U.S. patent application number 16/885767 was filed with the patent office on 2022-02-24 for anti-androgens for the treatment of non-metastatic castration-resistant prostate cancer.
The applicant listed for this patent is Aragon Pharmaceuticals, Inc.. Invention is credited to Arturo Molina.
Application Number | 20220054468 16/885767 |
Document ID | / |
Family ID | |
Filed Date | 2022-02-24 |
United States Patent
Application |
20220054468 |
Kind Code |
A9 |
Molina; Arturo |
February 24, 2022 |
Anti-Androgens For The Treatment Of Non-Metastatic
Castration-Resistant Prostate Cancer
Abstract
Described herein are methods of treating non-metastatic
castrate-resistant prostate cancer using an approved drug product
comprising apalutamide, enzalutamide or darolutamide. Also
described here are drug products containing apalutamide
enzalutamide or darolutamide, and methods of selling or offering
for sale an anti-androgen drug product.
Inventors: |
Molina; Arturo; (Los Altos
Hills, CA) |
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Applicant: |
Name |
City |
State |
Country |
Type |
Aragon Pharmaceuticals, Inc. |
San Diego |
CA |
US |
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Prior
Publication: |
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Document Identifier |
Publication Date |
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US 20200352926 A1 |
November 12, 2020 |
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Appl. No.: |
16/885767 |
Filed: |
May 28, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15967452 |
Apr 30, 2018 |
10702508 |
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16885767 |
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62630594 |
Feb 14, 2018 |
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62617745 |
Jan 16, 2018 |
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62572791 |
Oct 16, 2017 |
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International
Class: |
A61K 31/4439 20060101
A61K031/4439; A61P 35/00 20060101 A61P035/00; A61K 31/4166 20060101
A61K031/4166; A61K 31/4178 20060101 A61K031/4178; A61K 31/192
20060101 A61K031/192; A61K 31/4365 20060101 A61K031/4365; A61K
31/496 20060101 A61K031/496; A61K 31/427 20060101 A61K031/427; A61K
9/00 20060101 A61K009/00; A61K 31/4152 20060101 A61K031/4152; A61K
31/4155 20060101 A61K031/4155; A61K 31/426 20060101 A61K031/426;
A61K 31/00 20060101 A61K031/00 |
Claims
1-44. (canceled)
45. A method of improving metastasis free survival in a male human
with non-metastatic castration-resistant prostate cancer, said
method comprising administering to said male human an approved drug
product comprising enzalutamide in combination with androgen
deprivation therapy.
46. The method of claim 45, wherein the androgen deprivation
therapy consists of orchiectomy or gonadotropin-releasing hormone
agonists or antagonists
47. The method of claim 45, wherein the approved drug product
provides an increase in the metastasis-free survival of the male
human relative to the mean survival rate of a population of male
humans with non-metastatic castration-resistant prostate cancer,
said population having been administered a placebo in combination
with androgen deprivation therapy.
48. The method of claim 45, wherein a drug product label for a
reference listed drug for such approved drug product comprises
metastasis free survival data.
49. The method of claim 45, wherein a drug product label for a
reference listed drug for such approved drug product includes
instructions for treating non-metastatic castration resistant
prostate cancer.
50. The method of claim 45, further comprising selling such
approved drug product, wherein a drug product label for a reference
listed drug for such approved drug product includes instructions
for treating non-metastatic castration resistant prostate
cancer.
51. The method of claim 50, wherein the drug product label
comprises metastasis free survival data.
52. A method of improving metastasis free survival in a male human
with nonmetastatic castration-resistant prostate cancer, said
method comprising providing to said male human an approved drug
product comprising enzalutamide in combination with androgen
deprivation therapy, wherein the androgen deprivation therapy
consists of orchiectomy or gonadotropin-releasing hormone agonists
or antagonists.
53. The method of claim 52, wherein the androgen deprivation
therapy consists of orchiectomy or gonadotropin-releasing hormone
agonists or antagonists.
54. The method of claim 52, wherein a drug product label for a
reference listed drug for such approved drug product comprises
metastasis free survival data.
55. The method of claim 52, wherein a drug product label for a
reference listed drug for such approved drug product includes
instructions for treating non-metastatic castration resistant
prostate cancer.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 15/967,452, filed Apr. 30, 2018, which claims
the benefit of U.S. Provisional Application No. 62/630,594, filed
Feb. 14, 2018, U.S. Provisional Application No. 62/617,745, filed
Jan. 16, 2018, and U.S. Provisional Application No. 62/572,791,
filed Oct. 16, 2017, each of which are incorporated herein by
reference in their entirety.
FIELD OF THE INVENTION
[0002] Disclosed herein are methods of treating non-metastatic
castration-resistant prostate cancer with an approved drug product
containing an anti-androgen selected from the group consisting of
enzalutamide, apalutamide and darolutamide. Also disclosed are
methods of selling or offering for sale an approved drug product
containing an anti-androgen selected from the group consisting of
enzalutamide, apalutamide and darolutamide.
BACKGROUND OF THE INVENTION
[0003] Prostate cancer is the second most frequently diagnosed
cancer and the sixth leading cause of cancer death in males,
accounting for 14% (903,500) of the total new cancer cases and 6%
(258,400) of the total cancer deaths in males worldwide. The course
of prostate cancer from diagnosis to death is best categorized as a
series of clinical stages based on the extent of disease, hormonal
status, and absence or presence of detectable metastases: localized
disease, rising levels of prostate-specific antigen (PSA) after
radiation therapy or surgery with no detectable metastases, and
clinical metastases in the non-castrate or castrate stage. Although
surgery, radiation, or a combination of both can be curative for
patients with localized disease, a significant proportion of these
patients have recurrent disease as evidenced by a rising level of
PSA, which can lead to the development of metastases, especially in
the high-risk group--a transition to the lethal stage of the
disease.
[0004] Androgen depletion is the standard treatment with a
generally predictable outcome: decline in PSA, a period of
stability in which the tumor does not proliferate, followed by
rising PSA and regrowth as castration-resistant disease.
Historically, ADT has been the standard of care for patients with
metastatic prostate cancer.
[0005] Molecular profiling studies of castration-resistance
prostate cancers commonly show increased androgen receptor (AR)
expression, which can occur through AR gene amplification or other
mechanisms.
[0006] There is a need for a next-generation AR antagonist that
overcome the potential therapeutic deficiencies of existing
therapies. The disclosed methods are directed to these and other
important needs.
SUMMARY OF THE INVENTION
[0007] Described herein are methods of treating non-metastatic
castration-resistant prostate cancer comprising, consisting of, or
consisting essentially of administering a safe and effective amount
of at least one anti-androgen to a male human who has or is
suspected to have a non-metastatic castration-resistant prostate
cancer. In some embodiments, the non-metastatic
castration-resistant prostate cancer is a high risk non-metastatic
castration-resistant prostate cancer. In some embodiments, a male
human has said non-metastatic castration-resistant prostate cancer
and has a prostate-specific antigen doubling time (PSADT) that is
less than or equal to 10 months. In further embodiments, a male
human having said non-metastatic castration-resistant prostate
cancer has received at least one prior therapy for the treatment of
cancer, optionally wherein the prior therapy for the treatment of
cancer is bicalutamine or flutamide. In still further embodiments,
a male human having said non-metastatic castration-resistant
prostate cancer is treatment naive. In other embodiments, a male
human having said non-metastatic castration-resistant prostate
cancer is an adult.
[0008] In some embodiments, administration of the anti-androgen
provides an increase in the metastasis-free survival of a male
human. In some embodiments, administration of the anti-androgen
provides improved anti-tumor activity as measured by time to
metastasis (TTM), progression-free survival (PFS) rate, time to
symptomatic progression, overall survival (OS) rate, or time to
initiation of cytotoxic chemotherapy. In other embodiments,
administration of a safe and effective amount of the anti-androgen
results in no more than a grade 3 adverse event.
[0009] In some embodiments, the anti-androgen is a
second-generation anti-androgen. In certain embodiments, the
anti-androgen is apalutamide, enzalutamide or darolutamide. In
certain embodiments, the anti-androgen is apalutamide. In certain
embodiments, the anti-androgen is enzalutamide. In certain
embodiments, the anti-androgen is darolutamide.
[0010] In some embodiments, methods of treating non-metastatic
castration-resistant prostate cancer comprise, consist or, or
consist essentially of administering a safe and effective amount of
apalutamide to a male human with a non-metastatic
castration-resistant prostate cancer, wherein the apalutamide is
administered orally. In some embodiments, the apalutamide is
administered daily. In some embodiments, the apalutamide is
administered orally on a continuous daily dosage schedule. In
further embodiments, the apalutamide is administered orally at a
dose of about 240 mg per day. In other embodiments, the apalutamide
is administered orally at a dose of about 60 mg four times per
day.
[0011] In some embodiments, the apalutamide is present in a solid
oral dosage form. In some embodiments, the apalutamide is
formulated as a tablet. In some embodiments, the apalutamide is
formulated as a soft gel. In some embodiments, the apalutamide is
formulated as a hard shell capsule.
[0012] In some embodiments, the enzalutamide is present in a solid
oral dosage form. In some embodiments, the enzalutamide is
formulated as a tablet. In some embodiments, the enzalutamide is
formulated as a soft gel. In some embodiments, the enzalutamide is
formulated as a hard shell capsule.
[0013] In some embodiments, the darolutamide is present in a solid
oral dosage form. In some embodiments, the darolutamide is
formulated as a tablet. In some embodiments, the darolutamide is
formulated as a soft gel. In some embodiments, the darolutamide is
formulated as a hard shell capsule.
[0014] Also provided herein are methods of treating non-metastatic
castration-resistant prostate cancer comprising, consisting of, or
consisting essentially of administering a approved drug product
comprising apalutamide to a male human with a non-metastatic
castration-resistant prostate cancer, wherein the dose of
apalutamide is reduced when co-administered with one or more of:
[0015] (a) a CYP2C8 inhibitor, preferably gemfibrozil or
clopidogrel; or [0016] (b) a CYP3A4 inhibitor, preferably
ketoconazole or ritonavir.
[0017] In some embodiments, the apalutamide is not co-administered
with: [0018] (a) medications that are primarily metabolized by
CYP3A4, preferably darunavir, felodipine, midazolam or simvastatin;
[0019] (b) medications that are primarily metabolized by CYP2C19,
preferably diazepam or omeprazole; [0020] (c) medications that are
primarily metabolized by CYP2C9, preferably warfarin or phenytoin;
or [0021] (d) medications that are substrates of UGT, preferably
levothyroxine or valproic acid.
[0022] In further embodiments, the apalutamide is not
co-administered with: [0023] (a) medications that are P-gp
substrates, preferably fexofenadine, colchicine, dabigatran
etexilate or digoxin; or [0024] (b) BCRP/OATP1B1 substrates,
preferably lapatinib, methotrexate, rosuvastatin, or
repaglinide.
[0025] In another aspect, described herein are methods of selling
an anti-androgen comprising, consisting of, or consisting
essentially of placing an antiandrogen, e.g., darolutamide,
enzalutamide, apalutamide, into the stream of commerce wherein said
anti-androgen includes a package insert that contains instructions
for treating prostate cancer using the anti-androgen. In certain
embodiments, the anti-androgen is apalutamide.
[0026] In further aspects, described herein are methods of selling
an approved drug product containing an anti-androgen, e.g.,
darolutamide, enzalutamide, apalutamide, comprising, consisting of,
or consisting essentially of placing such drug product into the
stream of commerce wherein such drug product includes a package
insert that contains instructions for treating prostate cancer
using the anti-androgen. In certain embodiments, the anti-androgen
is apalutamide.
[0027] In still further aspects, described herein are methods of
offering for sale an anti-androgen comprising, consisting of, or
consisting essentially of offering to place the approved drug
product containing an anti-androgen, e.g., darolutamide,
enzalutamide, apalutamide into the stream of commerce wherein said
anti-androgen includes a package insert that contains instructions
for treating prostate cancer using the anti-androgen. In certain
embodiments, the anti-androgen is apalutamide
[0028] In certain embodiments, the invention is directed to a
method of selling an approved drug product comprising, consisting
of and/or consisting essentially of darolutamide, enzalutamide,
apalutamide, said method comprising, consisting of and/or
consisting essentially of a sale of such drug product, wherein a
label for a reference listed drug for such drug product includes
instructions for treating non-metastatic castration resistant
prostate cancer. In other embodiments, the drug product is an ANDA
drug product or a supplemental New Drug Application drug product.
In another aspect, in the case of apalutamide, the label for said
reference listed drug includes a daily dose of 240 mg apalutamide
and, in the case of enzalutamide, the label for the reference
listed drug includes a daily dose of 160 mg enzalutamide. In the
case of darolutamide, the label for the reference listed drug
includes a daily dose of 1200 mg darolutamide.
[0029] In certain embodiments, the invention is directed to a
method of offering for sale an approved drug product comprising,
consisting of and/or consisting essentially of apalutamide,
enzalutamide, or darolutamide, said method comprising, consisting
of and/or consisting essentially of offering for sale of such drug
product, wherein a label for a reference listed drug for such drug
product includes instructions for treating non-metastatic
castration resistant prostate cancer. In other embodiments, the
drug product is an ANDA drug product or a supplemental New Drug
Application drug product.
BRIEF DESCRIPTION OF THE DRAWINGS
[0030] The summary, as well as the following detailed description,
is further understood when read in conjunction with the appended
drawings. For the purpose of illustrating the disclosed methods,
the drawings show exemplary embodiments of the methods; however,
the methods are not limited to the specific embodiments disclosed.
In the drawings:
[0031] FIG. 1 illustrates tumor growth inhibition in
castration-resistant LNCaP/AR-Luc xenograft model after 28 days of
treatment with bicalutamide or apalutamide (ARN 509).
[0032] FIG. 2 is a schematic of the apalatamide phase III clinical
trial study design. For the screening phase, eligible subjects are
men .gtoreq.18 years old with high-risk NM-CRPC. Randomization
(2:1) is stratified by PSADT, use of bone sparing agent, presence
of loc-regional discease (N0-N1). Long-term follow-up phase is
every 4 months for survival with continued disease evaluations
every 16 weeks until documented disease progression. ADT=androgen
deprivation therapy, BICR=blinded independent central review,
PSADT=prostate specific antigen doubling time,
NM-CRPC=non-metastatic castration-resistant prostate cancer, and *
represents high-risk PSADT months.
[0033] FIG. 3 illustrates a Kaplan-Meier plot of blinded
independent central review (BICR) metastasis-free survival (MFS)
for the U.S. regulatory, intent-to-treat population.
[0034] FIG. 4 is a forest plot of blinded independent central
review (BICR) metastasis-free survival (MFS) for U.S. regulatory by
subgroups defined by baseline clinical disease characteristics
intent-to-treat population.
[0035] FIG. 5 illustrates a Kaplan-Meier plot of time to
symptomatic progression; intent-to-treat population.
[0036] FIG. 6 illustrates the effects of intrinsic/extrinsic
factors and other medications on apalutamide. .sup.aPharmacokinetic
(PK) parameters (Cmax and AUC) are for apalutamide, except in the
drug interaction studies, where they are for active moieties (i.e.,
unbound apalutamide+potency adjusted unbound N-desmethyl
apalutamide). .sup.bDegree of renal impairment was determined based
on eGFR using the modification of diet in renal disease (MDRD)
study equation; normal (.gtoreq.90 mL/min/1.73 m.sup.2), mild
(60-89 mL/min/1.73 m.sup.2), moderate (30-59 mL/min/1.73 m.sup.2).
.sup.cData included 2 subjects with severe renal impairment
(.ltoreq.29 mL/min/1.73 m.sup.2). .sup.dDegree of hepatic
impairment was determined based on Child-Pugh classification; mild
(Child-Pugh A), moderate (Child-Pugh). .sup.eA population PK
analysis demonstrated that mild hepatic impairment (based on the
National Cancer Institute criteria) does not influence the exposure
of apalutamide. .sup.f Effect on steady-state PK of active moieties
based on simulations. .sup.gSee Drug Interactions (7.1 and 7.2) and
use in Specific Populations (8.6 and 8.7).
[0037] FIG. 7 illustrates the effects of apalutamide on the
pharmacokinetics of other drugs. .sup.a Combination/no combination.
.sup.b S-warfarin was measured in the study. .sup.cBased on
simulations. .sup.d See Drug Interactions (7.3 and 7.4).
DETAILED DESCRIPTION OF THE INVENTION
[0038] It is to be appreciated that certain features of the
invention which are, for clarity, described herein in the context
of separate embodiments may also be provided in combination in a
single embodiment. That is, unless obviously incompatible or
specifically excluded, each individual embodiment is deemed to be
combinable with any other embodiment(s) and such a combination is
considered to be another embodiment. Conversely, various features
of the invention that are, for brevity, described in the context of
a single embodiment, may also be provided separately or in any
sub-combination. Finally, although an embodiment may be described
as part of a series of steps or part of a more general structure,
each said step may also be considered an independent embodiment in
itself, combinable with others.
[0039] The transitional terms "comprising," "consisting essentially
of," and "consisting" are intended to connote their generally in
accepted meanings in the patent vernacular; that is, (i)
"comprising," which is synonymous with "including," "containing,"
or "characterized by," is inclusive or open-ended and does not
exclude additional, unrecited elements or method steps; (ii)
"consisting of excludes any element, step, or ingredient not
specified in the claim; and (iii) "consisting essentially of limits
the scope of a claim to the specified materials or steps "and those
that do not materially affect the basic and novel
characteristic(s)" of the claimed invention. Embodiments described
in terms of the phrase "comprising" (or its equivalents), also
provide, as embodiments, those which are independently described in
terms of "consisting of and "consisting essentially of."
[0040] When a list is presented, unless stated otherwise, it is to
be understood that each individual element of that list, and every
combination of that list, is a separate embodiment. For example, a
list of embodiments presented as "A, B, or C" is to be interpreted
as including the embodiments, "A," "B," "C," "A or B," "A or C," "B
or C," or "A, B, or C."
[0041] Androgen receptor (AR) is a member of the steroid and
nuclear receptor superfamily. Among this large family of proteins,
only five vertebrate steroid receptors are known and include the
androgen receptor, estrogen receptor, progesterone receptor,
glucocorticoid receptor, and mineralocorticoid receptor. AR is a
soluble protein that functions as an intracellular transcriptional
factor. AR function is regulated by the binding of androgens, which
initiates sequential conformational changes of the receptor that
affect receptor-protein interactions and receptor-DNA
interactions.
[0042] AR is mainly expressed in androgen target tissues, such as
the prostate, skeletal muscle, liver, and central nervous system
(CNS), with the highest expression level observed in the prostate,
adrenal gland, and epididymis. AR can be activated by the binding
of endogenous androgens, including testosterone and
5-dihydrotestosterone (5a-DHT).
[0043] The androgen receptor (AR), located on Xql 1-12, is a 110 kD
nuclear receptor that, upon activation by androgens, mediates
transcription of target genes that modulate growth and
differentiation of prostate epithelial cells. Similar to the other
steroid receptors, unbound AR is mainly located in the cytoplasm
and associated with a complex of heat shock proteins (HSPs) through
interactions with the ligand-binding domain. Upon agonist binding,
AR goes through a series of conformational changes: the heat shock
proteins dissociate from AR, and the transformed AR undergoes
dimerization, phosphorylation, and translocation to the nucleus,
which is mediated by the nuclear localization signal. Translocated
receptor then binds to the androgen response element (ARE), which
is characterized by the six-nucleotide half-site consensus sequence
5'-TGTTCT-3' spaced by three random nucleotides and is located in
the promoter or enhancer region of AR gene targets. Recruitment of
other transcription co-regulators (including co-activators and
co-repressors) and transcriptional machinery further ensures the
transactivation of AR-regulated gene expression. All of these
processes are initiated by the ligand-induced conformational
changes in the ligand-binding domain.
[0044] AR signaling is crucial for the development and maintenance
of male reproductive organs including the prostate gland, as
genetic males harboring loss of function AR mutations and mice
engineered with AR defects do not develop prostates or prostate
cancer. This dependence of prostate cells on AR signaling continues
even upon neoplastic transformation. Androgen depletion (such as
using GnRH agonists) continues to be the mainstay of prostate
cancer treatment. However, androgen depletion is usually effective
for a limited duration and prostate cancer evolves to regain the
ability to grow despite low levels of circulating androgens.
Castration resistant prostate cancer (CRPC) is a lethal phenotype
and almost all of patients will die from prostate cancer.
Interestingly, while a small minority of CRPC does bypass the
requirement for AR signaling, the vast majority of CRPC, though
frequently termed "androgen independent prostate cancer" or
"hormone refractory prostate cancer," retains its lineage
dependence on AR signaling.
[0045] Prostate cancer is the second most common cause of cancer
death in men in the US, and approximately one in every six American
men will be diagnosed with the disease during his lifetime.
Treatment aimed at eradicating the tumor is unsuccessful in 30% of
men, who develop recurrent disease that is usually manifest first
as a rise in plasma prostate-specific antigen (PSA) followed by
spread to distant sites. Given that prostate cancer cells depend on
androgen receptor (AR) for their proliferation and survival, these
men are treated with agents that block production of testosterone
(e.g., GnRH agonists), alone or in combination with anti-androgens
(e.g., bicalutamide), which antagonize the effect of any residual
testosterone on AR. The approach is effective as evidenced by a
drop in PSA and regression of visible tumor (if present) in some
patients; however, this is followed by regrowth as a castration
resistant prostate cancer (CRPC) to which most patients eventually
succumb. Recent studies on the molecular basis of CRPC have
demonstrated that CRPC continues to depend on AR signaling and that
a key mechanism of acquired resistance is an elevated level of AR
protein (Nat. Med, 2004, 10, 33-39). AR targeting agents with
activity in castration sensitive and castration resistant prostate
cancer have great promise in treating this lethal disease.
[0046] The course of prostate cancer from diagnosis to death is
best categorized as a series of clinical states based on the extent
of disease, hormonal status, and absence or presence of detectable
metastases: localized disease, rising levels of prostate-specific
antigen (PSA) after radiation therapy or surgery with no detectable
metastases, and clinical metastases in the non-castrate or castrate
state. Although surgery, radiation, or a combination of both can be
curative for patients with localized disease, a significant
proportion of these patients have recurrent disease as evidenced by
a rising level of PSA, which can lead to the development of
metastases, especially in the high risk group--a transition to the
lethal phenotype of the disease.
[0047] Androgen depletion is the standard treatment with a
generally predictable outcome: decline in PSA, a period of
stability in which the tumor does not proliferate, followed by
rising PSA and regrowth as castration-resistant disease. Molecular
profiling studies of castration-resistance prostate cancers
commonly show increased androgen receptor (AR) expression, which
can occur through AR gene amplification or other mechanisms.
[0048] Anti-androgens are useful for the treatment of prostate
cancer during its early stages. However, prostate cancer often
advances to a `hormone-refractory` state in which the disease
progresses in the presence of continued androgen ablation or
anti-androgen therapy. Instances of antiandrogen withdrawal
syndrome have also been reported after prolonged treatment with
anti-androgens. Antiandrogen withdrawal syndrome is commonly
observed clinically and is defined in terms of the tumor regression
or symptomatic relief observed upon cessation of anti-androgen
therapy. AR mutations that result in receptor promiscuity and the
ability of these anti-androgens to exhibit agonist activity might
at least partially account for this phenomenon. For example,
hydroxyflutamide and bicalutamide act as AR agonists in T877A and
W741L/W741C AR mutants, respectively.
[0049] In the setting of prostate cancer cells that were rendered
castration resistant via overexpression of AR, it has been
demonstrated that certain anti-androgen compounds, such as
bicalutamide, have a mixed antagonist/agonist profile (Science,
2009 May 8; 324(5928): 787-90). This agonist activity helps to
explain a clinical observation, called the anti-androgen withdrawal
syndrome, whereby about 30% of men who progress on AR antagonists
experience a decrease in serum PSA when therapy is discontinued (J
Clin Oncol, 1993. 11(8): p. 1566-72).
Prostate Cancer Stages
[0050] In the early stages of prostate cancer, the cancer is
localized to the prostate. In these early stages, treatment
typically involves either surgical removal of the prostate or
radiation therapy to the prostate or observation only with no
active intervention therapy in some patients. In the early stages
where the prostate cancer is localized and requires intervention,
surgery or radiation therapy are curative by eradicating the
cancerous cells. About 30% of the time these procedures fail, and
the prostate cancer continues to progress, as typically evidenced
by a rising PSA level. Men whose prostate cancer has progressed
following these early treatment strategies are said to have
advanced or recurrent prostate cancer.
[0051] Because prostate cancer cells depend on the androgen
receptor (AR) for their proliferation and survival, men with
advanced prostate cancer are treated with agents that block the
production of testosterone (e.g., GnRH agonists), alone or in
combination with anti-androgens (e.g., bicalutamide), which
antagonize the effect of any residual testosterone on AR. These
treatments reduce serum testosterone to castrate levels, which
generally slows disease progression for a period of time. The
approach is effective as evidenced by a drop in PSA and the
regression of visible tumors in some patients. Eventually, however,
this is followed by regrowth referred to as castration-resistant
prostate cancer (CRPC), to which most patients eventually
succumb.
[0052] Castration-resistant prostate cancer (CRPC) is categorized
as non-metastatic or metastatic, depending on whether or not the
prostate cancer has metastasized to other parts of the body.
[0053] In some embodiments, prior to treatment with a
second-generation anti-androgen men with non-metastatic CRPC are
characterized as having the following:
[0054] 1. Histologically or cytologically confirmed adenocarcinoma
of the prostate without neuroendocrine differentiation or small
cell features, with high risk for development of metastases.
[0055] 2. Castration-resistant prostate cancer demonstrated during
continuous androgen deprivation therapy (ADT)/post orchiectomy. For
example defined as 3 consecutive rises of PSA, 1 week apart,
resulting in two 50% increases over the nadir, with the last PSA
>2 ng/mL.
[0056] 3. Maintain castrate levels of testosterone (<50 ng/dL
[1.72 nmol/L]) within 4 weeks of randomization and throughout the
study.
[0057] 4. Absence of distant metastasis by bone scan, CT or MRI
scans.
Anti-Androgens
[0058] As used herein, the term "anti-androgen" refers to a group
of hormone receptor antagonist compounds that are capable of
preventing or inhibiting the biologic effects of androgens on
normally responsive tissues in the body. In some embodiments, an
anti-androgen is a small molecule. In some embodiments, an
anti-androgen is an AR antagonist. In some embodiments, an
anti-androgen is an AR full antagonist. In some embodiments, an
anti-androgen is a first-generation anti-androgen. In some
embodiments, an anti-androgen is a second-generation
anti-androgen.
[0059] As used herein, the term "AR antagonist" or "AR inhibitor"
are used interchangeably herein and refer to an agent that inhibits
or reduces at least one activity of an AR polypeptide. Exemplary AR
activities include, but are not limited to, co-activator binding,
DNA binding, ligand binding, or nuclear translocation.
[0060] As used herein, a "full antagonist" refers to an antagonist,
which, at an effective concentration, essentially completely
inhibits an activity of an AR polypeptide. As used herein, a
"partial antagonist" refers an antagonist that is capable of
partially inhibiting an activity of an AR polypeptide, but that,
even at a highest concentration is not a full antagonist. By
`essentially completely` is meant at least about 80%, at least
about 90%, at least about 95%, at least about 96%, at least about
97%, at least about 98% at least about 99%, or greater inhibition
of the activity of an AR polypeptide.
[0061] As used herein, the term "first-generation anti-androgen"
refers to an agent that exhibits antagonist activity against a
wild-type AR polypeptide. However, first-generation anti-androgens
differ from second-generation anti-androgens in that
first-generation anti-androgens can potentially act as agonists in
castration resistant prostate cancers (CRPC). Exemplary
first-generation anti-androgens include, but are not limited to,
flutamide, nilutamide and bicalutamide.
[0062] As used herein, the term "second-generation anti-androgen"
refers to an agent that exhibits full antagonist activity against a
wild-type AR polypeptide. Second-generation anti-androgens differ
from first-generation anti-androgens in that second-generation
anti-androgens act as full antagonists in cells expressing elevated
levels of AR, such as for example, in castration resistant prostate
cancers (CRPC). Exemplary second-generation anti-androgens include
4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspir-
o[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide (also known as
apalutamide or ARN-509; CAS No. 956104-408);
4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimida-
zolidin-1-yl)-2-fluoro-N-methylbenzamide (also known as MDV3100 or
enzalutamide; CAS No: 915087-33-1) and RD162 (CAS No. 915087-27-3).
In some embodiments, a second-generation anti-androgen binds to an
AR polypeptide at or near the ligand binding site of the AR
polypeptide.
##STR00001##
4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspir-
o[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide (apalutamide)
##STR00002##
[0063]
4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thiox-
oimidazolidin-1-yl)-2-fluoro-N-methylbenzamide (enzalutamide)
[0064] In some embodiments, an anti-androgen contemplated in the
methods described herein inhibits AR nuclear translocation, such as
darolutamide, DNA binding to androgen response elements, and
coactivator recruitment. In some embodiments, an anti-androgen
contemplated in the methods described herein exhibits no agonist
activity in AR-overexpressing prostate cancer cells.
[0065] Apalutamide is a second-generation anti-androgen that binds
directly to the ligand-binding domain of AR, impairing nuclear
translocation, AR binding to DNA and AR target gene modulation,
thereby inhibiting tumor growth and promoting apoptosis.
Apalutamide binds AR with greater affinity than bicalutamide, and
induces partial or complete tumor regression in non-castrate
hormone-sensitive and bicalutamide-resistant human prostate cancer
xenograft models (Clegg et al. Cancer Res. Mar. 15, 2012 72; 1494).
Apalutamide lacks the partial agonist activity seen with
bicalutamide in the context of AR overexpression.
[0066] Darolutamide, BAY1841788 or ODM-201, is an AR antagonist
that includes two diastereomers --ORM-16497 and ORM-16555. It has
activity against known AR mutants that confer resistance to other
second-generation antiandrogens. Darolutamide binds to the AR with
high affinity, and impairs subsequent androgen-induced nuclear
translocation of AR and transcription of AR gene target. Matsubara,
N., Mukai, H., Hosono, A. et al. Cancer Chemother Pharmacol (2017)
80: 1063.
[0067] In one aspect described herein are methods of treating
non-metastatic castration-resistant prostate cancer comprising,
consisting of, or consisting essentially of administering a safe
and effective amount of an anti-androgen to a male human with a
non-metastatic castration-resistant prostate cancer. In another
aspect described herein are methods of treating a male human having
non-metastatic castration-resistant prostate cancer comprising,
consisting of, or consisting essentially of administering a safe
and effective amount of an anti-androgen to a male human with a
non-metastatic castration-resistant prostate cancer. In the
following disclosure, "methods of treating non-metastatic
castration-resistant prostate cancer," may alternatively be recited
as "methods of treating a male human having non-metastatic
castration-resistant prostate cancer." For the sake of brevity,
each possible alternative is not parsed out.
[0068] In a Phase II clinical trial of male humans with high risk
non-metastatic CRPC, treatment--naive metastatic CRPC and
metastatic CRPC that progressed after prior treatment with
abiraterone acetate (ZYTIGA) plus prednisone, oral administration
of 240 mg of apalutamide on a continuous daily dosing schedule was
very well tolerated and resulted in robust and durable PSA
responses, as well as evidence of objective responses. A total of
25 patients with chemotherapy and abiraterone acetate-plus
prednisone naive metastatic CRPC who had progressed on standard
androgen deprivation therapy (treatment-naive (TN) cohort) and 21
patients who progressed after treatment with abiraterone acetate
plus prednisone (PA cohort) were orally administered 240 mg of
apalutamide on a continuous daily dosing schedule. The primary
objective was to assess antitumor activity and PSA kinetics as
defined by the Prostate Cancer Clinical Trials Working Group
(PCWG2) criteria. Preliminary results demonstrated 12-week PSA
declines of >50% or more from baseline in 88% and 29% of the TN
and PA cohorts, respectively. The median time to PSA progression
was not reached for the TN cohort during the preliminary 12-week
period, and was 16 weeks in the PA cohort. In addition, the
objective response rate (by RECIST) was 63%> in the TN patients
presenting with measurable disease at baseline, further confirming
the antitumor activity of apalutamide.
[0069] A total of 47 patients with non-metastatic CRPC were orally
administered 240 mg of apalutamide on a continuous daily dosing
schedule. At 12 weeks of treatment, 91% of the patients had a
>50% decline in PSA as compared to baseline. At 24 weeks, the
percentage of patients who had >50% decline in PSA remained at
91% and the percentage of patients who had >90%>decline in
PSA was 55%>, confirming the durability of response to
apalutamide. The median time to PSA progression was not reached in
this observed time period.
Certain Terminology
[0070] The term "cancer" as used herein refers to an abnormal
growth of cells which tend to proliferate in an uncontrolled way
and, in some cases, to metastasize (spread).
[0071] The term "prostate cancer" as used herein refers to
histologically or cytologically confirmed adenocarcinoma of the
prostate.
[0072] The term "androgen-deprivation therapy (ADT)" refers to the
reduction of androgen levels in a prostate cancer patient to
castrated levels of testosterone (<50 ng/dL). Such treatments
can include orchiectomy or the use of gonadotropin-releasing
hormone agonists or antagonists. ADT includes surgical castration
(orchiectomy) and/or the administration of luteinizing
hormone-releasing hormone ("LHRH") agonists to a human. Examples of
LHRH agonists include goserelin acetate, histrelin acetate,
leuprolide acetate, and triptorelin palmoate. Physicians can
prescribe LHRH agonists in accordance with instructions,
recommendations and practices. This may include about 0.01 mg to
about 20 mg of goserelin over a period of about 28 days to about 3
months, preferably about 3.6 mg to about 10.8 mg of goserelin over
a period of about 28 days to about 3 months; about 0.01 mg to about
200 mg of leuprolide over a period of about 3 days to about 12
months, preferably about 3.6 mg of leuprolide over a period of
about 3 days to about 12 months; or about 0.01 mg to about 20 mg of
triptorelin over a period of about 1 month, preferably about 3.75
mg of triptorelin over a period of 1 month. About 50 mg of
histrelin acetate over a period of 12 months of histrelin acetate
or about 50 .mu.g per day of histrelin acetate.
[0073] The term "locally advanced prostate cancer" refers to
prostate cancer where all actively cancerous cells appear to be
confined to the prostate and the associated organs or neighbor
organs (e.g., seminal vesicle, bladder neck, and rectal wall).
[0074] The term "high-risk localized prostate cancer" refers to
locally advanced prostate cancer that has a probability of
developing metastases or recurrent disease after primary therapy
with curative intent. In some embodiments, high risk for
development of metastases is defined as prostate specific antigen
doubling time (PSADT) <20 months, <19 months, <18 months,
<17 months, <16 months, <15 months, <14 months, <13
months, <12 months, or <11 months, <10 months, <9
months, <8 months, <7 months, <6 months, <5 months,
<4 months, <3 months, <2 months, or <1 month. In some
embodiments, high risk for development of metastases is defined as
prostate specific antigen doubling time (PSADT)<10 months. In
some embodiments, high risk for development of metastases is
defined as having a high Gleason score or bulky tumor.
[0075] The term "castration-sensitive prostate cancer" refers to
cancer that is responsive to androgen-deprivation therapy (ADT)
either as localized disease, biochemical relapse or in the
metastatic setting.
[0076] The term "metastatic castration-sensitive prostate cancer"
refers to cancer that has spread (metastasized) to other areas of
the body, e.g., the bone, lymph nodes or other parts of the body in
a male, and that is responsive to androgen-deprivation therapy
(ADT).
[0077] The term "non-metastatic castration-sensitive prostate
cancer" refers to cancer that has not spread (metastasized) in a
male, and that is responsive to androgen-deprivation therapy (ADT).
In some embodiments, non-metastatic castration-sensitive prostate
cancer is assessed with bone scan and computed tomography (CT) or
magnetic resonance imaging (MM) scans.
[0078] The term "CRPC" as used herein refers to
castration-resistant prostate cancer. CRPC is prostate cancer that
continues to grow despite the suppression of male hormones that
fuel the growth of prostate cancer cells.
[0079] The term "metastatic castration-resistant prostate cancer"
refers to castration-resistant prostate cancer that has
metastasized to other parts of the human body.
[0080] The term "NM-CRPC" as used herein refers to non-metastatic
castration-resistant prostate cancer. In some embodiments, NM-CRPC
is assessed with bone scan and computed tomography (CT) or magnetic
resonance imaging (MM) scans.
[0081] The term "chemotherapy naive metastatic castration-resistant
prostate cancer" refers to metastatic castration-resistant prostate
cancer that has not been previously treated with a chemotherapeutic
agent.
[0082] The term "post-abiraterone acetate-prednisone treated
metastatic castration-resistant prostate cancer" refers to
metastatic castration-resistant prostate cancer that has already
been treated with abiraterone acetate.
[0083] In some embodiments, the non-metastatic castration-resistant
prostate cancer is a high risk non-metastatic castration-resistant
prostate cancer. The term "high risk NM-CRPC" refers to probability
of a man with NM-CRPC developing metastases. In some embodiments,
high risk for development of metastases is defined as prostate
specific antigen doubling time (PSADT)<20 months, <19 months,
<18 months, <17 months, <16 months, <15 months, <14
months, <13 months, <12 months, or <11 months, <10
months, <9 months, <8 months, <7 months, <6 months,
<5 months, <4 months, <3 months, <2 months, or <1
month. In some embodiments, high risk for development of metastases
is defined as prostate specific antigen doubling time (PSADT)<10
months. In some embodiments, high risk for development of
metastases is defined as having local-regional recurrence (e.g.
primary tumor bed, bladder neck, anastomotic area, pelvic lymph
nodes).
[0084] The terms "co-administration" or the like, as used herein,
encompass administration of the selected therapeutic agents to a
single patient, and are intended to include treatment regimens in
which the agents are administered by the same or different route of
administration or at the same or different time.
[0085] The term "pharmaceutical combination" as used herein, means
a product that results from the mixing or combining of more than
one active ingredient and includes both fixed and non-fixed
combinations of the active ingredients. The term "fixed
combination" means that the active ingredients, e.g., apalutamide
and a co-agent, are both administered to a patient simultaneously
in the form of a single unit or single dosage form. The term
"non-fixed combination" means that the active ingredients, e.g.,
apalutamide and a co-agent, are administered to a patient as
separate units or separate dosage forms, either simultaneously,
concurrently or sequentially with no specific intervening time
limits, wherein such administration provides safe and effective
levels of the two active ingredients in the body of the human male.
The latter also applies to cocktail therapy, e.g., the
administration of three or more active ingredients.
[0086] The term "FDHT-PET" refers to
18F-16P-fluoro-5a-dihydrotestosterone Positron Emission Tomography
and is a technique that uses a tracer based on dihydrotestosterone,
and allows for a visual assessment of ligand binding to the
androgen receptor in a patient. It may be used to evaluate
pharmacodynamics of an androgen receptor directed therapy [0099]
The term "continuous daily dosing schedule" refers to the
administration of a particular therapeutic agent without any drug
holidays from the particular therapeutic agent. In some
embodiments, a continuous daily dosing schedule of a particular
therapeutic agent comprises administration of a particular
therapeutic agent every day at roughly the same time each day.
[0087] The terms "treat" and "treatment" refer to the treatment of
a patient afflicted with a pathological condition and refers to an
effect that alleviates the condition by killing the cancerous
cells, but also to an effect that results in the inhibition of the
progress of the condition, and includes a reduction in the rate of
progress, a halt in the rate of progress, amelioration of the
condition, and cure of the condition. Treatment as a prophylactic
measure (i.e., prophylaxis) is also included.
[0088] The term "metastasis-free survival" or "MFS" refers to the
percentage of subjects in a study who have survived without cancer
spread for a defined period of time or death. MFS is usually
reported as time from the beginning of enrollment, randomization or
treatment in the study. MFS is reported for an individual or a
study population. In the context of treatment of CRPC with an
anti-androgen, an increase in the metastasis-free survival is the
additional time that is observed without cancer having spread or
death, whichever occurs first, as compared to treatment with
placebo. In some embodiments, the increase in the metastasis-free
survival is about 1 month, about 2 months, about 3 months, about 4
months, about 5 months, about 6 months, about 7 months, about 8
months, about 10 months, about 11 months, about 12 months, about 13
months, about 14 months, about 15 months, about 16 months, about 17
months, about 18 months, about 19 months, about 20 months, or
greater than 20 months. In some embodiments, administration of a
safe and effective amount of an anti-androgen provides an increase
in the metastasis-free survival of a male human, optionally wherein
the increase in the metastasis-free survival is relative to the
mean survival rate of a population of male humans with the
non-metastatic castration-resistant prostate cancer, said
population having been treated with a placebo. In some embodiments,
metastasis-free survival refers to the time from randomization to
the time of first evidence of BICR-confirmed bone or soft tissue
distant metastasis or death due to any cause, whichever occurs
first.
[0089] The term "time to metastasis" is the time from randomization
to the time of the scan that shows first evidence of BICR-confirmed
radiographically detectable bone or soft tissue distant metastasis.
In some embodiments, administration of a safe and effective amount
of an anti-androgen provides improved anti-tumor activity as
measured by time to metastasis (TTM).
[0090] The term "progression-free survival" is based on RECIST v1.1
and is defined as follows: For subjects with at least one
measurable lesion, progressive disease is defined as at least a 20%
increase in the sum of diameters of target lesions taking as
reference the smallest sum on study (this includes the baseline sum
if that is the smallest on study). In addition to the relative
increase of 20%, the sum must also demonstrate an absolute increase
of at least 5 mm. Furthermore, the appearance of one or more new
lesions is also considered progression. For subjects with only
non-measurable disease observed on CT or MM scans, unequivocal
progression (representative of overall disease status change) or
the appearance of one or more new lesions was considered
progression. For new bone lesions detected on bone scans, a second
imaging modality (e.g., CT or MM) was required to confirm
progression. In some embodiments, administration of a safe and
effective amount of an anti-androgen provides improved anti-tumor
activity as measured by progression-free survival rate.
[0091] The term "time to symptomatic progression" is defined as the
time from randomization to documentation in the CRF of any of the
following (whichever occurs earlier): (1) development of a
skeletal-related event (SRE): pathologic fracture, spinal cord
compression, or need for surgical intervention or radiation therapy
to the bone; (2) pain progression or worsening of disease-related
symptoms requiring initiation of a new systemic anti-cancer
therapy; or (3) development of clinically significant symptoms due
to loco-regional tumor progression requiring surgical intervention
or radiation therapy. In some embodiments, administration of a safe
and effective amount of an anti-androgen provides improved
anti-tumor activity as measured by time to symptomatic
progression.
[0092] The term "overall survival" is defined as the time from
randomization to the date of death due to any cause. Survival data
for subjects who are alive at the time of the analysis was to be
censored on the last known date that they were alive. In addition,
for subjects with no post-baseline information survival, data was
to be censored on the date of randomization; for subjects who are
lost to follow-up or who withdraw consent, data is censored on the
last known date that they were alive. In some embodiments,
administration of a safe and effective amount of an anti-androgen
provides improved anti-tumor activity as measured by overall
survival.
[0093] The term "time to initiation of cytotoxic chemotherapy" is
defined as the time from randomization to documentation of a new
cytotoxic chemotherapy being administered to the subject (e.g.,
survival follow-up CRF). Time to initiation of cytotoxic
chemotherapy for subjects who do not start a cytotoxic chemotherapy
is censored on the date of last contact. In some embodiments,
administration of a safe and effective amount of an anti-androgen
provides improved anti-tumor activity as measured by time to
cytotoxic chemotherapy.
[0094] The term "progression-free survival with the first
subsequent therapy (PFS2) is defined as the time from randomization
to investigator-assessed disease progression (PSA, radiographic,
symptomatic, or any combination) during first subsequent
anti-cancer therapy or death (any cause) prior to the start of the
second subsequent anti-cancer therapy, whichever occurs first.
Progression data for subjects without documented progression after
subsequent therapy is censored at the last date known to be
progression-free or date of death. In some embodiments,
administration of a safe and effective amount of an anti-androgen
provides improved anti-tumor activity as measured progression-free
survival with the first subsequent therapy.
[0095] Prostate specific antigen response and time to PSA
progression is assessed at the time of the primary analysis of MFS
according to the Prostate Cancer Working Group (PCWG2) criteria.
The time to PSA progression is calculated as the time from
randomization to the time when the criteria for PSA progression
according to PCWG2 are met.
[0096] The term "placebo" as used herein means administration of a
pharmaceutical composition that does not include a
second-generation anti-androgen. In the context of treatment of
CRPC, men that are administered an anti-androgen or placebo will
need to continue to maintain castrated levels of testosterone by
either co-administration of a GnRH agonist/antagonist or
orchiectomy.
[0097] The term "survival benefit" as used herein means an increase
in survival of the patient from time of randomization on the trial
of administered drug to death. In some embodiments, the survival
benefit is about 1, about 2, about 3, about 4, about 5, about 6,
about 7, about 8, about 9, about 10, about 15, about 20, about 25,
about 30, about 35, about 40, about 45, about 50, about 55, about
60, about 80, about 100 months or greater than 100 months.
[0098] The term "delay in symptoms related to disease progression"
as used herein means an increase in time in the development of
symptoms such as pain, urinary obstruction and quality of life
considerations from the time of randomization on the trial of
administered drug.
[0099] The term `randomization` as it refers to a clinical trial
refers to the time when the patient is confirmed eligible for the
clinical trial and gets assigned to a treatment arm.
[0100] The terms "kit" and "article of manufacture" are used as
synonyms.
[0101] The term "subject" and "patient" and "human" are used
interchangeably.
[0102] The term, "drug product" or "approved drug product" is
product that contains an active pharmaceutical ingredient that has
been approved for marketing for at least one indication by a
governmental authority, e.g., the Food and Drug Administration or
the similar authority in other countries.
[0103] The term "Reference Listed Drug (RLD)" is a drug product to
which new generic versions are compared to show that they are
bioequivalent. 21 CFR 314.3(b)) It is also a medicinal product that
has been granted marketing authorization by a Member State of the
European Union or by the Commission on the basis of a completed
dossier, i.e., with the submission of quality, pre-clinical and
clinical data in accordance with Articles 8(3), 10a, 10b or 10c of
Directive 2001/83/EC and to which the application for marketing
authorization for a generic/hybrid medicinal product refers, by
demonstration of bioequivalence, usually through the submission of
the appropriate bioavailability studies.
[0104] In the United States, a company seeking approval to market a
generic equivalent must refer to the RLD in its Abbreviated New
Drug Application (ANDA). For example, an ANDA applicant relies on
the FDA's finding that a previously approved drug product, i.e.,
the RLD, is safe and effective, and must demonstrate, among other
things, that the proposed generic drug product is the same as the
RLD in certain ways. Specifically, with limited exceptions, a drug
product for which an ANDA is submitted must have, among other
things, the same active ingredient(s), conditions of use, route of
administration, dosage form, strength, and (with certain
permissible differences) labeling as the RLD. The RLD is the listed
drug to which the ANDA applicant must show its proposed ANDA drug
product is the same with respect to active ingredient(s), dosage
form, route of administration, strength, labeling, and conditions
of use, among other characteristics. In the electronic Orange Book,
there will is a column for RLDs and a column for reference
standards. In the printed version of the Orange Book, the RLDs and
reference standards are identified by specific symbol. For an ANDA
based on an approved suitability petition (a petitioned ANDA), the
reference listed drug generally is the listed drug referenced in
the approved suitability petition.
[0105] A reference standard is the drug product selected by FDA
that an applicant seeking approval of an ANDA must use in
conducting an in vivo bioequivalence study required for approval.
FDA generally selects a single reference standard that ANDA
applicants must use in in vivo bioequivalence testing. Ordinarily,
FDA will select the reference listed drug as the reference
standard. However, in some instances (e.g., where the reference
listed drug has been withdrawn from sale and FDA has determined it
was not withdrawn for reasons of safety or effectiveness, and FDA
selects an ANDA as the reference standard), the reference listed
drug and the reference standard may be different.\
[0106] FDA identifies reference listed drugs in the Prescription
Drug Product, OTC Drug Product, and Discontinued Drug Product
Lists. Listed drugs identified as reference listed drugs represent
drug products upon which an applicant can rely in seeking approval
of an ANDA. FDA intends to update periodically the reference listed
drugs identified in the Prescription Drug Product, OTC Drug
Product, and Discontinued Drug Product Lists, as appropriate.
[0107] FDA also identifies reference standards in the Prescription
Drug Product and OTC Drug Product Lists. Listed drugs identified as
reference standards represent the FDA's best judgment at this time
as to the appropriate comparator for purposes of conducting any in
vivo bioequivalence studies required for approval.
[0108] In some instances when FDA has not designated a listed drug
as a reference listed drug, such listed drug may be shielded from
generic competition. If FDA has not designated a reference listed
drug for a drug product the applicant intends to duplicate, the
potential applicant may ask FDA to designate a reference listed
drug for that drug product.
[0109] FDA may, on its own initiative, select a new reference
standard when doing so will help to ensure that applications for
generic drugs may be submitted and evaluated, e.g., in the event
that the listed drug currently selected as the reference standard
has been withdrawn from sale for other than safety and efficacy
reasons.
[0110] In Europe, Applicants identify in the application form for
its generic/hybrid medicinal product, which is the same as a ANDA
or sNDA drug product, the reference medicinal product (product
name, strength, pharmaceutical form, MAH, first authorization,
Member State/Community), which is synonymous with a RLD, as
follows:
[0111] 1. The medicinal product that is or has been authorized in
the EEA, used as the basis for demonstrating that the data
protection period defined in the European pharmaceutical
legislation has expired. This reference medicinal product,
identified for the purpose of calculating expiry of the period of
data protection, may be for a different strength, pharmaceutical
form, administration route or presentation than the generic/hybrid
medicinal product.
[0112] 2. The medicinal product, the dossier of which is
cross-referred to in the generic/hybrid application (product name,
strength, pharmaceutical form, MAH, marketing authorization
number). This reference medicinal product may have been authorized
through separate procedures and under a different name than the
reference medicinal product identified for the purpose of
calculating expiry of the period of data protection. The product
information of this reference medicinal product will, in principle,
serve as the basis for the product information claimed for the
generic/hybrid medicinal product.
[0113] 3. The medicinal product (product name, strength,
pharmaceutical form, MAH, Member State of source) used for the
bioequivalence study(ies) (where applicable).
[0114] The different abbreviated approval pathways for drug
products under the FD&C Act the abbreviated approval pathways
described in section 505(j) and 505(b)(2) of the FD&C Act (21
U.S.C. 355(j) and 21 U.S.C. 23 355(b)(2), respectively).
[0115] According to the FDA
(www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid-
ances/UCM579751.pdf), the contents of which is incorporated herein
by reference), NDAs and ANDAs can be divided into the following
four categories:
[0116] (1) A "stand-alone NDA" is an application submitted under
section 505(b)(1) and approved under section 505(c) of the FD&C
Act that contains full reports of investigations of safety and
effectiveness that were conducted by or for the applicant or for
which the applicant has a right of reference or use.
[0117] (2) A 505(b)(2) application is an NDA submitted under
section 505(b)(1) and approved under section 505(c) of the FD&C
Act that contains full reports of investigations of safety and
effectiveness, where at least some of the information required for
approval comes from studies not conducted by or for the applicant
and for which the applicant has not obtained a right of reference
or use.
[0118] (3) An ANDA is an application for a duplicate of a
previously approved drug product that was submitted and approved
under section 505(j) of the FD&C Act. An ANDA relies on FDA's
finding that the previously approved drug product, i.e., the
reference listed drug (RLD), is safe and effective. An ANDA
generally must contain information to show that the proposed
generic product (a) is the same as the RLD with respect to the
active ingredient(s), conditions of use, route of administration,
dosage form, strength, and labeling (with certain permissible
differences) and (b) is bioequivalent to the RLD. An ANDA may not
be submitted if studies are necessary to establish the safety and
effectiveness of the proposed product.
[0119] (4) A petitioned ANDA is a type of ANDA for a drug product
that differs from the RLD in its dosage form, route of
administration, strength, or active ingredient (in a product with
more than one active ingredient) and for which FDA has determined,
in response to a petition submitted under section 505(j)(2)(C) of
the FD&C Act (suitability petition), that studies are not
necessary to establish the safety and effectiveness of the proposed
drug product.
[0120] A scientific premise underlying the Hatch-Waxman Amendments
is that a drug product approved in an ANDA under section 505(j) of
the FD&C Act is presumed to be therapeutically equivalent to
its RLD. Products classified as therapeutically equivalent can be
substituted with the full expectation that the substituted product
will produce the same clinical effect and safety profile as the
prescribed product when administered to patients under the
conditions specified in the labeling. In contrast to an ANDA, a
505(b)(2) application allows greater flexibility as to the
characteristics of the proposed product. A 505(b)(2) application
will not necessarily be rated therapeutically equivalent to the
listed drug it references upon approval.
[0121] The term "therapeutically equivalent to a reference listed
drug" is means that the drug product is a generic equivalent, i.e.,
pharmaceutical equivalents, of the reference listed drug product
and, as such, is rated an AB therapeutic equivalent to the
reference listed drug product by the FDA whereby actual or
potential bioequivalence problems have been resolved with adequate
in vivo and/or in vitro evidence supporting bioequivalence.
[0122] "Pharmaceutical equivalents" means drug products in
identical dosage forms and route(s) of administration that contain
identical amounts of the identical active drug ingredient as the
reference listed drug.
[0123] FDA classifies as therapeutically equivalent those products
that meet the following general criteria: (1) they are approved as
safe and effective; (2) they are pharmaceutical equivalents in that
they (a) contain identical amounts of the same active drug
ingredient in the same dosage form and route of administration, and
(b) meet compendial or other applicable standards of strength,
quality, purity, and identity; (3) they are bioequivalent in that
(a) they do not present a known or potential bioequivalence
problem, and they meet an acceptable in vitro standard, or (b) if
they do present such a known or potential problem, they are shown
to meet an appropriate bioequivalence standard; (4) they are
adequately labeled; and (5) they are manufactured in compliance
with Current Good Manufacturing Practice regulations
[0124] The term "bioequivalent" or "bioequivalence" is the absence
of a significant difference in the rate and extent to which the
active ingredient or active moiety in pharmaceutical equivalents or
pharmaceutical alternatives becomes available at the site of drug
action when administered at the same molar dose under similar
conditions in an appropriately designed study. Section 505
(j)(8)(B) of the FD&C Act describes one set of conditions under
which a test and reference listed drug shall be considered
bioequivalent:
[0125] the rate and extent of absorption of the [test] drug do not
show a significant difference from the rate and extent of
absorption of the [reference] drug when administered at the same
molar dose of the therapeutic ingredient under similar experimental
conditions in either a single dose or multiple doses; or the extent
of absorption of the [test] drug does not show a significant
difference from the extent of absorption of the [reference] drug
when administered at the same molar dose of the therapeutic
ingredient under similar experimental conditions in either a single
dose or multiple doses and the difference from the [reference] drug
in the rate of absorption of the drug is intentional, is reflected
in its proposed labeling, is not essential to the attainment of
effective body drug concentrations on chronic use, and is
considered medically insignificant for the drug.
[0126] Where these above methods are not applicable (e.g., for drug
products that are not intended to be absorbed into the
bloodstream), other scientifically valid in vivo or in vitro test
methods to demonstrate bioequivalence may be appropriate.
[0127] For example, bioequivalence may sometimes be demonstrated
using an in vitro bioequivalence standard, especially when such an
in vitro test has been correlated with human in vivo
bioavailability data. In other situations, bioequivalence may
sometimes be demonstrated through comparative clinical trials or
pharmacodynamic studies.
[0128] The terms "sale" or "selling" means transferring a drug
product, e.g., a pharmaceutical composition or an oral dosage form,
from a seller to a buyer.
[0129] The term "offering for sale" means the proposal of a sale by
a seller to a buyer for a drug product, e.g., a pharmaceutical
composition and an oral dosage form.
Routes of Administration and Pharmaceutical Compositions
[0130] Therapeutic agents described herein are administered in any
suitable manner or suitable formulation. Suitable routes of
administration of the therapeutic agents include, but are not
limited to, oral and parenteral (e.g., intravenous, subcutaneous,
intramuscular). All formulations are in dosages suitable for
administration to a human. A summary of pharmaceutical compositions
can be found, for example, in Remington: The Science and Practice
of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company,
1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack
Publishing Co., Easton, Pa. 1975; Liberman, H. A. and Lachman, L.,
Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y.,
1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems,
Seventh Ed. (Lippincott Williams & Wilkins 1999), herein
incorporated by reference for such disclosure.
[0131] The term "safe and effective amount" refers to an amount of
an active ingredient that elicits the desired biological or
medicinal response in a subject's biological system without the
risks outweighing the benefits of such response in accordance with
the Federal Food, Drug, and Cosmetic Act, as amended (secs.
201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. .sctn..sctn.
321-392). Safety is often measured by toxicity testing to determine
the highest tolerable dose or the optimal dose of an active
pharmaceutical ingredient needed to achieve the desired benefit.
Studies that look at safety also seek to identify any potential
adverse effects that may result from exposure to the drug. Efficacy
is often measured by determining whether an active pharmaceutical
ingredient demonstrates a health benefit over a placebo or other
intervention when tested in an appropriate situation, such as a
tightly controlled clinical trial.
[0132] The term "acceptable" with respect to a formulation,
composition or ingredient, as used herein, means that the
beneficial effects of that formulation, composition or ingredient
on the general health of the male human being treated substantially
outweigh its detrimental effects, to the extent any exist.
[0133] In some embodiments, administration of a safe and effective
amount of the anti-androgen results in no more than a grade 2
adverse event. In other embodiments, administration of a safe and
effective amount of anti-androgen results in no more than a grade 3
adverse event. In other embodiments, administration of a safe and
effective amount of anti-androgen results in no more than a grade 4
adverse event.
[0134] In some embodiments, the anti-androgen is present in a solid
oral dosage form. In some embodiments, the anti-androgen is
formulated as a tablet. In some embodiments, the anti-androgen is
apalutamide. In some embodiments, the anti-androgen is
enzalutamide. Solid oral dosage forms containing either apalutamide
or enzalutamide may be provided as soft gel capsules as disclosed
in WO2014113260 and CN104857157, each of which is incorporated
herein by reference, or as tablets as disclosed in WO2016090098,
WO2016090101, WO2016090105, and WO2014043208, each of which is
incorporated herein by reference. Techniques suitable for preparing
solid oral dosage forms of the present invention are described in
Remington's Pharmaceutical Sciences, 18th edition, edited by AR.
Gennaro, 1990, Chapter 89, and in Remington--The Science, and
Practice of Pharmacy, 21st edition, 2005, Chapter 45.
[0135] To prepare the pharmaceutical compositions of this
invention, the active pharmaceutical ingredient is intimately
admixed with a pharmaceutical carrier according to conventional
pharmaceutical compounding techniques, which carrier may take a
wide variety of forms depending of the form of preparation desired
for administration (e.g., oral or parenteral). Suitable
pharmaceutically acceptable carriers are well known in the art.
Descriptions of some of these pharmaceutically acceptable carriers
may be found in The Handbook of Pharmaceutical Excipients,
published by the American Pharmaceutical Association and the
Pharmaceutical Society of Great Britain.
[0136] In solid oral preparations such as, for example, dry powders
for reconstitution or inhalation, granules, capsules, caplets,
gelcaps, pills and tablets (each including immediate release, timed
release and sustained release formulations), suitable carriers and
additives include but are not limited to diluents, granulating
agents, lubricants, binders, glidants, disintegrating agents and
the like. Because of their ease of administration, tablets and
capsules represent the most advantageous oral dosage unit form, in
which case solid pharmaceutical carriers are obviously employed. If
desired, tablets may be sugar coated, gelatin coated, film coated
or enteric coated by standard techniques.
[0137] Preferably these compositions are in unit dosage forms from
such as tablets, pills, capsules, dry powders for reconstitution or
inhalation, granules, lozenges, sterile solutions or suspensions,
metered aerosol or liquid sprays, drops, or suppositories for
administration by oral, intranasal, sublingual, intraocular,
transdermal, rectal, vaginal, dry powder inhaler or other
inhalation or insufflation means.
[0138] These formulations are manufactured by conventional
formulation techniques. For preparing solid pharmaceutical
compositions such as tablets, the principal active ingredient is
mixed with a pharmaceutical carrier, e.g., conventional tableting
ingredients such as diluents, binders, adhesives, disintegrants,
lubricants, antiadherents, and gildants. Suitable diluents include,
but are not limited to, starch (i.e. corn, wheat, or potato starch,
which may be hydrolized), lactose (granulated, spray dried or
anhydrous), sucrose, sucrose-based diluents (confectioner's sugar;
sucrose plus about 7 to 10 weight percent invert sugar; sucrose
plus about 3 weight percent modified dextrins; sucrose plus invert
sugar, about 4 weight percent invert sugar, about 0.1 to 0.2 weight
percent cornstarch and magnesium stearate), dextrose, inositol,
mannitol, sorbitol, microcrystalline cellulose (i.e. AVICEL
microcrystalline cellulose available from FMC Corp.), dicalcium
phosphate, calcium sulfate dihydrate, calcium lactate trihydrate
and the like. Suitable binders and adhesives include, but are not
limited to acacia gum, guar gum, tragacanth gum, sucrose, gelatin,
glucose, starch, and cellulosics (i.e. methylcellulose, sodium
carboxymethylcellulose, ethylcellulose,
hydroxypropylmethylcellulose, hydroxypropylcellulose, and the
like), water soluble or dispersible binders (i.e. alginic acid and
salts thereof, magnesium aluminum silicate, hydroxyethylcellulose
[i.e. TYLOSE available from Hoechst Celanese], polyethylene glycol,
polysaccharide acids, bentonites, polyvinylpyrrolidone,
polymethacrylates and pregelatinized starch) and the like. Suitable
disintegrants include, but are not limited to, starches (corn,
potato, etc.), sodium starch glycolates, pregelatinized starches,
clays (magnesium aluminum silicate), celluloses (such as
crosslinked sodium carboxymethylcellulose and microcrystalline
cellulose), alginates, pregelatinized starches (i.e. corn starch,
etc.), gums (i.e. agar, guar, locust bean, karaya, pectin, and
tragacanth gum), cross-linked polyvinylpyrrolidone and the like.
Suitable lubricants and antiadherents include, but are not limited
to, stearates (magnesium, calcium and sodium), stearic acid, talc
waxes, stearowet, boric acid, sodium chloride, DL-leucine, carbowax
4000, carbowax 6000, sodium oleate, sodium benzoate, sodium
acetate, sodium lauryl sulfate, magnesium lauryl sulfate and the
like. Suitable gildants include, but are not limited to, talc,
cornstarch, silica (i.e. CAB-O-SIL silica available from Cabot,
SYLOID silica available from W.R. Grace/Davison, and AEROSIL silica
available from Degussa) and the like. Sweeteners and flavorants may
be added to chewable solid dosage forms to improve the palatability
of the oral dosage form. Additionally, colorants and coatings may
be added or applied to the solid dosage form for ease of
identification of the drug or for aesthetic purposes. These
carriers are formulated with the pharmaceutical active to provide
an accurate, appropriate dose of the pharmaceutical active with a
therapeutic release profile.
[0139] Binders suitable for use in the pharmaceutical compositions
provided herein include, but are not limited to, starches,
cellulose, and its derivatives (e.g., ethylcellulose, cellulose
acetate, carboxymethyl cellulose calcium, sodium carboxymethyl
cellulose, methylcellulose, hydroxypropyl methylcellulose),
polyviny 1 pyrrolidone, and mixtures thereof.
[0140] Examples of fillers suitable for use in the pharmaceutical
compositions provided herein include, but are not limited to,
microcrystalline cellulose, powdered cellulose, mannitol, lactose,
calcium phosphate, starch, pre gelatinized starch, and mixtures
thereof.
[0141] The binder or filler in pharmaceutical compositions is
typically present in from about 50 to about 99 weight percent of
the pharmaceutical composition or dosage form.
[0142] Disintegrants can be used in the compositions to provide
tablets that disintegrate when exposed to an aqueous environment.
Tablets that contain too much disintegrant may disintegrate in
storage, while those that contain too little may not disintegrate
at a desired rate or under the desired conditions. Thus, a
sufficient amount of disintegrant that is neither too much nor too
little to detrimentally alter the release of the active ingredients
should be used to form solid oral dosage forms. The amount of
disintegrant used varies based upon the type of formulation, and is
readily discernible to those of ordinary skill in the art. Typical
pharmaceutical compositions comprise from about 0.5 to about 15
weight percent of disintegrant, specifically from about 1 to about
5 weight percent of disintegrant. Disintegrants that can be used in
the pharmaceutical compositions provided herein include, but are
not limited to, croscarmellose sodium, crospovidone, sodium starch
glycolate, potato or tapioca starch, pre gelatinized starch, other
starches, other celluloses, gums, and mixtures thereof.
[0143] Lubricants that can be used in the pharmaceutical
compositions provided herein include, but are not limited to,
calcium stearate, magnesium stearate, mineral oil, light mineral
oil, glycerin, sorbitol, polyethylene glycol, other glycols,
stearic acid, sodium lauryl sulfate, sodium stearyl fumarate, talc,
hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil,
sunflower oil, sesame oil, olive oil, corn oil, and soybean oil),
zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures
thereof. Lubricants are typically used in an amount of less than
about 1 weight percent of the pharmaceutical compositions or dosage
forms into which they are incorporated.
[0144] Compressed tablet formulations may optionally be film-coated
to provide color, light protection, and/or taste-masking. Tablets
may also be coated so as to modulate the onset, and/or rate of
release in the gastrointestinal tract, so as to optimize or
maximize the biological exposure of the patient to the API.
[0145] Hard capsule formulations may be produced by filling a blend
or granulation of apalutamide or enzalutamide into shells
consisting of, for example, gelatin, or hypromellose.
[0146] Soft gel capsule formulations may be produced.
[0147] Pharmaceutical compositions intended for oral use may be
prepared from the solid dispersion formulations, and blended
materials described above in accordance with the methods described
herein, and other methods known to the art for the manufacture of
pharmaceutical compositions. Such compositions may further contain
one or more agents selected from the group consisting of sweetening
agents, flavoring agents, coloring agents, and preserving agents in
order to provide pharmaceutically elegant and palatable
preparations.
[0148] Tablets may contain the active ingredient in admixture with
non-toxic pharmaceutically acceptable excipients that are suitable
for the manufacture of tablets. These excipients may be for
example, inert diluents, granulating, and disintegrating agents,
binding agents, glidants, lubricating agents, and antioxidants, for
example, propyl gallate, butylated hydroxyanisole, and butylated
hydroxy toluene. The tablets may be uncoated or they may be film
coated to modify their appearance or may be coated with a
functional coat to delay disintegration, and absorption in the
gastrointestinal tract, and thereby provide a sustained action over
a longer period.
[0149] Compositions for oral use may also be presented as capsules
(e.g., hard gelatin) wherein the active ingredient is mixed with an
inert solid diluent, for example, calcium carbonate, calcium
phosphate or starch, or as soft gelatin capsules wherein the active
ingredient is mixed with liquids or semisolids, for example, peanut
oil, liquid paraffin, fractionated glycerides, surfactants or olive
oil. Aqueous suspensions contain the active materials in mixture
with excipients suitable for the manufacture of aqueous
suspensions. Dispersible powders and granules suitable for
preparation of an aqueous suspension by the addition of water
provide the active ingredient in mixture with a dispersing or
wetting agent, suspending agent, and one or more preservatives. In
certain embodiments of the invention, the pharmaceutical
compositions of the invention include a diluent system,
disintegrant, salt, lubricant, glidant, and filmcoat, at
concentrations of from about 3% w/w to about 58% w/w, from about 4%
w/w to about 20% w/w, from about 4% w/w to about 20% w/w, from
about 0.5% w/w to about 4% w/w, from about 0% w/w to about 2% w/w,
and from about 1% w/w to about 5% w/w respectively, or at from
about 18% w/w to about 40% w/w, from about 7% w/w to about 15% w/w,
from about 7% w/w to about 18% w/w, from about 1.0% w/w to about
3.0%, from about 0.1% w/w to about 1.0% w/w, and from about 2.0%
w/w to about 4.0% w/w, respectively. In certain embodiments, the
solid dispersion formulations are blended with a diluent, one or
more disintegrating agents, lubricants, and glidants. An exemplary
blended composition or oral dosage form includes mannitol,
microcrystalline cellulose, croscarmellose sodium, sodium chloride,
colloidal silica, sodium stearyl fumarate, and magnesium
stearate.
[0150] The disintegrant may be present in a concentration from
about 4% w/w to about 20% w/w or from about 7% w/w to about 15%
w/w. A salt may be also present, which may be sodium chloride,
potassium chloride or a combination thereof. The combination of
salts and disintegrant is present at a concentration from about 5%
w/w to about 35% w/w of the final pharmaceutical composition.
[0151] In certain embodiments, inactive ingredients of the core
tablet are: colloidal anhydrous silica, croscarmellose sodium,
hydroxypropyl methylcellulose-acetate succinate, magnesium
stearate, microcrystalline cellulose, and silicified
microcrystalline cellulose. In other embodiments, the tablets are
finished with a film-coating consisting of the following
excipients: iron oxide black, iron oxide yellow, polyethylene
glycol, polyvinyl alcohol, talc, and titanium dioxide
[0152] In other embodiments, a single unit dosage of the
pharmaceutical composition comprises, consists of, or consists
essentially of about 60 mg of apalutamide. In some embodiments,
multiple doses of the single unit dosage pharmaceutical composition
comprising, consisting of, or consisting essentially of about 60 mg
of apalutamide, e.g., 4 multiple or individual unit dosage forms,
are administered to the human. The total daily dose of apalutamide
may be about 240 mg per day.
[0153] In some embodiments, a single unit dosage of the
pharmaceutical composition comprises, consists of, or consists
essentially of about 40 mg of enzalutamide. In some embodiments,
multiple doses of the single unit dosage pharmaceutical composition
comprising, consisting of, or consisting essentially of about 40 mg
of enzalutamide, e.g., 4 multiple or individual unit dosage forms,
are administered to the human. The total daily dose of enzalutamide
may be about 160 mg per day.
[0154] In still further embodiments, a single unit dosage of the
pharmaceutical composition comprises, consists of, or consists
essentially of about 300 mg of darolutamide. In some embodiments,
multiple doses of the single unit dosage pharmaceutical composition
comprising, consisting of, or consisting essentially of about 300
mg of enzalutamide, e.g., 2 multiple or individual unit dosage
forms, are administered to the human. The total daily dose of
darolutamide may be about 1200 mg per day.
[0155] All formulations for oral administration are in dosage form
suitable for such administration.
Methods of Dosing and Treatment Regimens
[0156] In one aspect, described herein are methods of treating
non-metastatic castration-resistant prostate cancer comprising,
consisting of, or consisting essentially of administering a safe
and effective amount of an anti-androgen to a male human with a
non-metastatic castration-resistant prostate cancer, wherein the
apalutamide or enzalutamide is administered orally. In some
embodiments, the anti-androgen is administered daily. In some
embodiments, the anti-androgen is administered twice-a-day. In some
embodiments, the anti-androgen is administered three times a day.
In some embodiments, the anti-androgen is administered four times a
day. In some embodiments, the apalutamide is administered every
other day. In some embodiments, the anti-androgen is administered
weekly. In some embodiments, the anti-androgen is administered
twice a week. In some embodiments, the anti-androgen is
administered every other week. In some embodiments, the
anti-androgen is administered orally on a continuous daily dosage
schedule.
[0157] In one embodiment, the desired dose is conveniently
presented in a single dose or in divided doses administered
simultaneously (or over a short period of time) or at appropriate
intervals, for example as two, three, four or more sub-doses per
day. In some embodiments, the anti-androgen is conveniently
presented in divided doses that are administered simultaneously (or
over a short period of time) once a day. In some embodiments, the
anti-androgen is conveniently presented in divided doses that are
administered in equal portions twice-a-day. In some embodiments,
the anti-androgen is conveniently presented in divided doses that
are administered in equal portions three times a day. In some
embodiments, the anti-androgen is conveniently presented in divided
doses that are administered in equal portions four times a day.
[0158] In some embodiments, the anti-androgen is a
second-generation anti-androgen. In certain embodiments, the
anti-androgen is enzalutamide or apalutamide. In some embodiments,
the anti-androgen is enzalutamide. In some embodiments, the
anti-androgen is apalutamide. In some embodiments, the
anti-androgen is darolutamide.
[0159] In general, doses of apalutamide employed for treatment of
the diseases or conditions described herein in humans are typically
in the range of 10 mg to 1000 mg per day. In some embodiments,
apalutamide, enzalutamide or darolutamide is administered orally to
the human at a dose of about 30 mg per day to about 1200 mg per
day. In some embodiments, apalutamide is administered orally to the
human at a dose of about 30 mg per day to about 600 mg per day. In
some embodiments, apalutamide is administered orally to the human
at a dose of about 30 mg per day, about 60 mg per day, about 90 mg
per day, about 120 mg per day, about 160 mg per day, about 180 mg
per day, about 240 mg per day, about 300 mg per day, about 390 mg
per day, about 480 mg per day, about 600 mg per day, about 780 mg
per day, about 960 mg per day, or about 1200 mg per day.
[0160] In some embodiments, apalutamide is administered orally to
the human at a dose of about 240 mg per day. In some embodiments,
greater than 240 mg per day of apalutamide is administered to the
human. In some embodiments, the apalutamide is administered orally
to the human at a dose of about 60 mg four times per day. In some
embodiments, apalutamide is administered orally to the human on a
continuous daily dosing schedule.
[0161] In some embodiments, the enzalutamide is administered orally
at a dose of about 160 mg per day. In some embodiments, greater
than 160 mg per day of enzalutamide is administered.
[0162] In some embodiments, the darolutamide is administered orally
at a dose of about 1200 mg per day. In some embodiments, greater
than 1200 mg per day of darolutamide is administered.
[0163] In certain embodiments wherein improvement in the status of
the disease or condition in the human is not observed, the daily
dose of anti-androgen is increased. In some embodiments, a
once-a-day dosing schedule is changed to a twice-a-day dosing
schedule. In some embodiments, a three times a day dosing schedule
is employed to increase the amount of anti-androgen that is
administered.
[0164] In some embodiments, the amount of anti-androgen that is
given to the human varies depending upon factors such as, but not
limited to, condition and severity of the disease or condition, and
the identity (e.g., weight) of the human, and the particular
additional therapeutic agents that are administered (if
applicable).
[0165] In certain embodiments, the dose of antiandrogen, e.g.,
apalutamide, enzalutamide, or darolutamide is reduced when
co-administered with one or more of: [0166] (a) a CYP2C8 inhibitor,
preferably gemfibrozil or clopidogrel; or [0167] (b) a CYP3A4
inhibitor, preferably ketoconazole or ritonavir.
[0168] In some embodiments, the apalutamide is not co-administered
with: [0169] (a) medications that are primarily metabolized by
CYP3A4, preferably darunavir, felodipine, midazolam or simvastatin;
[0170] (b) medications that are primarily metabolized by CYP2C19,
preferably diazepam or omeprazole; [0171] (c) medications that are
primarily metabolized by CYP2C9, preferably warfarin or phenytoin;
or [0172] (d) medications that are substrates of UGT, preferably
levothyroxine or valproic acid.
[0173] In further embodiments, the apalutamide is not
co-administered with: [0174] (a) medications that are P-gp
substrates, preferably fexofenadine, colchicine, dabigatran
etexilate or digoxin; or [0175] (b) BCRP/OATP1B1 substrates,
preferably lapatinib, methotrexate, rosuvastatin, or
repaglinide.
[0176] In further embodiments, a male human having said
non-metastatic castration-resistant prostate cancer has received at
least one prior therapy for the treatment of cancer, optionally
wherein the prior therapy for the treatment of cancer is
bicalutamine or flutamide. In still further embodiments, a male
human having said non-metastatic castration-resistant prostate
cancer is treatment naive.
Kits/Articles of Manufacture
[0177] For use in the methods of use described herein, kits and
articles of manufacture are also described. Such kits include a
package or container that is compartmentalized to receive one or
more dosages of the pharmaceutical compositions disclosed herein.
Suitable containers include, for example, bottles. In one
embodiment, the containers are formed from a variety of materials
such as glass or plastic.
[0178] The articles of manufacture provided herein contain
packaging materials. Packaging materials for use in packaging
pharmaceutical products include, e.g., U.S. Pat. Nos. 5,323,907,
5,052,558 and 5,033,252. Examples of pharmaceutical packaging
materials include, but are not limited to, blister packs, bottles,
tubes, bags, containers, bottles, and any packaging material
suitable for a selected formulation and intended mode of
administration and treatment.
[0179] A kit typically includes labels listing contents and/or
instructions for use, and package inserts with instructions for
use. A set of instructions will also typically be included.
[0180] In one embodiment, a label is on or associated with the
container. In one embodiment, a label is on a container when
letters, numbers or other characters forming the label are
attached, molded or etched into the container itself; a label is
associated with a container when it is present within a receptacle
or carrier that also holds the container, e.g., as a package
insert.
[0181] In one embodiment, a label is used to indicate that the
contents are to be used for a specific therapeutic application. The
label also indicates directions for use of the contents, such as in
the methods described herein.
[0182] In certain embodiments, the pharmaceutical compositions are
presented in a pack or dispenser device which contains one or more
unit dosage forms containing a compound provided herein. The pack,
for example, contains metal or plastic foil, such as a blister
pack. In one embodiment, the pack or dispenser device is
accompanied by instructions for administration. In one embodiment,
the pack or dispenser is also accompanied with a notice associated
with the container in form prescribed by a governmental agency
regulating the manufacture, use, or sale of pharmaceuticals, which
notice is reflective of approval by the agency of the form of the
drug for human or veterinary administration. Such notice, for
example, is the labeling approved by the U.S. Food and Drug
Administration for prescription drugs, or the approved product
insert. In one embodiment, compositions containing a compound
provided herein formulated in a compatible pharmaceutical carrier
are also prepared, placed in an appropriate container, and labeled
for treatment of an indicated condition.
Methods of Sale
[0183] In another aspect, described herein are methods of selling
an anti-androgen comprising, consisting of, or consisting
essentially of placing the anti-androgen into the stream of
commerce wherein said anti-androgen includes a package insert that
contains instructions for safely and effectively treating prostate
cancer using the anti-androgen. In some embodiments, the
anti-androgen is a second-generation anti-androgen. In some
embodiments, the anti-androgen is darolutamide, enzalutamide or
apalutamide. In some embodiments, the anti-androgen is
darolutamide. In some embodiments, the anti-androgen is
enzalutamide. In some embodiments, the anti-androgen is
apalutamide.
[0184] In further aspects, described herein are methods of selling
a pharmaceutical composition containing anti-androgen comprising,
consisting of, or consisting essentially of placing such
pharmaceutical composition into the stream of commerce wherein such
pharmaceutical composition includes a package insert that contains
instructions for safely and effectively treating prostate cancer
using anti-androgen. In some embodiments, the anti-androgen is a
second-generation anti-androgen. In some embodiments, the
anti-androgen is enzalutamide or apalutamide. In some embodiments,
the anti-androgen is enzalutamide. In some embodiments, the
anti-androgen is apalutamide.
[0185] In still further aspects, described herein are methods of
offering for sale anti-androgen comprising, consisting of, or
consisting essentially of offering to place the anti-androgen into
the stream of commerce wherein said anti-androgen includes a
package insert that contains instructions for safely and
effectively treating prostate cancer using the anti-androgen. In
some embodiments, the anti-androgen is a second-generation
anti-androgen. In some embodiments, the anti-androgen is
darolutamide, enzalutamide or apalutamide. In some embodiments the
antiandrogen is darolutamide. In some embodiments, the
anti-androgen is enzalutamide In some embodiments, the
anti-androgen is apalutamide
EXAMPLES
[0186] These examples are provided for illustrative purposes only
and not to limit the scope of the claims provided herein.
Example 1: Pre-Clinical Development
[0187] ARN 509 (apalutamide) is a next-generation anti-androgen
that binds directly to the ligand-binding domain of androgen
receptor (AR), impairing nuclear translocation and DNA binding. The
mechanism of action of apalutamide is through antagonism of
androgen action and inhibition of AR nuclear translocation and DNA
binding to androgen response elements, a mechanism that is distinct
from the first generation anti-androgen, bicalutamide. Unlike
bicalutamide, apalutamide shows no significant agonist properties
in an in vitro model of CRPC (e.g., AR-over-expressing prostate
cancer cells; LNCaP/AR cells). Gene transcription of the
androgen-driven genes, PSA and TMPRSS2, is inhibited by apalutamide
and results in concentration-dependent reduction of these protein
levels in vitro. Apalutamide was also shown to reduce proliferation
of CRPC cells as well as increase apoptosis and necrosis in vivo.
These effects are supported by the anti-tumor activity of
apalutamide observed in murine tumor models of CRPC. In these
models, apalutamide showed dose-dependent tumor growth inhibition
and tumor regression that were superior to bicalutamide. FIG. 1
depicts the percent change in tumor volume and plasma
concentrations (filled circles above waterfall plot) of
bicalutamide and apalutamide on Day 28.
[0188] Apalutamide is a low clearance molecule with a moderate
volume of distribution and high bioavailability (when dosed with a
lipid-based formulation). Apalutamide was found to have a very low
turnover when incubated for up to 120 minutes with rat, dog, and
human liver S9 fraction and liver microsomes. The primary in vivo
metabolites were formed by N-demethylation and amide hydrolysis in
the rat and dog. In vitro, CYP3A4 may be partially involved in the
metabolism of apalutamide.
[0189] Apalutamide and its primary metabolite ARN000308 (M3) are
inducers of human CYP2B6 and CYP3A4 in hepatocytes at
concentrations up to 30 .mu.M. Apalutamide is a moderately potent
inhibitor of human cytochrome P450 isoform CYP2C8 (IC.sub.50=13.9
but a weak inhibitor of the other major isoforms (IC.sub.50>25
.mu.M); M3 is also a weak inhibitor of CYP major isoforms
(IC.sub.50>25 .mu.M).
[0190] Four metabolites have been identified with different
proportions between species. All four were assessed for their
on-target effects against the androgen receptor. Metabolite M1 was
found to be essentially inactive as an AR antagonist, while
metabolites M2 and M4 were approximately 30-fold less potent
against AR than apalutamide. Metabolite M3 was the most potent AR
antagonist, but was still 3-fold less potent than apalutamide.
Metabolite M3 is considered the predominant metabolite, with a
longer elimination half-life than apalutamide.
[0191] Single-dose and repeat-dose toxicology studies up to 13
weeks of dosing have been conducted in male Sprague Dawley (SD)
rats and male Beagle dogs (repeat-dose studies only). Acute
administration of apalutamide at 1,000 mg/kg was well tolerated in
SD rats, with no morbidity, mortality or significant effects on
body weight or serum chemistry markers.
[0192] In repeat-dose toxicology studies, apalutamide was well
tolerated at doses up to 100 mg/kg/day in the 13-weeks study in SD
rats and 10 mg/kg/day in Beagle dogs. In male SD rats, lethality
was observed at doses of 150 mg/kg/day and greater. The
morbidity/mortality observed at these doses occurred within the
first 5 days of dosing; however, animals that did survive at these
higher doses, appeared to develop a tolerance for the test article
with extended exposure. Clinical signs observed in the moribund
animals were piloerection, hypothermia, breathing abnormalities,
dehydration, and decreased activity. The cause of the
morbidity/mortality in male rats could not be determined by
pathologic examination. Key clinical pathology changes at doses of
150 mg/kg/day or greater included significant increases in
cholesterol (greater than 200% from controls), decreases in
erythrocytes, hemoglobin and hematocrit, and increases in
reticulocytes, platelets, leukocytes, lymphocytes, basophils, and
aPTT. The increase in cholesterol is attributed to the
anti-androgen activity of apalutamide and is believed to be
responsible for the stated hematologic changes. Examination of red
blood cell morphology revealed changes that were consistent with
excess cholesterol being transferred to the outer membrane of the
erythrocytes, resulting in a mild hemolytic anemia. Pharmacologic
effects were also observed in the male accessory sex organs
(epididymides, prostate, seminal vesicles and to a lesser degree,
the testes) at apalutamide doses as low as 50 mg/kg/day. Other
target organs in the rat that were observed at apalutamide doses of
150 mg/kg/day or higher included adrenals (also at 50 mg/kg/day),
liver, pituitary, thyroid, spleen, salivary glands, mammary gland,
and stomach. With the exception of the salivary glands and stomach,
the effects on those organs are also believed to be due to the
anti-androgen effect of apalutamide and in many cases are specific
to the physiology of the rat.
[0193] Once daily oral gavage dosing of apalutamide for 13 weeks
was well tolerated in male rats up to 100 mg/kg/day, i.e. the
highest dose tested. Pharmacologic changes characteristic of
anti-androgen compounds were noted in the adrenal gland, pituitary
gland, spleen, mammary gland, seminal vesicles, testes, prostate,
and epididymides, while changes in the spleen and bone marrow
correlated with a mild regenerative anemia. The 100 mg/kg/day dose
level was considered to be the no observed adverse effect level
(NOAEL) and was associated with steady-state (Day 91) plasma
C.sub.max and AUC.sub.0-24 h values of 30.1 .mu.g/mL and 521
.mu.gh/mL, respectively, for the parent compound.
[0194] In male Beagle dogs, seizures necessitating humane
euthanasia occurred at apalutamide doses of 25 mg/kg/day and
greater, 7 to 14 days after dosing was initiated. Daily
administration of 25 mg/kg/day of apalutamide resulted in tremors
and seizures in 3 of 8 animals after 1 week of dosing. The average
apalutamide concentration at the time of first observation of
central nervous system (CNS) toxicity was determined to be 30.2
.mu.g/mL, which was about 4-fold higher than the mean apalutamide
steady-state C.sub.max (7.55 .mu.g/mL) at the Phase 3 dose of 240
mg/day measured during repeated dosing in subjects with CRPC. It is
likely that the convulsive seizures observed in dogs at very high
doses are the result of apalutamide's functional antagonism of the
GABAA receptor. This is similar to what has been observed with
other second generation AR antagonists. The 10 mg/kg/day dose was
considered to be the NOAEL in the 28-day study, and was associated
with an apalutamide C.sub.max of 13.2 .mu.g/mL and an AUC.sub.0-24
of 290 .mu.gh/mL. Other clinical pathology and target organ changes
were limited to increases in cholesterol (up to 50% compared to
controls) and effects on the epididymides, prostate and testes at
all doses tested and attributed to the anti-androgen effect of
apalutamide.
[0195] Once daily oral capsule administration of apalutamide for 13
weeks was well tolerated in male dogs up to 10 mg/kg/day, i.e. the
highest dose tested. Gross and microscopic pathology changes and
organ weight changes characteristic of anti-androgen compounds were
noted in the pituitary gland, prostate, testes, and epididymides;
these changes were reversible and were attributable to the expected
pharmacologic effect of apalutamide. Based upon the lower body
weight performance in the group receiving 10 mg/kg/day, the 5
mg/kg/day dose was considered to be the NOAEL. Corresponding
steady-state (Day 91) plasma C.sub.max and AUC.sub.0-24h values
were 10.3 .mu.g/mL and 202 .mu.gh/mL, respectively, for the parent
compound.
Example 2: A Multicenter, Randomized, Double-Blind,
Placebo-Controlled, Phase III Study of ARN-509 in Men with
Non-Metastatic (M0) Castration-Resistant Prostate Cancer
Primary Objective
[0196] To demonstrate superiority in the MFS of men with high risk
NM-CRPC (i.e., a PSADT of 10 months) treated with apalutamide
versus placebo.
Secondary Objectives
[0197] To compare the following parameters in men with NM-CRPC
treated with apalutamide versus placebo: time to metastasis (TTM);
progression-free survival (PFS); time to symptomatic progression;
overall survival (OS); time to initiation of cytotoxic
chemotherapy; and safety and tolerability.
Other Objectives
[0198] To compare patient-reported outcomes (PROs) of
health-related quality of life and prostate cancer-specific
symptoms. [0199] To compare medical resource utilization (MRU) for
men with high risk NM-CRPC treated with apalutamide versus placebo.
[0200] To compare PSA Response Rate for men with high risk NM-CRPC
treated with apalutamide versus placebo. [0201] To compare time to
PSA progression for men with high risk NM-CRPC treated with
apalutamide versus placebo. [0202] To compare progression-free
survival with the first subsequent therapy (PFS2), for men with
high risk NM-CRPC treated with apalutamide versus placebo. [0203]
To evaluate the population pharmacokinetics (PK) of apalutamide.
[0204] To evaluate the effect of apalutamide on ventricular
repolarization in a subset of patients from selected clinical
sites. [0205] To evaluate exploratory biomarkers predictive of
response and resistance to apalutamide treatment.
Study Design
[0206] This was a multinational, randomized, double-blind,
placebo-controlled Phase 3 study of apalutamide compared with
placebo in subjects with high risk NM-CRPC. The study consisted of
a Screening Phase of up to 35 days before randomization to
establish eligibility and document baseline measurements, a
double-blind Treatment Phase (28-day treatment cycles; continuous
dosing), and a Long-term Follow-up Phase to monitor PFS, survival
status, subsequent prostate cancer therapy, PRO, and MRU. A total
of 1207 patients with NM-CRPC were randomized in a 2:1 ratio (806
subjects in the apalutamide arm and 401 subjects in the placebo
arm) to receive either apalutamide orally at a dose of 240 mg once
daily in combination with ADT (medical castration or surgical
castration) or placebo with ADT in a multicenter, double-blind,
clinical trial (Study 1). A diagrammatic representation of the
study design is presented in FIG. 2. The randomization was
stratified as follows: [0207] PSADT: <6 months vs. >6 months;
[0208] Bone-sparing agent use: Yes vs. No; and [0209] Loco-regional
disease: N0 vs. N1 (ie, nodal disease).
[0210] To ensure accurate and consistent determination of PSADT,
the Interactive Voice Response System (IVRS) provided PSADT
calculations (using a linear regression model of the natural
logarithm of PSA and time) based on PSA values by date entered by
the sites prior to randomization. Factors related to bone-sparing
agent use and local-regional disease were entered by the site
personnel at the time of randomization. Unblinding of treatment
assignment during the study for non-emergency safety reasons
occurred for 2 subjects.
[0211] Patients enrolled had a Prostate Specific Antigen (PSA)
Doubling Time (PSADT)<10 months. All patients who were not
surgically castrated received ADT continuously throughout the
study. Seventy-three percent (73%) of patients received prior
treatment with a first generation anti-androgen; 69% of patients
received bicalutamide and 10% of patients received flutamide.
Systemic corticosteroids were not allowed at study entry. PSA
results were blinded and were not used for treatment
discontinuation. Patients randomized to either arm were to continue
treatment until disease progression defined by blinded central
imaging review (BICR), initiation of new treatment, unacceptable
toxicity or withdrawal. Upon BICR-confirmed development of distant
metastatic disease, patients were offered ZYTIGA as an option for
the first subsequent treatment after study treatment
discontinuation.
Study Population
[0212] Men 18 years of age or older who had no radiographic
evidence of detectable distant metastases as determined by BICR
prior to study entry were eligible for the study.
Inclusion Criteria:
[0213] Subjects enrolled in this study were required to meet the
following key acceptance criteria: [0214] Histologically or
cytologically confirmed adenocarcinoma of the prostate without
neuroendocrine differentiation or small cell features, with high
risk for development of metastases, defined as PSADT <10 months.
PSADT is calculated using at least 3 PSA values obtained during
continuous ADT; [0215] Castration-resistant prostate cancer
demonstrated during continuous ADT, defined as 3 PSA rises at least
1 week apart, with the last PSA >2 ng/mL; [0216] Surgically or
medically castrated, with testosterone levels of <50 ng/dL. If
the patient is medically castrated, continuous dosing with a GnRH
analogue must have been initiated at least 4 weeks prior to
randomization and must be continued throughout the study to
maintain castrate levels of testosterone; [0217] Patients receiving
bone loss prevention treatment with bone-sparing agents indicated
for the treatment of osteoporosis at doses and dosing schedule
appropriate for the treatment of osteoporosis (e.g., denosumab
[PROLIA], zoledronic acid [RECLAST]) must be on stable doses for at
least 4 weeks prior to randomization; [0218] Patients who received
a first-generation anti-androgen (e.g., bicalutamide, flutamide,
nilutamide) must have at least a 4-week washout prior to
randomization AND must show continuing disease (PSA) progression
(an increase in PSA) after washout; [0219] Resolution of all acute
toxic effects of prior therapy or surgical procedure to Grade 1 or
baseline prior to randomization; [0220] Adequate organ function;
[0221] Signed and dated informed consent document indicating that
the patient (or legally acceptable representative) has been
informed of all pertinent aspects of the trial prior to
randomization.
Exclusion Criteria:
[0222] Subjects were not enrolled into the study if it was
determined upon pre-study examination that they met the following
key criteria: [0223] Presence of distant metastases confirmed by
BICR, including central nervous system (CNS) and vertebral or
meningeal involvement, or history of distant metastases. Exception:
Pelvic lymph nodes <2 cm in short axis (N1) located below the
iliac bifurcation are allowed; [0224] Symptomatic loco-regional
disease requiring medical intervention, such as moderate or severe
urinary obstruction or hydronephrosis, due to primary tumor (e.g.,
tumor obstruction of bladder trigone); [0225] Prior treatment with
next generation anti-androgens (e.g., enzalutamide); [0226] Prior
treatment with CYP17 inhibitors (e.g., abiraterone acetate,
orteronel, galerterone, ketoconazole, aminoglutethimide); [0227]
Prior chemotherapy for prostate cancer, except if administered in
the adjuvant/neoadjuvant setting; [0228] History of seizure or
condition that may pre-dispose to seizure (e.g., prior stroke
within 1 year prior to randomization, brain arteriovenous
malformation, Schwannoma, meningioma, or other benign CNS or
meningeal disease which may require treatment with surgery or
radiation therapy); [0229] Concurrent therapy with medications
known to lower the seizure threshold, products that may decrease
PSA levels, systemic corticosteroids, or other experimental
treatments. [0230] History or evidence of any of the following
conditions: [0231] Any prior malignancy (other than adequately
treated basal cell or squamous cell skin cancer, superficial
bladder cancer, or any other cancer in situ currently in complete
remission) within 5 years prior to randomization; [0232] Any of the
following within 6 months prior to randomization: Severe/unstable
angina, myocardial infarction, symptomatic congestive heart
failure, arterial or venous thromboembolic events (e.g., pulmonary
embolism, cerebrovascular accident including transient ischemic
attacks), or clinically significant ventricular arrhythmias; [0233]
Uncontrolled hypertension (systolic blood pressure >160 mmHg or
diastolic BP >100 mmHg). Patients with a history of uncontrolled
hypertension are allowed provided blood pressure is controlled by
anti-hypertensive treatment; [0234] Gastrointestinal disorder
affecting absorption; [0235] Active infection, such as human
immunodeficiency virus (HIV); and/or [0236] Any other condition
that, in the opinion of the Investigator, would impair the
patient's ability to comply with study procedures. Removal of
Subjects from Therapy or Assessment:
[0237] Subject participation could be discontinued before
completing the study for any of the following reasons: [0238]
Disease progression (confirmed by BICR); [0239] Subject withdrawal
of consent; [0240] Any adverse event that could not be adequately
managed with dose modifications (interruptions longer than 28 days
required discussion with the Sponsor); [0241] Lost to follow-up;
[0242] Any episode of seizure; [0243] Protocol violation requiring
discontinuation of study treatment; [0244] Non-compliance with
study procedures; and/or [0245] Sponsor request for early
termination of study.
Demographics and Baseline Characteristics:
[0246] Two thousand one hundred thirty-two (2,132) subjects signed
the informed consent and were screened. One thousand two hundred
and seven (1207) subjects were randomized. Of the 925 patients who
were ineligible, 517 subjects were ineligible due to the presence
of metastatic disease at screening. The following patient
demographics and baseline disease characteristics were balanced
between the treatment arms. The median age was 74 years (range
48-97) and 26% of patients were 80 years of age or older. The
racial distribution was 66% Caucasian, 5.6% Black, 12% Asian, and
0.2% other. Seventy-seven percent (77%) of patients in both
treatment arms had prior surgery or radiotherapy of the prostate. A
majority of patients had a Gleason score of 7 or higher (81%).
Fifteen percent (15%) of patients had <2 cm pelvic lymph nodes
at study entry. All patients enrolled were confirmed to be
non-metastatic by blinded central imaging review and had an Eastern
Cooperative Oncology Group Performance Status (ECOG PS) performance
status score of 0 or 1 at study entry.
Dosage and Administration
[0247] Apalutamide 240 mg (8.times.30 mg softgel capsules, then
4.times.60 mg tablets) or matching placebo were taken orally once
daily with or without food. With the softgel capsules only,
subjects could switch to a twice daily dosing regimen (4 tables
each period) if gastrointestinal issues arose with the once daily
schedule. If an apalutamide/placebo dose was missed, it was to be
omitted and not made up. For the purposes of this study, a
treatment cycle consisted of 4 weeks (28 days).
[0248] The dose and frequency of administration of the GnRH
analogue as ADT followed the prescribing information in the
respective label. Choice of GnRH analogue or dose could be adjusted
if clinically indicated to achieve and maintain castrate
concentrations of testosterone (<50 ng/dL).
Dose Modifications
[0249] Intrasubject dose interruptions and/or reductions were
permitted provided that study discontinuation criteria had not been
met. [0250] Subjects reported with treatment-related seizure of any
grade were to have study drug permanently discontinued. [0251] For
subjects reported with Grade 1-2 treatment-related adverse events
(TEAEs), short treatment breaks were to be instituted per the
discretion of the Investigator until the severity of the toxicity
decreased to Grade 1 or returned to baseline. If toxicity recurred,
dose reductions to the next lower dose level were allowed as per
the discretion of the Investigator. [0252] For subjects reported
with Grade 3-4 TEAEs other than seizure, study drug was to be held
until the severity of the toxicity decreased to Grade 1 or returned
to baseline. If toxicity recurred at Grade 3 or higher, the dose of
apalutamide was to be reduced to the next lower dose level. [0253]
A maximum of 2 dose level reductions was allowed (240 mg to 180 mg;
180 mg to 120 mg). [0254] Any subject requiring >28-day delay in
treatment due to TEAEs may have met one of the criteria for study
treatment discontinuation described in Section 3.3. Re-starting
study treatment after >28-day delay required discussion with the
Sponsor. Doses reduced for study treatment-related toxicities
should generally not be re-escalated, however, re-escalation back
to the previous dose level may have been permitted in consultation
with the Sponsor (or designee).
Prior and Concomitant Therapy
[0255] Every medication or treatment taken by the subject during
the study and the reason for administration was to be recorded on
the CRF. Continuous treatment with a GnRH analogue or surgical
castration was mandatory. Salvage radiation for loco-regional
pelvic disease and surgical procedures (e.g., transurethral
resection of the prostate [TURP], urethral and ureteral stent
placement) to treat localized progression or symptoms were allowed.
Details of prior prostate cancer related therapies are provided in
Table 1.
TABLE-US-00001 TABLE 1 Overall Summary of Prior Prostate Cancer
Therapy; Intent-to-treat Population ITT population Placebo (401)
Apalutamide (806) Total (1207) Previous prostate cancer therapy N
401 803 1204 Surgery or 307 (76.6%) 617 (76.6%) 924 (76.6%)
radiotherapy Surgery only 69 (17.2%) 159 (19.7%) 228 (18.9%)
Radiotherapy 85 (21.2%) 157 (19.5%) 242 (20.0%) only Both surgery
and 153 (38.2%) 301 (37.3%) 454 (37.6%) Radiotherapy Hormonal 400
(99.8%) 801 (99.4%) 1201 (99.5%) therapy GnRHa 387 (96.5%) 780
(96.8%) 1167 (96.7%) First generation 290 (72.3%) 592 (73.4%) 882
(73.1%) Anti androgen Orichiectomy 24 (6.0%) 47 (5.8%) 71 (5.9%)
Other 9 (2.2%) 17 (2.1%) 26 (2.2%) Chemotherapy 7 (1.7%) 17 (2.1%)
24 (2.0%) Other 32 (8.0%) 64 (7.9%) 96 (8.0%)
Common concomitant medications, reported for 50% or more subjects
included analgesics (apalutamide: 61%; placebo: 57%), agents acting
on the renin-angiotensin system (apalutamide: 55%; placebo: 50%),
and lipid modifying agents (apalutamide: 50%; placebo: 51%).
Prohibited Therapies
[0256] Drugs known to decrease the seizure threshold or cause
seizure or both were prohibited while receiving study treatment.
Other prohibited medications (per the exclusion criteria) included
herbal (e.g., saw palmetto) and non-herbal products that may
decrease PSA levels; systemic (oral/IV/IM) corticosteroids other
than short term use (<4 weeks); any other experimental
treatment; and agents indicated for the prevention of
skeletal-related events in patients with solid tumors (e.g.
denosumab [XGEVA]). Use of agents for prevention of osteoporosis
(e.g., denosumab [PROLIA]) was allowed during the study. Use of
5-.alpha. reductase inhibitors, estrogens and any other anti-cancer
therapy was to be discontinued at least 4 weeks prior to enrollment
to the study.
Restricted Therapies
[0257] Investigators were informed of the potential for drug-drug
interactions of apalutamide with concomitant medications,
particularly strong CYP3A4 inducers or drugs with a narrow
therapeutic index that are metabolized by CYP3A4 (apalutamide is an
inducer of CYP3A4), and strong CYP2C8 inhibitors (e.g.,
gemfibrozil). The potential for drug-drug interaction between
apalutamide and warfarin was not known. If a subject was taking
warfarin, investigators were advised to re-assess prothrombin
(PT)/international normalized ratio (INR) as clinically indicated
and adjust the dose of warfarin accordingly. Additionally, due to
possible resistance mechanisms, the concurrent use of systemic
corticosteroids during study treatment was not recommended;
short-term use (<4 weeks) was allowed if clinically indicated,
however, its use must have been tapered off as soon as
possible.
Dose Modification of Apalutamide
[0258] The majority of subjects were able to tolerate the full,
prescribed dose of the study medication with 79% of subjects in the
apalutamide arm and 85% of subjects in the placebo arm receiving no
dose modifications. There were more dose reductions reported for
subjects in the apalutamide arm (21%) compared with the placebo arm
(15%). More subjects in the apalutamide arm had one dose reduction
compared with the placebo arm (8.2% vs. 3.5%) while similar
proportions of subjects from both treatment arms had two dose
reductions (13% vs 11%, respectively). The most common reason for
dose reduction for subjects in the apalutamide arm was adverse
event (apalutamide arm: 11% vs. placebo arm: 3.3%) while "other"
was the most common reason for the placebo arm (apalutamide arm:
9.7%; placebo arm: 12%). There were more dose interruptions due to
TEAEs reported for subjects in the apalutamide arm (34%) compared
with the placebo arm (19%). More subjects in the apalutamide arm
had one dose interruption compared with the placebo arm (22% versus
13%) while similar proportions of subjects from both treatment arms
had two or more dose interruptions (6.6% versus 5.3%, respectively,
for 2 dose interruptions).
Efficacy Results
Primary Efficacy Analysis: Metastasis-Free Survival
[0259] Efficacy analyses were performed using the ITT population,
which included 1207 randomized subjects (806 subjects in the
apalutamide arm and 401 subjects in the placebo arm). The median
survival follow-up time for all subjects was 20.3 months.
[0260] The primary efficacy endpoint was metastasis-free survival
(MFS), defined as the time from randomization to the time of first
evidence of BICR-confirmed bone or soft tissue distant metastasis
or death due to any cause, whichever occurred first.
Metastasis-free survival data for subjects without metastasis or
death were censored on the date of the last tumor assessment (or,
if no tumor assessment was performed after the baseline visit, at
the date of randomization). Censoring rules based on FDA and CHMP
guidance were applied for analyses of MFS (referred to in the text
as US censoring or ex-US censoring). Treatment with apalutamide
significantly improved MFS.
[0261] The appearance of new metastatic lesions denoted disease
progression. For new bone lesions detected on bone scans, a second
imaging modality (e.g., CT or MRI) was required to confirm
progression.
[0262] Apalutamide decreased the risk of distant metastasis or
death by 72%. The median MFS for apalutamide was 41 months and was
16 months for placebo (see FIG. 3 and FIG. 4). The treatment effect
of apalutamide on MFS was favorable across all subgroups and
consistent with results for the total population. The
non-stratified analysis of MFS by BICR for all subjects and
subgroups is presented in FIG. 4. It is noteworthy that MFS for
subjects with a PSA doubling time of months (HR=0.29) was
consistent with results for subjects with a PSA doubling time of
>6 months (HR=0.30) and with results for the total study
population (HR=0.30; non-stratified analysis). Additionally,
benefit is also noted in all age subgroups, both NO and N1
subgroups, and subjects with 1 or prior hormonal therapies.
Secondary Endpoint Analysis
[0263] Patients treated with apalutamide and ADT showed significant
improvement over those treated with ADT alone for the following
secondary endpoints of time to metastasis (TTM), progression-free
survival (PFS), and time to symptomatic progression. In addition,
overall survival (OS) and time to initiation of cytotoxic
chemotherapy were also improved (see Table 2).
TABLE-US-00002 TABLE 1 Summary of Efficacy Analysis Apalutamide
Placebo (n = 806) (n = 401) HR Median Median (95% CI) Endpoint
(months) (months) p value.sup.1 Metastasis Free 40.5 16.2 0.28
(0.23-<0.0001 Survival (MFS) Time to Metastasis 40.5 16.6 0.27
(0.22-<0.0001 (TTM) Progression-free 40.5 14.7 0.29
(0.24-<0.0001 Survival (PFS) Time to Symptomatic NR NR .sup.
0.45 (0.32-<0.0001.sup.2 Progression Overall Survival (OS) NR
39.0 0.70 (0.47-0.0742 Time to Initiation of NR NR 0.44
(0.29-<0.0001 Cytotoxic Chemotherapy NR = Not reached .sup.1p
value from stratified log-rank test .sup.2Actual p value -
0.00000356; hence, OBF-type efficacy boundary of 0.00008 is crossed
in the interim analysis for Symptomatic Progression
[0264] Treatment with apalutamide significantly decreased the risk
of symptomatic progression by 55% compared with placebo. The
observed p-value (0.00000356) crossed the Obrien-Fleming (OBF)
efficacy boundary (p=0.00008) for significance. (see Table 2 and
FIG. 5).
[0265] Overall survival was longer for apalutamide than placebo
with a hazard ratio (HR) of 0.700 (95% CI: 0.472, 1.038). The
p-value was 0.0742, which did not meet the pre-specified value for
statistical significance.
[0266] Thirty-nine percent (39%) of patients treated with
apalutamide and 70% of patients treated with placebo discontinued
study treatment. A greater proportion (80%) of patients treated
with placebo received subsequent therapy compared to patients
treated with apalutamide (56%). Post-progression survival (PFS-2,
defined as the time to disease progression after first subsequent
therapy or death) was longer for patients treated with apalutamide
compared to those treated with placebo (HR=0.489; 95% CI: 0.361,
0.662; p<0.0001).
Safety Results
Data Sets Analyzed
[0267] Summaries of adverse events and other safety data are based
on the Safety Population that comprises the 1201 subjects who
received at least 1 dose of either apalutamide or placebo (803
subjects in the apalutamide arm and 398 subjects in the placebo
arm).
Adverse Events
[0268] The most common adverse reactions (15%) reported in the
randomized clinical study that occurred more commonly (>2%) in
the apalutamide arm were fatigue, skin rash, weight decreased,
arthralgia, and fall. Discontinuations due to adverse events were
reported for 11% of patients treated with apalutamide and 7% of
patients treated with placebo. There were no statistically
significant differences observed in the change from baseline
analysis of the Functional Assessment of Cancer Therapy-Prostate
(FACT-P) for the total score or any of the subscales between
patients on apalutamide added to ADT versus placebo with ADT. At
the time of the analysis, 61% of patients were still on apalutamide
and 30% of patients were still on placebo. Table 3 shows adverse
reactions on the apalutamide arm that occurred with a 2% absolute
increase in frequency compared to placebo or were events of special
interest.
TABLE-US-00003 TABLE 3 Adverse Reactions due to Apalutamide in
Study 1 Apalutamide Placebo N = 803 N = 398 All Grade All Grade
System/Organ Class Grades 3-4 Grades 3-4 Adverse reaction % % % %
General disorders and administration site conditions Fatigue.sup.4
30.4 0.9 21.1 0.3 Musculoskeletal and connective tissue disorders
Arthralgia.sup.4 15.9 0 7.5 0 Skin and subcutaneous tissue
disorders Skin rash.sup.1 23.8 5.2 5.5 0.3 Pruritus.sup.4 6.2 0.2
1.5 0 Nervous system disorders Seizure 0.2 0 0 0 Metabolism and
nutrition disorders Hypercholesterolemia 6.1 0 1.5 0
Hypertriglyceridemia 3.5 0.6 0.8 0.3 Injury, poisoning and
procedural complications Fracture.sup.2 11.7 2.7 6.5 0.8 Fall.sup.4
15.6 1.7 9.0 0.8 Investigations Weight decreased.sup.4 16.1 1.1 6.3
0.3 Endocrine disorders Hypothyroidism.sup.3 8.1 0 2.0 0
.sup.1 Includes rash, rashmaculo-papular, rash generalized,
urticaria, rash pruritic, rash macular, conjunctivitis, erythema
multiforme, rash papular, skin exfoliation, genital rash, rash
erythematous, stomatitis, drug eruption, mouth ulceration, rash
pustular, blister, papule, pemphigoid, skin erosion, and rash
vesicular .sup.2 Includes rib fracture, lumbar vertebral fracture,
spinal compression fracture, spinal fracture, foot fracture, hip
fracture, humerus fracture, thoracic vertebral fracture, upper limb
fracture, fractured sacrum, hand fracture, pubis fracture,
acetabulum fracture, ankle fracture, compression fracture, costal
cartilage fracture, facial bones fracture, lower limb fracture,
osteoporotic fracture, wrist fracture, avulsion fracture, fibula
fracture, fractured coccyx, pelvic fracture, radius fracture,
sternal fracture, stress fracture, traumatic fracture, cervical
vertebral fracture, femoral neck fracture, tibia fracture .sup.3
Includes hypothyroidism, blood thyroid stimulating hormone
increased, thyroxine decreased, autoimmune thyroiditis, thyroxine
free decreased, tri-iodothyronine decreased .sup.4 Grade 4
definitions do not exist for these reactions
1. Skin Rash
[0269] Skin rash associated with apalutamide was most commonly
described as macular or maculo-papular. Adverse events of skin rash
were reported for 24% of patients treated with apalutamide versus
5.5% of patients treated with placebo. Grade 3 skin rashes (defined
as covering >30% body surface area [BSA]) were reported with
apalutamide treatment (5.2%) versus placebo (0.3%). There were no
reported events of toxic epidermal necrolysis (TEN) or
Stevens-Johnson syndrome (SJS).
[0270] The onset of skin rash occurred at a median of 82 days of
apalutamide treatment and resolved within a median of 60 days from
onset of rash for 81% of patients. Medications utilized included
topical corticosteroids, systemic corticosteroids and oral
anti-histamines. Among patients with skin rash, dose interruption
occurred in 28% and dose reduction occurred in 12%. Skin rash
recurred in approximately half of patients who were re-challenged,
with no serious allergic reactions. Skin rash led to apalutamide
treatment discontinuation in 9% of patients who experienced skin
rash.
2. Falls and Fractures
[0271] Fracture was reported for 11.7% of patients treated with
apalutamide and 6.5% of patients treated with placebo. Half of the
patients experienced a fall within 7 days before the fracture event
in both treatment groups. Falls were reported for 15.6% of patients
treated with apalutamide versus 9.0% of patients treated with
placebo.
3. Hypothyroidism
[0272] Hypothyroidism was reported for 8.1% of patients treated
with apalutamide and 2.0% of patients treated with placebo based on
assessments of thyroid-stimulating hormone (TSH) every 4 months.
There were no grade 3 or 4 adverse events. Hypothyroidism occurred
in 28% of patients already receiving thyroid replacement therapy in
the apalutamide arm and in 5.9% of patients in the placebo arm. In
patients not receiving thyroid replacement therapy, hypothyroidism
occurred in 5.7% of patients treated with apalutamide and in 0.8%
of patients treated with placebo. Thyroid replacement therapy, when
clinically indicated, should be initiated or dose-adjusted.
4. Laboratory Abnormalities
[0273] Hypercholesterolemia was observed in 6.1% of patients
treated with apalutamide and 1.5% of patients treated with placebo.
Hypertriglyceridemia was observed in 3.5% of patients treated with
apalutamide and 0.8% of patients treated with placebo.
Conclusion
[0274] Apalutamide in combination with ADT showed superior efficacy
in comparison with ADT alone for patients with NM-CRPC. Apalutamide
plus ADT significantly improved MFS, TTM, PFS, and time to
symptomatic progression compared with ADT alone. Though survival
data are not yet mature at the time of this analysis for MFS,
treatment with apalutamide plus ADT resulted in favorable OS
compared with ADT alone. Additionally, a compelling result for time
to initiation of cytotoxic chemotherapy was observed. Significant
improvements were consistently observed across clinically relevant
endpoints including PSA response rate, time to PSA progression, and
progression-free survival during first subsequent therapy (PFS2).
There was no detrimental effect or worsening of symptoms that
impacted the quality of life from the addition of apalutamide to
ADT in this population of men with NM-CRPC who are generally
asymptomatic. With the exception of small numerical increases in
skin rash, fall, fracture, and hypothyroidism, when adjusted for
exposure, apalutamide in combination with ADT did not have a
clinically meaningful increase in the incidence of TEAEs compared
with subjects who received ADT alone. The majority of TEAEs
reported were Grade 1 or 2 and were not dose-limiting. Grade 3
events were manageable, being largely related to hypertension (in
both treatment arms) and skin rash (as a grouped term) in the
apalutamide arm with a low rate of treatment discontinuation due to
TEAEs in both treatment arms (11% in the apalutamide arm versus 7%
in the placebo arm). Collectively, the data demonstrate a favorable
benefit-risk profile of the apalutamide+ADT regimen for the
treatment of subjects with NM CRPC at high risk for metastasis.
Example 3: Pharmacodynamics and Pharmacokinetics
Pharmacodynamics
Cardiac Electrophysiology
[0275] The effect of apalutamide 240 mg once daily on the QT
interval was evaluated in patients with CRPC in a dedicated QT
study. There was no difference greater than 20 ms in the mean QT
interval change from baseline, based on the Fridericia correction
method, across all timepoints at steady-state.
Pharmacokinetics
[0276] A population PK analysis of apalutamide and its active
metabolite was conducted. Following repeat once-daily dosing,
apalutamide exposure (C.sub.max and area under the concentration
curve [AUC]) increased in a dose-proportional manner across the
dose range of 30 to 480 mg. Following administration of 240 mg once
daily, apalutamide steady state was achieved after 4 weeks and the
mean accumulation ratio was approximately 5-fold relative to a
single dose. At steady-state, mean (CV %) C.sub.max and AUC values
for apalutamide were 6 .mu.g/mL (28%) and 100 .mu.gh/mL (32%),
respectively. Daily fluctuations in apalutamide plasma
concentrations were low, with mean peak-to-trough ratio of 1.63. An
increase in apparent clearance (CL/F) was observed with repeat
dosing, likely due to induction of apalutamide's own
metabolism.
[0277] At steady-state, the mean (CV %) C.sub.max and AUC values
for the major active metabolite, N-desmethyl apalutamide, were 5.9
.mu.g/mL (18%) and 124 .mu.g/h/mL (19%), respectively. N-desmethyl
apalutamide is characterized by a flat concentration-time profile
at steady-state with a mean peak-to-trough ratio of 1.27. Mean (CV
%) AUC metabolite/parent drug ratio for N-desmethyl apalutamide
following repeat-dose administration was about 1.3 (21%). Based on
systemic exposure, relative potency, and pharmacokinetic
properties, N-desmethyl apalutamide likely contributed to the
clinical activity of apalutamide.
Absorption
[0278] After oral administration, median time to achieve peak
plasma concentration (t.sub.max) was 2 hours (range: 1 to 5 hours).
Mean absolute oral bioavailability is approximately 100%,
indicating that apalutamide is completely absorbed after oral
administration.
[0279] Administration of apalutamide to healthy patients under
fasting conditions and with a high-fat meal resulted in no
clinically relevant changes in C.sub.max and AUC. Median time to
reach t.sub.max was delayed about 2 hours with food (see FIG. 3)
[see Dosage and Administration (2.1)].
Distribution
[0280] The mean apparent volume of distribution at steady-state of
apalutamide is about 276 L. The volume of distribution of
apalutamide is greater than the volume of total body water,
indicative of extensive extravascular distribution.
[0281] Apalutamide and N-desmethyl apalutamide are 96% and 95%
bound to plasma proteins, respectively, and mainly bind to serum
albumin with no concentration dependency.
Elimination
[0282] The CL/F of apalutamide is 1.3 L/h after single dosing and
increases to 2.0 L/h at steady-state after once-daily dosing. The
mean effective half-life for apalutamide in patients is about 3
days at steady-state.
Metabolism
[0283] Following single oral administration of .sup.14C-labeled
apalutamide 240 mg, apalutamide, the active metabolite, N-desmethyl
apalutamide, and an inactive carboxylic acid metabolite accounted
for the majority of the .sup.14C-radioactivity in plasma,
representing 45%, 44%, and 3%, respectively, of the total
.sup.14C-AUC. Metabolism is the main route of elimination of
apalutamide. It is metabolized primarily by CYP2C8 and CYP3A4 to
form N-desmethyl apalutamide. Apalutamide and N-desmethyl
apalutamide are further metabolized to form the inactive carboxylic
acid metabolite by carboxylesterase. The contribution of CYP2C8 and
CYP3A4 in the metabolism of apalutamide is estimated to be 58% and
13% following single dose but changes to 40% and 37%, respectively
at steady-state.
Excretion
[0284] Apalutamide, mainly in the form of metabolites, is
eliminated primarily via urine. Following a single oral
administration of radiolabeled apalutamide, 89% of the
radioactivity was recovered up to 70 days post-dose: 65% was
recovered in urine (1.2% of dose as unchanged apalutamide and 2.7%
as N-desmethyl apalutamide) and 24% was recovered in feces (1.5% of
dose as unchanged apalutamide and 2% as N-desmethyl
apalutamide).
Specific Populations
[0285] The effects of renal impairment, hepatic impairment, age,
race, and other extrinsic factors on the pharmacokinetics of
apalutamide are summarized in FIG. 6. No clinically significant
differences in the pharmacokinetics of apalutamide and N-desmethyl
apalutamide were observed in subjects with mild (eGFR 60-89
mL/min/1.73 m.sup.2) or moderate renal impairment (eGFR 3059
mL/min/1.73 m.sup.2), mild (Child-Pugh A) or moderate (Child-Pugh
B) hepatic impairment, age ranging from 18 to 94 years, or between
different races. The potential effect of severe renal impairment or
end stage renal disease (eGFR 29 mL/min/1.73 m.sup.2) have not been
established due to insufficient data. Clinical and pharmacokinetic
data are not available for patients with severe hepatic impairment
(Child-Pugh Class C).
Example 4: Drug Interactions
Drug Interactions
Effect of Other Medications on Apalutamide
1. Strong CYP2C8 Inhibitors
[0286] In a drug-drug interaction study, the C.sub.max of
apalutamide decreased by 21% while AUC increased by 68% following
co-administration of apalutamide as a 240 mg single dose with
gemfibrozil (strong CYP2C8 inhibitor). Simulations suggest that
gemfibrozil may increase the steady-state C.sub.max and AUC of
apalutamide by 32% and 44%, respectively. For the active moieties
(sum of unbound apalutamide plus the potency-adjusted unbound
active metabolite), the steady-state C.sub.max and AUC may increase
by 19% and 23%, respectively (see FIG. 6).
2. Strong CYP3A4 Inhibitors
[0287] In a drug-drug interaction study, the C.sub.max of
apalutamide decreased by 22% while AUC was similar following
co-administration of apalutamide as a 240 mg single dose with
itraconazole (strong CYP3A4 inhibitor). Simulations suggest that
ketoconazole (strong CYP3A4 inhibitor) may increase the
steady-state C.sub.max and AUC of apalutamide by 38% and 51%,
respectively. For the active moieties, the steady-state C.sub.max
and AUC may increase by 23% and 28%, respectively (see FIG. 6).
3. CYP3A4/CYP2C8 Inducers
[0288] The effects of CYP3A4 or CYP2C8 inducers on the
pharmacokinetics of apalutamide have not been evaluated in vivo.
Simulations suggest that rifampin (strong CYP3A4 and moderate
CYP2C8 inducer) may decrease the steady-state C.sub.max and AUC of
apalutamide by 25% and 34%, respectively. For the active moieties,
the steady-state C.sub.max and AUC may decrease by 15% and 19%,
respectively (see FIG. 6).
4. Acid Lowering Agents
[0289] Apalutamide is not ionizable under relevant physiological pH
condition, therefore acid lowering agents (e.g. proton pump
inhibitor, H.sub.2-receptor antagonist, antacid) are not expected
to affect the solubility and bioavailability of apalutamide.
5. Drugs Affecting Transporters
[0290] In vitro, apalutamide and its N-desmethyl metabolite are
substrates for P-gp but not BCRP, OATP1B1, and OATP1B3. Because
apalutamide is completely absorbed after oral administration, P-gp
does not limit the absorption of apalutamide and therefore,
inhibition or induction of P-gp is not expected to affect the
bioavailability of apalutamide. Effect of Apalutamide on Other
Medications
[0291] The effects of apalutamide on the pharmacokinetics of other
drugs are summarized in FIG. 7.
1. Major CYP Isoform Substrates
[0292] In vitro studies showed that apalutamide and N-desmethyl
apalutamide are moderate to strong CYP3A4 and CYP2B6 inducers, are
moderate inhibitors of CYP2B6 and CYP2C8, and weak inhibitors of
CYP2C9, CYP2C19, and CYP3A4. Apalutamide and N-desmethyl
apalutamide do not affect CYP1A2 and CYP2D6 at therapeutically
relevant concentrations. In a drug-drug interaction study using a
cocktail approach, co-administration of apalutamide with single
oral doses of sensitive CYP substrates resulted in a 92% decrease
in the AUC of midazolam (CYP3A4 substrate), 85% decrease in the AUC
of omeprazole (CYP2C19 substrate), and 46% decrease in the AUC of
S-warfarin (CYP2C9 substrate). Apalutamide did not cause clinically
meaningful changes in exposure to the CYP2C8 substrate (see FIG.
7).
2. P-Gp, BCRP and OATP1B1 Substrates
[0293] Apalutamide was shown to be a weak P-gp and BCRP/OATP1B1
inducer clinically. A drug-drug interaction study using a cocktail
approach showed that co-administration of apalutamide with single
oral doses of sensitive transporter substrates resulted in a 30%
decrease in the AUC of fexofenadine (P-gp substrate) and 41%
decrease in the AUC of rosuvastatin (BCRP/OATP1B1 substrate) but
had no impact on C.sub.max (see FIG. 7).
3. UDP-Glucuronosyl Transferase (UGT) Substrates
[0294] Induction of CYP3A4 by apalutamide suggests that
UDP-glucuronosyl transferase (UGT) may also be induced via
activation of the nuclear pregnane X receptor (PXR). Concomitant
administration of apalutamide with medications that are substrates
of UGT can result in lower exposure to these medications.
4. OCT2, OAT1, OAT3 and MATEs Substrates
[0295] Based on in vitro data, inhibition of organic cation
transporter 2 (OCT2), organic anion transporter 3 (OAT3) and
multidrug and toxin extrusions (MATEs) by apalutamide and its
N-desmethyl metabolite cannot be excluded. No in vitro inhibition
of organic anion transporter 1 (OAT1) was observed. Simulations
suggest that apalutamide does not cause clinically meaningful
changes in exposure to metformin (OCT2/MATEs substrate) and
benzylpenicillin (OAT3 substrate) (see FIG. 7).
Example 5: Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
[0296] Long-term animal studies have not been conducted to evaluate
the carcinogenic potential of apalutamide. Apalutamide did not
induce mutations in the bacterial reverse mutation (Ames) assay and
was not genotoxic in either in vitro chromosome aberration test,
the in vivo rat micronucleus assay or the in vivo rat Comet
assay.
[0297] Male fertility is likely to be impaired by treatment with
apalutamide based on findings in repeat-dose toxicology studies
which were consistent with the pharmacological activity of
apalutamide. In repeat-dose toxicity studies in male rats (up to 26
weeks) and dogs (up to 39 weeks), atrophy, aspermia/hypospermia,
degeneration and/or hyperplasia or hypertrophy in the reproductive
system were observed at >25 mg/kg/day in rats (1.4 times the
human exposure based on AUC) and >2.5 mg/kg/day in dogs (0.9
times the human exposure based on AUC).
[0298] In a fertility study in male rats, a decrease in sperm
concentration and motility, copulation and fertility rates (upon
pairing with untreated females) along with reduced weights of the
secondary sex glands and epididymis were observed following 4 weeks
of dosing at >25 mg/kg/day (approximately equal to the human
exposure based on AUC). Effects on male rats were reversible after
8 weeks from the last apalutamide administration.
Example 6: Formulation of Apalutamide
[0299] Apalutamide/matched placebo were originally formulated as a
nonaqueous, lipid-based solution that was filled into 30 mg
strength, size 18 softgel oblong-shaped capsules (ARN-509 Softgel
Capsules, 30 mg), with a clear to hazy light yellow to yellow
color. Each 30 mg softgel capsule of apalutamide/matched placebo
contained the following inactive ingredients: vitamin E
d-.alpha.-tocopheryl polyethylene glycol succinate 1000 NF (Vitamin
E TPGS), polyethylene glycol 400 NF/EP (PEG 400), glycerol
monocaprylocaprate EP (Capmul MCM), caprylocaproyl macroglycerides
NF/EP (Acconon MC8-2), gelatin NF/EP (195 Acid Bloom), a 50:50
sorbitol/glycerin blend USP/EP, purified water USP/EP, medium chain
triglycerides NF/EP (fractionated coconut oil), and lecithin,
unbleached NF (Capsulec gel 60). The gelatin 195 Acid Bloom NF/EP
was derived from bovine origin and certified in accordance with
FDA's Guidance for Industry--The Sourcing and Processing of Gelatin
to Reduce the Potential Risk Posed by Bovine Spongiform
Encephalopathy (BSE) in FDA-regulated Products for Human Use
(September 1997). Placebo capsule was matched in size, color, and
shape to active study drug in order to maintain the study
blind.
[0300] Apalutamide/placebo softgel capsules were replaced with
tablets (commercial formulation) due to stability issues with the
capsule and large capsule burden for subjects (8 capsules compared
to 4 tablets). Newly enrolled subjects in the study received
tablets only whereas ongoing subjects at the time of the amendment
were switched from capsules to tablets. The apalutamide tablet
contained 60 mg of apalutamide and the following inactive
ingredients: hydroxypropyl methylcellulose-acetate succinate
(HPMC-AS), colloidal anhydrous silica, croscarmellose sodium,
microcrystalline cellulose, silicified microcrystalline cellulose,
and magnesium stearate. Commercially available OPADRY coating
powder was used for the film coating, which was comprised of
polyvinyl alcohol (partially hydrolyzed), titanium dioxide,
polyethylene glycol, talc, and colorants iron oxide yellow and iron
oxide black (E172). It was manufactured and provided under the
responsibility of the Sponsor. Placebo tablet was matched in size,
color, and shape to active study drug in order to maintain the
study blind.
Example 7 Final FDA Approved Drug Product Label
[0301] The FDA approved the following drug product label on Feb.
14, 2018 for ERLEADA.TM. (apalutamide), which will be the reference
listed drug for apalutamide.
[0302] The examples and embodiments described herein are for
illustrative purposes only and various modifications or changes
suggested to persons skilled in the art are to be included within
the spirit and purview of this application and scope of the
appended claims
* * * * *