Clinical trial NCT02213107
Conditions: Prostate Cancer
Keywords: prostate
Sponsor: University of Rochester
Start date: 2014-09-01; Completion date: 2023-10-31
Enrollment: 43 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Determine the effect of enzalutamide and dutasteride or finasteride on the time to prostatic-specific antigen level increase in patients age 65 or older.

Detailed description:
The primary objective of this study is to determine the effect of enzalutamide and dutasteride or finasteride on the time to prostatic-specific antigen progression in patients aged 65 or older receiving this combination as first line treatment for systemic prostate cancer.

To determine the safety and toxicities of the study drug combination.

To determine the time to prostatic-specific antigen nadir from the start of study treatment and to evaluate the absolute prostatic-specific antigen nadir as a result of the study drug combination

Arms: arm 1: Use of either 1. Enzalutamide and dutasteride or 2. Enzalutamide and finasteride.
Interventions: intervention 1: Enzalutamide and Dutasteride or finasteride
Intervention descriptions: intervention 1: Use of either two oral drugs together

1. Enzalutamide by mouth daily and dutasteride by mouth daily or
2. Enzalutamide by mouth daily and finasteride by mouth daily

Protocol documents:
Prot_SAP_000.pdf: 
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NCT02213107
ASTELLAS/MEDIVATION Inc. IIT 
CLINICAL RESEARCH PROTOCOL
A Phase II Study of Enzalutamide Plus Dutasteride/Finasteride as First 
Line Treatment for Vulnerable Patients ≥ 65 Years with Systemic 
Prostate Cancer
Investigational Products:
Enzalutamide, Dutasteride or Finasteride
Sponsor:
Astellas/Medivation Inc.
Protocol History
Original Protocol Date: September 23, 2013
Amendment # 1 Dated 31 March2014
Amendment # 2 Dated 18 June2014 
Amendment # 3  Dated 18 Sep2014 
Amendment # 4  Dated 05 May2015 
Amendment # 5  Dated 30 Sep2016 
Amendment # 6 Dated 14 Nov2016 
Amendment # 7 Dated 25May2017 
Amendment # 8 Dated 02June 2017 
Amendment # 9 Dated 20May2022 
Amendment #10 Dated 30Sep2022 
Amendment #11 Dated 23Nov2022 
Amendment #12 Dated 21 Jul 2023 
Amendment # 13 Dated 10 Oct 2023 
PRINCIPAL INVESTIGATOR
Chunkit Fung, MD, MSCE (Medical Oncology)
James P. Wilmot Cancer Center
University of Rochester
601 Elmwood Ave, Box 704
Rochester, NY 14642
Phone: (585) 273-5573
Fax: (585) 276-0350
Email: chunkit_fung@urmc.rochester.edu
CO-INVESTIGATOR
Supriya G. Mohile, MD, MS (Medical Oncology)
James P. Wilmot Cancer Center
601 Elmwood Avenue, Box 704
Rochester, NY 14642
Phone: (585) 276-3947
Fax: (585) 276-0350


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Email: supriya_mohile@urmc.rochester.edu
SITE PRINCIPAL INVESTIGATOR (Medical College of Wisconsin)
Deepak Kilari, MD (Medical Oncology)
Clinical Cancer Center
Medical College of Wisconsin
9200 W Wisconsin Ave 
Milwaukee, WI 53226
Phone: (414) 805-0577
Fax: (414) 805-4606
Email: dkilari@mcw.edu
SUB-INVESTIGATORS
Deepak M. Sahasrabudhe, MD (Medical Oncology)
James P. Wilmot Cancer Center
601 Elmwood Avenue, Box 704
Rochester, NY 14642
Peter Van Veldhuizen, MD (Medical Oncology)
James P. Wilmot Cancer Center
601 Elmwood Avenue, Box 704
Rochester, NY 14642
Sindhu Kadambi, MD (Medical Oncology)
James P. Wilmot Cancer Center
601 Elmwood Avenue, Box 704
Rochester, NY 14642
Adrienne Victor, MD (Medical Oncology)
James P. Wilmot Cancer Center
601 Elmwood Avenue, Box 704
Rochester, NY 14642
Brendan Guercio, MD (Medical Oncology) 
James P. Wilmot Cancer Center
601 Elmwood Avenue, Box 704
Rochester, NY 14642
Edward M. Messing, MD (Urology)
Department of Urology
University of Rochester Medical Center
601 Elmwood Avenue, Box 656
Rochester, NY 14642
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Kathryn Bylow, MD (Medical Oncology)
Clinical Cancer Center
Medical College of Wisconsin
9200 W Wisconsin Ave 
Milwaukee, WI 53226
John Burfeind, MD (Medical Oncology) 
Clinical Cancer Center
Medical College of Wisconsin 
9200 W Wisconsin Ave 
Milwaukee, WI 53226
BIOSTATISTICIAN
Andrea Baran, MS
Director, Biostatistical 
Consulting
Service
Department of Biostatistics and 
Computational Biology 
University
of Rochester Medical Center 
601 Elmwood Avenue, Box 630
Rochester NY 14642
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Contents
1.0
BACKGROUND
8
1.1
Rationale 
for 
Peripheral 
Androgen 
Blockade
9
1.2
University 
of 
Rochester 
– 
Peripheral 
Androgen 
Blockade 
Data
10
1.3
Rationale 
for 
Enzalutamide 
and 
5 
Alpha 
reductase 
inhibitor
10
1.4
Utility 
of 
Comprehensive 
Geriatric 
assessment
12
2.0
OBJECTIVES
13
2.1
Primary 
Objective
13
2.2
Secondary Objectives
13
2.3
Tertiary Objectives (Exploratory)
13
3.0
DRUG INFORMATION
14
3.1
Enzalutamide
14
3.1.1
Description
14
3.1.2
Pharmacology
14
3.1.3
Toxicology
15
3.1.4
Adverse 
Events
15
3.1.5
Pregnancy
16
3.2
Dutasteride
16
3.2.1
Description
16
3.2.2
Pharmacology
16
3.2.3
Toxicology
17
3.2.4
Adverse 
Events
18
3.2.5
Pregnancy
18
3.3
Finasteride
18
3.3.1
Description
18
3.3.2
Pharmacology
18
3.3.3
Toxicology
19
3.3.4
Adverse 
Events
20
3.3.5
Pregnancy
20
3.4
Blood 
Donation
20
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3.5
Selection 
of 
Doses 
Used 
in 
the 
Study
21
4.0
STAGING 
CRITERIA................................................................................................................
21
5.0
SELECTION OF STUDY POPULATION
21
5.1
Eligibility 
Criteria
21
5.2
Inclusion 
Criteria
22
5.2.1
Disease 
Related 
Criteria
22
5.2.2
Prior 
Therapy 
Related 
Criteria
22
5.2.3
Clinical 
Criteria
22
5.3
Exclusion Criteria
22
5.3.1
Disease 
Related 
Criteria
23
5.3.2
Prior 
Therapy 
Related 
Criteria
23
5.3.3
Clinical/Laboratory 
criteria
23
5.4
Regulatory 
Criteria
24
6.0
OVERALL 
STUDY 
DESIGN 
AND 
PLAN............................................................................................
24
7.0
TREATMENT 
PLAN
26
7.1
Treatment
26
7.2
Prior 
and 
Concomitant 
Therapy
26
7.2.1
Prohibited 
Medications
26
7.2.2
Permitted 
Medications
27
7.2.3
Non 
Drug 
Therapies
27
7.3
Treatment Compliance
27
7.4
Criteria 
for 
Removal 
from 
Protocol 
Treatment
28
7.5
Treatment Discontinuation
28
7.6
Follow 
up Period
29
7.7
Unscheduled 
Visits
29
8.0
STUDY CALENDAR.............................................................................................................
30
9.0
END POINT DEFINITIONS: EFFICACY ASSESSMENT
32
9.1
Primary Efficacy Assessment
32
9.2
Secondary Efficacy Assessments
32
9.2.1
Absolute 
PSA 
Response
32
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9.2.2
Time 
to 
PSA 
Nadir
32
9.2.3
Safety 
and 
Toxicity
32
9.3 Tertiary (Exploratory) Efficacy assessments
33
9.3.1
Change in 
Bone Health
33
9.3.2
Change 
in 
CGA 
Domains
33
9.3.3
Quality 
of 
life 
assessments- 
Functional 
Assessment 
of 
Cancer 
Therapy 
- 
P
35
10.0 STATISTICAL CONSIDERATIONS
35
10.1 Primary End-Point
35
10.2 Secondary 
End-Points
36
10.2.1Decline 
in 
PSA 
from 
Baseline 
to 
Nadir
36
10.2.2Time 
to 
PSA 
Nadir
36
10.2.3Safety 
and 
Toxicity
36
10.3Tertiary 
Endpoints
37
10.3.1
Changes 
in Bone Health
37
10.3.2 Changes in Comprehensive 
Geriatric Assessment
37
10.3.3
Quality 
of 
Life
37
11.0 Safety 
Assessments
37
11.1 Definition 
of 
an 
Adverse 
Event
37
11.2 Adverse Events - 
Severity Rating
40
11.3 Disease 
Progression as an Adverse Event
40
11.4 Serious Adverse Events and Unexpected Adverse Events - Definitions
41
11.5 Serious Adverse Events - Reporting
41
11.6 Procedure in Case of Pregnancy
43
11.7 Safety 
Analyses
44
12.0
TOXICITY ASSESSMENT AND DOSE REDUCTION/DOSE ADJUSTMENT..........................................
45
13.0 REGISTRATION GUIDELINES
46
13.1
Registration 
Timing
46
13.2 Investigator/Site requirement
46
13.3Other 
Registration 
guidelines
47
14.0 STUDY ADMINISTRATION
47
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14.1 Institutional 
Review 
Board 
or 
Independent 
Ethics 
Committee
47
14.2 Ethical 
Conduct 
of 
the 
Study
47
14.3 Patient Information and 
Informed Consent
48
14.4 Study Monitoring 
and Auditing
48
14.5Drug 
Supply
48
14.6 Storage and Labeling
49
14.6 Selection 
of 
Timing 
of 
Dose 
for 
Each 
Patient
49
14.7 Investigational Product Accountability
49
14.8 Data 
Quality 
Assurance
50
14.9 Retention 
of 
Records
50
14.10 Data 
Management
50
14.11
Study and 
Site Closure
51
15.0 BIBLIOGRAPHY......................................................................................................................
52
16.0 APPENDICES
57
16.1Appendix 
A: Performance 
Status 
Criteria
57
16.2Appendix 
B. 
RECIST 
1.1 
Criteria
58
16.3Appendix C: CTCAE Version 4.0
60
16.4Appendix 
D: 
Investigators 
Brochure
61
16.5Appendix E: Comprehensive Geriatric 
assessment tools
61
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1.0
BACKGROUND
Prostate cancer (PCa) is the most common non-cutaneous malignancy among 
elderly men, with over 60% of all PCa cases diagnosed in men over 65 years of 
age.(1) It is estimated that men 75 years and older contribute almost half (48%) of
all PCa cases presenting with overt distant metastases and more than half (53%) 
of all PCa deaths.(2) The estimated prevalence of PCa in men aged 75 years and older
is currently over a million and expected to quadruple by 2030, given the long natural 
history of the disease and aging of the population.(1, 3) Despite the more frequent 
diagnosis of PCa at an early stage with the widespread use of PSA, many of the 
patients (1 in 3) without known distant metastases at presentation will subsequently 
develop systemic disease that would require further treatment.(4) All of these statistics 
portend an increasing number of older men, including those in the oldest age groups, 
with a diagnosis of systemic prostate cancer who are likely to experience significant 
complications from standard treatment. Although the elderly are disproportionately 
affected by cancer, little attention has been given to the specific management of 
cancer
in this population. This is primarily due to underrepresentation of older patients in 
clinical trials, which in turn has greatly hindered our understanding of the effects of 
cancer treatment in the elderly. (5, 
6)
Systemic disease from prostate cancer includes biochemical recurrence (a rise in
PSA after definitive treatment with no radiographic evidence of disease 
elsewhere) as well as overt metastatic disease confirmed by imaging. Once the 
disease is systemic, the goal of treatments is only palliative and physicians should take
into account therapy-related side effects, which can adversely affect quality of life. For 
several decades the standard of care for the initial management of systemic PCa has 
been androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (LHRH)
agonist or antagonist. Side effects of ADT include but are not limited to weakness, 
osteoporosis, muscle wasting, metabolic syndrome, hot flashes, increased risk of 
diabetes, cardiovascular disease, depression, impotence, falls and cognitive/mood 
disorders.(7-10) While these untoward effects are tolerable in the young fit population, 
they can have significant adverse consequences in the elderly cancer patients with 
preexisting co-morbidities and functional impairment.(
8, 10, 11) Once ADT is initiated for
systemic disease, it is usually continued for life. Since older patients tend to be 
diagnosed with more indolent cancers and live with PCa as a chronic disease, they 
experience significant complications from ADT which become worse over time.(8) Some
elderly patients may require hospitalizations for complications related to ADT with a few
even requiring placement into nursing home facilities. Given the mechanism of ADT, it is
postulated that these effects are a direct result of low testosterone. In many elderly 
men, their testosterone levels do not return to pre-ADT levels after ADT is discontinued.
Therefore, even a limited trial of ADT may leave them at risk for long-lasting adverse 
effects from hypogonadism. Approximately one-third of patients are deemed high 
risk for side effects and toxicities from ADT.(8) Despite often being asymptomatic
from systemic cancer and in the absence of a clear survival benefit with 
early
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initiation of ADT, older patients continue to be subjected to substantial side 
effects from ADT with a decline in quality of life, falls (due to muscle 
weakness) 
and exacerbation of underlying chronic diseases (such as heart disease); hence 
exploration of alternate options in this population is urgently needed.
1.1
Rationale for Peripheral Androgen 
Blockade
Conventional antiandrogens, such as bicalutamide, bind to androgen receptors 
and competitively inhibit their interaction with testosterone and 
dihydrotestosterone (DHT). These agents do not result in a decrease in 
circulating androgen levels as they do not interfere with the hypothalamic 
pituitary axis and thereby have less adverse effects compared to ADT. When 
compared with medical or surgical castration in two randomized trials involving men with
advanced PCa, high dose bicalutamide was associated with improvement in symptoms,
quality of life (QOL), and lower incidence of hot flashes. However, survival outcomes for
metastatic PCa were inferior for patients on bicalutamide monotherapy compared to 
ADT in both of these trials.(12, 13). Subsequently a meta-analysis of eight trials 
comparing antiandrogen monotherapy with surgical or medical castration again found a
trend towards shorter overall survival (OS) for patients receiving antiandrogens. Based 
on these data, NCCN recommends against first-line antiandrogen monotherapy for men
with systemic disease.(14)
In an effort to increase upon the efficacy of antiandrogen therapy, 5-alpha reductase (5-
AR) inhibitors have been evaluated in patients with systemic PCa. These agents block 
the intraprostatic conversion of testosterone to DHT, which is the more potent form of 
androgen that is primarily responsible for cell proliferation; thus exerting their action at a
different site compared to non-steroidal antiandrogen which blocks the cytoplasmic DHT
receptor. 5-AR inhibitors, when used as monotherapy or combination therapy, are well 
tolerated since serum testosterone levels are maintained during treatment. The 
potential synergistic effect of 5-AR inhibitor with antiandrogens provided the 
rationale for using the combination for treatment of systemic PCa, which is 
referred to as peripheral androgen blockade (PAB).
Several phase 2 trials tested PAB in different settings, including biochemical relapse 
(in
an era in which the concept of PSA doubling time did not exist) and metastatic 
disease.
These studies reported that the majority of patients had a PSA response with good 
tolerance.(15-17) In one trial, after PSA nadir was achieved with bicalutamide, a second
PSA nadir was reached with sequential addition of finasteride, suggesting an additive 
effect of this combination.(16) In all of these studies, even though the combination was 
efficacious and well tolerated, the median age was 66 and the patients were fit with very
few other medical problems.
In the largest of these trials, CALGB 9782 (N= 99), the role of PAB (bicalutamide and 
finasteride) was evaluated in patients with biochemical relapse without 
radiographic
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evidence of disease. All patients had undergone prior definitive local therapy, had PSA 
between 1ng/mL and 10ng/mL, and their PSA doubling time was not calculated prior to 
enrollment as there was little understanding of the clinical relevance of this concept 
when the trial was designed.(17) A ≥80% PSA decline was seen in 96% patients, and 
the median time to PSA progression was 85 months. The toxicities were reported as 
mild.
1.2
University of Rochester – Peripheral Androgen Blockade 
Data
Based on the aforementioned clinical data of PAB, we examined retrospective data on 
elderly PCa patients (≥65 years) who were treated with PAB in lieu of ADT in the 
geriatric oncology clinic at the University of Rochester. The majority of these patients 
were treated on this regimen instead of ADT because they were deemed not fit for ADT
by their primary oncologists as a result of underlying health status issues (i.e., absolute
or relative contraindications to ADT) and these patients had no alternative treatment 
options. A retrospective analysis was performed subsequently to describe the 
characteristics and clinical outcomes of 21 elderly patients treated with PAB. The 
majority of these patients was considered either vulnerable or frail by validated 
comprehensive geriatric assessment (CGA) and therefore, at a very high risk for 
adverse effects from standard ADT. Reasons for not receiving ADT included cognitive 
impairment, multiple falls, and heart disease.
In this retrospective study, prostate cancer patients with asymptomatic hormonal naive
metastatic disease or biochemical recurrence with a short PSA doubling time (≤ 6 
months) were included. The median age at the start of PAB was 86 years. PSA 
response was seen in all patients treated with this combination with a median PSA 
decline of 92% from baseline. This PSA response lasted for a median of 10.5 months. 
None of the patients reported any major adverse effects or required treatment 
interruption while on this combination. This data was presented at the 2013 GU ASCO 
in Orlando, Florida and received general interest from oncologists managing elderly 
PCa patients.(18) For the first time, these results provide evidence that PAB is not only
feasible but also active and well tolerated in the vulnerable/frail older population.
Despite these results, there is still the need to establish a superior regimen with a
longer progression-free survival in an attempt to delay or possibly avoid ADT as
salvage therapy for these already vulnerable older men.
1.3
Rationale for Enzalutamide and 5 Alpha reductase 
inhibitor
Although treatment with bicalutamide and finasteride demonstrated clinical efficacy with
good tolerance in the elderly population, the median duration of PSA response was only
10.5 months. While PAB delayed the time to ADT in fit patients thereby preserving
their quality of life; PAB may be the only therapeutic option that many vulnerable
or frail patients could tolerate. Given the relatively brief duration of PSA response
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with bicalutamide and finasteride, there is a large unmet need for more effective novel 
therapies for elderly patients with hormonal naïve systemic prostate cancer.
Enzalutamide, unlike conventional antiandrogens, targets multiple steps in the androgen
receptor signaling pathway. It inhibits nuclear translocation of the androgen receptor, 
binding of androgen to the response elements, and coactivator recruitment.
Enzalutamide has greater affinity for the androgen receptor with greater antitumor 
efficacy in xenograft models as compared to conventional antiandrogens.(19, 20) 
Based on these data, a randomized phase 3 study (AFFIRM) was conducted to 
evaluate enzalutamide in patients with castrate resistant metastatic prostate cancer who
had progressed after chemotherapy. This study demonstrated a five month 
improvement in median overall survival in patients receiving enzalutamide compared to
placebo.(21) The median age of patients receiving enzalutamide was 69 years with 
24.9% of patients aged ≥75 years. Tolerance in all patients was reasonable.
Sternberg et al. presented the outcomes of elderly patients (>75 years) of this study at 
the GU ASCO 2013 annual meeting and concluded that enzalutamide was well 
tolerated with the most common adverse events being nausea and fatigue. However, 
this analysis did not describe underlying health status including falls, cognitive issues, 
and other complications which are present in many patients in this age range. (22) 
Recently, the preliminary results of a phase 2 trial that evaluated enzalutamide 
monotherapy in hormone naïve patients with systemic PCa were presented.(23) The 
median age in this study was 73 and all patients had ECOG performance status of 0.
However, underlying health status of these patients again was not described. At 25 
weeks of follow-up, the majority of patients had PSA responses- median PSA decrease
of 99.6% with good tolerance. The median time to disease progression had not been 
reached yet.
In the present study, either dutasteride or finasteride will be used as the 5-AR inhibitor 
for the PAB regimen. Dutasteride due to its higher potency in suppressing conversion of
testosterone to DHT (>90%) compared to that of finasteride (~70%) will be preferentially
considered. Dutasteride has a dual-enzyme inhibition mechanism that inhibits both type
1 and type 2 5-AR. Additionally, dutasteride has a much longer half-life when compared 
with finasteride (5 weeks vs. 5-6 hours). Previous studies have shown that dutasteride 
is well tolerated in older patients when used for chemoprevention.(24) The role of 
enzalutamide in combination with dutasteride and an LHRH agonist in the neoadjuvant 
setting is being evaluated in a phase 2 trial ( NCT01547299), which recently completed
accrual.
In the event, a trial eligible patients is unable to obtain dutasteride due to any reason 
including financial constraints, finasteride will be used as the 5-AR inhibitor for the PAB 
regimen. Finasteride is also well tolerated in older patients when used for 
chemoprevention.(25) Several phase 2 trials also noted the finasteride in combination
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with first generation non-steroidal antiandrogens is well tolerated and efficacious in the 
elderly.(17)
As the population is aging, we will continue to witness a rapid increase in the 
number of elderly PCa patients with systemic disease for whom the ideal 
treatment is not yet known. With the changing demographics, many clinical 
investigators are designing and conducting trials specifically to determine the best 
treatment for the elderly. The Food and Drug Administration (FDA) also recommends 
that drugs be studied in all age groups for which they will have significant utility, 
including the elderly, so that the true risks and benefits can be assessed. The purpose 
of adding a 5-AR inhibitor to an already potent antiandrogen is to maximize 
efficacy and prolong the duration of response, thereby delaying the time to 
progression. In the vulnerable and frail population, this combination may offer an 
opportunity for prolonged disease control as many of them may not be candidates for 
second line treatment after disease progression.
1.4
Utility 
of 
Comprehensive 
Geriatric 
assessment
Cancer is primarily a disease of the elderly, with individuals aged 65 years and over 
accounting for over 60% of all new cancers. Furthermore, 70% of cancer mortality 
occur in patients over the age of 65.(26) However there are only few evidence based 
guidelines to help manage these patients. Chronologic age and common assessment 
instruments in oncology (e.g., Karnofsky performance status) do not address critical 
geriatric domains that predict morbidity and mortality in the older patient (e.g., functional
status, comorbidity, social support). A prospective study of 500 older adults with 
cancer
demonstrated that traditional oncology functional assessment tools, including Karnofsky
performance score, could not identify older adults at risk for chemotherapy 
toxicity.
However, a predictive model that includes geriatric assessment questions could identify 
such individuals.(27) 
Despite the fact that the majority of cancer patients are in the older 
age groups, most oncologists have received little to no training in the care of older 
patients.(28) As a result, common problems facing an aging population of cancer 
patients may go unrecognized and have serious consequences.(29)
CGA includes a compilation of reliable and validated tools to assess geriatric domains 
such as comorbidity, functional status, physical performance, cognitive status, 
psychological status, nutritional status, medication review, and social support.(30-51) 
CGA can detect unsuspected conditions that may affect cancer treatment in more than 
50% of older patients.(52) CGA can help identify the vulnerable older individual who is 
likely to benefit from and tolerate standard therapy, as well as the seemingly fit older 
individual who is apt to experience undue side effects and requires a modified treatment
plan. Repetto et al. demonstrated that CGA added information to standard oncology 
performance measures, such as Karnofsky performance score, which is a one item 
measure of function that was validated in younger patients.(53, 54) CGA has 
great
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potential to identify areas of vulnerability and interventions that could help improve 
outcomes (e.g., reducing chemotherapy toxicity) in older cancer patients.(50, 55, 56) 
The initial study of this tool illustrated feasibility as demonstrated by a short mean time
to completion of 27 minutes. Furthermore, 90% of patients were satisfied with the 
questionnaire length and 78% were able to complete the self-administered portion on
their own.(57) CGA was also found to be feasible for use by the Cancer and Aging 
Leukemia Group-B (CALGB 360401).(55) Previous clinical studies, including the 
FOCUS 2 trial, have demonstrated that incorporating CGA can help better assess 
toxicities and aid with management decisions.(58) .
A comprehensive health assessment similar to the CGA was utilized in the study. 
Eligibility for the study was similar to that used in this study; patients were eligible if their
physicians deemed them not fit for standard therapy. Treatments were administered 
with an upfront dose reduction and escalated if the patient tolerated the first 
treatments.(58). Based on these data, the current study will incorporate CGA to assess
the safety profile and toxicities of the proposed PAB regimen in this older, more 
vulnerable study population.
2.0
OBJECTIVES
2.1
Primary 
Objective
• To determine the effect of the enzalutamide and 5-AR inhibitor on the time to 
PSA progression in patients aged 65 or older receiving this combination as first
line treatment for systemic prostate cancer
2.2
Secondary 
Objectives
• To evaluate the absolute PSA nadir as a result of combination treatment
• To determine the time to PSA nadir from the start of 
treatment
• To determine the safety and toxicities of the study drug combination
2.3
Tertiary Objectives 
(Exploratory)
• To determine if the study drug combination affects bone health
• To determine if the study drug combination affects comprehensive geriatric
assessment domains
• To determine if the study drug combination affects quality of life
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3.0
DRUG INFORMATION
Investigator’
s Brochures will be provided upon request (Appendix D).
3.1
Enzalutamide
3.1.1 Description
General: Enzalutamide is an androgen receptor inhibitor. The chemical name is 4-{
3-[
4-
cyano-3-(trifluoromethyl) phenyl]
-5, 5- dimethyl-4-oxo-2-ulfanylideneimidazolidin-1-yl}
-2-
fluoro-N-methylbenzamide. Enzalutamide is a white crystalline non-hygroscopic solid. It
is practically insoluble in water.
Molecular weight is 464.44
Molecular formula is C21H16F4N4O2S
3.1.2 Pharmacology
Mechanism of action: Enzalutamide is an androgen receptor inhibitor that acts on 
multiple steps in the androgen receptor signaling pathway. Enzalutamide has been 
shown to competitively inhibit androgen binding to androgen receptors and inhibit 
androgen receptor nuclear translocation and interaction with DNA. A major metabolite,
N-desmethyl enzalutamide, exhibited similar in vitro activity to enzalutamide.
Enzalutamide decreased proliferation and induced cell death of prostate cancer cells in
vitro and decreased tumor volume in a mouse prostate cancer xenograft model.
Pharmacokinetics: Data indicate the pharmacokinetics of enzalutamide and its major 
active metabolite (N-desmethyl enzalutamide) evaluated in patients with metastatic 
castration-resistant prostate cancer and healthy male volunteers note a linear two- 
compartment model with first-order absorption. The median time to reach maximum 
plasma enzalutamide concentrations (Cmax) is 1 hour (range 0.5 to 3 hours).With the 
daily dosing regimen, enzalutamide steady state is achieved by Day 28, and 
enzalutamide accumulates approximately 8.3-fold relative to a single dose. Daily 
fluctuations in enzalutamide plasma concentrations are low (mean peak-to-trough ratio 
of 1.25). At steady state, enzalutamide showed approximately dose proportional 
pharmacokinetics over the daily dose range of 30 to 360 mg. A single 160 mg oral dose
was administered to healthy volunteers with a high-fat meal or in the fasted condition. A
high-fat meal did not alter the AUC to enzalutamide or N-desmethyl enzalutamide.
Enzalutamide is 97% to 98% bound to plasma proteins, primarily albumin. N-desmethyl 
enzalutamide (active metabolite) is also 95% bound to plasma proteins. Following single
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oral administration of 14C-enzalutamide, its metabolites were detected up to 77 days 
post dose. In vitro, human CYP2C8 and CYP3A4 are responsible for the metabolism of 
enzalutamide. Based on in vivo and in vitro data, CYP2C8 is primarily responsible for 
the formation of the active metabolite (N-desmethyl enzalutamide). Enzalutamide is 
primarily eliminated by hepatic metabolism. The mean terminal half-life (t1/2) for 
enzalutamide in patients after a single oral dose is 5.8 days (range 2.8 to 10.2 
days).
3.1.3 Toxicology
Animal studies
Long-term animal studies have not been conducted to evaluate the carcinogenic 
potential of enzalutamide. Enzalutamide did not induce mutations in the bacterial 
reverse mutation (Ames) assay and was not genotoxic in either the in vitro mouse 
lymphoma thymidine kinase (Tk) gene mutation assay or the in vivo mouse 
micronucleus assay. Based on nonclinical findings in repeat-dose toxicology studies, 
which were consistent with the pharmacological activity of enzalutamide, male fertility 
may be impaired by treatment. In a 26-week study in rats, atrophy of the prostate and 
seminal vesicles was observed at ≥ 30 mg/kg/day (equal to the human exposure based 
on AUC). In 4 and 13-week studies in dogs, hypospermatogenesis and atrophy of the 
prostate and epididymitis were observed at ≥ 4 mg/kg/day (0.3 times the human 
exposure based on AUC).
3.1.4 Adverse Events
Adverse Events with Possible Relationship to Enzalutamide
Likely (>20%)
Less Likely (≤20%)
Rare but 
Serious 
(<3%)
Asthenic conditions
Peripheral edema
Seizure
Back pain
Musculoskeletal pain
PRES
Arthralgia
Muscular weakness
Diarrhea
Hypertension
Hot flush
Headache
Dizziness
Paraesthesia
Spinal cord compression and cauda equina
syndrome
Upper respiratory tract infections
Insomnia
Neutropenia
ALT elevation
Elevation in bilirubin
Hematuria
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PRES:posterior reversible encephalopathy syndrome
3.1.5 Pregnancy
Enzalutamide can cause fetal harm when administered to a pregnant woman based on 
its mechanism of action and is contraindicated in women who are or may become 
pregnant. Sexually active men with partners in child bearing age group are 
recommended contraceptive use when taking this medication.
3.2
Dutasteride
3.2.1 Description:
General: Dutasteride is chemically designated as (5α
, 17β
)-N-{
2,5 
bis(trifluoromethyl)phenyl}
-3-oxo-4-azaandrost-1-ene-17-carboxamide. Dutasteride is a
white to pale yellow powder with a melting point of 242° to 250°C. It is soluble in ethanol
(44 mg/mL), methanol (64 mg/mL), and polyethylene glycol 400 (3 mg/mL), but it is 
insoluble in water.
Molecular weight of 528.5 
Molecular formula: 
C27H30F6N2O2
3.2.2 Pharmacology
Mechanism of action: Dutasteride inhibits the conversion of testosterone to DHT. DHT is
the androgen primarily responsible for the initial development and subsequent 
enlargement of the prostate gland. Testosterone is converted to DHT by the enzyme 5-
AR, which exists as 2 isoforms, type 1 and type 2. The type 2 isoenzyme is primarily 
active in the reproductive tissues, while the type 1 isoenzyme is also responsible for 
testosterone conversion in the skin and liver. Dutasteride is a competitive and specific 
inhibitor of both type 1 and type 2, 5-AR isoenzymes, with which it forms a stable 
enzyme complex. Dissociation from this complex has been evaluated under in vitro and
in vivo conditions and is extremely slow. Dutasteride does not bind to the human 
androgen receptor.
Pharmacokinetics: Following administration of a single 0.5-mg dose of a soft gelatin 
capsule, time to peak serum concentrations (Tmax) of dutasteride occurs within 2 to 3 
hours. Absolute bioavailability is approximately 60% (range: 40% to 94%). When the 
drug is administered with food, the maximum serum concentrations were reduced by 
10% to 15%. This reduction is of no clinical significance. Pharmacokinetic data following
single and repeat oral doses show that dutasteride has a large volume of distribution 
(300 to 500 L). Dutasteride is highly bound to plasma albumin (99.0%) and alpha-1 acid
glycoprotein (96.6%). The maximum effect of daily doses of dutasteride on the reduction
of DHT is dose dependent and is observed within 1 to 2 weeks.
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In vitro studies showed that dutasteride is metabolized by the CYP3A4 and CYP3A5 
isoenzymes. Both of these isoenzymes produced the 4′
-hydroxydutasteride, 6- 
hydroxydutasteride, and the 6, 4′
-dihydroxydutasteride metabolites. In addition, the 15- 
hydroxydutasteride metabolite was formed by CYP3A4. In human serum following 
dosing to steady state, unchanged dutasteride, 3 major metabolites (4′
- 
hydroxydutasteride, 1,2-dihydrodutasteride, and 6-hydroxydutasteride), and 2 minor 
metabolites (6,4′
-dihydroxydutasteride and 15-hydroxydutasteride), as assessed by 
mass spectrometric response, have been detected.
Dutasteride and its metabolites were excreted mainly in feces. As a percent of dose, 
there was approximately 5% unchanged dutasteride (~1% to ~15%) and 40% as 
dutasteride-related metabolites (~2% to ~90%). Only trace amounts of unchanged 
dutasteride were found in urine (<1%). Following daily dosing, dutasteride serum 
concentrations achieve 65% of steady-state concentration after 1 month and 
approximately 90% after 3 months. Due to the long half-life of dutasteride, serum 
concentrations remain detectable (greater than 0.1 ng/mL) for up to 4 to 6 months after
discontinuation of treatment. The terminal elimination half-life of dutasteride is 
approximately 5 weeks at steady state.
3.2.3 Toxicology
Animal studies
A 2-year carcinogenicity study was conducted in B6C3F1 mice at doses of 3, 35, 250, 
and 500 mg/kg/day for males and 3, 35, and 250 mg/kg/day for females; an increased 
incidence of benign hepatocellular adenomas was noted at 250 mg/kg/day (290-fold the 
MRHD of a 0.5-mg daily dose) in female mice only. Two of the 3 major human 
metabolites have been detected in mice. The exposure to these metabolites in mice is 
either lower than in humans or is not known. Dutasteride was tested for genotoxicity in a 
bacterial mutagenesis assay (Ames test), a chromosomal aberration assay in CHO cells
and a micronucleus assay in rats. The results did not indicate any genotoxic potential of 
the parent drug. Two major human metabolites were also negative in either the Ames 
test or an abbreviated Ames test.
Treatment of sexually mature male rats with dutasteride at 0.1-to 110-fold the MRHD 
(animal doses of 0.05, 10, 50, and 500 mg/kg/day for up to 31 weeks) resulted in dose- 
and time-dependent decreases in fertility; reduced cauda epididymal (absolute) 17 
sperm counts but not sperm concentration (at 50 and 500 mg/kg/day); reduced weights 
of the epididymis, prostate, and seminal vesicles; and microscopic changes in the male 
reproductive organs. The fertility effects were reversed by recovery week 6 at all doses, 
and sperm counts were normal at the end of a 14-week recovery period.
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3.2.4 Adverse Events
Adverse Events with Possible Relationship to Dutasteride
Likely (>20%)
Less Likely (≤20%)
Rare but Serious
<3%)
Impotence
Angioedema
Libido decreased
Cardiac failure,
Ejaculation disorders
Depressed mood
Gynecomastia (including breast 
tenderness, and breast enlargement)
Dizziness
Localized 
hypersensitivity
Pruritus, rash, skin
reactions
Urticaria
TSH increased
3.2.5 Pregnancy
Pregnancy Category X. Dutasteride is contraindicated for use in women of childbearing
potential and during pregnancy. Sexually active men with partners in child bearing age
group are recommended contraceptive use when taking this medication.
3.3
Finasteride
3.3.1 Description:
General: Finasteride is 4-azaandrost-1-ene-17-carboxamide, N-(1,1-dimethylethyl)-3- 
oxo-,(5α
,17β
)-. 
Finasteride is a white crystalline powder with a melting point near 250°C.
It is freely soluble in chloroform and in lower alcohol solvents, but is practically insoluble
in water
Molecular weight of 372.55. 
Molecular formula: C23H36N2O2
3.3.2 Pharmacology
Mechanism of action: Finasteride is a competitive and specific inhibitor of Type II 5α
-
reductase with which it slowly forms a stable enzyme complex. Turnover from this
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complex is extremely slow (t½ ∼ 30 days). This has been demonstrated both in vivo 
and in vitro. Type II 5α
-reductase metabolizes testosterone to DHT in the prostate 
gland, liver and skin. DHT induces androgenic effects by binding to androgen receptors 
in the cell nuclei of these organs.
Pharmacokinetics: The mean bioavailability of finasteride 5-mg tablets was 63% (range
34-108%), based on the ratio of area under the curve (AUC) relative to an 
intravenous
(IV) reference dose. Maximum finasteride plasma concentration averaged 37 ng/mL 
(range, 27-49 ng/mL) and was reached 1-2 hours postdose. Bioavailability of finasteride
was not affected by food. Mean steady-state volume of distribution was 76 liters (range,
44-96 liters). Approximately 90% of circulating finasteride is bound to plasma proteins. 
There is a slow accumulation phase for finasteride after multiple dosing.
Finasteride is extensively metabolized in the liver, primarily via the cytochrome P450 
3A4 enzyme subfamily. Two metabolites, the t-butyl side chain monohydroxylated and 
monocarboxylic acid 10 metabolites, have been identified that possess no more than 
20% of the 5α
-reductase inhibitory activity of finasteride. In healthy young subjects 
(n=15), mean plasma clearance of finasteride was 165 mL/min (range, 70-279 mL/min)
and mean elimination half-life in plasma was 6 hours (range, 3-16 hours). Following an
oral dose of 14C-finasteride in man (n=6), a mean of 39% (range, 32-46%) of the dose
was excreted in the urine in the form of metabolites; 57% (range, 51-64%) was excreted
in the feces.
The mean terminal half-life of finasteride in subjects ≥70 years of age was 
approximately 8 hours (range, 6-15 hours; n=12), compared with 6 hours (range, 4-12
hours; n=12) in subjects 45-60 years of age. As a result, mean AUC(0-24 hr) after 17
days of dosing was 15% higher in subjects ≥70 years of age than in subjects 45-60 
years of age (p=0.02).
3.3.3 Toxicology
Animal studies
No evidence of a tumorigenic effect was observed in a 24-month study in Sprague- 
Dawley rats receiving doses of finasteride up to 160 mg/kg/day in males and 320 
mg/kg/day in females. These doses produced respective systemic exposure in rats of 
111 and 274 times those observed in man receiving the recommended human dose of 5
mg/day. All exposure calculations were based on calculated AUC(0-24 hr) for animals 
and mean AUC(0-24 hr) for man (0.4 μg•
hr/mL).
No evidence of mutagenicity was observed in an in vitro bacterial mutagenesis assay, a 
mammalian cell mutagenesis assay, or in an in vitro alkaline elution assay. In an in vitro 
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chromosome aberration assay, using Chinese hamster ovary cells, there was a slight 
increase in chromosome aberrations. These concentrations correspond to 4000-5000 
times the peak plasma levels in man given a total dose of 5 mg. In an in vivo 
chromosome aberration assay in mice, no treatment-related increase in chromosome 
aberration was observed with finasteride at the maximum tolerated dose of 250 
mg/kg/day (228 times the human exposure) as determined in the carcinogenicity 
studies. In sexually mature male rabbits treated with finasteride at 543 times the human 
exposure (80 mg/kg/day) for up to 12 weeks, no effect on fertility, sperm count, or 
ejaculate volume was seen.
3.3.4 Adverse Events
Adverse Events with Possible Relationship to Fuinasteride
Likely (>20%)
Less Likely (≤20%)
Rare but Serious
<3%)
Orthostatic hypotension
Angioedema
Dizziness
Cardiac failure,
Ejaculation disorders
Depressed mood
Decreased libido
Altered mental 
status
Gynecomastia (including breast 
tenderness, and breast enlargement)
Localized 
hypersensitivity
Pruritus, rash, skin
reactions
Urticaria
3.3.5 Pregnancy
Pregnancy Category X. Finasteride is contraindicated for use in women of childbearing
potential and during pregnancy. Sexually active men with partners in child bearing age
group are recommended contraceptive use when taking this medication.
3.4
Blood 
Donation
Men being treated with study drugs should not donate blood until at least 6 months have
passed following their last dose. The purpose of this deferred period is to prevent 
administration of study drug to a pregnant female transfusion recipient, for which this 
drug is not safe.
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3.5
Selection of Doses Used in the Study
The recommended dose of enzalutamide is 160 mg/day based on the data from 
several trials. The durability of disease suppression was similar between the 150 
mg/day and the 240 mg/day dose cohorts in post-chemotherapy patients in the Phase 
1-2 study.(59) 
Given 
this 
comparable efficacy, 
with dose-dependent increases 
of Grade
3 fatigue (0% at 150 mg/day vs. 9% at 240 mg/day), and reports of seizure at high 
doses (one witnessed event at 360 mg/day and another at 600 mg/day), a dose of 160 
mg/day was believed to have the optimal risk/benefit profile and was selected for 
investigation in a phase 3 randomized double blind trial (AFFIRM). (21) The results of
this trial indicated efficacy with good tolerance, therefore based on all the above data, 
we 
plan 
to 
use 
the 
recommended 
dose 
of 
enzalutamide 
160 
mg/day 
for the 
current 
trial.
The recommended dose of dutasteride is 0.5 mg/day. The current dose is selected 
based upon the results of a placebo controlled phase III study in patients with benign 
prostate hypertrophy in which dutasteride 0.5 mg administered once daily.(60) This 
dose was well tolerated by patients in the study, including those in the older population.
The recommended dose of finasteride is 5mg/day. The current dose is selected based 
upon the results of placebo controlled study( PLESS) in which finasteride 5mg was 
administered once daily.(61) Similar dosage was also evaluated in combination with 
first generation antiandrogens and was noted to be well tolerated and 
efficacious.(16)
4.0
STAGING CRITERIA
The AJCC Seventh Edition, 2010 will be used in evaluating patients by the treating 
investigators for staging purposes.
5.0
SELECTION 
OF STUDY POPULATION
5.1
Eligibility Criteria
The study population will include men aged 65 years and older with hormonally naïve, 
progressive, 
systemic 
PCa 
(either 
biochemical 
recurrence 
with 
a 
PSA 
doubling 
time 
of 
<9
months or hormonal naive metastatic disease confirmed by imaging) who are not 
candidates for treatment with ADT because the anticipated risk of ADT may outweigh 
the potential benefits as determined by the treating physician. The treating physician
will determine whether the patient would have a high risk of side effects from standard 
ADT. This 
eligibility criteria 
has been 
incorporated 
previously 
in other clinical 
trials
focused on cancer treatment in the elderly, such as the FOCUS-2 trial which used 
this eligibility to enroll older patients with advanced colorectal cancer for dose-modified 
chemotherapy.(58) Physicians in the FOCUS2 trial deemed the patient “
not fit”
 
for
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standard of care therapy as part of the eligibility criteria for enrollment. In the current trial
case report forms (CRF) will be record details as to why each patient was considered for
the trial and not ADT.
Each of the criteria in the following section must be met in order for a patient to be
considered eligible for registration.
5.2
Inclusion 
Criteria
Patients must meet the following inclusion criteria:
5.2.1 Disease Related Criteria
1. Histologically 
or 
cytologically 
confirmed 
adenocarcinoma 
of 
the 
prostate 
without
neuroendocrine differentiation or small cell features.
2. Patients 
with 
systemic PCa 
as 
defined 
by 
either a) 
hormonal 
naïve 
metastatic 
PCa
with radiographic evidence of visceral or osseous metastasis or b) biochemical 
recurrence PCa that fulfills all of the following criteria:
• A 
minimum 
of 
three 
rising 
PSA 
levels 
with 
an 
interval 
of 
≥ 
1week 
between 
each
test.
• The 
PSA value at the screening visit should be ≥ 2 ng/ml.
• PSA doubling time ≤ 9 months.
3. Patients should be 65 years or older.
4. Patients who are deemed “
not fit”
 by CGA or at high risk for side effects from ADT
as determined by the treating physician. A case report form will be used to 
document the specifics of why each eligible patient is not considered an ideal
candidate for ADT.
5. Serum testosterone level > 1.7 nmol/L (50 ng/dL) at the screening visit (non-
castrate)
5.2.2 Prior Therapy Related 
Criteria
6
. Patients could have received hormonal therapy, (ADT), as part of definitive 
treatment for previous 
localized PCa. However, they should be off 
any 
hormonal
therapy for greater than six months prior to entry to clinical trial.
5.2.3 Clinical 
Criteria
7
. ECOG performance status of 0 to 2.
8
. Able to swallow the study drug and comply with study requirements.
5.3
Exclusion Criteria
Patients must NOT meet any of the following exclusion criteria:
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5.3.1 Disease Related Criteria
1. Severe concurrent disease or infection that, in the judgment of the investigator,
would make the patient inappropriate for enrollment.
2. Known brain metastases. Brain imaging studies are not required for eligibility if 
the patient has no neurologic signs or symptoms suggestive of brain metastasis.
However, if brain imaging studies are performed, they must be negative for 
disease.
3. Patient is receiving treatment for another active malignancy excluding localized
cutaneous squamous or basal cell carcinoma.
5.3.2 Prior Therapy Related 
Criteria
4. Prior treatment for systemic prostate cancer with the exception of single agent
first generation non-steroidal anti androgen( bicalutamide, flutamide and 
nilatumade), which they could have taken for up to 2 weeks prior to the start of
investigational combination. A washout period is not required.
5. Prior treatment with enzalutamide
6. Treatment with ADT, , ketoconazole, abiraterone, 5-AR inhibitors (finasteride, 
dutaster
ide), estrogens, or chemotherapy in an ad
juvant sett
ing w
ith
in 6 months of 
enrollment 
(Day 
1 
visit) or 
plans 
to 
initiate 
treatment 
with 
any 
of 
these 
treatments.
7. Treatment with therapeutic immunizations for prostate cancer (e.g., 
PROVENGE®) 
or 
plans 
to 
initiate 
treatment 
with 
any 
of 
these treatments during
the study period.
8. Use of herbal products that may decrease PSA levels (e.g., saw palmetto) or
systemic corticosteroids greater than the equivalent of 10 mg of 
prednisone/prednisolone per day within 4 weeks of enrollment (Day 1 visit) or
plans to initiate treatment with any of these treatments during the 
study.
9. Radiation 
therapy 
within 
3 
weeks 
(if 
single 
fraction 
of 
radiotherapy 
within 
2 
weeks)
and radioisotope therapy within 8 weeks of enrollment (Day 1 visit).
10.Participation in a previous clinical trial of an investigational agent that blocks
androgen synthesis within six months.
11.Participation in a previous clinical trial of enzalutamide.
12.Use 
of 
an 
investigational 
agent 
within 
4 
weeks 
of 
enrollment 
(Day 
1 
visit) 
or 
plans
to initiate treatment with an investigational agent during the study.
13.Concomitant use of strong or moderate CYP2C8 or CYP3A4 inhibitors or
inducers for subjects receiving dutasteride as the 5ARI (see Appendix F)
5.3.3 Clinical/Laboratory 
criteria
14.History of seizure, including any febrile seizure, loss of consciousness, or 
transient ischemia attack within 12 months of enrollment (Day 1 visit), or any
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condition that may pre-dispose to seizure (e.g., prior stroke, brain arteriovenous
malformation, head trauma with loss of consciousness requiring hospitalization)
15.Clinically significant cardiovascular disease 
including:
• Myocardial 
infarction within 6 months
• Uncontrolled angina within 3 months
• Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or
patients with history of congestive heart failure NYHA class 3 or 4 in the past,
unless a screening echocardiogram or multi-gated acquisition scan (MUGA)
performed within 3 months results in a left ventricular ejection fraction that is ≥
45%
• Hypotension (systolic blood pressure < 86 millimeters of mercury [mmHg] or
bradycardia with a heart rate <
 50 beats per minute;
• Uncontrolled hypertension as indicated by a resting systolic blood pressure of
170 mmHg or diastolic blood pressure > 105 mmHg at the Screening or Study
Day 1 visit;
16.Gastrointestinal disorder affecting absorption (e.g., gastrectomy, active peptic ulcer
within last 3 months)
17.Major 
surgery within 4 weeks prior to enrollment (Day 1 visit)
18.Absolute neutrophil count <
 1,500/µL, platelet count <
 100,000/µL, and 
hemoglobin < 5.6 mmol/L (9 g/dL) at the Screening visit; (NOTE: patients may not
have received any growth factors or blood transfusions within 7 days of the 
hematologic laboratory values obtained at the Screening visit)
5.4
Regulatory 
Criteria
Patients or their legally authorized representative must be informed of the 
investigational nature of this study and must sign and give written informed consent in 
accordance with institutional and federal guidelines. Voluntary written informed consent 
must be obtained before registration or performance of any study-related procedure not 
part of normal medical care, with the understanding that the patient may withdraw 
consent at any time without prejudice to future medical care.
6.0
OVERALL 
STUDY 
DESIGN 
AND 
PLAN
This study is a phase 2 open label efficacy and safety clinical trial evaluating the 
combination of oral enzalutamide (160 mg/day) and a 5-ARI either dutasteride (0.5 
mg/day) or finasteride (5mg/day)in patients with systemic PCa. The study will enroll
patients at two sites: University of Rochester Medical Center and the clinical cancer
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center at the Froedtert &
 Medical College of Wisconsin. Approximately 40 patients will 
be enrolled.
Patients will receive study treatment until disease progression is documented and 
confirmed as defined by 1) PSA rise with or without radiographic evidence of disease 
progression or 2) the occurrence of a skeletal-related event. The occurrence of an 
adverse event, where continued administration of study drug is deemed not in the 
patient'
s 
best 
interest 
by 
the 
investigator 
and/or 
the 
sponsor, 
will 
also 
result 
in 
the 
removal
of the patient from therapy. All patients will be treated with the study drug for a minimum 
of 12 weeks before assessment for disease progression unless the patient develops 
significant treatment-related toxicity or worsening symptoms due to rapid disease 
progression.
The consensus guidelines of the Prostate Cancer Clinical Trials Working Group 2 have 
been taken into consideration for the determination of disease progression in the 
study.(62) Disease progression based on PSA is defined as an increase in the PSA that 
is ≥25% and ≥ 2ng/ml above the nadir PSA value. A confirmatory PSA is required three 
or more weeks later and it should demonstrate persistent elevation. Patients should 
continue 
on 
study treatment 
until 
this 
confirmatory 
PSA testing 
is 
performed 
to 
document 
PSA 
progression. Radiographic 
disease 
progression 
is 
defined 
by 
Response 
Evaluation 
Criteria in Solid Tumors (RECIST 1.1) (Appendix B) for soft tissue disease or the 
appearance of two or more new bone lesions on bone scan.
The following assessments will be performed during the course of the clinical trial as 
detailed in section 8.0: soft tissue and visceral disease on computed tomography (CT) 
scan or on magnetic resonance imaging (MRI), bone disease on radionuclide bone 
scans, skeletal related events, analgesics use, Comprehensive Geriatric Assessment, 
Functional Assessment of Cancer Therapy-Prostate (FACT-P) and PSA. Radiologic 
studies will be read on site. Each site will ideally designate the same radiologist who will 
evaluate the images for any one patient for the duration of the trial. Repeat imaging for 
assessment of radiographic progression 
is 
not required once radiographic progression 
is 
determined.
Patients 
without 
radiographic 
evidence 
of 
metastatic 
disease 
at 
the 
time 
of 
enrollment 
will
obtain repeat imaging only at the time of documented PSA progression or as clinically 
indicated. For patients with radiographic evidence of metastatic disease at enrollment, 
disease assessment with radiographic studies should be performed as detailed in section
8.0 
and 
may 
be 
performed 
more frequently 
if 
clinically 
indicated. Chest 
imaging 
may 
include either chest X-ray or CT chest at the discretion of the treating 
physician.
CGA 
will 
be 
used 
to 
capture 
baseline 
heath 
status 
prior 
to 
treatment 
and 
repeated 
at 
pre- 
specified 
intervals 
to document 
toxicities 
related 
to treatment 
and 
to assess 
any 
changes 
in functional status from baseline. A geriatric oncologist or his/her designee at each 
respective institution will administer CGA.
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Forty patients will be recruited and treated until disease progression or meeting any 
reason for removal from treatment (see section 7.4). The primary efficacy end-point for 
this 
trial 
is 
PSA 
progression-free 
survival 
(PFS), 
which 
is 
defined 
as 
the 
length 
of 
time that 
a given subject will be alive and free from PSA progression as defined above in section 
6.0.
Throughout the study, safety and tolerability of study treatment will be assessed by the 
monitoring of adverse events, vital signs, physical examinations, and laboratory studies
per 
study 
calendar. 
The 
PI 
will 
monitor 
safety 
data 
on 
an 
ongoing 
basis. 
Patients 
will 
have
a Safety Follow-up visit 30 days after their last dose of study drug or prior to the initiation 
of another systemic antineoplastic therapy, whichever occurs first. Serious adverse 
events will be collected for 30 days after the patient'
s last dose of study drug. After 
treatment discontinuation, subsequent antineoplastic therapy and survival status will be
assessed.
7.0
TREATMENT PLAN
For treatment or dose modification related questions, please contact Chunkit Fung, MD
(E-mail: chunkit_fung@urmc.rochester.edu or Phone: (585) 273-5468)
7.1
Treatment
All patients will receive either a combination of enzalutamide 160 mg oral daily and 
dutasteride 0.5 mg oral daily or enzalutamide 160 mg oral daily and finasteride 5 mg 
oral daily until disease progression or other reasons for removal from treatment protocol.
(see section 7.4). The type of 5-AR inhibitor used for each patient will depend on 
insurance 
approval. 
Dutasteride 
will 
be the 5AR-Inhibitor of 
choice given its 
slightly better
efficacy. If for any reason dutasteride cannot be obtained, finasteride would be 
administered.
7.2
Prior and Concomitant 
Therapy
All concomitant medication(s) including any medications taken within four weeks prior to
the Day 1 visit will be collected. Concomitant medications include all vitamins, herbal 
remedies, over the counter, and prescription medications. Intermittent or as needed 
(prn) use of any medication during the study indicates the possible occurrence of an 
adverse event and must be noted as such and be recorded.
7.2.1 Prohibited Medications
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The following medications are prohibited within 4 weeks prior to the start of study
drug treatment and are prohibited during the course of the study:
•Chemotherapeutic, immunotherapeutic and biologic agents
•Systemic glucocorticoids greater than the equivalent of 10 mg per day of
prednisone/prednisolone (unless needed for stress steroids or to treat
presumed adrenal insufficiency)
•Estrogens
•Herbal 
medications that may affect PSA levels (i.e., saw palmetto)
•Androgens (testosterone, dihydroepiandrosterone [DHEA]
, etc.).
Use 
of 
bisphosphates 
or 
rank-ligand 
inhibitor 
is 
allowed 
but 
doses 
should 
be 
documented during the study period.
The 
use 
of 
strong 
or 
moderate 
CYP2C8 
or 
CYP3A4 
inducers 
or 
inhibitors 
(see
Appendix F) is prohibited while on study for patients receiving 
dutasteride.
Patients on therapies known to be weak inhibitors/inducers or narrow-therapeutic-
index 
substrates 
of 
CYP2C8 
or 
CYP3A4 
should 
be 
evaluated 
for 
clinically 
significant
drug interactions, but may participate in the study with appropriate monitoring and
management.
Deviation from the above guidelines should occur only if absolutely necessary for the
well-being of the patient. Any deviations to the medication/treatment guidelines are to
be recorded.
7.2.2 Permitted Medications
Patients are allowed to take prescription medications as long as they are not considered
to interact with the study drug as listed in the prohibited medication list. All prescription 
medications should be reported to the study personnel. Patients concomitantly using 
warfarin will need to have their INR monitored closely.
7.2.3 Non Drug Therapies
Patients are allowed to take over the counter supplements, including multivitamins. All
non-prescription therapies should be reported to the study personnel
7.3
Treatment Compliance
Study drug accountability will be performed at pre-specified study visits to document
compliance 
with 
the 
dosing 
regimen. 
Patients 
will 
be 
asked 
to 
bring 
back 
all 
remaining
study drug and all study drug packaging at the beginning visit of each cycle for drug
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accountability. 
Treatment 
compliance 
will 
be 
defined 
as 
the 
number 
of 
capsules 
taken 
during the study divided by the expected number of capsules, multiplied by 100%. 
Capsules 
that 
are 
not 
returned 
will 
be 
considered 
to 
have 
been 
taken, 
unless 
otherwise
specified. Compliance will be assessed at each specified visit by review of a pill diary
and/or by questioning patients as to compliance. Compliance will be recorded in the
source documentation.
7.4
Criteria 
for 
Removal 
from 
Protocol 
Treatment
• Disease progression as defined by 1) PSA rise with or without radiographic 
evidence of disease progression or 2) the occurrence of a skeletal-related event
(see section 6.0)
• Unacceptable toxicity very likely related to study 
drugs
• Off study treatment for ≥ 30 
days
• Initiation of new systemic treatment for 
PCa
• The patient may withdraw from the study at any time for any reason
• Death
• Product not available
• Lost to follow-up
• Decision by 
sponsor
7.5
Treatment Discontinuation
Patients 
will 
be 
advised 
in 
the 
written 
informed 
consent 
form that 
they 
have 
the 
right 
to withdraw from study drug treatment at any time without prejudice, or may be 
withdrawn at any time at the discretion of the investigator or the sponsor. If 
medically 
indicated, 
the investigator 
or 
the 
sponsor 
may 
withdraw 
study drug 
from 
a 
patient in the event of an intercurrent illness, adverse event, other reasons 
concerning the health or well-being of the patient, or in the case of lack of 
cooperation, non-compliance, protocol violation, or other administrative 
reasons.
Patients removed from therapy for any reason should continue to be followed for
the 
collection 
of 
safety 
data as 
outlined 
in 
the 
adverse 
event 
reporting 
section 
and
the Safety follow-up visit 
procedures. For patients who decline further 
clinic study 
visits, telephone contact should be attempted to review for adverse events 30 
days after the last dose of study drug or prior to the initiation of another systemic 
antineoplastic therapy, whichever occurs first. All serious adverse events will be
followed until resolution, until the event has stabilized and/or become chronic, 
until it has been determined that the event was caused by an etiology other than 
the study drug, or through 30 days, whichever comes first.
Reasonable effort should be made to contact any patient lost to follow-up during the
course of the study in order to complete study-related assessments and retrieve any
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outstanding data and 
study drug. Following unsuccessful telephone contact, an effort 
to 
contact the patient by mail using a method that provides proof of receipt should be 
attempted. 
Such 
efforts 
should 
be 
documented 
in 
the 
source 
documents. 
All 
reasons 
for 
discontinuation of treatment must be documented.
7.6
Follow up Period
All patients will be followed until study closure, death, or patient’
s decision to withdraw
consent. Data will be collected at pre-specified intervals as detailed in the study 
calendar (see section 8.0) to assess safety and efficacy. After treatment 
discontinuation, subsequent antineoplastic therapy and survival status will be assessed
for the duration of follow up.
7.7
Unscheduled Visits
Unscheduled visits may be performed at any time during the study whenever necessary 
to assess for or follow-up on adverse events, at the patient'
s request, or as deemed 
necessary by the investigator. The date and reason for the unscheduled visit should 
be 
recorded in the source documentation. The following activities can be completed at 
unscheduled visits (other than those exclusively for return or re-supply of study 
drug):
• 12-lead ECG (if medically 
indicated);
• Vital signs (blood pressure, heart rate, respiratory rate, 
temperature);
• Laboratory assessment (hematology and 
chemistry);
• Enquire from the patient and record the time that study medication was taken on
the preceding 2 days;
• Brief history and physical examination; ECOG performance status;
• Record concomitant medications; Record adverse 
event
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2023
8.0
STUDY CALENDAR@
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 6
Cycle 7
Cycle 8
Cycle 9
β
W
W
W
W
W
W
W
W
W
W
W
W
Study Day α
PRE
STUD
Yα
1
3
7
13
19
25
37
49
61
73
85
97
FU Prior to
ProgressionΣ
∞,
Safety FU
Within 30
days after
last 
treatment
dose
FU After
ProgressionΦ
REQUIRED STUDIES
PHYSICAL
History and Physical
Exam
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight and 
Performance Status
X
X
X
X
X
X
X
X
X
X
X
X
X
x
X
Blood Pressure
X
X
X
X
X
X
X
X
X
X
X
X
X
x
X
Disease Assessment
X
X
X
X
X
X
X
X
X
X
X
X
Toxicity Notation
X
X
X
X
X
X
X
X
X
X
X
x
X
Comprehensive
Geriatric 
AssessmentΨ
X
X
X
X
x
LABORATORY
Serum PSA
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum Testosterone
X
X
X
X
X
Serum 
Dihydrotestosterone
X
X
X
CBC/Differential
/P
late
lets/Hemog
lob
i 
n
X
X
X
X
X
X
X
X
X
X
X
x
X
Comprehensive 
Metabolic Panel
X
X
X
X
X
X
X
X
X
X
X
x
X
X-RAY and SCANS
DEXAΩ
X
X
CT of Abdomen and
Pelvis≠
X
X
X
x≠
Bone scan≠
X
X
X
X≠
Chest Imaging≠
X
X
X
X≠
TREATMENT
Enzalutamide€
X
X
X
X
X
X
X
X
X
5-AR inhibitor€
X
X
X
X
X
X
X
X
X
Prophylactic Breast
Radiation¶
X
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2023
@ Study visits from the Covid-19 pandemic (starting in March 2020) and moving forward can be performed via telemedicine technology. Study team should adhere to study 
procedures as outlined by study calendar above except for weight and physical examination, including vital signs (e.g. temperature, heart rate, pulse oximetry, and respiratory rate). 
We expect subjects to report blood pressure measurements performed by themselves or care providers within +
- 7 days of study visit while on study treatment. Study drug may be 
shipped to patients undergoing a telemedicine visit.
α Except for week 1 visit, there is a window of +
/-4 weeks for subsequent follow up visits. Prestudy labs/visit to be no more than 3 weeks prior to cycle 1, Day 1 Pre enrollment scans 
must be obtained within 28 days of day1 treatment/
Σ Patients off protocol treatment secondary to reasons other than progression will have physical exams and PSA for disease assessment performed every 6 months for first year and 
as clinically indicated thereafter.
∞ Patients with stable disease and on protocol treatment beyond week 97 will be followed every 12 weeks until disease progression.
Φ After disease progression, follow-up will occur every 6 months (+
/- 2 months) for first year after disease progression and as clinically indicated thereafter. Each subsequent antineoplastic 
therapy and survival status are the only required data point following progression.
Ψ Comprehensive geriatric assessment (CGA) will be performed at baseline, end of cycle 1 and every 24 weeks during the study protocol until week 61 and at the time of progression.
FACT-P will be performed along with CGA
Ω DEXA scan must be obtained within 2 years prior to registration for all patients. Follow-up DEXA scans should be obtained after 2 years of protocol treatment for patients not 
receiving denosumab or bisphosphonates. DEXA scan is not indicated for those who are on treatment with bisphosphonates or denosumab.
≠
 For patients without radiographic evidence of metastatic disease at enrollment of study protocol, disease assessment with radiographic studies are not necessary unless there is 
evidence of PSA progression (see Section 6.0) or clinically indicated. For patients with radiographic evidence of metastatic disease at enrollment of study protocol, disease 
assessment with radiographic studies should be performed as indicated in the above study calendar and may be performed more frequently if clinically indicated by the same methods 
used at baseline. Chest Imaging may include either chest X-ray or CT chest at the discretion of the treating physician. After week 97, for patients with stable PSA, scans to be 
performed at the time of progression or as clinically indicated
€ Treatment will be given daily and will continue until disease progression or other reason for discontinuation of protocol treatment (see Section 7.4) Study drug will be dispensed every 
12 +
/- 4 weeks and a 120 day supply of medication will be provided at each 
visit.
¶
 This procedure is not mandatory but should be discussed with all patients enrolled in the protocol and can also be considered during the treatment course to prevent further
worsening of breast tenderness when considered appropriate..
Β
 Followed until death, study closure, or withdrawal of consent.
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9.0
END 
POINT 
DEFINITIONS: 
EFFICACY 
ASSESSMENT
9.1
Primary Efficacy Assessment
The primary efficacy assessment will be PSA PFS, which is defined as the length of 
time that a given subject will be alive and free from PSA progression. All patients will be
treated with the study drugs for a minimum of 12 weeks before assessment for disease
progression unless the patient develops significant treatment-related toxicity or 
worsening symptoms due to rapid disease progression. PSA progression will be 
defined according to the consensus guidelines of the Prostate Cancer Clinical Trials 
Working Group 2. For patients with a PSA decline at week 13 compared to the baseline
value at the time of enrollment, the PSA progression date will be defined as the first 
date (after week 13) when there is a ≥25% increase and an absolute ≥ 2ng/ml increase
in PSA compared to the PSA nadir. For patients with a PSA rise at week 13, the PSA 
progression date will be defined as the first date (before week 13) when there is a ≥ 
25% increase and an absolute increase of ≥ 2 ng/ml in PSA compared to the baseline 
value at the time of enrollment. A confirmatory PSA is required three or more weeks 
after the date of PSA progression and it should demonstrate persistent 
elevation.
9.2
Secondary Efficacy Assessments
9.2.1 Absolute PSA Response
Failure to achieve a PSA of ≤ 4 ng/ml after seven months of combined ADT has been
shown to be a negative predictor for survival in the SWOG 9346 trial.(63) We will report
the 
PSA 
nadir 
value 
after 
initiation 
of 
study 
drugs 
and 
measure 
the 
absolute 
and 
relative
PSA declines from the baseline PSA at the time of study enrollment.
9.2.2 Time to PSA Nadir
We will assess the time to PSA nadir, which is defined as the time to achieve the lowest
PSA value after initiation of study drugs. The prognostic significance of the time to PSA
nadir is yet to be defined but Choueiri et al. suggested that a faster time to reach a PSA
nadir 
after 
the 
initiation 
of ADT 
was 
associated 
with 
shorter 
survival 
duration 
in men 
with
hormonal naïve metastatic prostate cancer.(64)
9.2.3
Safety and 
Toxicity
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We will assess the safety and toxicity of this drug combination through routine history 
and physicals as well as serial monitoring of blood work, all of which will be recorded 
and reviewed periodically. Adverse events will be defined according to CTCAE version
4.0 (Appendix C).
9.3 Tertiary (Exploratory) Efficacy 
assessments
9.3.1 Change 
in 
Bone 
Health
ADT 
is 
known 
to effect 
bone 
strength. 
Compared 
to 
men 
with 
prostate 
cancer 
who 
do 
not 
receive treatment with ADT, patients with prostate cancer treated with ADT have a 13- 
30% 
increased 
risk 
of 
osteoporotic 
fractures.(65) 
Loss 
of 
lean 
muscle 
mass 
coupled 
with 
declined strength from ADT predisposes to a high risk of falls, which in the setting of 
osteoporosis 
leads 
to 
increased 
fracture 
risk. 
To 
determine 
the 
impact 
of 
study 
treatments 
of bone health, we will assess changes in bone density by comparing results of DEXA 
scans prior to and at the end of study treatment. To accurately examine their impact on 
bone health, only patients who are on the study drugs for at least 1 year will be included 
for this analysis. Additionally, due to the bone strengthening effects of bisphosphonates 
and denosumab, patients who receive these therapies will be excluded from this 
secondary endpoint analysis.
9.3.2 Change in CGA 
Domains
ADT, which includes orchiectomy or administration of GnRH agonists/antagonists, 
remains the mainstay of treatment for hormone naïve patients who present with 
biochemical 
recurrence 
or 
metastatic 
disease. 
Testosterone 
depletion 
secondary 
to 
ADT
causes a myriad of side effects, which include decreased libido, muscle strength, 
increased risk of falls and cognitive changes. All these changes have been well 
characterized 
and 
captured 
using 
a 
CGA 
in 
numerous 
studies. 
The 
current 
trial 
would 
be
utilizing periodic CGA to capture any side effects related to the study drug combination
that would otherwise not be recognized to provide a better understanding of the safety
profile of the drug combination specifically in the vulnerable/frail elderly 
population.
During 
geriatric 
assessments, 
the 
various 
domains 
as 
listed 
in 
the 
table 
below 
will 
be 
measured
DOMAIN
TOOL
SCORE SIGNIFYING
IMPAIRMENT
Physical function
 ADL
IADL
Any 
ADL 
or 
IADL
impairment
Fall history
 Any history of fall
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Objective physical
performance
SPPB
≤ 9
Comorbidity
Average number of
comorbid conditions
>5
Nutrition
BMI
MNA
<21
≤ 11
Social support
OARS Medical 
Social
Support
Any deficit 
noted
Polypharmacy
Number of 
tota
l
medications
≥5 medications
Psychological
GDS
> 5
Cognition
BOMC
MoCA
>10
<26
Screening
VES-13
≥3
ADL: 
Activity of 
daily living
GDS: Geriatric Depression scale
MNA: Mini 
nutritional assessment
IADL: 
Instrumental activity of daily living
SPPB: 
Short 
physical 
performance 
battery
BOMC: B
lessed or
ientat
ion-memory-concentrat
ion
BMI: Body mass index
MoCA: Montreal cognitive 
assessment
VES: Vulnerable elderly survey
In a study published by Bylow et al., fifty elderly men (>70 years) receiving ADT for 
systemic Pca(80% with biochemical recurrence), underwent CGA at baseline (while on 
ADT) 
and three months later. (10)Fall history in the study population 
was also recorded. 
All domains listed in the above table were assessed during these visits. Of the 50 men, 
24% 
had 
impairment 
in 
ADLs, 
42 
% had 
impairment 
in 
IADLs, 56% 
had abnormal 
SPPB 
findings 
and 
22 
% 
reported 
falls 
at 
the time 
of 
first assessment. Among 
the forty 
patients 
who completed the follow up CGA at 3 months, 20% had worsening SPPB scores and 
falls were common, even in patients with no prior falls. The results of this study 
demonstrated that a substantial number of of elder patients are vulnerable to frail at 
baseline, and are at risks of significant functional and physical decline after even short 
term ADT. This study also reiterates that CGA adds significant information in not only 
documenting baseline health status but is also instrumental in monitoring toxicities that 
would otherwise not be captured. More importantly, administration of serial CGA is 
feasible 
and 
hence, 
the 
current 
study 
will 
utilize 
serial 
CGA 
besides 
other 
tools 
to 
monitor 
adverse events
9.3.3
Quality of life assessments- Functional Assessment of Cancer Therapy - 
P
The FACT-P is a multidimensional, self-reported quality of life instrument 
specifically 
designed for use with prostate cancer patients. It consists of 27 core
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α
α
α
items which assess patient function in four domains: Physical, Social/Family, 
Emotional, and Functional well-being, which is further supplemented by 12 site 
specific items 
to assess for prostate 
related symptoms. Each item is rated on a 0 to 
4 Likert-type scale, and then combined to produce subscale scores for each 
domain, as well as a global quality of life score with higher scores representing 
better quality of life.
10.0 STATISTICAL CONSIDERATIONS
10.1 Primary End-Point
The primary efficacy end-point for this trial is PSA progression-free survival (PFS) 
defined as the length of time that a given subject will be alive and free from PSA 
progression. Median PSA-PFS and 1-year and 2-year PSA-PFS probabilities will be 
estimated using the Kaplan-Meier method, with 95% confidence intervals constructed
based on Greenwood’
s variance estimator, which is the default approach in SAS 9.3.
(66-68) 
Confidence 
intervals 
for 
the 
median 
are 
given 
by {t 
: 
Sˆ(t) 
− 
0.5}2 ≤ χ
2Vˆ[Sˆ(t)]},
where t represents all time points satisfying the inequality, Sˆ(t) is the Kaplan-Meier
estimate of PSA-PFS, χ
2 is a chi-square score with one degree of freedom
corresponding to the chosen confidence level (for 95% confidence χ
2 = 3.84 ), and
Vˆ[Sˆ(t)] is the Greenwood’
s variance estimator. [
64]
 Confidence intervals for the 1-year
and 2-year survival probabilities will be constructed as Sˆ(t) ±
 z Vˆ[Sˆ(t)]
1/ 2 , where z
α is
the standard normal score. (67)
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=00
.7
.2
14
× 
a
0n
.2
d8
1/
.9
46
0
It should be noted that in the absence of loss to follow-up (i.e., if vital status and PSA- 
progression status are known for each subject at the end of the study), Sˆ(t) 
coincides
with the observed proportion of subjects alive and without PSA progression by time t
and Vˆ[Sˆ(t)] 
coincides 
with 
the usual 
estimator 
of 
the 
variance 
of 
a 
sample 
proportion
Vˆ[Sˆ(t)] 
= 
[Sˆ(t)][1− 
Sˆ(t)]/ 
n , 
where n is 
the number 
of subjects 
in 
the 
study. [
65]
Sample size justification: The median PSA-PFS times under null and alternatives 
hypothesis are assumed to be 1.44 and 3.04 years (the corresponding 1 year PSA-PFS 
rates are 50% and 72% respectively). Based on this assumption, the one sample log- 
rank test shows that a sample size of n=36 has 82% power (two-sided test with
significance level 0.05) to reject the null hypothesis if the median survival time is at least
3.04years. Taking into account of withdrawal or loss to follow-up (no more than 10% for the first year),
we plan to recruit 40 patients in the study.
Expected margin of error (one-half of the confidence width) of the 95% confidence intervals for S (t) 
can
be approximated by1.96
. For 1-year and 2-year[S 
(t)][1 
− S 
(t)]/ n
PSA-PFS this gives 1.96
= 0.15 ,
respectively. In addition to the number and percentage of subjects alive and without PSA progression at 
1 and 2 years of follow-up, we will report separately numbers and percentages of subjects alive and with
PSA progression, dead without PSA progression, and dead with PSA progression. The causes of death 
and the incidence of clinical progression will also be reported.
10.2 Secondary End-Points
10.2.1 Decline in PSA from Baseline to 
Nadir
This will be expressed for each subjects in the absolute value and as percentage,
displayed for the entire study cohort as a water-fall plot, and summarized with the
median (with a 95% confidence interval), first and third quartiles, and the absolute
range.
10.2.2 Time to PSA Nadir
This will be expressed for each subjects as the absolute value, displayed for the entire 
study cohort as a water-fall plot, and summarized with the median (with a 95% 
confidence interval), first and third quartiles, and the absolute range.
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10.2.3 Safety and 
Toxicity
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This will be examined by documenting the type and grade of each adverse event (as 
defined by CTCAE, appendix C) at baseline and at each follow-up visit.(69) These data
will be summarized with counts and percentages. In addition, each grade 3 or 4 adverse
event will be described separately, and the plausibility of its causation by the study drug
combination will be discussed.
10.3 Tertiary 
Endpoints
10.3.1 Changes in Bone 
Health
This will be expressed as a difference between the mean T scores on bone 
densitometry at baseline and at 2 years of follow-up (Section 8.0). A 95% confidence 
interval for the difference will be constructed using the standard approach for paired 
measurements [
67]
. We will also compute the frequency and the percentage of subjects
with osteopenia (T score = -1.0 to -2.5) and osteoporosis (T score <
 - 2.5) at baseline 
and at 2 years of follow-up.
10.3.2
Changes in Comprehensive Geriatric 
Assessment
Analysis of this aim will be descriptive and will describe mean, median, standard 
deviations 
of scores at baseline and at 
follow up time points. CGA deficits over 6 months 
will 
be 
captured. Each 
domain 
will 
be 
evaluated 
individually 
and 
scores 
will 
be 
compared 
between baseline and 6 months. Overall CGA deficits will be examined and the 
proportion 
of 
patients 
who 
decline 
in 
more 
than 
1 
domain 
will 
be 
determined 
for 
these 
time 
points.
10.3.3 Quality of Life
This will be measured by the FACT-P tool. (70)For each of the 27 core items and 12 site- 
specific items, mean score for the study cohort will be computed at baseline and at 
specified follow-up visits (Section 8.0). These means will be plotted against follow-up 
time and visually assessed for evidence of an upward or a downward trend. For each 
item, an upward or a downward trend in mean scores over time will indicate 
improvement or deterioration in a given dimension of quality of life (i.e., the dimension 
measured by that item). Changes in mean scores from baseline will be calculated at 3 
months and at 6 months after therapy initiation and will be reported with 95% confidence 
intervals.
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11.0 Definition of an Adverse 
Event
An adverse event or experience is defined as any symptom, sign, illness, or untoward
experience 
(including 
a 
clinically significant laboratory 
finding classified as 
grade ≥ 
3 
by
the National Cancer Institute'
s Common Terminology Criteria for Adverse Events 
[CTCAE]
; 
appendix 
C) 
that 
develops 
or 
worsens 
during 
the 
course 
of 
the 
study, 
whether
or not the event is considered related to study drug. Any adverse event should be 
recorded only after the first dose of study drug is taken. Serious adverse events are 
recorded from the time the informed consent form is signed.
Where a diagnosis is possible, it is preferable to record it rather than a series of terms
relating to the diagnosis.
An abnormality identified during a medical test (e.g., laboratory parameter, vital sign,
ECG data, physical exam) should be defined as an AE only if the abnormality meets
one of the following criteria:
• Induces clinical signs or symptoms.
• Requires active 
intervention.
• Requires interruption or discontinuation of study medication.
• The abnormality or investigational value is clinically significant in the opinion
of the investigator.
All adverse events, whether or not related to the study drug, must be fully and 
completely documented.
Adverse events are detected in two ways:
•
Clinical: symptoms reported by the patient or signs detected on examination;
•
Ancillary 
Tests: 
clinically 
significant 
abnormalities 
of 
vital 
signs, 
ECG, 
laboratory
tests, and other diagnostic procedures.
An adverse event does not include:
•
Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, 
transfusion); 
however, 
the 
condition 
that 
leads 
to 
the procedure 
is 
an 
adverse 
event;
•
Pre-existing diseases or conditions present or detected prior to the start of study
drug administration that does not worsen;
•
Situations 
where 
an 
untoward 
medical 
event 
has 
not 
occurred 
(e.g., 
hospitalization
for elective surgery, social and/or convenience admissions);
•
Overdose 
of 
either 
study 
drug 
or 
concomitant 
medication 
without 
any 
signs/
symptoms
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Relationship to Study Drug: The reasonable possibility of an adverse event'
s 
relationship 
to 
study drug 
is 
to 
be assessed 
with 
careful 
medical 
consideration 
at the 
time 
of evaluation of the adverse event. The PI’
s opinion may be sought in those cases in 
which the Investigator is unable to make an independent judgment. The following 
definitions are to be used:
Descriptor
Definition
Unrelated
Adverse event is clearly not related to the investigational
drug (s)
Unlikely
Adverse event 
is 
doubtfully 
related 
to 
the investigational
drug (s)
Page 38 of 82
Possible
Adverse event is may be related to the investigational drug
(s)
Probable
Adverse event is likely related to the investigational drug (s)
Definite
Adverse 
event is clearly 
related to the investigational 
drug
(s)
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The 
following 
criteria 
will 
be 
used 
as 
guidelines 
for 
determining 
the 
attribution 
of 
an 
adverse event to the study drug:
Unrelated
There is no possible relationship to the study drug. The 
temporal relationship between drug exposure and the 
adverse 
event 
onset/course 
is 
unreasonable 
or 
incompatible,
or a causal relationship to study drug is implausible.
Unlikely
The study drug is believed to be not reasonably related to the
adverse 
event, 
although 
a 
causal 
relationship 
cannot 
be 
ruled
out. While the temporal relationship between drug exposure
and the adverse event onset/course does not preclude 
causality, 
there is 
a clear 
alternate cause that is more 
likely to
have caused the adverse event than the study drug.
Possible
The causal relationship to the study drug is uncertain. The
temporal relationship between drug exposure and the 
adverse event onset/course is reasonable or unknown, 
dechallenge 
or 
rechallenge 
information 
is 
either 
unknown 
or
equivocal, 
and 
while 
other 
potential 
causes 
may 
not 
exist, 
a
causal relationship to the study drug does not appear 
probable.
Probable
There is a high degree of certainty for a causal relationship 
between 
the study drug 
and the adverse 
event. 
The temporal
relationship between drug exposure and the adverse event 
onset/course is reasonable, there is a clinically compatible 
response 
to 
dechallenge, 
other 
causes 
have 
been 
eliminated,
and the event must be definitive pharmacologically or 
phenomenologically, using a satisfactory rechallenge 
procedure if necessary.
Definite
Causal relationship is certain. The temporal relationship 
between 
drug 
exposure 
and 
the 
adverse 
event 
onset/course
is reasonable, there is a clinically compatible response to 
dechallenge, other causes have been eliminated, and the 
event must be definitive pharmacologically or 
phenomenologically, using a satisfactory rechallenge
procedure if necessary.
In the event that a patient is withdrawn from the study because of an adverse event, it 
must 
be 
recorded. 
Adverse 
events 
will 
be 
monitored 
until 
resolution 
or 
until 
the event 
has 
stabilized and/or reached a new baseline. If an adverse event remains unresolved at the 
conclusion of the study, a clinical assessment will be made by the investigator to 
determine whether continued follow-up of the adverse event is warranted.
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The investigator must record all directly observed adverse events and all spontaneously 
reported adverse events. At each 
visit, the investigator will ask the patient 
a non-specific 
question (e.g., "Have you noticed anything different since your last visit?"
) to assess 
whether any adverse event has been experienced since the last report or visit. Adverse 
events will be identified and documented. The severity and the relationship to the study 
drug will be determined and reported.
Note 
that 
any 
intermittent 
or 
as 
needed 
use 
of 
any 
medication 
(and 
specifically 
any 
newly prescribed medication) during the course of a study may indicate the 
occurrence of an adverse event that may need to be recorded.
Serious 
adverse 
events 
will 
be 
collected 
and 
reported 
from the 
time the patient 
signs
the informed consent form until the Safety Follow-Up visit. Non-serious adverse 
events will be collected from the time of first study drug dosing until the Safety 
Follow-Up visit.
11.1 Adverse Events - Severity 
Rating
Sever
ity 
descr
ibes 
the 
intens
ity
 of a 
spec
if
ic event (as 
in 
m
i
ld, moderate, 
or severe 
chest pa
in); 
the event itself, however, may be of relatively minor medical sign
ificance (such as severe 
headache). This is not the same as "
serious,"
 which is based on patient/event outcome or 
action criteria. The severity of an adverse event will be graded following the CTCAE v4.0 
(appendix C).
11.2 Disease Progression as an Adverse Event
It is anticipated that a proportion of patients will experience disease progression. 
Disease 
progression per 
se 
should NOT 
be 
reported 
as an 
adverse 
event. If 
there
are separate ident
if
iab
le 
c
l
in
ica
l seque
lae that resu
lt from d
isease progress
ion, these
sequelae are reportable as adverse events.
11.3 Serious Adverse Events and Unexpected Adverse Events - 
Definitions
A 
Ser
ious 
Adverse Event 
or react
ion 
is 
any 
untoward 
med
ica
l 
occurrence 
at any 
dose 
that:
• Resu
lts in 
death;
• Is l
ife
 
threaten
ing 
(
i.e., the 
pat
ient was 
at immed
iate
 r
isk 
of death 
at 
the
time 
of 
the 
event). 
"
Life-threatening" 
does 
not 
include 
an 
event 
that
hypothetically 
might 
have 
caused 
death 
if 
it 
were 
more 
severe. 
For
example, 
drug-induced 
hepatitis 
that 
resolved 
without 
evidence 
of 
hepatic 
failure would not be considered life-threatening even though
drug-induced hepatitis can be fatal;
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• Requ
ires 
inpat
ient
 
hosp
ita
l
izat
ion 
or 
pro
longat
ion 
of 
ex
ist
ing
hospitalization;
• Resu
lts 
in 
pers
istent 
or 
s
ign
if
icant 
d
isab
i
l
ity/
incapac
ity 
(
i.e., 
a 
substant
ia
l
disruption 
of 
the 
patient'
s 
ability 
to 
carry 
out 
normal 
life 
functions);
• Is 
a 
congen
ita
l 
anoma
ly/b
irth 
defect.
In 
addition, medical 
and 
scientific judgment 
should 
be exercised 
in 
deciding 
whether 
other 
s
ituat
ions 
shou
ld 
be 
cons
idered 
a 
ser
ious 
adverse 
event 
(
i.e., 
important
 
med
ica
l 
events 
that 
may not be immed
iate
ly
 l
ife-threaten
ing
 or resu
lt in death, but may jeopard
ize 
the pat
ient 
or 
may require medical or surgical intervention to prevent one of the other outcomes listed in 
the definition above). Examples of such medical events include (but are not limited to): 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in in-patient hospital
ization, or the 
deve
lopment 
of 
drug 
dependency 
or 
drug abuse. 
In 
th
is 
study, 
a 
documented 
se
izure 
shou
ld 
be reported as a medically important serious adverse event.
11.4 Serious Adverse Events - 
Reporting
The study team should report serious adverse events (SAEs) to the DSMC using the 
SAE report form on University of Rochester’
s OnCore platform. If the SAE(s) is related 
to study medication and is unexpected (SUSARs), the SAE(s) should be reported to the
DSMC and RSRB within 5 days and to the FDA within 7 days. If the SAE(s) is 
unrelated to study medication and/or expected, the SAE(s) report needs to be 
completed, including all follow up information, prior to the next scheduled review of the 
study by DSMC. To report SAEs, the Investigator will also submit a SAE report to 
Astellas by either e-mail or fax, within the same timeframe as required by the 
DSMC.
For participating sites that do not have access to the University of Rochester’
s OnCore
platform, they can use the MedWatch Form 3500 to report non-SUSAR SAE(s) and the
MedWatch Form 3500A to report SUSAR(s) to the sponsor-investigator. Then, the 
sponsor-investigator team will enter the SAEs/SUSARs into the SAE report form on the
University of Rochester’
s OnCore platform using the same timeline as detailed above.
For all SUSARs, the MedWatch 3500A form should be completed and faxed to Astellas
and FDA by either e-mail or fax, within 7 days. If submission of SUSARs to FDA or
Astellas or Medivation is not possible within 7 days, the Investigator’
s local drug safety
contact (e.g., DSMC, IRB, etc.) should be informed by phone.
The SUSAR documentation, including the Medwatch 3500A Form and available source 
records should be emailed or faxed to:
Astellas Pharma Global Development – United States
Email: Safety-us@us.astellas.com
Fax number: (847) 317-1241
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The following minimum information is required for the initial report: 
Study number/IIT regulatory identifier
Subject number, sex and age
The date of report
The start date of the event
As much information as is known about the event at the time
Suspected causal relationship to the study drug
Whether the event is known to occur in relation to the study drug (i.e., expectedness)
Follow-up information for the event should be sent within promptly (within 7 days) as 
necessary.
It 
is 
the 
respons
ib
i
l
ity 
of 
the 
invest
igator
 
to 
report 
ser
ious 
adverse 
events 
to their local 
IRB/IECs according to their policies.
All 
serious 
adverse 
events 
should 
be 
recorded 
once 
the 
informed 
consent 
form 
is 
s
igned 
and 
must 
be 
reported 
w
ith
in 
the 
t
imeframe 
as 
d
iscussed 
above 
by facsimile to the 
person listed 
below
Name: Chunkit Fung 
SAE Fax: (585) 276-0350
Ema
i
l: chunk
it_fung@urmc.rochester.edu 
Cell: (267) 973-4448
Follow up reports should include the same information as the initial report with any 
updates or corrections needed. In addition, they should include the details of study 
drug administration, and as many details of the serious adverse event as are known, 
including 
the 
date 
of 
onset, 
the 
intensity, 
the 
treatment, 
and 
the relationship 
to 
study 
drug. SAE reports must include sufficient detail so that the DSMC can determine the
CTCAE term, severity, toxicity grade, expectedness, relatedness, treatment 
required, and a follow up report documenting resolution and whether there are 
sequelae. 
If 
the 
patient 
died, 
the 
report 
should 
include 
the 
cause 
of death 
and 
whether
or 
not 
the 
death 
was 
related 
to 
study 
drug, 
as 
well 
as 
the 
autopsy findings if available.
Do not delay reporting a suspected serious adverse event in order to obtain additional 
informat
ion.
 
Any 
add
it
iona
l 
informat
ion
 shou
ld be reported 
in 
a follow-up to the initial report.
All serious adverse events will be followed until resolution or until the event has 
stab
i
l
ized and/or reached a new base
l
ine. All ser
ious adverse events cont
inu
ing at the 
completion of the study must be followed to determine outcome. All serious adverse 
events 
occurr
ing 
between 
the t
imes 
the 
pat
ient 
s
igns 
the 
informed
 
consent and 
30 
days 
after 
the 
patient'
s 
last 
dose 
of 
study 
drug 
or 
prior 
to 
the 
initiation 
of 
another 
systemic 
ant
ineop
last
ic 
therapy, wh
ichever occurs 
f
irst, must be 
recorded, reported, and 
fo
l
lowed 
up by the investigator using the procedure described above.
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11.5 Procedure in Case of 
Pregnancy
The effect of enzalutamide in pregnant and lactating women is not known, and the 
exposure of a fetus or nursing infant is considered a potential risk. Enzalutamide can 
cause fetal harm when administered to a pregnant woman based on its mechanism of 
action. Subjects receiving enzalutamide are advised to use 2 acceptable methods of 
birth control (one of which must include a condom as a barrier method of contraception)
starting at the time of screening for an enzalutamide study and continuing throughout 
the course of treatment and for at least three months after enzalutamide is discontinued.
Dutasteride is contraindicated for use in women of childbearing potential and during 
pregnancy. Dutasteride prevents conversion of testosterone to DHT, a hormone 
necessary for normal development of male genitalia. In animal reproduction and 
developmental toxicity studies, dutasteride inhibited normal development of external 
genitalia in male fetuses. Therefore, dutasteride may cause fetal harm when 
administered to a pregnant woman. If this drug is used during pregnancy or if the patient 
becomes pregnant while taking it, the patient should be apprised of the potential hazard
to the fetus
If during the conduct of the clinical trial, a male subject impregnates his partner, the 
subject should report the pregnancy to the Investigator. The Investigator should report
the pregnancy to the Sponsor as an SAE within 24 hours of awareness of the event. 
The expected date of delivery or expected date of the end of the pregnancy, last 
menstruation, estimated fertility date, pregnancy result and neonatal data etc., should 
be included in this information.
The Investigator should report the outcome of the pregnancy (independent of outcome,
eg. full term delivery, pre-term delivery, spontaneous abortion, induced abortion, 
stillbirth, death of newborn, congenital anomaly [
including anomaly in a miscarried fetus,
etc]
 in accordance with the same reporting procedure as for SAEs. The date of 
outcome of the pregnancy, gestational age, date of birth and neonatal data etc., should
be included in this information.
11.6 Monitoring 
Plan
This study will be monitored according to the Wilmot Cancer Institute’
s Data and Safety 
Monitoring Plan for Clinical Studies. The monitor must be allowed access to all protocol 
regulatory and source documents to assess compliance with the protocol, federal regulations, 
and good clinical practices. The monitor will assess data for completeness of source documents 
and confirm data being recorded in the EDC is accurate. For remote monitoring, the sites will 
provide source documents as required. The regulatory binder, patient cases, and drug 
accountability will be reviewed at monitoring visits.
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11.7 Safety 
Analyses
The Data Safety Monitoring Committee (DSMC) at the Wilmot Cancer Institute, University
of Rochester, provides oversight of study progress and safety by review of accrual and 
adverse events semi-annually or more if concerns arise. Any adverse events requiring 
expedited review per protocol will be submitted to the chair of this committee for 
determination as to whether further action is required. This committee will meet after 6 
patients have been enrolled and received at least one cycle of therapy. If > 3 patients 
have delays in treatment administration due to toxicity, the protocol will be closed to 
accrual pending review and discussion with the principal investigators.
The safety coordinator will monitor adverse event rates utilizing the University of 
Rochester Cancer Center Clinical trial database. If the study has had two or more of the 
same SAE’
s reported in a month or more than six of the same SAEs in six months, the 
DSMC 
will 
review 
the summary of 
SAEs, discuss events 
with 
the study chair, and 
conduct
a detailed review with the study chair. The DSMC will determine if further action is 
required. A copy of the DSMC report will be sent to all participating sites for review and 
submission to their local IRB.
12.0 TOXICITY ASSESSMENT AND DOSE REDUCTION/DOSE
ADJUSTMENT
A
l
l pat
ients w
i
l
l be assessed for safety w
ith frequent h
istory and phys
ica
l exams a
long 
with 
CGA 
at 
pre-spec
if
ied 
interva
ls,
 
and 
at 
Unschedu
led 
V
is
its 
if 
necessary, 
inc
lud
ing
chemistries and hematology (see Section 8.0).
The 
study 
will 
utilize 
the 
CTCAE 
(NCI 
Common 
Terminology 
Criteria 
for 
Adverse 
Events) 
Version 
4.0 
for 
toxicity 
and 
Serious 
Adverse 
Event 
reporting. 
A 
copy 
of 
the
CTCAE Version 4.0 can be downloaded from the CTEP home page 
(http://ctep.cancer.gov.) 
A
l
l 
appropr
iate 
treatment 
areas 
shou
ld 
have 
access 
to 
a 
copy
of the CTCAE version 4.0 (appendix C)
General dose modification considerations
• M
issed 
doses 
are 
to 
be 
om
itted rather 
than 
made up
• If 
mu
lt
ip
le 
tox
ic
it
ies 
are 
exper
ienced, 
dose 
mod
if
icat
ion 
w
i
l
l 
be 
based 
on 
the
toxicity requiring the largest dose reduction
• Reduct
ions 
are 
based 
on the 
dose 
g
iven 
in 
the 
preced
ing 
cyc
le 
and 
are 
based
on toxicities observed since the prior toxicity evaluation
• Dose 
mod
if
icat
ions 
are 
requ
ired 
for 
Grade 
3 
or 
Grade 
4 
adverse 
events 
(AEs) 
or
intolerable Grade 2 AE that are considered at least possibly related to 
enzalutamide or dutasteride
• Tox
ic
it
ies w
i
l
l be assessed 
and 
reported 
as 
spec
if
ied 
in 
the 
study 
ca
lendar
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• Dose levels are defined below
Dose Level
Enzalutamide
Dutasteride /Finasteride
0
160 mg daily
0.5/5 mg daily
-1
120 mg daily
0.5/5 mg daily
-2
80mg daily
0.5/5 mg daily
An adverse event, using the common terminology definition, is any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom or disease 
tempora
l
ly 
assoc
iated 
with 
the 
use 
of 
med
ica
l 
treatment 
that 
may 
or 
may 
not 
be 
re
lated 
to 
the 
treatment. 
Ser
ious 
adverse 
event 
are 
def
ined 
as 
grade 
3 
and 
4 
tox
ic
it
ies that 
are 
believed to potentially impact the safety of the participant. Any patient with SAE that 
cannot 
be 
ame
l
iorated 
with 
the 
use 
of 
adequate 
med
ica
l 
intervent
ion
 
shou
ld 
have 
the
ir 
treatment 
interrupted until the toxicity improves to a Grade 2 or lower severity. Once 
toxicity improves, at the discretion of the treating physician the study combination can 
be re-started at a reduced dose (-1). Should the patient continue to have intolerable 
grade 
2 
or 
higher 
toxicity 
even 
at 
a 
reduced 
dose 
(-1), 
at 
the 
discretion 
of 
the 
treating 
phys
ic
ian 
the 
study comb
inat
ion 
can be 
further 
reduced 
to leve
l
 
-2. Pat
ients 
w
ith 
SAE 
or 
intolerable grade 2 toxicity Patients with SAE while on dose -2 will permanently 
d
iscont
inue study drug. The study coord
inator shou
ld be not
if
ied of all SAE. Also if the 
study 
drug 
is 
delayed 
for 
more 
than 
4 
weeks 
for 
any 
reason 
or 
if 
a 
dose 
reduction 
of 
enza
lutam
ide be
low 
80 
mg da
i
ly 
is 
requ
ired, pat
ients w
i
l
l 
be 
removed 
from the 
protoco
l 
treatment.
Dutaster
ide/ 
f
inaster
ide is 
inc
luded
 
in 
th
is 
reg
imen 
to 
potent
ia
l
ly 
increase
 the 
eff
icacy 
of 
enza
lutam
ide 
and 
to 
pro
long 
the 
durat
ion 
of 
response. 
Dutaster
ide 
is 
ava
i
lab
le 
on
ly 
as
0.5 
mg 
capsu
les. F
inaster
ide 
is 
ava
i
lab
le 
on
ly 
as 
5 
mg 
capsu
les. 
In 
the event grade 
3 
or
grade 4 tox
ic
ity occurs and is known to be re
lated to dutaster
ide or f
inaster
ide a
lone, 5 
AR-inhibitor 
should 
be 
held 
permanently. 
In 
the 
event 
of 
an 
occurrence 
of 
a 
SAE 
that
cannot be attributed directly to either enzalutamide or 5- AR inh
ibitor, the study 
combination 
should 
be 
held 
until 
toxicity 
improves 
to 
grade 
2 
or 
lower 
and 
treatment 
restarted at dose level -1.
For 
treatment 
or 
dose 
mod
if
icat
ion 
re
lated 
quest
ions, 
p
lease 
contact 
Chunk
it 
Fung, 
MD
at (585) 273-5573 or Deepak Kilari, MD at (414) 805-4600
13.0 REGISTRATION 
GUIDELINES
13.1 Registration Timing
Patient’
s 
enrollment 
must 
occur 
up 
to 
28 
days 
prior 
to 
the 
start 
of 
treatment 
with 
the
study 
drug 
combination. 
All 
patients 
must 
have 
a 
signed 
informed 
consent 
prior 
to
registration.
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13.2 Investigator/Site requirement
This study is supported by Astellas and Medivation Inc.
Pr
ior 
to 
recru
itment of 
a pat
ient for th
is 
study, 
each invest
igator
 
must have 
a 
NCI Invest
igator 
number and must maintain an active investigator registration status through the annual 
submission of a complete investigator registration packet (FDA form 1572 with original 
signature, current CV, Supplemental Investigator Data Form with signature and Financial 
D
isc
losure 
form 
with 
or
ig
ina
l s
ignature) 
to the 
Pharmaceut
ica
l 
Management Branch 
CTEP, 
DCTD, NCI.
Each investigator or group of investigators at a clinic site must obtain IRB approval for
the protocol and submit IRB approval and supporting documentation to the regulatory
office before they can enroll patients.
13.3Other Registration 
guidelines
A
l
l pat
ients w
i
l
l be 
reg
istered through the centra
l 
off
ice/coord
inat
ing s
ite wh
ich is 
located
at the
James P. Wilmot Cancer Center 
Un
ivers
ity of Rochester Med
ica
l Center
Rochester, NY, 14642
Any 
quest
ion 
regard
ing 
e
l
ig
ib
i
l
ity 
or 
that 
may 
ar
ise 
dur
ing 
the 
conduct 
of 
the 
study 
should be addressed to
Name: Chunkit Fung 
SAE 
Fax: 
(585) 
276-0350
Ema
i
l: chunk
it_fung@urmc.rochester.edu 
Cell: (267) 973-4448
14.0 STUDY ADMINISTRATION
Regulatory and Ethical Considerations
14.1 Institutional Review Board or Independent Ethics 
Committee
Prior to the initiation of the study, the Principle Investigator will obtain written 
confirmation from the Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) that the IRB/IEC is properly constituted and compliant with all the local 
requirements and regulations. A copy of the confirmation will be provided to the sponsor
of the study. The investigator will provide the IRB/IEC with all appropriate material, 
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including the protocol, current Investigator’
s Brochure, the informed consent document,
and other written information provided to the patients. The trial will not be initiated until 
appropriate IRB/IEC approval of the protocol and the informed consent document and 
all recruiting materials are obtained in writing by the investigator and copies are 
received by the sponsor. Appropriate reports on the progress of the study will be made 
to the IRB/IEC and the sponsor by the investigator in accordance with applicable 
governmental regulations and in agreement with policy established by the 
IRB/IEC.
Ethical Conduct of the 
Study
This study will be conducted under the principles of the World Medical Association 
(WMA) Declaration of Helsinki under its most recent amendment (by the 52nd WMA 
General Assembly, Edinburg, Scotland, October 2000, with a Note of Clarification on 
Paragraph 29 added by the WMA General Assembly, Washington 2002 and on 
Paragraph 30 added by the WMA General Assembly, Tokyo 2004), and including Good 
Clinical Practices (GCP) according to International Conference on Harmonisation (ICH)
guidelines. Specifically, this study is based on adequately performed laboratory and
animal experimentation; the study will be conducted under a protocol reviewed and
approved
14.2 Patient Information and Informed 
Consent
All parties will ensure protection of patient personal data and will not include patient 
names on any reports, publications, or in any other disclosures, except where required 
by laws. In case of data transfer, the sponsor will maintain high standards of 
confidentiality and protection of patient personal data. Additional patient confidentiality 
issues are covered in the Clinical Trial Agreement and in the informed consent form 
signed by the patient.
A properly executed, written, informed consent, in compliance with the Declaration of 
Helsinki, ICH GCP, United States (US) Code of Federal Regulations (CFR) for 
Protection of Human Subjects (21 CFR 50.25[
a,b]
, CFR 50.27, and CFR Part 56, 
Subpart A), and local regulations, will be obtained from each patient prior to entering the
patient into the trial. The investigator will prepare the informed consent form (ICF) and 
provide the documents to the IRB and sponsor for review. The investigator will provide 
copies of the signed ICF to each patient and will maintain copies in the patient’
s record 
file.
14.3 Study Monitoring and 
Auditing
All aspects of the study will be monitored closely by the site PIs and the coordinating 
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center. Remote monitoring will be conducted according to GCP and standard operating 
procedures for compliance with applicable government regulations.
14.4 Drug Supply
Astellas/Medivation 
Inc. 
will supply enzalutamide. 
The 
drug will be shipped 
directly to the 
Investigational Pharmacy at the two recruiting sites, which will in turn dispense the 
medication 
through 
the 
study 
coordinator 
to 
the 
patient. 
Dutasteride/Finasteride 
would 
be 
dispensed 
from 
a 
retail 
pharmacy 
through 
a 
prescription 
written 
by 
the 
treating 
provider.
Storage and 
Labeling
All 
study 
drugs 
shipped 
to 
the 
investigator 
will 
be 
accompanied 
by 
a 
packaging 
slip 
which
will detail the contents of the shipment. The investigator or the authorized designee must
sign and date the form where indicated confirming receipt of the investigational product
shipment as listed. This form should be retained for investigators records.
Study drugs will be stored in a secure location with limited access and within the 
following temperature range: 59°F to 86°F (15°C to 30°C). Bottles will be labeled with the
study protocol number, medication or kit number, contents, directions for use, storage 
directions, clinical trial statement, and sponsor. Patients will be instructed to store study
drug at room temperature out of the reach of children. Only authorized site staff may 
supply or administer investigational product.
Only 
subjects 
enrolled 
in 
the 
study 
should 
receive 
the 
investigational 
products, 
in 
accordance with the applicable regulatory requirements.
14.6 Selection 
of 
Timing 
of Dose for 
Each Patient
Enzalutamide 
is 
administered 
orally 
once 
daily. 
Enzalutamide 
should 
be 
taken 
as 
close 
to the same time each day as possible and can be taken with or without food. The 
capsules should be swallowed whole and not chewed or opened
Dutasteride or Finasteride is to be co-administered with enzalutamide and taken once 
daily as well. The capsules should be swallowed whole and not chewed or opened, as 
contact with the capsule contents may result in irritation of the oropharyngeal mucosa. 
Dutasteride can be administered with or without food. If dosing of either drug is 
missed 
on one day 
for any reason, 
double-dosing should NOT occur the following 
day. 
Patients 
should 
hold 
their 
dose 
of study 
drug 
as 
instructed 
by 
the 
treating 
physician.
14.7 Investigational Product Accountability
The investigator must maintain accurate records (including dates and lot numbers) of 
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returned by each patient must be recorded on a Drug Accountability Log completed by 
the investigator, study coordinator, or pharmacist. All remaining study supplies, opened
or unopened, must be returned to the sponsor (or designee) at the end of the study or 
destroyed on site according to the site'
s standard operating procedures only after study
drug accountability has been completed and with approval of the study PI. All records 
must be made available to the sponsor (or designee) and appropriate regulatory 
agencies upon request. 
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Data Quality Assurance
Clinical Procedures
Members 
of 
the 
study 
staff 
or 
their 
designee(s) 
will 
educate 
the 
site 
personnel 
about 
the 
investigational product, protocol requirements, case report forms, monitoring 
requirements, and reporting of serious adverse events.
To ensure compliance with all applicable regulatory requirements, the sponsor or any 
regulatory 
agency may conduct an inspection of this study. Such audits/inspections can 
occur at any time during or after completion of the study. If such an audit were to occur, 
the 
investigator 
and 
the 
institution 
agree 
to 
allow 
the 
auditor/ 
inspector 
direct 
access 
to 
all 
documents and to allocate his/her time and the time of his/her staff to the 
auditor/inspector to discuss findings and relevant issues.
14.8 Retention of Records
The investigator must make study data accessible to the authorized representatives of 
the sponsor (or designee) and Regulatory Agency (e.g., FDA) inspectors upon request.
A file for each patient must be maintained that includes the signed informed consent 
form and copies of all source documentation related to that patient. The investigator 
must ensure the reliability and availability of source documents from which the 
information on the case report form was derived.
Patient identity information recorded will be maintained for 15 years on the Patient 
Confidentiality Log. Investigators must maintain all study documentation for a period of 
2 years following the approval date of the drug combination, or until 2 years after the 
investigational drug program is discontinued. Study documentation includes the 
Investigator'
s Brochure, signed protocol and amendments; signed informed consents; 
notification of serious adverse events and related reports; any dispensing and 
accountability logs; shipping records of investigational product and trial related 
materials; documentation of the financial aspects of the trial, insurance statement, and 
signed agreement between involved parties; dated and documented IRB/IEC approval,
and approval of regulatory authority(ies); normal laboratory values; decoding 
procedures for blinded trials; initiation visit report; curricula vitae and all correspondence
pertaining to the conduct of the study. The sponsor will notify the principal investigator 
when any records may be discarded.
14.9
Data 
Management
Clinical data management will be performed by the investigator according to procedures 
described 
in a comprehensive 
Data Management 
Plan that will be subject to review and 
approval by the Sponsor. The Data Management Plan will include procedures for all 
aspects 
of 
the 
processing 
of 
the 
data 
from 
this 
study. 
In 
particular, 
the 
Data 
Management 
Plan will include a list of the Standard Operating Procedures that apply to this study. 
Adverse events and medications will be coded using MedDRA and the World Health 
Organization 
Drug 
Dictionary 
(WHO-DD), 
respectively. 
The 
Data 
Management 
Plan 
will 
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include specific details of which version of these dictionaries has been 
used.         
14.10Study and Site 
Closure
Following completion of the study, the investigator will conduct the following activities in 
conjunction with the site staff, as appropriate
• Return of all the study data as appropriate to the Sponsor
• Data queries
• Accountability, 
reconciliation 
and 
arrangements 
for unused 
investigational
products
• Review of site study records for 
completion.
If the study is prematurely discontinued, all study data must be returned to the 
sponsor. In addition, arrangements will be made for all unused investigational products 
in accordance with the applicable sponsor procedures for the study to be 
returned.
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JS, 
Greer 
JA, 
Muzikansky 
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Gallagher 
ER, 
Admane 
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Jackson 
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et 
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palliative 
care
for 
patients 
with 
metastatic 
non-small-cell 
lung 
cancer. 
The 
New 
England 
journal 
of 
medicine. 
2010;363(8):733-42.
55.
Hurria 
A, 
Cirrincione 
CT, 
Muss 
HB, 
Kornblith 
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Barry 
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Artz 
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assessment in cooperative group clinical cancer trials: CALGB 360401. J Clin Oncol. 2011;29(10):1290-6.
56.
Pal 
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Hurria 
A. 
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the 
older 
patient 
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understanding 
frailty 
and
the geriatric assessment. CA Cancer J Clin. 2010;60(2):120-32.
57.
Hurria 
A, 
Gupta 
S, 
Zauderer 
M, 
Zuckerman 
EL, 
Cohen 
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et 
al. 
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a 
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2005;104(9):1998-2005.
58.
Seymour 
MT, 
Thompson 
LC, 
Wasan 
HS, 
Middleton 
G, 
Brewster 
AE, 
Shepherd 
SF, 
et 
al. 
Chemotherapy options in elderly and frail patients with metastatic colorectal cancer (MRC FOCUS2): an
open-label, randomised factorial trial. The Lancet. 2011;377(9779):1749-59.
59.
Scher 
HI, 
Beer 
TM, 
Higano 
CS, 
Anand 
A, 
Taplin 
M-E, 
Efstathiou 
E, 
et 
al. 
Antitumour 
activity 
of
MDV3100 in castration-resistant prostate cancer: a phase 1–2 study. The 
Lancet.375(9724):1437-46.
60.
Roehrborn 
CG, 
Boyle 
P, 
Nickel 
JC, 
Hoefner 
K, 
Andriole 
G. 
Efficacy 
and 
safety 
of 
a 
dual 
inhibitor 
of
5-alpha-reductase 
types 
1 
and 
2 
(dutasteride) 
in 
men 
with 
benign 
prostatic 
hyperplasia. 
Urology. 
2002;60(3):434-41.
61.
McConnell 
JD, 
Bruskewitz 
R, 
Walsh 
P, 
Andriole 
G, 
Lieber 
M, 
Holtgrewe 
HL, 
et 
al. 
The 
effect 
of 
finasteride 
on 
the 
risk 
of 
acute 
urinary 
retention 
and 
the 
need 
for 
surgical 
treatment 
among 
men 
with
benign prostatic hyperplasia. Finasteride Long-Term Efficacy and Safety Study Group. The New England
journal 
of medicine. 1998;338(9):557-63.
62.
Scher 
HI, 
Halabi 
S, 
Tannock 
I, 
Morris 
M, 
Sternberg 
CN, 
Carducci 
MA, 
et 
al. 
Design 
and 
End 
Points
of 
Clinical 
Trials 
for 
Patients 
With 
Progressive 
Prostate 
Cancer 
and 
Castrate 
Levels 
of 
Testosterone: 
Recommendations 
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Prostate 
Cancer 
Clinical 
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of 
Clinical 
Oncology. 
2008;26(7):1148-59.
63.
Hussain 
M, 
Tangen 
CM, 
Higano 
C, 
Schelhammer 
PF, 
Faulkner 
J, 
Crawford 
ED, 
et 
al. 
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prostate-specific antigen value after androgen deprivation is a strong independent predictor of survival
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(INT-0162). 
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TK, 
Xie 
W, 
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Amico 
AV, 
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Pomerantz 
M, 
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therapy. 
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2009;115(5):981-7.
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Mittan 
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Perez 
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Basler 
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Bruder 
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2002;87(8):3656-61.
66.
Collett D. Modelling binary data: CRC Press; 2003.
67.
Ron 
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1982;38(1):29-
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68.
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69.
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1997;50(6):920-8.
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16.0APPENDICES
16.1 Appendix A: Performance Status 
Criteria
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Description
Percent
Description
100
Normal, no complaints, no 
evidence of disease.
0
Normal activity. Fully active, able to
carry on all pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of 
disease.
80
Normal activity with effort; some 
signs or symptoms of disease.
1
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary nature (e.g., light 
housework, office work).
70
Cares for self, unable to carry on 
normal activity or to do active 
work.
60
Requires occasional assistance, 
but is able to care for most of 
his/her needs.
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.
50
Requires considerable 
assistance and frequent medical
care.
40
Disabled, requires special care 
and assistance.
3
In bed >50% of the time. Capable 
of only limited self-care, confined to
bed or chair more than 50% of 
waking hours.
30
Severely disabled, 
hospitalization indicated. Death 
not imminent.
20
Very sick, hospitalization 
indicated. Death not imminent.
4
100% bedridden. Completely 
disabled. Cannot carry on any self- 
care. Totally confined to bed or 
chair.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.
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16.2 Appendix B. RECIST 1.1 
Criteria
RECIST 1.1
Measurable 
Disease: Tumor 
Lesions
Tumor lesions must be accurately measured in at least one dimension
(longest diameter in the plane of measurement is to be recorded with a
minimum size of):
-
10mm by CT scan (CT scan slice thickness no greater than 5mm)
-
10mm caliper measurement by clinical exam (lesions which cannot
be accurately measured with calipers should be recorded as non-
measurable)
-
20mm by chest X-ray
Measurable 
Disease: Malignant
Lymph Node
Sum of the diameters (longest for non-nodal lesions, short axis for 
nodal lesions)
Measure SHORT axis:
-
Target lesion if short axis > 
1.5cm
-
Non-target if short axis 1.0 to <1.5cm or 
pathological
-
Normal lymph node if short axis < 
1.0cm
Add ACTUAL short axis measurement to sum of longest diameters of
non-nodal lesions.
Target Lesions
All measurable lesions:
-
Up to 5 target lesions max in 
total
-
Up to 2 target lesions max per 
organ
Non-Target 
Lesions
All other lesions (site of disease). Measurements are not required and 
these lesions should be followed as:
-
Present
-
Absent
-
Unequivocal progression
New Lesions
The appearance of new malignant lesions denotes disease progression.
Methods for 
Evaluation of 
Measurable 
Disease
All measurements should be taken and recorded in metric notation, using 
a ruler, calipers, or digital measurement tool. All baseline evaluations 
should 
be performed as closely as 
possible 
to the beginning of treatment 
and never more than 4 weeks before the beginning of the 
treatment.
The same method of assessment and the same technique should be
used to characterize each identified and reported lesion at baseline and
during follow-up. Imaging-based evaluation should always be 
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rather than clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical exam.
Clinical lesions: Clinical lesions will only be considered measurable 
when they are superficial and P10mm diameter as assessed using 
calipers (e.g. skin nodules). For the case of skin lesions, documentation
by color photography including a ruler to estimate the size of the lesion
is suggested. As noted above, when lesions can be evaluated by both 
clinical exam and imaging, imaging evaluation should be undertaken 
since it is more objective and may also be reviewed at the end of the 
study.
Chest X-ray: Chest CT is preferred over chest X-ray, particularly 
when
progression is an important endpoint, since CT is more sensitive than 
X-ray, particularly in identifying new lesions. However, lesions on chest
X-ray may be considered measurable if they are clearly defined and 
surrounded by aerated lung.
CT, MRI: CT is the best currently available and reproducible method to 
measure lesions selected for response assessment. This guideline has 
defined measurability of lesions on CT scan based on the assumption 
that CT slice thickness is 5mm or less. When CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion
should be twice the slice thickness. MRI is also acceptable in certain 
situations (e.g. for body scans).
Ultrasound: Ultrasound is not useful in assessment of lesion size and 
should not be used as a method of measurement. Ultrasound 
examinations cannot be reproduced in their entirety for independent 
review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will
be taken from one assessment to the next. If new lesions are identified
by ultrasound in the course of the study, confirmation by CT or MRI is 
advised. If there is concern about radiation exposure at CT, MRI may 
be used instead of CT in selected instances.
Endoscopy, laparoscopy: The utilization of these techniques for 
objective tumor evaluation is not advised. However, they can be useful
to confirm complete pathological response when biopsies are obtained
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or to determine relapse in trials where recurrence following complete 
response or surgical resection is an endpoint.
Tumor markers: Tumor markers alone cannot be used to assess 
objective tumor response. If markers are initially above the upper 
normal limit, however, they must normalize for a patient to be 
considered in complete response. Because tumor markers are disease
specific, instructions for their measurement should be incorporated into
protocols on a disease specific basis. Specific guidelines for both CA- 
125 response (in recurrent ovarian cancer) and PSA response (in 
recurrent prostate cancer), have been published. In addition, the 
Gynecologic Cancer Intergroup has developed CA125 progression 
criteria which are to be integrated with objective tumor assessment for
use in first-line trials in ovarian cancer.
Cytology, histology: These techniques can be used to differentiate 
between PR and CR in rare cases if required by protocol (for example,
residual lesions in tumor types such as germ cell tumors, where known
residual benign tumors can remain).
When effusions are known to be a potential adverse effect of treatment 
(e.g. with certain taxane compounds or angiogenesis inhibitors), 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.
PET/CT: The low dose or attenuation correction CT portion of a PET- 
CT is not always of optimal diagnostic CT quality for use with RECIST
measurements. However, if the site can document that the CT 
performed as part of a PET-CT is of identical diagnostic quality to a
diagnostic CT, then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with 
conventional CT.
16.3 Appendix C: CTCAE Version 
4.0
http://evs.nci.nih.gov/ftp1/CTCAE/About.html
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16.4 Appendix D: Investigators 
Brochure
Will be provided upon request
16.5 Appendix E: Comprehensive Geriatric assessment 
tools
Attached to the protocol
16.6Appendix F: Prohibited Concomitant 
Medications
Attached to the protocol
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ADL.pdf
FACT-P.pdf
Medication List.pdf
MNA_BMI.pdf
MOCA v. 8.1.pdf
SPPB.pdf
APPENDIX 
F. Strong 
and Moderate CYP2C8 and 
CYP 
3A4 Inducers and 
Inhibitors
NOTE: 
This 
list 
may 
not 
be 
comprehensive 
– 
review 
each 
patient’s 
medications 
prior 
to
enrollment and at every clinic visit.
CYP2C8 Strong &
 
Moderate INDUCERS
CYP2C8 Strong &
 
Moderate INHIBITORS
CYP3A4 Strong &
 
Moderate INDUCERS
CYP3A4 Strong &
Moderate 
INHIBITORS∞
Carbamazepine
Efavirenz
Carbamazepine
Aprepitant
Phenobarbital
Gemfibrozil
Efavirenz
Atazanavir
Phenytoin
Montelukast
Phenobarbital
Clarithromycin
Primidone
Rifampin
Pioglitazone
Trimethoprim
Phenytoin
Primidone
Conivaptan
Darunavir
Rifabutin
Diltiazem
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Rifampin
Erythromycin
St. John’
s Wort
Fluconazole
Fosamprenavir
Grapefruit Juice
Indinavir
Itraconazole
Ketoconazole
Nefazodone
Nelfinavir
Posaconazole
Ritonavir
Saquinavir
Telithromycin
Verapamil
Voriconazole
i ∞CYP3A4 
Strong 
& 
Moderate 
Inhibitors 
applies 
to 
dutasteride/enzalutamide 
combination 
therapy 
only, 
and 
not
finasteride / enzalutamide combination therapy
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ICF_001.pdf: 
MONCT02213107DEL CONSENT FORM
NCT02213107
A Phase II Study of Enzalutamide Plus 
Dutasteride/Finasteride as First Line Treatment for 
Vulnerable Patients ≥ 65 Years with Systemic Prostate 
Cancer
Principal Investigator: Chunkit Fung, 
MD
This consent form describes the research study, what you may expect if you decide to 
take part and important information to help you make your decision. Please read this 
form carefully.
The study staff will explain this study to you. Please ask questions about anything that is not 
clear before you agree to participate. You may take this consent form home to think about and 
discuss with family or friends.
• Being in this study is voluntary – it is your choice.
• If you join this study, you can change your mind and stop at any time.
• If you choose not to take part, your routine medical care will not be changed in any way.
• There are risks from participating and you should understand what these mean to you.
Introduction
You are being asked to take part in this study because you are age 65 or older and will 
require treatment for prostate cancer.
This study is being conducted at the University of Rochester’s James P. Wilmot Cancer Institute 
and the Clinical Cancer Center at the Medical College of Wisconsin. At the University of 
Rochester this study is being conducted by Dr. Chunkit Fung and Dr. Supriya Mohile.
Purpose of Study
The purpose of this study is to see how long treatment with enzalutamide and dutasteride or 
enzalutamide and finasteride will keep the Prostate Specific Antigen (PSA) from rising, and may 
control cancer growth in patients aged 65 or older receiving this combination as first time treatment
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for systemic prostate cancer. PSA is a protein produced by the prostate tissue, which is used as a 
marker to determine prostate cancer growth. The study will also monitor the impact of this drug 
combination on quality of life and other issues relevant to the elderly.
The standard treatment for systemic prostate cancer usually includes Androgen Deprivation 
Therapy (ADT), which lower a man’s testosterone level. ADT can have side effects that are more 
difficult to tolerate for older patients with cancer. Some treatments that are available for patients 
are better tolerated, but do not keep the PSA from rising for very long.
Treatment with enzalutamide has been well-tolerated in research studies involving the elderly and 
has been shown to decrease PSA, increasing the amount of time it takes for the cancer to 
progress. Studies with dutasteride and finasteride also suggest good tolerability and PSA outcomes 
compared to standard of care for the elderly. This study is being done to see if the combination of 
the two drugs (enzalutamide and dutasteride or enzalutamide and finasteride) will still be tolerable 
in the elderly population and to measure how well the drugs affect the PSA. Both the combinations 
of enzalutamide and dutasteride, as well as enzalutamide and finasteride are not currently 
approved as first time treatment for prostate cancer. Dutasteride will be the agent of choice.
However, if for any reason dutasteride cannot be obtained, finasteride would be administered.
Description of Study Procedures
If you decide to take part in this study, you will be asked to undergo some initial tests to ensure that 
you meet all the criteria necessary to take part in the study. Once you have completed your initial 
testing and meet the eligibility criteria, you will be offered the chance to undergo breast radiation to 
prevent breast tenderness, a potential side effect of treatment. Your doctor will discuss this 
possibility with you based on your current health status.
You will then be asked to take a combination of 2 oral (taken by mouth) drugs daily. The drugs 
used on this study are either 160mg of enzalutamide (4 tablets) and 0.5mg of dutasteride (1 tablet), 
or a combination of 160mg of enzalutamide (4 tablets) and 5 mg of finasteride (1 tablet), which will 
be taken each day for a 28-day cycle. Treatment will continue as long as you are tolerating 
treatment and your prostate cancer is either responding to treatment or remains stable.
During the study you will have the following assessments:
• You will be asked about your medical history and current medications you are taking.
• You will have physical exams (including vital signs, blood pressure, weight, temperature)
• You will have periodic Comprehensive Geriatric Assessments, which would include 
assessment of health areas specific to the elderly (i.e. quality of life, ability to perform 
basic daily activities, memory, physical performance, mood, and social support)
• You will have routine blood work such as Complete Blood Count with differential, 
Comprehensive Metabolic Panel, Prostate Specific Antigen (PSA) and Testosterone levels. 
Routine blood samples are usually 3 to 5 mL (approximately 1 teaspoon or less).
• You will have a research blood draw for serum dihydrotestosterone (a hormone) at four time 
points: pre-study, at Cycle 4, Cycle 9, and at 30 days after your last treatment dose. Some of 
the study drugs, dutasteride or finasteride, can inhibit this hormone so we will measure your 
blood level to see if these agents lower the dihydrotestosterone levels.
•
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These tests may include (as recommended by your doctor):
Routine CT scans of the chest, abdomen and pelvis.
Routine bone scans to look for bone metastases
Routine bone density scans (DEXA)
Routine chest X-rays
If you stop study treatment for reasons other than progressive disease (your cancer has gotten  
worse) you will have physical exams and PSA for disease assessment performed every 6 months for 
the first year and as clinically indicated thereafter. If you stop study treatment because your disease  
has gotten worse, we would like to follow up with physical exams every 6 months for the first year 
after disease progression and as clinically  indicated thereafter.
Number of Subjects
Approximately 40 subjects from 2 study centers (University of Rochester and the Medical College of 
Wisconsin) will take part in this research. Locally, about 20 subjects will participate.
Duration of the Study
Your participation in the study is expected to last until the study medications do not work for 
the prostate cancer or your decision to withdraw from the study. After you no longer use the 
study medications, we will continue to follow up with you long-term survival and safety data.
Risks of Participation
Androgen deprivation therapy (ADT) is the standard treatment for systemic prostate cancer. 
However, older patients may not tolerate the side effects of ADT. This study examines a new 
combination treatment (enzalutamide and dutasteride or enzalutamide and finasteride) that may or 
may not benefit you. In addition, you may have side effects while on the study. Everyone taking 
part in the study will be watched carefully for any side effects. Side effects may be mild or very 
serious. Many side effects go away soon after discontinuing treatment, some could have lasting 
effects.
Risks and side effects of Enzalutamide
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Common side effects associated with the use of enzalutamide are:
•Constipation
• Weight loss
•Decreased appetite
•Diarrhea
•Falls
•Feeling tired (fatigue)
•Swelling of the limbs
•Pain in joints
• Weakness in the muscles
•Pain in muscles and bones


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•Back pain
•Headache
•Anxiety
•Trouble falling or staying asleep
•Blood in urine
•Hot flush (hot flash)
•High blood pressure (hypertension)
•Altered taste in mouth
Rare side effects associated with the use of enzalutamide are:
•Low white blood cell count (needed to fight infection)
•Hallucination (seeing or feeling things that are not there)
•Dry skin
•Itching
•Restless leg syndrome (an uncontrollable urge to move a part of the body, usually the leg)
•Gynecomastia (enlarged male breast)
Serious but infrequently reported side effects in enzalutamide-treated patients are:
•Seizures: Some people have had seizures during treatment with enzalutamide. If you take 
enzalutamide you may be at risk of having a seizure. You should avoid activities where a sudden 
loss of consciousness could cause serious harm to yourself or others. Tell your healthcare provider 
right away if you have had an episode of loss of consciousness or seizure
•Posterior reversible encephalopathy syndrome (PRES): There have been rare reports of PRES, a 
rare, reversible condition involving the brain, in patients treated with enzalutamide. If you have a 
seizure, worsening headache, confusion, blindness or other vision problems, please contact your 
doctor right away. Your doctor will stop enzalutamide if you develop PRES.
Risks and side effects of Dutasteride
The most common side effects of dutasteride include:
• trouble getting or keeping an erection (impotence)*
• a decrease in sex drive (libido)*
• ejaculation problems*
• enlarged or painful breasts.
Serious but infrequently reported side effects of dutasteride include:
• swelling of your face, tongue, or throat
• skin reactions, such as skin peeling
If you notice breast lumps or nipple discharge, you should talk to your healthcare provider.
*Some of these events may continue after you stop taking dutasteride.
Men who have taken this drug should not donate blood for at least six months after discontinuation of 
the drug.
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Risks and side effects of Finasteride
The most common side effects of finasteride include:
• a decrease in sex drive (libido)*
• ejaculation problems*
• enlarged or painful breasts.
• dizziness
Serious but infrequently reported side effects of dutasteride include:
• swelling of your face, tongue, or throat
• skin reactions, such as skin peeling
*Some of these events may continue after you stop taking finasteride.
Risks of Combined Treatment with Enzaludamide and Dutasteride/Finasteride
There is limited past experience in the use of combined therapy with enzalutamide and dutasteride 
or enzalutamide and finasteride in the treatment of prostate cancer. Therefore, there may be 
unknown risks associated with this combined treatment regimen. The risks of the known side 
effects listed above may be more or less severe when the two drugs are used in combination.
There may be other new side effects that may be discovered when using this combined treatment.
You will be informed immediately of any new risks or changes in risks that are discovered during 
the study.
Fertility and Pregnancy Risks
Enzalutamide blocks the action of the male sex hormone, so it can cause infertility and impotence 
and may contribute to loss of muscle and bone mass, hot flashes or breast growth. Although the 
risk of getting your partner pregnant while taking enzalutamide is low, there is a risk of harm to the 
fetus. Therefore, you must agree to utilize effective birth control methods to ensure that your 
partner does not become pregnant in order to participate in this trial.
Dutasteride and finasteride have been shown to reduce sperm count, semen volume, and sperm 
movement. However, the effect of these agents on male fertility is not known. Given the risk of 
harm to the fetus, you must agree to utilize effective birth control methods to ensure that your 
partner does not become pregnant in order to participate in this trial. Women of childbearing 
potential should not handle this medication, as it can be absorbed through the skin and could cause 
birth defects.
You and/or your partner (if still of child bearing age) must agree to use a highly effective birth 
control method while you are participating in this trial. Examples of highly effective birth control are 
double- barrier (condom or diaphragm, with spermicidal jelly). Women can use an intrauterine 
device; injectable, or implanted hormonal contraceptives, which are considered highly effective.
Oral hormonal contraceptives should only be used in combination with another method. Please 
RSRB Approval Date: 6/26/2023
Expiration Date: 2/15/2024
discuss with your study doctor if the contraception method(s) you are using are acceptable.


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Benefits of Participation
You might not benefit from being in this research study. The potential benefit to you from being in 
this study might be that your cancer would be controlled longer.
New Study Findings
If we discover anything that might make you change your mind about continuing in the study, we 
will let you know.
Alternatives to Participation
Your other choices may include:
•
Getting treatment or care for your cancer without being in a research study.
• Taking part in another research study
•
Getting no treatment.
If you decide that you don’t want any more treatment, one of your options is called “comfort care.” 
Comfort care 
includes pain medication and other support. It aims to maintain your comfort and dignity 
rather than cure disease. Usually this care can be provided at home.
If you think you might prefer comfort care, please discuss this with your family, friends and 
your doctor.
Talk to your study doctor about your choices before you decide to take part in this study.
Sponsor Support
The University of Rochester is receiving payment from Astellas and Medivation, the 
companies supplying the study drug enzalutamide, for conducting this research study.
Costs
RSRB Approval Date: 6/26/2023
Expiration Date: 2/15/2024
You and/or your health insurance company will be billed for parts of the study that are standard care 
for your disease. Standard of care tests, procedures, and medications are those that you would 
undergo or receive as part of treatment for your condition whether you were participating in 
a research study or not. Your health insurance company may or may not pay for these charges. You 
will be responsible for all of the costs linked with this study that are related to standard care and 
are not covered by other payers (HMO, health insurance company, etc.), such as co-pays, 
deductibles, and other out-of-pocket expenses that you would normally be required to pay for the 
treatment of your cancer.
The study drug enzalutamide will be provided by the study sponsors at no cost to you. The drugs 
dutasteride and finasteride used in the study are commercially available and will be billed to 
you or your insurance company. The type of agent used for each patient will depend on insurance 
approval. Dutasteride will be the agent of choice. However, if for any reason dutasteride cannot be 
obtained, finasteride would be administered. Procedures that are done only for the study, such as 
the blood draw for serum dihydrotestosterone and the Comprehensive Geriatric Assessments will


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be paid for by the study and will not be billed to you or your insurance company.
You might have unexpected expenses from being in this study. Ask your study doctor to discuss 
the costs that will or will not be covered by the sponsor. This discussion should 
include who will pay 
the costs of treating possible side effects.
Payments
You will not be paid for participating in this study.
Circumstances for Dismissal
There are some cases where you could be removed from the study without your consent. You 
may be withdrawn from the study if your disease becomes worse or if your doctor feels that 
staying in the study is harmful to your health. You may be withdrawn from the study if you do not 
keep appointments for study visits, if you experience a treatment delay of more 30 days, or if you 
cannot complete study activities. You will also be withdrawn from the study if you will need to start 
a new treatment for prostate cancer.
You also may decide that you no longer wish to participate in this research study. If you decide you 
would like to stop being in this study, we ask that you notify your study doctor or study coordinator 
of your decision to stop participation. You will be asked to complete one additional end-of-study 
visit for safety follow-up.
Early Termination
To ensure your safety after you have stopped the study drug, you will be asked to return 
approximately 30 days after your last dose to complete an end-of-study visit which will include 
physical exam, review of medical history and current medications, and end-of study blood 
work.
If you come off treatment due to the progression of you cancer, information about any other 
cancer therapies you may receive and how they work for you will be monitored until the study 
closes.
If you come off treatment early for any other reason other than the progression of your cancer, 
information about your physical exams and PSA test results will be collected to monitor the status 
of your cancer until the study closes.
Compensation for Injury
RSRB Approval Date: 6/26/2023
Expiration Date: 2/15/2024
If you are directly injured by the drug that is being studied, or by the clinical procedures solely 
required to participate in the study, you may need to pay for treatment of your injuries, but you will 
not be required to pay for emergency medical treatment provided at Strong Memorial Hospital or 
Highland Hospital. The University may seek payment for this care from your health insurer or third 
parties. Decisions regarding care and compensation for any other research related injury will be 
made on a case-by-case basis.


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Confidentiality of Records and Authorization to Use and Disclose Information for Research 
Purposes
For subjects enrolled at the University of Rochester/Strong Memorial Hospital, the results from 
laboratory tests, exams and other tests conducted for this study will be in the Strong Memorial 
Hospital electronic medical record, along with documentation of your study visit.
The University of Rochester makes every effort to keep the 
information collected from you private. In 
order to do so, we will 
limit access of research 
information collected on this study to 
include only 
trained research personnel assigned to this study. Sometimes, however, researchers need to share 
information that may 
identify you with people that work for the University, regulators or the study 
sponsor.
If you have never received a copy of the University of Rochester Medical Center (URMC) and Affiliates 
Notice of Privacy Practices, please ask the investigator for one.
What information may be used and given to others?
The study doctor will get your personal and medical information. For example:
• Research records
• Records about phone calls made as part of this research
• Records about your study visits
• Past and present medical records related to the study
• Results of medical tests
Who may use and give out information about you?
• The study doctor and the study staff
• URMC and Affiliates
Your information may be given to:
• The Department of Health and Human Services
• The University of Rochester
• Astellas/Medivation
• The U.S. Food and Drug Administration (FDA) may also need to 
inspect study records at 
some point during the study or even after 
it has been completed. In the event that this should 
occur, every effort will be made to keep 
identifying 
information about you private.
Why will this information be used and/or given to others?
• To do the research
• To study the results
• To see if the research was done right
If the results of this study are made public, information that identifies you will not be used.
What if I decide not to give permission to use and give out my health information?
Then you will not be able to be in this research study.
RSRB Approval Date: 6/26/2023
Expiration Date: 2/15/2024
May I review or copy my information?


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Yes, but only after the research is over.
How long will this be permission be valid?
This permission will last indefinitely.
May I cancel my permission to use and disclose information?
Yes. You may cancel your permission to use and disclose your health information at any time. You 
do this by sending written notice to the study doctor. Upon receiving the written notice, the study 
team will no longer use or disclose your health information and you will not be able to stay in this 
study. Information that has already been gathered may need to be used and given to others for the 
validity of the study.
May I withdraw from the study?
Yes. If you withdraw your permission to be in the study, no new health information identifying you will 
be gathered after that date. Information that has already been gathered may still be used and given 
to others.
Is my health information protected after it has been given to others?
No. There is a risk that your information will be given to others without your 
permission.
A description of this clinical trial will be available on the internet at: http://www.Clinical Trials.gov, as 
required by U.S. Law. This web site will not include information that can identify you. At most, the 
web site will include a summary of the results. You can search this web site at any time.
Contact Persons
For more information concerning this research or if you feel that your participation has resulted in 
any research related injury, emotional or physical discomfort, please contact:
Dr. Chunkit Fung at 585-275-5863 (24-hours).
Please contact the University of Rochester Research Subjects Review Board at 265 Crittenden Blvd., 
CU 420315, Rochester, NY 14642, Telephone (585) 276-0005 or (877) 449-4441 for the following 
reasons:
• You wish to talk to someone other than the research staff about your rights as a research 
subject;
• To voice concerns about the research;
• To provide input concerning the research process;
• In the event the study staff could not be reached.
Voluntary Participation
RSRB Approval Date: 6/26/2023
Expiration Date: 2/15/2024
Taking part in this study is voluntary. You are free not to take part or to withdraw at any time, for 
whatever reason. No matter what decision you make, there will be no penalty or loss of benefit


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to which you are entitled. In the event that you do withdraw from this study, the information you 
have already provided will be kept in a confidential manner.
*****************************************************************************************
SIGNATURE/DATES
After reading and discussing the information in this consent form you should understand:
• Why this study is being done;
• What will happen during the study;
• Any possible risks and benefits to you;
• Other options you may have instead of being in the study;
• How your personal information will be protected;
• What to do if you have problems or questions about this study.
Subject Consent
I have read (or have had read to me) the contents of this consent form and have been encouraged 
to ask questions. I have received answers to my questions. I agree to participate in this study. I 
have received (or will receive) a signed copy of this form for my records and future reference.
Subject Name (Printed by Subject)
Signature of Subject
Date
Person Obtaining Consent
I have read this form to the subject and/or the subject has read this form. I will provide the 
subject with a signed copy of this consent form. An explanation of the research was given and 
questions from the subject were solicited and answered to the subject’s satisfaction. In my 
judgment, the subject has demonstrated comprehension of the information. I have given the 
subject adequate opportunity to read the consent before signing.
Name and Title (Print)
Signature of Person Obtaining Consent
Date
RSRB Approval Date: 6/26/2023
Expiration Date: 2/15/2024