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Cancer Therapy: Clinical
Androgen Receptor Modulation Optimized for
Response (ARMOR) Phase I and II Studies:
Galeterone for the Treatment of Castration-
Resistant Prostate Cancer
Bruce Montgomery
1
, Mario A. Eisenberger
2
, Matthew B. Rettig
3
, Franklin Chu
4
,
Roberto Pili
5
, Joseph J. Stephenson
6
, Nicholas J. Vogelzang
7
, Alan J. Koletsky
8
,
Luke T. Nordquist
9
, William J. Edenfield
10
, Khalid Mamlouk
11
, Karen J. Ferrante
11
, and
Mary-Ellen Taplin
12
Abstract
Purpose: Galeterone is a selective, multitargeted agent that
inhibits CYP17, antagonizes the androgen receptor (AR), and
reduces AR expression in prostate cancer cells by causing an
increase in AR protein degradation. These open-label phase I
and II studies [Androgen Receptor Modulation Optimized
for Response-1 (ARMOR1) and ARMOR2 part 1] evaluated
the efficacy and safety of galeterone in patients with treat-
ment-naive nonmetastatic or metastatic castration-resistant
prostate cancer (CRPC) and established a dose for further
study.
Experimental Design: In ARMOR1, 49 patients received
increasing doses (650–2,600 mg) of galeterone in capsule
formulation; 28 patients in ARMOR2 part 1 received increasing
doses (1,700–3,400 mg) of galeterone in tablet formulation for
12 weeks. Patients were evaluated biweekly for safety and
efficacy, and pharmacokinetic parameters were assessed.
Results: In ARMOR1,across all doses, 49.0% (24/49) achieveda
30% decline in prostate-specific antigen (PSA; PSA30) and
22.4% (11/49) demonstrated a 50% PSA decline (PSA50). In
ARMOR2 part 1, across all doses, PSA30 was 64.0% (16/25) and
PSA50 was 48.0% (12/25). In the 2,550-mg dose cohort, PSA30
was 72.7% (8/11) and PSA50 was 54.5% (6/11). Galeterone was
well tolerated; the most common adverse events were fatigue,
increased liver enzymes, gastrointestinalevents, and pruritus. Most
were mild or moderate in severity and required no action and there
were no apparent mineralocorticoid excess (AME) events.
Conclusions: The efficacy and safety from ARMOR1 and
ARMOR2 part 1 and the pharmacokinetic results support the
galeterone tablet dose of 2,550 mg/d for further study. Galeterone
was well tolerated and demonstrated pharmacodynamic changes
consistent with its selective, multifunctional AR signaling inhibi-
tion. Clin Cancer Res; 22(6); 1356–63. 2015 AACR.
Introduction
Despite recent advances in the treatment of castration-resistant
prostate cancer (CRPC), prostate cancer remains the second most
common cancer-related mortality in men in the United States (1).
The development of a new generation of therapies targeting the
androgen axis has been based on an expanded understanding of
the molecular mechanisms of CRPC. It is now understood that in
the clinical setting of castrate levels of serum testosterone, prostate
tumors adapt by upregulating tissue androgens and androgen
receptors (AR) to maintain proliferation. Tumor androgen levels
remain sufficiently elevated to stimulate ARs as a result of tumor
conversion of circulating adrenal androgens and de novo androgen
synthesis (2–5). In addition, prostate cancer adapts to androgen-
deprivation therapy by AR gene amplification, upregulation of AR
transcripts, or protein expression (6, 7). Thus, inhibition of the
synthesis of nongonadal androgens and blockade of AR remain
key targets in CRPC therapy.
Abiraterone and enzalutamide have improved outcomes for
patients with metastatic CRPC (mCRPC). Although abiraterone
and enzalutamide have been shown to improve overall survival
(OS), these agents are not curative and not without safety and
tolerability issues (8–11). In addition, a significant proportion of
patients do not respond; and in those who do respond, therapy
will eventually fail because of the development of resistance
(9, 10, 12–14). A major component of resistance to second-
generation AR-targeting agents may be mediated by AR splice
1
University of Washington,Seattle, Washington.
2
Sidney Kimmel Com-
prehensive Cancer Center at Johns Hopkins University, James Bucha-
nan Brady Urological Institute, Baltimore, Maryland.
3
UCLA Jonsson
Comprehensive Cancer Center, Los Angeles, California.
4
San Berna-
dino Urological Associates, San Bernadino, California.
5
Indiana
University School of Medicine, Indianapolis, Indiana.
6
Institute for
Translational Oncology Research, Greenville, South Carolina.
7
Com-
prehensive Cancer Centers of Nevada and U.S. Oncology Research,
Las Vegas, Nevada.
8
Lynn Cancer Institute, Boca Raton, Florida.
9
Urol-
ogy Cancer Center and GU Research Network, Omaha, Nebraska.
10
Greenville Hospital System and University Medical Center, Green-
ville, South Carolina.
11
Tokai Pharmaceuticals, Cambridge, Massachu-
setts.
12
Dana-Farber Cancer Institute, Boston, Massachusetts.
Note: Supplementary data for this article are available at Clinical Cancer
Research Online (http://clincancerres.aacrjournals.org/).
Corresponding Author: Mary-Ellen Taplin, Dana-Farber Cancer Institute, 450
Brookline Avenue, Boston, MA 02215. Phone: 617-632-3237; Fax: 617-632-2165;
E-mail: Mary_Taplin@dfci.harvard.edu
doi: 10.1158/1078-0432.CCR-15-1432
2015 American Association for Cancer Research.
Clinical
Cancer
Research
Clin Cancer Res; 22(6) March 15, 2016
1356
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variants, such as AR-V7, which are produced in tumor cells as a
result of aberrant RNA splicing of the wild-type AR transcript. The
resultant truncated AR protein lacks the C-terminal domain to
which androgen binds and is the primary site of action of
nonsteroidal antiandrogens such as enzalutamide. Furthermore,
splice variants have been shown to be constitutively active tran-
scription factors, leading to the activation of androgen-responsive
genes even at castrate levels of androgens (15, 16). Mutations in
the AR may also contribute to resistance in CRPC, and AR point
mutations allow activation of the receptor by nonphysiologic
ligands (e.g., cortisol, progesterone, flutamide, bicalutamide;
refs. 17, 18, 19). As a result, androgen-independent, but
AR-dependent, tumor growth occurs, and tumors become resis-
tant to therapeutic agents that alter androgen production (e.g.,
abiraterone) or antagonize binding to the AR (e.g., bicalutamide,
enzalutamide). Recent data demonstrated that patients with
detectable circulating tumor cells harboring AR-V7 had inferior
responses to abiraterone or enzalutamide, including inferior
prostate-specific antigen (PSA) response, clinical and radiograph-
ic progression-free survival (PFS), and poor OS (12, 13).
Galeterone is a selective, multitargeted agent that disrupts
androgen signaling at multiple points in the pathway. Preclinical
data have shown that galeterone is a selective potent CYP17
inhibitor and a potent AR antagonist, but unlike other available
agents that target androgen signaling, galeterone reduces AR
expression in prostate cancer cells by causing an increase in AR
protein degradation (20–26). Preclinical in vitro and in vivo data
have shown that galeterone treatment in prostate cancer models
resulted in a significant reduction in both full-length AR and AR-
V7 splice variant levels. In addition, galeterone has been shown to
have activity against AR point mutations T878A (20-25) and, in
preliminary findings, to have activity in cells expressing the AR
point mutation F876L (27).
This article reports the safety and efficacy of galeterone in a
phase I study, Androgen Receptor Modulation Optimized for
Response (ARMOR1), and the dose-escalation component of the
phase II ARMOR2 study (ARMOR2 part 1). The dose-escalation
component of ARMOR2 was conducted to determine the phase II
and phase III dose of a galeterone spray dry dispersion (SDD)
tablet. This formulation was developed after a healthy volunteer
study confirmed a significant food effect with the capsule formu-
lation that was used in ARMOR1 (Supplementary Data). The SDD
tablet formulation was shown in a healthy volunteer study to not
be affected by food, providing similar exposure (area under the
concentration-time curve, AUC) in fed and fasted states (28).
Results of this study also demonstrated equivalent serum con-
centrations using either 1,700 mg of the SDD tablet or 2,600 mg of
the capsule, which was the highest dose studied in ARMOR1.
Thus, the dose-escalation portion of ARMOR2 was conducted to
evaluate the safety and tolerability of escalating doses of the SDD
formulation and to determine the recommended dose for
ARMOR2 part 2 and ARMOR3.
Patients and Methods
Patients
Eligible men had histologically confirmed nonmetastatic (M0)
or metastatic (M1) adenocarcinoma of the prostate, a life expec-
tancy of >12 weeks, and progressive disease despite ongoing
androgen-deprivation therapy. Patients were required to have
progressive disease according to Prostate Cancer Clinical Trials
Working Group 1 [PCWG1] criteria (29) in ARMOR1, or PCWG2
criteria (30) in ARMOR2 part 1, ongoing treatment with gonad-
otropin-releasing hormone analogs or orchiectomy (serum tes-
tosterone <50 mg/dL), and an Eastern Cooperative Oncology
Group (ECOG) performance status of 1. ARMOR1 excluded
patients who had previously received chemotherapy, ketocona-
zole, abiraterone, or enzalutamide. ARMOR2 part 1 permitted the
enrollment of abiraterone-refractory patients, provided it had
been discontinued 4 weeks before enrollment and that the
duration of therapy was 6 months before PSA progression or
>6 weeks with documentation of an initial response followed by
PSA progression. Previous ketoconazole treatment was permitted
upon agreement between the investigator and the study sponsor.
Patients with nonhepatic visceral metastases and/or tumor-asso-
ciated bone pain that required active pain management were
excluded from ARMOR1. Patients with indeterminate lung
nodules were eligible. Other exclusion criteria included any
previous radium-223, strontium, or samarium therapy within 8
weeks of enrollment; radiotherapy 4 weeks before enrollment or
completed radiotherapy in ARMOR1; or radiotherapy 3 weeks
(2 weeks for single-fraction radiotherapy) in ARMOR2 part 1.
Patients were excluded if they had previous treatment with inves-
tigational drugs or agents that could have interfered with the
efficacy and safety assessments. Patients with abnormal labora-
tory test results, including serum creatinine level >1.5 times the
upper limit of normal (ULN), liver function test results >1.5
ULN, hemoglobin level 9.0 g/dL, platelet count 100 10
9
/L,
absolute neutrophil count 1.5 10
9
/L, and serum potassium
level <3.5 mmol/L, were ineligible, as were those with serious
concurrent illnesses or conditions, including heart failure, uncon-
trolled hypertension, angina, active autoimmune disease, or
gastrointestinal disorders or gastric bypass surgery that could have
interfered with study medication absorption. Written informed
consent was obtained from participants before enrollment.
Study design
ARMOR1 (NCT00959959) was a phase I, multicenter, open-
label, dose-escalation study conducted in collaboration with the
Department of Defense Prostate Cancer Clinical Trials Consor-
tium, designed to assess the tolerability, safety, and efficacy of oral
Translational Relevance
Despite the recent advances in the understanding and
treatment of metastatic castration-resistant prostate cancer
(mCRPC), it remains a lethal disease. Androgen receptor (AR)
signaling remains a primary target of therapy, as the under-
standing of both the disease and mechanisms of resistance
expand. Galeterone, a selective, multitargeted agent, is distinct
from other mCRPC therapies in that it combines the mechan-
isms of current agents—CYP17 inhibition and AR antago-
nism—with the novel mechanism of increasing AR protein
degradation. These first assessments of galeterone in mCRPC
identified a well-tolerated dose that resulted in clinically
significant reductions in prostate-specific antigen, and dem-
onstrate the potential of this agent. In vitro data and results of
these studies have informed future investigation of galeterone,
which will include AR-related biomarker analyses.
Galeterone for Metastatic Castration-Resistant Prostate Cancer
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galeterone for chemotherapy-naive patients with CRPC. The
primary goals were to find the optimal dose of galeterone with
an acceptable safety profile, defined as an observed dose-lim-
iting toxicity (DLT) rate of 35%, and to identify a dose for
further phase II study. The dose equivalence component of
ARMOR2 (i.e., part 1; NCT01709734) evaluated the pharma-
cokinetics (PK), safety, and efficacy of a new formulation of
galeterone with improved bioavailability. A micronized pow-
der formulation (capsule) was used in ARMOR1 and an SDD
formulation was used in ARMOR2 part 1. These studies were
designed and monitored in accordance with Sponsor proce-
dures, which comply with the ethical principles of Good
Clinical Practice, as required by the major regulatory author-
ities, and in accordance with the Declaration of Helsinki and
the FDA regulations. The protocols were approved by the
institutional review board of each study site.
In ARMOR1, galeterone capsules (micronized powder, 325
mg) were administered orally as (i) 650 mg in the evening, (ii)
975 mg in the evening, (iii) 975 mg in the morning, (iv) 1,300 mg
in the evening, (v) 1,950 mg in the evening, (vi) 1,950 mg divided
into morning and evening doses, (vii) 2,600 mg in the evening, or
(viii) 2,600 mg divided into morning and evening doses, accord-
ing to the cohort they entered. All doses were administered with a
patient-selected meal, except for the 975 mg morning dose cohort,
which received a high-fat, high-calorie nutritional supplement
(Novasource Renal, Nestle HealthCare Nutrition, Florham Park,
NJ) in place of the meal. Enrollment target was 6 patients per dose
cohort. If an acceptable safety profile was determined by the
internal monitoring committee (IMC; DLT rate 35% or 2of
6 patients in cohorts of 6 patients), subsequent dose levels and
schedules were opened for enrollment. If 3 of 6 patients expe-
rienced DLTs, dose de-escalation was required. DLTs were defined
as any study drug–related grade 3 or higher adverse event [AE;
National Cancer Institute Common Terminology Criteria for
Adverse Events (CTCAE) version 4.0] considered to be possibly,
probably, or definitely related to the study drug.
In ARMOR2 part 1, galeterone SDD tablets (425 mg) were
administered at doses of 1,700, 2,550, and 3,400 mg once daily
with the morning meal. Enrollment target was 6 patients per dose
level. Dose escalation occurred when no clinically significant
grade 2 or greater sustained AEs or serious, unexpected grade 3
or higher AEs occurred in a dose group 2 weeks after the last
patient in that cohort received his first dose.
The planned treatment duration of both studies was 12 weeks,
with optional extension dosing for eligible patients based on
safety and tolerability during the 12-week phase. Extension dos-
ing was continued until the patient withdrew, experienced unac-
ceptable toxicity, the disease progressed, or the patient died.
Assessments
Safety assessments, conducted at baseline and every 2 weeks
during the 12-week study and every 4 weeks during the optional
extension phase, included physical examination, vital signs, elec-
trocardiogram (ECG), serum chemistry, hematology, urinalysis,
and performance status. AEs that occurred during the study and up
to 30 days after the last dose of study drug were collected, coded
according to Medical Dictionary of Regulatory Activities, version
12.1, and graded using CTCAE version 4.0. PSA was determined at
each study visit.
In the first 4 dosing cohorts of ARMOR1, blood samples for PK
analysis were obtained predose and at 4 hours on day 1. In the
remaining cohorts, blood samples were obtained before (hour
0) and 1, 2, 4, and 6 hours after the first dose on day 1. At all
remaining visits, if the regimen for the cohort included a
morning dose, blood samples were obtained at 6 hours after
their dose; for all other cohorts, blood samples were obtained
at any time during the visit. In ARMOR2 part 1, blood samples
forPKanalyseswereobtainedbefore(hour0)and2,3,4,5,
and 6 hours after the day 1 dose, and predose on days 7, 14, 21,
28, and 84. Additional samples were obtained in consenting
patients on day 1 at 8, 12, 16, and 24 hours postdose and on
day 84 at 2, 3, 4, 5, 6, 8, 12, 16, and/or 24 hours postdose.
Blood samples were also obtained at each study visit of
ARMOR2 part 1 for determination of pregnenolone, 17-hydro-
xyprogesterone, deoxycorticosterone, 11-deoxycortisol, cortico-
sterone, cortisol, dehydroepiandrosterone sulfate (DHEAS),
androstenedione, and testosterone concentrations.
Data Analysis
Efficacy endpoints included the proportion of responders [PSA
decrease 50% [PSA50] and 30% (PSA30)], maximal decrease
in PSA from baseline to 12 weeks or PSA nadir, changes from
baseline in tumor response as assessed by bone scan and CT or
MRI using PCWG2 and RECIST v1.1. PSA efficacy was based on
the intent-to-treat population (ITT), defined as enrolled patients
who received at least 1 dose of study drug. Response was based on
measurable disease in both studies. Time to progression, PFS
defined as the time from first dose of study drug until objective
CRPC progression or death, whichever occurred first, and OS were
the endpoints assessed in the ARMOR1 extension phase. Descrip-
tive statistics were used for most variables (n, mean, SD, median,
minimum, and maximum for continuous variables and frequency
and percentage for categorical variables).
Results
Patients
Baseline patient and disease characteristics are presented
in Table 1. In ARMOR1, 49 patients were enrolled in 8 cohorts,
with 6 patients in each, except cohort 4, which enrolled 7 patients.
Twelve patients discontinued the study before completion of 12
weeks because of treatment-emergent AEs [TEAEs; n¼5; nausea,
chronic obstructive pulmonary disease exacerbation (event onset
before dosing), elevated aspartate aminotransferase/alanine ami-
notransferase levels (AST/ALT; n¼2), acute renal failure
[reversible after resolution of rhabdomyolysis, which occurred
while the patient was receiving simvastatin therapy and became
evident after the patient fell], disease progression (n¼5), or
withdrawal of consent/personal choice [n¼2; Table 2)]. Twenty-
two of the 37 patients who completed the study were eligible for
the optional extension phase, and 21 patients were dosed. Over-
all, all patients received 650 to 2,600 mg galeterone daily for <1to
20 months. In ARMOR2 part 1, 28 patients were enrolled in 3
dosing cohorts, with 6 patients in the 1,700-mg cohort, 14 in the
2,550-mg cohort (abiraterone-resistant, n¼3), and 8 in the
3,400-mg cohort. Six patients discontinued the study before 12
weeks because of TEAEs [n¼4; angioedema (in an African-
American who was receiving the angiotensin-converting enzyme
inhibitor, lisinopril), rash, weakness, and tremulousness] or dis-
ease progression (n¼2). All 3 patients with abiraterone-resistant
disease completed the 12-week phase of the study. Nineteen of 22
patients who completed the study participated in the optional
Montgomery et al.
Clin Cancer Res; 22(6) March 15, 2016 Clinical Cancer Research1358
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extension phase; 2 of the patients with abiraterone-resistant
disease were not eligible for the extension because of disease
progression (Table 2). Overall duration of therapy ranged from <1
month to 14 months.
Safety and tolerability
ARMOR1. Safety reviews were completed after all patients were
dosed in each cohort and the IMC recommended continued
escalation following review of all doses. There were 2 deaths, 1
from disease progression and 1 from acute septic shock followed
by acute metabolic acidosis and renal failure, which was not
related to galeterone. All patients experienced at least 1 TEAE
during the 12-week phase, with most being mild or moderate in
severity (91.5%) and comparable among cohorts. The majority
(73%) of the AEs required no action. The most common
TEAEs were fatigue [17 patients (34.7%)], increased AST level
[16 patients (32.7%)], increased ALT level [15 patients (30.6%)],
nausea [12 patients (24.5%)], diarrhea [11 patients (22.4%)], and
pruritus [11 patients (22.4%); Table 3]. The most common
treatment-related TEAEs were increased AST level [7 patients
(14.3%)], nausea [5 patients (10.2%)], increased bilirubin level
[4 patients (8.2%)], fatigue [4 patients (8.2%)], and diarrhea
[3 patients (6.1%)]. The majority of patients (85.7%) in the
extension phase experienced mild or moderate TEAEs that were
consistent with those reported during the treatment phase.
ARMOR2 Part 1. Galeterone tablets were well tolerated at all
doses, as assessed by the IMC. Safety reviews were completed after
all patients were dosed in each cohort, and the IMC recommended
continued escalation. Most patients (93%) experienced at least 1
TEAE, with the majority (91%) being grade 1 or 2 in severity and
comparable among cohorts. Most (72%) AEs required no inter-
vention. There were no DLTs at any dose level. The most common
TEAEs were nausea [13 patients (46.4%)], fatigue [9 patients
(32.1%)], pruritus [9 patients (32.1%)], vomiting [8 patients
(28.6%)], and decreased appetite [6 patients (21.4%); Table 3].
The most common treatment-related TEAEs were nausea
[10 patients (35.7%)]; pruritus [9 patients (32.1%)]; fatigue,
vomiting, and decreased appetite [6 patients (21.4%] for each);
and constipation, diarrhea, increased ALT level, and dizziness
[3 patients (10.7%)] for each). Although edema and hypokalemia
were observed, they were independent events in different patients
and no combined apparent mineralocorticoid excess events were
seen (Table 4).
Pharmacokinetics
The PK analysis plan of ARMOR1 was not designed to fully
characterize the PK of galeterone. There was no consistency or
dose dependence with respect to plasma concentrations and
regimen. There was little or no difference in mean concentrations
in the single daily doses, with only the 650-mg dose demonstrat-
ing lower mean concentrations, and the PK of the 975-mg dose
was no different after the supplement, compared with a patient-
selected meal. Dividing the dose did not have a significant effect
on exposure (AUC).
The PK analysis plan of ARMOR2 was not designed to fully
characterize the PK of galeterone. The ARMOR2 part 1 PK
parameters after single doses of 1,700, 2,550, and 3,400 mg
of the SDD tablet formulation were similar among doses.
Exposure, expressed as AUC from predose to 6 hours postdose
(AUC
0–6
), was 2,646 1,748 h ng/mL, 2,684 2,043 h ng/mL,
Table 2. Treatment cohorts and patient disposition
ARMOR1—Galeterone capsules ARMOR2 Part 1–Galeterone SDD tablets
(N¼49) (N¼28)
Dosing cohort
Enrolled,
n
Completed
12-week
study, n
Entered
extension
phase, nCohort
Enrolled,
n
Completed
12-week
study, n
Entered
extension
phase, n
650 mg with meal 6 3 3 1,700 mg 6 6 6
975 mg with meal 6 5 2 2,550 mg 14 11 9
1,300 mg with meal 6 5 3 3,400 mg 8 5 4
1,950 mg with meal 7 5 2
975 mg with supplement
a
64 4
1,950 mg divided doses with meal 6 5 2
b
2,600 mg with meal 6 5 2
2,600 mg divided doses with meal 6 5 3
a
Novasource Renal, Nestle HealthCare Nutrition, Florham Park, New Jersey.
b
Three patients were eligible for the extension phase; however, only 2 patients were dosed with galeterone.
Table 1. Baseline characteristics
Characteristic
ARMOR1 ARMOR2 Part 1
(N¼49) (N¼28)
Age, median (range), y 68 (47–89) 70 (48–90)
Ethnicity, n(%)
White 43 (87.8) 24 (85.7)
African-American or black 3 (6.1) 2 (7.1)
Asian 1 (2.0) 1 (3.6)
Other 2 (4.1) 1 (3.6)
Metastatic disease (M1), n(%) 25 (51.0) 24 (85.7)
Bone, n25 24
Nodal, n15 10
Bone and nodal, n98
Visceral (liver and/or lung), n71
Visceral and bone, n61
Visceral and nodal, n30
Soft tissue (not nodal, liver, or lung), n17 11
Previous therapies, n(%)
Medical and/or surgical castration 49 (100) 28 (100)
Immunotherapy 1 (2) 2 (7.1)
Radiotherapy 27 (55) 16 (57.1)
Surgery 24 (49) 12 (42.9)
Abiraterone NA 3 (10.7)
Enzalutamide NA 0
ECOG, n(%)
0 45 (91.8) 22 (78.6)
1 4 (8.2) 5 (17.9)
Missing 0 1 (3.6)
Gleason score, median (range)
a
7(6–10) 8 (6–10)
PSA, median (range), ng/dL 24 (6–200.6) 17.6 (3.3–6,760)
Abbreviations: NA, not applicable.
a
Data were missing in 2 patients in ARMOR1 and 1 patient in ARMOR 2 Part 1.
Galeterone for Metastatic Castration-Resistant Prostate Cancer
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and 2,528 1,529 h ng/mL for the 1,700, 2,550, and 3,400 mg
doses, respectively.
Efficacy endpoints
ARMOR1. The ITT population for PSA efficacy included 49
patients. Across all doses tested, 24 of 49 (49.0%) achieved a
PSA30 and 11 of 49 patients (22.4%) demonstrated PSA50
(Fig. 1A). During the study, one patient in the 650 mg/d group
discontinued his gonadotropin-releasing hormone analog and
one patient in the 975 mg/d group underwent transurethral
resection of the prostate. Excluding these patients, across groups
the PSA30 was 51.1% (24/47) and the PSA50 was 23.4% (11/47).
An increase in response rate was observed with higher doses. At
the 2,600 mg dose, 9 of 12 patients (75.0%) demonstrated a
PSA30 and 5 of 12 patients (41.7%) demonstrated a PSA50. There
was no difference in PSA response between groups that had
divided dosing and groups that had once-daily dosing. Of the
evaluable patients [those with measurable target lesions at screen-
ing or baseline who had a follow-up scan at the 14-week (final)
study visit; n¼17], 2 patients had a partial response (PR) and 10
patients had stable disease (SD), according to RECIST. In the
extension phase, disease progression ultimately occurred in 20 of
the 21 patients. No consistent trends were observed in time to
progression (range, 14–592 days), PFS, or OS [shortest: 189 days,
cohort 3 (1,300 mg/d)] between treatment cohorts. Best overall
response assessed by RECIST was SD in 13 of 17 patients (76.5%)
in the extension phase; the remaining 4 patients had disease
progression.
ARMOR2 Part 1. The ITT population for PSA efficacy in treatment-
na€
ve patients included 25 patients. Three patients had received
prior abiraterone treatment. Across the 3 doses in treatment-naive
patients, the decline in PSA from baseline in the ITT population
was 30% in 16 of 25 patients (64.0%) and 50% in 12 of 25
patients (48.0%). In the 2,550-mg dose cohort, 8 of 11 treatment-
naive patients (72.7%) had a 30% decline in PSA from baseline
and 6 of 11 patients (54.5%) had a 50% decline in PSA from
baseline. In the 1,700-mg dose cohort 50% (3/6 patients)
achieved a PSA30 and PSA50. In the 3,400 mg dose cohort,
62.5% (5/8 patients) achieved a PSA30 and 37.5% (3/8 patients)
achieved a PSA50 (Fig. 1B). One patient in the 2,550-mg/d group
had only 1 post-baseline PSA measurement (performed at
2 weeks) and 1 patient in the 3,400 mg/d group had no post-
baseline measurement of PSA. Excluding these patients, the
PSA30 and PSA50 were 80% and 60% in the 2,550 mg/d group,
and 71.4% and 42.9% in the 3,400 mg/d group. Of the 3 patients
treated with 2,550 mg/d who had prior treatment with abirater-
one, 1 patient (33%) achieved PSA30, 1 patient had a maximal
percent change of 2%, and 1 patient had an increase from
baseline. Of the 26 evaluable patients with measurable disease
at baseline, 20 (76.9%) patients had SD and 1 patient had PR at 12
weeks.
Steroidogenic pathway markers
Galeterone resulted in overall reductions in median serum
testosterone, DHEAS, and androstenedione concentrations.
Median corticosterone level was increased from a median baseline
of 204 ng/dL to 1,377.5 ng/dL at week 12, and cortisol and
deoxycorticosterone levels were generally unchanged (Table 5).
Discussion
Results of ARMOR1 and ARMOR2 part 1 demonstrated that
galeterone, an agent that previous studies have shown inhibits
androgen production, blocks the ligand-binding domain of AR,
and suppresses AR levels in vitro, is safe and shows promising PSA
Table 3. Treatment-emergent AEs occurring in >10% of patients in ARMOR1 or ARMOR2 Part 1
ARMOR1 ARMOR2 Part 1
(N¼49) (N¼28)
AE
Grade 1 or
2, n(%)
Grade 3 or
higher, n(%)
Grade 1 or
2, n(%)
Grade 3 or
higher, n(%)
Abdominal pain 5 (10.2) 0 1 (3.6) 0
Increased alkaline phosphatase level 7 (14.3) 0 0 0
Increased ALT level 7 (14.3) 8 (16.3) 1 (3.6) 3 (10.7)
Decreased appetite 6 (12.2) 0 6 (21.4) 0
Arthralgia 6 (12.2) 0 1 (3.6) 0
Increased AST level 13 (26.5) 3 (6.1) 1 (3.6) 1 (3.6)
Back pain 1 (2.0) 0 3 (10.7) 0
Increased bilirubin level 6 (12.2) 1 (2.0) 0 0
Constipation 5 (10.2) 0 3 (10.7) 1 (3.6)
Cough 7 (14.3) 0 3 (10.7) 0
Diarrhea 11 (22.4) 0 4 (14.3) 1 (3.6)
Dizziness 3 (6.1) 0 3 (10.7) 0
Fall 0 0 3 (10.7) 0
Fatigue 16 (32.7) 1 (2.0) 9 (32.1) 0
Nausea 12 (24.5) 0 13 (46.4) 0
Pruritus 11 (22.4) 0 9 (32.1) 0
Rash 5 (10.2) 0 0 1 (3.6)
Urinary tract infection 4 (8.2) 0 4 (14.3) 0
Vomiting 6 (12.2) 0 8 (28.6) 0
Decreased weight 5 (10.2) 0 4 (14.3) 0
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.
Table 4. Summary of Potential AME AEs in ARMOR1 or ARMOR2 Part 1
Number of
incidences AE
Attribution:
related/unrelated
a
1 Grade 2 hypokalemia 1/0
3 Grade 3 hypokalemia 1/2
1 Grade 1 peripheral edema 0/1
3 Grade 2 peripheral edema 2/1
a
All events were individual occurrences and not considered AME symptoms.
Montgomery et al.
Clin Cancer Res; 22(6) March 15, 2016 Clinical Cancer Research1360
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responses in patients with mCRPC. Results from phase I healthy
volunteer PK studies and the PK results of ARMOR2 part 1 support
a 2,550 mg/d dose of galeterone SDD tablet for use in future trials.
All doses tested had similar safety and tolerability profiles.
Results of these studies demonstrate that galeterone is well tol-
erated in men with CRPC, with infrequent grade 3 and 4 toxicities.
The most common treatment-related AEs were nausea, vomiting,
fatigue, pruritus, and decreased appetite. Of these events, the vast
majority (90%) were grade 1 or 2 and did not require any
intervention. Of note, there were no apparent mineralocorticoid
excess AEs, supporting results of preclinical studies demonstrating
the specificity of galeterone for CYP17 lyase compared with
hydroxylase (19). This hypothesis is further supported by the
steroidogenic marker results showing no change in deoxycorti-
costerone or cortisol and a small increase in corticosterone,
relative to a large increase observed with abiraterone even in the
absence of coadministration of steroids with galeterone (31). The
reductions in testosterone are slightly less than those seen at full
dose abiraterone, but similar to that found in the dose escalation
study (31).
Significant PSA declines were observed with all dose levels.
Patients in ARMOR1 had an overall PSA30 and PSA50 of 49% and
22%, respectively, with the highest dose (2,600 mg) showing
PSA30 and PSA50 of 75% and 42%, respectively. In ARMOR2 part
1, 2,550 mg of the SDD tablet formulation, the dose found to
-100
-75
-50
-25
0
25
50
75
100
Maximal PSA change from baseline (%)
1,950 mg/d
(n = 13)
2,600 mg/d
(n = 12)
1,300 mg/d
(n = 6)
975 mg/d
(n = 12)
650 mg/d
(n = 6)
*
-100
-75
-50
-25
0
25
50
75
100
Maximal PSA change from baseline (%)
**
1,700 mg/d
(n = 6)
2,550 mg/d
(n = 11)
3,400 mg/d
(n = 7)
Figure 1.
A, the maximal percentage of change
in PSA from baseline at 12 weeks by
total daily dose in treatment-naive
patients in ARMOR1 (n¼49).
Patterned data points reflect 1 patient
who discontinued his gonadotropin-
releasing hormone analog (650 mg/d
group) and 1 patient who underwent
transurethral resection of the prostate
(975-mg/d group). B, the maximal
percentage of change in PSA from
baseline by total daily dose in
evaluable treatment-naive patients in
ARMOR2 Part 1 (n¼25). Patterned
data point reflects a patient who only
had 1 post-baseline PSA measurement
(at 2 weeks). One patient in the
3,400 mg/d group (n¼8) is not
included in the graph because no post-
baseline PSA measurements were
completed. Abiraterone-refractory
patients (N¼3) were not included in
this analysis. Reference lines: green,
50%; orange, 30%. , maximal PSA
values >100% increase from baseline.
Table 5. Median (range) concentrations of the steroidogenic pathway markers
in ARMOR2 Part 1
Median (range)
Steroid Baseline Week 12
Testosterone, ng/dL 7.5 (3–22) 2 (<1–14)
Androstenedione, ng/dL 32 (7–81) 14 (<5–34)
DHEAS, mg/dL 37.5 (<15–220) 18 (<15–105)
Corticosterone, ng/dL 204 (<20–874) 1,377.5 (97–4,375)
Deoxycorticosterone, ng/dL <16 (<16–18) <16 (<16–89)
Cortisol, mg/dL 14.7 (1.8–28.7) 18.1 (4.1–35)
Galeterone for Metastatic Castration-Resistant Prostate Cancer
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provide exposure similar to that of 2,600 mg of the capsule,
resulted in greater PSA30 and PSA50 of 80% and 60%, respec-
tively. These results are comparable with those observed in phase I
and II trials of abiraterone and enzalutamide (8, 11, 31). Of
note, these results were marginally better than the 3,400 mg
(PSA30 ¼71%, PSA50 ¼43%) and 1,700 mg (PSA30 ¼50%,
PSA50 ¼50%) doses.
Although ARMOR1 showed that increasing the dose resulted in
a better PSA response, a phase I healthy volunteer PK study
showed that the capsule formulation was confounded by a food
effect and resulted in exposure that plateaued above 1,950 mg
(Appendix; ref. 28). The lack of a clear food effect in ARMOR1
could be attributed to the study design, in that the blood sampling
strategy was not optimal for assessment of PK parameters, and
patient-selected meals precluded assessment of the effect of fat
and calories.
ARMOR2 part 1 served as a bridging study between the original
capsule formulation and the SDD tablet formulation, which was
developed to have improved relative bioavailability over the
capsule. In PK studies in healthy volunteers, the SDD tablet was
shown to result in dose-related increases in exposure that were
similar in fed and fasted states that plateaued at doses above
2,550 mg (32). In addition, it was found that the exposure after
1,700 mg of the SDD tablet was similar to that with 2,600 mg of
the original capsule formulation—the dose in ARMOR1 that
resulted in the best efficacy numbers (28). ARMOR2 part 1
evaluated increasing doses of the SDD tablet formulation starting
at the 1,700 mg dose. The PK results of this study showed that
there was no increase in exposure with higher doses. Although the
lack of increase in exposure between the 1,700 and the 2,550 mg
dose was not consistent with earlier PK evaluations of the SDD
tablet, it could again be attributed to study design, in that the
sampling strategy was not optimal for a full PK assessment. The
results from the PK, safety and PSA decline data support the choice
of the 2,550 mg dose for use in phase II and III clinical studies. The
phase II studies have been completed and are in follow-up, and
the phase III study is planned (ARMOR3-SV). The ability of
galeterone to target splice variant AR through enhanced degrada-
tion suggests that it may have potential activity in tumors expres-
sing these resistant variants. The phase III, ARMOR3-SV study will
target splice variant (AR-V7) positive tumors and is based on PSA
responses seen patients with C-terminal loss in the treatment
na€
ve cohort of ARMOR2 (33).
Conclusion
The efficacy and safety results from ARMOR1 and ARMOR2
part 1, and the PK results from phase I healthy volunteer studies
and ARMOR2 part 1 support the recommended dose of galeter-
one 2,550 mg daily taken with food for ARMOR2 part 2 and the
phase III study (ARMOR3-SV) using the SDD tablet formulation
with improved bioavailability. Galeterone is well tolerated in
CRPC patients and demonstrates pharmacodynamic changes
consistent with its selective multifunctional AR signaling inhibi-
tion. The analysis of galeterone is ongoing in expanded patient
cohorts in ARMOR2 part 2 and is ongoing for a phase III trial
(ARMOR3-SV) comparing galeterone with enzalutamide in treat-
ment-naive patients with mCRPC whose prostate tumors express
the AR-V7 splice variant.
Disclosure of Potential Conflicts of Interest
L.T. Nordquist is a consultant/advisory board member for Bayer Pharma-
ceuticals. W.J. Edenfield reports receiving speakers bureau honoraria from
Astellas and Novartis. K.J. Ferrante holds ownership interest (including
patents) in, and is a consultant/advisory board member for Tokai Pharmaceu-
ticals. M.-E. Taplin reports receiving commercial research grants, other com-
mercial research support, speakers bureau honoraria from, and is a consultant/
advisory board member for Tokai Pharmaceuticals. No potential conflicts of
interest were disclosed by the other authors.
Authors' Contributions
Conception and design: B. Montgomery, M.A. Eisenberger, M.B. Rettig,
N.J. Vogelzang, M.-E. Taplin
Development of methodology: B. Montgomery, K. Mamlouk, M.-E. Taplin
Acquisition of data (provided animals, acquired and managed patients,
provided facilities, etc.): B. Montgomery, M.B. Rettig, F. Chu, R. Pili,
J.J. Stephenson, N.J. Vogelzang, A.J. Koletsky, W.J. Edenfield, K. Mamlouk,
M.-E. Taplin
Analysis and interpretation of data (e.g., statistical analysis, biostatistics,
computational analysis): B. Montgomery, M.A. Eisenberger, J.J. Stephenson,
N.J. Vogelzang, K. Mamlouk, M.-E. Taplin
Writing, review, and/or revision of the manuscript: B. Montgomery,
M.A. Eisenberger, M.B. Rettig, F. Chu, R. Pili, J.J. Stephenson, N.J. Vogelzang,
A.J. Koletsky, L.T. Nordquist, W.J. Edenfield, K. Mamlouk, K.J. Ferrante,
M.-E. Taplin
Administrative, technical, or material support (i.e., reporting or organizing
data, constructing databases): B. Montgomery, K. Mamlouk, M.-E. Taplin
Study supervision: B. Montgomery, J.J. Stephenson, A.J. Koletsky, W.J. Eden-
field, K. Mamlouk
Other (study data review and clinical interpretation in preparation for
writing of the article): K.J. Ferrante
Grant Support
Data analysis support was provided by Sarah Hunter of Cd3. Technical
editorial and medical writing support was provided by Beth Kamp, PharmD.
Funding for this support was provided by Tokai Pharmaceuticals, Cambridge,
MA.
The costs of publication of this article were defrayed in part by the payment of
page charges. This article must therefore be hereby marked advertisement in
accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received June 16, 2015; revised September 29, 2015; accepted October 11,
2015; published OnlineFirst November 2, 2015.
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Galeterone for Metastatic Castration-Resistant Prostate Cancer
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