Clinical trial NCT03279250
Conditions: Prostate Adenocarcinoma Stage IIB Prostate Cancer AJCC v8 Stage IIC Prostate Cancer AJCC v8 Stage IIIA Prostate Cancer AJCC v8 Stage IIIC Prostate Cancer AJCC v8
Sponsor: M.D. Anderson Cancer Center
Start date: 2017-10-13; Completion date: 2021-05-11
Enrollment: 86 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase II trial studies how well apalutamide and gonadotropin-releasing hormone analog with or without abiraterone acetate work in treating participants with prostate cancer prior to surgery. Apalutamide and abiraterone acetate may stop the growth of cancer cells either by killing the cells or by blocking some of the enzymes needed for cell growth. Hormone therapy, using gonadotropin-releasing hormone analog, may fight prostate cancer by lowering the amount of testosterone the body makes. Giving apalutamide, gonadotropin-releasing hormone analog, and abiraterone acetate may work better in treating participants with prostate cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess the rate of pathologic stage =\< pT2N0 at prostatectomy for Group A (gonadotropin-releasing hormone analog \[luteinizing hormone releasing hormone agonist (LHRHa)\] plus apalutamide 240 mg orally \[PO\] daily for 6 months as preoperative therapy) and Group B (LHRHa plus apalutamide 240 mg PO daily plus abiraterone acetate 1000 mg PO daily and prednisone 5 mg PO once daily \[QD\] for 6 months as preoperative therapy).

SECONDARY OBJECTIVES:

I. To assess the tumor epithelium volume following treatment in groups A and B. II. To assess the rate of positive surgical margins in Group A and Group B. III. To assess the time to prostate specific antigen (PSA) recurrence (TTRPSA). IV. To assess the safety profile of the two treatment arms (apalutamide with and without abiraterone acetate and low dose prednisone) for six months in a preoperative setting.

EXPLORATORY OBJECTIVES:

I. Assessment of the steroid hormone metabolome in blood plasma and tissue by liquid chromatography tandem mass spectrometry.

II. Assessment of androgen signaling (canonical and non-canonical) and candidate pathways of resistance to androgen signaling inhibition by protein and ribonucleic acid (RNA) analysis.

III. Assessment of citrate intracellular tricarboxylic acid cycle (TCA) metabolite concentrations with liquid chromatography-tandem mass spectrometry (LCMS/MS).

IV. Proportion of patients who achieve pathological complete response (CR). V. Hyperpolarized 1-13C-pyruvate imaging at study entry and at 3 months in Arm A and Arm B.

OUTLINE: Participants are randomized to 1 of 2 arms.

ARM A: Participants receive gonadotropin-releasing hormone analog (leuprolide, goserelin, or triptorelin as determined by treating physician) intramuscularly (IM) once every 3 months and apalutamide PO QD. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Beginning no less than 48 hours after completion of therapy, participants undergo radical prostatectomy.

ARM B: Participants receive gonadotropin-releasing hormone analog and apalutamide as in arm A, abiraterone acetate PO QD, and prednisone PO QD. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Beginning no less than 48 hours after completion of therapy, participants undergo radical prostatectomy.

After completion of study treatment, participants are followed for 4 weeks.

Arms: arm 1: Participants receive gonadotropin-releasing hormone analog (leuprolide, goserelin, or triptorelin as determined by treating physician) IM once every 3 months and apalutamide PO QD. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Beginning no less than 48 hours after completion of therapy, participants undergo radical prostatectomy. arm 2: Participants receive gonadotropin-releasing hormone analog and apalutamide as in arm A, abiraterone acetate PO QD, and prednisone PO QD. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Beginning no less than 48 hours after completion of therapy, participants undergo radical prostatectomy.
Interventions: intervention 1: Abiraterone Acetate intervention 2: Apalutamide intervention 3: Gonadotropin-releasing Hormone Analog intervention 4: Prednisone intervention 5: Radical Prostatectomy
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO intervention 3: Given IM intervention 4: Given PO intervention 5: Undergo radical prostatectomy

Protocol documents:
Prot_SAP_000.pdf: 
Protocol # 2016-0527 
January 11, 2021, 
Page 1 of 44 
 
 
 
 
 
MD Anderson IND Sponsor Cover Sheet 
 
Protocol ID 
2016-0527 
Protocol Title 
A Pre-Operative Study to Assess the Effects of Apalutamide 
plus LHRH Agonist 
or Apalutamide plus Abiraterone Acetate plus LHRH 
Agonist for Six Months for Prostate Cancer Patients 
at High Risk for Recurrence 
 
Protocol Phase 
Phase 11 
Protocol Version 10 
Version Date 
01/11/2021 
 
Protocol PI 
Christopher J. Logothetis MD 
Department 
Genitourinary Medical 
Oncology 
MD Anderson Cancer Center 
1155 Pressler Street, Unit 1374 
Houston, TX 77030 
Phone:  (713) 563-0894 
Email: eefstathiou@mdanderson.org 
 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
136288 
 
 
 
Biostatistician: 
Becky Slack Tidwell, MS 
1400 Pressler Street, Unit 1411 
Houston, TX 77030 
Email: rsslack@mdanderson.org 
 
 
Funding and Drug Supply: Janssen Scientific Affairs, LLC 
 
 
 
MDACC Version Tracking Table 
Version 00 
04/14/2017 
Pre-submission packet 
Version 01 
05/01/2017 
CRC 
Version 02 
05/26/2017 
CRC Resubmission 
Version 03 
06/19/2017 
IRB Submission 
Version 04 
06/19/2017 
IRB Resubmission 
Version 05 
06/19/2017 
IRB Resubmission 
Version 06 
09/14/2017 
IRB Resubmission 
Version 07 
02/13/2018 
IRB Resubmission 
Version 08 
01/04/2019 
IRB Resubmission 
Version 09 
04/23/2019 
IRB Resubmission 
Version 10 
01/11/2021 
IRB Resubmission 


Protocol # 2016-0527 
January 11, 2021, 
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SCHEMA 
   
 
 
 


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January 11, 2021, 
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TABLE OF CONTENTS 
 
Page 
 
 
Contents 
1.0 
OBJECTIVES ........................................................................................................ 4 
2.0 
BACKGROUND .................................................................................................... 4 
3.0 
PATIENT SELECTION .......................................................................................... 9 
4.0 
TREATMENT PLAN ......................................................................................................13 
5.0 
DOSING DELAYS/DOSE MODIFICATIONS....................................................... 20 
6.0 
ADVERSE EVENTS ............................................................................................ 25 
7.0 
PHARMACEUTICAL INFORMATION ................................................................. 30 
8.0 
STUDY CALENDAR ............................................................................................ 32 
9.0 
MEASUREMENT OF EFFECT ............................................................................ 34 
10.0  STATISTICAL CONSIDERATIONS .................................................................... 34 
11.0  ETHICAL ASPECTS ............................................................................................ 38 
APPENDIX 1 ................................................................................................................. 39 
APPENDIX 2 ................................................................................................................. 40 
APPENDIX 3 ................................................................................................................. 41 
APPENDIX 4: ................................................................................................................ 42 


Protocol # 2016-0527 
January 11, 2021, 
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1.0 
OBJECTIVES 
 
1.1. 
Primary Objectives 
 
To assess the rate of pathologic stage ≤ pT2N0 at prostatectomy for Group A (LHRHa 
plus apalutamide 240 mg PO daily for 6 months as preoperative therapy) and Group B 
(LHRHa plus apalutamide 240 mg PO daily plus abiraterone acetate 1000 mg PO daily 
and prednisone 5 mg PO QD for 6 months as preoperative therapy) 
 
1.2. 
Secondary Objectives 
 
• To assess the tumor epithelium volume following treatment in groups A and B 
• To assess the rate of positive surgical margins in Group A and Group B. 
• To assess the time to PSA recurrence (TTRPSA) 
• To assess the safety profile of the two treatment arms (apalutamide with and 
without abiraterone acetate and low dose prednisone) for six months in a 
preoperative setting. 
 
1.3 
Exploratory Objectives 
 
• Assessment of the steroid hormone metabolome in blood plasma and tissue by 
liquid chromatography tandem mass spectrometry 
• Assessment of androgen signaling (canonical and non-canonical) and candidate 
pathways of resistance to androgen signaling inhibition by protein and RNA 
analysis 
• Assessment of citrate intracellular TCA cycle metabolite concentrations with 
LCMS/MS 
• Proportion of patients who achieve pathological CR 
• Hyperpolarized 1-13C-pyruvate imaging at study entry and at 3 months in Arm A 
and Arm B. 
 
2.0 
BACKGROUND 
 
2.1 
Introduction 
 
Many patients diagnosed with localized prostate cancer are curable with local therapy, 
however approximately 20% of patients in modern series initially present with locally 
advanced or high-grade prostate cancer not amenable to a single therapeutic approach 
i.e. surgery or radiation therapy alone. The prostate cancer experience with 
preoperative therapy over the past 15 years has differed significantly from other solid 
tumors; pathologic complete response is rarely achieved with first generation anti- 


Protocol # 2016-0527 
January 11, 2021, 
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androgens including flutamide and cyproterone or LHRH analogues alone. The addition 
of pre-operative chemotherapy has provided similarly disappointing results. While pCR 
remains elusive, several studies of pre-operative androgen ablations have reported 
reduction in the rate of positive surgical margins, rates of lymph node involvement, and 
increased rates of organ confined disease. Importantly, such trials have failed to impact 
outcomes to date for a variety of reasons. Ensuing knowledge challenges the potential 
association of pCR with improved outcomes and underscores the importance of minimal 
residual tumor volume. Moreover high risk locally advanced prostatic carcinoma is 
characteristic for biologic heterogeneity that invariably will govern responsiveness to 
therapeutic choices suggesting the need for predictive markers of outcome. 
 
In recent years, three pre-operative trials incorporating a new generation of androgen- 
targeting agents including abiraterone and enzalutamide have been reported. These 
have documented rates of conversion to pathologic stage ≤pT2N0 ranging from 40- 
55%;1,2,3 reinforcing the anticipated association with underlying biologic heterogeneity 
within this disease stage . Correlative biomarkers have been evaluated, and while these 
remain investigational at this time, with further validation these may ultimately be used 
to provide a predictive framework to identify patients with high risk localized disease 
who will benefit from intensive pre-operative androgen deprivation. 
 
Combination anti-androgen therapy with abiraterone and enzalutamide has 
demonstrated safety and profound depletion of intraprostatic androgens in metastatic 
CRPC 3,4. Localized prostate cancer is dependent on androgens for proliferation, 
providing the rationale for moving a combination approach with LHRHa, apalutamide 
and abiraterone acetate to the hormone-naïve but high-risk prostate cancer setting. We 
hypothesize that intensification of pre-operative androgen deprivation will further 
decrease intraprostatic androgens, leading to decreased cell proliferation and less 
advanced pathologic stage at prostatectomy. 
 
Apalutamide is an investigational agent not yet approved by the FDA, and is an 
androgen receptor antagonist similar in structure to enzalutamide, an FDA-approved 
agent for the treatment of metastatic CRPC. Both agents prevent AR translocation to 
the nucleus and binding to androgen response elements. A proposed advantage of 
Apalutamide over enzalutamide may include an improved therapeutic index including 
limited CNS toxicity.5 Phase I/II trials have demonstrated safety and tolerance in 
humans.6 
 
2.2 
Agents 
 
i. 
Apalutamide is an androgen-receptor antagonist that prevents AR translocation 
to the nucleus and binding to androgen response elements. In preclinical models, 
Apalutamide produced responses in both castration-sensitive and castration- 
resistant human prostate cancer xenograft models and showed maximal 
antitumor efficacy in these models at a three-fold lower dose and approximately 
nine-fold lower plasma level than enzalutamide, suggestive of a higher 
therapeutic index.5 


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The first in-human phase I study of Apalutamide was published in 2013, and a 
recommended phase II dose of 240mg PO daily was established. This study 
reported ≥50% decline in PSA at 12 weeks in 46.7% of patients, with grade 1/2 
fatigue the most frequently reported adverse effect.6 
 
ii. 
LHRH Agonists (ie, Leuprolide Acetate, Goserelin, Triptorelin) 
At the time of diagnosis localized prostate cancers are categorized as low, 
intermediate or high risk based on clinical stage, prostate specific antigen (PSA) 
level/velocity and tumor Gleason score. Patients who fall into intermediate and 
high risk categories have unacceptably high relapse rates (30-80%) after primary 
local therapy or salvage local approaches. The standard systemic treatment for 
prostate cancer is androgen deprivation therapy (ADT) most commonly 
administered with an LHRHa with/without an antiandrogen. Treatment of systemic 
prostate cancer with ADT is not curative as patients develop castration resistant 
prostate cancer (CRPC). 
 
To date, ADT in high risk localized prostate cancer patients using LHRHa alone 
has reduced prostate volume by roughly 30% and decreased the rate of positive 
surgical margins, but has not been shown to improve the biochemical relapse rate 
for patients who undergo radical prostatectomy. However, because the addition of 
novel androgen targeting agents like abiraterone and Apalutamide to LHRHa 
further lowers androgen levels compared to LHRHa alone in CRPC, there is a 
strong scientific rationale to test whether this more potent combination therapy can 
improve surgical outcomes. 
 
iii. 
Abiraterone Acetate 
Abiraterone acetate (ZYTIGA) is converted in vivo to abiraterone, an androgen 
biosynthesis inhibitor that inhibits 17 α hydroxylase/C17, 20-lyase (CYP17). This 
enzyme is expressed in testicular, adrenal and prostatic tumor tissues and is 
required for androgen biosynthesis. 
 
CYP17 catalyzes two sequential reactions: 1) the conversion of pregnenolone and 
progesterone to their 17α-hydroxy derivatives by 17α-hydroxylase activity and 2) 
the subsequent formation of dehydroepiandrosterone (DHEA) and 
androstenedione, respectively, by C17, 20 lyase activity. DHEA and 
androstenedione are androgens and are precursors of testosterone. Inhibition of 
CYP17 by abiraterone can also result in increased mineralocorticoid production by 
the adrenals. 
 
Abiraterone acetate has received marketing approval in more than 100 countries 
for the treatment of men with metastatic castration-resistant prostate cancer 
(mCRPC) after docetaxel treatment. It is also approved for the treatment of 
mCRPC in men who have not previously received chemotherapy. The pre- 
operative combination proposed in this protocol is not FDA approved. 


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2.3 
Rationale 
 
Abiraterone has demonstrated activity in patients with mCRPC who have progressed on 
hormonal and currently available chemotherapeutic options. Apalutamide is a novel, 
potent inhibitor of the androgen receptor that has demonstrated safety in patients with 
CRPC. Both alterations in the steroid metabolism and the androgen receptor are 
implicated in the clinically observed resistance to castration. Importantly as we have 
first reported in the more advanced disease setting each agent alone induces 
physiologic feedbacks that may contribute to treatment resistance. Taken together, 
these observations provide compelling rationale to combine optimum medical 
castration, inhibition of the androgen receptor, and altered androgen biosynthesis in 
patients at high risk for recurrence. 
 
The proposed study will examine this combination in the pre-operative, hormone-naïve 
but high risk setting. A prior phase II study has examined pre-operative LHRHa plus 
abiraterone compared with LHRHa alone in patients with localized high risk prostate 
cancer (LHRPC). At the time of prostatectomy, pathology staging ≤ pT2N0 occurred in 
24/44 (54.5%) for Abiraterone plus LHRHa versus 8/21 (33.1%) for LHRHa alone, P = 
0.21. Tumor Epithelial density for Abiraterone plus LHRHa was lower compared to 
LHRHa alone (P < 0.0001). Post-treatment prostate-specific antigen (PSA) nadir was ≤ 
0.2 ng/ml in 41/44 (93.2%) for Abiraterone + LHRHa versus 3/21 (14.3%) for LHRHa 
alone (P < 0.0001). For the cohort of patients receiving abiraterone and LHRHa, higher 
ARV7, GR, both by protein and RNA assays were associated with increased residual 
tumor. These findings suggest resistance emerges within 3 months of androgen 
signaling inhibition despite universal serum PSA declines, which have clinical 
implications on designing combinational treatment strategies for LHRPC. 
 
Another phase II study has examined pre-operative LHRHa plus abiraterone plus 
enzalutamide compared with LHRHa plus abiraterone. Complete molecular 
characterization of these results are still pending, but suggestions of early resistance 
and responsiveness were identified, with tumors with favorable pathology stage (≤ 
pT2N0) demonstrating higher canonical androgen signaling 
 
The studies summarized above have outline proposed biomarker profiles of resistance 
and responsiveness to LHRHa alone, LHRHa plus abiraterone, and LHRHA plus 
abiraterone plus enzalutamide. The proposed study will add to these results by 
characterizing the biomarker profiles of responsiveness and resistance to apalutamide 
plus LHRHa and apalutamide plus LHRHa plus abiraterone. These profiles may 
ultimately provide the framework for personalized pre-operative treatment for LHRPC. 
 
This knowledge will build on our understanding of the effect of optimum androgen 
inhibition in the setting of newly diagnosed, high-risk prostate cancer. The findings will 
lead to a framework that will allow us to personalize androgen signaling targeted 
therapy, by stage of progression, within individual patients and assure the safe use of 
the drug and the development of a rational combination therapy. Exploratory biomarker 
studies will be used to explore the subset of patients who benefit most from two-agent 


Protocol # 2016-0527 
January 11, 2021, 
Page 8 of 44 
 
 
 
or three-agent pre-operative androgen ablation, and a subset with early resistance. 
Ultimately, biomarker patterns of pre-operative androgen resistance may be used to 
guide intensification of alternative therapies for patients who demonstrate resistance 
despite maximal androgen ablation. 
 
2.4 
Correlative Studies Background 
 
The diagnosis of prostate cancer is dependent on core needle biopsy, as will be our 
assessments of correlative biomarkers (discussed below) in the proposed study. Core 
needle biopsy is associated with morbidity, and is by definition susceptible to 
overlooking areas of interest due to sampling. The ramifications of our current reliance 
on prostate biopsies are demonstrated by the significant number of patients who are up- 
staged at the time of prostatectomy. 
 
2.4.1 
Magnetic resonance spectroscopy 
 
Hyperpolarized magnetic resonance spectroscopy (MRS) is a functional imaging 
technique that allows for acquisition of detailed metabolic information during non- 
invasive MR imaging, eliminating both the sampling error and the morbidity associated 
with core needle biopsy. Incorporating MRS into our assessment of high-risk localized 
prostate cancer will validate its use in this setting and allow for comprehensive 
assessment of metabolism in all foci of prostate cancer. We hypothesize that pre- 
operative intensive androgen depletion will also have differential effects on citrate flux in 
responders and non-responders. Normal prostate cells have the unique characteristic 
of accumulating and secreting high concentrations of citrate, usually employed by 
eukaryotic cells in the oxidative metabolism of carbohydrates via the tricarboxylic acid 
(TCA) cycle. Loss of this high citrate concentration is an early hallmark of malignant 
transformation, and is consistently observed in prostate cancers. In prostate cancer 
cells, citrate is diverted to anabolic pathways including fatty acid (FA) synthesis and de 
novo testosterone synthesis via acetyl-CoA; therefore citrate serves as the central link 
between intermediary metabolism and androgen signaling in the prostate cancer cell. 
Citrate flux profiles after pre-operative androgen deprivation will enable non-invasive 
monitoring of efficacy, that when paired with cell density and molecular characterization 
will enable early identification resistance to androgen deprivation in the localized setting. 
 
 
2.4.2 
Laboratory Biomarkers 
 
Efstathiou and Titus have presented and published extensively on molecular 
characterization of CRPC treated with Abiraterone, enzalutamide and the combination 
in the metastatic setting. Responders to both Abiraterone and enzalutamide have 
increased nuclear N-terminal AR staining and ≥10% CYP17 tumor expression. These 
studies serve as proof of principle that molecular characterization can yield predictive 
information. 


Protocol # 2016-0527 
 
April 23, 2019, 
Page 9 of 44 
 
 
3.0 PATIENT SELECTION 
 
3.1 Eligibility Criteria 
 
a) Patients must have histologically or cytologically confirmed adenocarcinoma of 
the prostate with no histological variants (such as small cell, sarcomatoid, pure 
ductal cancer, transitional cell carcinoma). 
 
b) Patients may have received one prior depot injection of LHRH agonist or LHRH 
antagonist ( degarelix) within 30 days prior to study entry. Patients who have 
received any other prior hormonal therapy or any chemotherapy for prostate 
cancer will be excluded. 
 
(Patients who have discontinued finasteride or dutasteride or testosterone 
supplementation for at least 2 weeks will be allowed to enroll) 
 
3.1.1 
Each patient must meet the following criteria to be enrolled in this study: 
 
 
1) 
Be willing/able to adhere to the prohibitions and restrictions specified in this 
protocol. 
2) 
Have signed an informed consent document indicating that the subject 
understands the purpose of and procedures required for the study and is willing 
to participate in the study. 
3) 
Written Authorization for Use and Release of Health and Research Study 
Information has been obtained. 
4) 
Age >18 years. Because no dosing or adverse event data are currently 
available on the use of Abiraterone in combination with apalutamide (in patients 
<18 years of age, children are excluded from this study. 
5) 
Pathology review at MD Anderson (Note: if patient’s prostate biopsy was not 
read at MD Anderson, it must be reviewed at the study site to confirm eligibility). 
6) 
Prostate Biopsy. If previous biopsy has been performed within 3 months of 
screening, second biopsy procedure will not be required, if archival biopsies 
and at least one formalin fixed paraffin embedded biopsy tissue block 
containing tumor is available. (Refer to section 4.2.5) 
 
7) 
The following tumor stage and Gleason scores: 
• Clinical ≥stage T1c/T2 tumor with Gleason score ≥8 
• Clinical stage ≥T2b tumor with Gleason score ≥7 and PSA >10 ng/ml 
8) 
Serum testosterone >150 ng/dL. For patients treated up to 1 month of LHRH 
agonist, a testosterone measurement prior to the LHRH treatment will be used 


Protocol # 2016-0527 
April 23, 2019 
Page 10 of 44 
 
 
 
to determine eligibility, and must have been > 150 ng/dL. If no testosterone 
level is available from before LHRHa injection up to 30 days prior to study entry, 
the patient will be ineligible. 
9) 
Patient is suitable for prostatectomy. 
10) 
No evidence of metastatic disease as determined by imaging procedures. 
11) 
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. 
12) 
Hemoglobin ≥9.0 g/dL independent of transfusion. 
13) 
Platelet count ≥100,000/µL. 
14) 
Patients should have adequate bone marrow function defined as an absolute 
peripheral neutrophil count (ANC) >1,000. 
15) 
Creatinine clearance ≥50 mL/min 
16) 
Serum potassium ≥3.5 mmol/L. 
17) 
Serum bilirubin ≤ 1.5x ULN or ALT and AST ≤ 2.5x ULN 
18) 
Serum Albumin ≥ 3.0 g/dl 
19) 
Able to swallow the study drug whole as a tablet. 
20) 
Patients must have normal coagulation profile and no history of substantial non- 
iatrogenic bleeding diathesis. 
21) 
Agrees to use a condom (even men with vasectomies) and another effective 
method of birth control if he is having sex with a woman of childbearing 
potential or agrees to use a condom if he is having sex with a woman who is 
pregnant while on study drug and for 3 months following the last dose of study 
drug. Must also agree not to donate sperm during the study and for 3 months 
after receiving the last dose of study drug. 
22) 
Willing to take abiraterone acetate on an empty stomach; no food should be 
consumed at least two hours before and for at least one hour after the dose of 
abiraterone acetate is taken. 
23) 
Life expectancy of greater than 12 months. 
 
3.2 
Exclusion Criteria 
 
 
1) 
Patients who have had any prior chemotherapy or radiotherapy for prostate 
cancer. 
2) 
Patients who have had >1 LHRH agonist or antagonist depot injection or 
received depot injection >30 days before study entry. 
3) 
Patients may not be receiving any other investigational agents. 
4) 
Patients may not be receiving the concomitant administration of any systemic 
therapy, biologic therapy, or other agents with anti-tumor activity against 
prostate cancer while the are on study. 


Protocol # 2016-0527 
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5) 
Patients with known metastatic prostate cancer. 
6) 
History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to Leuprolide acetate, abiraterone acetate, prednisone or 
apalutamide or other agents used in the study. 
7) 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, 
cardiac arrhythmia, or psychiatric illness/social situations that would limit 
compliance with study requirements. 
8) 
HIV-positive patients on combination antiretroviral therapy are ineligible 
because of the potential for pharmacokinetic interactions with apalutamide and 
abiraterone. Appropriate studies will be undertaken in patients receiving 
combination antiretroviral therapy when indicated. 
9) 
Avoid concomitant strong CYP3A4 inducers during abiraterone acetate 
treatment. If a strong CYP3A4 inducer must be co-administered, increase the 
abiraterone acetate dosing frequency. 
10) 
Avoid co-administration of abiraterone acetate with CYP2D6 substrates that 
have a narrow therapeutic index. If an alternative treatment cannot be used, 
exercise caution and consider a dose reduction of the concomitant CYP2D6 
substrate. 
 
11. 
patients receiving medications known to lower the seizure threshold are 
ineligible unless discontinued or substituted at least 4 weeks prior to study entry. 
 
These include: 
 
• Aminophylline/theophylline; 
• Atypical antipsychotics (e.g., clozapine, olanzapine, risperidone, ziprasidone); 
• Bupropion; 
• Lithium; 
• Pethidine; 
• Phenothiazine antipsychotics (e.g., prochlorperazine (compazine), 
chlorpromazine, mesoridazine, thioridazine); 
• Tricyclic and tetracyclic antidepressants (e.g., amitriptyline, desipramine, 
doxepin, imipramine, maprotiline, mirtazapine). 
 
 
 
12. Chronically uncontrolled hypertension, defined conventionally as consistent systolic 
pressures above 170 or diastolic pressures above 110 despite anti-hypertensive 
therapy. Note that this is NOT a criterion related to particular BP results at the time of 
assessment for eligibility, nor does it apply to acute BP excursions that are related to 
iatrogenic causes, acute pain or other transient, reversible causes. (For example 
doctor’s visit related stress i.e. “white coat syndrome”. 


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13. Requirement for corticosteroids greater than the equivalent of 10 mg of 
prednisone daily for more than 2 weeks. 
14. Poorly controlled diabetes defined by Hemoglobin A1C > 9.0 at screening 
15. Active or symptomatic viral hepatitis or chronic liver disease. 
16. Known history of pituitary or adrenal dysfunction. 
17. Other malignancy, except non-melanoma skin cancer, that is active or has a ≥ 
30% probability of recurrence within 12 months. 
18. History of gastrointestinal disorders (medical disorders or extensive surgery) 
which may interfere with the absorption of the study drug. 
19. Prior hormone therapy for prostate cancer including orchiectomy, antiandrogens, 
ketoconazole, or estrogens (5-α reductase inhibitors allowed), or LHRH 
agonists/antagonists (*Note: LHRH allowed if begun within 1 month of Day 1). 
20. Prior systemic treatment with an azole drug within four weeks of Cycle 1 Day1. 
21. Current enrollment in an investigational drug or device study or participation in 
such a study within 30 days of Cycle 1 Day 1. 
22. Allergies, hypersensitivity, or intolerance to prednisone, LHRH analog or 
excipients of prednisone LHRH analog, abiraterone acetate and apalutamide. 
23. Previous use of abiraterone acetate or other investigational CYP17 inhibitor (e.g., 
TAK-700). 
24. Previous investigational antiandrogens (e.g., apalutamide, enzalutamide, BMS- 
641988). 
25Condition or situation which, in the investigator’s opinion, may put the patient 
at significant risk, may confound the study results, or may interfere significantly 
with patient’s participation in the study. 
26. 
Patients unable to tolerate transrectal ultrasound. 
27. 
Anti-androgens (steroidal or non-steroidal) such as cyproterone acetate, 
flutamide, nilutamide, bicalutamide, etc. other than assigned study drug unless 
given for <=4 weeks. 
28. Estrogens, progestational agents such as megestrol, medroxyprogesterone, 
DES, cyproterone, spironolactone > 50 mg/kg, etc. unless discontinued at 
least two weeks prior to randomization 
29. Androgens such as testosterone, dehydroepiandrosterone [DHEA], etc. unless 
discontinued at least two weeks prior to randomization. 
30. Herbal products that may decrease PSA levels (e.g., saw palmetto) unless 
discontinued two weeks prior to randomization 
31. Active infection or other medical condition that would make prednisone/ 
prednisolone (corticosteroid) use contraindicated. 


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32. Severe hepatic impairment (Child-Pugh Class C). 
33. History of significant bleeding disorder unrelated to cancer, including: 
• Diagnosed congenital bleeding disorders (e.g., von Willebrand’s 
disease) 
• Diagnosed acquired bleeding disorder within one year (e.g., acquired 
anti-factor VIII antibodies) of screening visit. 
• History of GI bleeding within 3 months of screening visit requiring ≥2 
units packed red blood cells. 
 
3.2.1 
Clinically significant cardiovascular disease including: 
 
• Myocardial infarction within 6 months of Screening visit; 
• Uncontrolled angina within 3 months of Screening visit; 
• Congestive heart failure New York Heart Association (NYHA) class 3 or 4, 
or subjects with history of congestive heart failure NYHA class 3 or 4 in the 
past, or history of anthracycline or anthracenedione (mitoxantrone) 
treatment, unless a screening echocardiogram or multi-gated acquisition 
scan (MUGA) performed within three months of the Screening visit results 
in a left ventricular ejection fraction that is ≥ 50%. 
• History of clinically significant ventricular arrhythmias (e.g., ventricular 
tachycardia, ventricular fibrillation, torsade de pointes). 
• Prolonged corrected QT interval by the Fridericia correction formula (QTcF) 
on the screening Electrocardiogram (ECG) > 470 msec. 
• History of Mobitz II second degree or third degree heart block without a 
permanent pacemaker in place. 
• Hypotension (systolic blood pressure < 86 mmHg or bradycardia with a 
heart rate of <50 beats per minute on the Screening ECG., unless 
pharmaceutically induced and thus reversible (i.e. beta blockers). 
 
3.3 
Inclusion of Minorities 
 
Men of all races and ethnic groups are eligible for this trial. 
 
4.0 TREATMENT PLAN 
 
4.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis. Reported adverse events and 
potential risks for apalutamide, leuprolide, and abiraterone acetate are described in 
Section 6. Appropriate dose modifications for apalutamide and abiraterone acetate are 
described in Section 5.0. No investigational or commercial agents or therapies other 
than those described below may be administered with the intent to treat the patient's 
malignancy. 


Protocol # 2016-0527 
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REGIMEN DESCRIPTION 
Agent 
Premedications/ 
Precautions 
Dose 
Route Schedule 
Cycle 
Length 
Leuprolide* 
22.5 mg 
IM 
IM every 
3 months 
4 
weeks 
(28 
days) 
Abiraterone 
Acetate 
Take on an 
empty stomach 
1000 mg 
PO 
Daily, 
days 1-28 
Prednisone 
5 mg 
PO 
QD, days 
1-28 
Apalutamide 
240 mg 
PO 
Daily, 
days 1-28 
* Any analogue or antagonist of equivalent dosing and schema as long as the total 
dosing does not exceed 6 months. 
 
4.1.1 Apalutamide 
 
No specific prophylactic or supportive care regimen is required. 
 
4.1.2 Abiraterone Acetate 
 
Co-administration with prednisone 5mg PO QD is indicated for the prevention of 
mineralocorticoid excess. 
 
4.1.3 LHRH Agonist/ Antagonist 
 
No specific prophylactic or supportive care regimen is required. 
 
4.1.4 Medication Compliance 
Compliance (individual drugs) within 80% of instructed dose and schedule is expected of 
participants each cycle. Variations in dosing within expected compliance will not 
constitute a protocol deviation or violation. Missed dosed may be documented in the 
electronic case report form. 
 
 
4.2 
Surgical Procedures 
 
4.2.1 
Radical Prostatectomy 
 
Tissue from the prostatectomy and baseline pretreatment prostate biopsies will be 
collected for correlative studies. 
 
4.2.2 
Extent of Operation 
 
All patients will have a planned radical prostatectomy. 
 
4.2.3 
Timing of Prostatectomy 


Protocol # 2016-0527 
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The surgery will be planned at the end of Cycle 6. Patients must be off apalutamide and, 
if applicable, abiraterone acetate no less than 48 hours prior to surgery. Prednisone 
discontinuation will be up to provider’s determination. To permit flexibility in surgical 
scheduling a study window of a maximum of four weeks will be allowed. In the event the 
surgery is delayed, the patient will be required to return to the clinic for safety 
assessment. 


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Surgery will be performed only after recovery from any side effects from abiraterone 
acetate or apalutamide to a level considered safe for surgery. In the event of delayed 
recovery, the patient will be maintained on LHRHa until the clinical condition permits 
surgery. 
 
4.2.4 Assessment of Surgical Complication 
 
It will be the responsibility of the attending surgeon to accurately tabulate complications 
and the progress of the surgical procedure. Specifically tabulated will be the duration of 
anesthesia, blood product requirement blood loss, fluid requirement, and gross 
description of the operative field (presence or absence of desmoplasia). 
 
4.2.5 
Prostate Tissue Handling 
 
An archival tumor tissue block (or at least 20 unstained slides from the tumor tissue 
block; archived or recent) or fresh frozen tissue in liquid nitrogen will be required from 
the patient’s initial prostate biopsy. These will be reviewed by the pathologist for 
confirmation of cancer and Gleason scoring. The patient will not be required to undergo 
a second biopsy procedure prior to starting study therapy (screening) if archival biopsies 
and unstained slides are available. 
 
In order to preserve androgen levels in tissues, open intraoperative cores biopsies will 
be obtained prior to prostatectomy. The biopsies must be obtained prior to ligation of the 
vascular supply to the prostate. A minimum of 6 biopsies will be obtained attempting to 
focus on known regions of cancer. Each biopsy core should be placed in a separate 2 
ml screwtop cryotube and immediately snap frozen in liquid nitrogen or dry ice/ethanol 
bath and stored at -80°C. If there is palpable tumor, it is recommended that at least 3 
cores be obtained from the area of suspected tumor. 
 
To process the radical prostatectomy specimen post-operatively, the following 
procedures must be followed: 
 
• The prostate will be inked in four colors depicting left, right, superior and inferior 
sections and serially sectioned. 
Alternate coronal sections will be numbered sequentially from apex to base, 
divided into 4 quadrants (also labeled clockwise from the superoposterior 
quadrant as A, B, C, D) and immediately frozen in OCT (liquid nitrogen or dry 
ice/ethanol bath) for subsequent evaluation. The alternate sections will be placed 
in formalin, then processed and imbedded in paraffin using the tissue-tek®vip® 6 
system (for histology analysis) and stored in the Prostate Tissue Bank at MDACC 
for future analysis. The coronal sections embedded in OCT will be stored, in the 
GU biorepository located at MDACC, for future analysis. 
Any future additional analyses not specified in this protocol will be agreed upon 
by prior approval from Janssen Scientific Affairs, LLC. 
• Tissue samples collected on this study for future analysis are optional and not a 
requirement to be enrolled on this protocol. 


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4.2.7 
Correlative Biomarkers 
 
 
For all patients who provide informed consent, prostate tumor and normal prostate tissue 
will be obtained by macrodissection when possible. Testosterone and DHT and steroid 
metabolites of interest will be analyzed by a research laboratory at MD Anderson. 
 
Standard methods such as IHC and whole exome sequencing will be used to assess 
prostate tumor for canonical and non-canonical androgen signaling proliferation cell 
cycle neuroendocrine markers, angiogenesis (CD31, VEGF, VEGFR,) and other 
relevant biomarkers likely associated with steroid metabolism and prostate cancer will 
be analyzed by the Stanford Alexander laboratory at MD Anderson. 
 
Transcriptomic characterization of the tumor will be conducted in the Laboratory of Dr. 
Mark Titus at MD Anderson. Where available, analysis will be carried out on the pre- 
prostatectomy specimens, and prostatectomy specimens using fresh frozen tissue for 
primary tumor. RNA Analysis will include long non coding RNA (lnRNA) examples as 
per www.lncrnadb.org; oncomir RNA; and micro RNA (miRNA) such as #205, 146, 1256 
and let7. DNA analysis will also be performed.8,9 DNA analysis will also be performed. 
Upon completion of research any remained tissue or other sample will be returned to 
institutional tissue bank after publication of research. Patient Identity will be 
safeguarded in accordance with HIPAA and MDACC guidelines. 
 
 
 
4.3 
General Concomitant Medication and Supportive Care Guidelines 
 
4.3.1 
Effects of Apalutamide on Drug Metabolizing Enzymes 
 
Because there is a potential for interaction of apalutamide with other concomitantly 
administered drugs through the cytochrome P450 system, the concurrent use of all 
other drugs, over-the-counter medications, or alternative therapies will be recorded in 
the patient’s medical records. The Principal Investigator should be alerted by the 
research nurse or study coordinator performing current medication review at 
each study visit if the patient is taking any agent known to affect or with the 
potential to affect selected CYP450 isoenzymes. 
In vitro, CYP3A4 and CYP2C8 are the enzymes primarily responsible for the 
metabolism of apalutamide. 
 
Coadministration of a strong CYP3A4 inhibitor (itraconazole) had no clinically 
meaningful effect on the PK of apalutamide and its metabolite JNJ-56142060 (M3). 
Coadministration of a strong CYP2C8 inhibitor (gemfibrozil) increased the AUC of 
apalutamide by 68% but decreased the AUC of JNJ-56142060 (M3) by 15%. Use 


Protocol # 2016-0527 
April 23, 2019 
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caution if strong CYP2C8 inhibitors (eg, gemfibrozil) are coadministered with 
apalutamide. 
 
The effects of CYP3A4 inducers or CYP2C8 inducers on the PK of apalutamide have 
not been evaluated in vivo. Coadministration of apalutamide with the following drugs 
that can induce CYP3A4 or CYP2C8 should be avoided as coadministration with any of 
these agents may decrease apalutamide plasma concentrations. Alternative therapies 
should be used when available. 
 
• Strong CYP3A4 inducers: phenytoin, carbamazepine, rifampin, rifabutin, 
rifapentin, phenobarbital, efavirenz, tipranivir, St. John's wort 
• CYP2C8 inducers: rifampin 
 
4.3.2 
Effects of Abiraterone on Drug Metabolizing Enzymes 
 
Abiraterone acetate is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In 
a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 
substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was 
given with abiraterone acetate 1000 mg daily and prednisone 5 mg twice daily. Avoid 
co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow 
therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise 
caution and consider a dose reduction of the concomitant CYP2D6 substrate drug. 
 
In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone was 
increased by 46% and the AUCs for M-III and M-IV, the active metabolites of 
pioglitazone, each decreased by 10%, when pioglitazone was given together with a 
single dose of 1000 mg abiraterone acetate. Although these results indicate that no 
clinically meaningful increases in exposure are expected when abiraterone acetate is 
combined with drugs that are predominantly eliminated by CYP2C8, patients should be 
monitored for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic 
index if used concomitantly with abiraterone acetate. 
 
4.3.3 
Drugs that Inhibit or Induce CYP3A4 Enzymes 
 
1) Based on in vitro data, abiraterone acetate is a substrate of CYP3A4. The effects 
of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, 
atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, 
voriconazole) or inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, 
rifapentine, and phenobarbital) on the pharmacokinetics of abiraterone have not 
been evaluated, in vivo. Avoid or use with caution, strong inhibitors and inducers 
of CYP3A4 during abiraterone acetate treatment.Avoid concomitant strong 
CYP3A4 inducers during abiraterone acetate treatment. If a strong CYP3A4 
inducer must be co-administered, increase the abiraterone acetate dosing 
frequency. 


Protocol # 2016-0527 
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2) 
Avoid co-administration of abiraterone acetate with CYP2D6 substrates that have 
a narrow therapeutic index. If an alternative treatment cannot be used, exercise 
caution and consider a dose reduction of the concomitant CYP2D6 substrate 
 
 
4.3.4 
Previous Medication (Drugs and Therapies) 
 
Medication taken within four weeks prior to registration must be captured in the medical 
record. At each visit, all concomitant treatments, including blood and blood products, 
must be reported on the source documentation. Concomitant medications must also be 
documented at the time of discontinuation and at the 30 day follow-up visit. 
 
The dosage and regimen of the following medications and any chronic permitted 
concomitant medications should be stabilized for 4 weeks prior to Day 1 and held 
constant throughout the study: 
 
• Bisphosphonates 
• Denosumab (or other RANK-ligand inhibitor) 
• GnRH agonist/antagonist 
 
No other new systemic therapy or new radiotherapy for treatment of prostate cancer is 
permitted while subject is on study. 
 
The following medications are prohibited while the subject is on study drug: 
 
• Chemotherapeutic, biologic, or other agents with anti-tumor activity against 
prostate cancer other than assigned study drug. 
• Anti-androgens (steroidal or non-steroidal) such as cyproterone acetate, 
flutamide, nilutamide, bicalutamide, etc. other than assigned study drug. 
• Estrogens, progestational agents such as megestrol, medroxyprogesterone, 
DES, cyproterone, etc. 
• Androgens such as testosterone, dehydroepiandrosterone [DHEA], 
etc.Ketoconazole. 
• Herbal products that may decrease PSA levels (e.g., saw palmetto). 
 
Medications that inhibit platelet function and anticoagulants should be used with caution 
while the subject is on study drug, including: 
 
• Aspirin or aspirin-containing combinations. 
• Clopidogrel, dipyridamole, tirofiban, dipyridamole, epoprostenol, eptifibatide, and 
cilostazol. 
• Abciximab, ticlopidine, cilostazol, warfarin. 
• Heparin/low molecular weight heparin [eg, danaparoid, dalteparin, tinzaparin, 
enoxaparin]. 
• Use of heparin for flushes of intravenous lines is allowed. 


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4.4 
Duration of Therapy 
 
In the absence of treatment delays due to adverse events, treatment may continue for 6 
cycles or until one of the following criteria applies: 
 
Χ 
Disease progression, 
 
Χ 
Intercurrent illness that prevents further administration of treatment, 
Χ 
Unacceptable adverse events(s), 
Χ 
Patient decides to withdraw from the study, or 
 
Χ 
General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 
4.5 
Duration of Follow Up 
 
Patients will be followed for 4 weeks after removal from study or until death, whichever 
occurs first. Patients removed from study for unacceptable adverse events will be 
followed until resolution or stabilization of the adverse event. 
 
4.6 
Criteria for removal from Study 
 
To discontinue Study Treatment, any of the criteria below must be met: 
 
• The patient completed 6 cycles of study treatment. 
• Sustained side effects: patients who have sustained toxicities, such as 
hyperglycemia or hypertension that do not return to NCI CTCAE (version 
4.03) grade 1 or less with appropriate medical management, should be 
discontinued from the study treatment phase. All end-of-study treatment 
procedures should be conducted. The patient will be followed to 4 weeks after 
the EOS visit. 
• Dosing noncompliance: study treatment administration and dosing compliance 
will be assessed on Day 1 of all cycles and at Pre-surgery/End of Study Visit. A 
count of study treatment will be conducted during this visit and patient dosing 
compliance will be assessed. If dosing compliance is not >75% in the absence of 
toxicity, patient should be re-instructed regarding proper dosing procedures 
and continue in the protocol. Subsequent dosing compliance procedure will be 
conducted at each study visit. If a patient misses 14 or more doses within 4 
weeks, the patient should be discontinued from the study treatment phase. All 
end-of-study treatment procedures should be followed. The patient will be 
followed to 4 weeks after the EOS visit. 


Protocol # 2016-0527 
April 23, 2019 
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• Initiation  of  new  anticancer  treatment:  patients  will  be  discontinued  from 
the study treatment when investigator, in  his  or  her  judgment,  determines 
new treatment for prostate cancer is warranted. All end-of-study treatment 
procedures should be conducted and the patient will be followed to 4 weeks after 
the EOS Visit. 
Administration of prohibited medications: the patient will be discontinued from the 
protocol treatment when prohibited drug is administered. All end-of-study treatment 
procedures should be conducted and the patient will be followed to 4 weeks after the 
EOS visit. Supportive care medications are permitted with their use following 
institutional guidelines.  The  concurrent  administration  of other anticancer 
therapy, 
including cytotoxic, hormonal, or  immunotherapy  is  prohibited  during  study 
treatment phase. Use of other investigational drug therapy for any reason is prohibited. 
 
Patient met Grade 4 criteria for elevated Liver Function Tests or the criteria for dose 
discontinuation of non-mineralocorticoid based side-effects. 
Subjects experiencing toxicity considered to be related to the use of prednisone for which 
a dose reduction is needed, which that would require discontinuation of study drugs. 
 
5.1 
DOSING DELAYS/DOSE MODIFICATIONS 
 
In subjects who experience toxicity who cannot be ameliorated by the use of adequate 
medical intervention, dose reductions can be performed. In these cases dose reductions 
of abiraterone acetate should be performed first, followed by reduction in apalutamide 
doses (if needed). 
 
For abiraterone acetate, 2 dose reductions are allowed, though dosing may be interrupted 
without a dose reduction. Patients who experience a Grade 3 or greater toxicity 
considered to be related to abiraterone acetate will be dose reduced per the following 
schema. At each dose reduction, one tablet of abiraterone acetate will be removed, e.g., 
4→3 tablets, and 3→2 tablets. Any return to protocol dose level after dose reduction or 
after treatment interruption must follow documentation of adverse event resolution and a 
discussion with the Principal Investigator. Dosing with abiraterone may be held for up to 
28 days without discontinuation from therapy. 
 
Patients who experience a Grade 3 or greater toxicity considered to be related to 
apalutamide that cannot be ameliorated by the use of adequate medical intervention 
should have their treatment interrupted until the toxicity improves to a Grade 2 or lower 
severity. Patients may subsequently be re-started on study drug at a reduced dose as per 
the discretion of the Principal Investigator. Dosing with apalutamide may be held for up to 
28 days without discontinuation from therapy. Subjects will remain on abiraterone acetate 
and prednisone during apalutamide dose interruption. 
 
No dose reductions for leuprolide or prednisone are allowed. Subjects experiencing 
toxicity considered to be related to the use of prednisone for which a dose reduction is 
needed will require discontinuation of study drugs. 
 
Subjects should be able to take all four study drugs (abiraterone acetate, apalutamide, 


Protocol # 2016-0527 
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Page 21 of 44 
 
 
 
leuprolide, and prednisone) to participate in the study. An interruption of one of these 
drugs is allowed as per instruction above.  
Discontinuation of one of these drugs, while continuing the two other drugs, is permitted 
per investigator’s discretion. 
 
 
Study treatment will be stopped in all patients experiencing grade 4 toxicity which is 
clinically significant per PI discretion. Patients will be recommended to proceed to 
planned surgery upon recovery. 
 
 
 
5.2 
Dose Modification Tables 
 
Dose modifications are provided as guidance and should not replace the 
investigator’s own clinical judgment. 
Table 5.1.1 Dose Modifications for Toxicity Attributed to Apalutamide 
 
 
Toxicity 
Dose of abiraterone acetate 
Dose of apalutamide 
Dose of prednisone 
Grade 1 or 2 
No change 
No change 
No change 
≥Grade 3 or higher 
No change 
Hold until Grade 1 or baseline, resume 
at full dose 
No change 
First Recurrence 
≥Grade 3 
No change 
Hold until Grade 1 or baseline, resume 
at 180 mg (3 tablets) 
No change 
Second Recurrence 
≥Grade 3 
No change 
Hold until Grade 1 or baseline, resume 
at 120 mg (2 tablets) 
No change 
Third Recurrence 
≥Grade 3 
No change 
Discontinue 
No change 
First occurrence of 
seizure of any grade 
or Grade 4 
neurotoxicity 
No change 
Discontinue 
No change 


Protocol # 2016-0527 
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Page 22 of 44 
 
 
 
5.1.2 Dose Modifications for Rash 
Dose modifications are provided as guidance and should not replace 
the investigator’s own clinical judgment. 
 
Dose modifications for rash are allowed only for apalutamide and are summarized in below table. 
If the skin rash has any component of desquamation, mucosal involvement, or pustules, stop dosing with 
apalutamide, refer to dermatologist for evaluation, and a skin biopsy is recommended (in addition to the 
interventions listed in below Table) If the skin rash is Grade 3 or higher, asking the subject to consent to 
documentation by a photograph and further evaluation by a dermatologist should also be considered. 
 
Severity 
Intervention 
Grade 1 
• 
Continue apalutamide at current dose 
• 
Initiate dermatological treatmenta 
o 
Topical steroid cream AND 
o 
Oral Antihistamines 
• 
Monitor for change in severitya 
Grade 2 (or symptomatic 
Grade 1)b 
• 
Hold apalutamide for up to 28 days 
• 
Initiate dermatological treatmenta 
o 
Topical steroid cream AND 
o 
Oral Antihistamines 
• 
Monitor for change in severitya 
o 
If rash or related symptoms improve, reinitiate apalutamide when rash 
is Grade≤1. Consider dose reduction at a 1 dose level reductionc. 
Grade ≥3d 
• 
Hold apalutamide for up to 28 days 
• 
Initiate dermatological treatmenta 
o 
Topical steroid cream AND 
o 
Oral Antihistamines AND 
o 
Consider short course of oral steroids 
• 
Reassess after 2 weeks (by site staff), and if the rash is the same or has 
worsened, initiate oral steroids (if not already done) and refer the subject to 
a dermatologist 
o 
Reinitiate apalutamide at a 1 dose level reductionc when rash is 
Grade≤1. 
o 
If the dose reduction will lead to a dose less than 120mg, the study 
drug must be stopped (discontinued) 
• 
If after 28 days, rash has not resolved to Grade≤1, contact study PI. 
 
Note: Rash may be graded differently according to the type of rash and associated symptoms. For example, maculo- 
papular rash is graded by body surface area covered and not severity of the rash. Please consult NCI-CTCAE 
Version 4.03 for specific grading criteria for other types of rash. 
a Obtain bacterial/viral cultures if infection is suspected 
b Subject presents with other rash related symptoms such as pruritus, stinging, or burning 
c 1 dose level reduction = 60mg (1 apalutamide tablet) 
d If there is blistering or mucosal involvement, stop apalutamide dosing immediately and contact PI 
e If a subject previously started oral corticosteroids, continue for at least 1 week after resumption of 
reduced dose of apalutamide. If the proposed total oral steroid use will exceed 28 days, contact PI. 


Protocol # 2016-0527 
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Table 5.1.3 Dose Modifications for LFT Abnormalities Attributed to Abiraterone 
Acetate 
 
Dose modifications are provided as guidance and should not replace the investigator’s own clinical judgment. 
 
Toxicity 
Dose of abiraterone acetate 
Dose of apalutamide 
Dose of prednisone 
Grade 1 or 2 
No change 
No change 
No change 
Grade 3 
Hold until return to baseline 
or to AST or ALT 
≤2.5 x ULN and total bilirubin 
≤1.5 x ULN, resume at 750 
mg (3 tablets) 
Hold until return to baseline 
No change 
Recurrence 
Grade 3 
Hold until return to baseline 
or to AST or ALT 
≤2.5 x ULN and total bilirubin 
≤1.5 x ULN, resume at 500 
mg (2 tablets) 
Hold until return to baseline 
No change 
Grade 4 
Discontinue AA treatment 
Hold until return to baseline 
No change or consider 
tapering if AA discontinued 
Concurrent 
elevation of 
AST/ALT > 3x 
ULN with bilirubin 
>2x ULN (unless 
the concurrent 
elevation is related 
to biliary 
obstruction or other 
causes unrelated to 
study treatment) 
Discontinue AA treatment 
No change or consider 
tapering if AA discontinued 
 
AA=abiraterone acetate; ALT=alanine aminotransferase; AST=aspartate aminotransferase; LFT=liver function tests; 
ULN=upper limit of normal 


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Table 5.1.4 Dose Modifications for Hypokalemia Attributed to Abiraterone Acetate 
 
Dose modifications are provided as guidance and should not replace the investigator’s own clinical judgment. 
 
 
Toxicity 
Dose of abiraterone acetate 
Dose of apalutamide 
Dose of prednisone 
Grade 1 or 2 
Initiate oral potassium 
supplementation, titrate to 
≥3.5 to ≤5.0 mmol/L, 
maintenance at ≥4.0 mmol/L 
recommended 
No change 
No change 
≥Grade 3 
Hold and initiate IV potassium 
and cardiac monitoring 
No change 
No change or consider tapering if 
AA is discontinued 
 
 
 
 
Table 5.1.5 Dose Modifications for Hypertension and Edema/Fluid Retention 
Attributed to Abiraterone Acetate 
 
Dose modifications are provided as guidance and should not replace the investigator’s own clinical judgment. 
 
 
 
Toxicity 
Dose of abiraterone acetate 
Dose of apalutamide 
Dose of prednisone 
Grade 1 or 2 
No change 
No change 
No change 
≥Grade 3 
Hold until Grade 1 or 
baseline, resume at full dose 
No change 
No change 
First 
Recurrence 
≥Grade 3 
Hold until Grade 1 or baseline, 
resume at 750 mg (3 tablets) 
No change 
No change 
Second 
Recurrence 
≥Grade 3 
Hold until Grade 1 or baseline, 
resume at 500 mg (2 tablets) 
No change 
No change 
Third 
Recurrence 
≥Grade 3 
Discontinue 
No change 
No change or consider 
tapering if AA is discontinued 


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6.1 
ADVERSE EVENTS 
 
6.2 
Adverse Event Monitoring 
 
Adverse events will be evaluated according to the NCI CTCAE Version 4.03 on a 
continuous basis starting from when the patient takes the first dose of abiraterone acetate 
or apalutamide to follow up visits. Events, such as abnormal laboratory values, considered 
by the principal investigator to be not clinically significant (related to the study or study 
drug) will not be documented. The investigator (or physician designee) is responsible 
for verifying and providing source documentation for all adverse events and 
assigning the attribution for all adverse events for subjects enrolled. If abnormal lab 
values, which were not pre-existing or which worsened after the first dose of study drug, 
meet Common Terminology Criteria (CTC) for reporting as adverse events (AE), they will 
be documented in the AE source document and captured in an institutionally approved 
database. For the lab results that do not meet the CTC for reporting as an AE, they will 
be considered not clinically significant (NCS). No additional documentation will be 
required to neither specify NCS lab results nor require physician investigator signature 
 
6.3 
Adverse Events for Apalutamide 
 
In a phase I dose-finding trial of apalutamide, treatment-emergent AEs were reported in 
97% of subjects. Related treatment-emergent AEs were reported in 93% of subjects. 
Serious adverse events (SAEs) were reported in 23% of subjects. 7% of subjects 
experienced SAEs assessed as treatment-related. Grade 3 AEs were reported in 17% of 
subjects; no Grade 4 AEs were reported. Adverse events leading to permanent 
discontinuation of study drug were reported in 10% of subjects. No deaths were reported. 
Treatment-related AEs observed in >10% of subjects were fatigue (53%), nausea (30%), 
abdominal pain (20%), diarrhea (17%), arthralgia (13%), dyspnea (13%), hot flush (13%), 
and peripheral sensory neuropathy (13%). 
 
In Phase II studies, all subjects experienced at least 1 treatment-emergent AEs. Related 
treatment-emergent AEs were reported in 87% of subjects. Serious adverse events 
were reported in 27% of subjects; no subject experienced an SAE assessed as 
retreatment-related. Grade 3 AEs were reported in 34% of subjects; Grade 4 AEs were 
reported in 3% of subjects. Adverse events leading to permanent discontinuation of 
study drug were reported in 10% of subjects. Two deaths were reported. 
 
6.4 
Adverse Event List(s) for Abiraterone Acetate 
 
• Joint swelling or discomfort 
• Muscle aches and fatigue 


Protocol # 2016-0527 
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• Fluid retention 
• Hot flashes 
• Hypertension 
• Diarrhea 
• GERD 
• Hypokalemia 
• Hepatotoxicity 
• Acute liver failure/hepatitis which might be fatal 
• Allergic alveolitis 
 
Refer to the package insert for a comprehensive list of adverse events. 
 
Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess 
 
Abiraterone acetate may cause hypertension, hypokalemia, and fluid retention as a 
consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Co- 
administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) 
drive, resulting in a reduction in the incidence and severity of these adverse reactions. 
Use caution when treating patients whose underlying medical conditions might be 
compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those 
with heart failure, recent myocardial infarction or ventricular arrhythmia. The safety of 
abiraterone acetate in patients with left ventricular ejection fraction <50% or NYHA 
Class III or IV heart failure has not been established because these patients were 
excluded from the randomized clinical trial. Monitor patients for hypertension, 
hypokalemia, and fluid retention at least once a month. Control hypertension and correct 
hypokalemia before and during treatment with abiraterone acetate. 
 
Adrenocortical Insufficiency 
 
Adrenocortical insufficiency has been reported in clinical trials in patients receiving 
abiraterone acetate in combination with prednisone, following interruption of daily 
steroids and/or with concurrent infection or stress. Use caution and monitor for 
symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn 
from prednisone, have prednisone dose reductions, or experience unusual physiologic 
stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse 
reactions associated with mineralocorticoid excess seen in patients treated with 
abiraterone acetate. If clinically indicated, perform appropriate tests to confirm the 
diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be 
indicated before, during and after physiologically stressful situations. 
 
Hepatotoxicity 
 
Marked increases in liver enzymes leading to drug discontinuation or dosage 
modification have occurred. Measure serum transaminases (ALT and AST) and 
bilirubin levels prior to starting treatment with abiraterone acetate, every two weeks for 
the first three months of treatment, and monthly thereafter. In patients with baseline 
moderate hepatic impairment receiving a reduced abiraterone acetate dose, measure 


Protocol # 2016-0527 
April 23,, 2019 
Page 27 of 44 
 
 
 
ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, 
every two weeks for the following two months of treatment and monthly thereafter. If 
elevations in ALT and/or AST greater than 5 × upper limit of normal (ULN) or total 
bilirubin greater than 3.0 × ULN occur in patients with baseline moderate hepatic 
impairment, discontinue abiraterone acetate and do not re-treat patients with 
abiraterone acetate. 
 
The safety of abiraterone acetate re-treatment of patients who develop AST or ALT 
greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is 
unknown. 
 
Refer to the package insert for a comprehensive list of adverse events associated with 
abiraterone acetate. 
 
6.5 
Adverse Event List(s) for LHRH Agonist/ Antagonist 
 
• Hot flashes, characterized by sudden intense feelings of heat over the face and 
body, often with sweating. 
• Decrease in sexual desire 
• Osteopenia and osteoporosis with chronic use 
• Headaches 
• Pain or local skin reaction at the injection site 
• Fluid retention 
• Potentially life-threatening blood clots are rare but serious potential AE’s 
• Allergic reaction 
 
Refer to the package insert for a comprehensive list of adverse events. 
 
6.6 
Adverse Event List(s) for Prednisone 
 
• Mood changes, rarely severe 
• GERD 
• Glucose intolerance 
• Increased intra-ocular pressure 
• Cushing syndrome, immunosuppression, and adrenocortical and pituitary 
unresponsiveness in times of stress (with prolonged use) 
 
Refer to the package insert for a comprehensive list of adverse events. 
 
6.7 
Adverse Event Characteristics 
 
CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 


Protocol # 2016-0527 
April 23,, 2019 
Page 28 of 44 
 
 
 
4.03 will be utilized for AE reporting. All appropriate treatment areas should have 
access to a copy of the CTCAE version 4.03. A copy of the CTCAE version 4.03 can be 
downloaded from the CTEP web site (http://ctep.cancer.gov). We will collect data in 
accordance with phase II trials from the table below. 
Recommended Adverse Event Recording Guidelines 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
Phase I 
Phase I 
Phase I 
Phase I 
Phase I 
Phase II 
Phase II 
Phase II 
Phase III 
Phase III 
Unlikely 
Phase I 
Phase I 
Phase I 
Phase I 
Phase I 
Phase II 
Phase II 
Phase II 
Phase III 
Phase III 
Possible 
Phase I 
Phase I 
Phase I 
Phase I 
Phase I 
Phase II 
Phase II 
Phase II 
Phase II 
Phase II 
Phase III 
Phase III 
Phase III 
Phase III 
Probable 
Phase I 
Phase I 
Phase I 
Phase I 
Phase I 
Phase II 
Phase II 
Phase II 
Phase II 
Phase II 
Phase III 
Phase III 
Phase III 
Phase III 
Definitive 
Phase I 
Phase I 
Phase I 
Phase I 
Phase I 
Phase II 
Phase II 
Phase II 
Phase II 
Phase II 
Phase III 
Phase III 
Phase III 
Phase III 
 
 
6.7 
Serious Adverse Event Reporting (SAE) for MD Anderson-Sponsored IND 
Trials 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of 
either the investigator or the sponsor, it results in any of the following outcomes: 
 
• Death 
• A life-threatening adverse drug experience – any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience that, had it 
occurred in a more severe form, might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based 
upon appropriate medical judgment, they may jeopardize the patient or subject and may 


Protocol # 2016-0527 
April 23,, 2019 
Page 29 of 44 
 
 
 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse (21 CFR 312.32). 
 
• Important medical events as defined above, may also be considered 
serious adverse events. Any important medical event can and should be 
reported as an SAE if deemed appropriate by the Principal Investigator or 
the IND Sponsor, IND Office. 
 
• All events occurring during the conduct of a protocol and meeting the definition of 
a SAE must be reported to the IRB in accordance with the timeframes and 
procedures outlined in “The University of Texas M. D. Anderson Cancer Center 
Institutional Review Board Policy for Investigators on Reporting Unanticipated 
Adverse Events for Drugs and Devices”. Unless stated otherwise in the protocol, 
all SAEs, expected or unexpected, must be reported to the IND Office, 
regardless of attribution (within 5 working days of knowledge of the event). 
 
• All life-threatening or fatal events, that are unexpected, and related to the 
study drug, must have a written report submitted within 24 hours (next working 
day) of knowledge of the event to the Safety Project Manager in the IND Office. 
 
• Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for 
safety reporting to the IND Office and MDACC IRB. 
 
• Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last study treatment/intervention, unless the 
participant withdraws consent. Serious adverse events must be followed until 
clinical recovery is complete and laboratory tests have returned to baseline, 
progression of the event has stabilized, or there has been acceptable resolution 
of the event. 
 
• Additionally, any serious adverse events that occur after the 30 day time period 
that are related to the study treatment must be reported to the IND Office. This 
may include the development of a secondary malignancy. 
 
6.8 
Reporting to FDA: 
 
• Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety 
Project Manager IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure that serious adverse 
events are reported according to the Code of Federal Regulations, Good Clinical 
Practices, the protocol guidelines, the sponsor’s guidelines, and Institutional Review 
Board policy. 


Protocol # 2016-0527 
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Page 30 of 44 
 
 
 
6.9 
Investigator Communications with Janssen Scientific Affairs, LLC 
 
6.9.1 
Possible Reports That Janssen Scientific Affairs, LLC May Receive 
 
• Serious Adverse Events Exceptions (See Appendix 2) 
• Adverse Events of Special Interest (See Appendix 3) 
• Safety data includes adverse events (AE)s 
• Product quality complaints (PQC’s) 
• Special situations including pregnancies 
• SAEs 
• Non-serious AEs 
 
6.9.2 
Transmission Methods 
 
The following methods are acceptable for transmission of safety information to the 
Janssen Scientific Affairs, LLC: 
• Electronically via Janssen SECURE Email service (preferred) 
• For business continuity purposes, if SECURE Email is non-functional: 
• Facsimile (fax), receipt of which is evidenced in a successful fax transmission 
report 
• Telephone (if fax is non-functional). 
 
Please use the contact information and process information provided by Janssen 
Scientific Affairs, LLC. 
 
7.1 
PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or 
commercial agents administered in this study can be found starting in Section 6.0. 
 
7.2 
Apalutamide 
 
Apalutamide is an immediate-release oral tablet containing 60 mg of Form B drug 
substance, with a non-functional green film coat. 
 
7.3 
Abiraterone 
 
• Abiraterone acetate 250 mg tablets are white to off-white, oval tablets debossed 
with AA250 on one side. Abiraterone acetate 250 mg tablets are available in 
high-density polyethylene bottles of 120 tablets. 
• Food effect: Abiraterone acetate must be taken on an empty stomach. No food 
should be consumed for at least two hours before the dose of abiraterone acetate 
is taken and for at least one hour after the dose of abiraterone acetate is taken. 


Protocol # 2016-0527 
April 23, 2019 
Page 31 of 44 
 
 
 
Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold 
higher, respectively, when a single dose of abiraterone acetate was administered 
with a meal compared to a fasted state. The safety of these increased exposures 
has not been assessed. 
 
7.4 
Handling abiraterone acetate and apalutamide tablets 
 
• These medicines may cause harm to the unborn child if taken by women who are 
pregnant. They should not be taken by women who are breast-feeding. Women 
who are pregnant or who may be pregnant should wear gloves if they need to 
touch abiraterone acetate or apalutamide tablets. Study staff and caregivers will 
be notified of this information, to ensure the appropriate precautions are taken. 
 
7.5 
Pharmacy Storage Requirements 
 
• The study treatment must be stored in a secure area and administered only to 
patients entered into the clinical study in accordance with the conditions specified 
in this protocol. Bottles of study treatment should be stored at 20°C to 25°C 
(68°F to 77°F); excursions are permitted to 15°C to 30°C (59°F to 86°F) in the 
original container/closure with the cap on tightly; it should never be refrigerated. 
Additional information is provided in the abiraterone acetate and apalutamide 
respective Investigator’s Brochure. 
 
7.6 
Leuprolide acetate 
 
• Leuprolide acetate 22.5 mg is available in a prefilled dual-chamber syringe 
containing sterile lyophilized microspheres which, when mixed with diluent, 
become a suspension intended as an intramuscular injection to be given once 
every 3 months 
 
7.7 
Prednisone 
 
• Prednisone 5 mg tablets are white to off-white, round tablets debossed with 
MP51 on one side. 


Protocol # 2016-0527 
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Page 32 of 44 
 
 
 
8.0 
STUDY CALENDAR 
 
 
All events have a 
window of +/- 7 
days 
Screening 
C1D1c 
Day 15 
of  
Cycle 1, 
2 & 3 
Day 1 
of 
Cycles 
2,3,5, 
& 6 
C4D1 
Pre-Surgery 
Visit/End of 
Treatment 
Surgerye 
4 Weeks Post- 
Surgeryj 
Physical Exam at 
MD Anderson 
Xa 
X 
X 
X 
X 
Vital Signs 
Xa 
X 
X 
X 
X 
Weight 
Xa 
X 
X 
Height 
Xa 
ECOG PS 
Xa 
X 
X 
X 
X 
CBC/diff and pit 
Xa 
X 
X 
X 
Serum 
Chemistry 
Xa,b 
Xb 
Xb 
Xb 
Xb 
Liver Function Tests 
(AST, ALT, LDH, 
ALK-P, total 
Bilirubin) 
Xd 
Xd 
Xd 
Xd 
Xd 
Xd 
Xd 
PT/PTT 
Xa 
X 
PSA 
a 
X 
X 
X 
X 
X 
HGB A1C, 
ACTH 
a 
X 
X 
X 
X 
X 
Serum 
Testosterone 
a 
X 
X 
TSH Monitoring 
Xa,f 
Xf 
Xf 
Xf 
Urinalysis 
Xa 
X 
X 
CT Scan Abd/ 
CT Scan or MRI 
Pelvis 
Xa 
Magnetic 
Resonance 
Spectroscopy/ 
MRI of 
ProstateK 
X 
X 
Prostate Biopsy 
Xh 
Chest X-Ray or CT 
Chest 
Xa 
X 
X 
MUGA or ECHO 
Xa 


Protocol # 2016-0527 
April 23, 2019 
Page 33 of 44 
 
 
 
All events have 
a window of +/- 
7 days 
Screening 
C1D1c 
Day 15 
of  
Cycle 1, 
2 & 3 
Day 1 
of 
Cycles 
2, 3, 5, 
& 6 
C4D1 
Pre- 
Surgery 
Visit/End 
of 
Treatmen 
t 
Surgerye 
4 Weeks Post- 
Surgery 
Monitor Adverse 
Events 
 
Concomitant 
Medications 
 
Bone Scan 
Xa 
Blood for 
Correlative 
Studies 
Xa,i 
Xi 
Xg,i 
Xi 
Xi 
Tissue for 
Correlative 
Studies 
Xi 
Archived Tissue 
for Correlative 
Studies 
Xh 
 
a) Within 30 days of registration 
b) Serum Chemistry with electrolytes: albumin, calcium, lactate dehydrogenase (LDH), sodium, potassium, 
chloride, magnesium, carbon dioxide, creatinine, BUN, total protein, Vitamin D 25OH and glucose. At 
screening and the pre-surgery visit, C4D1 the following will also be done: total cholesterol, high density 
lipoprotein (HDL), low density lipoprotein (LDL), cholesterol and triglycerides. 
c) If visit occurs within 7 days of screening visit, C1D1 procedures will not be repeated. 
d) Liver Function Tests ONLY: AST, ALT, LDH, ALKP and Total Bilirubin. These LFTs may be done at a local 
physician’s office. Results should be faxed to MDACC. 
e) Study medication will be continued up to 48 hours prior to surgery 
f) 
Thyroid stimulating hormone (TSH) should be evaluated throughout the study (with T3 and T4 done only if 
TSH is abnormal). 
g) Occurs at cycles 2,3, and 6 
h) If previous biopsy has been perform with 3 months of screening, second biopsy procedure will not be required, 
if archival biopsies and unstained slides are available. 
i) Optional Procedure 
j) Patients who are free of PSA recurrence at the 4 week post-surgery follow-up will continue to be followed until 
PSA recurrence, death, or until 6 months after the last patient is enrolled, whichever comes first. 
 
kOptional procedure. 


Protocol # 2016-0527 
April 23, 2019 
Page 34 of 44 
 
 
 
Correlative studies will include: 
 
1. Assessment of the steroid hormone metabolome in blood plasma (pretreatment, C3 
and C6) and tissue by liquid chromatography tandem mass spectrometry. Measured 
components will be testosterone, dihydrotestosterone, androstenedione, and 
pregnenolone. 
2. Assessment of steroid signaling components including: 
• Protein and DNA/RNA assessment of canonical and noncanonical androgen 
signaling including glucocorticoid receptor. Markers of cell cycle angiogenesis 
and neuroendocrine markers 
• AR copy number by PC pre, during, and post-treatment in the primary tumor 
microenvironment 
3. Assessment of intracellular TCA cycle metabolite concentrations with LCMS/MS 
assessment of pyruvate and lactate, and assessment of citrate concentration 
4. Proportion of patients who achieve pathological CR 
5. Cell density in Group A and Group B on prostatectomy 
6. Hyperpolarized 1-13C-pyruvate imaging at study entry and at 3 months and 6 
months in Arm A and Arm B. MRS data obtained at baseline and at three months 
will be compared with pyruvate, lactate and citrate concentrations as determined by 
LCMS/MS in #3 above. 
 
9.0 
MEASUREMENT OF EFFECT 
 
Assessment of effect will be assessed by reporting pathologic T and N stage at the time 
of prostatectomy. 
 
10.0 
STATISTICAL CONSIDERATIONS 
10.1 
General Considerations 
The goal of this trial is to estimate clinical efficacy of both treatment arms while also having 
sufficient patients to achieve secondary and exploratory objectives.  At the completion of the 
original 66 patients, no patients had been able to be measured hyperpolarized 1-13C-pyruvate 
imaging results due to a delay in approval of the FDA IND for this procedure. In order to accomplish 
this goal, an additional 20 patients are planned for the revised protocol in March 2019.  This is 
reasonable based on the observed safety and efficacy to date.  Among the 34 patients receiving 
surgery, 15 have achieved the primary endpoint, which is very close to the target improvement.  
There are no alternative effective treatments for these patients.  No patients have died prior to 
going to surgery. 
 
10.2 Study Design/Endpoints 
 
10.2.1 
Primary Endpoint 
 
The primary endpoint is the rate of pathologic stage ≤ pT2N0 at prostatectomy. Patients 
who do not undergo prostatectomy will be included in this evaluation as not achieving 
pathologic stage ≤ pT2N0. 
 


Protocol # 2016-0527 
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10.2.2 
Secondary/Exploratory Endpoints 
 
• Tumor epithelium volume in the surgical specimen 
• Presence of positive surgical margins in the surgical specimen 


Protocol # 2016-0527 
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• Time to PSA recurrence (TTRPSA) will be measured from the date of 
randomization until PSA recurrence, death, or date of last follow-up without 
recurrence. 
• Adverse events according to CTCAE (version 4.03) and attribution to study 
treatment 
• Steroid hormone metabolome in blood plasma and tissue by liquid 
chromatography tandem mass spectrometry 
• Protein and RNA analysis results of canonical and non-canonical androgen 
signaling candidate pathways of resistance to androgen signaling inhibition 
• Citrate intracellular TCA cycle metabolite concentrations 
• Pathological response 
• Hyperpolarized 1-13C-pyruvate imaging results 
 
10.2 Sample Size/Accrual Rate 
 
A previous study of neoadjuvant LHRHa alone in high risk localized prostate cancer as 
defined in this study demonstrated a rate of pathologic ≤ pT20N0 of 33.3%. Taking this 
as P0, we propose a P1 of 55% for each arm. The original sample size of 33 patients 
per arm would provide 82% power to detect a documented ≤ pT20N0 of 33% vs. 55% 
based on a one- sided binomial test with a targeted 5% significance level. The actual 
significance level for this test is 0.047. Calculations were performed in PASS 2005. We 
propose the same P1 in both arms, as there is insufficient data to support the 
hypothesis that one arm will be superior to the other among these patients. With the 
increased sample size of 43 patient per arm, we would have nearly 90% power to 
detect the same difference and 80% power to detect a difference of 33% vs. 52%. 
 
With the March 2019 protocol ammendment eighty-six patients will be enrolled and 
randomized equally over a 12-18 month period. Our group has extensive experience 
conducting neoadjuvant trials for prostate cancer with both androgen deprivation 
therapy and chemotherapy. Furthermore, we have recent experience with conducting 
trials on intensive androgen deprivation such as the one proposed; a recent pre-
operative androgen deprivation trial comparing LHRH agonist plus abiraterone vs LHRH 
agonist plus abiraterone plus enzalutamide opened in October 2013, accrued 62 
patients over the following 14 months, and first results were reported as an abstract at 
ASCO 2015. A similar timeline is expected with the proposed protocol. The original 66 
patients were enrolled between Nov 2017 and January 2019 in just over 14 months.  
The next 20 are expected to accrue at a similar rate, allowing completion within 4-5 
months after re-initiation enrollment. 
 
10.3 Randomization 
 
This is a randomized, parallel, single-stage phase II trial. A total of 86 patients will be 
randomized via permuted block randomization of random block sizes to Group A 
(LHRHa + apalutamide) or Group B (LHRHa + apalutamide + abiraterone acetate) in a 
1:1 ratio. 
Randomization will be performed in CORe in collaboration with the trial 
biostatistician. 


Protocol # 2016-0527 
April 23, 2019 
Page 37 of 44 
 
 
 
• If an arm is stopped for safety reasons as described below, then randomization 
will stop and the other arm will continue to accrue as a single arm trial. 
 
 
As all patients will be newly diagnosed with high risk localized prostate cancer, no 
stratification is proposed. 
 
10.4 Interim Analysis 
 
Monitoring for safety will be implemented separately for each arm based on the method 
of Thall et al. (1995) using an initial cohort of 6 patients and then continuously 
thereafter. The first assessment will occur once the first 6 patients have been treated 
for the first cycle, with continuous monitoring implemented monthly. Calculations were 
performed in MultcLean 2.1. We will continue enrollment during assessment of each 
arm so the average number of patients treated will be slightly larger than the calculated 
operating characteristics, but the overrun expected is only 1-1.5 patients per arm per 
month. 
 
For trial monitoring and decisions about future trials, extreme toxicities (TOX) will be 
defined as any adverse event preventing surgery or death from any cause before 
surgery. A patient who voluntarily leaves the trial for any reason, including toxicity, but is 
still able to have surgery off protocol will not count as having a TOX. Denote the 
probability of TOX by θT. Our stopping rule is given by the following probability 
statement: Pr (θT > 0.20 | data) >0.95. That is, we will stop the relevant arm of the trial 
if, at any time during the study, we determine that there is more than an 95% chance 
that the TOX rate is more than 20% in that arm. TOX rate is estimated with a prior θT ~ 
beta (1, 1) for the current study. The stopping boundaries for this toxicity rule are to 
terminate the arm if the number of patients with TOX compared to the number of 
patients having received treatment exceeds the limits in the table below. Each arm will 
stop at 33 patients, but if there are 11 or more TOX events by the end, then that 
combination will be unsafe for future trials at these doses in this patient population. 
Accrual will not be held during TOX review. Patients who started treatment early enough 
to complete the first cycle will be included. However, a TOX event may occur later and 
will be counted at the next monthly monitoring. The operating characteristics are 
described below. 
 
Stopping Criteria for Excessive TOX for Each Arm 
If there are this many (or more) 
patients with TOX: 
3 
4 
5 
6 
7 
8 
9 10 
11 
12 
 
13 
Stop the arm if there are this many 
(or fewer) evaluable 
patients: 
6 
9 
13 
16 
20 
24 
28 31 
35 
39 
43* 
*Always stop with 43 patients, but if 13 or more have TOX, then this combination is 


Protocol # 2016-0527 
April 23, 2019 
Page 38 of 44 
 
 
 
not safe for further investigation in these patients. 
 
The operating characteristics are described in Table 4. Note, that with 0 patients missing 
surgery due to toxicity or death out of the 66 enrolled (34 with surgery so far) prior to the 
revision, these operating characteristics are not accounting for the good toxicity profile so 
far.  The probability of stopping early is overestimated and numbers of patients treated may 
be underestimated. 
 
Table 4. The Operating Characteristics under Varying Toxicity Rates 
True Overall 
Toxicity Rate 
Probability of 
Stopping Early 
Average number of 
patients Treated* 
Median (25th 
%ile, 75th %ile) 
0.05 
0.003 
42.9 
43 (43, 43) 
0.10 
0.02 
42.2 
43 (43, 43) 
0.20 
0.24 
35.9 
43 (43, 43) 
0.30 
0.70 
23.2 
20 (6, 43) 
0.40 
0.96 
13.1 
8 (6, 16) 
0.50 
>0.99 
8.6 
6 (6, 9) 
*The average number of patients treated may be slightly higher due to allowing accrual 
to continue during assessment. 
 
The Investigator is responsible for completing a safety/Efficacy summary report and 
submitting it to the IND office Medical Affairs and Safety Group for review. This should 
be submitted after the first 6 evaluable patients per cohort reach 6 months after starting 
study treatment, and every 10 evaluable patients per arm, thereafter 
 
10.5 Analysis Plan 
 
Patient characteristics will be summarized using descriptive statistics for each arm. For 
the primary endpoint, we will provide a point estimate and 95% confidence interval of 
the proportion of patients with pathologic stage ≤ pT2N0 at prostatectomy for each arm. 
 
Secondary and exploratory continuous endpoints will be summarized descriptively and 
graphically. Comparisons between two the arms or patient subgroups will use a t-test or 
non-parametric alternative as indicated. Secondary and exploratory categorical 
endpoints will be summarized using proportions with 95% confidence intervals. 
Comparisons between the two arms will use a chi-square test or Fisher’s exact if 
indicated. TTRPSA will be summarized by Kaplan-Meier estimates and confidence 
intervals. Treatment-related adverse events will be summarized according to CTCAE 
v4.03, and the incidence of SAE and 95% confidence interval will be provided overall as 
well as for each major affected organ category. We will explore whether subsets of 
patients will benefit more from one arm than then other with logistic regression for 
pathologic stage ≤ pT2N0 or Cox regression for TTRPSA. 
 
10.6 Analysis Populations 


Protocol # 2016-0527 
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10.6.1 Toxicity Evaluable 
 
All patients will be evaluable for toxicity from the time of their first treatment with 
apalutamide, abiraterone or leuprolide. 
 
10.6.2 Response Evaluable 
 
All randomized patients will be included in the primary analysis as part of an intention to 
treat analysis. 
 
Exploratory analyses will be performed on all patients with available information 
depending on tissue procurement, especially at diagnostic and 3 month biopsy. The 
number of patients included in each exploratory analysis will be reported with the results 
of that analysis. 
 
11.1 
ETHICAL ASPECTS 
 
11.2 Privacy of Personal Data 
 
The collection and processing of personal data from subjects enrolled in this study will 
be limited to those data that are necessary to fulfill the objectives of the study. 
 
This data must be collected and processed with adequate precautions to ensure 
confidentiality and compliance with applicable data privacy protection laws and 
regulations. Appropriate technical and organizational measures to protect the personal 
data against unauthorized disclosures or access, accidental or unlawful destruction, or 
accidental loss or alteration must be put in place. Personnel whose responsibilities 
require access to personal data agree to keep the identity of subjects confidential. 
 
Data will be entered into MD Anderson institutionally approved and compliant 
database(s). The database(s) have secure portal that requires users to login with 
validated credentials, uses approved encryption protocols as defined by institutional 
information security standards. Systems have granular data access controls to ensure 
that the minimal amount of information required to complete a task is presented, can 
handle de-linking and de-identification of patient information to maintain patient 
confidentiality if necessary. The system(s) are 21 CFR 11 compliant. Standard data 
collection, storage procedures, and quality assurance procedures will be followed, to 
ensure integrity and auditability of all information entered. 
All patients will be registered in the University of Texas M. D. Anderson Cancer Center 
Office of Research Administration database. Registration will occur following informed 
consent process and prior to initiation of investigational intervention(s). All eligibility 
criteria must be satisfied. 


Protocol # 2016-0527 
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11.3 Long-Term Retention of Samples for Additional Future Research 
 
Samples will only be used to understand apalutamide or abiraterone acetate, to 
understand prostate cancer, to understand differential drug responders, and to develop 
tests/assays related to apalutamide or abiraterone acetate. The research may begin at 
any time during the study or the post study period. 
 
Stored samples will be coded throughout the sample storage and analysis process and 
will not be labeled with personal identifiers. Subjects may withdraw their consent for their 
samples to be stored for research. 
 
 
 
APPENDIX 1 
 
Performance Status Criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
about more than 50% of waking 
 
 
 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, 
able to carry on all pre-disease 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
performance without restriction. 
1 
Symptoms, but ambulatory. 
Restricted in physically 
strenuous activity, but 
ambulatory and able to carry 
out work of a light or sedentary 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
nature (e.g., light housework, 
office work). 
2 
In bed <50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry 
out any work activities. Up and 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable 
assistance and frequent medical 
care. 
hours. 
3 
In bed >50% of the time. 
Capable of only limited self- 
care, confined to bed or chair 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, 
hospitalization indicated. Death 
more than 50% of waking 


Protocol # 2016-0527 
April 23, 2019 
Page 40 of 44 
 
 
 
hours. 
not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any 
self-care. Totally confined to 
bed or chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
APPENDIX 2 
 
Serious Adverse Events Exceptions 
 
 
• 
A standard procedure for protocol therapy administration will not be reported as a 
serious adverse event. Hospitalization for a complication of therapy administration 
will be reported as a serious adverse event. 
• 
A procedure for protocol/disease-related investigations (eg, surgery, scans, 
sampling for laboratory tests, or biomarker blood sampling). Hospitalization or 
prolonged hospitalization for a complication of such procedures remains a 
reportable serious adverse event. 
• 
Surgery or procedure planned before entry into the study. Note: Hospitalizations that 
were planned before the signing of the ICF, and where the underlying condition for 
which the hospitalization was planned has not worsened, will not be considered 
serious adverse events. Any adverse event that results in a prolongation of the 
originally planned hospitalization is to be reported as a new serious adverse event. 
• 
Disease progression should not be recorded as an adverse event or serious adverse 
event term; instead, signs and symptoms of clinical sequelae resulting from disease 
progression/lack of efficacy will be reported if they fulfill the serious adverse event 
definition. 


Protocol # 2016-0527 
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Page 41 of 44 
 
 
 
APPENDIX 3 
 
Adverse Events of Special Interest 
 
Adverse events of special interest are events that the Janssen Scientific Affairs, LLC is 
actively monitoring as a result of a previously identified signal (even if non-serious). 
There are no adverse events of special interest identified for apalutamide or 
abiraterone acetate. 


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APPENDIX 4: 
 
PROHIBITED OR RESTRICTED MEDICATIONS OR SUPPLEMENTS WHILE ON 
STUDY 
 
Medications that are PROHIBITED while on study: 
• Aminophylline/theophylline 
• Atypical antipsychotics (e.g., clozapine, olanzapine, risperidone, ziprasidone) 
• Buproprion 
• Lithium 
• Meperidine and pethidine 
• Phenothiazine antipsychotics (e.g., chlorpromazine, mesoridazine, thioridazine) 
• Tricyclic and tetracyclic antidepressants (e.g., amitriptyline, desipramine, 
doxepin, imipramine, maprotiline, mirtazapine) 
 
Supplements that are RESTRICTED while on study: 
 
• Pomegranate 
 
Medications that are RESTRICTED while on study: 
 
Investigators should refer to the apalutamide Investigator’s Brochure and associated 
addenda for complete details on the drug interaction potential of apalutamide. 
Highlights of drug interaction are summarized below. 
 
• . 
• 
Medications that inhibit CYP2C8 or CYP3A4: Co-administration of a strong CYP2C8 or 
CYP3A4 inhibitor is predicted to increase the steady-state exposure of the active moieties 
(sum of unbound apalutamide plus the potency-adjusted unbound N-desmethyl 
apalutamide). No initial dose adjustment is necessary however, consider reducing the 
apalutamide dose based on individual tolerability (see Section 6.2). Mild or moderate 
inhibitors of CYP2C8 or CYP3A4 are not expected to affect the exposure of apalutamide. 
• Effect of apalutamide on drug metabolizing enzymes: Apalutamide is a strong inducer of 
CYP3A4 and CYP2C19, and a weak inducer of CYP2C9 in humans. Concomitant use of 
apalutamide with medications that are primarily metabolized by CYP3A4, CYP2C19, or 
CYP2C9 can result in lower exposure to these medications. Substitution for these 
medications is recommended when possible or evaluate for loss of efficacy if medication 
is continued. Concomitant administration of apalutamide with medications that are 
substrates of UGT can result in decreased exposure. Use caution if substrates of UGT must 
be co-administered with apalutamide and evaluate for loss of efficacy. 
• 
Effect of apalutamide on drug transporters: Apalutamide was clinically shown to be a weak 
inducer of P-gp, BCRP, and OATP1B1. Concomitant use of apalutamide with medications 
that are substrates of P-gp, BCRP, or OATP1B1 can result in lower exposure 


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of these medications. Use caution if substrates of P-gp, BCRP or OATP1B1 must be co- 
administered with apalutamide and evaluate for loss of efficacy if medication is continued. 
• 
Abiraterone is a moderate inhibitor of CYP2D6 in humans. Caution is advised when AA is 
administered with medicinal products activated by or metabolized by CYP2D6, particularly 
with medicinal products that have a narrow therapeutic index. Dose reduction of medicinal 
products with a narrow therapeutic index that are metabolized by CYP2D6 should be 
considered. 
• Abiraterone is a weak inhibitor of CYP2C8 in humans. When AA is combined with drugs 
that are predominantly eliminated by CYP2C8, subjects should be monitored for signs of 
toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used 
concomitantly with AA. 


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• Corticosteroids (Oral, IV, or IM): due to possible resistance mechanisms, which 
may be contributed by glucocorticoid receptor signaling, concurrent use of 
corticosteroids during the study is not recommended; short term use (≤ 4 
weeks) will be allowed if clinically indicated, however, its use must be tapered 
off as soon as possible. 
 
 
Additional Information on CYP450 Drug Interactions 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginter 
actionslabeling/ucm093664.htm 
 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx 


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