see Section 5.5). 
See Appendix B for the schedule of assessments. 
5.1 
Pre-Treatment Period 
Informed consent must be obtained prior to initiation of any clinical screening procedure that is 
performed solely for the purpose of determining eligibility for research. However, evaluations 
performed as part of routine care prior to informed consent can be utilized as screening 
evaluations if permitted by the site’s IRB/EC policies. Informed consent may be obtained greater 
than 28 days before randomization. At informed consent a study site representative will use the 
web-based IRT to register subjects. The IRT will assign a unique subject identifier; subject 
identifiers are not to be re-assigned if a subject is determined to be ineligible, and subjects are to 
maintain their original identifier if re-screening is required or if the subject experiences a change 
in study site or investigator. 
To determine subject eligibility as stipulated in Section 4, subjects will undergo required 
screening evaluations as outlined in Appendix A and described in Section 5.6. Qualifying 
screening assessments must be performed within 21 days before randomization unless otherwise 

 
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stated. If there is a change in clinical status after screening and prior to randomization, these 
assessments are to be repeated as clinically indicated. Eligibility criteria will be based on local 
laboratory values, which must be forwarded to the local laboratory management vendor. Study 
eligibility is based on a subject meeting all of the study inclusion criteria and none of the 
exclusion criteria at screening. 
A subject who signs informed consent but fails to satisfy all eligibility criteria for any reason will 
be considered a screen failure. Data on the following will be collected for all screen failures: 
• Informed consent information 
• Failed inclusion/exclusion criteria 
• Demographics 
• Serious adverse events (SAEs) 
5.2 
Treatment Period 
Subjects eligible after completing all screening evaluations will be randomly assigned in a 1:1 
fashion (Section 3.4) to receive cabozantinib in combination with atezolizumab or second NHT. 
Subjects should receive their first dose of study drug treatment within 3 days after 
randomization. 
While the subject is receiving study treatment, the subject’s clinical status is to be evaluated by 
an investigator at each clinic visit to confirm that the subject is suitable for continuing study 
treatment and to make timely decisions regarding any dose reduction (cabozantinib and NHT 
only), interruption/delay, or restarting of study treatment. Clinical laboratory results from 
samples obtained during clinic visits and tumor assessments from imaging visits are to be 
reviewed by an investigator.  
The following are reminders for procedures and assessments during the treatment period: 
• Cabozantinib and second NHTs are dosed once daily (prednisone is dosed twice daily).  
• Doses of atezolizumab should be administered every 3 weeks and no more frequently 
than every 19 days (see Section 6.2.3.1). If atezolizumab administration is not delayed for 
AE management, it should be administered within 24 days of the prior atezolizumab 
dose. Atezolizumab dosing can be delayed for up to 12 weeks, after which the Sponsor 
should be contacted to discuss potential treatment continuation. 
o Atezolizumab may be withheld for a period of time beyond 12 weeks to allow for 
corticosteroids to be reduced to ≤ 10 mg/day oral prednisone or equivalent. The 

 
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acceptable length of the extended period of time must be based on an assessment of 
benefit−risk by the Investigator and in alignment with the protocol requirements for 
the duration of treatment and documented by the Investigator. The Sponsor is 
available to advise as needed. 
• Specific laboratory tests must be performed at an RSV and evaluated within 72 hours 
prior to each administration of atezolizumab (see Section 5.6.5). These assessments are 
not required prior to the first dose if there has been no change in subject’s clinical status 
since screening. 
• Safety will be assessed on a schedule based on date of first dose as described in 
Section 5. RSVs must occur at least every 3 weeks (± 3 days), even if there is a study 
treatment dose delay. In the experimental arm, an RSV is required within 72 hours prior 
to each planned infusion of atezolizumab (vital signs must be assessed within 60 min 
prior to initiation of the infusion), even if fewer than 3 weeks have elapsed since the last 
RSV. Once atezolizumab is restarted after a treatment delay, RSVs are to occur at least 
every 3 weeks (± 3 days) thereafter. 
• For subjects receiving abiraterone plus prednisone, serum ALT, AST, and total bilirubin 
assessments (liver function tests [LFTs]) are to be performed every 2 weeks for the first 
12 weeks of treatment, in addition to at each RSV (Appendix B). If an LFT visit 
coincides with an RSV, duplicate LFTs do not need to be performed. After the first 
12 weeks of treatment, LFTs will continue to be performed at each RSV.  
• Unscheduled visits may occur at any time (Section 5.5).  
• Radiographic tumor assessments are to be performed every 9 weeks (± 7 days) through 
Week 28 (ie, the first three on-study tumor assessments) and then every 12 weeks 
(± 7 days) relative to the date of randomization and irrespective of the dates of RSVs. For 
more details, see Section 5.6.6. PSA, HRQOL, and pain assessments after RSV1 are to 
occur with scheduled radiographic tumor assessments. For more details, see Sections 
5.6.7, 5.6.8, and 5.6.9, respectively. 
• PK, anti-drug antibodies (ADA), and biomarker sample collection schedules are per 
schedule of assessments (Appendix A and Appendix B). 
The schedule of tumor assessments should be maintained regardless of whether study treatment 
is given, reduced, held or discontinued until a criterion for ending radiographic assessments is 
met (see Section 5.6.6.1).  

 
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In accordance with the ITT principle, radiographic tumor, PSA, HRQOL, and pain assessments, 
and survival follow-up, are to be performed per protocol even for subjects randomized who 
never receive study treatment.  
Subjects may receive study treatment, even after protocol-defined progression, until they are no 
longer clinically benefitting in the opinion of the Investigator, unless they 1) need subsequent 
systemic anticancer treatment or urgent tumor-directed alternative medical intervention (eg, to 
CNS metastases), 2) experience unacceptable toxicity, or 3) have any other reason for treatment 
discontinuation as listed in the protocol (Section 3.5.1). In the absence of such, continued 
treatment after radiographic progression may occur in subjects who meet both of the following 
criteria: 
• Clinical benefit per Investigator judgment 
• ECOG performance status 0 or 1 
Crossover among treatment arms will not be allowed. 
Study completion is defined in Section 3.5.3 
5.3 
Post-Treatment Period 
A first Post-Treatment Follow-up Visit (FU-1) for safety assessment is to occur at least 30 (+14) 
days after the date of the decision to permanently discontinue study treatment (defined as the 
later of the date of the decision of the Investigator to permanently discontinue study treatment or 
the date of the last dose of study treatment taken by the subject). A second follow-up visit (FU-2) 
for safety evaluation will be conducted approximately 100 days (±14 days) after the date of the 
decision to permanently discontinue study treatment. Refer to Appendix B for a description of all 
the assessments at this visit. Further details on follow-up and data collection requirements for 
AEs, SAEs, and AESIs are summarized in Appendix J.  
Adverse events are to be documented and/or followed as described in Section 8.4. 
In addition, subjects are to be contacted every 8 weeks (± 7 days) after FU-2 to assess survival 
status and document receipt of nonprotocol anticancer therapy (NPACT). This will continue until 
the subject expires or the Sponsor decides to discontinue collection of these data in the study. 
Every effort must be made to collect these protocol-specific evaluations unless consent to 
provide these data is withdrawn.  
At each contact, the Investigator (or designee) will determine the subject’s survival status and 
collect information on any systemic NPACT the subject has received. If the subject has died, the 
Investigator will record the date and cause of death as best can be determined. All efforts must be 

 
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undertaken by the study sites to determine the date of death (or date subject last known alive at 
the time of a data cutoff). This may include, but not necessarily be limited to, telephone contacts, 
communication at study visits, registered letters, and reviews of local obituaries and government 
death records. If a subject is lost to follow-up, multiple attempts to contact the study subject or 
designee must be documented in the subject records. 
Unless new systemic anticancer therapy has been initiated, HRQOL, PSA, pain, and radiographic 
tumor assessments are to continue regardless of whether study treatment is given, reduced, held, 
or discontinued until the date of the last tumor imaging assessment as described in Section 5.6.6. 
Consequently, these assessments may be required in the Post-Treatment Period for some 
subjects. 
5.4 
Maintenance Phase/Treatment after Study Completion 
The purpose of the Maintenance Phase is to continue to provide long-term access to study 
drug(s) to subjects who are deriving clinical benefit even after the study objectives have been 
completed (see Section 3.5.3). When sufficient data have been collected to adequately evaluate 
all study endpoints, the Sponsor may initiate a Maintenance Phase. Upon initiation of the 
Maintenance Phase, the Sponsor considers the safety and efficacy profile of the experimental 
treatment regimen within this study to have been sufficiently established, and data analyses 
required for regulatory purposes to have been completed. The Sponsor is to notify the sites if or 
when the study will enter the Maintenance Phase or if an alternative post-Study Completion 
option will be implemented (Section 6.3). 
In the Maintenance Phase, subjects on assigned study treatment will continue to receive study 
treatment until a criterion for protocol-defined discontinuation has been met (Section 3.5.1). 
Subjects in the Maintenance Phase are to undergo periodic safety assessments (including local 
laboratory tests, ECG, symptom-directed physical examination and vital signs) and tumor 
assessments every 12 weeks (or more frequently as clinically indicated) for as long as they are in 
this phase (Appendix C). 
In order to continue to collect important safety information on subjects still enrolled in the study, 
reporting of SAEs, AESIs (Table 8-1), and other reportable events (pregnancy and medication 
errors with sequelae) is to continue per protocol (Section 8.2.3). 

 
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Furthermore, the following AEs, whether serious or not, are to be reported using the same 
process as for reporting SAEs described in the protocol Section 8.2 (though SAE reporting 
timeline requirements do not apply to non-serious events reported in these categories): 
• Adverse events of special interest (AESIs) 
• Adverse events, whether serious or not, leading to study treatment discontinuation 
• Adverse events, whether serious or not, leading to study treatment dose modification (ie, 
causing study treatment to be interrupted, delayed, or reduced) 
Study drug accountability is to continue as described in Section 6.5. 
5.5 
Unscheduled Visits or Assessments 
If the Investigator determines that a subject should be monitored more frequently or with 
additional laboratory parameters assessments than indicated by the protocol-defined visit 
schedule, unscheduled visits or assessments are permitted. Local laboratory results obtained at 
unscheduled visits must be forwarded to the local laboratory management vendor. If multiple 
results are obtained within a short time frame (eg, within a given day or over the course of a few 
days), results representative of the subject’s clinical course are to be submitted (every result need 
not be provided).  
5.6 
Procedure Details 
This section describes evaluations to be performed and items to be recorded or available on 
source documents. Data from some required evaluations may not be collected on study case 
report forms (Section 16.4). 
5.6.1 
Demographics, Baseline Characteristics, Medical and Cancer History 
Demographics at screening will include age at informed consent, medical and cancer history, 
surgical history, radiation therapy history, and systemic anticancer treatment history including 
names of agents and administration dates. To ensure subject privacy, date of birth and subject 
initials will not be collected by the Sponsor. 
5.6.2 
Physical Examination 
Physical examinations will include height (screening visit only), weight, and an assessment of 
the following systems: skin, head, eyes, ears, nose, throat, respiratory system, cardiovascular 
system, GI system, neurological condition, blood and lymphatic systems, and the 
musculoskeletal system. Symptom-directed physical examination will be conducted on RSV1 
before first dose of study treatment and after randomization. Any ongoing/intercurrent condition 

 
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prior to first dose must be recorded as medical history. Significant new findings that begin or 
worsen after first dose must be recorded as AEs. 
The ECOG performance status of the subject will be assessed during screening and at each 
scheduled safety assessment starting on RSV1 (Appendix D). 
Refer to Appendix B for the schedule of physical examination and performance status 
assessments. 
5.6.3 
Vital Signs 
Vital signs including 5-minute sitting blood pressure, pulse, respiratory rate, and temperature 
will be assessed at screening, at all scheduled safety visits, and at all unscheduled visits if 
possible. On atezolizumab infusion days, vital signs should be assessed within 60 min prior to 
initiation of the infusion, and further vital sign assessment should be performed during and after 
the infusion as clinically indicated.  
Refer to Appendix B for the schedule of these assessments. 
5.6.4 
Electrocardiogram (ECG) Assessments 
At screening and during the study, single ECG assessments will be performed with standard 
12-lead ECG equipment according to standard procedures to determine the corrected QT interval 
calculated by the Fridericia formula (QTcF). If at any time a single ECG shows a QTcF with an 
absolute value > 480 ms at screening or > 500 ms at RSV1 onwards or an increase in QTcF of 
> 60 ms above baseline at RSV1 onwards, two additional ECGs at intervals of approximately 
3 min must be performed within 30 min after the initial ECG, and the average of these three 
consecutive results for QTcF will be used as the value assessed (see Section 6.6.1.1.16). 
ECGs will be performed at the time points indicated in Appendix B. An ECG assessment is not 
required prior to the first dose if there has been no change in subject’s clinical status since 
screening per Investigator judgment. 
Abnormalities in the ECG that lead to a change in subject management (eg, dose reduced or 
interrupted, treatment discontinued, or requirement for additional medication or monitoring) or 
result in clinical signs and symptoms are considered clinically significant for the purposes of this 
study and will be deemed AEs. If values meet criteria defining them as serious, they must be 
reported as SAEs (Section 8.2). 

 
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The Fridericia formula is depicted below for calculation of the QTcF value. 
 
QT = measured QT interval in milliseconds; RR = measured R to R interval (which can 
be derived from the heart rate as 60/heart rate) 
5.6.5 
Laboratory Assessments 
Laboratory analytes that will be measured for this study are listed in Table 5-1. The schedule for 
screening assessments is provided in Appendix A. The schedule for laboratory assessments is 
provided in Appendix B. Laboratory tests to establish eligibility must be done within 21 days 
before randomization unless otherwise stated. If there is a change in clinical status after 
screening and prior to randomization, these assessments are to be repeated as clinically indicated. 
Hematology, serum chemistry, coagulation, UPCR including components, 24-hour urine protein, 
serum testosterone, PSA, hepatitis, and thyroid function tests are to be performed by a local 
laboratory. Results from these tests must be forwarded to the study local laboratory management 
vendor at screening and at any scheduled or unscheduled visit. If multiple results are obtained 
within a short time frame (eg, within a given day or over the course of a few days), results 
representative of the subject’s clinical course are to be submitted (every result need not be 
provided). 
Results or status from routine (dipstick) analysis and microscopic urine examination tests will be 
recorded on CRFs but will not be submitted to the study local laboratory management vendor. 
Other specific laboratory test information: 
• To confirm suitability for treatment, all laboratory tests must be performed within 21 days 
prior to administering the first dose of study treatment. Tests performed on RSV1 should be 
available to and deemed acceptable by the Investigator prior to any treatment being 
administered. 
• Serum chemistry, hematology, coagulation, and urinalysis laboratory samples must be 
collected at an RSV within 72 hours and the results must be reviewed before any 
atezolizumab infusion administered on study. If the subject has symptoms indicative of a 
thyroid function disorder, thyroid function test results are to be reviewed prior to 

 
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administering atezolizumab. These assessments are not required prior to the first dose if there 
has been no change in subject’s clinical status since screening. 
• Direct and indirect bilirubin assessments are not required when the total bilirubin is normal or 
low. 
• UPCR tests are to be performed at every RSV through RSV17, then at every 2 RSVs 
thereafter. UPCR tests are not required prior to the first dose if there has been no change in 
subject’s clinical status since screening per Investigator judgment. 
• For subjects receiving abiraterone plus prednisone, serum ALT, AST, and total bilirubin 
assessments (LFTs) are to be performed every 2 weeks for the first 12 weeks of treatment, in 
addition to at each RSV (Appendix B). If an LFT visit coincides with an RSV, duplicate LFTs 
do not need to be performed. After the first 12 weeks of treatment, LFTs will continue to be 
performed at each RSV.  
• Serum testosterone will be assessed at screening only. 
• C-reactive protein (CRP) test will be performed at screening only, if available at the local 
laboratory. For subjects already enrolled, CRP analyses may be performed on available 
screening samples. 
• HIV test will be performed at screening if required by local regulation. Do not forward results 
from this test to the study local laboratory management vendor. 

 
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Table 5-1: 
Local Laboratory Panels 
Hematology 
• white blood cell (WBC) 
count with differential (ANC, 
basophils, eosinophils, 
lymphocytes, monocytes) 
• hematocrit 
• platelet count 
• red blood cell count 
• hemoglobin 
 
Coagulation 
• prothrombin time (PT)/ 
International Normalized 
Ratio (INR)  
• partial thromboplastin time 
(PTT) 
 
Thyroid function 
• thyroid-stimulating hormone 
(TSH) 
• free thyroxine (T4) 
Serum Chemistry 
• albumin 
• total alkaline phosphatase (ALP) 
• amylase (if available) 
• alanine amino transferase (ALT) 
• aspartate amino transferase (AST) 
• blood urea nitrogen (BUN) or urea 
• C-reactive protein (CRP [screening 
only, if available]) 
• calcium  
• bicarbonate (if available) 
• chloride 
• creatinine 
• γ-glutamyltranspeptidase (GGT) 
• glucose  
• lactate dehydrogenase (LDH) 
• lipase  
• magnesium 
• phosphorus 
• potassium 
• sodium 
• total bilirubin (conjugated and 
unconjugated fractions if total 
bilirubin is high) 
• total protein 
  
Urine Chemistry 
• protein (spot urine; fully 
quantitative) 
• creatinine (spot urine; fully 
quantitative) 
• urine protein/creatinine ratio 
(UPCR; spot urine) 
• 24-hour urine protein: 
perform at the discretion of 
the Investigator based on 
increases in UPCR from 
routine assessments 
 
 
Virology 
• hepatitis B surface antigen, 
(screening) 
• hepatitis C antibody (with 
reflex testing of HCV RNA if 
antibody test is positive 
[screening]) 
• HIV test (if required by local 
regulation [screening]) 
Urinalysis 
(Dipstick or Routine per 
Institutional Standard) 
• pH 
• specific gravity 
• ketones 
• protein 
• glucose 
• nitrite 
• urobilinogen  
• leukocyte esterase 
• blood 
Microscopic Urine Examination 
• Perform at the discretion of the 
Investigator based on results or 
routine urinalysis or as clinically 
indicated 
 
 
 
 
Other Laboratory Analyses 
• testosterone (serum, screening 
only)  
• prostate-specific antigen 
(PSA) 
 
 
 

 
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Table 5-2: 
Estimation of the Creatinine Clearance by Cockcroft and Gault 
Based on serum creatinine in conventional units (mg/dL) 
• Males: (140 – age) × weight (kg)/(serum creatinine × 72) 
Based on serum creatinine in SI units (µmol/L) 
• Males: [(140 – age) × weight (kg)/(serum creatinine)] × 1.23 
Abnormalities in any clinical laboratory test (including tests not required per protocol) that leads 
to a change in subject management (eg, dose interrupted or reduced, treatment discontinued, 
requirement for additional medication or monitoring) are considered clinically significant for the 
purposes of this study and should be reported as AEs. If laboratory values constitute part of an 
event that meets criteria defining it as serious, the event (with associated laboratory values) 
needs to be reported as an SAE (see Section 8.2).  
5.6.6 
Tumor Assessments 
5.6.6.1 
General 
Radiographic response and PD will be determined using RECIST 1.1 (Appendix H). For the 
purpose of determination of the multiple-primary endpoint, PFS, and of the secondary endpoint, 
ORR, central review of radiographic images will be conducted by a BIRC. The additional 
endpoint of PFS per PCWG3 will be determined by soft tissue progression based on CT/MRI per 
RECIST 1.1 or bone disease progression based on bone scan per PCWG3 and will be assessed 
by BIRC. All radiographic tumor assessments will be promptly sent to the BIRC until the 
primary analysis for the primary endpoint of PFS is completed. The BIRC will also review prior 
radiation history data for the purpose of selection of target lesions. Sites will be provided with 
instructions on how images should be collected and submitted to the BIRC. Radiographic 
assessments per RECIST 1.1 as per the Investigator may be used for treatment decisions; that is, 
study treatment(s) may be discontinued upon locally determined radiographic progression if the 
patient is no longer felt to be clinically benefitting. Study staff shall ensure that no images 
contain personal data as defined by applicable local, regional, and international laws and 
regulations. 
Radiographic tumor assessments will include the following:  
Chest / Abdomen / Pelvis (CAP): Computerized tomography (CT) of CAP or chest CT and 
abdomen/pelvis magnetic resonance imaging (MRI) will be performed in all subjects at 

 
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screening prior to randomization. Tumor assessments after randomization are to be performed 
every 9 weeks ± 7 days through Week 28 (ie, the first three on-study tumor assessments), and 
then every 12 weeks ± 7 days as per PCWG3 guidelines. Additional imaging of potential disease 
sites should be performed whenever radiographic disease progression (PD) is suspected. 
Brain: MRI (or CT) of the brain will be performed only if clinically indicated at screening. After 
randomization, MRI (or CT) scans of the brain are only required in subjects with known brain 
metastasis or if clinically indicated following the same post-baseline frequency as the imaging 
for CAP. MRI is the preferred method for brain scans. If CT of the brain is performed instead of 
MRI, ambiguous results must be confirmed by MRI unless MRI is contraindicated. Note: For 
eligibility requirements regarding prior treatment of brain metastasis, refer to Section 4.3. 
Bone: Technetium-99m bone scans (TBS) are to be performed at screening for all subjects. 
Evidence of or suspicion for soft tissue masses extending from bone must be corroborated with 
CT at screening. If a screening CT scan shows measurable soft tissue disease extending from 
bone, that soft tissue disease must be followed by on-study CT when CAP imaging (not 
capturing the lesion) is done. After randomization, TBS are to be performed on all subjects on 
the same schedule as for CAP. Subjects who report new symptoms associated with new or 
worsening bone scan lesions must have bone-directed CT performed (unless already captured by 
routine CT), which are to continue on the same schedule as for CAP. 
Subjects who are treated beyond radiographic disease progression will continue to undergo 
tumor assessments at the frequency described above until study treatment is discontinued. 
The same imaging modalities used at screening must be used for subsequent tumor assessments 
after randomization. If there is clinical concern regarding the administration of any contrast, then 
a non-contrast CAP imaging study is acceptable as a screening assessment if it clearly 
demonstrates soft tissue disease that can be followed without the need for contrast. If, at a follow 
up imaging time point, the use of contrast is prohibited (eg, due to acquired impaired renal 
function or contrast allergy) then the same modality should be used without contrast. 
Tumor assessments should continue on the protocol-defined schedule, relative to the date of 
randomization, regardless of whether study treatment is given, reduced, held or discontinued. 
Guidance for continuation or termination of tumor assessments based on subject status is 
provided in Table 5-3.  

 
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Table 5-3: 
Criteria for Discontinuing Radiographic Assessments 
Subject Status 
Action with Radiographic Assessments 
Study 
Treatment 
Discontinued? 
Investigator-Assessed rPD 
per RECIST 1.1 Reached? 
No 
No 
Continue radiographic assessments 
No 
Yes 
Continue radiographic assessments (ie, 
Investigator-assessed clinical benefit after 
radiographic progression) 
Yes 
No 
Continue radiographic assessments unless receipt of 
new systemic therapy has been documented 
Yes 
Yes 
Discontinue radiographic assessments 
rPD, radiographic progressive disease; RECIST 1.1, Response Evaluation Criteria for Solid Tumors version 1.1. 
Investigators are encouraged, if any doubt or ambiguities exist about radiographic progression, to 
continue study treatment if the subject is tolerating it acceptably, repeat radiographic tumor 
imaging at the next scheduled time point, and delay determination of progression until the 
findings indicating radiographic progression are unequivocal. Radiographic progression 
determined by the Investigator does not necessarily warrant discontinuation of tumor 
assessments or study treatment. 
Refer to Appendix B for the schedule for these assessments. 
5.6.6.2 
Confirmation of Tumor Response and Tumor Progression 
For subjects with an overall response of PR or CR per RECIST 1.1 by the Investigator at a given 
time point, a repeat assessment is to be performed no fewer than 4 weeks after the criteria for 
response are first met. This may be performed at the next scheduled tumor assessment. 
In order to identify potential delayed immune-mediated tumor response, subjects with an overall 
response of PD per RECIST 1.1 who continue with study treatment because of evidence of 
clinical benefit as assessed by the Investigator should have tumor measurement outcomes 
confirmed by the Investigator after the initial Investigator-assessed PD criteria were met. This is 
to be performed no later than the next scheduled tumor assessment. Unless subjects 1) need 
subsequent systemic anticancer treatment or urgent tumor-directed alternative medical 
intervention (eg, to CNS metastases), 2) experience unacceptable toxicity, or 3) have any other 
reason for treatment discontinuation as listed in the protocol (Section 3.5.1), continuation of 

 
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study treatment after documentation of PD is allowed for those who meet both of the following 
criteria: 
• 
Clinical benefit per Investigator judgment 
• 
ECOG performance status of 0 or 1 
Subjects who are eligible to continue with study treatment must provide additional written 
informed consent. 
For subjects who continue treatment after the documentation of radiographic PD, regularly 
scheduled imaging will continue until treatment discontinuation. 
5.6.6.3 
Blinded Independent Radiology Committee (BIRC) 
All radiological studies acquired at all scheduled time points and any additional (unscheduled) 
radiological images acquired to evaluate for potential metastatic disease must be sent to the 
BIRC preferably in original Digital Imaging and Communications in Medicine (DICOM) format 
(as detailed in the Site-specific Imaging Core Manual). The BIRC will evaluate prior radiation 
history for the purpose of valid identification of target lesions and all images in a central and 
independent fashion as further described in Section 12.2. Electronic transfer of scan files (via 
FTP, HTTP, or similar means) is preferred, although transfer on physical media (such as DVDs 
or CDs) is acceptable. For digital media, each disk should contain one time point for one subject. 
The site is expected to maintain a copy of digital data for the retention period applicable to the 
protocol, GCPs, and federal, international and/or state legal and medical requirements. The 
Sponsor and or designee will retain the media for the life of the study. 
5.6.7 
Prostate-Specific Antigen Assessments 
Serum PSA levels will be assessed in all subjects at screening. Subsequent assessments will 
occur with scheduled imaging. PSA assessments should not be used to make study treatment 
decisions in this study. Refer to Appendix A and Appendix B for the schedule for these 
assessments. 
5.6.8 
Health-related Quality of Life Assessments 
Health-related quality of life (HRQOL) assessments will be performed using the instruments 
EuroQol Health questionnaire EQ-5D-5L (Appendix K) and EORTC questionnaire QLQ-C30 
(Appendix L). The EQ-5D-5L is a standardized instrument for use as a measure of self-reported 
general health status. It comprises 5 dimensions (mobility, self-care, usual activities, 
pain/discomfort, and anxiety) and a visual analog rating scale (VAS). The utility data generated 

 
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from EQ-5D-5L assessments are recommended for and commonly used in cost effectiveness 
analysis. The EORTC QLQ-C30 is a core questionnaire that is validated for assessment of 
quality of life of cancer patients. It consists of functional scales (physical, role, cognitive, 
emotional, and social), symptom scales (fatigue, pain, and nausea and vomiting), global health 
status and quality of life scale, and several single-item symptom measures.  
The first HRQOL assessment will be prior to first dose of study treatment on RSV1, and 
subsequent assessments will occur with scheduled imaging. Subjects will continue completing 
questionnaires regardless of whether study treatment is given, reduced, held, or discontinued 
until the date of the last tumor imaging assessment or study completion. Consequently these 
assessments may be required in the Post-Treatment Period for some subjects (Appendix B).  
Subjects are to complete the questionnaires prior to each clinic visit or, if completed on the day 
of the visit, before seeing the study site personnel. If a clinic visit is not possible, subjects should 
complete the questionnaires as per schedule and return it to the site either during the next visit or 
send it to the site (eg, fax or postal mail). Ideally, study subjects should not receive any 
information about their most recent medical results prior to completing the questionnaires in 
order to ascertain that their reporting not be influenced by such information when completing the 
questionnaires. Subjects are to independently respond to questionnaires on their own. At clinic 
visits, questionnaires should be carefully reviewed by the study staff at the site for completeness.  
Subjects who are not compliant with completing the questionnaires should be reminded by the 
Investigator that these reports are an essential part of the study and timely completion is required.  
Every effort should be made by the study site to retrieve all HRQOL questionnaires, including 
the assessment following radiographic progression or discontinuation of study treatment, and to 
keep them at the site as source documentation.  
Translated copies of the EQ-5D-5L and EORTC QLQ-C30 questionnaires, if required, and 
instructions for filling them out will be provided to each study site in a separate study manual. 
HRQOL assessments will no longer be collected if the study transitions to the Maintenance 
Phase. 
5.6.9 
Pain Assessments 
Assessment of pain will be self-reported by each subject using an 11-point (from 0 to 10) NRS 
measuring worst pain in the last week, with 0 representing “No Pain” and 10 representing “Pain 
as Bad as You Can Imagine” (Appendix M). The 11-point NRS measuring worst pain severity is 
a validated and commonly used assessment across diseases and treatment (Dworkin et al 2005). 

 
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Baseline pain assessments will be performed prior to first dose of study treatment on RSV1, and 
subsequent pain assessments will be performed with scheduled imaging. 
In addition, new or increased use of analgesics from baseline will continuously be assessed by 
the Investigator. A new analgesic is defined as one that is taken for at least seven consecutive 
days after, but not prior to, randomization. Increased use is defined as an increased dose of an 
analgesic taken after randomization relative to baseline (ie, dose taken at screening) for 
analgesics taken for at least seven consecutive days.  
Subjects will continue reporting pain scores and analgesic use regardless of whether study 
treatment is given, reduced, held, or discontinued until the date of the last tumor imaging 
assessment or study completion. Consequently these assessments may be required in the Post-
Treatment Period for some subjects (Appendix B).  
Subjects are to complete the pain assessments at the start of each clinic visit. Ideally, study 
subjects should not receive any information about their most recent medical results prior to 
completing the pain assessment to minimize bias. Subjects are to independently respond to pain 
questionnaires on their own.   
Every effort should be made by the study site to administer all pain assessments, including the 
assessment following radiographic progression or discontinuation of study treatment, and to keep 
them at the site as source documentation. 
Translated copies of the pain questionnaire, if required, and instructions for filling them out will 
be provided to each study site in a separate study worksheet. Pain assessments will no longer be 
collected if the study transitions to the Maintenance Phase. 
5.6.10 
Symptomatic Skeletal Events 
Symptomatic skeletal events will be continuously assessed from RSV1 through the FU-2 visit. 
The definition of an SSE is an instance of any one of the following: radiation therapy to bone, 
surgery to bone, spinal cord compression, or symptomatic fracture. 
5.6.11 
Health Care Resource Utilization 
Health care resource utilization parameters will be collected from randomization through the 
FU-2 visit. These include hospital admissions, emergency room visits, intensive care unit 

 
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admissions, length of stay, surgeries, and transfusions. These data will not be collected in the 
Maintenance Phase. 
5.6.12 
Pharmacokinetic Assessments 
Blood samples for PK assessment will be obtained from all subjects in the cabozantinib plus 
atezolizumab combination arm. Samples will be collected for plasma cabozantinib concentration 
measurement predose on RSV1, RSV2, RSV3, RSV4, and RSV5. The results will be used to 
confirm exposure to cabozantinib and to further characterize the population PK and 
exposure-response relationships for cabozantinib taken in combination with atezolizumab in this 
population. 
Serum concentrations of atezolizumab will be measured in the cabozantinib plus atezolizumab 
combination arm. Samples will be collected for serum atezolizumab concentration measurement 
predose on RSV1, RSV3, RSV5, and RSV9, RSV16, RSV19, and FU-1 and FU-2 visits. The 
results will be used to confirm exposure to atezolizumab. 
Collection of PK samples may be halted early or sampling frequency may be modified at the 
discretion of the Sponsor.  
5.6.13 
Immunogenicity Assessments 
Blood samples will be obtained from all subjects in the cabozantinib plus atezolizumab 
combination arm for immunogenicity assessment (anti-drug antibodies [ADA]) predose on 
RSV1, RSV3, RSV5, RSV9, RSV16, RSV19, and FU-1 and FU-2 visits. Samples may be 
analyzed for neutralizing ADA response to atezolizumab if ADA testing is positive, as 
applicable. 
5.6.14 
Biomarker Assessments 
The schedule of biomarker assessments is specified in Appendix A and Appendix B. The 
samples include: 
• Tumor samples (archival or fresh tumor biopsy; recommended but not required)  
o If archival tumor tissue is not available, a fresh tumor biopsy may be obtained 
prior to first dose of study treatment 
o A fresh tumor tissue biopsy may also be performed at disease progression. 
• Peripheral blood 
Please refer to Section 6.6.1.1.7 for guidance regarding biopsies.  

 
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Exploratory analyses may include but are not limited to the following: 
• Targets of the study drugs (eg, PD-L1, MET) and relevant biomarker expression levels  
• Tumor characteristics (eg, immune cell infiltration, tumor mutational burden [TMB]) in 
tumor specimens  
• Plasma biomarkers (eg, cytokines/chemokines) 
• Circulating tumor cells (CTCs) 
• Circulating tumor (ctDNA) 
A pharmacogenetic blood sample will be collected pre-dose on the first day of treatment (RSV1) 
and may be used for genotyping/single nucleotide polymorphism/copy number variation analysis 
to correlate genetic variation with the pharmacokinetics, safety, tolerability, and/or response to 
the study drug combination. This sample may also be used for assay development to facilitate 
identification of novel predictive biomarker profiles and improve treatment strategies. 
Collection of biomarker samples may be halted early or sampling frequency may be modified at 
the discretion of the Sponsor. These samples will no longer be collected if the study transitions to 
the Maintenance Phase. 
5.6.15 
Overall Survival 
Overall survival will be assessed every 8 weeks (± 7 days) after the FU-2 visit, which occurs 
100 days (±14 days) after discontinuation of study treatment. Subjects will be followed until 
death, withdrawal of consent for non-interventional study assessments, or Sponsor decision to no 
longer collect these data. Receipt of subsequent NPACT will also be collected during follow-up 
contacts. If a subject withdraws consent to participate in the study, information regarding 
survival status may be obtained from public records such as government vital statistics or 
obituaries, as permitted by local regulations.  
5.7 
Protocol Deviations 
A protocol deviation is defined as any change, divergence, or departure from the requirements or 
procedures of this protocol or from ICH GCP. Efforts should be made to limit deviations. The 
Investigator is responsible for promptly reporting protocol deviations as applicable to their 
IRB/EC and/or to the Sponsor per IRB/EC policy. The Sponsor will determine the effect of the 
protocol deviation on the scientific soundness of the clinical study and subject safety, and 
determine whether additional reports or actions are required. For important or repeated protocol 
deviations, additional action may include site re-training, hold or closure of enrollment, and/or 
site termination.  

 
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6 
TREATMENTS 
6.1 
Composition, Formulation, and Storage 
At study sites, all study medication will be stored as described in the appropriate prescribing 
information for that country (if applicable) or the pharmacy manual and inventoried in 
accordance with applicable local regulations. Special accommodations during the global 
COVID-19 pandemic are described in Appendix N. 
6.1.1 
Study Treatment 
6.1.1.1 
Cabozantinib Tablets 
The Sponsor will provide each investigator adequate supplies of cabozantinib, which will be 
supplied as 20-mg yellow film-coated round tablets. The components of the tablets are listed in 
Table 6-1.  
Table 6-1: 
Cabozantinib Tablet Components and Composition 
Ingredient  
Function 
% w/wa 
Cabozantinib Drug Substance (
 drug load as free base) 
Active Ingredient 
Microcrystalline Cellulose (Avicel® PH-102) 
Filler 
Lactose Anhydrous (60M) 
Filler 
Hydroxypropyl Cellulose (EXF) 
Binder 
Croscarmellose Sodium (Ac-Di-Sol®) 
Disintegrant 
Colloidal Silicon Dioxide 
Glidant 
Magnesium Stearate 
Lubricant 
 film coating which includes  
HPMC 2910/hypromellose 6 cp, titanium dioxide, triacetin, and iron oxide 
yellow 
Film Coating 
HPMC, Hydroxypropyl methylcellulose 
a weight fraction, expressed in percentage  
Refer to the Pharmacy Manual for details on storage and handling of cabozantinib. 
6.1.1.2 
Atezolizumab 
Atezolizumab is an Fc-engineered, humanized, monoclonal antibody (non-glycosylated IgG1 
kappa immunoglobulin) produced in Chinese hamster ovary cells with a calculated molecular 
mass of 145 kDa.  
The Sponsor will provide each investigator with adequate supplies of atezolizumab, which will 
be supplied as a 1200 mg/20 mL (60 mg/mL) colorless to slightly yellow solution in single-dose 
vials. Atezolizumab solution contains the following inactive ingredients: glacial acetic acid, 
CI
CI
CCI

 
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L-histidine, sucrose, and polysorbate 20. Refer to the package insert (or the local label) and the 
pharmacy manual for additional information and instructions for preparing atezolizumab for 
infusion. Commercially sourced solution used as diluent (0.9% NaCl) should be obtained by 
investigative sites according to local regulations. 
6.1.1.3 
Novel Hormonal Therapy (Abiraterone with Prednisone, or Enzalutamide) 
Subjects in the control arm will receive the Investigator’s choice (as selected prior to 
randomization) of one of the following: 
• Abiraterone (1000 mg po qd) plus prednisone (5 mg po bid) 
• Enzalutamide (160 mg po qd) 
Refer to the most current local prescribing information appropriate to the respective site location 
for detailed information on abiraterone, prednisone, and enzalutamide. All drugs will be 
provided centrally by the Sponsor or locally by the site, subsidiary or designee, depending on the 
local operational and/or regulatory requirements. 
6.2 
Treatment Schedule of Administration  
6.2.1 
Experimental Arm: Cabozantinib in Combination with Atezolizumab 
Cabozantinib at a dose of 40 mg (2 × 20 mg tablets) will be administered orally, once daily. 
Atezolizumab will be administered at a standard dosing regimen of 1200 mg as an IV infusion 
once every 3 weeks. 
Subjects will receive study treatment with cabozantinib and atezolizumab as long as they 
continue to experience clinical benefit as assessed by the Investigator (Section 5.6.6.2) or until 
unacceptable toxicity, the need for subsequent systemic anticancer treatment, or until any other 
reasons for treatment discontinuation listed in the protocol (Section 3.5.1). Subjects may be 
allowed to discontinue one component of the study treatment but continue to receive the other; 
Investigators are encouraged to consult with the Sponsor before doing so. 
For guidance on dose modifications, interruptions, delays, or discontinuations due to AEs, refer 
to Section 6.6.1.  
6.2.2 
Control Arm: NHT (Abiraterone with Prednisone, or Enzalutamide) 
The recommended dose for abiraterone is 1000 mg po qd. Abiraterone is to be taken with 
prednisone (5 mg po bid). Dose reduction of abiraterone to 500 mg qd is permitted for 
hepatotoxicity.  

 
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The recommended dose for enzalutamide is 160 mg po qd. Dose reduction of enzalutamide to 
120 mg qd or 80 mg qd is permitted for toxicity.  
Subjects will receive study treatment with either 1) abiraterone with prednisone, or 
2) enzalutamide as long as they continue to experience clinical benefit as assessed by the 
Investigator (Section 5.6.6.2) or until unacceptable toxicity, the need for subsequent systemic 
anticancer treatment, or until any other reasons for treatment discontinuation listed in the 
protocol (Section 3.5.1). Subjects randomized to the control arm may not switch from their 
pre-assigned NHT to the other NHT while on study. 
For detailed guidance on the administration of abiraterone plus prednisone, and enzalutamide, 
refer to the most current prescribing information appropriate to the respective site location. 
6.2.3 
Study Drug Administration in the Clinic 
The first dose of study treatment is to occur within 3 days after randomization. RSV1 is to occur 
no more than 72 hours prior to the first dose of study treatment. The first doses of all study 
treatments are to be administered at the clinic. 
6.2.3.1 
Experimental Arm: Cabozantinib plus Atezolizumab  
Atezolizumab  
For subjects on the experimental arm (cabozantinib in combination with atezolizumab), 
atezolizumab is to be administered first. 
Atezolizumab should be administered every 3 weeks and no more frequently than every 
19 days. If atezolizumab administration is not delayed for AE management, it should be 
administered within 24 days of the prior atezolizumab dose. Doses of atezolizumab are 
scheduled to be administered intravenously at the clinic by infusion on Day 1 of each 21-day 
cycles (-2 days/+3 days). Cycles may be longer than 3 weeks if atezolizumab treatment is 
delayed due to toxicity or other reasons. 
The infusion of atezolizumab (1200 mg fixed dose) will be prepared according to local 
prescribing information or the pharmacy manual. The IV administration of atezolizumab can 
only occur in a clinical setting with staff experienced in managing of infusion-related reactions 
(IRRs) and with access to emergency services. The initial IV infusion of atezolizumab will be 
given over 60 min (± 15 min) without premedication for potential IRRs or cytokine-release 
syndrome (CRS). Subsequent IV infusions may be given over 30 min (± 10 min) if the initial 
infusion is tolerated. If a subject experiences an infusion-related reaction, or if clinically 

 
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indicated, vital signs should be measured every 15 (± 5) minutes during subsequent infusions 
and at 30 (± 10) minutes after each subsequent infusion. Premedication for IRRs or CRS is 
allowed after the initial infusion. No bolus or IV push of atezolizumab is allowed. Dose delays 
will be allowed for toxicities suspected to be due to atezolizumab administration. Atezolizumab 
infusion requirements and guidance are summarized in Table 6-2.  
Table 6-2: 
Atezolizumab Infusion Requirements and Guidance 
First Infusion 
Subsequent Infusions 
• 
No premedication is permitted. 
• 
Vital signs (blood pressure, pulse, respiratory rate, 
and temperature) should be recorded within 60 min 
prior to the infusion. 
• 
Atezolizumab should be infused over 60 (± 15) min. 
• 
If clinically indicated, vital signs should be recorded 
during the infusion at 15, 30, 45, and 60 min (± 5 min 
for all time points) during the infusion and at 
30 (± 10) min after the infusion. 
• 
Subjects should be informed about the possibility of 
delayed post-infusion symptoms and instructed to 
contact their study physician if they develop such 
symptoms. 
• 
If the subject experienced an IRR or CRS with any 
previous infusion, premedication with 
antihistamines, antipyretics, and/or analgesics may 
be administered for subsequent doses at the 
discretion of the investigator. 
• 
Vital signs should be recorded within 60 min prior 
to the infusion. 
• 
Atezolizumab should be infused over 
30 (± 10) min if the previous infusion was tolerated 
without an IRR or CRS, or 60 (± 15) min if the 
subject experienced an IRR or CRS with the 
previous infusion. 
• 
If the subject experienced an IRR or CRS or if 
clinically indicated, vital signs should be measured 
every 15 (± 5) minutes during subsequent 
infusions and at 30 (± 10) min after each 
subsequent infusion. 
CRS, cytokine-release syndrome; IRR, infusion-related reaction 
After the completion of IV administration of the first dose of atezolizumab in the clinic, the 
subject will wait for at least 1 hour before taking cabozantinib. If the subject develops an 
infusion reaction or CRS, the oral administration of cabozantinib will be delayed or interrupted 
until the subject has recovered and the Investigator believes that it is safe to administer 
cabozantinib. For management of IRRs or CRS refer to Appendix G. 
Cabozantinib  
Subjects will fast (with the exception of water) for at least 2 hours before receiving cabozantinib. 
Upon completion of the 2-hour fast, the subject will receive the oral dose of cabozantinib with a 
minimum of 8 oz (240 mL) of water in the clinic and then the subject will continue to fast for 
1 hour while under observation at the clinic.  
For cabozantinib dosing on subsequent dosing days refer to Section 6.2.4. 

 
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6.2.3.2 
Control Arm: Abiraterone plus Prednisone, or Enzalutamide  
Abiraterone plus Prednisone 
On the first dosing day subjects are to take abiraterone on an empty stomach, either one hour 
before or two hours after a meal, while under observation at the clinic to monitor for potential 
AEs. The tablets are to be swallowed whole with water and should not be crushed or chewed. 
The first oral dose of prednisone will be taken with abiraterone while under observation in the 
clinic to monitor for potential AEs. The second oral dose of prednisone may be taken outside the 
clinic. Prednisone is to be taken with food and should be swallowed whole and not broken, 
divided, or chewed. 
Subsequent doses of abiraterone and prednisone will be self-administered outside the clinic 
(Section 6.2.5). 
Enzalutamide 
On the first dosing day subjects will take enzalutamide, with or without food, while under 
observation at the clinic to monitor for potential AEs. The capsules are to be swallowed whole 
and not to be chewed, dissolved, or opened. 
Subsequent doses of enzalutamide will be self-administered outside the clinic (Section 6.2.5). 
Refer to the most current abiraterone, prednisone, and enzalutamide prescribing information 
appropriate to the respective site location for details regarding recent major label changes, 
indication and usage, dosage and administration, dose modifications, contraindications, warnings 
and precautions, adverse reactions, drug interactions, and use in specific populations. 
6.2.4 
Experimental Arm: Cabozantinib Administration Outside the Clinic 
Subjects in the experimental arm (cabozantinib + atezolizumab) should take cabozantinib outside 
the clinic at approximately the same time every day, preferentially before going to bed, and 
should adhere to the fasting requirements described in this section.  
Subjects are to fast (with the exception of water) for at least 2 hours before taking their dose. 
After the 2-hour fast, subjects are to take cabozantinib with a full glass of water (minimum of 
8 oz or 240 mL) with no food intake for one more hour post-dose. If the subject’s schedule 
requires taking cabozantinib during the day, the subject is to be instructed to follow the same 
fasting recommendations.  

 
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Tablets should not be crushed or chewed. Grapefruit and Seville oranges (and products made 
from them) should be avoided while being treated with cabozantinib.  
Subjects are to be instructed to not make up vomited doses and to maintain the planned dosing 
schedule. Subjects are not to make up for missed doses if more than 12 hours have elapsed after 
the time the subject would usually take cabozantinib. In the event of missed doses, subjects are 
not to take 2 doses to make up for the one the subject missed. 
Any unused study treatment must be returned to the study site for drug accountability and 
disposal.  
6.2.5 
Control Arm: Abiraterone with Prednisone, or Enzalutamide Administration 
outside the Clinic 
Abiraterone plus Prednisone 
Abiraterone should be taken orally once daily. Abiraterone should be taken on an empty 
stomach, either one hour before or two hours after a meal. The tablets are to be swallowed whole 
with water and not crushed or chewed. Subjects should be instructed that if a dose of abiraterone 
is missed, the prescribed dose should be taken the following day. Subjects should not take more 
than the prescribed doses of abiraterone or prednisone each day. 
Prednisone is to be taken with abiraterone. Prednisone is to be taken orally twice daily with food 
and should be swallowed whole and not broken, divided, or chewed. For missed doses, subjects 
should be told to take the missed dose as soon as they remember. If it is almost time for the next 
dose, the missed dose should be skipped and the medicine taken at the next regularly schedule 
time. Subjects should not take an extra dose to make up for the missed dose. Subjects should be 
warned not to discontinue the use of prednisone abruptly or without medical supervision. 
Enzalutamide 
Enzalutamide should be taken orally once daily, at the same time each day. Enzalutamide can be 
taken with or without food. The capsules are to be swallowed whole and not to be chewed, 
dissolved, or opened. Subjects should be instructed that if a dose of enzalutamide is missed, the 
prescribed dose should be taken as soon as remembered on that day. If the daily dose is missed, 
then the prescribed dose should be taken at the regular time the next day. Subjects should not 
take more than the prescribed dose of enzalutamide each day. 
Refer to the most current abiraterone, prednisone, and enzalutamide prescribing information 
appropriate to the respective site location for more details regarding recent major label changes, 

 
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indication and usage, dosage and administration, dose modifications, contraindications, warnings 
and precautions, adverse reactions, drug interactions, and use in specific populations. 
6.3 
Treatment after Study Completion 
After study completion (see Section 3.5.3), subjects who continue to demonstrate clinical benefit 
may be eligible to receive Exelixis-supplied study treatment for the maximum treatment duration 
specified in Section 6.2 during the Maintenance Phase. Alternatively, study treatment may be 
provided via a rollover study requiring approval by the responsible health authority and ethics 
committee or through another mechanism at the discretion of Exelixis.  
Exelixis reserves the right to terminate access to Exelixis-supplied study treatment if any of the 
following occur:  
a) The study is terminated due to safety concerns. 
b) The development of atezolizumab or cabozantinib is terminated for other reasons, 
including but not limited to lack of efficacy and/or not meeting the study objectives (eg, 
the null hypothesis is rejected for neither PFS nor OS).  
c) The participant can obtain medication from a government-sponsored or private health 
program.  
In all cases Exelixis will follow local regulations. Exelixis will work with study investigators to 
act in the best interest of subjects. 
6.4 
Compliance 
Subject compliance with outpatient study treatment will be assessed by the site using drug 
dispensing and return records, infusion logs, progress notes about dose reductions/interruptions, 
and subject interview. These data will not be directly recorded in the CRF; rather, the CRF will 
capture infusion details and, for oral study treatment, intervals of constant dose and reasons for 
changes in dose level (eg, a new record completed each time dose level changes, including 
periods where no dose was taken, and the reason for a dose level change). 
6.5 
Study Treatment Accountability 
The Investigator or designee will maintain accurate records of receipt of all study treatment 
including dates of receipt. In addition, accurate records will be kept regarding when and how 
much study treatment is dispensed and used by each subject in the study. Reasons for deviation 
from the expected dispensing regimen must also be recorded. Drug accountability will be 

 
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performed periodically by the Sponsor or designee at interim monitoring visits. At completion of 
the study, to satisfy regulatory requirements regarding drug accountability, all unused study 
treatment will be reconciled and destroyed according to applicable state, federal, and local 
regulations. 
6.6 
Safety Considerations 
Subjects will be monitored for SAEs from the time of signing informed consent and for 
nonserious AEs from first dose of study treatment. Monitoring for nonserious AEs continues 
through the FU-1 visit (FU-2 visit for AESIs [Table 8-1] regardless of seriousness and for 
unrelated SAEs). Longer monitoring periods are required for related SAEs and certain other 
events as described in Section 8.4. Further details for follow-up and data collection requirements 
for AEs, SAEs, and AESIs are summarized in Appendix J. Subjects will be instructed to notify 
their physician immediately for any occurring AE. Causality assessment of AEs should, at a 
minimum, take into account confounding factors such as underlying disease and concomitant 
medications. Adverse event severity will be graded by the Investigator according to CTCAE v5.  
For the combination study treatment (experimental arm), the following should be taken into 
consideration in decisions regarding management for treatment-related side effects:  
• Cabozantinib and atezolizumab have class-specific safety profiles based on their mechanisms 
of action but may also cause AEs that overlap. For management of AEs clearly attributed to 
cabozantinib or atezolizumab, independent dose modification for either agent is allowed.  
o 
Examples of VEGFR-TKI associated AEs caused by cabozantinib are hypertension 
and hand-foot syndrome. 
o 
Examples of AESIs caused by atezolizumab are pneumonitis and endocrinopathies.  
• For AEs without clear attribution to either study treatment, management of toxicity should 
include dose modifications of both agents per the discretion of the Investigator.  
o Examples of overlapping AEs are diarrhea and transaminase increases. 
As a general approach, all AEs should be managed with supportive care including both 
pharmacological and non-pharmacological treatments according to consensus management 
guidelines at the earliest signs of toxicity considered related to study treatment.  
Study treatment may be continued following mild AEs if appropriate supportive care has been 
initiated to ameliorate symptoms. Should this be ineffective and toxicities become unacceptable, 

 
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dose modifications of study treatment should be considered to prevent worsening of toxicity. 
Moderate to severe AEs usually require dose modifications including dose reductions and/or 
interruptions. 
Although most irAEs observed with immunomodulatory agents have been mild and limiting, in 
severe cases immune-mediated toxicities may require acute management with topical 
corticosteroids, systemic corticosteroids, or other immunosuppressive agents. Given that the 
discontinuation of atezolizumab alone may not lead to rapid alleviation of symptoms and may 
not be sufficient for management of some irAEs, such events should be recognized early and 
treated promptly to avoid potential major complications. For detailed guidance on the 
management of irAEs associated with atezolizumab, see Section 6.6.2.1. 
Dose interruptions and/or reductions of cabozantinib or delays of atezolizumab (atezolizumab 
reductions are not allowed) for AEs may occur at any time and independently at the discretion of 
the Investigator. If either or both study treatments are interrupted for more than 12 weeks, the 
Sponsor should be contacted to discuss potential treatment continuation. Atezolizumab may be 
withheld for a period of time beyond 12 weeks to allow for corticosteroids to be reduced to 
≤ 10 mg/day oral prednisone or equivalent. The acceptable length of the extended period of time 
must be based on an assessment of benefit−risk by the Investigator and in alignment with the 
protocol requirements for the duration of treatment and documented by the Investigator. The 
Sponsor is available to advise as needed.  
For recommendations on dose modifications of cabozantinib treatment, see Section 6.6.1; for 
recommendations on dose modifications of atezolizumab treatment, see Section 6.6.2. 
Dose interruptions or reductions of abiraterone or of enzalutamide for AEs may also occur at any 
time at the discretion of the Investigator. If study treatment is interrupted for more than 
12 weeks, the Sponsor should be contacted to discuss potential treatment continuation. Refer to 
the most current abiraterone, prednisone, or enzalutamide prescribing information appropriate to 
the respective site location for details regarding dose interruptions and dose modifications.  
6.6.1 
Management of AEs Associated with Cabozantinib 
The assigned dose for cabozantinib in the experimental arm is 40 mg qd. Considerations for 
management of AEs associated with cabozantinib are presented below.  
• Two dose reduction levels of cabozantinib (20 mg daily, and 20 mg every other day 
[qod]) are permitted on the experimental arm (see Table 6-3). 

 
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• Dose modification criteria for treatment-related AEs of cabozantinib are shown in Table 
6-4. 
• Guidance for dose reinstitution and reescalation after dose interruptions and/or reductions 
are as follows:  
o If the subject recovers from his toxicities to ≤ Grade 1 per CTCAE v5 or to the 
baseline value (or lower) and the AE was unrelated to cabozantinib, then cabozantinib 
may be restarted with no change in dose.  
o If the subject recovers from his toxicities to ≤ Grade 1 or to the baseline value (or 
lower) and the AE was deemed possibly related to cabozantinib, then cabozantinib 
may be restarted at the same dose or at a reduced dose (see Table 6-4), as deemed 
appropriate by the Investigator. Furthermore, subjects who initiated treatment with 
cabozantinib at 40 mg and experience a possibly related AE of Grade 1 or 2 severity 
may be restarted with no dose change after recovery of the toxicities to ≤ Grade 1 or 
to the baseline value (or lower) if appropriate supportive care can prevent or 
minimize the risk of the AE. 
o Subjects receiving a dose of 20 mg every other day (qod) on the experimental arm 
who have cabozantinib interrupted may be restarted at the same dose if deemed safe 
at the discretion of the Investigator. Subjects unable to tolerate a dose of 20 mg every 
other day (qod) must discontinue cabozantinib. 
o Reescalation to the previous dose may be allowed at the discretion of the Investigator 
but no sooner than 2 weeks beyond recovery to Grade 1 (or baseline grade) with the 
event deemed tolerable and easily managed by optimized supportive treatment.  
o Dose reescalation is not allowed following a cabozantinib-related dose reduction for 
Grade 4 hematological toxicities or Grade 4 AEs affecting major organs (eg, CNS, 
cardiac, hepatic, renal, pulmonary, GI). 
• Guidelines for the management of specific AEs of cabozantinib such as GI disorders, non-GI 
fistula formation, hemorrhage, thromboembolic events, hypertension, stomatitis and 
mucositis, skin disorders, osteonecrosis, proteinuria, nervous system disorders, hepatocellular 
toxicity, infections and infestations, blood system disorders, fatigue, weight loss, QTc 
prolongation, electrolyte disorders, endocrine disorders, and respiratory disorders are 
provided in Section 6.6.1.1. 

 
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Table 6-3: 
Dose Levels of Cabozantinib (Oral Dosing) 
Assigned Starting 
Dose 
First Dose Level 
Reduction 
Second Dose Level 
Reduction 
Third Dose Level 
Reduction 
40 mg daily (qd) 
(Experimental arm) 
20 mg daily (qd) 
20 mg every other day 
(qod)a  
No dose reduction 
permitted 
a Cabozantinib will be discontinued in the experimental arm if a dose of 20-mg cabozantinib every other day is 
not tolerated.  
Table 6-4: 
General Dose Modification Guidelines for Cabozantinib-Related AEs 
CTCAE v5 Grade 
Recommended Guidelines for Management 
Grade 1 or 2 AEs that are tolerable 
and are easily managed 
Add supportive care as indicated. Continue cabozantinib at 
the current dose level if AE is manageable and tolerable. 
Grade 1 or 2 AEs that are intolerable 
and cannot be adequately managed 
Grade 3 AEs (except clinically 
non-relevant laboratory abnormalities) 
Cabozantinib should be interrupted unless the toxicity can be 
easily managed with a dose reduction of cabozantinib and 
optimal medical care.  
Note: It is recommended that dose interruptions be as brief as 
possible. 
Grade 4 AEs (except clinically 
non-relevant laboratory abnormalities) 
Cabozantinib must be interrupted immediately.  
In general, cabozantinib should be discontinued unless the 
following criteria are met:  
• 
Subject is deriving clear clinical benefit as determined 
by the investigator and agreed by the Sponsor 
• 
Toxicity can be managed with a dose reduction of 
cabozantinib following recovery to Grade 1 (or 
baseline) and optimal medical care  
Sponsor must be contacted to discuss treatment continuation 
upon resolution of AEs.  
AE, adverse event. 
Note: Cabozantinib dose modification criteria for specific medical conditions are provided in Section 6.6.1.1.  

 
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6.6.1.1 
Warnings, Precautions, and Management Guidelines for Adverse Events 
Associated with Cabozantinib Treatment 
The most frequent AEs experienced by ≥ 20% of subjects treated with cabozantinib in 
descending order of frequency were diarrhea, fatigue, nausea, decreased appetite, vomiting, 
weight decreased, PPE, constipation, hypertension, dysgeusia, dysphonia, and asthenia. For a full 
description of the safety profile of cabozantinib, refer to the cabozantinib Investigator’s 
Brochure. 
Other medically important but less frequent AEs include arterial thrombotic AEs (eg, TIA, and 
MI) and venous thrombotic AEs (eg, DVT and PE), severe hemorrhagic events, proteinuria, 
wound healing complications, GI perforation, abscesses including intra-abdominal and pelvic 
abscess, GI and non-GI fistula formation, osteonecrosis, and reversible posterior 
leukoencephalopathy syndrome (RPLS; preferred term: posterior reversible encephalopathy 
syndrome [PRES]). 
Adverse events associated with laboratory test abnormalities that were experienced by ≥ 5% of 
cabozantinib-treated subjects in descending order of frequency were anemia, AST increased, 
ALT increased, hypothyroidism, hypokalemia, hypomagnesemia, thrombocytopenia, 
hypocalcemia, hypophosphatemia, lactate dehydrogenase (LDH) increased, lipase increased, 
neutropenia, hyponatremia, alkaline phosphatase (ALP) increased, leukopenia, 
and hyperglycemia. 
Adverse events may occur within the first few weeks in the course of treatment with 
cabozantinib, as cabozantinib is expected to reach steady state exposure at approximately 
2 weeks following first dose. Events that generally have an early onset include hypocalcemia, 
hypokalemia, thrombocytopenia, hypertension, PPE, abdominal pain, mucosal inflammation, 
constipation, diarrhea, and vomiting. Adverse events should be managed with supportive care at 
the earliest signs of toxicity. Dose reductions and treatment interruptions should be considered. 
Dose reductions are recommended for events that, if persistent, could become serious or 
intolerable (Table 6-3). 
Cabozantinib should be permanently discontinued for the following AEs regardless of whether 
these events are deemed related to cabozantinib: visceral perforation or fistula formation, serious 
and life-threatening rhabdomyolysis, severe hemorrhage, serious arterial thromboembolic events, 
nephrotic syndrome, hypertension with life threatening consequences, persistent uncontrolled 
hypertension despite optimal medical management, and RPLS. 

 
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6.6.1.1.1 Gastrointestinal Disorders 
Gastrointestinal (GI) perforation, GI fistula, and intra-abdominal and pelvic abscess: After 
starting treatment with cabozantinib, subjects should be monitored for early signs of GI 
perforation such as abdominal pain, nausea, emesis, constipation, and fever especially if known 
risk factors for developing GI perforation or fistula (Turnage and Badgwell 2016) are present. 
Discontinue cabozantinib and initiate appropriate management in subjects who have been 
diagnosed with GI perforation or fistula. 
Diarrhea: Subjects should be instructed to notify their physician immediately at the first signs of 
poorly formed or loose stool or an increased frequency of bowel movements. Guidelines for the 
evaluation and management of diarrhea are shown in Table 6-5. Administration of 
antidiarrheal/antimotility agents is recommended at the first sign of diarrhea as initial 
management. Some subjects may require concomitant treatment with more than one antidiarrheal 
agent. When therapy with antidiarrheal agents does not control the diarrhea to tolerable levels, 
cabozantinib should be temporarily interrupted or dose reduced. When the diarrhea is controlled, 
retreatment with cabozantinib may be acceptable per Investigator decision. In addition, general 
supportive measures should be implemented such as continuous oral isotonic hydration, 
correction of fluid and electrolyte abnormalities, small frequent meals, and stopping lactose-
containing products, high-fat meals, and alcohol. 
Recurrent or prolonged diarrhea can be associated with anal or perianal skin erosions which 
increase the risk for anal abscesses, fistulas, or proctitis. Good personal hygiene should be 
emphasized. Regular examinations of the perianal region should be performed whenever diarrhea 
has occurred during treatment with cabozantinib. Infections of the perianal region should be 
treated per local guidelines. 

 
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Table 6-5: 
Management of Diarrhea Associated with Cabozantinib 
Status 
Management 
Tolerable Grade 1-2 
(duration < 48 h) 
• 
Continue with study treatment and consider dose reduction 
• 
Initiate treatment with an antidiarrheal agent (eg, loperamide 4 mg followed 
by 2 mg after each episode of diarrhea [maximum: 16 mg loperamide per 
day]) 
• 
Dietary modifications (eg, small lactose-free meals, bananas and rice) 
• 
Intake of isotonic fluids (1-1.5 L/day) 
• 
Re-assess after 24 hours: 
o 
Diarrhea resolving to baseline bowel habits: gradually add solid 
foods and discontinue or decrease antidiarrheal treatment after 12 h 
diarrhea-free interval 
• 
Diarrhea not resolving: Continue/resume antidiarrheal treatment 
Intolerable Grade 2, 
Grade 2 > 48 h,  
or ≥ Grade 3 
• 
Interrupt study treatment 
• 
Ask subject to attend clinic 
• 
Rule out infection (eg, stool sample for culture) 
o 
Administer antibiotics as needed (eg, if fever or Grade 3-4 
neutropenia persists > 24 h) 
• 
Administer fluids (1-1.5 L/day orally or IV, as appropriate) for hydration or 
to correct electrolyte abnormalities 
• 
For Grade 3-4 or complicated lower-grade diarrhea consider hospitalization 
and IV hydration 
• 
Re-assess after 24 h 
o 
Diarrhea resolving to baseline bowel habits or Grade ≤ 1: consider 
restarting study treatment at reduced dose 
o 
Diarrhea not resolving: Start and or continue antidiarrheal treatment 
(eg, loperamide 4 mg followed by 2 mg after each episode of 
diarrhea [maximum: 16 mg loperamide per day]). Consider starting 
second line antidiarrheal or referral to gastroenterologist  
 
Nausea and vomiting: Antiemetic agents are recommended as clinically appropriate for treatment 
or prophylaxis of nausea and vomiting, along with supportive care. Dehydration and electrolyte 
abnormalities may be associated with vomiting and monitoring for and correction of fluid and 
electrolyte disturbances should be implemented. Antiemetic medications should be assessed for 
potential drug interactions (refer to Section 7.3 for further details). 
6.6.1.1.2 Non-Gastrointestinal Fistula 
Complications from radiation therapy especially of the thoracic cavity including mediastinum 
have been identified as a possible predisposing risk factor for non-GI fistula formation in 
subjects undergoing treatment with VEGF pathway inhibitors. 

 
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Discontinue cabozantinib and initiate appropriate management in subjects who have been 
diagnosed with a non-GI fistula. 
6.6.1.1.3 Hemorrhage 
Hemorrhagic events, including serious and sometimes fatal events, have been reported with 
cabozantinib. Subjects should be monitored for bleeding events with serial complete blood 
counts and physical examination while on study. The risk of hemorrhage in cabozantinib-treated 
subjects with brain metastases has not been thoroughly analyzed. Subjects enrolled with treated 
and stable brain metastases should be monitored with a high index of suspicion if symptoms that 
could be due to a CNS hemorrhage occur. 
Cabozantinib should be discontinued in subjects with serious and life-threatening bleeding 
events or recent hemoptysis (≥ 2.5 mL of red blood). 
6.6.1.1.4 Thromboembolic events  
Thromboembolic events are frequent in cancer subjects due to procoagulant changes induced by 
the malignancy or anticancer therapy. Deep vein thrombosis (DVT) and pulmonary 
embolism (PE) have been observed in clinical studies with cabozantinib, including fatal events. 
Subjects who develop a PE and/or DVT should have study treatment interrupted until therapeutic 
anticoagulation is established. Treatment with cabozantinib may be resumed in subjects with PE 
or DVT if it is determined that the event is uncomplicated and that the subject is deriving clinical 
benefit from cabozantinib treatment and that anticoagulation does not place them at a significant 
risk that outweighs the benefit of resuming treatment per discretion of the Investigator. 
Therapeutic doses of LMWH or the direct factor Xa inhibitors rivaroxaban, edoxaban, or 
apixaban are allowed for the management of thrombotic events. Other oral anticoagulants 
including, but not limited to, platelet inhibitors (eg, clopidogrel or ticagrelor), warfarin, 
dabigatran, and betrixaban, and chronic use of aspirin above low dose levels for cardioprotection 
per local applicable guidelines are not allowed until 4 weeks after cabozantinib has been 
permanently discontinued.  
Arterial thrombotic events (eg, TIA, myocardial infarction) have been observed in studies with 
cabozantinib. Further treatment with cabozantinib should be discontinued in subjects who 
develop an acute myocardial infarction, cerebral infarction, or any other clinically significant 
arterial thromboembolic complication, regardless of causality assessment. 
6.6.1.1.5 Hypertension 
Table 6-6 provides treatment guidelines for hypertension deemed related to cabozantinib. Blood 
pressure should be monitored in a constant position visit to visit, either sitting or supine in a 

 
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relaxed setting. Decisions to reduce or interrupt the dose of study treatment must be based on BP 
readings taken by a medical professional and must be confirmed with a second measurement at 
least 5 minutes following the first measurement.  
Cabozantinib should be discontinued in subjects with hypertension with life threatening 
consequences or when urgent intervention is indicated, and appropriate medical management 
should be initiated. 

 
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Table 6-6: 
Management of Hypertension Associated with Cabozantinib 
Criteria for Dose Modifications 
Treatment/Cabozantinib Dose Modification 
> 150 mm Hg (systolic)a and < 160 mm Hg 
OR 
> 90 mm Hg (diastolic) and < 110 mm Hg 
 
• 
Optimize antihypertensive medications by adding new or 
additional antihypertensive medications and/or increase 
dose of existing medications. 
• 
Reduce cabozantinib treatment by one dose level if optimal 
antihypertensive therapy (usually to include 3 agents) does 
not result in BP ≤ 150 mm Hg systolic and ≤ 90 mm Hg 
diastolic 
• 
If subject is symptomatic, interrupt cabozantinib treatment 
and restart only if symptoms have resolved and BP is 
≤ 150 mm Hg systolic and ≤ 90 mm Hg diastolic 
≥ 160 mm Hg (systolic) 
OR 
≥ 110 mm Hg (diastolic) 
• 
Reduce cabozantinib by one dose level or interrupt 
cabozantinib treatment per Investigator discretion. 
Treatment should be interrupted if upper limits of systolic 
BP (≥ 160 mm Hg) or diastolic BP (≥ 110 mm Hg) are 
sustained and not adequately manageable, or if systolic BP 
is > 180 mm Hg, or if subject is symptomatic. 
• 
Add new or additional anti-hypertensive medications and/or 
increase dose of existing medications and monitor subject 
closely for hypotension. If optimized antihypertensive 
therapy (usually to include 3 agents) does not result in BP 
≤ 150 mm Hg systolic and ≤ 90 mm Hg diastolic, 
cabozantinib treatment should be dose reduced further or 
interrupted 
• 
Re-start cabozantinib treatment at reduced dose and 
re-escalate only if BP falls to and is sustained at 
≤ 150 mm Hg systolic and ≤ 90 mm Hg diastolic 
Hypertension with life threatening 
consequences (eg, malignant hypertension, 
transient or permanent neurologic deficit, 
hypertensive crisis); urgent intervention 
indicated 
 
• 
Discontinue cabozantinib treatment 
• 
Initiate appropriate medical management 
BP, blood pressure. 
a The Investigator may decide to initiate or adjust antihypertensive treatment at a lower threshold than systolic BP > 150 mm 
Hg or diastolic BP > 90 mm Hg based on their clinical judgment and assessment of the individual subject. 
 
6.6.1.1.6 Stomatitis and Mucositis 
Preventive measures may include a comprehensive oral examination to identify and treat any 
potential risk for complications before study treatment is initiated. Appropriate correction of 
local factors should be instituted as indicated, such as modification of ill-fitting dentures and 
appropriate care of gingivitis. During treatment with cabozantinib, good oral hygiene and 

 
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standard local treatments such as non-traumatic and non-irritating cleansing, and oral rinses 
(eg, with a weak solution of salt and baking soda) should be maintained. Lips should be kept 
moisturized with lip balm. The use of lipstick, lip-gloss, and Vaseline should be avoided. 
Local treatment should be instituted at the earliest onset of symptoms. Obtain bacterial/viral 
culture if oral infection is suspected and treat infection as clinically indicated.  
6.6.1.1.7 Skin and Subcutaneous Tissue Disorders 
Wound healing and surgery: Cabozantinib has the potential to cause wound healing 
complications and wound dehiscence, which may even occur long after a wound has been 
considered healed. Therefore, surgical and traumatic wounds must not only be completely healed 
prior to starting cabozantinib treatment but must also be monitored for wound dehiscence, wound 
infection and other signs of impaired wound healing while the subject is being treated with 
cabozantinib. If dehiscence occurs, cabozantinib treatment should not be restarted until complete 
healing has taken place. 
Treatment with cabozantinib should be stopped at least 28 days prior to elective surgery (for 
tumor biopsies at least 10 days before the procedure). The decision to resume treatment with 
cabozantinib after surgery or biopsies should be based on clinical judgment of adequate wound 
healing. 
For biopsies collected via major surgery, please consult with the Sponsor. 
Palmar-plantar erythrodysesthesia (PPE; also known as hand-foot syndrome), skin rash 
(including blister, erythematous rash, macular rash, skin exfoliation, dermatitis acneiform, and 
papular rash), pruritus, dry skin, erythema, pigmentary changes, and alopecia have been reported 
with cabozantinib. All subjects on study should be advised on prophylactic measures including 
the use of emollients, removal of calluses, avoidance of exposure of hands and feet to hot water 
leading to vasodilatation, protection of pressure-sensitive areas of hands and feet, and use of 
cotton gloves and socks to prevent injury and keep the palms and soles dry. 
Early manifestations include tingling, numbness, mild hyperkeratosis, and symmetrical red and 
swollen areas on the palms and soles. The lateral sides of the fingers or periungual zones may 
also be affected. Adequate interventions are required to prevent worsening of skin symptoms 
such as blisters, desquamations, ulcerations, or necrosis of affected areas. Analgesics may be 
required for pain control. 
Aggressive management of symptoms is recommended, including early dermatology referral. 
Treatment recommendations in response to PPE are summarized in Table 6-7. 

 
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Table 6-7: 
Management of Palmar-plantar Erythrodysesthesia (PPE) Associated with 
Cabozantinib 
CTCAEv5 Grade  
Action To Be Taken  
Grade 1 
Cabozantinib treatment may be continued at the current dose if PPE is clinically 
insignificant and tolerable. Otherwise, cabozantinib should be reduced to the next 
lower dose level. Start urea 20% cream twice daily AND clobetasol 0.05% cream 
once daily. Reassess at least weekly; if PPE worsens at any time or does not 
improve after 2 weeks, proceed to the intervention guidelines for Grade 2. 
Grade 2  
Cabozantinib treatment may be continued if PPE is tolerated. Cabozantinib 
should be dose reduced or interrupted if PPE is intolerable. Continue urea 20% 
cream twice daily AND high potency steroid cream (eg, clobetasol 0.05%) once 
daily and add analgesics (eg, NSAIDs/gamma-aminobutyric acid agonists) for 
pain control if needed. Reassess at least weekly; if PPE worsens or affects 
self-care, proceed to the intervention guidelines for Grade 3. 
Grade 3 
Interrupt cabozantinib treatment until severity decreases to Grade 1 or 0. 
Continue treatment of skin reaction with high potency steroid cream (eg, 
clobetasol 0.05%) twice daily AND analgesics. Resume cabozantinib at a 
reduced dose if PPE recovers to Grade ≤ 1. Discontinue subject from study 
treatment if PPE does not improve within 6 weeks. 
CTCAE, Common Terminology Criteria for Adverse Events; NSAID, non-steroidal anti-inflammatory drug; PPE, palmar-
plantar erythrodysesthesia 
 
6.6.1.1.8 Osteonecrosis 
Osteonecrosis has been reported in subjects treated with cabozantinib. Additional risk factors 
include use of bisphosphonates and denosumab, chemotherapy and anti-angiogenic drugs, use of 
corticosteroids, local radiotherapy, and dental or orofacial surgery procedures.  
Osteonecrosis of the jaw (ONJ) can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, 
tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain 
or slow healing of the mouth or jaw after dental surgery may also be manifestations of 
osteonecrosis. 
Advise subjects regarding oral hygiene practice and to quickly report symptoms to investigator. 
Caution should be used in subjects receiving bisphosphonates. 
Invasive dental procedures should be avoided. In cases where dental procedures are unavoidable, 
treatment with cabozantinib should be interrupted for at least 4 weeks prior to the procedure and 
resumed after complete wound healing has occurred. Bone healing may often require a 
protracted time. 

 
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6.6.1.1.9 Proteinuria 
Proteinuria has been reported with cabozantinib. Proteinuria should be monitored by measuring 
UPCR or 24-hour urine protein assessment. Table 6-8 provides treatment guidelines for 
proteinuria deemed related to cabozantinib.  
Cabozantinib should be discontinued in subjects who develop nephrotic syndrome 
(proteinuria > 3.5 grams per day in combination with low blood protein levels, high cholesterol 
levels, high triglyceride levels, and edema).  
Table 6-8: 
Management of Proteinuria Associated with Cabozantinib 
Severity of Proteinuria 
(UPCR) 
Management of Proteinuria 
≤ 1 mg/mg 
(≤ 113.1 mg/mmol) 
• 
No change in cabozantinib treatment or monitoring 
> 1 and < 3.5 mg/mg 
(> 113.1 and < 395.9 
mg/mmol) 
• 
Consider confirming with a 24-h urine protein assessment within 7 days 
• 
No change in cabozantinib treatment required if UPCR ≤ 2 mg/mg or urine 
protein ≤ 2 g/24 h on 24-h urine collection. 
• 
Dose reduce or interrupt cabozantinib treatment if UPCR > 2 mg/mg on 
repeat UPCR testing or urine protein > 2 g/24 h on 24-h urine collection. 
Continue cabozantinib on a reduced dose if UPCR decreases to < 2 mg/mg. 
Consider interrupting cabozantinib treatment if UPCR remains > 2 mg/mg 
despite a dose reduction until UPCR decreases to < 2 mg/mg. Restart 
cabozantinib treatment at a reduced dose after a dose interruption unless 
otherwise approved by Sponsor. 
• 
If UPCR > 2 mg/mg, repeat UPCR monitoring within 7 days and once per 
week. If UPCR < 2 mg/mg on 2 consecutive readings, UPCR monitoring 
can revert to protocol-specific times. (Second reading is confirmatory and 
can be done within 1 week of first reading.) 
≥ 3.5 mg/mg 
(≥ 395.9 mg/mmol) 
• 
Interrupt cabozantinib treatment pending repeat UPCR monitoring within 
7 days and/or 24-h urine protein.  
• 
If ≥ 3.5 mg/mg on repeat UPCR monitoring, continue to interrupt 
cabozantinib treatment and check UPCR every 7 days. If UPCR decreases 
to < 2 mg/mg, restart cabozantinib treatment at a reduced dose and 
monitoring of UPCR until it remains < 2 mg/mg on two consecutive 
measurements. If UPCR monitoring is determined to be stable (< 20% 
change) for 1 month then continue with UPCR monitoring per protocol or 
as clinically indicated. 
Nephrotic syndrome 
• 
Discontinue cabozantinib treatment 
UPCR, urine protein/creatinine ratio. 
 

 
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6.6.1.1.10 Nervous System Disorders 
Cabozantinib appears to represent minimal risk of adverse neurological effects based on 
nonclinical Good Laboratory Practice (GLP)-compliant toxicology studies. Dysphonia, 
dysgeusia, headache, dizziness, confusional state, convulsion, depression, memory impairment, 
hypoesthesia, peripheral neuropathy, insomnia, ataxia, and encephalopathy have been observed 
in clinical studies with cabozantinib. The development of any new or progressive, unexplained 
neurological symptoms should be assessed for underlying causes. 
RPLS has been reported. RPLS should be considered in any subject presenting with seizures, 
headache, visual disturbances, confusion or altered mental function. Cabozantinib treatment 
should be discontinued in subjects with RPLS. 
6.6.1.1.11 Hepatocellular Toxicity 
Elevations of aminotransferases (ALT and AST) and bilirubin have been observed during 
treatment with cabozantinib. It is recommended that subjects with elevation of ALT, AST, and/or 
bilirubin have more frequent laboratory monitoring of these parameters. If possible, hepatotoxic 
concomitant medications should be discontinued in subjects who develop increased values of 
ALT, AST, or bilirubin, and other causes (eg, cancer-related, or infection) should be evaluated. 
Management guidelines for hepatotoxicity (hypertransaminasemia) related to cabozantinib 
treatment are provided in Table 6-9. 

 
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Table 6-9: 
Management of Hepatotoxicity Associated with Cabozantinib 
Severity of Transaminase (ALT or AST) 
Elevation by CTCAE 
Treatment/Cabozantinib Dose Modification 
Grade 1 
• Dose adjustment is usually not required. 
• Consider discontinuing concomitant hepatotoxic 
medications and adding supportive care as indicated.  
Grade 2 
• Interrupt cabozantinib. 
• Restart cabozantinib, at the same dose or a reduced dose at 
Investigator discretion, after laboratory abnormalities have 
resolved to no higher than CTCAE Grade ≤ 1 or baseline 
grade. 
Grade ≥ 3 
• Interrupt cabozantinib and consider more frequent 
monitoring of ALT and/or AST. 
• Restart cabozantinib at a reduced dose after lab 
abnormalities have resolved to CTCAE Grade ≤ 1 or 
baseline grade. 
• Discontinue if lab abnormalities cannot be reversed 
despite interruption of cabozantinib or if Grade 3 or higher 
abnormality recurs upon rechallenge. 
ALT or AST > 8 × ULN 
OR 
ALT or AST > 3 × ULN in combination with 
total bilirubin > 2 × ULN without reasonable 
other explanation, consistent with DILI 
• Discontinue cabozantinib 
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CTCAE, Common Terminology Criteria for Adverse 
Events; DILI, drug-induced liver injury 
  
6.6.1.1.12 Infections and Infestations 
Infections are commonly observed in cancer subjects. Predisposing risk factors include decreased 
immune status (eg, after myelosuppressive anticancer therapies, splenectomy), destructive 
growth of the underlying malignancy including bone marrow infiltration with suppression of 
normal hematopoiesis, as well as the presence of IV devices.  
Infections and abscesses should be treated with appropriate local care and systemic therapy. 
Cabozantinib should be interrupted until adequate healing has taken place. 

 
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6.6.1.1.13 Blood and Lymphatic System Disorders 
Hematological toxicities (ie, neutropenia and thrombocytopenia) and associated complications 
have been observed after administration of cabozantinib and may be managed with dose 
interruptions and/or dose reductions. Subjects with hematologic toxicities may require additional 
or more frequent laboratory tests according to institutional guidelines. 
Dose reductions or dose interruptions for hematological toxicities are not mandated but can be 
applied as clinically indicated. Supportive care for thrombocytopenia or anemia, such as 
transfusions, may be managed according to institutional guidelines. The use of 
colony-stimulating growth factors should be considered. Febrile neutropenia or evidence of 
infection associated with neutropenia must be assessed immediately and treated appropriately 
and in a timely manner according to institutional guidelines. 
6.6.1.1.14 Fatigue 
Common causes of fatigue, such as anemia, deconditioning, emotional distress (depression 
and/or anxiety), poor nutrition, dehydration, sleep disturbance, and hypothyroidism should be 
ruled out and treated according to standard of care. Pharmacological management should be 
considered after disease-specific morbidities have been excluded when not prohibited.  
6.6.1.1.15 Weight Loss 
Anorexia and weight loss should be managed according to local standard of care including 
nutritional support. Pharmacologic therapy should be considered for appetite enhancement when 
not prohibited by a particular protocol. 
6.6.1.1.16 Corrected QT Prolongation 
The effect of orally administered cabozantinib 140 mg qd on QTc interval was evaluated in a 
placebo-controlled study in subjects with medullary thyroid cancer (MTC). A mean increase in 
QTcF of 10-15 ms was observed after 4 weeks after initiating cabozantinib treatment. A 
concentration-QTc relationship could not be definitively established. Changes in cardiac wave 
form morphology or new rhythms were not observed. No cabozantinib-treated subjects in this 
study had a QTcF > 500 ms. Review of the larger safety database (approximately 5000 subjects 
exposed to cabozantinib in clinical trials and in post-marketing experience) confirmed the 
absence of safety concerns associated with QT prolongation. There were no events of torsades de 
pointes reported. 
Concomitant treatment with strong cytochrome P450 (CYP) 3A4 inhibitors, which may increase 
cabozantinib plasma concentrations, should be avoided.  

 
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If at any time on study there is an increase in QTcF to an absolute value > 480 ms at screening or 
> 500 ms at RSV1 onwards or an increase in QTcF of > 60 ms above baseline at RSV1 onwards, 
two additional ECGs must be performed with intervals not less than 3 min apart within 30 min 
after the initial ECG. 
If the average QTcF from the three ECGs is > 500 ms or there is an increase of > 60 ms above 
baseline, the following actions must be taken: 
• Interrupt cabozantinib treatment 
• Immediately notify the Sponsor 
• Hospitalize symptomatic subjects (eg, with palpitations, dizziness, syncope, orthostatic 
hypotension, a significant ventricular arrhythmia on ECG) for a thorough cardiology 
evaluation and management 
• Consider cardiology consultation for asymptomatic subjects for evaluation and management 
• Check electrolytes, especially magnesium, potassium and calcium; correct abnormalities as 
clinically indicated 
• Check concomitant medications for any medication that may have contributed to QT 
prolongation, and if possible, discontinue these medications (http://www.qtdrugs.org) 
• Send ECGs to central ECG reader for independent read 
• Repeat ECG triplicates hourly until the average QTcF is ≤ 500 ms and the average increase is 
≤ 60 ms above baseline, or a consulting cardiologist or appropriate expert determines that the 
frequency of ECGs may revert to the schedule in the protocol. 
Subjects with QTc prolongation and symptoms must be monitored closely until the QTc 
elevation and symptoms have resolved. Cabozantinib treatment may be restarted but only at a 
reduced dose level if all of the following conditions are met: 
• Symptoms are determined to be unrelated to the QT interval prolongation 
• Cabozantinib treatment has been interrupted through a minimum of 1 week following the 
return of the QTcF to ≤ 500 ms and ≤ 60 ms above baseline. 
• QT prolongation can be unequivocally associated with an event other than cabozantinib 
administration and is treatable/has been resolved  
• Sponsor has reviewed all available information and has agreed to the continuation of study 
treatment. 
Following reinitiation of study treatment, ECGs must be repeated weekly for 2 weeks, then every 
2 weeks for 1 month, then according to the protocol-defined time points. 
Cabozantinib treatment must be permanently discontinued if either of the following applies: 
• Cardiac evaluation confirms that symptoms are the consequence of QT interval prolongation 
• Recurrence of QTcF prolongation after reinitiation of study treatment at a reduced dose 

 
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6.6.1.1.17 Electrolyte Disorders 
Serum electrolyte imbalance including hyponatremia, hypokalemia, hypomagnesemia, 
hypocalcemia, and hypophosphatemia have been reported during treatment with cabozantinib. 
There are many causes for an electrolyte imbalance including loss of body fluids (eg, from 
prolonged vomiting or diarrhea), inadequate diet, kidney disease and use of certain concomitant 
medications (eg, diuretics). Electrolyte imbalance may create a variety of symptoms. Examples 
include weakness, fatigue, confusion, muscle spasm, constipation, and irregular heartbeat. Serum 
electrolyte levels should be monitored closely while receiving cabozantinib. Clinically relevant 
electrolyte disorders should be managed according to the dose modification guidelines as 
outlined in Table 6-4 or as clinically indicated. Standard clinical practice guidelines should be 
used for management of electrolyte disorders and may include oral or IV replacement. 
6.6.1.1.18 Endocrine Disorders 
Treatment-emergent elevation of thyroid-stimulating hormone (TSH) has been observed with 
cabozantinib treatment. Currently available data are insufficient to determine the mechanism of 
thyroid function test alterations and its clinical relevance. Management of thyroid dysfunction 
(eg, symptomatic hypothyroidism) should follow accepted clinical practice guidelines. 
6.6.2 
Management of AEs Associated with Atezolizumab 
The assigned dose for atezolizumab is 1200 mg IV every 3 weeks. Infusion will occur every 
three weeks (-2 days). 
• Dose interruptions are allowed for atezolizumab (see Table 6-10), but dose reductions are not 
allowed.  
• Dose modification criteria for irAEs and for guidance on reinstituting atezolizumab are 
shown in Table 6-11. 
• If corticosteroids are initiated for treatment of irAEs, they must be tapered over ≥ 1 month to 
≤ 10 mg/day oral prednisone or equivalent before atezolizumab can be resumed. 
• Guidelines for the management of IRRs and CRS, irAEs for atezolizumab (ie, pneumonitis, 
hepatitis, diarrhea/colitis, myocarditis, endocrinopathies including hypophysitis, and 
infection) and other AESIs are provided in Section 6.6.2.1. 

 
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Table 6-10: 
Dose Interruptions of Atezolizumab 
Assigned dose 
Dose Interruptions 
1200-mg atezolizumab IV q3w 
At any time to manage unacceptable AEs including AESIs 
AE, adverse event; AESI, adverse event of special interest; q3w, once every 3 weeks  
 
Table 6-11: 
Guidance Overview for Atezolizumab Treatment Modifications 
CTCAE v5 Grade 
Recommended Management 
Grade 1* or 2 pneumonitis 
Grade 1** pericarditis 
Grade 1 immune-mediated myelitis*** 
Grade 1 or 2 facial paresis**** 
Grade 2 nephritis 
Grade 2 hepatic events 
Grade 2 or 3 diarrhea or colitis 
Grade 2 or 3 myositis 
Symptomatic adrenal insufficiency; Grade 2 or 3 
hypophysitis; or Grade 3 or 4 hyperglycemia, 
hypothyroidism, or hyperthyroidism  
Grade 2 ocular inflammatory toxicity 
Grade 2 or 3 pancreatitis or increases in amylase and/or 
lipase levels to > 2.0 - 5.0 × ULN, regardless of signs or 
symptoms, or to > 5.0 × ULN  
Grade 3 or 4 infection 
Grade 2 infusion-related reactions or cytokine-release 
syndrome 
Grade 3 rash 
Suspected Stevens-Johnson syndrome or toxic epidermal 
necrolysis (any grade) 
Other Grade 2 or 3 atezolizumab-associated AEs 
Note: The guidance below applies to 
all events listed on the left column 
Delay treatment with atezolizumab 
Treatment may be resumed in subjects 
following recovery to Grade 0-1. 
* For Grade 1 pneumonitis, consider 
withholding atezolizumab. 
** For Grade 1 pericarditis, withhold 
treatment with atezolizumab and 
conduct a detailed cardiac evaluation to 
determine the etiology and manage 
accordingly 
***Continue atezolizumab unless 
symptoms worsen or do not improve 
****If event resolves fully, resume 
atezolizumab 
 
 

 
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CTCAE v5 Grade 
Recommended Management 
Grade 2 - 4 myocarditis  
Grade 2 - 4 immune-mediated pericardial disorders 
Grade 2 - 4 immune-mediated myelitis 
Grade 4 myositis and/or recurrent Grade 3 myositis 
Grade 3 or 4 pneumonitis 
Grade 3 or 4 nephritis  
Grade 3 or 4 hepatic events 
Grade 3 or 4 immune-mediated neuropathy, including facial 
paresis 
Grade 4 diarrhea or colitis 
Grade 4 hypophysitis and/or recurrent hypophysitis 
Life-threatening immune-mediated hypothyroidism or 
hyperthyroidism 
Myasthenic syndrome/myasthenia gravis, Guillain-Barré or 
meningoencephalitis (all grades) 
Grade 3 or 4 ocular inflammatory toxicity 
Grade 4 or recurrent Grade 2 or 3 pancreatitis 
Grade 3 or 4 infusion-related reactions or cytokine-release 
syndrome 
Grade 4 rash 
Confirmed Stevens Johnson syndrome or toxic epidermal 
necrolysis (any grade) 
Other Grade 4 or recurrent Grade 3 atezolizumab-associated 
AEs 
Note: The guidance below applies to 
all events listed on the left column. 
Permanently discontinue atezolizumab 
 
 
AE, adverse event; ULN, upper limit of normal. 
Note: Additional information for atezolizumab dose modification criteria and treatment recommendations for 
irAEs and infusion reactions are provided in Section 6.6.2.1.  
6.6.2.1 
Warnings, Precautions, and Management Guidelines for Adverse Events 
Associated with Atezolizumab Treatment 
The following are general recommendations for management of any other AEs that may occur 
and are not specifically listed in the following subsections.  
• Patients and family caregivers should receive timely and up-to-date information about 
immunotherapies, their mechanism of action, and the clinical profile of possible 

 
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IRAEs prior to initiating therapy and throughout treatment and survival follow-up. 
There should be a high level of suspicion that new symptoms are treatment related.  
• In general, atezolizumab therapy should be continued with close monitoring for 
Grade 1 toxicities, with the exception of some neurologic toxicities. 
• Consider holding atezolizumab for most Grade 2 toxicities and resume when 
symptoms and/or laboratory values resolve to Grade 1 or better. Corticosteroids 
(initial dose of 0.5-1 mg/kg/day of prednisone or equivalent) may be administered.  
• For Grade 2 recurrent or persistent (lasting for more than 5 days) events, treat as a 
Grade 3 event. 
• Hold atezolizumab for Grade 3 toxicities and initiate treatment with high-dose 
corticosteroids (1-2 mg/kg/day prednisone or equivalent). Corticosteroids should be 
tapered over 1 month to 10 mg/day oral prednisone or equivalent, before 
atezolizumab can be resumed. If symptoms do not improve within 48 to 72 hours of 
high-dose corticosteroid use, other immunosuppressants may be offered for some 
toxicities.  
• In general, Grade 4 toxicities warrant permanent discontinuation of atezolizumab 
treatment, with the exception of endocrinopathies that are controlled by hormone-
replacement therapy. 
The most common AEs reported in ≥ 20% of subjects treated with atezolizumab include fatigue, 
decreased appetite, nausea, urinary tract infection, pyrexia, and constipation (Tecentriq USPI).  
Subjects treated with atezolizumab may also develop IRRs or CRS as well as irAEs such as 
myocarditis, pericardial disorders, pneumonitis, hepatitis, colitis, nephritis, endocrinopathies 
(hypophysitis, thyroid disorders, adrenal insufficiency, Type 1 diabetes), skin disorders and 
severe cutaneous adverse reactions, ocular events, neurological toxicity (myasthenic 
syndrome/myasthenia gravis, Guillain-Barré syndrome, meningoencephalitis, myelitis, or facial 
paresis), pancreatitis, myositis, and embryo-fetal toxicity. Management guidance for 
atezolizumab-associated AEs is provided in Sections 6.6.2.1.1 through 6.6.2.1.16. 
For details on warnings & precautions, possible AEs and management guidance of AEs, and use 
in special patient populations refer to the local prescribing information of atezolizumab and the 
atezolizumab Investigator’s Brochure. In addition, Investigators may be informed separately of 
any new urgent safety concerns that may arise through direct communication from the Sponsor 
(eg, Dear Investigator Letters). 
6.6.2.1.1 
Infusion-Related Reaction and Cytokine-Release Syndrome  
IRRs are known to occur with the administration of monoclonal antibodies and have been 
reported with atezolizumab. These reactions, which are thought to be due to release of cytokines 

 
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and/or other chemical mediators, occur within 24 hours of atezolizumab administration and are 
generally mild to moderate in severity. 
CRS is defined as a supraphysiologic response following administration of any immune therapy 
that results in activation or engagement of endogenous or infused T cells and/or other immune 
effector cells. Symptoms can be progressive, always include fever at the onset, and may include 
hypotension, capillary leak (hypoxia), and end-organ dysfunction (Lee et al 2019). CRS has been 
well documented with chimeric antigen receptor T-cell therapies and bispecific T-cell engager 
antibody therapies but has also been reported with immunotherapies that target PD-1 or PD-L1 
(Rotz et al 2017; Adashek and Feldman 2019), including atezolizumab. 
No premedication is indicated for the first administration of atezolizumab. However, subjects 
who experience an IRR or CRS with atezolizumab may receive premedication with 
antihistamines, antipyretics, and/or analgesics (eg, acetaminophen) for subsequent infusions. 
Metamizole (dipyrone) is prohibited in treating atezolizumab-associated IRRs because of its 
potential for causing agranulocytosis. 
There may be significant overlap in signs and symptoms of IRRs and CRS, and in recognition of 
the challenges in clinically distinguishing between the two, consolidated guidelines for medical 
management of IRRs and CRS are provided in Appendix G. 
Severe COVID-19 appears to be associated with a CRS involving the inflammatory cytokines 
interleukin (IL)-6, IL-10, IL-2, and IFN-γ (Merad and Martin 2020). If a patient develops 
suspected CRS during the study, a differential diagnosis should include COVID-19, which 
should be confirmed or refuted through assessment of exposure history, appropriate laboratory 
testing, and clinical or radiologic evaluations per Investigator judgment. If a diagnosis of 
COVID-19 is confirmed, the disease should be managed as per local or institutional guidelines. 
For subjects who develop COVID-19 while on study, the Investigator is to evaluate the overall 
risk-benefit ratio for the subject to determine whether holding study treatment(s) is in the best 
interest of the subject. 
6.6.2.1.2 
Immune-Related Pulmonary Events 
Pulmonary events may present as new or worsening cough, chest pain, fever, dyspnea, fatigue, 
hypoxia, pneumonitis, and pulmonary infiltrates. Subjects should be assessed for pulmonary 
signs and symptoms throughout the study and will also have CT scans of the chest performed at 
every tumor assessment.  

 
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All pulmonary events should be thoroughly evaluated for other commonly reported etiologies 
such as pneumonia or other infections, lymphangitic carcinomatosis, pulmonary embolism, heart 
failure, chronic obstructive pulmonary disease, or pulmonary hypertension. COVID-19 
evaluation should be performed per institutional guidelines where relevant. Management 
guidelines for pulmonary events are provided in Table 6-12. 
Table 6-12: 
Management Guidelines for Immune-Related Pulmonary Events, Including 
Pneumonitis 
Severity of Event  
Management 
Grade 1  
• 
Continue atezolizumab and monitor closely 
• 
Re-evaluate on serial imaging 
• 
Consider subject referral to pulmonary specialist 
• 
For Grade 1 pneumonitis, consider withholding atezolizumab 
Grade 2 
• 
Withhold atezolizumab for up to 12 weeks after event onset a 
• 
Refer subject to pulmonary and infectious disease specialists and consider 
bronchoscopy or BAL with or without transbronchial biopsy 
• 
Initiate treatment with 1−2 mg/kg/day oral prednisone or equivalent. 
• 
Resume atezolizumab if event resolves to Grade 1 or betterb 
• 
Permanently discontinue atezolizumab and contact the Sponsor if event does not 
resolve to Grade 1 or better while withholding atezolizumabc, d 
• 
For recurrent events, or events with no improvement after 48–72 hours of 
corticosteroids, treat as a Grade 3 or 4 event 
Grade 3 or 4 
• 
Permanently discontinue atezolizumab and contact the Sponsorc 
• 
Bronchoscopy or BAL with or without transbronchial biopsy is recommended. 
• 
Initiate treatment with 1−2 mg/kg/day IV methylprednisolone or equivalent. 
• 
If event does not improve within 48 hours after initiating corticosteroids, consider 
adding an immunosuppressive agent 
• 
If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month 
• 
Oral or IV broad-spectrum antibiotics should be administered in parallel to the 
immunosuppressive treatment 
BAL, bronchoscopic alveolar lavage. 
a Atezolizumab may be withheld for a period of time beyond 12 weeks after event onset to allow for corticosteroids (if 
initiated) to be reduced to ≤ 10 mg/day oral prednisone or equivalent. The acceptable length of the extended period of time 
must be based on an assessment of benefit−risk by the Investigator and in alignment with the protocol requirements for the 
duration of treatment and documented by the Investigator. The Sponsor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or equivalent 
before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully recovered from the 
immune-related event. The decision to rechallenge subjects with atezolizumab should be based on Investigator's assessment 
of benefit−risk and documented by the Investigator. The Sponsor is available to advise as needed. 
d In case of pneumonitis, atezolizumab should not be resumed after permanent discontinuation.  

 
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6.6.2.1.3 
Immune-Related Colitis or Diarrhea 
Immune-related colitis has been associated with the administration of atezolizumab. 
Management guidelines for diarrhea or colitis are provided in Table 6-13. 
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies. For events of significant duration or magnitude or associated with signs of systemic 
inflammation or acute-phase reactants (eg, increased c-reactive protein, platelet count, or 
bandemia): perform sigmoidoscopy (or colonoscopy, if appropriate) with colonic biopsy, with 
three to five specimens for standard paraffin block to check for inflammation and lymphocytic 
infiltrates to confirm colitis diagnosis.  

 
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Table 6-13: 
Management Guidelines for Immune-Related Diarrhea or Colitis 
Severity of 
Event 
Management 
Grade 1 
• 
Continue atezolizumab 
• 
Initiate symptomatic treatment 
• 
Endoscopy is recommended if symptoms persist for > 7 days 
• 
Monitor closely 
Grade 2 
• 
Withhold atezolizumab for up to 12 weeks after event onset a 
• 
Initiate symptomatic treatment 
• 
If strong clinical suspicion for immune-mediated colitis, start empiric IV steroids while 
waiting for definitive diagnosis. 
• 
Subject referral to GI specialist is recommended 
• 
For recurrent events or events that persist > 5 days, initiate treatment with 1−2 mg/kg/day 
oral prednisone or equivalent. If the event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• 
Resume atezolizumab if event resolves to Grade 1 or betterb 
• 
Permanently discontinue atezolizumab and contact the Sponsor if event does not resolve to 
Grade 1 or better while withholding atezolizumabc 
Grade 3 
• 
Withhold atezolizumab for up to 12 weeks after event onset a 
• 
Refer subject to GI specialist for evaluation and confirmatory biopsy 
• 
Initiate treatment with 1−2 mg/kg/day IV methylprednisolone or equivalent and convert to 
1−2 mg/kg/day oral prednisone or equivalent upon improvement. If event does not 
improve within 48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent. 
• 
Resume atezolizumab if event resolves to Grade 1 or betterb 
• 
Permanently discontinue atezolizumab and contact the Sponsor if event does not resolve to 
Grade 1 or better while withholding atezolizumabc 
Grade 4 
• 
Permanently discontinue atezolizumab and contact the Sponsorc 
• 
Refer subject to GI specialist for evaluation and confirmatory biopsy 
• 
Initiate treatment with 1−2 mg/kg/day IV methylprednisolone or equivalent and convert to 
1−2 mg/kg/day oral prednisone or equivalent upon improvement 
• 
If event does not improve within 48 hours after initiating corticosteroids, consider adding 
an immunosuppressive agent 
• 
If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month 
GI, gastrointestinal; IV, intravenous 
a Atezolizumab may be withheld for a period of time beyond 12 weeks after event onset to allow for corticosteroids (if 
initiated) to be reduced to ≤ 10 mg/day oral prednisone or equivalent. The acceptable length of the extended period of time 
must be based on an assessment of benefit−risk by the Investigator and in alignment with the protocol requirements for the 
duration of treatment and documented by the Investigator. The Sponsor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or equivalent 
before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully recovered from the 
immune-related event. The decision to rechallenge subjects with atezolizumab should be based on Investigator's assessment 
of benefit−risk and documented by the Investigator. The Sponsor is available to advise as needed. 

 
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6.6.2.1.4 
Immune-related Endocrinopathies 
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders have been 
associated with the administration of atezolizumab. Management guidelines for endocrine events 
are provided in Table 6-14. 
Monitor for signs and symptoms of hypophysitis. Subjects with unexplained symptoms such as 
headache, fatigue, myalgias, impotence, mental status changes, or constipation should be 
investigated for the presence of thyroid, pituitary, or adrenal endocrinopathies. The subject 
should be referred to an endocrinologist if an endocrinopathy is suspected. Thyroid-stimulating 
hormone (TSH) and free triiodothyronine (T3) and thyroxine (T4) levels should be measured to 
determine whether thyroid abnormalities are present. Pituitary hormone levels and function tests 
(eg, TSH, growth hormone, luteinizing hormone, follicle-stimulating hormone, testosterone, 
prolactin, adrenocorticotropic hormone [ACTH] levels and ACTH stimulation test), and MRI of 
the brain (with detailed pituitary sections) may help to differentiate primary pituitary 
insufficiency from primary adrenal insufficiency. 
Table 6-14: 
Management Guidelines for Endocrine Events 
Event 
Management 
Hypophysitis 
(pan-hypopituitarism) 
Grade 2-3 
• 
Withhold atezolizumab for up to 12 weeks after event onseta 
• 
Refer subject to endocrinologist 
• 
Perform brain MRI (pituitary protocol) 
• 
Initiate treatment with 1-2 mg/kg/day IV methylprednisolone or equivalent 
and convert to 1-2 mg/kg/day oral prednisone or equivalent upon 
improvement 
• 
Initiate hormone replacement therapy if clinically indicated 
• 
If event resolves to Grade 1 or better, resume atezolizumabc 
• 
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact the 
Sponsorb 
• 
For recurrent hypophysitis, treat as a Grade 4 event 
Hypophysitis (pan-
hypopituitarism) Grade 4 
• 
Permanently discontinue atezolizumab and contact the Sponsorb 
• 
Refer subject to endocrinologist 
• 
Perform brain MRI (pituitary protocol) 
• 
Initiate treatment with 1-2 mg/kg/day IV methylprednisolone or equivalent 
and convert to 1-2 mg/kg/day oral prednisone or equivalent upon 
improvement 
• 
Initiate hormone replacement therapy if clinically indicated 

 
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Event 
Management 
Hypothyroidism 
Grade 1 
• 
Continue atezolizumab 
• 
Initiate treatment with thyroid replacement hormone 
• 
Monitor TSH closely 
Hypothyroidism 
Grade 2 
• 
Consider withholding atezolizumab. 
• 
Initiate treatment with thyroid replacement hormone. 
• 
Monitor TSH closely. 
• 
Consider patient referral to endocrinologist. 
• 
Resume atezolizumab when symptoms are controlled and thyroid function is 
improving. 
Hypothyroidism 
Grade 3 and 4 
• 
Withhold atezolizumab 
• 
Initiate treatment with thyroid replacement hormone 
• 
Monitor TSH closely 
• 
Refer to endocrinologist 
• 
Admit patient to the hospital for developing myxedema (bradycardia, 
hypothermia and altered mental status). 
• 
Resume atezolizumab when symptoms are controlled and thyroid function is 
improving 
• 
Permanently discontinue atezolizumab and contact the Sponsor for life-
threatening immune-mediated hypothyroidism.b 
Hyperthyroidism 
Grade 1 
TSH ≥ 0.1 mU/L and < 0.5 mU/L: 
• 
Continue atezolizumab 
• 
Monitor TSH every 4 weeks 
• 
Consider subject referral to endocrinologist 
TSH < 0.1 mU/L: 
• 
Follow guidelines for Grade 2 hyperthyroidism 
• 
Consider subject referral to endocrinologist 
Hyperthyroidism 
Grade 2 
• 
Consider withholding atezolizumab 
• 
Initiate treatment with anti-thyroid drug such as methimazole or carbimazole 
as needed 
• 
Consider subject referral to endocrinologist 
• 
Resume atezolizumab when symptoms are controlled and thyroid function is 
improving 
Hyperthyroidism 
Grade 3 and 4 
• 
Withhold atezolizumab 
• 
Initiate treatment with anti-thyroid drugs such as methimazole or 
carbimazole as needed 
• 
Refer to endocrinologist 
• 
Resume atezolizumab when symptoms are controlled and thyroid function is 
improving 
• 
Permanently discontinue atezolizumab and contact the Sponsor for 
life-threatening immune-mediated hyperthyroidismb 

 
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Event 
Management 
Symptomatic adrenal 
insufficiency 
Grade 2−4  
• 
Withhold atezolizumab for up to 12 weeks after event onseta  
• 
Refer subject to endocrinologist 
• 
Perform appropriate imaging 
• 
Initiate treatment with 1−2 mg/kg/day IV methylprednisolone or equivalent 
and convert to 1−2 mg/kg/day oral prednisone or equivalent upon 
improvement 
• 
Resume atezolizumab if event resolves to Grade 1 or better and subject is 
stable on replacement therapy c  
• 
Permanently discontinue atezolizumab and contact the Sponsor if event does 
not resolve to Grade 1 or better or subject is not stable on replacement 
therapy while withholding atezolizumabb 
Hyperglycemia 
Grade 1 or 2  
• 
Continue atezolizumab 
• 
Investigate for diabetes. If subject has Type 1 diabetes, treat as a Grade 3 
event. If subject does not have Type 1 diabetes, treat as per institutional 
guidelines.  
• 
Monitor for glucose control 
Hyperglycemia 
 Grade 3 or 4 
• 
Withhold atezolizumab 
• 
Initiate treatment with insulin 
• 
Evaluate for diabetic ketoacidosis and manage as per institutional guidelines 
• 
Monitor for glucose control 
• 
Resume atezolizumab when symptoms resolve and glucose levels are stable 
IV, intravenous; MRI, magnetic resonance imaging; TSH, thyroid-stimulating hormone.  
a Atezolizumab may be withheld for a period of time beyond 12 weeks after event onset to allow for corticosteroids (if 
initiated) to be reduced to ≤ 10 mg/day oral prednisone or equivalent. The acceptable length of the extended period of time 
must be based on an assessment of benefit−risk by the Investigator and in alignment with the protocol requirements for the 
duration of treatment and documented by the Investigator. The Sponsor is available to advise as needed. 
b Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully recovered from the 
immune-related event. The decision to rechallenge subjects with atezolizumab should be based on Investigator's assessment 
of benefit−risk and documented by the Investigator. The Sponsor is available to advise as needed. 
c If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or equivalent 
before atezolizumab can be resumed. 
6.6.2.1.5 
Immune-Related Dermatologic Events 
Treatment-emergent rash has been associated with atezolizumab. The majority of cases of rash 
were mild in severity and self-limiting, with or without pruritus. Although uncommon, cases of 
severe cutaneous adverse reactions such as Stevens-Johnson syndrome and toxic epidermal 
necrolysis have been reported with atezolizumab. A dermatologist should evaluate persistent 
and/or severe rash or pruritus. A biopsy should be considered unless contraindicated. 
Management guidelines for dermatologic events are provided in Table 6-15. 

 
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Table 6-15: 
Atezolizumab Management Guidance of Immune-Related Dermatologic 
Events 
Severity of Event 
Management of Skin Disorder 
Grade 1 
• 
Continue atezolizumab 
• 
Consider treatment with topical corticosteroids and/or other symptomatic 
therapy (eg, antihistamines) 
Grade 2 
• 
Continue atezolizumab 
• 
Consider subject referral to dermatologist for evaluation and, if indicated, 
biopsy 
• 
Initiate treatment with topical corticosteroids 
• 
Consider treatment with higher-potency topical corticosteroids if event does 
not improve 
• 
If unresponsive to topical corticosteroids, consider oral prednisone 
0.5 mg/kg/day 
Grade 3 
• 
Delay atezolizumab for up to 12 weeks after event onseta 
• 
Refer subject to dermatologist for evaluation and, if indicated, biopsy 
• 
Initiate treatment with 10 mg/day oral prednisone or equivalent, increasing 
dose to 1− 2 mg/kg/day if event does not improve within 48− 72 hours 
• 
Resume atezolizumab if event resolves to Grade 1 or betterb 
• 
Permanently discontinue atezolizumab and contact Sponsor if event does 
not resolve to Grade 1 or better while whitholding atezolizumabc 
Grade 4 
• 
Permanently discontinue atezolizumab and contact Sponsorc     
Stevens-Johnson syndrome or 
toxic epidermal necrolysis 
(any grade) 
Additional guidance for Stevens-Johnson syndrome or toxic epidermal 
necrolysis: 
• 
Withhold atezolizumab for suspected Stevens-Johnson syndrome or toxic 
epidermal necrolysis 
• 
Confirm diagnosis by referring subject to a specialist (dermatologist, 
ophthalmologist, or urologist as relevant) for evaluation and, if indicated, 
biopsy 
• 
Follow the applicable treatment and management guidelines above 
• 
If Stevens-Johnson syndrome or toxic epidermal necrolysis is confirmed, 
permanently discontinue atezolizumab 
a Atezolizumab may be withheld for a period of time beyond 12 weeks after event onset to allow for corticosteroids (if 
initiated) to be reduced to ≤ 10 mg/day oral prednisone or equivalent. The acceptable length of the extended period of time 
must be based on an assessment of benefit−risk by the Investigator and in alignment with the protocol requirements for the 
duration of treatment and documented by the Investigator. The Sponsor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or equivalent 
before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully recovered from the 
immune-related event. The decision to rechallenge subjects with atezolizumab should be based on Investigator's assessment 
of benefit−risk and documented by the Investigator. The Sponsor is available to advise as needed. 

 
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6.6.2.1.6 
Immune-Related Ocular Events 
Treatment-emergent ocular events have been associated with atezolizumab. An ophthalmologist 
should evaluate visual complaints (eg, uveitis, retinal events). Management guidelines for ocular 
events are provided in Table 6-16. 
Table 6-16: 
Atezolizumab Management Guidance of Immune-Related Ocular Events 
Severity of Event 
Management of Ocular Event 
Grade 1 
• 
Continue atezolizumab 
• 
Subject referral to ophthalmologist is strongly recommended 
• 
Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy 
• 
If symptoms persist, treat as a Grade 2 event 
Grade 2 
• 
Delay atezolizumab for up to 12 weeks after event onseta 
• 
Subject referral to ophthalmologist is strongly recommended 
• 
Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy 
• 
Resume atezolizumab if event resolves to Grade 1 or betterb 
• 
Permanently discontinue atezolizumab and contact the Sponsor if event 
does not resolve to Grade 1 or better while withholding atezolizumabc 
Grade 3 or 4 
• 
Permanently discontinue atezolizumab and contact the Sponsorc 
• 
Refer subject to ophthalmologist 
• 
Initiate treatment with 1− 2 mg/kg/day oral prednisone or equivalent 
• 
If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month 
a Atezolizumab may be withheld for a period of time beyond 12 weeks after event onset to allow for corticosteroids (if 
initiated) to be reduced to ≤ 10 mg/day oral prednisone or equivalent. The acceptable length of the extended period of time 
must be based on an assessment of benefit−risk by the Investigator and in alignment with the protocol requirements for the 
duration of treatment and documented by the Investigator. The Sponsor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or equivalent 
before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully recovered from the 
immune-related event. The decision to rechallenge subjects with atezolizumab should be based on Investigator's assessment 
of benefit−risk and documented by the Investigator. The Sponsor is available to advise as needed. 
 
6.6.2.1.7 
Immune-Related Meningoencephalitis 
Immune-related meningoencephalitis is an identified risk associated with the administration of 
atezolizumab. Immune-related meningoencephalitis should be suspected in any subject 
presenting with signs or symptoms suggestive of meningitis or encephalitis, including, but not 
limited to, headache, neck pain, confusion, seizure, motor or sensory dysfunction, and altered or 
depressed level of consciousness. Encephalopathy from metabolic or electrolyte imbalances 

 
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needs to be distinguished from potential meningoencephalitis resulting from infection (bacterial, 
viral, or fungal) or progression of malignancy, or secondary to a paraneoplastic process.  
All subjects being considered for meningoencephalitis should be urgently evaluated with a CT 
scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or edema. If deemed 
safe by the treating physician, a lumbar puncture should be performed and a neurologist should 
be consulted. 
Subjects with signs and symptoms of meningoencephalitis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 6-17. 
Table 6-17: 
Management Guidelines for Immune-Related Meningoencephalitis 
Severity of Event 
Management 
All grades 
• 
Permanently discontinue atezolizumab and contact the Sponsor 
• 
Refer subject to neurologist 
• 
Initiate treatment with 1−2 mg/kg/day IV methylprednisolone or equivalent 
and convert to 1−2 mg/kg/day oral prednisone or equivalent upon improvement 
• 
If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent 
• 
If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month 
IV, intravenous. 
 
6.6.2.1.8 
Immune-Related Motor and Sensory Neuropathy 
Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent 
atezolizumab. Patients may present with signs and symptoms of sensory and/or motor 
neuropathy. Diagnostic work-up is essential for an accurate characterization to differentiate 
between alternative etiologies. Management guidelines for neurologic disorders are provided in 
Table 6-18, with specific guidelines for myelitis provided in Table 6-19. 

 
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Table 6-18: 
Management Guidelines for Immune-Related Neurologic Disorders 
Event 
Management 
Immune-related 
neuropathy 
Grade 1 
• 
Continue atezolizumab 
• 
Investigate etiology 
• 
Any cranial nerve disorder (including facial paresis) should be managed as per 
Grade 2 management guidelines below 
Immune-related 
neuropathy, including 
facial paresis, 
Grade 2  
• 
Withhold atezolizumab for up to 12 weeks after event onseta 
• 
Investigate etiology and refer subject to neurologist 
• 
Initiate treatment as per institutional guidelines 
• 
For general immune-related neuropathy: 
− 
Resume atezolizumab if event resolves to Grade 1 or betterb 
− 
Permanently discontinue atezolizumab and contact the Sponsor if event does 
not resolve to Grade 1 or better while withholding atezolizumabc 
• 
For facial paresis 
− 
If event resolves fully, resume atezolizumabb 
− 
If event does not resolve fully while withholding atezolizumab, permanently 
discontinue atezolizumab and contact the Sponsorc 
Immune-related 
neuropathy, including 
facial paresis, 
Grade 3 or 4 
• 
Permanently discontinue atezolizumab and contact the Sponsorc 
• 
Refer subject to neurologist 
• 
Initiate treatment as per institutional guidelines 
Myasthenia gravis and 
Guillain-Barré 
syndrome, 
any grade 
• 
Permanently discontinue atezolizumab and contact the Sponsor 
• 
Refer subject to neurologist 
• 
Initiate treatment as per institutional guidelines 
• 
Consider initiation of 1−2 mg/kg/day oral or IV prednisone or equivalent 
IV, intravenous. 
a Atezolizumab may be withheld for a period of time beyond 12 weeks after event onset to allow for corticosteroids (if 
initiated) to be reduced to ≤ 10 mg/day oral prednisone or equivalent. The acceptable length of the extended period of time 
must be based on an assessment of benefit−risk by the Investigator and in alignment with the protocol requirements for the 
duration of treatment and documented by the Investigator. The Sponsor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or equivalent 
before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully recovered from the 
immune-related event. The decision to rechallenge subjects with atezolizumab should be based on Investigator's assessment 
of benefit−risk and documented by the Investigator. The Sponsor is available to advise as needed. 

 
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Table 6-19: 
Management Guidelines for Immune-Mediated Myelitis 
Event 
Management 
Immune-mediated myelitis, 
Grade 1 
• 
Continue atezolizumab unless symptoms worsen or do not improve. 
• 
Investigate etiology and refer patient to a neurologist.  
Immune-mediated myelitis, 
Grade 2 
• 
Permanently discontinue atezolizumab and contact the Sponsor.  
• 
Investigate etiology and refer patient to a neurologist. 
• 
Rule out infection. 
• 
Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day oral 
prednisone. 
Immune-mediated myelitis, 
Grade 3 or 4 
• 
Permanently discontinue atezolizumab and contact the Sponsor. 
• 
Refer patient to a neurologist. 
• 
Initiate treatment as per institutional guidelines. 
 
6.6.2.1.9 
Immune-Related Pancreatitis 
Symptoms of abdominal pain associated with elevations of amylase and lipase, suggestive of 
pancreatitis, have been associated with the administration of atezolizumab. The differential 
diagnosis of acute abdominal pain should include pancreatitis. Appropriate work-up should 
include an evaluation for ductal obstruction, as well as serum amylase (if available) and lipase 
tests. Management guidelines for pancreatic events, including pancreatitis, are provided in Table 
6-20. 

 
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Table 6-20: 
Management Guidelines for Pancreatic Events, Including Pancreatitis 
Event 
Management 
Amylase and/or lipase 
> ULN - 1.5 × ULN, 
Grade 1 
• 
Continue atezolizumab 
• 
Monitor amylase (if available) and lipase prior to dosing 
Amylase and/or lipase  
> 1.5 - 2.0 × ULN, or 
> 2.0 - 5.0 × ULN and 
asymptomatic,  
Grade 2 
Amylase and/or lipase > 1.5 - 2.0 × ULN: 
• 
Continue atezolizumab 
• 
Monitor amylase (if available) and lipase weekly 
• 
For prolonged elevation (eg, > 3 weeks), consider treatment with 10 mg/day 
oral prednisone or equivalent 
Asymptomatic with amylase and/or lipase > 2.0 - 5.0 × ULN: 
• 
Treat as Grade 3 amylase and/or lipase elevation 
Amylase and/or lipase  
> 2.0 - 5.0 × ULN with 
signs or symptoms,  
or > 5.0 × ULN,  
Grade 3 or 4 
• 
Withhold atezolizumab for up to 12 weeks after event onseta 
• 
Refer subject to GI specialist 
• 
Monitor amylase (if available) and lipase every other day 
• 
If no improvement, consider treatment with 1−2 mg/kg/day oral prednisone or 
equivalent 
• 
Resume atezolizumab if event resolves to Grade 1 or betterb 
• 
Permanently discontinue atezolizumab and contact the Sponsor if event does 
not resolve to Grade 1 or better while withholding atezolizumabc 
• 
For recurrent events, permanently discontinue atezolizumab and contact the 
Sponsorc 
Immune-related 
pancreatitis, Grade 2d or 3 
 
• 
Withhold atezolizumab for up to 12 weeks after event onseta 
• 
Refer subject to GI specialist 
• 
Initiate treatment with 1−2 mg/kg/day IV methylprednisolone or equivalent 
and convert to 1−2 mg/kg/day oral prednisone or equivalent upon 
improvement 
• 
Resume atezolizumab if event resolves to Grade 1 or betterb 
• 
Permanently discontinue atezolizumab and contact the Sponsor if event does 
not resolve to Grade 1 or better while withholding atezolizumabc 
• 
For recurrent events, permanently discontinue atezolizumab and contact the 
Sponsorc  

 
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Immune-related 
pancreatitis, Grade 4 
• 
Permanently discontinue atezolizumab and contact the Sponsorc 
• 
Refer subject to GI specialist 
• 
Initiate treatment with 1−2 mg/kg/day IV methylprednisolone or equivalent 
and convert to 1−2 mg/kg/day oral prednisone or equivalent upon 
improvement 
• 
If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent 
• 
If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month 
CTCAE, Common Terminology Criteria for Adverse Events; GI, gastrointestinal; IV, intravenous; ULN, upper limit of 
normal. 
a Atezolizumab may be withheld for a period of time beyond 12 weeks after event onset to allow for corticosteroids (if 
initiated) to be reduced to ≤ 10 mg/day oral prednisone or equivalent. The acceptable length of the extended period of time 
must be based on an assessment of benefit−risk by the Investigator and in alignment with the protocol requirements for the 
duration of treatment and documented by the Investigator. The Sponsor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or equivalent 
before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully recovered from the 
immune-related event. The decision to rechallenge subjects with atezolizumab should be based on Investigator's assessment 
of benefit−risk and documented by the Investigator. The Sponsor is available to advise as needed.  
d Per CTCAE v5, Grade 2 pancreatitis requires radiological findings in addition to enzyme elevation.  
6.6.2.1.10 
Immune-Mediated Cardiac Events 
Immune-Related Myocarditis 
Immune-mediated myocarditis has been associated with the administration of atezolizumab. 
Immune-mediated myocarditis should be suspected in any subject presenting with signs or 
symptoms suggestive of myocarditis including, but not limited to, laboratory (eg, B-type 
natriuretic peptide) or cardiac imaging abnormalities, dyspnea, chest pain, palpitations, fatigue, 
decreased exercise tolerance, or syncope. Myocarditis may also be a clinical manifestation of 
myositis or associated with pericarditis and should be managed accordingly. Immune-mediated 
myocarditis needs to be distinguished from myocarditis resulting from infection (commonly 
viral; eg, in a subject who reports a recent history of gastrointestinal illness), ischemic events, 
underlying arrhythmias, exacerbation of preexisting cardiac conditions, or progression of 
malignancy. 
All subjects with possible myocarditis should be urgently evaluated by performing cardiac 
enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as 
appropriate per institutional guidelines. A cardiologist should be consulted. An endomyocardial 
biopsy may be considered to enable a definitive diagnosis and appropriate treatment, if clinically 
indicated. 

 
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Subjects with signs and symptoms of myocarditis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 6-21. 
Immune-Mediated Pericardial Disorders 
Immune-mediated pericarditis should be suspected in any patient presenting with chest pain and 
may be associated with immune-mediated myocarditis. Immune-mediated pericardial effusion 
and cardiac tamponade should be suspected in any patient presenting with chest pain associated 
with dyspnea or hemodynamic instability. Patients should be evaluated for other causes of 
pericardial disorders such as infection (commonly viral), cancer related (metastatic disease or 
chest radiotherapy), cardiac injury related (post myocardial infarction or iatrogenic), and 
autoimmune disorders, and should be managed accordingly. All patients with suspected 
pericardial disorders should be urgently evaluated by performing an ECG, chest X-ray, 
transthoracic echocardiogram, and cardiac MRI as appropriate per institutional guidelines. A 
cardiologist should be consulted. Pericardiocentesis should be considered for diagnostic or 
therapeutic purposes, if clinically indicated. Patients with signs and symptoms of pericarditis, 
pericardial effusion, or cardiac tamponade, in the absence of an identified alternate etiology, 
should be treated according to the guidelines in Table 6-21. Withhold treatment with 
atezolizumab for Grade 1 pericarditis and conduct a detailed cardiac evaluation to determine the 
etiology and manage accordingly. 
Table 6-21: 
Management Guidelines for Immune-Related Cardiac Events 
Event 
Management 
Immune-related myocarditis, 
Grades 2-4 
 
Immune-mediated pericardial 
disorders, Grades 2-4 
• 
Permanently discontinue atezolizumab and contact the Sponsor 
• 
Refer subject to cardiologist 
• 
Initiate treatment as per institutional guidelines and consider antiarrhythmic 
drugs, temporary pacemaker, ECMO, VAD, or pericardiocentesis as appropriate 
• 
Initiate treatment with 1-2 mg/kg/day IV methylprednisolone or equivalent and 
convert to 1-2 mg/kg/day oral prednisone or equivalent upon improvement 
• 
If event does not improve within 48 hours after initiating corticosteroids, consider 
adding an immunosuppressive agent 
• 
If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month 
ECMO, extracorporeal membrane oxygenation; IV, intravenous; VAD, ventricular assist device. 
6.6.2.1.11 
Immune-Related Nephritis 
Immune-mediated nephritis has been associated with the administration of atezolizumab. 
Eligible subjects must have adequate renal function. Renal function, including serum creatinine, 
should be monitored throughout study treatment. Subjects with abnormal renal function should 
be evaluated and treated for other more common etiologies (including prerenal and postrenal 

 
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causes, and concomitant medications such as non-steroidal anti-inflammatory drugs). Refer the 
subject to a renal specialist if clinically indicated. A renal biopsy may be required to enable a 
definitive diagnosis and appropriate treatment. 
Atezolizumab should be withheld for moderate (Grade 2) immune-related nephritis and 
permanently discontinued for severe nephritis (Grade 3 or 4). Refer subjects to a renal specialist 
and consider renal biopsy and supportive measures as indicated. Corticosteroids and/or 
additional immunosuppressive agents should be administered as clinically indicated. Refer to the 
current atezolizumab Investigator’s Brochure for further guidance on the management of 
immune-related nephritis. 
Subjects with signs and symptoms of nephritis, in the absence of an identified alternate etiology, 
should be treated according to the guidelines in Table 6-22. 
Table 6-22: 
Management Guidelines for Immune-Related Nephritis 
Event 
Management 
Renal event,  
Grade 1 
• 
Continue atezolizumab  
• 
Monitor kidney function closely, including creatinine and urine protein, until values 
resolve to within normal limits or to baseline values  
Renal event,  
Grade 2 
• 
Withhold atezolizumab for up to 12 weeks after event onset a  
• 
Refer subject to renal specialist  
• 
Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral prednisone  
• 
If event resolves to Grade 1 or better, resume atezolizumab b  
• 
If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab and contact the Sponsor c 
Renal event,  
Grade 3 or 4 
• 
Permanently discontinue atezolizumab and contact the Sponsor  
• 
Refer subject to renal specialist and consider renal biopsy  
• 
Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral prednisone  
• 
If event does not improve within 48 hours after initiating corticosteroids, consider 
adding an immunosuppressive agent  
• 
If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month  
a Atezolizumab may be withheld for a longer period of time (ie, > 12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone. The acceptable length 
of the extended period of time must be based on an assessment of benefit−risk by the Investigator and in alignment 
with the protocol requirements for the duration of treatment and documented by the Investigator. The Sponsor is 
available to advise as needed.  
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 10 mg/day oral 
prednisone before atezolizumab can be resumed.  
c Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully recovered from 
the immune-related event. The decision to rechallenge subjects with atezolizumab should be based on Investigator's 
assessment of benefit−risk and documented by the Investigator. The Sponsor is available to advise as needed. 

 
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6.6.2.1.12 
Immune-Related Myositis 
Immune-related myositis has been associated with the administration of atezolizumab. Myositis 
or inflammatory myopathies are a group of disorders sharing the common feature of 
inflammatory muscle injury; dermatomyositis and polymyositis are among the most common 
disorders. Initial diagnosis is based on clinical (muscle weakness, muscle pain, skin rash in 
dermatomyositis), biochemical (serum creatinine-kinase increase), and imaging 
(electromyography/MRI) features and is confirmed with a muscle biopsy. 
Subjects with possible myositis should be referred to a rheumatologist or neurologist. Subjects 
with possible myositis should be monitored for signs of myocarditis. 
Subjects with signs and symptoms of myositis, in the absence of an identified alternate etiology, 
should be treated according to the guidelines in Table 6-23. 

 
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Table 6-23: 
Management Guidelines for Immune-Related Myositis 
Event 
Management 
Immune-related myositis, 
Grade 1 
• 
Continue atezolizumab 
• 
Refer subject to rheumatologist or neurologist 
• 
Initiate treatment as per institutional guidelines 
Immune-related myositis, 
Grade 2 
• 
Withhold atezolizumab for up to 12 weeks after event onseta and contact 
Sponsor. 
• 
Refer subject to rheumatologist or neurologist 
• 
Initiate treatment as per institutional guidelines  
• 
Consider treatment with corticosteroid equivalent to 1-2 mg/kg/day IV 
methylprednisolone and convert to 1-2 mg/kg/day oral prednisone or 
equivalent upon improvement 
• 
If corticosteroids are initiated and event does not improve within 48 hours after 
initiating corticosteroids, consider adding an immunosuppressive agent 
• 
If event resolves to Grade 1 or better, resume atezolizumabb 
• 
If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab and contact the Sponsor c 
Immune-related myositis, 
Grade 3 
• 
Withhold atezolizumab for up to 12 weeks after event onseta and contact the 
Sponsor 
• 
Refer subject to rheumatologist or neurologist 
• 
Initiate treatment as per institutional guidelines 
• 
Respiratory support may be required in more severe cases 
• 
Initiate treatment with corticosteroid equivalent to 1-2 mg/kg/day IV 
methylprednisolone or higher dose bolus if subject is severely compromised 
(eg, cardiac or respiratory symptoms, dysphagia, or weakness that severely 
limits mobility); convert to 1-2 mg/kg/day oral prednisone or equivalent upon 
improvement 
• 
If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent 
• 
If event resolves to Grade 1 or better, resume atezolizumabb 
• 
If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab and contact the Sponsor.c 
• 
For recurrent events, treat as a Grade 4 event. Permanently discontinue 
atezolizumab and contact the Sponsorc 

 
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Event 
Management 
Immune-related myositis, 
Grade 4 
• 
Permanently discontinue atezolizumab and contact the Sponsorc 
• 
Refer subject to rheumatologist or neurologist 
• 
Initiate treatment as per institutional guidelines  
• 
Respiratory support may be required in more severe cases 
• 
Initiate treatment with corticosteroid equivalent to 1-2 mg/kg/day IV 
methylprednisolone or higher dose bolus if subject is severely compromised 
(eg, cardiac or respiratory symptoms, dysphagia, or weakness that severely 
limits mobility); convert to 1-2 mg/kg/day oral prednisone or equivalent upon 
improvement 
• 
If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent 
• 
If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month 
IV, intravenous 
a Atezolizumab may be withheld for a period of time (ie, > 12 weeks after event onset) to allow for corticosteroids (if 
initiated) to be reduced to ≤ 10 mg/day oral prednisone or equivalent. The acceptable length of the extended period of time 
must be based on an assessment of benefit−risk by the Investigator and in alignment with the protocol requirements for the 
duration of treatment and documented by the Investigator. The Sponsor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or equivalent 
before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully recovered from the 
immune-related event. The decision to rechallenge subjects with atezolizumab should be based on Investigator's assessment 
of benefit−risk and documented by the Investigator. The Sponsor is available to advise as needed. 
 
6.6.2.1.13 
Immune-Related Hepatic Events 
Immune-related hepatitis has been associated with the administration of atezolizumab. Eligible 
subjects must have adequate liver function, as manifested by measurements of total bilirubin and 
hepatic transaminases, and liver function will be monitored throughout study treatment. 
Management guidelines for hepatic events are provided in Table 6-24. 
Subjects with right upper-quadrant abdominal pain and/or unexplained nausea or vomiting 
should have LFTs performed immediately and reviewed before administration of the next dose 
of study drug. 
For subjects with elevated LFTs, concurrent medication, viral hepatitis, and toxic or neoplastic 
etiologies should be considered and addressed, as appropriate. 

 
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Table 6-24: 
Management Guidelines for Hepatic Events 
Severity of Event 
Management 
Hepatic event, Grade 1 
• 
Continue atezolizumab 
• 
Monitor LFTs until values resolve to within normal limits or to 
baseline values 
Hepatic event, Grade 2 
All events: 
• 
Monitor LFTs more frequently until return to baseline values  
Events of > 5 days’ duration: 
• 
Withhold atezolizumab for up to 12 weeks after event onseta 
• 
Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day 
oral prednisone 
• 
Resume atezolizumab if event resolves to Grade 1 or better b 
• 
Permanently discontinue atezolizumab and contact the Sponsor if 
event does not resolve to Grade 1 or better while withholding 
atezolizumabc 
Hepatic event, Grade 3 or 4 
• 
Permanently discontinue atezolizumab and contact the Sponsorc 
• 
Consider subject referral to GI specialist for evaluation and liver 
biopsy to establish etiology of hepatic injury  
• 
Immediately initiate treatment with 1−2 mg/kg/day equivalent to 
1−2 mg/kg/day oral prednisone 
• 
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent 
• 
If event resolves to Grade 1 or better, taper corticosteroids over 
≥ 1 month 
GI, gastrointestinal; LFT, liver function test. 
a Atezolizumab may be withheld for a period of time beyond 12 weeks after event onset to allow for corticosteroids (if 
initiated) to be reduced to ≤ 10 mg/day oral prednisone or equivalent. The acceptable length of the extended period of time 
must be based on an assessment of benefit−risk by the Investigator and in alignment with the protocol requirements for the 
duration of treatment and documented by the Investigator. The Sponsor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or equivalent 
before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully recovered from the 
immune-related event. The decision to rechallenge subjects with atezolizumab should be based on Investigator's assessment 
of benefit−risk and documented by the Investigator. The Sponsor is available to advise as needed. 
The finding of an elevated ALT or AST (> 3 × ULN) in combination with either an elevated total 
bilirubin (> 2 × ULN) or clinical jaundice in the absence of cholestasis or other causes of 
hyperbilirubinemia is considered to be an indicator of severe liver injury (as defined by Hy's 
Law). Therefore, either of the following conditions requires permanent discontinuation of all 
study drugs, including atezolizumab, and reporting of the occurrence as a serious adverse event: 
• Treatment-emergent ALT or AST > 3 × ULN in combination with total bilirubin > 2 × ULN 

 
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• Treatment-emergent ALT or AST > 3 × ULN in combination with clinical jaundice 
6.6.2.1.14 
Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome 
Immune-mediated reactions may involve any organ system and may lead to hemophagocytic 
lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS).  
Clinical and laboratory features of severe CRS overlap with HLH, and HLH should be 
considered when CRS presentation is atypical or prolonged. 
Subjects with suspected HLH should be diagnosed according to published criteria by McClain 
and Eckstein (2014). A subject should be classified as having HLH if five of the following eight 
criteria are met: 
• Fever ≥ 38.5°C 
• Splenomegaly 
• Peripheral blood cytopenia consisting of at least two of the following: 
− Hemoglobin < 90 g/L (9 g/dL) (< 100 g/L [10 g/dL] for infants < 4 weeks old) 
− Platelet count < 100 × 109/L (100,000/µL) 
− ANC < 1.0 × 109/L (1000/µL) 
• Fasting triglycerides > 2.992 mmol/L (265 mg/dL) and/or fibrinogen < 1.5 g/L 
(150 mg/dL) 
• Hemophagocytosis in bone marrow, spleen, lymph node, or liver 
• Low or absent natural killer cell activity 
• Ferritin > 500 mg/L (500 ng/mL) 
• Soluble interleukin 2 (IL-2) receptor (soluble CD25) elevated ≥ 2 standard deviations 
above age-adjusted laboratory-specific norms 
 
Subjects with suspected MAS should be diagnosed according to published criteria for systemic 
juvenile idiopathic arthritis by Ravelli et al (2016). A febrile subject should be classified as 
having MAS if the following criteria are met: 
• Ferritin > 684 mg/L (684 ng/mL) 
• At least two of the following: 
− Platelet count ≤ 181 × 109/L (181,000/µL) 
− AST ≥ 48 U/L 
− Triglycerides > 1.761 mmol/L (156 mg/dL) 
− Fibrinogen ≤ 3.6 g/L (360 mg/dL) 
 

 
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Subjects with suspected HLH or MAS should be treated according to the guidelines in Table 
6-25. 
Table 6-25: 
Management Guidelines for Suspected Hemophagocytic Lymphohistiocytosis 
or Macrophage Activation Syndrome 
Event 
Management 
Suspected HLH or MAS 
• 
Permanently discontinue atezolizumab and contact the Sponsor 
• 
Consider patient referral to hematologist 
• 
Initiate supportive care, including intensive care monitoring if indicated per 
institutional guidelines 
• 
Consider initiation of IV corticosteroids, an immunosuppressive agent, 
and/or anti-cytokine therapy 
• 
If event does not respond to treatment within 24 hours, contact Sponsor and 
initiate treatment as appropriate according to published guidelines (La Rosée 
2015; Schram and Berliner 2015; La Rosée et al 2019) 
• 
If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent 
• 
If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month 
HLH, hemophagocytic lymphohistiocytosis; IV, intravenous; MAS, macrophage activation syndrome 
6.6.2.1.15 
Other Atezolizumab-Associated Immune-Related Adverse Events 
For management of other irAEs not included in Sections 6.6.2.1.1 through 6.6.2.1.14, the 
following general management guidance should be applied: 
• Grade 2 or 3: delay atezolizumab dosing up to 12 weeks until irAE recovers to Grade 0-1 and 
corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day 
• Grade 4 or recurrent Grade 3: permanently discontinue atezolizumab 
6.6.2.1.16 
Embryo-Fetal Toxicity 
Based on its mechanism of action, atezolizumab can cause fetal harm when administered to a 
pregnant woman. Animal studies have demonstrated that inhibition of the PD-L1/PD-1 pathway 
can lead to increased risk of immune-related rejection of the developing fetus resulting in fetal 
death. If atezolizumab is used during pregnancy, or if the subject becomes pregnant while taking 
atezolizumab, advise the subject of the potential risk to a fetus. Advise females of reproductive 
potential to use highly effective contraception as defined in Appendix E during treatment with 
atezolizumab and for at least 5 months after the last dose. 

 
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6.6.3 
Warnings, Precautions, and Management Guidelines for Adverse Events 
Associated with Abiraterone Plus Prednisone 
Abiraterone 
The most common adverse reactions (≥ 10%) associated with abiraterone are fatigue, arthralgia, 
hypertension, nausea, edema, hypokalemia, hot flush, diarrhea, vomiting, upper respiratory 
infection, cough, and headache. 
The most common laboratory abnormalities (> 20%) associated with abiraterone are anemia, 
elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, 
hyperglycemia, and hypokalemia. 
Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: Abiraterone 
may cause hypertension, hypokalemia, and fluid retention as a consequence of increased 
mineralocorticoid levels resulting from CYP17 inhibition. Subjects taking abiraterone should be 
monitored for hypertension, hypokalemia, and fluid retention at least once a month. 
Hypertension and hypokalemia should be controlled before and during treatment with 
abiraterone. 
Subjects whose underlying medical conditions might be compromised by increases in blood 
pressure, hypokalemia or fluid retention, such as those with heart failure, recent myocardial 
infarction, cardiovascular disease, or ventricular arrhythmia should be closely monitored. 
Adrenocortical Insufficiency: Adrenal insufficiency has been observed in patients taking 
abiraterone. Adrenocortical insufficiency has been reported in patients receiving abiraterone in 
combination with prednisone, following interruption of daily steroids and/or with concurrent 
infection or stress. Subjects should be monitored for symptoms and signs of adrenocortical 
insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose 
reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency 
may be masked by adverse reactions associated with mineralocorticoid excess seen in patients 
treated with abiraterone. If clinically indicated, appropriate tests to confirm the diagnosis of 
adrenocortical insufficiency should be performed. Increased dosage of corticosteroids may be 
indicated before, during, and after stressful situations. 
Hepatotoxicity: Abiraterone has been associated with severe hepatic toxicity, including fulminant 
hepatitis, acute liver failure, and deaths. Serum transaminases (ALT and AST) and bilirubin 
levels should be measured prior to starting treatment with abiraterone, every two weeks for the 
first three months of treatment, and every three weeks thereafter. Serum total bilirubin, AST, and 
ALT should be measured promptly if clinical symptoms or signs suggestive of hepatotoxicity 
develop. Elevations of AST, ALT, or bilirubin from the subject’s baseline should prompt more 

 
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frequent monitoring. If at any time AST or ALT rises above 5 × ULN, or the bilirubin rises 
above 3 × ULN, interrupt abiraterone treatment and closely monitor liver function.  
Re-treatment with abiraterone at a reduced dose level may take place only after return of liver 
function tests to the subject’s baseline or to AST and ALT less than or equal to 2.5 × ULN and 
total bilirubin less than or equal to 1.5 × ULN. 
Abiraterone must be permanently discontinued for subjects who develop a concurrent elevation 
of ALT greater than 3 × ULN and total bilirubin greater than 2 × ULN in the absence of biliary 
obstruction or other causes responsible for the concurrent elevation. 
Refer to the most current local prescribing information appropriate to the respective study site 
location for additional details on warnings, precautions, possible AEs and management guidance 
for AEs associated with abiraterone. 
For specific warnings and precautions regarding the use of prednisone please refer to the most 
current local prescribing information appropriate to the respective study site location.  
6.6.4 
Warnings, Precautions, and Management Guidelines for Adverse Events 
Associated with Enzalutamide 
The most common adverse reactions (≥ 10%) that occurred more frequently (≥ 2% over placebo) 
in enzalutamide-treated patients from randomized placebo-controlled clinical trials were 
asthenia/fatigue, decreased appetite, hot flush, arthralgia, dizziness/vertigo, hypertension 
headache, and weight decreased. 
Seizure: Seizure occurred in 0.4% of patients receiving enzalutamide. In patients with 
predisposing factors, seizures were reported in 2.2% of patients. Subjects should be advised of 
the risk of developing a seizure while receiving enzalutamide and of engaging in any activity 
where sudden loss of consciousness could cause serious harm to themselves or others. 
Enzalutamide must be permanently discontinued in subjects who develop a seizure during 
treatment. 
Posterior Reversible Encephalopathy Syndrome (PRES): There have been reports of 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. A diagnosis of PRES 
requires confirmation by brain imaging, preferably MRI. Discontinue enzalutamide in subjects 
who develop PRES. 

 
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Hypersensitivity: Hypersensitivity reactions, including edema of the face, tongue, or lip have 
been observed with enzalutamide in clinical trials. Pharyngeal edema has been reported in post-
marketing cases. Subjects who experience any symptoms of hypersensitivity should temporarily 
discontinue enzalutamide and promptly seek medical care. Enzalutamide must be permanently 
discontinued for serious hypersensitivity reactions. 
Ischemic Heart Disease: In clinical studies, ischemic heart disease occurred more commonly in 
patients on the enzalutamide arm compared to the placebo arm. Subjects should be monitored for 
signs and symptoms of ischemic heart disease. Management of cardiovascular risk factors, such 
as hypertension, diabetes, or dyslipidemia should be optimized. Enzalutamide must be 
discontinued for Grade 3-4 ischemic heart disease. 
Falls and fractures: Falls and fractures occurred in patients receiving enzalutamide. Subjects 
should be evaluated for fracture and fall risk. Subjects at risk for fractures should be monitored 
and managed according to established treatment guidelines, and the use of bone-targeted agents 
should be considered. 
Embryo-Fetal Toxicity: The safety and efficacy of enzalutamide have not been established in 
females. Based on animal reproductive studies and mechanism of action, enzalutamide can cause 
fetal harm and loss of pregnancy when administered to a pregnant female. Advise males with 
female partners of reproductive potential to use effective contraception during treatment with 
enzalutamide and for 3 months after the last dose of enzalutamide. Enzalutamide should not be 
handled by females who are or may become pregnant 
Refer to the most current local prescribing information appropriate to the respective study site 
location for additional details on warnings, precautions, possible AEs and management guidance 
for AEs associated with enzalutamide. 
7 
CONCOMITANT MEDICATION AND THERAPY 
Concomitant medication taken by the subject from 28 days before first dose of study treatment 
through 30 days after the date of the decision to discontinue study treatment must be 
documented. Additionally, concomitant medications classified as immunosuppressive agents, 
including systemic corticosteroids, must be documented through 100 days after the date of the 
decision to discontinue study treatment.   
Guidance on allowed, prohibited, and restricted therapies described in the subsequent sections 
must be followed throughout the study. 

 
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7.1 
Allowed Therapies 
• Antiemetics and antidiarrheal medications are allowed prophylactically according to standard 
clinical practice if clinically indicated.  
• Granulocyte colony-stimulating factors (G-CSF or GM-CSF) are allowed if used per clinical 
guidelines (eg, ASCO or ESMO guidelines).  
• Bisphosphonates and/or denosumab can be used to control bone loss or hypercalcemia if the 
benefit outweighs the risk per the Investigator’s discretion (Section 6.6.1.1.8). 
Note: osteonecrosis of the jaw has been reported in subjects using bisphosphonates and/or 
denosumab. Oral examinations are recommended at screening to determine eligibility and 
periodically during the study. In addition, subjects should be advised regarding oral hygiene 
practice and to quickly report symptoms to the Investigator. Frequent monitoring for 
potentially overlapping toxicities with study treatment is recommended.  
• Transfusions and hormone replacement should be utilized as indicated by standard clinical 
practice. 
• Topical, inhaled, intranasal, and/or intraarticular corticosteroids are allowed. For the 
experimental arm prophylactic systemic corticosteroids are allowed for control of infusion 
reactions and must be tapered to a dose level ≤ 10 mg/day of prednisone equivalent before 
next atezolizumab administration. If corticosteroids are initiated for the treatment of irAEs 
(except transfusion reactions), they must be tapered over ≥ 1 month to ≤ 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed unless otherwise specified in 
the AE management guidance (Section 6.6) or the atezolizumab Investigator’s Brochure. 
Prophylactic steroid treatment for subjects with contrast allergies prior to tumor imaging is 
allowed. A short course of systemic steroids for acute medical conditions (such as worsening 
of COPD and gout flare) is allowed but steroids must be tapered to ≤ 10 mg/day oral 
prednisone or equivalent before the subsequent dose of atezolizumab. Local injections of 
steroids for local medical conditions may be allowed upon Sponsor’s approval. Adrenal 
replacement steroid doses > 10 mg daily prednisone equivalent are permitted in the absence 
of active autoimmune disease. 
• Individualized anticoagulation therapy with heparin or the direct factor Xa inhibitors 
rivaroxaban, edoxaban, or apixaban is allowed if it can be provided safely and effectively 
under the following circumstances (for restrictions on oral anticoagulants, see Section 7.2):  

 
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o Low dose low molecular weight heparins (LMWH) for prophylactic use are allowed if 
clinically indicated and the benefit outweighs the risk per the Investigator’s discretion.  
o At the time of the first dose of study treatment, therapeutic doses of LMWH or the 
direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban are allowed if the 
subject has no known brain metastasis, clinically significant hemorrhage, or 
complications from a thromboembolic event from the anticoagulation regimen or 
tumor, and the subject has been on a stable dose of the anticoagulant for at least 
1 week before randomization. 
o After first dose of study treatment, therapeutic doses of LMWH or the direct factor Xa 
oral inhibitors rivaroxaban, edoxaban, or apixaban are allowed if clinically indicated 
(eg, for the treatment of DVT), and the benefit outweighs the risk per the 
Investigator’s discretion. For management of thromboembolic complications while on 
study, refer to Section 6.6.1.1.4.  
o Considerations for use of anticoagulation therapy: Accepted clinical guidelines 
regarding appropriate management while receiving any kind of anticoagulation 
therapy must be followed. This includes, but is not limited to, subject education 
regarding potential adverse drug reactions, monitoring laboratory parameters, dose 
adjustments (eg, due to kidney dysfunction). Caution is warranted in settings 
associated with an increased risk for bleeding such as gastrointestinal cancers, 
urothelial cancers, gastrointestinal mucosal abnormality (eg, mucositis), renal or 
hepatic impairment, thrombocytopenia, arterial hypertension, or prior history of 
gastrointestinal bleed. For direct factor Xa inhibitors, the potential for drug-drug 
interaction with other concomitant medications, as well as gastrointestinal absorption, 
should be considered. Aspirin and other nonsteroidal anti-inflammatory drugs 
(NSAIDs) should not be used concomitantly with heparin or factor Xa inhibitors due 
to the increased risk for bleeding complications. The risks and benefits of the use of 
anticoagulants should be reassessed on a regular basis. For more information regarding 
the use of anticoagulants, refer to the prescribing information of the anticoagulant and 
accepted clinical practice guidelines. 
• Considerations for use of COVID-19 vaccine: At this time, there are limited data 
available for the use of COVID-19 vaccines in specific subsets of individuals such as the 
immunocompromised and cancer patients, including those receiving anticancer therapy 
such as cabozantinib, atezolizumab, and NHTs. The decision to proceed with vaccination 

 
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for subjects enrolled in this clinical study rests with the treating physician and the subject 
and should be taken after consideration of all safety precautions provided by the 
manufacturers of the vaccines and local health authorities. Please note, immunizations 
with live, attenuated COVID-19 vaccines or any experimental vaccines are not allowed. 
Exelixis will monitor all available information and provide additional guidance as 
appropriate. 
Potential drug interactions with cabozantinib are summarized in Section 7.3.1. The drug 
interaction potential of atezolizumab is unknown (Section 7.3.2). Refer to the local prescribing 
information and the atezolizumab Investigator’s Brochure. Potential drug interactions with 
abiraterone plus prednisone, and enzalutamide are summarized in Section 7.3.3 and 
Section 7.3.4, respectively. 
7.2 
Prohibited or Restricted Therapies 
7.2.1 
Prohibited or Restricted Therapies in Both Arms 
The following therapies are prohibited in both arms until study treatment has been permanently 
discontinued or until otherwise specified: 
• Any investigational agent or investigational medical device. 
• Any nonprotocol systemic anticancer treatment (eg, chemotherapy, immunotherapy, 
radionuclides [eg, radium-233], hormonal therapies, PARP inhibitors, other drugs or herbal 
products used specifically for the treatment of the cancer under investigation) with the 
exception of ongoing androgen deprivation therapy (ADT) with a gonadotropin-releasing 
hormone (GnRH) analog in subjects who have not undergone bilateral orchiectomy. 
The following therapies should be avoided in both arms until study treatment has been 
permanently discontinued or until otherwise specified: 
• Local anticancer treatment including palliative radiation, ablation, embolization, or surgery 
with impact on tumor lesions should not be performed until radiographic progression per 
RECIST 1.1 has been established. If clinically unavoidable the Investigator should consult 
the Sponsor prior to the procedure for safety guidance, if possible.  
• Erythropoietic stimulating agents (eg, epoetin alfa and darbepoetin alfa) should not be used 
based on a report of increased risk of tumor recurrence/progression associated with 
erythropoietin (Wright et al 2007). 

 
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• Concomitant medications that are known to prolong the QTc interval should be avoided in 
subjects until they have permanently discontinued study treatment (refer to 
http://www.qtdrugs.org for a list of drugs which have the potential to prolong the QTc 
interval). 
7.2.2 
Prohibited or Restricted Therapies in the Experimental Arm 
In addition to the therapies listed in Section 7.2.1, the following therapies are prohibited in the 
experimental (cabozantinib and atezolizumab) arm until study treatment has been permanently 
discontinued or until otherwise specified: 
• Oral anticoagulants (unless otherwise specified in Section 7.1) including, but not limited to, 
platelet inhibitors (eg, clopidogrel or ticagrelor), warfarin, dabigatran, betrixaban, and 
chronic use of aspirin above low dose levels for cardioprotection per local applicable 
guidelines, until 4 weeks after cabozantinib has been permanently discontinued. 
• Immunosuppressive agents including immunosuppressive doses of systemic corticosteroids 
except when atezolizumab has been permanently discontinued. See Section 7.1 for allowed 
corticosteroids.  
• Live vaccines are prohibited while on study and until 5 months after last atezolizumab dose 
(eg, intranasal influenza, measles, mumps, rubella, oral polio, Bacillus Calmette-Guérin, 
yellow fever, varicella, and TY21a typhoid vaccines). The use of inactivated (killed) 
vaccines for the prevention of infectious disease is allowed. 
• Metamizole (dipyrone) because of its potential for causing agranulocytosis (see 
Section 6.6.2.1.1). 
In addition to the therapies listed in Section 7.2.1, the following therapies should be avoided in 
the experimental (cabozantinib and atezolizumab) arm until study treatment has been 
permanently discontinued or until otherwise specified: 
• Chronic co-administration of cabozantinib with strong inducers of the CYP3A4 family 
(eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John’s 
Wort) may significantly decrease cabozantinib concentrations and should be 
avoided. Selection of alternate concomitant medications with no or minimal CYP3A4 
enzyme induction potential is recommended.  

 
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• Caution must be used when discontinuing treatment with a strong CYP3A4 inducer in a 
subject who has been concurrently receiving a stable dose of cabozantinib, as this could 
significantly increase the exposure to cabozantinib.  
• Co-administration of cabozantinib with strong inhibitors of the CYP3A4 family 
(eg, boceprevir, conivaptan, posaconazole, ketoconazole, itraconazole, clarithromycin, 
atazanavir, indinavir, nefazodone, nelfinavir, saquinavir, ritonavir, lopinavir, telaprevir, 
telithromycin, and voriconazole) may increase cabozantinib concentrations and should be 
avoided. Grapefruit, star fruit, and Seville oranges may also increase plasma concentrations 
of these study drugs and should be avoided. 
Additional information on potential drug interactions with cabozantinib and atezolizumab are 
summarized in Section 7.3.1 and Section 7.3.2, respectively. 
7.2.3 
Prohibited or Restricted Therapies in the Control Arm (NHT) 
In addition to the therapies listed in Section 7.2.1, the following therapies should be avoided in 
the control (NHT) arm until study treatment has been permanently discontinued or until 
otherwise specified: 
Abiraterone: 
• Avoid concomitant strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, 
rifabutin, rifapentine, phenobarbital, and St. John’s Wort) during abiraterone treatment.  
• Avoid co-administration of abiraterone with CYP2D6 substrates that have a narrow 
therapeutic index (eg, thioridazine).  
Enzalutamide: 
• Avoid co-administration of enzalutamide with strong CYP2C8 inhibitors, as they can 
increase the plasma exposure to enzalutamide. 
• Avoid co-administration of enzalutamide with strong CYP3A4 inducers (eg, 
carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, and St. John’s 
Wort), as they can decrease the plasma exposure to enzalutamide. 
• Avoid co-administration of enzalutamide with narrow therapeutic index drugs that are 
metabolized by CYP3A4 (eg, alfentanil, cyclosporine, dihydroergotamine, ergotamine, 
fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (eg, phenytoin) and 

 
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CYP2C19 (eg, S-mephenytoin), as enzalutamide may decrease the plasma exposure of 
these drugs. 
Please refer to the most current abiraterone, prednisone, and enzalutamide prescribing 
information appropriate to the respective site location for detailed information on prohibited or 
restricted therapies in the control arm. Potential drug interactions with abiraterone plus 
prednisone, and enzalutamide are summarized in Section 7.3.3 and Section 7.3.4, respectively. 
7.3 
Potential Drug Interactions  
7.3.1 
Potential Drug Interactions with Cabozantinib 
Cytochrome P450: Data from a clinical drug interaction study (Study XL184-008) show that 
clinically relevant steady-state concentrations of cabozantinib appear to have no marked effect 
on the area under the plasma concentration-vs-time curve (AUC) of co-administered 
rosiglitazone, a CYP2C8 substrate. Therefore, cabozantinib is not anticipated to markedly inhibit 
CYP2C8 in the clinic, and by inference, is not anticipated to markedly inhibit other CYP450 
isozymes that have lower [I]/Ki values compared to CYP2C8 (ie, CYP2C9, CYP2C19, CYP2D6, 
CYP1A2, and CYP3A4). In vitro data indicate that cabozantinib is unlikely to induce 
cytochrome P450 enzymes, except for possible induction of CYP1A1 at high cabozantinib 
concentrations (30 μM).  
Cabozantinib is a CYP3A4 substrate and a weak substrate for CYP2C9 (but not a CYP2D6, 
CYP2C8, CYP2C19, CYP2B6, or CYP1A2 substrate), based on data from in vitro studies. 
Results from a clinical pharmacology study, XL184-006, showed that concurrent administration 
of cabozantinib with the strong CYP3A4 inducer, rifampin, resulted in an approximately 77% 
reduction in cabozantinib exposure (AUC values) after a single dose of cabozantinib in healthy 
volunteers. Chronic co-administration of cabozantinib with strong inducers of the CYP3A4 
family (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. 
John’s Wort) may significantly decrease cabozantinib concentrations. The chronic use of strong 
CYP3A4 inducers should be avoided (Appendix I). Other drugs that induce CYP3A4 should be 
used with caution because these drugs have the potential to decrease exposure (AUC) to 
cabozantinib. Selection of alternate concomitant medications with no or minimal CYP3A4 
enzyme induction potential is recommended.  
Results from a clinical pharmacology study, XL184-007, showed that concurrent administration 
of cabozantinib with the strong CYP3A4 inhibitor, ketoconazole, resulted in a 38% increase in 
the cabozantinib exposure (AUC values) after a single dose of cabozantinib in healthy 
volunteers. Co-administration of cabozantinib with strong inhibitors of the CYP3A4 family 

 
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(eg, boceprevir, conivaptan, posaconazole, ketoconazole, itraconazole, clarithromycin, 
atazanavir, indinavir, nefazodone, nelfinavir, saquinavir, ritonavir, lopinavir, telaprevir, 
telithromycin, and voriconazole) may increase cabozantinib concentrations. Grapefruit, star fruit 
and Seville oranges may also increase plasma concentrations of cabozantinib and should be 
avoided. Strong CYP3A4 inhibitors should be avoided and other drugs that inhibit CYP3A4 
should be used with caution because these drugs have the potential to increase exposure (AUC) 
to cabozantinib (Appendix I). Selection of alternate concomitant medications with no or minimal 
CYP3A4 enzyme inhibition potential is recommended.  
Please refer to the drug interaction tables at the following websites for lists of substrates, 
inducers, and inhibitors of selected CYP450 isozyme pathways: 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-
table-substrates-inhibitors-and-inducers 
Protein Binding: Cabozantinib is highly bound (≥ 99.7%) to human plasma proteins. Therefore, 
highly protein bound drugs should be used with caution with cabozantinib, because there is a 
potential displacement interaction that could increase free concentrations of cabozantinib and/or 
a co-administered highly protein-bound drug (and a corresponding increase in pharmacologic 
effect). 
Other Interactions: Food may increase exposure levels of cabozantinib by 57%, so fasting 
recommendations should be followed. In vitro data suggest that cabozantinib is unlikely to be a 
substrate for P-glycoprotein, but it does appear to have the potential to inhibit the P-glycoprotein 
transport activity. Therefore, cabozantinib may have the potential to increase plasma 
concentrations of co-administered substrates of P-glycoprotein. Additional details related to 
these overall conclusions can be found in the cabozantinib Investigator Brochure. 
Administration of the proton pump inhibitor (PPI) esomeprazole resulted in no 
clinically-relevant effect on cabozantinib plasma PK in healthy volunteers. Therefore, 
concomitant use of gastric pH modifying agents (ie, PPIs, H2 receptor antagonists, and antacids) 
is not contraindicated in subjects administered cabozantinib. 
Additional details regarding potential drug interactions with cabozantinib can be found in the 
cabozantinib Investigator Brochure. 

 
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7.3.2 
Potential Drug Interactions with Atezolizumab 
Cytochrome P450 enzymes, as well as conjugation/glucuronidation reactions, are not involved in 
the metabolism of atezolizumab. No drug interaction studies for atezolizumab have been 
conducted. There are no known interactions with other medicinal products or other form of 
interactions. For additional details refer to the local prescribing information and the atezolizumab 
Investigator’s Brochure. 
7.3.3 
Potential Drug Interactions with Abiraterone and Prednisone 
In vitro studies showed that abiraterone is a substrate of CYP3A4. In a drug interaction trial, 
co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 
55%. Therefore, avoid concomitant strong CYP3A4 inducers during abiraterone treatment.  
Abiraterone is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. In 
a CYP2D6 drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) 
were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with 
abiraterone 1,000 mg qd and prednisone 5 mg bid. Therefore, avoid co-administration of 
abiraterone with substrates of CYP2D6 with a narrow therapeutic index (eg, thioridazine) should 
be avoided. 
In a CYP2C8 drug interaction trial in healthy subjects, the AUC of pioglitazone (CYP2C8 
substrate) was increased by 46% when pioglitazone was given together with a single dose of 
1,000 mg abiraterone. Therefore, subjects should be monitored closely for signs of toxicity 
related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with 
abiraterone. 
For additional details regarding potential drug interactions with abiraterone, refer to Appendix I 
and the most current prescribing information appropriate to the respective site location. 
For information regarding potential drug interactions with prednisone, refer to the most current 
prescribing information appropriate to the respective site location. 
7.3.4 
Potential Drug Interactions with Enzalutamide 
Co-administration of a strong CYP2C8 inhibitor (gemfibrozil) increased the composite area 
under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl 
enzalutamide by 2.2-fold. Therefore, avoid co-administration of enzalutamide with strong 
CYP2C8 inhibitors. 

 
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Co-administration of rifampin (strong CYP3A4 inducer and moderate CYP2C8 inducer) 
decreased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 37%. 
Therefore, avoid co-administration of strong CYP3A4 inducers (eg, carbamazepine, 
phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, St. John’s Wort) with enzalutamide. 
Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in 
humans. At steady-state, enzalutamide reduced the plasma exposure to midazolam (CYP3A4 
substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Avoid 
concomitant use of enzalutamide with narrow therapeutic index drugs that are metabolized by 
CYP3A4 (eg, alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, 
quinidine, sirolimus and tacrolimus), CYP2C9 (eg, phenytoin) and CYP2C19 (eg, 
S-mephenytoin), as enzalutamide may decrease their exposure. 
For additional details on potential drug interactions with enzalutamide, refer to Appendix I and 
the most current prescribing information appropriate to the respective site location. 
8 
SAFETY 
8.1 
Adverse Events and Laboratory Abnormalities 
8.1.1 
Adverse Events Definition 
An AE is any untoward medical occurrence in a subject who has been enrolled in a clinical study 
and who may have been administered an investigational product, regardless of whether or not the 
event is assessed as related to the study 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, regardless of whether or not the event is 
assessed as related to the investigational product.  
All untoward events that occur after informed consent through the FU-1 visit (FU-2 visit for 
SAEs and certain other events [Table 8-1]) are to be recorded by the investigational site. At each 
scheduled and unscheduled visit, AEs are to be identified and assessed based upon study 
procedures, routine and symptom-directed clinical investigations, and subject query/report. The 
AE follow-up period is provided in Section 8.4 and further details are provided in Appendix J. 
An AE does not include: 
• A medical or surgical procedure (eg, surgery, endoscopy, tooth extraction, or 
transfusion); an AE is the underlying condition that leads to the procedure. 

 
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• Pre-existing diseases or conditions present or detected before start of study drug(s) 
administration that do not worsen or increase in severity or frequency after the 
administration of study drug(s). 
• Situations where an untoward medical occurrence has not occurred (eg, hospitalization 
for a planned procedure prior to study enrollment or for elective surgery for a condition 
that has not worsened on study; social and/or convenience admissions to grant families a 
respite in caring for a subject). 
• Overdose of study drug(s) or concomitant medication without any signs or symptoms. 
 
8.1.2 
Adverse Events Causality Assessment 
Assessment of the relationship of the AE to the study treatment by the Investigator will be based 
on the following two definitions: 
• Not Related: An event is assessed as not related to study drug(s) if it can be reasonably 
attributable to another cause such as subject’s pre-existing medical history/risk factors, 
underlying disease, concurrent illness, or concomitant medications/therapies. 
• Related: An event is assessed as related to study drug(s) when there is at least a reasonable 
possibility of a causal relationship between a suspected study drug(s) and an AE. The term 
“reasonable possibility” means that there are facts, evidence or arguments to support a causal 
relationship. 
8.1.3 
Adverse Events Grading 
The severity of an event and the seriousness are not to be considered synonymous. The severity 
is grading the intensity of an event. The seriousness of event is based on the subject/event 
outcome or action criteria. All AEs will be assessed for severity using the National Cancer 
Institute (NCI) CTCAE v 5.0 guidelines. If a particular AE is not listed in the NCI-CTCAE, the 
following criteria will be used: 
• Grade 1 = Mild (event results in mild or transient discomfort, not requiring or needing 
only minimal intervention or treatment; does not limit or interfere with daily activities 
[eg, insomnia, mild headache]) 
• Grade 2 = Moderate (event is sufficiently discomforting so as to limit or interfere with 
daily activities; may require interventional treatment [eg, fever requiring antipyretic 
medication]) 

 
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• Grade 3 = Severe (event results in significant symptoms that prevent normal daily 
activities; may require hospitalization or invasive intervention) 
• Grade 4 = Life threatening or disabling 
• Grade 5 = Death 
8.1.4 
Laboratory Abnormalities and Other Clinical Investigations 
All laboratory data required by this protocol and any other clinical investigations (eg, ECGs and 
vital signs) will be reviewed by the Investigator. Any abnormal value that leads to a subject 
developing any clinical sequelae such as symptoms or change in subject management (eg, study 
drug dose reduction or delay or requirement for additional medication or monitoring) and are 
considered to be of clinical significance by the Investigator will be reported as an AE or SAE as 
appropriate, unless this value is consistent with the subject’s present disease state or is consistent 
with values obtained prior to entry into the study. 
8.2 
Serious Adverse Events  
8.2.1 
Serious Adverse Events Definitions 
The SAE definition and reporting requirements are in accordance with the ICH Guideline for 
Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, 
Topic E2A. 
An SAE is defined as any untoward medical occurrence that at any dose: 
• Results in death. 
• Is life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to 
an event or reaction in which the subject was at immediate risk of death at the time of the 
event or reaction; it does not refer to an event or reaction which hypothetically might have 
caused death if it were more severe in the opinion of the Investigator.) 
• Requires inpatient hospitalization or results in prolongation of an existing hospitalization, 
except for the following: 
- 
A surgery or procedure that was planned before the subject entered the study and which 
is part of the planned study procedure. 
- 
Nonmedical reasons (eg, elective hospitalizations for social reasons or due to long travel 
distances or for prophylactic patient observation), in the absence of an AE. 

 
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• Results in significant incapacity or substantial disruption of the ability to conduct normal life 
functions. 
• Is a congenital anomaly or birth defect. 
• Is an important medical event that may not be immediately life-threatening, result in death, or 
require hospitalization, but may be considered an SAE when, based upon appropriate medical 
judgment, it jeopardizes the subject or may require medical or surgical intervention to 
prevent one of the outcomes listed above.  
8.2.2 
Serious Adverse Events Reporting Rules 
As soon as an Investigator becomes aware of an AE that meets the criteria for an SAE, the 
Investigator will document the SAE to the extent that information is available. 
SAEs, regardless of causal relationship, must be reported to the Sponsor or designee within 
24 hours of the Investigator’s knowledge of the event by submitting the completed SAE report 
form and any other pertinent SAE information as indicated in the SAE Reporting form (or in the 
SAE Reporting form Completion Guidelines) and confirming the report was received. Forms for 
reporting SAEs and contact information will be provided to the study sites. 
All SAEs that must be recorded in an eCRF or on an SAE Reporting form are as follows: 
• All SAEs that occur after informed consent and through the FU-2 visit (ie, 100 [±14] days 
after the date of the decision to permanently discontinue study treatment, defined as the later 
of the date of the decision of the Investigator to permanently discontinue study treatment or 
the date of the last dose of study treatment taken by the subject). 
• Any SAEs assessed as related to study treatment or study procedures, even if the SAE occurs 
after the FU-2 visit. 
Note: If the subject does not meet the eligibility criteria during screening, then SAEs only need 
to be reported from the time the subject signs the informed consent until the day when the 
subject has been determined to not be eligible for study participation. 
SAEs that occur after informed consent through the FU-2 visit must also be recorded on the CRF 
page.  
The minimum information required for the initial SAE reporting includes identity of 
Investigator, site number, subject number, the SAE term(s), the specification of any serious 

 
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criteria, severity (CTCAE grade), the Investigator’s assessment of causal relationship between 
the event(s) and each study treatment, study treatment details (ie, start date, dosing, frequency, 
etc), and an event description. 
Following the initial SAE reporting, the Investigator will continue to monitor the subject’s 
clinical condition leading to the follow-up SAE reporting that may include updates on any 
performed investigations (eg, laboratory, imaging, consult notes), diagnostic evidence to support 
reported SAE term(s), medications or other therapeutic measures used to treat the event(s), 
action taken with the study treatment because of the event(s), and the outcome/resolution. 
Furthermore, the Investigator may be required to provide supplementary information such as 
hospital discharge summary, autopsy report, or death certificate, as requested by the Sponsor’s 
Drug Safety personnel or designee. 
When reporting SAEs, the following additional point should be considered: 
• When the diagnosis of an SAE is known or suspected, the Investigator will report the 
diagnosis or syndrome as the primary SAE term, rather than as signs or symptoms. Signs and 
symptoms may then be described in the event description.  
8.2.2.1 
Reporting Fatal/Death Cases 
The term “Death” will not be reported as an SAE, but as an outcome of a specific SAE, unless 
the event preceding the death is unknown. Terms of “Unexplained Death” or “Death from 
unknown origin” may be used when the cause is unknown. In these circumstances the 
Investigator must investigate the cause of death by collecting any available information 
(eg, clinical manifestation, date/time, location, death certificate, etc) and if an underlying 
diagnosis/etiology was identified, the SAE term should be amended accordingly. If an autopsy 
was performed, the autopsy report should be provided.  
As a general rule, only one SAE should be considered as the primary cause of death (per 
investigator’s opinion) and reported with an outcome of “Fatal,” serious criterion of “Death” and 
severity Grade 5. Any other serious events ongoing at the time of death should be reported as 
non-fatal SAEs. All deaths should be recorded in the AE and Death CRF as AEs, even if they 
occur after the follow-up period. 
8.2.2.2 
Reporting Disease Progression Cases 
It is anticipated that during this study a proportion of subjects will experience underlying cancer 
progression on or after discontinuation of study treatment. In this context, subjects may 

 
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experience multiple clinical manifestations (eg, asthenia, general physical health deterioration, 
ascites, increasing edema, dyspnea, bleeding, multi-organ failure, etc) that may be attributed to 
the underlying cancer progression. In general, any observed clinical manifestations meeting at 
least one SAE criterion should be reported as individual SAE terms. Relevant information on the 
underlying cancer progression should be provided in the SAE description and be recorded in the 
the CRF. Reporting of the underlying “prostate cancer progression” as an SAE term should 
generally be avoided and should be reserved for fatal prostate cancer progression or situations 
when the clinical manifestation is non-specific (eg, general physical health deterioration) or in 
case of a documented terminal underlying disease without another clear cause of death (eg, for 
fatal cancer progression occurring in hospice). 
8.2.3 
Regulatory Reporting 
The Sponsor or its designee is responsible for reporting relevant SAEs to the relevant regulatory 
authorities, and participating investigators, in accordance with applicable global and/or local 
regulatory requirements. 
In subjects with advanced cancer, natural progression of malignancy may occur; hence any 
progression of underlying malignancy, for which the study drug(s) are administered, is being 
considered an expected event for regulatory reporting purposes. 
Reporting of SAEs by the Investigator to his or her IRB/ECs will be done in accordance with the 
standard operating procedures and policies of the IRB/EC. Adequate documentation must be 
maintained showing that the IRB/EC was properly notified. 
Updates to the protocol, Investigator’s Brochure (IB), and informed consent due to new safety 
signals will be performed per regulatory requirements. Events that require notification of 
significant safety information may be communicated by a Dear Investigator (or similar) letter to 
participating sites and relevant health authorities with a subsequent update of protocol, 
Investigator’s Brochure, and informed consent. 
8.3 
Adverse Events of Special Interest for Atezolizumab 
Adverse events of special interest (AESIs) consist of immune-mediated AEs associated with 
ICIs, cases of potential drug-induced liver injury (DILI), and suspected transmission of an 
infectious agent by the study treatment (Table 8-1).  
AESIs will be reported to the Sponsor or designee via eCRF or using the SAE reporting form 
irrespective of whether the event is serious or nonserious; all AESIs must be reported within 24 
hours using the SAE reporting process as described in Section 8.2.2.  

 
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Guidance for management of immune-mediated AEs associated with atezolizumab is provided in 
Section 6.6.2 and can also be found in the local prescribing information and Investigator’s 
Brochure for atezolizumab. 
Table 8-1: 
Adverse Events of Special Interest for Atezolizumab 
Event 
• 
Cases of potential DILI that include an elevated ALT or AST in combination with either an 
elevated bilirubin or clinical jaundice, as defined by Hy's Law and based on the following 
observations: 
o 
Treatment-emergent ALT or AST > 3 × ULN in combination with total bilirubin > 2 × 
ULN  
o 
Treatment-emergent ALT or AST > 3 × ULN in combination with clinical jaundice 
• 
Suspected transmission of an infectious agent by the study treatment, as defined below 
o 
Any organism, virus, or infectious particle (eg, prion protein transmitting transmissible 
spongiform encephalopathy), pathogenic or non-pathogenic, is considered an infectious 
agent. A transmission of an infectious agent may be suspected from clinical symptoms 
or laboratory findings that indicate an infection in a patient exposed to a medicinal 
product. This term applies only when a contamination of study treatment is suspected. 
• 
Systemic lupus erythematosus 
• 
Events suggestive of hypersensitivity, infusion-related reactions, cytokine release syndrome, 
hemophagocytic lymphohistiocytosis, and macrophage activation syndrome  
• 
Nephritis 
• 
Ocular toxicities (eg, uveitis, retinitis, optic neuritis) 
• 
≥ Grade 2 cardiac disorders (eg, atrial fibrillation, myocarditis, pericarditis) 
• 
Vasculitis 
• 
Autoimmune hemolytic anemia 
• 
Severe cutaneous reactions (eg, Stevens-Johnson syndrome, bullous dermatitis, toxic epidermal 
necrolysis) 
• 
Grade ≥ 3 diarrhea 
• 
Myelitis 
• 
Facial paresis 
ALT, alanine aminotransferase; AST, aspartate aminotransferase; DILI, drug-induced liver injury; ULN, upper 
limit of normal. 
8.3.1 
General Information on Immune-Related Adverse Events 
The immune-modulating properties of immune checkpoint-inhibitors, such as the anti-PD-L1 
antibody atezolizumab, are able to unbalance the immunologic tolerance and generate a subset of 
AEs (called irAEs) with an autoimmune inflammatory pathomechanism. IrAEs may involve 
every organ or tissue (Michot et al 2016). Most irAEs occur within the first 12 weeks of 

 
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exposure to ICIs but some may appear with a delayed onset. Diagnosis of irAEs should be based 
on exposure to an ICI and a reasonable immune-based mechanism of the observed AE. 
Whenever possible, histologic examination or other immune-based diagnostic evaluations should 
be used to support the diagnosis. Other etiologic causes including AEs from tumor progression 
should be ruled out. 
The spectrum of irAEs is wide and can be general or organ-specific. Examples of general irAEs 
in subjects treated with ICIs are fatigue, fever, and chills. Organ-specific irAEs include 
dermatitis (rash, pruritus, vitiligo, oral mucositis, and gingivitis), enterocolitis (diarrhea with 
abdominal pain and clinical or radiological evidence of colonic inflammation), and 
endocrinopathies (pituitary, thyroid, adrenal, testes). Diagnosis of endocrine dysfunction is 
challenging with relatively unspecific symptoms. Additional laboratory testing of the endocrine 
axes may be helpful: prolactin (pituitary-hypothalamic function), T4 and TSH (pituitary-thyroid 
function), luteinizing hormone (LH) and follicle-stimulating hormone (FSH; pituitary-gonadal 
function), adrenocorticotropic hormone (ACTH) and cortisol (pituitary-adrenal function).  
Additional organ-specific irAEs include hepatitis (AST/ALT increases, hepatomegaly, periportal 
edema, periportal lymphadenopathy, lymphocyte infiltration of periportal tissue and surrounding 
primary biliary ducts) and pneumonitis (acute interstitial pneumonia). Less frequent irAEs 
include neurologic disorders (myasthenia gravis, Guillain-Barré syndrome, aseptic meningitis, 
myelitis, facial paresis), ocular AEs (uveitis), renal AEs (interstitial nephritis), cardiac AEs 
(myocarditis or immune-mediated pericardial disorders), skin-related AEs (Stevens-Johnson 
syndrome, toxic epidermal necrolysis), and pancreatic AEs (lipase increase). 
8.4 
Follow-Up of Adverse Events 
Nonserious AEs (see below for AESIs [Table 8-1]) are to be recorded in the CRF through the 
FU-1 visit. The status of unrelated SAEs that are ongoing after the date of the decision to 
discontinue study treatment will be documented through the FU-2 visit. 
All AESIs (regardless of seriousness) and all related SAEs that are ongoing at the FU-2 visit, and 
AEs assessed as related that led to study treatment discontinuation that are ongoing at the FU-2 
visit are to be followed until: 
• The AE has resolved  
• The AE has improved to Grade 2 or lower  
• The Investigator determines that the event has become stable or irreversible. 
Further details on follow-up procedures are summarized in Appendix J. 

 
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All deaths should be recorded in the AE and Death CRF as AEs, even if they occur after the 
follow up period. 
8.5 
Other Safety Considerations 
8.5.1 
Pregnancy 
Use of highly effective methods of contraception (Appendix E) is very important during the 
study and must continue for 4 months (16 weeks) after the last dose of cabozantinib in the 
experimental arm (cabozantinib + atezolizumab), 3 weeks after the last dose of abiraterone 
(control arm), or 3 months (12 weeks) after the last dose of enzalutamide (control arm). 
Furthermore, subjects must refrain from donating sperm and are required to use condoms in 
order to avoid transmission of study treatment in semen for the same periods described above. If 
a partner of a subject becomes pregnant during the study, the Sponsor will ask the pregnant 
partner to consent to be followed through the end of her pregnancy and for the infant to be 
followed for at least 6 months after birth.  
The Investigator must inform the Sponsor of the partner’s pregnancy. Forms for reporting 
pregnancies will be provided to the study sites upon request. The outcome of a pregnancy and 
the medical condition of any resultant offspring must be reported to the Sponsor or designee. 
Any birth defect or congenital anomaly must be reported as an SAE and any other untoward 
events occurring during the pregnancy must be reported as AEs or SAEs, as appropriate. 
Subjects should seek advice and consider fertility preservation before receiving study treatment. 
8.5.2 
Special Situation Reporting 
Any study medication overdose, misuse, abuse, or study medication error (excluding missed 
doses) that results in an AE or SAE requires reporting to the Sponsor or designee according to 
the guidance for AE and SAE reporting (Sections 8.1 and 8.2, respectively).  
A Medication Error Notification Form should be completed and sent to the Sponsor following 
any suspected medication error.  
In case of overdose, the Sponsor Medical Monitor or designee should be contacted promptly to 
discuss how to proceed. Any AEs that occur as a result of an overdose have to be treated 
according to clinical standard practice.  
Please refer to the cabozantinib Investigator’s Brochure for additional management 
recommendations for an overdose of cabozantinib, and to the most current prescribing 

 
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information appropriate to the respective site location for management of overdoses of 
abiraterone, prednisone, or enzalutamide. 
9 
STATISTICAL CONSIDERATIONS 
Details of the planned analyses, including any modifications implemented prior to conducting 
analyses, will be provided in a separate Statistical Analysis Plan (SAP) that will be finalized 
before the primary endpoint analysis is performed. Any sensitivity analyses or other strategies if 
needed to assess and address consequences of the COVID-19 pandemic on trial conduct and 
study data will be provided in the SAP. The statistical principles applied in the design and 
planned analyses of this study are consistent with ICH E9 and FDA Guidance for Industry: 
Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics (2018). 
9.1 
Analysis Populations 
The following populations will be employed for statistical analyses. 
9.1.1 
Intent-to-Treat Population 
The Intent-to-Treat (ITT) population will consist of all subjects who are randomized, regardless 
of whether any study treatment or the correct study treatment is received.  
9.1.2 
PFS Intent-to-Treat Population 
The first 324 subjects that are randomized (based upon Greenwich Mean Time randomization 
date/time values) to the experimental arm or control arm will be considered as the PFS Intent-to-
Treat (PITT) population. The population may be extended to the first 400 subjects randomized if 
a review of accumulating events suggests that the number of events required may not (or may 
take much longer than expected to) be reached (due to permanent censoring) among the first 
324 subjects originally planned.  
9.1.3 
Safety Population 
The Safety population will consist of all subjects who receive any amount of study treatment. 
Analyses based on the Safety population will be performed according to the actual treatment 
received. Data handling rules for subjects who received incorrect study treatment will be 
described in the SAP.  
9.2 
Primary Efficacy Endpoints 
The multiple-primary efficacy endpoints are duration of PFS per RECIST 1.1 and OS.  

 
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9.2.1 
Definitions 
9.2.1.1 
Duration of Progression Free Survival 
Duration of PFS is defined as the time from randomization to the earlier of either radiographic 
PD per RECIST 1.1 or death due to any cause. The definition of disease progression and 
censoring rules for the primary analysis are described in Section 9.2.2.1. 
9.2.1.2 
Duration of Overall Survival 
Duration of OS is defined as the time from date of randomization to date of death due to any 
cause. For subjects who are alive at the time of data cutoff or are permanently lost to follow-up, 
duration of OS will be right censored at the earlier of the following: date the subject withdrew 
consent from all follow-up, data cutoff date, or the date the subject was last known to be alive.  
9.2.2 
Primary Analysis 
9.2.2.1 
Progression-Free Survival 
The primary analysis of PFS is event-driven and will be conducted after at least 202 events have 
been observed in the PITT population (see Section 9.1.2). It is designed to include progression 
events as determined per RECIST 1.1 by the BIRC. Clinical deterioration determined by the 
Investigator will not be considered progression events.  
General censoring rules for the primary analysis of PFS are described below: 
• Subjects who receive systemic NPACT, nonprotocol radiation therapy (other than to bone), 
or surgery to resect target lesions before experiencing an event will be right censored at the 
date of the last tumor assessment prior to the date of initiation of subsequent therapy/surgery. 
If there is no such tumor assessment post randomization, the subject will be right censored on 
the date of randomization. 
• Subjects who have not experienced an event (and are not otherwise censored) at the time of 
data cutoff will be right censored on the date of their last tumor assessment post 
randomization that is on or prior to the data cutoff. If there is no such tumor assessment post 
randomization, the subject will be right censored on the date of randomization. 
• Subjects who miss 2 or more scheduled tumor assessments followed by an event will be right 
censored on the date of their most-recent tumor assessment prior to the missing assessments. 
If there is no such tumor assessment post randomization, the subject will be right censored on 
the date of randomization. 

 
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Hypothesis testing between the two treatment arms will be performed using the stratified 
log-rank test with a 2-sided 0.002 level of significance. The stratification factors will be the same 
as those used to stratify the randomization (see Section 3.4). 
The median duration of PFS and the associated 95% and 99.8% CIs for each treatment arm will 
be estimated using the Kaplan-Meier method. The HR with 95% and 99.8% CIs will be 
estimated using a Cox regression model and will include the same stratification factors described 
above. 
In the primary analysis of PFS, if the p-value for the stratified log-rank test is statistically 
significant and the HR (λ cabozantinib + atezolizumab/ λ NHT) is < 1, the null hypothesis of no difference 
between the two treatment arms in PFS will be rejected and it will be inferred that PFS is 
superior in the experimental (cabozantinib + atezolizumab) group compared with the control 
(NHT) group. 
9.2.2.2 
Overall Survival 
The primary analysis of OS is event-driven and will be conducted after at least 340 deaths have 
been observed in the ITT population (Section 9.1.1). 
Hypothesis testing between the two treatment arms will be performed using the stratified 
log-rank test with a 2-sided α level of significance (the α level will be defined per Section 9.5). 
The stratification factors will be the same as those used to stratify the randomization. 
The median duration of OS and the associated 95% and 1-α % CI for each treatment arm will be 
estimated using the Kaplan-Meier method. The HR with 95% and 1-α % CIs will be estimated 
using a Cox regression model and will include the same stratification factors described above. 
Two interim analyses of OS are planned at approximately the 32% and 76% information 
fractions. Details are provided in Section 9.8. 
At any analysis of OS (interim or primary), if the p-value for the stratified log-rank test is 
statistically significant and the HR (λ cabozantinib + atezolizumab/ λ NHT) is < 1, the null hypothesis of no 
difference in OS between the two treatment arms will be rejected and it will be inferred that OS 
is superior in the experimental (cabozantinib + atezolizumab) group compared with the control 
(NHT) group. 

 
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9.2.2.3 
Supportive Analyses 
Supportive (sensitivity) analyses will be conducted using all PFS events and subjects in the ITT 
population at the time of the primary PFS analysis. Additional sensitivity analyses of PFS will be 
defined in the SAP using alternative event definitions (such as PFS per PCWG3) and censoring 
schemes to account for partial or completely missing assessments, address bias due to tumor 
assessment timing, and to evaluate the impact of potentially informative censoring. These 
analyses will be performed using the same statistical methods described for the primary analysis.  
Exploratory analyses of the effect of baseline characteristics, stratification factors, and other 
variables on PFS will be conducted using Cox regression models and subgroup analyses 
performed employing Kaplan-Meier methods. 
9.3 
Secondary Efficacy Endpoint 
Formal hypothesis testing is planned for the secondary efficacy endpoint of ORR. 
9.3.1 
Definitions 
9.3.1.1 
Objective Response Rate 
The secondary endpoint is ORR and is defined as the proportion of subjects for whom the best 
overall response at the time of data cutoff is a CR or PR as assessed by the BIRC per 
RECIST 1.1, which is confirmed by a subsequent visit ≥ 28 days later. Subjects who do not have 
any post-baseline tumor assessments will be counted as non-responders 
9.3.2 
Objective Response Rate 
ORR will be tested using the Cochran-Mantel-Haenszel test (stratified by the randomization 
stratification factors) at the 2-sided α level (the α level will be defined per Section 9.5) in the ITT 
population with measurable disease at baseline, provided the null hypothesis for OS is rejected in 
favor of the experimental arm (cabozantinib + atezolizumab) at the interim or final OS analysis. 
Point estimates of ORR and corresponding CI estimates calculated by exact methods will be 
provided. 
9.4 
Additional Endpoints 
Details of the planned analyses of these endpoints will be provided in the SAP: 
• PSA response rate 
• Duration of radiographic response per RECIST 1.1 (per Investigator and BIRC) 
• Duration of PFS per PCWG3 per BIRC, defined as the time from randomization to the 
earlier of radiographic PD based on CT/MRI per RECIST 1.1, bone disease progression 
based on bone scans per PCWG3, or death due to any cause   

 
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• Time to PSA progression 
• Time to SSE 
• Time to pain progression, defined as earlier of:  
• ≥ 2 point increase in pain score compared to baseline in an 11-point NRS 
measuring worst pain in the last week 
• New or increased analgesic use from baseline (for analgesics taken for at least 7 
consecutive days) 
• Time to chemotherapy 
• Health care resource utilization 
• Change in mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, 
and global health as assessed by the EuroQol Health questionnaire EQ-5D-5L and 
EORTC questionnaire QLQ-C30 
• Safety as assessed through the evaluation of adverse events (AEs), including immune-
related adverse events (irAEs)  
• Pharmacokinetics (PK) of cabozantinib given in combination with atezolizumab 
• Immunogenicity of atezolizumab given in combination with cabozantinib 
• Correlation of immune cell, tumor cell, and plasma biomarker analyses with clinical 
outcomes 
9.5 
Control of Type I Error 
Inflation of Type 1 error associated with multiple primary endpoints will be controlled by a 
closed testing procedure that employs modified Bonferroni and fallback methods. The study-
wise 2-sided alpha of 0.05 will be nominally divided between multiple primary endpoints PFS 
(0.002) and OS (0.048) with pre-specified alpha levels passed from significant endpoints to those 
to be tested next per the pre-specified testing strategy. 
Two interim analyses of OS are planned (see Section 9.8). Inflation of Type 1 error associated 
with interim analyses will be controlled using a Lan-DeMets O’Brien-Fleming (LD-OF) alpha-
spending function.  
Inflation of Type 1 error associated with testing the secondary endpoint of ORR will be 
controlled by applying a hierarchical testing procedure. ORR will only be tested if the null 
hypothesis for OS is rejected in favor of the experimental arm (cabozantinib + atezolizumab). 
Testing and alpha reallocation will proceed as follows: 
At the primary PFS analysis, test PFS at 0.002 level. Then: 

 
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1. If PFS is significant, re-allocate 0.002 alpha to OS and conduct the planned interim and final 
analyses of OS per LD-OF at 0.05 allocated alpha 
a. If OS is not significant at any analysis, procedure ends 
b. If OS is significant at any analysis, re-allocate its 0.05 alpha to ORR and test ORR at 
0.05 
2. If PFS is not significant, conduct the planned interim and final analyses of OS per LD-OF at 
0.048 allocated alpha 
a. If OS is not significant at any analysis, procedure ends 
b. If OS is significant at any analysis, re-allocate its 0.048 alpha to ORR and test ORR at 
0.048 
i. If ORR is significant at 0.048, retest PFS at 0.05 
ii. If ORR is not significant at 0.048, procedure ends  
The median duration of PFS and the associated 95% and 99.8% CIs for each treatment arm will 
be estimated using the Kaplan-Meier method. The HR with 95% and 99.8% CIs will be 
estimated using a Cox regression model and will include the same stratification factors described 
above. 
9.6 
Safety Analyses 
All safety analyses will be performed using the Safety population. No formal statistical 
comparisons between the two treatment arms are planned. 
9.6.1 
Adverse Events 
Adverse event terms recorded on the CRFs will be mapped to preferred terms using the Medical 
Dictionary for Regulatory Activities (MedDRA). The Investigator will classify the severity of 
AEs using the CTCAE v5 and will judge each event to be “not related” or “related” to study 
treatment. 
A treatment emergent adverse event (TEAE) is defined as any event that begins or worsens on or 
after date of first dose of study treatment. Only TEAEs with an onset date through the 30-day 
post-treatment follow-up visit (100-day post-treatment follow-up visit for SAEs and AESIs 
consisting of conditions listed in Table 8-1) will be tabulated in summary tables. 
The frequency and percentage of subjects with TEAEs will be tabulated for overall incidence by 
system organ class and/or preferred term by treatment arm. Related TEAEs, serious TEAEs, 
related serious TEAEs, high-grade TEAEs, Grade 5 TEAEs, and TEAEs resulting in study 

 
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treatment discontinuation will be similarly summarized. Summaries by worst reported severity 
for each event within a subject will also be provided.  
At each level of summarization, a subject will be counted only once for each AE preferred term 
he/she experiences within that level (ie, multiple episodes of events with the same preferred 
terms will be counted only once). 
All reported subject deaths will be summarized by treatment group, cause of death, and 
relationship to study treatment. 
9.6.2 
Laboratory Test Results 
Laboratory test results will be summarized by treatment group to evaluate worst post-baseline 
CTCAE grade and shifts or changes from baseline.  
9.6.3 
Other Safety Endpoints 
Changes or shifts from baseline in vital signs, performance status, and QTc interval will be 
summarized by treatment group. 
The number of subjects experiencing dose reduction (cabozantinib and NHTs only), interruption, 
and/or discontinuation due to an AE will be provided. 
Concomitant medications will be standardized using the World Health Organization drug 
dictionary and summarized by class and preferred term. 
9.7 
Power and Sample Size 
The study is designed to provide adequate power for comparisons of both PFS and OS endpoints 
between the experimental (combination regimen) and control (NHT) arms. Compared with OS, a 
smaller sample size is needed to provide reasonable power for PFS. As a result, the number of 
events necessary to trigger the primary analysis of PFS could be reached before the study is fully 
accrued, and PFS events could be biased toward shorter progression times were PFS evaluated in 
the larger sample size required for OS. Thus, to reduce bias toward shorter progression times, 
this study employs a “trial within a trial” design (Hessel 2016) to allow longer, more robust PFS 
follow-up among fewer subjects than the total required for OS. Futility and interim analyses of 
PFS are not planned. 
For PFS, a total of 202 events in the first 324 subjects randomized in the combination and second 
NHT control arms provide the study with 90% power for a 2-sided log-rank test with a 0.002 
level of significance to detect a hypothesized true HR of 0.54. Assuming an exponential 

 
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distribution of PFS, this corresponds to an 85% increase in median PFS from 4 months to 
7.4 months. In the current design, the minimum observed effect that would result in statistical 
significance for PFS is a HR of 0.65, a 55% improvement in median PFS from 4 to 6.2 months.  
For OS, a total of 340 deaths among all 580 subjects randomized in the combination and second 
NHT arms are required to provide 90% power to detect an HR of 0.70 using the log-rank test and 
a 2-sided significance level of 0.048. Assuming an exponential distribution for OS, this 
corresponds to a 43% increase in median survival from 14 months to 20 months. Under this 
design, the minimum observed effect that would result in statistical significance for the primary 
analysis of OS is an HR of 0.80, a 25% improvement in median from 14 to 17.5 months. 
Two interim analyses of OS are planned and will include all subjects randomized to combination 
and second NHT control arms at the time of each analysis. The first interim analysis of OS will 
be conducted at the time of primary analysis of PFS. This is expected to occur at approximately 
the 32% information fraction for OS. The second interim analysis of OS is planned at 
approximately the 76% information fraction. Inflation of Type 1 error associated with these 
interim analyses will be controlled using LD-OF alpha-spending functions based upon a total 
alpha allocation for OS that depends upon whether the PFS result is significant.  
With an average accrual rate of ~24 subjects per month (3 subjects per month for 5 months, 
26 subjects per month from 6 to 15 months, and 37 subjects per month from month 16 onward) 
and using a 1:1 treatment allocation ratio among the experimental and control arms, a total of 
580 subjects (290 subjects in each arm) are required to observe the required number of events 
within the planned study duration (approximately 24 months accrual; approximately 21 months 
to observe the required PFS events and approximately 37 months to observe the required deaths 
for OS). These estimates are based upon the statistical assumptions, adjusted to accommodate the 
time required for all study sites to be activated and for subject recruitment to reach full potential. 
The true intervals required to meet these milestones may be longer or shorter due to divergence 
from assumptions, or due to the impact of the global COVID-19 pandemic on subject enrollment 
and other aspects of study conduct. The estimates for the timing of event-driven analyses do not 
include the additional months required for event ascertainment, data quality review, data analysis 
and interpretation. 
The sample size may be increased up to an additional 25% if a review of the accumulating data 
suggests that the COVID-19 pandemic has caused the rate of study dropout or non-compliance to 
increase to a degree that the ability to adequately evaluate study endpoints may be undermined. 

 
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An overview of the endpoints and operating characteristics is shown in Table 9-1: 
Table 9-1: 
Summary of Endpoint Analysis 
Accrual per month 
Max 37 after 16 months* 
Randomization allocation 
1:1 
Endpoint: 
PFS: Primary 
Endpoint 
OS: Primary 
Endpoint 
 Power 
90% 
90% 
 Alpha allocated (2-sided) 
0.002 
0.048 
 # of interim analyses (approximate information fraction) 
0 (NA) 
2 (32%, 76%) 
 Assumed median control vs experimental (months) 
4 vs 7.4 
14 vs 20 
 Assumed HR 
0.54 
0.70 
 Number of events 
202 
340 
 N for analysis 
324 (PITT population) 
580 (ITT Population) 
 Time to enroll (months) 
16 
24 
 Time to trigger event (months) 
21 
37 
 Maximum HR to reject Ho (experimental median 
in months) 
0.65 (6.2)  
0.80 (17.5) 
Ho, null hypothesis; HR, hazard ratio; ITT, intent-to-treat; NA, not applicable; OS, overall survival; PITT, PFS intent-to-treat; 
PFS, progression-free survival 
* Accrual: 3/month until 5 months, 26/month from 6-15 month and 37/month from 16 months onward. 
 
9.8 
Interim Analyses  
The number of events required to evaluate OS is based upon assumptions currently available and 
provides high power to detect the smallest clinically meaningful difference in OS under these 
assumptions. However, as there is uncertainty in the assumptions, interim analyses provide an 
opportunity to stop the trial early if the treatment benefit of the experimental arm is larger than 
expected, potentially allowing the new regimen to become available sooner to this patient 
population. 
Two interim analyses of OS are planned and will include all subjects randomized to combination 
and second NHT control arms at the time of each analysis. The first interim analysis of OS will 
be conducted at the time of primary analysis of PFS. This is expected to occur at approximately 
the 32% information fraction for OS. The second interim analysis of OS is planned at 
approximately the 76% information fraction. Inflation of Type 1 error associated with these 
interim analyses will be controlled using LD-OF alpha-spending functions based upon a total 
alpha allocation for OS that depends upon whether the PFS result is significant. 
Details and boundaries for testing OS at interim and the final analyses are shown in Table 9-2. 

 
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Table 9-2: 
Boundaries for Interim and Final Analyses of Overall Survival 
 
PFS is significant 
PFS is not significant 
OS alpha 
0.05 
0.048 
OS analysis 
information 
fraction 
Approximate 
# of events 
Analysis 
Time 
Critical 
p-value 
Max HR 
to reject 
Critical 
p-value 
Max HR to 
reject 
    32% 
109 
21 
0.00015 
0.484 
0.00013 
0.481 
    76% 
258 
30 
0.020 
0.748 
0.019 
0.747 
    100% 
340 
37 
0.044 
0.804 
0.042 
0.802 
HR, hazard ratio; PFS, progression-free survival; OS, overall survival 
Due to logistical considerations in event ascertainment and operational planning and conduct, the 
actual analyses may include more or fewer events than the target information fractions. The 
actual critical values employed at the interim and final analyses of OS will depend upon the 
actual information fraction at the time of the analyses. 
If the null hypothesis of no difference in OS is rejected at a planned interim OS analysis in favor 
of the experimental arm (cabozantinib + atezolizumab), no subsequent testing of OS is planned. 
10 
OTHER ANALYSES 
10.1 
Pharmacokinetic Analysis 
The plasma concentration of cabozantinib will be analyzed by designated laboratory using a 
validated bioanalytical method. Descriptive statistics (eg, number, mean and/or median, standard 
deviation, and coefficient of variation) will be used to summarize the concentration-time data per 
visit. Where appropriate, these data may be combined with data from other studies as part of a 
meta-analysis (ie, population PK analysis). The effect of cabozantinib exposure on biomarkers, 
clinical safety parameters (eg, selected AEs) or clinical response may also be explored.  
Serum concentrations of atezolizumab will also be measured. Descriptive statistics (eg, number, 
mean and/or median, standard deviation, and coefficient of variation) will be used to summarize 
the concentration-time data per visit. 

 
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10.2 
Immunogenicity Analyses 
Results of anti-drug antibody (ADA) testing (immunogenicity) will be summarized overall as the 
number of subjects with ADA at any time point. The association between human ADA 
incidence, PK, and efficacy and/or safety outcomes may be explored. 
10.3 
Biomarker Analyses 
Analyses may include correlation of biomarker data (eg, biomarker expression levels, mutation 
status) with clinical response.  
11 
DATA QUALITY ASSURANCE 
Accurate and reliable data collection will be assured by verification and cross-check of the 
eCRFs against the Investigator’s records by the study monitor (source document verification) 
and by the maintenance of a drug–dispensing log by the Investigator. Authorized study site 
personnel will enter data directly into a computerized eCRF database (ie, EDC system). Study 
databases will be subject to electronic and manual quality assurance procedures. 
12 
STUDY COMMITTEES 
12.1 
Independent Data Monitoring Committee (IDMC) 
An IDMC will be established to monitor the safety of the study on a regular basis. The 
committee will operate independently from the Sponsor and the clinical investigators. To 
minimize the potential introduction of bias, these individuals will not have any direct contact 
with the study site personnel or subjects and will not be authors on publications resulting from 
the study. IDMC members will be selected for their expertise in oncology.  
This IDMC will convene regularly. The primary responsibilities of the IDMC are to: 
• Review the accumulating safety data on a regular and an ad hoc basis 
• Make recommendations to the Sponsor regarding the continued conduct of the study based 
upon their evaluation of safety and efficacy data 
Safety data will be provided at regular intervals to the IDMC in the form of summary reports or 
data listings. To allow the evaluation of safety in the context of potential benefit, OS data 
(including Kaplan-Meier curves) may be reviewed by the IDMC at the time of safety summary 
reviews. The IDMC will have access to subjects’ individual treatment assignments. 

 
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General stopping rules are as follows: 
• The IDMC members will use their expertise, experience and judgment to evaluate the safety 
data from the trial and recommend to Exelixis whether the trial should continue, be modified, 
or be stopped early for safety concerns. No formal rules for making these recommendations 
based upon safety data are planned. 
The IDMC will communicate major safety concerns and recommendations regarding study 
modification or termination to the Sponsor’s senior management. 
Details of the composition, role, operational considerations, and stopping guidelines will be 
provided in a separate IDMC charter. 
12.2 
Blinded Independent Radiology Committee (BIRC) 
A BIRC will be established to evaluate tumor scans and prior radiation history data of trial 
subjects in a central, blinded, and independent fashion (see also Section 5.6.6.3). The BIRC will 
be comprised of board-certified radiologists who will determine radiographic response and 
progression following randomization. Additional imaging results may be requested by the 
Sponsor for BIRC review. 
Additional details regarding BIRC member qualification, training, methods, procedures, and 
other issues relevant to committee operations will be described in the BIRC Charter. 
12.3 
Clinical Steering Committee (CSC) 
The Clinical Steering Committee consists of physicians who have an expertise in treating 
patients with prostate cancer. The CSC will provide critical scientific guidance including, but not 
limited to, protocol design and implementation and interpretation of clinical study results.  
12.4 
Corporate Safety Governance 
The Sponsor has an established internal safety governance structure which oversees the 
monitoring of the safety and benefit-risk profile for all investigational products on an ongoing 
basis across all ongoing company-sponsored clinical studies. 
13 
ETHICAL ASPECTS 
13.1 
Local Regulations 
The study must fully adhere to the principles outlined in “Guideline for Good Clinical Practice” 
(GCP) ICH E6 Tripartite Guideline (June 2017) and remain consistent with the most recent 
version of the Declaration of Helsinki. The investigator will ensure that the conduct of the study 

 
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complies with the basic principles of GCP as outlined in the current version of 21 Code of 
Federal Regulations, subpart D, Part 312, “Responsibilities of Sponsors and Investigators” 
Part 50, “Protection of Human Subjects” and Part 56, “Institutional Review Boards.”  
13.2 
Informed Consent 
Sample ICFs will be supplied to each site. The Sponsor or its designee must review any proposed 
deviations from the sample ICF. The final IRB/EC-approved document must be provided to the 
Sponsor for regulatory purposes. 
It is the responsibility of the Investigator, or a person designated by the Investigator, to obtain 
written informed consent from each subject participating in this study after adequate explanation 
of the aims, methods, anticipated benefits, and potential hazards of the study. In the case where 
the subject is unable to read, an impartial witness must be present during the entire informed 
consent discussion. After the subject has orally consented to participation in the trial, the 
witness’ signature on the form will attest that the information in the consent form was accurately 
explained and understood. A copy of the ICF must be provided to the subject. If applicable, the 
ICF will be provided in a certified translation of the subject’s language. 
The CRF for this study contains a section for documenting informed subject consent, and this 
must be completed appropriately. Signed ICFs must remain in each subject’s study file and must 
be available for verification by study monitors at any time. If new safety information results in 
significant changes in the risk/benefit assessment, the consent form will be reviewed and updated 
as necessary. All subjects (including those already being treated) will be informed of the new 
information, will be given a copy of the revised form, and must give their consent to continue in 
the study. 
13.3 
Institutional Review Board/Ethics Committee (IRB/EC) 
This study is being conducted under a United States Investigational New Drug application or 
other Clinical Trial Application, as appropriate. This protocol (and any modifications) and 
appropriate consent procedures must be reviewed and approved by an IRB/EC. This board must 
operate in accordance with current local, regional, and federal regulations. The Investigator will 
send a letter or certificate of IRB/ EC approval to the Sponsor (or designee) before subject 
enrollment and whenever subsequent modifications to the protocol are made. 
13.4 
Disposition of Subject Samples 
Protocol-defined analyses are anticipated to result in depletion of all or almost all research 
samples. If a subject requests destruction of their tissue and blood samples, the Sponsor will 

 
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make every attempt to destroy the samples. The Sponsor will notify the Investigator in writing 
that samples have been destroyed. 
14 
CONDITIONS FOR MODIFYING THE PROTOCOL 
If deemed necessary, protocol modifications will be prepared, reviewed, and approved by the 
Sponsor representatives. 
All protocol modifications must be submitted to the IRB/EC for information and approval in 
accordance with local requirements, and to regulatory agencies if required. Approval must be 
obtained before any changes can be implemented, except for changes necessary to eliminate an 
immediate hazard to study subjects or those that involve only logistical or administrative aspects 
of the trial (eg, change in monitor or change of telephone number). 
15 
CONDITIONS FOR TERMINATING THE STUDY  
The study will be considered complete if the null hypothesis is rejected for the primary endpoint 
of OS (experimental vs control arm) in either of the planned interim analyses or if the final 
planned analysis for OS has been conducted (irrespective of the results). 
The Sponsor reserves the right to terminate the study, and Investigators reserve the right to 
terminate their participation in the study, at any time. Should this be necessary, the Sponsor and 
the Investigator will arrange the procedures on an individual study basis after review and 
consultation. In terminating the study, the Sponsor and the Investigator will ensure that adequate 
consideration is given to the protection of the subjects’ interests. 
16 
STUDY DOCUMENTATION, CASE REPORT FORMS, AND RECORD 
KEEPING 
16.1 
Investigator’s Files and Retention of Documents 
The Investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into two separate categories as follows: (1) the Investigator’s study file and 
(2) subjects’ clinical source documents. 
The investigator’s study file will contain the protocol and protocol amendments, CRFs (site 
contents will be converted to digital storage format [eg, compact disc] for archiving), query 
forms, IRB/EC and governmental approvals with correspondence, sample informed consent, 
drug records, staff curriculum vitae and authorization forms, and other appropriate documents 
and correspondence. 

 
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Subjects’ clinical source documents to record key efficacy and safety parameters independent of 
the CRFs include the subjects’ hospital/ clinic records; physician’s and nurse’s notes; the 
appointment book; original laboratory, ECG, electroencephalogram, x-ray, pathology and special 
assessment reports; signed ICFs; consultant letters; and subject screening and enrollment logs.  
The Investigator must keep these two categories of documents on file for the maximum period 
required by applicable regulations and guidelines, institution procedures, or for the period 
specified by the Sponsor or designee, whichever is longer. After that period, the documents may 
be destroyed subject to local regulations with prior written permission from the Sponsor. If the 
Investigator wants to assign the study records to another party or move them to another location, 
the Sponsor must be notified in advance. 
If the Investigator cannot guarantee the archiving requirements at the study site for any or all of 
the documents, special arrangements must be made between the Investigator and the Sponsor to 
store these in a sealed container outside of the study site so that they can be returned sealed to the 
Investigator in case of a regulatory audit. When source documents are required for the continued 
care of the subject, appropriate copies should be made for storing outside of the study site. 
16.2 
Source Documents and Background Data 
Upon request, the Investigator will make available for review to the Sponsor any required 
background data from the study documentation or clinic records. In case of special problems or 
governmental queries or requests for audit inspections, it is also necessary to have access to the 
complete study records, provided that subject confidentiality is protected. 
16.3 
Audits and Inspections 
The Investigator ensures that source documents for this study must be made available, after 
appropriate notification, to qualified personnel from the Sponsor’s Quality Assurance Unit (or 
designee) or to health authority inspectors. The verification of the CRF data must be by direct 
inspection of source documents. 
16.4 
Case Report Forms 
The term “case report form” (CRF) includes EDC screens or forms for studies that utilize EDC. 
For enrolled subjects, all and only data for the procedures and assessments specified in this 
protocol and required by the CRFs are to be submitted on the appropriate CRF (unless source 
data are transmitted to the Sponsor or a designee electronically, eg, laboratory data). Data from 
some procedures required by the protocol, such as physical examinations, will be recorded only 
on the source documents and will not be transcribed to CRFs. Additional procedures and 

 
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assessments may be performed as part of the Investigator’s institution or medical practice 
standard of care. Otherwise, data for unscheduled or additional assessments are to remain in the 
subject’s medical record and are not to be recorded on CRFs unless specifically requested. 
The CRF casebook must be completed and signed by the Investigator or authorized delegate 
from the study staff. This also applies to records for those subjects who fail to complete the 
study. If a subject stops dosing or terminates from the study, the dates and reasons must be noted 
on the CRF. 
The Investigator should ensure the accuracy, completeness, legibility, and timeliness of the data 
reported to the Sponsor in the CRF and in all required reports. 
The Sponsor’s data management personnel (or designees) may, in specific circumstances, 
modify study data – without changing the meaning of the data – to ensure the dataset complies 
with conventions required for successful data extract, thesaurus coding, or uniform reporting and 
does not cause these processes to fail. Examples of these administrative changes include: 
• Substitution of non-standard ASCII characters (codes 128-255) or deletion of carriage returns 
(code 13) that are incompatible with the SAS XPT file format (eg, accented letters replaced 
with non-accented ones; e for é) 
• Splitting multiple verbatim AE terms into multiple records (eg, “nausea and vomiting” to 
separate records for “nausea” and “vomiting”) 
• Reformatting failed eligibility criteria numbers for uniformity or specificity (eg, changing 
“2 a” to “2A”; or “2” to “2A” based on corroborating evidence from the clinical database) 
• Changing cause of death from “unknown” to “unknown cause of death” to facilitate coding 
in the MedDRA thesaurus 
Such changes follow a pre-defined documented process and can be clearly identified in the 
database audit trial. By participating in this study, investigators agree that such administrative 
changes are permissible without their specific prior approval. A list of all specific changes made 
can be provided to investigators upon request at any time. 
17 
MONITORING THE STUDY 
The responsible Sponsor monitor (or designee) will contact and visit the Investigator regularly 
and will be allowed on request to inspect the various records of the trial (CRFs and other 

 
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pertinent data), provided that subject confidentiality is maintained in accordance with local 
requirements. 
It will be the monitor’s responsibility to inspect the CRFs at regular intervals throughout the 
study to verify both adherence to the protocol and the completeness, consistency, and accuracy 
of the data being entered on them. The monitor is to have access to laboratory test reports and 
other subject records needed to verify the entries on the CRF. The Investigator (or designee) 
must agree to cooperate with the monitor to ensure that any problems detected in the course of 
these monitoring visits are resolved.  
18 
CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT RECORDS 
The Investigator must assure that subjects’ anonymity will be maintained and that their identities 
are protected from unauthorized parties. On CRFs or other documents submitted to the Sponsor 
or designees, subjects are to be identified by identification codes and not by their names. The 
Investigator should keep a subject enrollment log showing codes, names, and addresses. The 
Investigator must maintain documents not for submission to the Sponsor or designees 
(eg, subjects’ written consent forms) in strict confidence. 
All tumor scans, research samples, photographs, and results from examinations, tests, and 
procedures may be sent to the Sponsor and its partners or designees for review. 

 
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19 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS 
The results of this study may be published or presented at scientific meetings. The Investigator 
agrees to submit all manuscripts or abstracts to the Sponsor for review at least 30 days before 
submission. This allows the Sponsor to protect proprietary information and to provide comments 
based on information from other studies that may not yet be available to the Investigator. 
In the event that the Sponsor coordinates a publication or presentation of study results from all 
study sites, the participation of the Investigator(s) or other representatives of the study site(s) as 
named author(s) shall be determined in accordance with Sponsor policy. Authorship will be 
assigned in accordance with contribution to design, execution, and interpretation and analysis of 
the study. 
The Sponsor may, at its sole option, provide funding to support the development, submission, 
and/or presentation of publications for scientific/medical journals or conferences. For 
publications coordinated by the Sponsor, the Sponsor may also provide funding to support travel 
and conference registration for the presenting author to attend the conference for the sole purpose 
of presenting the publication. 
20 
COMPLIANCE WITH DATA PROTECTION LAWS 
The Sponsor, as Data Controller, ensures that all processing activities involving personal data 
performed in the scope of this Study are compliant with, but not limited to, the requirements by 
EU General Data Protection Regulation (GDPR 679/2016), its subsequent amendments and any 
additional national laws on Data Protection, recommendations and guidelines as applicable.  
To comply with the applicable rules on the protection of personal data, specifically regarding the 
implementation of the organizational and technical arrangements aiming to avoid unauthorised 
access, disclosure, dissemination, alteration or loss of information and processed personal data, 
the Sponsor has implemented and maintains the following measures:  
• restriction and monitoring of physical access to the offices and information processing 
facilities to employees, personnel and approved visitors 
• ensuring appropriate and restricted user access relevant to the function and type of 
activity performed in relation to the clinical trial 
• implementing the pseudonymisation and encryption of personal data, as appropriate 

 
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• implementing the ability to ensure the ongoing confidentiality, integrity, availability and 
resilience of processing systems and services  
• implementing network, application, database security by means of firewalls and 
antivirus/anti-malware; ensuring detection of malware purposed for unauthorized 
deletion, blocking, copying of information, disabling security measures and response to 
such attacks 
• means to restore the availability and access to personal information in a timely manner in 
the event of a physical or technical incident  
• logging of security events/incidents in information systems  
• implementing procedures that cover reporting, analysis, monitoring and resolution of 
security incidents 
• ensuring that information systems, computers and software involved in the performance 
of the services provided in the Study are backed up 
• a process for regularly testing, assessing and evaluating the effectiveness of technical and 
organisational measures for ensuring the security of the processing  
• implementing procedures to capture within reasonable time-manner any personal data 
breach occurred 
• implementing procedures and practices for securing destruction of paper documents 
containing personal data 
• implementing business continuity procedures ensuring that THE SPONSOR can continue 
to provide services through operational interruption 
All locations, personnel and information systems that are used to perform services for the Study 
will be covered. 
The Sponsor will ensure technical and organizational security measures described above, are 
regularly reviewed and updated to take into account any evolution on technological 
developments. 

 
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The Sponsor may apply additional specific statutory requirements, where applicable in the 
national laws, and will implement the necessary security measures even if they are not expressly 
listed above. 
Besides the already above-mentioned technical and organizational measures, the Sponsor, by 
means of internal measures and imposed contractual clauses to the selected sub-contractors, 
ensures the confidentiality of records and personal data of subjects. 
With exception of the activities in the scope of the on-site monitoring, the name of the patient 
will neither be asked for, nor recorded by the the Sponsor. An identification number will be 
allocated to each patient registered in the Study. This number will identify the patient and will be 
included on all case report forms and corresponding material and data associated with the 
patient. In order to avoid identification errors, the site number will also be reported on the case 
report forms. 
Monitors acting on behalf of the Sponsor will have access to fully identifiable information only 
in the scope of the on-site monitoring visits, and only for the source data verification mandatory 
under clinical trial framework, including the ICH-GCP obligations applicable to the conduct of 
the Study. Staff involved in the performance of this task is bound by any additional stricter 
confidentiality clauses imposed upon them, as compared to other staff members.   
The Sponsor has put in place a functional process of reporting of any data breach occurring at the 
Sponsor’s or its sub-contractor’s facilities and premises. In case of the occurrence of any data 
breach, the Sponsor will immediately apply relevant measures to mitigate the risks to data 
subjects as appropriate in relation to the specific context of the data breach, taking into account 
its source, underlying intentions, possibilities of recovery, etc. Any data breach presenting risks 
to the rights and freedoms of data subjects will be reported to the relevant supervisory data 
protection authority within 72 hours of the Sponsor becoming aware of the data breach. In 
addition, in case of occurrence of a high-risk breach, data subjects will be informed by the the 
Sponsor (via clinical Study site).
21 
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APPENDICES 
Appendix A: Screening Assessments 
To determine subject eligibility as stipulated in Section 4, subjects will undergo required 
screening evaluations as outlined in this appendix and described in Section 5.6. Qualifying 
screening assessments must be performed within 21 days before randomization unless otherwise 
stated. If there is a change in clinical status after screening and prior to randomization, these 
assessments are to be repeated as clinically indicated and deemed acceptable prior to 
randomization. Study eligibility is based on a subject meeting all inclusion criteria and no 
exclusion criteria at screening. 
Screening Assessments: 
Assessment 
Screeninga 
(before randomization) 
Informed consent 
Xb 
Demographics, medical and cancer history 
≤ 28 days 
Physical examination + weight + height  
≤ 21 days 
Vital signs 
≤ 21 days 
ECOG 
≤ 21 days 
12-lead ECG  
≤ 21 days 
Hematology, chemistry, PSA, serum testosterone, 
PT/INR, PTT, thyroid function tests, UPCR 
including componentsc, g  
≤ 21 days 
Urinalysisc 
≤ 21 days 
Hepatitis screeningd 
≤ 21 days 
HIV testing (if required by local regulations) 
≤ 21 days 
Tumor assessment: Chest CT, Abdomen/Pelvis CT 
or MRI, technetium bone scan 
≤ 28 days 
Tumor assessment: Brain MRI (or CT) if clinically 
indicated 
≤ 28 days 
Tumor assessment: Bone CT if clinically indicated 
≤ 28 days 
Analgesic Usee 
Document those taken within 28 days before 
randomization. 
Archival tumor tissue (if available) 
Xf 
Concomitant medications 
Document those taken within 28 days before 
randomization. 
Adverse events 
Document Serious AEs and AESIs from informed consent. 

 
XL184-315 Protocol Amendment 5.0 
Page 189 of 232 
AE, adverse event; AESI, adverse of special interest; CT, computerized tomography; EC, ethics committee; ECG, 
electrocardiogram; ECOG, Eastern Cooperative Oncology Group; HCV, hepatitis C virus; HIV, human immunodeficiency virus; 
IRB, institutional review boards; MRI, magnetic resonance imaging; PSA, prostate specific antigen; PT/INR, prothrombin 
time/international normalized ratio; PTT, partial thromboplastin time; RNA, ribonucleic acid; UPCR, urine protein/creatinine 
ratio  
a Results of screening assessments must be reviewed before randomization to confirm subject eligibility.  
b Informed consent may be obtained more than 28 days prior to randomization but must be provided before any study-specific 
procedures are performed; however, evaluations performed as part of routine care prior to informed consent can be utilized as 
screening evaluations if permitted by the site’s IRB/EC policies. 
c See Section 5.6.5 and the Laboratory Manual for more detailed information on laboratory assessments 
d Hepatitis B surface antigen and Hepatitis C antibody (with reflex testing of HCV RNA if antibody test is positive). 
e Baseline dose will be determined for analgesics taken for at least 7 consecutive days during screening. 
f Available archived tumor tissue can be provided during the screening evaluation period up to week 7. If archival tumor tissue 
is not available, a fresh tumor biopsy may be obtained prior to first dose of study treatment. 
g Direct and indirect bilirubin assessments are not required when the total bilirubin is normal or low. 

 
XL184-315 Protocol Amendment 5.0 
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Appendix B: Schedule of Assessments from Randomization Onwards 
The schedule of required assessments is presented in this appendix. Following randomization, 
assessments for safety are to occur during routine safety visits (RSVs). Routine Safety Visit 1 
(RSV1) is to occur no more than 72 hours prior to the first dose of any study treatment(s). First 
dose of study treatment(s) is to occur within 3 days after randomization.  
After RSV1, subsequent RSVs are required at least every 3 weeks (± 3 days) (ie, no more than 3 
weeks [± 3 days] apart). If there is a dose delay for any study treatment, subjects must return to 
the site for an RSV at least every 3 weeks (± 3 days) during the dose delay and follow up with 
additional unscheduled visits or telephone calls weekly (or more frequently) as clinically 
indicated to monitor subject safety and appropriateness for resumption of study treatment. See 
the schedule below for safety assessments to be performed at each RSV. 
In the experimental arm, an RSV is required within 72 hours prior to each planned infusion of 
atezolizumab (vital signs must be assessed within 60 min prior to initiation of the infusion), even 
if fewer than 3 weeks have elapsed since the last RSV. Once atezolizumab is restarted after a 
treatment delay, RSVs are to occur at least every 3 weeks (± 3 days) thereafter (ie, RSV schedule 
resets on date of infusion). 
Imaging (CT, MRI, TBS), PSA, HRQOL, and pain assessments are to be performed at protocol-
defined intervals based on the date of randomization; all subsequent time points for these 
assessments will occur at a defined time interval and will not be modified as a result of 
modifications or discontinuations of treatment administration. After randomization, these 
assessments are to be performed every 9 weeks (± 7 days) through Week 28 and then every 
12 weeks (± 7 days). See Sections 5.6.6.1, 5.6.7, 5.6.8, and 5.6.9, respectively, for details. 
Unscheduled visits for safety evaluations are allowed at any time (see Section 5.5). 
Special accommodations during the global COVID-19 pandemic are described in Appendix N. 

 
XL184-315 Protocol Amendment 5.0 
Page 191 of 232 
The following are reminders for procedures and assessments during the treatment period: 
• Cabozantinib and second NHTs are dosed once daily (prednisone is dosed twice daily).  
• Doses of atezolizumab should be administered every 3 weeks and no more frequently 
than every 19 days (see Section 6.2.3.1). If atezolizumab administration is not delayed for 
AE management, it should be administered within 24 days of the prior atezolizumab 
dose. Atezolizumab dosing can be delayed for up to 12 weeks, after which the Sponsor 
should be contacted to discuss potential treatment continuation. 
o Atezolizumab may be withheld for a period of time beyond 12 weeks to allow for 
corticosteroids to be reduced to ≤ 10 mg/day oral prednisone or equivalent. The 
acceptable length of the extended period of time must be based on an assessment of 
benefit−risk by the Investigator and in alignment with the protocol requirements for 
the duration of treatment and documented by the Investigator. The Sponsor is 
available to advise as needed.   
• Specific laboratory tests must be performed at an RSV and evaluated within 72 hours 
prior to each administration of atezolizumab (see Section 5.6.5). These assessments are 
not required prior to the first dose if there has been no change in subject’s clinical status 
since screening. 
• Safety will be assessed on a schedule based on date of first dose as described above. 
RSVs must occur at least every 3 weeks (± 3 days), even if there is a study treatment dose 
delay. In the experimental arm, an RSV is required within 72 hours prior to each planned 
infusion of atezolizumab (vital signs must be assessed within 60 min prior to initiation of 
the infusion), even if less than 3 weeks have elapsed since the last RSV. Once 
atezolizumab is restarted after a treatment delay, RSVs are to occur at least every 3 weeks 
(± 3 days) thereafter. Unscheduled visits may occur at any time. 
• For subjects receiving abiraterone plus prednisone, serum ALT, AST, and total bilirubin 
assessments (LFTs) are to be performed every 2 weeks for the first 12 weeks of 
treatment, in addition to at each RSV (see schedule below). If an LFT visit coincides with 
an RSV, duplicate LFTs do not need to be performed. After the first 12 weeks of 
treatment, LFTs will continue to be performed at each RSV.  
• Radiographic tumor assessments are to be performed every 9 weeks (± 7 days) through 
Week 28 and then every 12 weeks (± 7 days) relative to the date of randomization and 
irrespective of the dates of RSVs. PSA, HRQOL, and pain assessments after RSV1 are to 
occur with scheduled radiographic tumor assessments.   

 
XL184-315 Protocol Amendment 5.0 
Page 192 of 232 
• PK, anti-drug antibodies (ADA), and biomarker sample collection schedules are per 
schedule of assessments.

 
XL184-315 Protocol Amendment 5.0 
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Post-Randomization  
Post-Treatment 
Assessment 
RSV1  
(To occur no 
more than 72 
hours prior 
to 1st dose. ) 
After RSV1, subsequent RSVs are required 
at least every 3 weeks (ie, no more than 3 weeks apart), even if treatment is held.   
For atezolizumab dose delays: an RSV is required within 72h prior to each planned infusion, 
resetting next RSV interval 
Unscheduled Visito 
FU-1p 
FU-2q 
RSV2 (±3 Days) 
RSV3 (±3 Days) 
RSV4 (±3 Days) 
RSV5 (±3 Days) 
RSV6 (±3 Days) 
RSV7 (±3 Days) 
RSV8 (±3 Days) 
RSV9 (±3 Days) 
RSV10 through 
RSV 17 
(±3 Days) 
Each RSV after 
RSV17 until 
treatment is 
discontinued  
(±3 Days) 
30-Day Post 
Treatment 
Follow-Up  
(+14 Days) 
100-Day 
Extended 
Follow-Up  
(±14 Days) 
Directed physical 
examination + weight 
(Section 5.6.2) 
pre-dose 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Perform 
assessment(s) 
as clinically 
indicated (see 
Section 5.5) 
X 
X 
Vital signs 
(Section 5.6.3)  
pre-dose 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG performance status 
(Section 5.6.2) 
pre-dose 
X 
X 
X 
X 
X 
X 
X 
X 
X 
until imaging 
discontinued 
 
 
12-lead ECGa, c 
(Section 5.6.4) 
pre-dose 
X 
X 
 
X 
 
X 
 
X 
Every 4 RSVs 
eg, RSV13, RSV17, etc 
 
 
Hematology, chemistry, 
PT/INR, PTT, urinalysisb,c,t  
(Section 5.6.5) 
pre-dose 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Experimental 
Arm: 
 Every RSV 
Control Arm: 
Every 2 RSVs 
eg, RSV17, 
RSV19, etc 
X 
 
Thyroid function tests  
(TSH and free T4)b, c 
(Section 5.6.5) 
pre-dose 
X 
X 
X 
X 
 
 
 
X 
Every 4 RSVs 
eg, RSV13, RSV17, etc 
X 
 
Additional serum ALT, 
AST, and total bilirubin tests 
(subjects receiving 
abiraterone/prednisone)t 
(Section 5.6.5 ) 
pre-dose 
For subjects receiving abiraterone plus prednisone, serum ALT, AST, and total bilirubin assessments 
(LFTs) are to be performed on Week 3 Day 1 (W3D1 [± 3 days]), W5D1 (± 3 days), W7D1 (± 3 
days), W9D1 (± 3 days), W11D1 (± 3 days), and W13D1 (± 3 days), in addition to at each RSVs. 
After W13D1, LFTs will continue to be performed at each RSV. 
X 
 
UPCR (including 
components)b, c, d 
(Section 5.6.5) 
pre-dose 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Every 2 RSVs 
eg, RSV17, 
RSV19, etc 
X 
 
Analgesic use assessmentse 
(Section 5.6.9) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Symptomatic skeletal events 
assessmentsf 
(Section 5.6.10) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

 
XL184-315 Protocol Amendment 5.0 
Page 194 of 232 
 
Post-Randomization  
Post-Treatment 
Assessment 
RSV1  
(To occur no 
more than 72 
hours prior 
to 1st dose. ) 
After RSV1, subsequent RSVs are required 
at least every 3 weeks (ie, no more than 3 weeks apart), even if treatment is held.   
For atezolizumab dose delays: an RSV is required within 72h prior to each planned infusion, 
resetting next RSV interval 
Unscheduled Visito 
FU-1p 
FU-2q 
RSV2 (±3 Days) 
RSV3 (±3 Days) 
RSV4 (±3 Days) 
RSV5 (±3 Days) 
RSV6 (±3 Days) 
RSV7 (±3 Days) 
RSV8 (±3 Days) 
RSV9 (±3 Days) 
RSV10 through 
RSV 17 
(±3 Days) 
Each RSV after 
RSV17 until 
treatment is 
discontinued  
(±3 Days) 
30-Day Post 
Treatment 
Follow-Up  
(+14 Days) 
100-Day 
Extended 
Follow-Up  
(±14 Days) 
Health Care Utilizationg 
(Section 5.6.11) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
(Section 7)  
Document from 28 days before randomization through 30 days after decision to discontinue study treatment. Concomitant medications classified as 
immunosuppressive agents, including systemic corticosteroids, must be documented through 100 days after the date of the decision to discontinue study treatment.   
Adverse events (Section 8) 
Document new or worsening events (see Section 8.1). Adverse events information will be collected at all study visits and may also be collected at any time over the 
phone or by spontaneous subject report. Certain AEs and all SAEs that are ongoing 30 days after last dose of study treatment are to be followed until resolution or 
determination by the investigator that the event is stable or irreversible (see Section 8.4). 
Serum PSA 
(Section 5.6.7) 
PSA assessments will occur with scheduled imaging: 
 every 9 weeks ± 7 days through Week 28, and then every 12 weeks ± 7 days. 
  
Tumor assessments: Chest 
CT, abdomen/pelvis 
CT/MRI; brain MRI/CT (if 
with baseline brain mets or 
symptom/sign-initiated); 
technetium bone scan; and 
CT of bone (only if 
clinically indicated) 
(Section 5.6.6) 
Tumor assessments are to be performed every 9 weeks ± 7 days from the date of randomization through Week 28 (ie, the first three post-randomization tumor 
assessments) and then every 12 weeks ± 7 days. These assessments are to continue until meeting protocol defined criteria for discontinuing imaging irrespective of 
whether study treatment is given, held, or discontinued and independent of the timing of the RSVs. 
For subjects who discontinue study treatment before Investigator-assessed radiographic PD, tumor assessments are to continue per the protocol defined schedule until 
Investigator-assessed radiographic PD per RECIST 1.1.  
For subjects who continue to receive study treatment after Investigator-assessed radiographic PD because of Investigator-assessed clinical benefit that outweighs the 
potential risks, tumor assessments are to continue per the protocol defined schedule until study treatment is permanently discontinued.  
HRQOL (EQ-5D-5L and 
QLQ-C30; Section 5.6.8)h 
pre-dose 
HRQOL assessments will occur when scheduled imaging is performed: every 9 weeks ± 7 days through Week 28, and then every 12 weeks ± 7 
days. 
Pain assessmentsi 
(Section 5.6.9) 
pre-dose 
Pain assessments will occur when scheduled imaging is performed: every 9 weeks ± 7 days through Week 28, and then every 12 weeks ± 7 days.  
PK blood samples for 
cabozantinib 
(Experimental arm)j, k, 
(Section 5.6.12) 
pre-dose 
pre-
dose  
pre-
dose 
pre-
dose 
pre-
dose 
 
 
 
 
 
 
 
 
 
PK blood samples for 
atezolizumab (Experimental 
arm)j, k  
(Section 5.6.12) 
pre-dose 
 
pre-
dose 
 
pre-
dose 
 
 
 
pre-
dose 
pre-
dose on 
RSV16 
pre-dose on 
RSV19 
 
X 
X 

 
XL184-315 Protocol Amendment 5.0 
Page 195 of 232 
 
Post-Randomization  
Post-Treatment 
Assessment 
RSV1  
(To occur no 
more than 72 
hours prior 
to 1st dose. ) 
After RSV1, subsequent RSVs are required 
at least every 3 weeks (ie, no more than 3 weeks apart), even if treatment is held.   
For atezolizumab dose delays: an RSV is required within 72h prior to each planned infusion, 
resetting next RSV interval 
Unscheduled Visito 
FU-1p 
FU-2q 
RSV2 (±3 Days) 
RSV3 (±3 Days) 
RSV4 (±3 Days) 
RSV5 (±3 Days) 
RSV6 (±3 Days) 
RSV7 (±3 Days) 
RSV8 (±3 Days) 
RSV9 (±3 Days) 
RSV10 through 
RSV 17 
(±3 Days) 
Each RSV after 
RSV17 until 
treatment is 
discontinued  
(±3 Days) 
30-Day Post 
Treatment 
Follow-Up  
(+14 Days) 
100-Day 
Extended 
Follow-Up  
(±14 Days) 
Blood samples for 
immunogenicity 
(Experimental arm)j, k 
(Section 5.6.13)  
pre-dose 
 
pre-
dose 
 
pre-
dose 
 
 
 
pre-
dose 
pre-
dose on 
RSV16 
pre-dose on 
RSV19 
 
X 
X 
Optional tumor tissuel 
(Section 5.6.14) 
X 
An optional tumor biopsy may be collected at disease progression. 
Pharmacogenetic blood 
samplem(Section 5.6.14) 
pre-dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood - plasma biomarker 
samples (Section 5.6.14) 
pre-dose 
X 
 
 
X 
 
 
 
 
 
 
 
optional 
 
Blood – Cell and/or plasma 
pharmacogenomic samples 
(Section 5.6.14) 
pre-dose 
X 
 
 
 
 
 
 
 
 
 
 
optional 
 
Cabozantinib (Experimental 
Arm) 
dispensing/ 
reconciliationr 
(Sections 6.4 and 6.5) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Cabozantinib (Experimental 
Arm) administrationn 
(Sections 6.2.3.1 and 6.2.4) 
X 
1st dose to 
occur ≤ 3 days 
after 
randomization. 
1st daily dose 
given in clinic 
after first dose 
of 
atezolizumab. 
Subsequent daily doses self-administered by subject at home at bedtime thereafter until study 
treatment is discontinued. 
 
 
 

 
XL184-315 Protocol Amendment 5.0 
Page 196 of 232 
 
Post-Randomization  
Post-Treatment 
Assessment 
RSV1  
(To occur no 
more than 72 
hours prior 
to 1st dose. ) 
After RSV1, subsequent RSVs are required 
at least every 3 weeks (ie, no more than 3 weeks apart), even if treatment is held.   
For atezolizumab dose delays: an RSV is required within 72h prior to each planned infusion, 
resetting next RSV interval 
Unscheduled Visito 
FU-1p 
FU-2q 
RSV2 (±3 Days) 
RSV3 (±3 Days) 
RSV4 (±3 Days) 
RSV5 (±3 Days) 
RSV6 (±3 Days) 
RSV7 (±3 Days) 
RSV8 (±3 Days) 
RSV9 (±3 Days) 
RSV10 through 
RSV 17 
(±3 Days) 
Each RSV after 
RSV17 until 
treatment is 
discontinued  
(±3 Days) 
30-Day Post 
Treatment 
Follow-Up  
(+14 Days) 
100-Day 
Extended 
Follow-Up  
(±14 Days) 
Atezolizumab (Experimental 
Arm) administration n  
(Section 6.2.3.1) 
X 
1st dose to 
occur ≤ 3 days 
after 
randomization. 
Vital signs 
must be 
assessed within 
60 min prior to 
initiation of the 
infusion. 
 
 
 Doses of atezolizumab should be administered every 3 weeks and no more frequently than every 19 
days. If atezolizumab administration is not delayed for AE management, it should be administered 
within 24 days of the prior atezolizumab dose. 
 
If the atezolizumab dose is delayed, subjects must have an RSV at least every 3 weeks during the 
delay and follow up with additional unscheduled visits or telephone calls weekly (or more frequently) 
as clinically indicated to monitor subject safety and appropriateness for resumption of study 
treatment.  
An RSV is required within 72h (and laboratory results reviewed) prior to each planned infusion, even 
if less than 3 weeks have elapsed since the last RSV. Vital signs must be assessed within 60 min prior 
to initiation of the infusion. 
 
Once atezolizumab is re-started, RSVs are to occur at least every 3 weeks (± 3 days) thereafter 
(ie, RSV schedule resets on date of infusion). 
 
 
 
Abiraterone/prednisone, or 
enzalutamide (Control Arm) 
dispensing/ 
reconciliationr 
(Sections 6.4 and 6.5) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Every 3 
weeks 
Every 3 weeks 
 
 
 
Abiraterone/prednisone, or 
enzalutamide (Control Arm) 
administrationn  
(Sections 6.2.3.2 and 6.2.5) 
X 
1st dose to 
occur ≤ 3 days 
after 
randomization. 
1st daily dose 
given in clinic.  
Subsequent daily doses self-administered by subject at home thereafter until study treatment is 
discontinued. 
 
 
 

 
XL184-315 Protocol Amendment 5.0 
Page 197 of 232 
 
Post-Randomization  
Post-Treatment 
Assessment 
RSV1  
(To occur no 
more than 72 
hours prior 
to 1st dose. ) 
After RSV1, subsequent RSVs are required 
at least every 3 weeks (ie, no more than 3 weeks apart), even if treatment is held.   
For atezolizumab dose delays: an RSV is required within 72h prior to each planned infusion, 
resetting next RSV interval 
Unscheduled Visito 
FU-1p 
FU-2q 
RSV2 (±3 Days) 
RSV3 (±3 Days) 
RSV4 (±3 Days) 
RSV5 (±3 Days) 
RSV6 (±3 Days) 
RSV7 (±3 Days) 
RSV8 (±3 Days) 
RSV9 (±3 Days) 
RSV10 through 
RSV 17 
(±3 Days) 
Each RSV after 
RSV17 until 
treatment is 
discontinued  
(±3 Days) 
30-Day Post 
Treatment 
Follow-Up  
(+14 Days) 
100-Day 
Extended 
Follow-Up  
(±14 Days) 
Non-protocol anti-cancer 
treatment and survival status  
(Section 5.6.15) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subjects 
will be 
contacted 
every 8 
weeks (+ 
7 days) 
after 
follow-
up visit 
until 
death. 
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRF, case report form; CT, computerized tomography; ECG, electrocardiogram; ECOG, Eastern Cooperative 
Oncology Group; FU-1, 30-Day Post-Treatment Follow-up Visit; FU-2, 100-Day Post-Treatment Follow-up Visit; HRQOL, health-related quality of life; IP, investigational 
product; LFT, liver function test; MRI, magnetic resonance imaging; NRS, numeric rating scale; PSA, prostate specific antigen; PT/INR, prothrombin time/international 
normalized ratio; PTT, partial thromboplastin time; PD, progressive disease; PK, pharmacokinetic; RECIST, Response Evaluation Criteria in Solid Tumors; RSV, routine safety 
visit; SSE, symptomatic skeletal events; T4, thyroxine; TSH, thyroid-stimulating hormone; UPCR, urine protein/creatinine ratio 
a If at any time a single ECG shows a QTcF with an absolute value > 480 ms at screening or > 500 ms at RSV1 onwards or an increase in QTcF of > 60 ms above baseline at 
RSV1 onwards, two additional ECGs at intervals of approximately 3 min must be performed within 30 min after the initial ECG, and the average of these three consecutive 
results for QTcF will be used as the value assessed. If the average QTcF from the three ECGs is > 500 ms or there is an increase of > 60 ms above baseline, send ECGs to central 
ECG reader. 
b See Section 5.6.5 and the Laboratory Manual for more detailed information on laboratory assessments. 
c These assessments are not required prior to the first dose if there has been no change in subject’s clinical status since screening. Serum chemistry, hematology, coagulation, and 
urinalysis laboratory results must be reviewed before any atezolizumab infusion administered on study. If the subject has symptoms indicative of a thyroid function disorder, 
thyroid function test results are to be reviewed prior to administering atezolizumab. All laboratory results (with the exception of routine urinalyses) must be provided to the local 
laboratory management vendor. 
d Perform 24-hour urine protein test at the discretion of the Investigator based on increase in UPCR from routine assessments. 
e New or increased use of analgesics from baseline will be continuously assessed by the Investigator. A new analgesic is defined as one that is taken for at least seven consecutive 
days after, but not prior to, randomization. Increased use of an analgesic is defined as an increased dose of an analgesic taken for at least seven consecutive days after 
randomization relative to the baseline dose. These assessments are to be performed regardless of whether study treatment is given, reduced, held or discontinued until the date of 
the last tumor imaging assessment or study completion. Consequently these assessments may be required in the Post-Treatment Period for some subjects. 
f The definition of an SSE is an instance of any one of the following: radiation therapy to bone, surgery to bone, spinal cord compression, or symptomatic fracture. 
g Collection of hospital admissions, emergency room visits, intensive care unit admissions, length of stay and relevant procedures (eg, surgeries, radiotherapy, embolization, 
transfusions) from randomization through the FU-2 visit. 

 
XL184-315 Protocol Amendment 5.0 
Page 198 of 232 
h HRQOL forms are to be administered and collected prior to any other study-related activities for scheduled visits. Questionnaires are to be completed prior to the clinic visit or if 
completed on the day of the visit prior to seeing the study site personnel. These assessments are to be performed regardless of whether study treatment is given, reduced, held or 
discontinued until the date of the last tumor imaging assessment or study completion. Consequently these assessments may be required in the Post-Treatment Period for some 
subjects. 
i Assessment of pain will be self-reported by each subject using an 11-point NRS measuring the worst pain in the last week. Subjects are to complete the pain assessment at the 
start of each clinic visit (pre-dose at RSV1). These assessments are to be performed regardless of whether study treatment is given, reduced, held or discontinued until the date 
of the last tumor imaging assessment or study completion. Consequently these assessments may be required in the Post-Treatment Period for some subjects. 
j For subjects in the experimental arm, the PK samples for cabozantinib and atezolizumab are to be taken prior to atezolizumab infusion. The Investigator will ask the subject for 
the date and time of the most recent prior dose of cabozantinib and this information will be recorded in source documents and on the appropriate CRF page. 
k If there is a dose delay for atezolizumab, PK and immunogenicity samples are still to be taken at the RSVs as shown. See the Laboratory Manual for more detailed information 
on PK and immunogenicity assessments. 
l If no archival tumor tissue is available, an optional fresh tumor biopsy may be collected prior to first dose. Baseline tumor tissue is to be shipped within 3 weeks of first dose. An 
optional biopsy may be collected at disease progression. See Section 6.6.1.1.7 for guidance regarding biopsies.  
m If collection of the required pharmacogenetic blood sample is missed on day of first dose, it can be collected subsequently. 
n Combination of cabozantinib/atezolizumab, or abiraterone/prednisone, or enzalutamide administered until disease progression or no longer clinically benefitting.  
o Unscheduled visits for safety evaluations are allowed at any time.  
p A first Post-Treatment Follow-up Visit (FU-1) for safety evaluation is to occur at least 30 (+14) days after the date of the decision to permanently discontinue study treatment, 
defined as the later of the decision to permanently discontinue study treatment or the last dose of study treatment. 
q A second follow up visit (FU-2) for safety evaluation will be conducted approximately 100 days (±14 days) after the date of the decision to permanently discontinue study 
treatment, defined as the later of the decision to permanently discontinue study treatment or the last dose of study treatment. 
r Oral IP dispensing to the subject may be adjusted if RSVs are performed less than 3 weeks apart or the dose is adjusted, and the subjects has an adequate oral IP supply. 
s If an LFT visit coincides with an RSV, duplicate LFTs do not need to be performed. 
t Direct and indirect bilirubin assessments are not required when the total bilirubin is normal or low. 
 

 
XL184-315 Protocol Amendment 5.0 
Page 199 of 232 
Appendix C: Maintenance Phase  
When sufficient data have been collected to adequately evaluate all study endpoints, the Sponsor 
may initiate a Maintenance Phase. Upon initiation of the Maintenance Phase, the Sponsor 
considers the safety and efficacy profile of the experimental treatment regimen within this study 
to have been sufficiently established for regulatory purposes. The Sponsor is to notify the sites if 
or when the study will enter the Maintenance Phase or if an alternative post-Study Completion 
option will be implemented (Section 6.3). 
In the Maintenance Phase subjects will continue to receive active study treatment until a criterion 
for protocol-defined discontinuation has been met (Section 3.5.1). Subjects in the Maintenance 
Phase are to undergo periodic safety assessments (including local laboratory tests, ECG, 
symptom-directed physical examination and vital signs) and tumor assessments every 12 weeks 
(or more frequently as clinically indicated) for as long as they are in this phase. 
In order to continue to collect important safety information on subjects still enrolled in the study, 
reporting of SAEs, AESIs (Table 8-1), and other reportable events (pregnancy and medication 
errors with sequelae) is to continue per protocol (Section 8.2). 
Furthermore, the following events (whether serious or not) are to be reported using the same 
process as for reporting SAEs described in protocol Section 8.2 (though SAE reporting timeline 
requirements do not apply to non-serious events reported in these categories): 
• Adverse events of special interest (AESIs) 
• Adverse events, whether serious or not, leading to study treatment discontinuation 
• Adverse events, whether serious or not, leading to study treatment dose modification (ie, 
causing study treatment to be interrupted, delayed, or reduced) 
Subjects who discontinue study treatment in the Maintenance Phase, or who had previously 
discontinued study treatment but had not yet completed the Post-Treatment Follow-Up Visits (ie, 
FU-1 and FU-2) at the time the transition to the Maintenance Phase, will undergo the final safety 
assessment at the Post-Treatment Follow-up Visits. Upon initiation of the Maintenance Phase, no 
further follow up is required for any subject who has completed the FU-1 and FU-2 Visits. 
Study drug accountability is to continue as described in Section 6.5. 

 
XL184-315 Protocol Amendment 5.0 
Page 200 of 232 
See the Maintenance Phase Schedule of Assessments below. To receive study treatment supplies 
it may be necessary for subjects to visit the study site more frequently than clinic visits for safety 
and tumor evaluations performed per standard of care. 
Site monitoring visits may occur at a reduced frequency but must be frequent enough to ensure 
adherence to GCP, protocol compliance, adequate subject safety follow-up, study drug 
accountability, and reporting of SAEs and other reportable events. 
During the Maintenance Phase no data are to be entered into CRFs. The safety data will continue 
to be collected in the Argus database, summarized in table format, and appended to the final 
clinical study report. Imaging data from tumor assessments during the Maintenance Phase will be 
collected by the sites, but not included in the final clinical study report. 
 
 
 
 

 
XL184-315 Protocol Amendment 5.0 
Page 201 of 232 
Schedule of Assessments: Maintenance Phase 
Assessment 
Study Period / Visit 
While Subject is Receiving 
Study Treatment 
(Until Treatment is 
Permanently Discontinued) 
Post-Treatment 
Follow-Up Visits 
(ie, FU-1 and 
FU-2) 
Study drug accountability 
Every time study drug is 
dispensed 
a 
Study treatment 
Atezolizumab infusion (q3w);  
Cabozantinib (po qd) 
OR 
Abiraterone (po qd) + 
prednisone (po bid) 
OR 
Enzalutamide (po qd) 
Study treatment may continue 
until a criterion for 
discontinuation is met 
(Section 3.5.1). 
- 
Safety evaluation: 
symptom-directed physical examination, vital signs 
hematology, chemistry, PT/INR, PTT, urine analysis, 
UPCR, thyroid function tests and ECG 
 
Every 12 weeksb 
a 
Reporting of SAEs, AESIs, and other reportable events 
(pregnancy, medication errors with sequelae) 
Submit reports to Sponsor per Section 8.2 
Reporting of AEs (including AESIs): 
• leading to study treatment discontinuation 
• leading to study treatment dose modification (ie, 
causing study treatment to be withheld or reduced) 
Submit reports to Sponsor per the same process 
as for reporting SAEs per Section 8.2 
 
SAE reporting timeline requirements do not apply to 
non-serious events reported in these categories 
Tumor assessments: 
CT of chest; CT/MRI of abdomen and pelvis; MRI (or 
CT) of brain (in subjects with known brain metastasis or 
if clinically indicated); and technetium bone scan and (if 
needed) CT of bone 
Every 12 weeksb 
- 
AE, adverse event; AESI, adverse event of special interest; bid, twice daily; CT, computerized tomography; ECG, 
electrocardiogram; FU-1, 30-Day Post-Treatment Follow-up Visit; FU-2, 100-Day Post-Treatment Follow-up Visit; MRI, 
magnetic resonance imaging; po, orally administered; PT/INR, prothrombin time/international normalized ratio; PTT, partial 
thromboplastin time; q3w, every 3 weeks; qd, once daily; SAE, serious adverse event; UPCR, urine protein/creatinine ratio  
No data will be entered into electronic case report forms. Do not submit local laboratory results to the study local laboratory 
management vendor, radiographic images to the study central imaging vendor, or ECGs to the study central ECG vendor. 
a Subjects should return all unused study medication and undergo a safety evaluation per schedule of assessments. 
b Safety and tumor assessments in the Maintenance Phase may occur more frequently as clinically indicated. 

 
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Appendix D: Performance Status Criteria 
ECOG Performance Status Scale (reference only) 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (eg, light 
housework, office work). 
2 
In bed < 50% of the time. 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 
In bed > 50% of the time. Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair. 
5 
Dead. 
 
 
 

 
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Appendix E: Highly Effective Methods of Contraception 
In Inclusion Criterion #13 (Section 4.2), sexually active fertile subjects and their partners must 
agree to use highly effective methods of contraception that alone or in combination result in a 
failure rate of less than 1% per year when used consistently and correctly during the course of 
the study and until the end of relevant systemic exposure, defined as 4 months (16 weeks) after 
the last dose of cabozantinib in the experimental arm (cabozantinib + atezolizumab), 3 weeks 
after the last dose of abiraterone (control arm), or 3 months (12 weeks) after the last dose of 
enzalutamide (control arm).  
The effect of cabozantinib on the PK of contraceptive steroids has not been investigated. 
Because oral contraceptives might possibly not be considered as “effective methods of 
contraception,” they should be used together with another method. 
Contraception guidance for subjects with partner(s) of childbearing potential  
Subjects with partners of childbearing potential are eligible if they agree to the following during 
the treatment and until the end of relevant systemic exposure, defined as 4 months (16 weeks) 
after the last dose of cabozantinib in the experimental arm (cabozantinib + atezolizumab), 
3 weeks after the last dose of abiraterone (control arm), or 3 months (12 weeks) after the last 
dose of enzalutamide (control arm). 
• Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the Investigator. 
• Subjects are required to use a condom during study duration and until end of relevant 
systemic exposure, defined as 4 months (16 weeks) after the last dose of cabozantinib in 
the experimental arm (cabozantinib + atezolizumab), 3 weeks after the last dose of 
abiraterone (control arm), or 3 months (12 weeks) after the last dose of enzalutamide 
(control arm). 
• Female partners of subjects in the study are to consider use of effective methods of 
contraception until the end of relevant systemic exposure in the male participant, defined 
as 4 months (16 weeks) after the last dose of cabozantinib in the experimental arm 
(cabozantinib + atezolizumab), 3 weeks after the last dose of abiraterone (control arm), or 
3 months (12 weeks) after the last dose of enzalutamide (control arm). 
Subjects with a pregnant or breastfeeding partner must agree to remain abstinent from penile-
vaginal intercourse or use a male condom during each episode of penile penetration during the 

 
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treatment and until 4 months (16 weeks) after the last dose of cabozantinib in the experimental 
arm (cabozantinib + atezolizumab), 3 weeks after the last dose of abiraterone (control arm), or 
3 months (12 weeks) after the last dose of enzalutamide (control arm). Refrain from donating 
sperm these same periods. 
Contraception guidance for female partners of childbearing potential 
One of the highly effective methods of contraception listed below, in combination with one 
acceptable barrier method below, is required during study duration and until the end of relevant 
systemic exposure, defined as 4 months (16 weeks) after the last dose of cabozantinib in the 
experimental arm (cabozantinib + atezolizumab), 3 weeks after the last dose of abiraterone 
(control arm), or 3 months (12 weeks) after the last dose of enzalutamide (control arm). Local 
laws and regulations may require use of alternative and/or additional contraception methods.  
Highly effective contraceptive methods that are user dependent: These methods have a failure 
rate of < 1% per year when used consistently and correctly. Typical use failure rates may differ 
from those when used consistently and correctly. Use should be consistent with local regulations 
regarding the use of contraceptive methods for participants participating in clinical studies.  
• Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation 
o Oral, intravaginal, or transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation 
o Oral or injectable 
Highly effective contraceptive methods that are user independent: 
• Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation 
• Hormonal methods of contraception including oral contraceptive pills containing a 
combination of estrogen and progesterone, vaginal ring, injectables, implants and 
intrauterine hormone-releasing system 
• Intrauterine device 
• Bilateral tubal occlusion 

 
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• Vasectomized partner 
o A vasectomized partner is a highly effective contraception method provided that the 
absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used 
• Sexual abstinence 
o Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study drug. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the study and the preferred and usual lifestyle of the 
participant. 
- 
It is not necessary to use any other method of contraception when complete 
abstinence is elected. 
Acceptable barrier methods for use in combination with a highly effective method: 
• Male or female condom with or without spermicide 
• Diaphragm with spermicide 
• Cervical cap with spermicide 
• Vaginal sponge with spermicide 
Unacceptable as a Sole Method of Contraception: 
• Male or female condom with or without spermicide. Male and female condoms cannot be 
used simultaneously 
• Diaphragm with spermicide 
• Cervical cap with spermicide 
• Vaginal sponge with spermicide 
• Progestogen-only oral hormonal contraception of which inhibition of ovulation is not the 
primary mechanism of action 

 
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• Periodic abstinence (eg, calendar, symptothermal, post-ovulation methods) 
• Withdrawal (eg, coitus interruptus). 
• Spermicide only 
• Lactation amenorrhea method 
 
 
 
 

 
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Appendix F: Preexisting Autoimmune Diseases and Immune Deficiencies 
Subjects should be carefully questioned regarding their history of acquired or congenital immune 
deficiencies or autoimmune disease. Subjects with any history of immune deficiencies or 
autoimmune disease listed in the table below are excluded from participating in the study. 
Possible exceptions to this exclusion could include: 
• Subjects with a medical history of such entities as atopic disease or childhood arthralgias 
where the clinical suspicion of autoimmune disease is low  
• Subjects with a history of autoimmune-related hypothyroidism on a stable dose of thyroid 
replacement hormone, controlled Type 1 diabetes mellitus and on an insulin regimen, or 
asthma that requires intermittent use of bronchodilators 
• Subjects with transient autoimmune manifestations of an acute infectious disease that 
resolved upon treatment of the infectious agent (eg, acute Lyme arthritis)  
Caution should be used when considering atezolizumab for subjects who have previously 
experienced a severe or life−threatening skin adverse reaction or pericardial disorder while 
receiving another immunostimulatory anticancer agent.    
The Sponsor is available to advise on any uncertainty over autoimmune exclusions. 
Autoimmune Diseases and Immune Deficiencies 
Acute disseminated 
encephalomyelitis 
Addison disease 
Ankylosing spondylitis 
Antiphospholipid antibody 
syndrome 
Aplastic anemia 
Autoimmune hemolytic anemia 
Autoimmune hepatitis 
Autoimmune hypoparathyroidism 
Autoimmune hypophysitis 
Autoimmune myelitis 
Autoimmune myocarditis 
Autoimmune orchitis 
Autoimmune thrombocytopenic 
purpura 
Behçet disease 
Bullous pemphigoid 
Chronic fatigue syndrome 
Chronic inflammatory 
demyelinating polyneuropathy 
Churg-Strauss syndrome 
Crohn’s disease  
Dermatomyositis 
Diabetes mellitus type 1 
Dysautonomia 
Epidermolysis bullosa acquisita 
Gestational pemphigoid 
Giant cell arteritis 
Goodpasture syndrome 
Graves disease 
Guillain-Barré syndrome 
Hashimoto disease 
IgA nephropathy 
Inflammatory bowel disease 
Interstitial cystitis 
Kawasaki disease 
Lambert-Eaton myasthenia 
syndrome 
Lupus erythematosus 
Lyme disease - chronic 
Meniere syndrome 
Mooren ulcer 
Morphea 
Multiple sclerosis 
Myasthenia gravis 
Neuromyotonia 
Opsoclonus myoclonus syndrome 
Optic neuritis 
Ord thyroiditis 
Pemphigus 
Pernicious anemia 
Polyarteritis nodosa 
Polyarthritis 
Polyglandular autoimmune 
syndrome 
Primary biliary cholangitis 
Psoriasis 
Reiter syndrome 
Rheumatoid arthritis 
Sarcoidosis 
Scleroderma 
Sjögren’s syndrome 
Stiff-Person syndrome 
Takayasu arteritis 
Ulcerative colitis 
Vitiligo 
Vogt-Koyanagi-Harada disease 
Wegener granulomatosis 

 
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Appendix G: Infusion-Related Reaction and Cytokine-Release Syndrome Guidelines  
Event 
Management 
Grade 1a:  
Feverb with or without 
constitutional symptoms  
• Immediately interrupt infusion. 
• Upon symptom resolution, wait for 30 minutes and then restart infusion 
at half the rate being given at the time of event onset. 
• If the infusion is tolerated at the reduced rate for 30 minutes, the 
infusion rate may be increased to the original rate. 
• If symptoms recur, discontinue infusion of this dose. 
• Administer symptomatic treatmentc, including maintenance of IV fluids 
for hydration. 
• In case of rapid decline or prolonged CRS (> 2 days) or in patients with 
significant symptoms and/or comorbidities, consider managing as per 
Grade 2. 
• For subsequent infusions, consider administration of oral premedication 
with antihistamines, antipyretics, and/or analgesics, and monitor 
closely for IRRs and/or CRS. 
Grade 2a:  
Feverb with hypotension not 
requiring vasopressors 
and/or 
Hypoxia requiring low-flow 
oxygend by nasal cannula or 
blow-by 
 
• 
Immediately interrupt infusion. 
• 
Upon symptom resolution, wait for 30 minutes and then restart 
infusion at half the rate being given at the time of event onset. 
• 
If symptoms recur, discontinue infusion of this dose. 
• 
Administer symptomatic treatmentc.  
• 
For hypotension, administer IV fluid bolus as needed. 
• 
Monitor cardiopulmonary and other organ function closely (in the 
ICU, if appropriate). Administer IV fluids as clinically indicated and 
manage constitutional symptoms and organ toxicities as per 
institutional practice. 
• 
Rule out other inflammatory conditions that can mimic CRS (eg, 
sepsis). If no improvement within 24 hours, initiate workup and assess 
for signs and symptoms of HLH or MAS. 
• 
Consider IV corticosteroids (eg, methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
• 
Consider anticytokine therapye. 
• 
Consider hospitalization until complete resolution of symptoms. If 
no improvement within 24 hours, manage as per Grade 3, that is, 
hospitalize patient (monitoring in the ICU is recommended), 
permanently discontinue atezolizumab, and contact the Sponsor. 
• 
If symptoms resolve to Grade 1 or better for 3 consecutive days, the 
next dose of atezolizumab may be administered. For subsequent 
infusions, consider administration of oral premedication with 
antihistamines, antipyretics, and/or analgesics and monitor closely 
for IRRs and/or CRS. 
• If symptoms do not resolve to Grade 1 or better for 3 consecutive days, 
contact the Sponsor. 

 
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Event 
Management 
Grade 3a: 
Feverb with hypotension 
requiring a vasopressor (with or 
without vasopressin) 
and/or 
Hypoxia requiring high-flow 
oxygend by nasal cannula, face 
mask, non-rebreather mask, or 
venturi mask 
 
• 
Permanently discontinue atezolizumab and contact the Sponsorf. 
• 
Administer symptomatic treatmentc. 
• 
For hypotension, administer IV fluid bolus and vasopressor as needed. 
• 
Monitor cardiopulmonary and other organ function closely; 
monitoring in the ICU is recommended. Administer IV fluids as 
clinically indicated, and manage constitutional symptoms and organ 
toxicities as per institutional practice. 
• 
Rule out other inflammatory conditions that can mimic CRS (eg, 
sepsis). If no improvement within 24 hours, initiate workup and assess 
for signs and symptoms of HLH or MAS. 
• 
Administer IV corticosteroids (eg, methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
• 
Consider anticytokine therapye. 
• 
Hospitalize patient until complete resolution of symptoms. If no 
improvement within 24 hours, manage as per Grade 4, that is, admit 
patient to ICU and initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as needed; for patients 
who are refractory to anticytokine therapy, experimental treatments 
may be considered at the discretion of the Investigator and in 
consultation with the Sponsor. 
Grade 4a: 
Feverb with hypotension requiring 
multiple vasopressors (excluding 
vasopressin) 
and/or 
Hypoxia requiring oxygen by 
positive pressure (eg, CPAP, 
BiPAP, intubation and mechanical 
ventilation) 
• 
Permanently discontinue atezolizumab and contact the Sponsorf. 
• 
Administer symptomatic treatmentc. 
• 
Admit patient to ICU and initiate hemodynamic monitoring, 
mechanical ventilation, and/or IV fluids and vasopressors as needed. 
Monitor other organ function closely. Manage constitutional 
symptoms and organ toxicities as per institutional practice. 
• 
Rule out other inflammatory conditions that can mimic CRS (eg, 
sepsis). If no improvement within 24 hours, initiate workup and assess 
for signs and symptoms of HLH or MAS. 
• 
Administer IV corticosteroids (eg, methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
• 
Consider anticytokine therapye. For patients who are refractory to 
anticytokine therapy, experimental treatmentsg may be considered at 
the discretion of the Investigator and in consultation with the Sponsor. 
• 
Hospitalize patient until complete resolution of symptoms. 
ASTCT, American Society for Transplantation and Cellular Therapy; BiPAP, bi-level positive airway pressure; 
CAR, chimeric antigen receptor; CPAP, continuous positive airway pressure; CRS, cytokine-release syndrome; 
CTCAE, Common Terminology Criteria for Adverse Events; eCRF, electronic Case Report Form; HLH, 
hemophagocytic lymphohistiocytosis; ICU, intensive care unit; IRR, infusion-related reaction; MAS, macrophage 
activation syndrome; NCCN, National Cancer Comprehensive Network; NCI, National Cancer Institute. 
Note: The management guidelines have been adapted from NCCN guidelines for management of CAR 
T-cell-related toxicities (Version 2.2019). 
a 
Grading system for these management guidelines is based on ASTCT consensus grading for CRS. NCI 
CTCAE v5 should be used when reporting severity of IRRs, CRS, or organ toxicities associated with CRS on 
the Adverse Event eCRF. Organ toxicities associated with CRS should not influence overall CRS grading. 
b 
Fever is defined as temperature ≥ 38°C not attributable to any other cause. In patients who develop CRS and 
then receive antipyretic, anticytokine, or corticosteroid therapy, fever is no longer required when subsequently 
determining event severity (grade). In this case, the grade is driven by the presence of hypotension and/or 
hypoxia. 

 
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c 
Symptomatic treatment may include oral or IV antihistamines, antipyretics, analgesics, bronchodilators, 
and/or oxygen. For bronchospasm, urticaria, or dyspnea, additional treatment may be administered as per 
institutional practice. 
d 
Low flow is defined as oxygen delivered at ≤ 6 L/min, and high flow is defined as oxygen delivered at 
> 6 L/min. 
e 
There are case reports where anticytokine therapy has been used for treatment of CRS with immune 
checkpoint inhibitors (Rotz et al 2017; Adashek and Feldman 2019), but data are limited, and the role of such 
treatment in the setting of antibody-associated CRS has not been established. 
f 
Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully recovered 
from the event. The decision to rechallenge subjects with atezolizumab should be based on Investigator's 
assessment of benefit−risk and documented by the Investigator. The Sponsor is available to advise as needed. 
For subsequent infusions, administer oral premedication with antihistamines, antipyretics, and/or analgesics, 
and monitor closely for IRRs and/or CRS. Premedication with corticosteroids and extending the infusion time 
may also be considered after assessing the benefit-risk ratio. 
g 
Refer to Riegler et al 2019 for information on experimental treatments for CRS. 
 
 
 

 
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Appendix H: Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) 
Adapted from Eisenhauer et al 2009 
Definitions 
Baseline: Baseline is defined as the most recent assessment performed prior to randomization. 
Baseline assessments must be performed within the period defined in the protocol eligibility 
criteria.  
Measurable lesions: Except for lymph nodes as described below, measurable lesions are defined 
as those that can be accurately measured in at least 1 dimension (longest diameter to be recorded) 
as ≥ 10 mm with CT scan (if CT scans have slice thickness greater than 5 mm the minimum size 
for a measurable lesion is twice the slice thickness).  
• 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 no greater 
than 5 mm). At baseline and in follow-up, only the short axis will be measured and recorded. 
• MRI may be substituted for contrast-enhanced CT for lesions at some anatomical sites, but 
not for lesions in the lungs. The minimum size for measurability is the same as for CT 
(10 mm) as long as the scans are performed with slice thickness of 5 mm and no gap. If MRI 
is performed with thicker slices, the size of a measurable lesion at baseline should be twice 
the slice thickness. In the event there are interslice gaps, this also needs to be considered in 
determining the size of measurable lesions at baseline. 
• Bone lesions may only be considered measurable if there is a soft tissue component (lytic or 
mixed lytic-blastic) and the long axis diameter is at least 10 mm. 
Nonmeasurable lesions: All other lesions (or sites of disease), including small lesions (longest 
diameter < 10 mm or pathological lymph nodes with ≥10 to < 15 mm short axis), are considered 
nonmeasurable. Lymph nodes that have a short axis < 10 mm are considered nonpathological 
and are not be recorded or followed. Leptomeningeal disease, lytic or mixed lytic-blastic bone 
lesions, ascites, pleural/pericardial effusions, lymphangitis cutis/ pulmonitis, and abdominal 
masses (not followed by CT or MRI), are considered as nonmeasurable. Following a time point 
response of CR, non-target lymph node lesions and new lymph node lesions must be measured to 
determine if they are or become pathologic in size. 

 
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Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, are to be identified as target lesions and measured 
and recorded at baseline. Target lesions are to be selected on the basis of their size (lesions with 
the longest diameter), be representative of all involved organs, and be those that lend themselves 
to reproducible repeated measurements. It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance the next largest lesion 
that can be measured reproducibly should be selected. Target lesions will be measured at each 
assessment (longest axis for nonnodal lesions, shortest axis for measurable malignant nodal 
lesions). 
Nontarget lesions: All other lesions (or sites of disease) including all non-measurable lesions 
(including pathological lymph nodes with ≥ 10 to <15 mm short axis) and all measurable lesions 
over and above the 5 target lesions are to be identified as non-target lesions and recorded at 
baseline. Measurements of these lesions are generally not required, but the presence, absence, or 
in rare cases unequivocal progression of each is to be recorded throughout follow-up. Lymph 
nodes that have a short axis < 10mm are considered non-pathological and are not to be recorded 
or followed. Following a time point response of CR, non-target lymph node lesions and new 
lymph node lesions must be measured to determine if they are or become pathologic in size. 
To be considered progression of non-target lesions in the presence of measurable disease, 
unequivocal progression is defined as substantial worsening in non-target disease such that, even 
in the presence of SD or PR in target disease, the overall tumor burden has increased sufficiently 
to merit discontinuation of the therapy.  
Special Consideration 
Lesions by clinical examination will not be used for response in this study. 
Cystic lesions 
• Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor nonmeasurable) since they are, by 
definition, simple cysts. 
• Cystic lesions thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if noncystic 
lesions are present in the same subject, these are preferred for selection as target lesions. 

 
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Bone lesions 
• Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions.  
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross-sectional imaging techniques such as CT can be considered as 
measurable lesions and new lesions if the soft tissue component meets the definition of 
measurability described above. 
• Purely blastic bone lesions (best identified by CT scan) do not meet the criteria for selection 
as target or non-target lesions or new lesions. 
Lesions with prior local treatment 
• Lesions that have had external beam radiotherapy (EBRT) or locoregional therapies such as 
radiofrequency (RF) ablation must show evidence of progressive disease based on 
RECIST 1.1 to be deemed a target lesion.  
 
Imaging Methods 
The same method of assessment and the same technique used to characterize each identified and 
reported lesions at baseline should be used during each follow-up assessment. All measurements 
should be taken and recorded in metric notation using a ruler or calipers. Imaging based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being followed 
cannot be imaged but assessed by clinical examination (referring to biopsy-proven visible 
lesion(s) on the chest). 
Chest x-ray: Chest x-ray will not be used for response assessment in this study. 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion is twice the slice thickness. MRI is 
also acceptable in certain situations (eg, for body scan) except for lung.  
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI 
is variable globally. As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease. 
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond 

 
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the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans. Body scans 
should be performed with breath-hold scanning techniques, if possible. 
Positron emission tomography will not be used for response assessment in this study. 
Ultrasound: Ultrasound will not be used for response assessment in this study. 
Bone scans may be used to assess the presence or disappearance of bone lesions.  
Tumor Markers: Tumor markers may be evaluated for changes but will not be used to determine 
progressive disease in this study. 
Cytology, Histology: The cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment can be considered if the measurable tumor has met criteria 
for response or stable disease in order to differentiate between response (or stable disease) and 
progressive disease.  
Time Point Assessments 
The frequency and schedule of tumor assessments is defined in the protocol. The schedule is to 
be maintained regardless of whether study treatment is reduced, interrupted, delayed, or 
discontinued. 
At baseline, tumors and lymph nodes are classified and documented as target or nontarget lesions 
per the definitions provided above. It is possible to record multiple nontarget lesions involving 
the same organ as a single item (eg, ‘multiple liver metastases’). At all postbaseline (follow-up) 
evaluations the baseline classification (target, nontarget) is to be maintained and lesions are to be 
documented and described in a consistent fashion over time (eg, recorded in the same order on 
source documents). 
At each assessment, a sum of the diameters (longest for nonnodal lesions, short axis for nodal 
lesions) for all target lesions will be calculated and included in source documents. The baseline 
sum of the diameters (SoD) will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease. The lowest SoD (nadir) since (and 
including) the baseline value will be used as reference for evaluating progression. 

 
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After baseline, target lesions should have the actual size documented, if possible, even if the 
lesions become very small. If in the opinion of the radiologist the lesion has likely disappeared, 
0 mm should be recorded. If the lesion is present but too small to measure, an indicator for ‘too 
small to measure’ should be included in source documents. 
For target lesions, measurements should be taken and recorded in metric notation.  
Nontarget lesions are to be assessed qualitatively (present, resolved, or unequivocal progression) 
and new lesions, if any, are to be documented separately. 
At each evaluation, progression status is to be determined based upon the time point status for 
target lesions, nontarget lesions, and new lesions. 
Finding of new lesions should not be attributable to differences in scanning technique, change in 
imaging modality or findings thought to represent something other than tumor. Necrosis of pre-
existing lesions as part of a response to treatment should be excluded before defining a ‘new’ 
cystic lesion. A lesion identified on a follow-up study in an anatomical location that was not 
scanned at baseline is considered a new lesion. If a new lesion is equivocal because of its small 
size, repeat scans need to confirm there is definitely a new lesion, and progression should be 
declared using the date of the initial scan. 
Time point progression cannot be based solely on bone scan findings. Bone scans are to be used 
to direct corroborative imaging with CT if necessary. These CT findings will be used for the 
determination of progression. 
 

 
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TIME POINT RESPONSE CRITERIA 
 
Target Lesion Time Point Response (TPR) 
Complete Response  
(CR) 
Disappearance of all target lesions. All pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 
mm. 
Partial Response 
(PR) 
At least a 30% decrease in SoD of target lesions, taking as a reference the 
baseline SoD. 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD. 
Progressive Disease   
(PD) 
At least a 20% increase in the SoD of target lesions, taking as a reference 
the smallest (nadir) SoD since (and including) baseline. In addition to the 
relative increase of 20%, the SoD must also demonstrate an absolute 
increase of at least 5 mm.  
Not Applicable (NA) 
No target lesion identified at baseline. 
Unable to Evaluate   
(UE) 
One or more target lesions are not imaged and the remainder of the SoD 
compared with the nadir SoD does not meet the criterion for PD. 
SoD, baseline sum of diameters (longest for non-nodal lesions; short axis for nodal lesions). 
If the target lesion for a subject meet the criteria for both PR and PD at a given time point, the target lesion 
response is PD. 
If the nadir of SoD is 0 (ie, the subject had a prior target lesion CR), the reappearance of any prior target 
lesion to any degree constitutes PD. 
 
 
Non-Target Lesion Time Point Response (TPR) 
Complete Response  
(CR) 
Disappearance of all non-target lesions. All lymph nodes must be non-
pathological in size (<10 mm short axis). 
Non-CR / Non-PD 
Persistence of one or more non-target lesion(s). 
Progressive Disease   
(PD) 
Unequivocal progression of non-target lesions. Unequivocal progression 
should normally not trump target lesion status. It must be representative 
of overall disease status change, not a single lesion increase. 
Not Applicable (NA) 
No non-target lesions identified at screening. 
Unable to Evaluate   
(UE) 
One or more non-target lesions are not imaged and the remaining non-
target lesions do not meet the criterion for PD. 
 
 
 

 
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New Lesion Time Point Response (TPR) 
Yes 
Lesion present at follow-up visit either for the very first time or re-
appearing (ie, lesion was present at baseline, disappeared at a follow-up 
visit and re-appeared later). Note: The appearance of one or more new 
lesions on CT or MRI scan is considered progression if these findings 
are unequivocally not due to a change in the imaging technique or 
modality. On bone scan, new lesions are not sufficient to qualify as PD. 
Confirmation should be obtained by performing CT of the area of 
concern to confirm results of bone scan.  
No 
No new lesions present at follow-up. 
Unable to Evaluate   
(UE) 
Subject not assessed or incompletely assessed for new lesions. 
 
 

 
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Evaluation of Overall Time Point Response 
Target Lesion TPR 
Non-target lesion TPR 
New lesion TPR 
Overall TPR 
CR 
CR or NA 
No 
CR* 
CR 
Non-CR/non-PD 
No 
PR* 
CR 
UE 
No 
PR* 
PR 
 Non-PD or NA or UE 
No 
PR* 
SD 
Non-PD or NA or UE 
No 
SD 
UE 
Any except PD 
No 
UE 
PD 
Any 
No or Yes 
PD 
Any 
PD 
No or Yes 
PD 
Any 
Any 
Yes 
PD** 
NA 
CR 
No 
CR* 
NA 
Non-CR/Non-PD 
No 
Non-CR/non-PD 
NA 
UE 
No 
UE 
CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease, UE, unable to 
evaluate; NA, not applicable (no such lesions at screening); Any, CR, PR, SD, PD, NA, or UE. 
The overall response at a given time point does not depend upon the overall response assigned at any prior 
or subsequent time point (ie, confirmation requirement are not considered when assigning time point 
responses). 
* Subjects with an overall response of CR or PR must have a follow-up tumor assessment performed no 
less than 4 weeks after the criteria for response are first met (this may be performed at the next scheduled 
tumor assessment). However, the presence, absence, or status at this follow up assessment is not considered 
when assigning a time point response at prior time points. 
 
** If a lesion disappears and reappears at a subsequent time point it should continue to be measured. 
However, the subject’s response at the point in time when the lesion reappears will depend upon the status 
of his/her other lesions. For example, if the subject’s tumor had reached a CR status and the lesion 
reappeared, then the subject would be considered PD at the time of reappearance. In contrast, if the tumor 
status was a PR or SD and one lesion which had disappeared then reappears, its maximal diameter should 
be added to the sum of the remaining lesions for a calculated response. 
Furthermore, in order to identify potential delayed immune-mediated tumor response, subjects with an 
overall response of PD per RECIST 1.1 who continue with study treatment because of evidence of clinical 
benefit as assessed by the Investigator should have a follow-up tumor assessment no less than 4 weeks after 
the initial PD criteria were met. This may be performed at the next scheduled tumor assessment. However, 
the presence, absence, or status at this follow up assessment is not considered when assigning a time point 
response at prior time points. 
 

 
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Confirmation 
The main goal of confirmation of objective response is to avoid overestimating the response rate 
observed. For subjects with an overall response of PR or CR at a given time point, a follow-up 
tumor assessment must be performed no less than 4 weeks after the criteria for response are first 
met. This may be performed at the next scheduled tumor assessment.  
In order to identify potential delayed immune-mediated tumor response, subjects with an overall 
response of PD per RECIST 1.1 who continue with study treatment because of evidence of 
clinical benefit as assessed by the Investigator should have a follow-up tumor assessment no less 
than 4 weeks after the initial PD criteria were met. This may be performed at the next scheduled 
tumor assessment. 
However, the presence, absence, or status at these follow up assessments is not considered when 
assigning a time point response at prior time points.  
Best Overall Response 
Best overall response, incorporating confirmation requirements, will be derived during statistical 
analysis from the series of time point responses and need not be considered when assigning 
response at each time point. 
 
 

 
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Appendix I: List of Substrates, Inducers, and Inhibitors of Selected CYP450 Isozymes  
Experimental Arm (cabozantinib and atezolizumab) 
Cabozantinib is a CYP3A4 substrate (Section 7.3.1). 
Chronic co-administration of cabozantinib with drugs known to be strong inducers of the 
CYP3A4 family may decrease cabozantinib concentrations and therefore should be avoided 
during treatment with cabozantinib. St. John’s Wort (Hypericum perforatum) is also known to be 
an inducer of CYP3A4 and should be avoided. 
Co-administration of cabozantinib with strong inhibitors of the CYP3A4 family may increase 
cabozantinib concentrations and should be avoided during treatment with cabozantinib. 
Grapefruit, star fruit and Seville oranges may also increase plasma concentrations of 
cabozantinib and should be avoided during treatment with cabozantinib. 
Control Arm (abiraterone with prednisone, or enzalutamide) 
Abiraterone 
Abiraterone is a substrate of CYP3A4 (Section 7.3.3). Avoid co-administration of strong 
CYP3A4 inducers as they may decrease abiraterone concentrations.  
Abiraterone is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8 
(Section 7.3.3). Co-administration of abiraterone with CYP2D6 substrates may increase 
concentrations of these substrates, therefore avoid concomitant use with CYP2D6 substrates that 
have a narrow therapeutic index. Subjects should be monitored closely for signs of toxicity 
related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with 
abiraterone. 
Enzalutamide 
Avoid co-administration of enzalutamide with strong CYP2C8 inhibitors and strong CYP3A4 
inducers (Section 7.3.4).  
Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in 
humans (Section 7.3.4). Avoid concomitant use of enzalutamide with narrow therapeutic index 
drugs that are metabolized by CYP3A4 (eg, alfentanil, cyclosporine, dihydroergotamine, 
ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (eg, phenytoin) 
and CYP2C19 (eg, S-mephenytoin), as enzalutamide may decrease the plasma exposure of these 
drugs.  
 

 
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Strong Inhibitors of CYP3A4 
Strong Inducers of CYP3A4 
Antivirals 
Boceprevir 
Cobicistat 
Conivaptan 
Danoprevir 
Dasabuvir 
Elvitegravir 
Indinavir  
Lopinavir  
Nelfinavir 
Ombitasvir  
Paritaprevir 
Ritonavir  
Saquinavir 
Telaprevir  
Tipranavir  
Anti-Fungals 
Itraconazole 
Ketoconazole 
Posaconazole 
Voriconazole 
Antibiotics 
Clarithromycin 
Telithromycin 
Troleandomycin 
Conivaptan 
Diltiazem 
Grapefruit juice/star fruit/Seville oranges 
Idelalisib 
Nefazodone 
Carbamazepine 
Efavirenz 
Enzalutamide 
Erythromycin 
Mitotane 
Modafinil 
Nevirapine 
Oxcarbazepine 
Phenytoin 
Rifampin 
St. John’s Wort 
CYP3A4 Substrates with Narrow Therapeutic 
Index 
Alfentanil 
Cyclosporine 
Dihydroergotamine 
Ergotamine 
Fentanyl 
Pimozide 
Quinidine 
Sirolimus 
Tacrolimus 
Strong CYP2C8 Inhibitors 
Gemfibrozil  
CYP2D6 Substrates with Narrow Therapeutic Index 
Thioridazine 
CYP2C9 Substrates with Narrow Therapeutic Index 
Phenytoin 
CYP2C19 Substrates with Narrow Therapeutic Index 
S-mephenytoin 
This table is not all-inclusive. Please refer to the FDA website for the most updated lists of 
substrates, inducers, and inhibitors of selected CYP450 isozyme pathways: 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-
table-substrates-inhibitors-and-inducers 

 
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Appendix J: Collection, Follow-Up, and Documentation Requirements for AEs, AESIs, 
and SAEs 
All adverse events (AEs) that are not serious and not AESIs (AEs of special interest; Table 8-1) 
that start or worsen after the first dose of study treatment through the 30-day post-treatment 
follow-up (FU-1) visit are to be entered into the electronic CRF data capture system (EDC). Such 
events continuing at the FU-1 visit are to be documented as “ongoing” in the EDC and do not 
require further documentation for study purposes. These events do not require a Drug Safety 
SAE report to be completed. 
Additional requirements apply to the following events: 
• All serious adverse events (SAEs) that are judged by the Investigator to be not related to 
study treatment that start or worsen after the subject’s initial informed consent through the 
100-day post-treatment follow-up (FU-2) visit are to have a Drug Safety SAE report 
completed. Such events continuing at the FU-2 visit are to be documented as “ongoing” in 
the EDC and do not require further documentation for study purposes. 
• All AEs leading to study treatment discontinuation that are judged by the Investigator to be 
related to study treatment that are continuing at the FU-2 visit are to be followed by the 
Investigator until resolution, defined as: fully resolved or ≤ Grade 2 severity or the event is 
deemed stable/irreversible by the Investigator. In the EDC, only documentation of the status 
of “ongoing” at the FU-2 visit is required. If serious, the requirements for related SAEs 
apply. 
• All AESIs (regardless of seriousness) that start or worsen after the subject’s initial informed 
consent through the FU-2 visit are to have a Drug Safety SAE report completed and be 
entered into the EDC. Such events continuing at the FU-2 visit are to be followed until 
resolution, with evidence of resolution provided on updates to the Drug Safety SAE report. In 
the EDC, only documentation of the status of “ongoing” at the FU-2 visit is required. 
• All SAEs that are judged by the Investigator to be related to study treatment that start or 
worsen at any time after the subject’s initial informed consent are to have a Drug Safety SAE 
report completed. Such events that occur prior to the FU-2 visit are to be entered into the 
EDC. Such events continuing at the FU-2 visit are to be followed until resolution, with 
evidence of resolution provided on updates to the Drug Safety SAE report. In the EDC, only 
documentation of the status of “ongoing” at the FU-2 visit is required. 
Summaries of the event surveillance (Table J-1) and follow-up requirements (Table J-2) are 
shown in the following page:

 
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Table J-1: 
Requirements for Documenting the Incidence of AEs, SAEs and AESIs 
Event type 
Event surveillance period (inclusive): 
EDC CRFa 
Drug Safety SAE Report 
Period 
start 
Period 
stop 
Period 
start 
Period 
stop 
AE: nonserious, non-AESI 
first dose 
FU-1 
NA 
NA 
SAE: not related 
IC 
FU-2 
IC 
FU-2 
Related AE leading to study treatment discontinuation  
first dose 
EOT date 
NA (if nonserious) 
NA (if nonserious) 
AESI: nonserious (AESIs: irAEs, potential DILI, Other; Table 
8-1) 
IC 
FU-2 
IC 
FU-2 
Related SAE 
IC 
FU-2 
IC 
ever 
All Deaths 
IC 
End of Trial 
IC 
FU2 
AE, adverse event; AESI, adverse event of special interest (Table 8-1); EDC, electronic CRF data capture system; CRF, case report form; DILI, drug-induced liver injury; 
EOT date, end of treatment date (later of the date of decision to discontinue study treatment or date of last dose); FU-1, follow-up visit 30 (+14) days after EOT date; FU-2, 
follow-up visit 100 (±14) days after EOT date; IC, informed consent; irAE, immune-related AE; NA, not applicable; SAE, serious AE. 
a 
See CRF completion guidelines for instructions regarding the appropriate page(s) to be completed 
 
Table J-2: 
Requirements for Following up on Events Documented and Reported as Defined in Table J-1 
Event type 
Event follow-up requirements 
If ongoing at… 
…follow until… 
…and document following on: 
Source documents 
EDC CRFa 
Drug Safety 
SAE Report 
AE: nonserious, non-AESI 
FU-1 
NA 
status at FU-1 
status at FU-1 
NA 
SAE: not related, non-AESI 
FU-2 
NA 
status at FU-2 
status at FU-2 
status at FU-2 
Related AE leading to study treatment discontinuation  
FU-2 
Resolutionb 
evidence of resolution 
status at FU-2 
NA (if nonserious) 
AESI: regardless of seriousness (AESIs: irAEs, potential 
DILI, Other; Table 8-1) 
FU-2 
Resolutionb 
evidence of resolution 
status at FU-2 
evidence of resolution 
Related SAE 
FU-2 
Resolutionb 
evidence of resolution 
status at FU-2 
evidence of resolution 
AE, adverse event; AESI, adverse event of special interest (Table 8-1); EDC, electronic CRF data capture system; CRF, case report form; DILI, drug-induced liver injury; 
EOT date, end of treatment date (later of the date of decision to discontinue study treatment or date of last dose); FU-1, follow-up visit 30 (+14) days after EOT date; FU-2, 
follow-up visit 100 (±14) days after EOT date; IC, informed consent; irAE, immune-related AE; NA, not applicable; SAE, serious AE. 
a 
See CRF completion guidelines for instructions regarding the appropriate page(s) to be completed 
b 
Defined as: AE is fully resolved or ≤ Grade 2 severity or the event is deemed stable/irreversible by the Investigator 

 
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Appendix K: EuroQoL Questionnaire EQ-5D-5L, USA (English) Sample Version 
Under each heading, please the ONE box that best describes your health TODAY. 
CCI

 CCI

 
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Appendix L: EORTC QLQ-C30 Questionnaire, English Sample Version 3 
CCI

 
XL184-315 Protocol Amendment 5.0 
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CCI

 
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Appendix M: 11-point Numeric Rating Scale (NRS) for Pain Assessments 
 
 
CCI

 
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Appendix N: COVID-19 Instructions 
This appendix describes contingencies and accommodations for sites and subjects impacted by 
the COVID-19 pandemic. In response to the evolving circumstances of the pandemic, the 
Sponsor will provide ongoing guidance to Investigators on study conduct to ensure subject safety 
and maintain the scientific integrity of the study. Investigators must also maintain awareness of 
and respond to instructions and guidelines from their local regulatory authorities during the 
pandemic. These will be temporary measures and are applicable only during the pandemic, and 
as necessary to abide by local public health requirements. These measures will be repealed back 
to the measures described in the full study protocol, including Appendix A, Appendix B, and 
Appendix C, as soon as the situation (governmental rules, benefit/risk assessment for the trial) 
allows. 
Under the exceptional circumstances of the COVID-19 pandemic where randomized subjects are 
not able or willing to physically access the site clinic, the following accommodations may be 
permitted if allowed by local and other applicable regulations (Note: special accommodations are 
not permitted for screening assessments): 
• Safety assessments should still be performed unless the Investigator and Sponsor agree that 
specific assessments may be missed as long as this occurs in accordance with all applicable 
local regulations. However, at a minimum, the Investigator or designee must regularly 
contact the subject (eg, by phone) to ascertain the subject’s condition and occurrence of any 
symptom-based AEs per the relevant protocol-defined visit schedule. If available, results of 
any remote assessments performed by a non-study local oncologist or primary care physician 
must be sent to the Investigator for review and documentation. If components of the safety 
assessment cannot be collected or the timing of safety assessments needs to be adjusted, it 
may be possible to continue with study treatment but this will have to be discussed on a case-
by-case basis with the Medical Monitor. Any remote laboratory assessments must be 
performed by laboratories accredited by the local jurisdiction. 
• Tumor assessments may be performed at another radiology facility rather than at the study 
site (this option is not available in Germany). Such facilities should perform tumor 
assessments in accordance with the protocol, but alternative image acquisition protocols (eg, 
single post-contrast vs triple phase) may be accepted if the preferred modality is not 
available. The treatment modality (eg, CT scan or MRI) should be the same as that utilized 
since the start of study entry in order to avoid discrepancies in imaging interpretation. 
Imaging should be performed within or as close to the study visit window for scheduled 

 
XL184-315 Protocol Amendment 5.0 
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imaging time points as possible. The study site must collect tumor images generated off site 
in a timely fashion for review and documentation by the Investigator and submission to the 
BIRC. 
• Alternative methods of distribution of oral treatment to subjects may be considered in 
accordance with the study site’s local policies and all applicable regulations. Confirmation of 
drug receipt will be obtained by sites. 
• Intravenous study treatment should generally only be administered at the study site, but 
circumstances may arise where the subject may receive infusions in another location under 
the supervision of the Investigator, with the approval of the Sponsor, and in accordance with 
all applicable regulations. 
If logistical challenges in providing study treatment or performing study-related assessments 
result in temporary interruption of all study treatment for greater than 12 weeks, subjects are 
required to permanently discontinue study treatment unless permitted to continue by the Sponsor. 
If it becomes necessary to employ any of the accommodations described in this appendix of 
COVID-19 Instructions, Investigators are to document each incident in source records as 
COVID-related. To comply with emerging regulatory guidance that such accommodations be 
reported and their impact on the study assessed, these will be collected by the Sponsor (or 
designee) as protocol-deviations. However, no corrective action will generally be expected if this 
appendix is followed. 
Subjects are to be informed of changes to standard procedures resulting from effects of the 
COVID-19 pandemic, and if necessary, subject consent is to be acquired. If additional consent is 
necessary during the course of the study but cannot be immediately obtained from the subject in 
writing, the Investigator is to describe to the subject the additional information requiring consent, 
obtain verbal consent from the subject, document such consent in the subject file, and follow up 
with written consent the next time a subject returns to the site. This does not apply to initial 
consent to enter the study; in this case, written consent is still required. 
For subjects who develop COVID-19 while on study, the Investigator is to evaluate the overall 
risk-benefit ratio for the subject to determine whether holding study treatment(s) is in the best 
interest of the subject.  
Any cases of confirmed or suspected COVID-19 infections should follow the general AE 
reporting requirements defined in the protocol. For any confirmed or suspected COVID-19 cases, 

 
XL184-315 Protocol Amendment 5.0 
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the Investigator is responsible for assessing if the event should be reported as a SAE using their 
clinical judgment. The Investigator should further consider whether the diagnosis meets the 
criteria of being a significant medical event. 
When recording data missing, impacted, or related to COVID-19 in the electronic CRFs, the 
conventions below are to be employed. Also refer to updated CRF Completion Guidelines and 
site communication memos for additional instructions for how to document data missing or 
impacted by COVID-19. 
Case Report Form 
Instructions 
Adverse Event CRF 
• 
Record COVID-19 diagnoses as “COVID-19” 
• 
Record suspected cases as “suspected COVID-19” 
• 
If death is the outcome of such an event, the CTCAE grade should be 
assigned as ‘5’. 
See the CRF instructions for how to enter fatal events that started at a 
lower grade 
End of Study Treatment 
CRFs 
• 
Investigators are to use their best judgment to identify the primary 
reason for study treatment discontinuation. 
• 
If study treatment ended primarily due to a logistical issue associated 
with the COVID-19 pandemic and was unrelated to cancer 
progression or any AE: 
o Indicate “Other” as the reason for treatment discontinuation 
and describe the reason in the Specify field, including the 
term “COVID-19”. 
For example – Other, Specify: “Subject unable to travel due 
to COVID-19 restrictions ” 
• 
If study treatment ended primarily due to an AE caused by COVID-
19 or suspected COVID-19: 
o Indicate “AE/SAE unrelated to progression of disease under 
study”  
o Record the AE on the Adverse Event CRF as described 
above with Action Taken = “Treatment Discontinued” 
End of Radiographic 
Follow-Up CRF 
• 
If radiographic assessments ended primarily due to a logistical issue 
or AE caused by COVID-19 or suspected COVID-19: 
o Indicate “Other” as the reason for discontinuation and 
describe the reason in the Specify field, including the term 
“COVID-19.” 
For example – Other, Specify: “Subject unable to travel due 
to COVID-19 restrictions ” or “Subject discontinued due to 
hospitalization for suspected COVID-19.” In the latter 
example, also record the AE on the Adverse Event CRF as 
“suspected COVID-19” 
Study Treatment CRFs 
• 
If study treatment was held or delayed solely due to a logistical issue 
associated with the COVID-19 pandemic: 
o For oral study treatment CRFs: Indicate “Other” as the 
reason the dosing interval ended and describe the reason in 
the Specify field, including the term “COVID-19”. 

 
XL184-315 Protocol Amendment 5.0 
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o For IV dosing CRFs: Enter “Yes” for “Dose delayed from 
prior infusion” and “Reason for dose delay” should be 
entered as “Other” and describe the reason in the Specify 
field, including the term “COVID-19” (if/when ‘Specify’ 
field is available) 
For example – Other, Specify: “Subject unable to travel due 
to COVID-19 restrictions”