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110 Treatment of CastrationResistant Prostate Cancer
Emmanuel S. Antonarakis, MD • Michael A. Carducci, MD • Mario A. Eisenberger, MD
Clinical Considerations
Novel Approaches
Cytotoxic Chemotherapy
Conclusions
Palliative Management
D
uring the past several decades, endocrine manipulations
developed to inhibit hormone-dependent prostate cancer
growth and differentiation have constituted the basic
strategy for the systemic control of prostate cancer. Suppression
of gonadal testosterone is the central principle of
androgen-deprivation therapy (ADT), and this represents one of the most effective systemic palliative treatments known for solid tumors. Although it is extremely
effective initially, virtually all patients eventually
develop clinical evidence of treatment resistance. The
outcomes with endocrine therapy have not changed significantly during the past few decades. Progression-free
and overall survival figures of patients with metastatic
disease with various methods of ADT have ranged from
12 to 20 months and 24 to 36 months, respectively (Leuprolide Study Group, 1984; Crawford et al, 1989; Denis et al, 1993;
Eisenberger et al, 1998). Whereas somewhat longer survival
times are reported in the more recent studies, this is
most likely due to a “lead time” effect observed in contemporary populations of patients. The development of
hormone resistance (i.e., cancer progression despite castrate levels of serum testosterone) is virtually a universal
issue that affects all patients treated with ADT. Undoubtedly, further improvement in the outcome of patients
with metastatic castration-resistant prostate cancer
(CRPC) rests on the use of nonhormonal approaches that
can effectively control the growth of the disease.
During recent years, clinical investigations testing nonhormonal approaches have shown that systemic chemotherapy
improves survival and quality of life in patients with castrationresistant (i.e., hormone-refractory) disease. Advances in the understanding of the biology of prostate cancer and characterization of
key molecular pathways have added an important new dimension
for treatment and the opportunity to design disease-specific targeted treatment approaches. Evolving data suggest that targeted
approaches may play an important role in treatment of prostate
cancer that may improve the outcome of our patients.
Progress in cell and molecular biology during the past decade
has also enhanced our understanding of the mechanisms involved
in the progression of prostate cancer, and this may provide the
opportunity for rational planning of the appropriate timing of
2954
systemic therapeutic intervention with the objective of preventing
or delaying progression of disease to lethal proportions. Cancer
cells demonstrating the castration-refractory phenotype
can be identified during early stages of development of
prostate cancer. Somatic alterations of the androgen
receptor are frequently observed in patients with evidence of disease progression after androgen deprivation.
It has also been demonstrated that during cancer progression, in the absence of androgens, a molecularly
altered androgen receptor can still undergo liganddependent activation by other hormones such as estrogens and progestational agents and non–ligand-dependent
activation by growth factors and cytokines (Feldman and
Feldman, 2001; Gelmann, 2002; Nelson WG et al, 2003). The
observation that the androgen receptor can still be activated even after long-term gonadal ablation suggests
that it continues to play an important role in prostate
cancer growth and may indeed be a reasonable target
for treatment in patients with androgen-independent
disease.
In the presence of androgens, prostatic cancer growth is based
on a cell proliferation rate that exceeds that of cell death (Isaacs
et al, 1992). Androgen ablation primarily affects the cell death rate
by inducing a swift apoptotic cascade. As the tumor progresses
the threshold of apoptosis progressively rises to a point
at which cell proliferation exceeds cell death (Berges et al,
1995). This results in the accumulation of endocrine-independent
cells that eventually dominate the biologic behavior of prostate
cancer in late stages.
Preclinical data suggest that the relatively low growth
fraction expressed by adenocarcinoma of the prostate
(compared with other common tumor types) may be a
determining factor to explain the relative insensitivity
to conventional cytotoxic chemotherapy. The proliferation rate of prostate cancer cells, which is directly proportional to the growth fraction, appears to increase
with tumor progression especially after androgen ablation. Cell proliferation antigens, such as Ki-67 expressed by
cycling cells (Cattoretti et al, 1992), may have important prognostic and therapeutic implications because most conventional cytotoxic chemotherapeutic agents available are usually more effective
CHAPTER 110 ● Treatment of Castration-Resistant Prostate Cancer
in tumors with high proliferative rates such as lymphomas, small
cell lung carcinomas, and germ cell tumors of the testis.
Changes in differentiation pathways in prostate cancer have
been increasingly emphasized, particularly in the form of neuro-­
endocrine/anaplastic cells (diSant’Agnese, 1995). Evolving experience with cytotoxic chemotherapy suggests that this aggressive
clinical entity may be responsive to treatment regimens frequently
employed for comparable tumors at other sites with similar
phenotypic characteristics, such as small cell carcinoma of the
lung. There is strong evidence to support the relationship between
prostate cancer growth and various peptide growth factors
(Djakiew et al, 1991; Steiner, 1993; Hofer et al, 1995; Sherwood
et al, 1998; Kaplan et al, 1999; Nelson WG et al, 2003). Peptide
growth factors may also exert their effects through the activation
of the androgen receptor. Androgens are capable of inducing
stromal production of various growth factors that could replace
the androgen requirements for cell growth and differentiation
(Lee, 1996). In addition, cytokines released primarily by stromal
cells, such as interleukin-6, may also be important in the pathogenesis of prostate cancer. Indeed, small molecule inhibitors and
other modalities of treatment (e.g., monoclonal antibodies) are
being actively designed to target intracellular pathways associated
with the expression of various growth factors and their receptors.
Such strategies have involved inhibition of receptor tyrosine
kinase activity and other intracellular molecular pathways of
signal transduction as well as other critical pathways of cell growth
and survival.
CLINICAL CONSIDERATIONS
Disease Assessment
and Treatment Selection
Conventional staging criteria, such as the TNM staging
system, do not describe the extent of disease beyond a
simple anatomic classification. Treatment practices
result in the creation of different disease states as
described by Scher and colleagues (2008). This system
allows classification of patients in a more clinically
applicable fashion and is increasingly being used
throughout the literature. Figure 110–1 illustrates the
natural history of prostate cancer relative to treatment
practices and identifies the various paradigms according
to the response status to different therapies. Throughout
2955
this chapter prognostic and therapeutic considerations are largely
based on the concepts proposed by this classification. A complete
disease evaluation is required to estimate the outcome and to
make therapeutic decisions. Critical baseline components include
extent of disease, mode and site of progression (rising prostatespecific antigen [PSA] level alone, new bone metastasis, visceral
and nodal metastasis), presence or absence of symptoms, and
response to prior endocrine treatment. Regular monitoring with
serial bone scintiscans and serum PSA levels during hormone treatment provides important information in patients demonstrating
evidence of disease progression while they are receiving hormone
therapy. Table 110–1 describes the postprogression survival of
patients with distant metastatic disease who demonstrated progression of disease while on hormone therapy in a large prospective trial (Eisenberger et al, 1995). The data shown in this table
illustrate the broad range in postprogression survival according to
the mode of progression (PSA only vs. bone scintiscan progression)
and according to the extent of bone metastases. This observation
highlights the importance of establishing precisely the predominant mode of progression in these patients and underlines the
need for serial determinations of all laboratory, clinical, and radiologic data. It also provides critical information for the interpretation of subsequent clinical trials with regard to time-dependent
outcomes, such as time to disease progression and survival. Usually
the first manifestation of disease progression after hormone
therapy is a rising serum PSA level. In patients with metastatic
disease, a rise in serum PSA level precedes evidence of advancing
disease in the bone scintiscan, and during this time patients may
remain relatively asymptomatic (Eisenberger et al, 1995). Routine
evaluation of serum testosterone levels may provide important
information for the choice of treatment. This is especially important when there are reasons to suspect treatment noncompliance
Table 110–1. Metastatic Castration-Resistant Prostate Cancer:
Survival According to Mode of Progression
MODE OF
PROGRESSION
MINIMAL DISEASE,
MEDIAN SURVIVAL
EXTENSIVE DISEASE,
MEDIAN SURVIVAL
40 months
23 months
18 months
11 months
PSA only
PSA + bone scintiscan
Data from Eisenberger M, Crawford E, McLeod D, et al. The prognostic significance
of prostate specific antigen in stage D2 prostate cancer: interim evaluation of
Intergroup 0105. Proc Am Soc Clin Oncol 1995;14:abstract 613.
Death
from
other
causes
Figure 110–1. Prostate cancer clinical states.
PSA, prostate-specific antigen. (Modified from
Scher HI, Halabi S, Tannock I, et al. Design and
end points of clinical trials for patients with
progressive prostate cancer and castrate levels
of testosterone: recommendations of the
Prostate Cancer Clinical Trials Working Group. J Clin Oncol 2008;26:1148–59.)
Clinically
localized
disease
Biochemical
relapse
(rising PSA)
Nonmetastatic
hormonesensitive
Nonmetastatic
castrationresistant
Metastatic
hormone
sensitive
Metastatic
castrationresistant
(1st line)
Metastatic
castrationresistant
(2nd line)
Prostate
cancer
related
death
2956
SECTION XVI ● Prostate
or if the choice of prior treatment involved regimens known not
to result in a sustained suppression of serum testosterone to castrate levels (e.g., monotherapy with nonsteroidal antiandrogens,
low-dose estrogens, or 5α-reductase inhibitors).
For several years it has been postulated that discontinuation of androgen suppression in nonorchiectomized patients may adversely influence the outcome of
disease in terms of progression and survival (Taylor et al,
1993). Similarly, it has been shown that administration
of exogenous testosterone and its derivatives may indeed
produce a significant clinical flare that results in severe
pain and neurologic, urologic, and coagulation complications in a small proportion of patients (Fowler and
Whitmore, 1981; Manni et al, 1988). In a retrospective analysis of 205 patients with castration-resistant disease
treated with chemotherapy, various prognostic variables
including orchiectomy were evaluated by Hussain and
associates (1994). A multivariate analysis failed to indicate a significant correlation between prior orchiectomy
and improved time to disease progression and survival.
In these patients all medical forms of androgen deprivation were discontinued at least 4 weeks before initiation
of chemotherapy and, contrary to that suggested by
Taylor and colleagues (1993), this did not significantly
affect outcomes. Until this issue is resolved the general
consensus is to maintain all patients on luteinizing
hormone–releasing hormone (LH-RH) agonists indefinitely, even during the course of chemotherapy.
Another important management aspect relates to antiandrogen
withdrawal effects (Scher and Kelly, 1993; Small and Srinivas,
1995; Small et al, 2004). Discontinuation of antiandrogens
(both steroidal and nonsteroidal) can result in shortterm clinical responses expressed by decreases in PSA
levels, symptomatic benefits, and, less frequently, objective improvements in soft tissue and bone metastasis in
a small proportion of patients. Because of this, it has been
recommended that in patients treated with antiandrogens in combination with other forms of androgen deprivation (e.g., LH-RH
agonists) the first step should involve the discontinuation of these
agents and careful observation including serial monitoring of PSA
levels for a period of 4 to 8 weeks before embarking on the next
therapeutic maneuver.
The next step is to determine which modality of treatment
should be employed first, either administration of second-line
hormonal manipulation or cytotoxic chemotherapy. There is an
increasing body of data on second-line endocrine therapies suggesting that there may be a role for this approach before institution of chemotherapy (Small and Vogelzang, 1997; Small et al,
2004; Ryan 2006; Ang et al, 2009). Although initial response rates
range between 20% and 60%, the median duration of such
responses is short ranging, between 2 and 4 months. Agents that
have been reported to produce some benefit in this setting include
diethylstilbestrol (Smith et al, 1986), aminoglutethimide (Sartor
and Myers, 1995), ketoconazole (Small et al, 2004), as well as
corticosteroids (Storlie et al, 1995). In view of the potential
higher toxicity profile associated with cytotoxic chemotherapy, a sequential hormonal approach may be a reasonable alternative for those patients with relatively
limited metastatic disease who remain asymptomatic at
the time of disease progression (e.g., rising serum PSA
value without other clinical manifestations).
Another important consideration is the initial clinical assessment of the potential biologic behavior of these tumors.
Evolving data evaluating the role of PSA dynamics
suggest that the PSA doubling time (PSADT) predicts for
the rapidity of bone scintiscan progression and survival
(D’Amico et al, 2005; Armstrong et al, 2007; Robinson et al, 2008).
Patients with PSADTs shorter than 3 months have a particularly rapid clinical course and should be considered
for more aggressive management approaches. In addition,
poorly differentiated and anaplastic/neuroendocrine tumors
usually have a low likelihood of significant and durable responses
to androgen deprivation. The anaplastic/neuroendocrine phenotype is rare and requires special therapeutic considerations. It has
been suggested that systematic biopsies of disease sites in patients
with clinically aggressive disease and relatively low serum PSA
levels may demonstrate evidence of a neuroendocrine component
by immunostaining, which may be of prognostic and therapeutic
significance (see later). The usefulness of systematic biopsies in all
patients with extensive metastasis and relatively low PSA levels,
however, needs to be better defined before routine clinical
application.
Nonmetastatic CastrationResistant Disease
The extraordinary stage migration that has affected all stages of
prostate cancer has profoundly modified the spectrum of clinical
presentation of patients with castration-resistant disease. An
increasing number of patients now begin androgen deprivation at
very early stages of their disease course, often at the first sign of a
rising PSA, before clinical and radiologic evidence of metastasis is
present. This group of patients, termed the M0 (nonmetastatic)
castrate-resistant subset, is now seen in increasing proportions in
the clinic. Given the changes in treatment practices with early
initiation of androgen deprivation, it is conceivable that these
numbers will continue to increase. At this time data on the natural
history of these patients are evolving.
A number of clinical trials using second-line hormonal manipulations and noncytotoxic interventions (bone-targeted treatments)
focusing on time to development of bone metastasis are providing
some useful information. A report of 201 patients from a prospective clinical trial comparing the effects of the bisphosphonate
zoledronate and placebo in biochemically progressing (M0),
castrate-resistant disease suggests that the time to bone scintiscan
positivity may be very long. At 2 years, only 33% of these patients
had evidence of bone metastasis, with a median time to bone
metastasis in this group of 30 months. The baseline PSA level
(>10 ng/mL) and the PSA velocity independently predicted time
to bone metastasis and survival (Smith et al, 2005). In a retrospective review of a similar group of patients prescribed ADT before
the development of metastatic disease the median time to clinical
metastasis was 9 months. The pretreatment PSA level and the PSA
nadir on ADT predicted this outcome (Dotan et al, 2005). The
wide difference observed with these two reports (30 months vs. 9
months for time to bone scan metastasis) underscores the heterogeneity of this group of patients and the need for careful prospective evaluation. Their outcome is dependent on various factors,
among which are pre-ADT characteristics (pretreatment PSA level,
PSADT, initial stage, Gleason score), as well as response to hormonal treatment. The rate of progression may be estimated by PSA
constructs such as PSADT and PSA velocity.
At present there is no consensus on the most appropriate management for these patients, although the sequential endocrine
approach is the most commonly employed therapeutic modality.
CHAPTER 110 ● Treatment of Castration-Resistant Prostate Cancer
A trial investigating the relative efficacy of a second-line endocrine
manipulation versus a docetaxel-based chemotherapy regimen in
nonmetastatic disease was closed prematurely because of poor
accrual. More data are needed to characterize the natural history
and to define the best treatment approach of the M0 castrate
subset, which represents an important evolving new paradigm.
Metastatic Castration-Resistant Disease
Patients with metastatic CRPC represent a heterogeneous group with respect to their clinical status at the
time of disease progression (Fig. 110–2). Metastatic adenocarcinoma of the prostate has an overwhelming predilection to involve the bone. Although the explanation for this
unique metastatic pattern has not been completely elucidated it
probably reflects the combination of various biologic factors starting at the time of metastatic spread. Circulating prostatic adenocarcinoma cells are arrested in the cortical and medullary bone
spaces, where they subsequently adhere to bone surfaces through
specific receptors for moieties such as integrins, collagens, laminin,
and other bone-derived proteins. Cell growth is subsequently promoted by various factors such as hormones, growth factors, and
stromal-epithelial biologic interactions, most of which operate in
the bone marrow. Expansion of tumor from the bone may cause
pain, compression, or pathologic fractures, and extensive bone
marrow replacement may cause impairment in hematologic
function.
Clinical involvement of visceral sites is relatively
uncommon even in patients with widespread castrationresistant disease. Table 110–2 illustrates the distribution of
metastatic sites reported in selected chemotherapy phase 2 and
phase 3 trials. These figures suggest that clinical evidence of visceral metastasis is observed in less than 10% of patients, whereas
about 20% have demonstrable soft tissue nodal disease. Because
the majority of tumor burden in metastatic prostate cancer is
2957
found in bone, responses to treatment (e.g., tumor shrinkage) in
soft tissue sites alone (e.g., nodal or visceral sites) may not reflect
a major treatment benefit because it represents only a small proportion of the overall disease burden.
Patients with metastatic CRPC may present with a range of
hematologic problems caused primarily by the disease or by its
treatment. Anemia is the most common hematologic abnormality,
which can be explained by a variety of factors, such as anemia of
chronic disease, bone marrow invasion, blood loss, and rarely
secondary to a microangiopathic hemolytic anemia usually associated with a consumption coagulopathy (disseminated intravascular coagulation). A decrease in the red blood cell count of
patients with advanced CRPC commonly results from a
combination of factors, such as prior treatment with
local irradiation of bone marrow, systemic use of radiopharmaceuticals, long-term androgen deprivation, and
systemic chemotherapy, as well as from extensive bone
marrow invasion by tumor resulting in substantial
decrease in bone marrow reserves. The use of erythropoietin
can be effective, especially in patients with a history of long-term
androgen suppression, and repeated administration may require
the use of iron preparations. However, erythropoietin-stimulating
agents should be used with caution, because evidence is now
emerging that these agents may increase mortality in cancer
patients (Bennett et al, 2008). Granulocytopenia and thrombocytopenia are most commonly a complication of
extensive radiation therapy or systemic chemotherapy.
Rarely, rapidly growing tumors with bone marrow involvement
result in pancytopenia. Thrombocytosis is also a nonspecific manifestation associated with various neoplastic conditions, including
prostate cancer. Clotting complications associated with thrombocytosis are rarely seen in patients with prostate cancer, and treatment is not usually necessary.
Among the most important urologic sequelae
in patients with advanced prostate cancer is the
Table 110–2. Typical Distribution of Metastatic Sites in Patients with Castration-Resistant Prostate Cancer Entered in Clinical Trials
Metastatic Site
STUDY
Hudes et al, 1992
Pienta et al, 1994
Sella et al, 1994
Moore et al, 1994
Eisenberger et al, 1995
Tannock et al, 2004
Petrylak et al, 2004
NO. PATIENTS
36
42
39
27
109
1006
674
Figure 110–2. Clinical heterogeneity of castrationresistant prostate cancer. Subpopulations
according to their type of progression after
androgen deprivation. PSA, prostate-specific
antigen. *The percentages illustrated represent an
estimation based on the distribution reported in
multiple trials reviewed by the authors.
Bone
36
42
36
22
108
915
579
(100%)
(100%)
(92%)
(81%)
(99%)
(91%)
(86%)
Lung
Liver
0
3
3
2
6
2
5
3
2
4
(0%)
(7%)
(8%)
(9%)
(6%)
67 (10%)
PSA
progression
alone
15-20%*
7
13
9
10
15
57 (8%)
(19%)
(31%)
(23%)
(37%)
(14%)
168 (25%)
Soft tissue/visceral
negative bone scan
< 10%*
Positive bone scan
90%*
Bone scan
+
PSA
progression
70%*
Soft Tissue–Nodal
(6%)
(12%)
(8%)
(7%)
(4%)
Symptomatic
progression
alone
10-15% ??*
Newly
positive
bone scan
Soft tissue
visceral
progression
negative
bone scan
2958
SECTION XVI ● Prostate
development of obstructive uropathy. This complication,
related to the primary disease, can be devastating in terms of
quality of life and may even have major therapeutic implications.
Besides an increased incidence of infection and pain, obstructed
kidneys may critically impair renal function to a point where
various chemotherapeutic agents (which depend largely on renal
mechanisms for their clearance) cannot be safely employed. In
general, patients who are otherwise candidates for treatment with
cytotoxic drugs are best first managed by relief of obstruction
either with placement of internal stents or by percutaneous
nephrostomies.
One of the greatest emergencies in oncology is the development
of epidural spinal cord compression (Sorensen et al, 1990). Because
of the frequent involvement of vertebral bodies by metastatic
prostate cancer, the incidence of cord compression is of particular
concern (see later).
Key Points: Clinical Considerations
l Evaluate
the extent and aggressiveness of the disease.
that the critical issues are presence or absence of
metastases, clinical versus biochemical relapse, presence of
symptoms (e.g., pain), and PSA kinetics (e.g., PSA doubling
time, PSA velocity).
l Consider secondary hormonal manipulations before initiation of cytotoxic chemotherapy.
l Realize
CYTOTOXIC CHEMOTHERAPY
Evaluation of Treatment Efficacy
The evaluation of chemotherapy based on uncontrolled clinical
trials in patients with metastatic prostate cancer is usually confounded by significant methodologic challenges. The most
common metastatic site is bone (nonmeasurable disease), manifested by diffuse osteoblastic lesions that cannot be measured
reliably by current methods to allow assessments of therapeutic
benefits. Soft tissue or visceral metastatic sites (measurable disease)
that allow serial measurements are uncommon (see Table 110–2)
and represent only a small fraction of the total burden of the
disease. Selection of bi-dimensionally measurable disease sites to
assess therapeutic efficacy with serial “tumor measurements” has
been the subject of significant criticism. Patients with soft tissue
metastasis (especially visceral disease) are considered by many a
subgroup with biologic and clinical features distinct from those of
the usual patient with prostate cancer who presents with bone
metastasis only. A number of prognostic models evaluating baseline and post-treatment characteristics have been developed
(Smaletz et al, 2002; Halabi et al, 2003; Armstrong et al, 2007).
Among various clinical and laboratory parameters with consistent
prognostic significance are baseline functional status (performance
status), presence of pain, and pretreatment hemoglobin levels
(cutoffs range from 10 to 12 g/dL). Other possible parameters are
the baseline PSA level, extent of bone scintiscan involvement
(number of lesions or pattern/distribution of bone involvement),
and presence of visceral disease. Semi-quantitative methods to
evaluate PSA mRNA expression in circulating cells (using reverse
transcriptase/polymerase chain reaction) and various PSA constructs (e.g., PSADT and PSA velocity) are among the post-treatment
parameters most likely to be of prognostic significance (Kantoff
et al, 2001; Scher et al, 2004; Armstrong et al, 2007).
Preclinical observations have suggested that several drugs may
reduce PSA secretion without affecting tumor growth (Larocca
et al, 1991; Eisenberger and Nelson, 1996; Seckin et al, 1996).
Whereas these laboratory observations are likely to be clinically
relevant, assays used to evaluate a separate drug effect on PSA
secretion still require careful validation. A PSA consensus meeting
developed by several leading investigators in the field generated
initial guidelines with regard to the use of the PSA test for clinical
trials in patients with CRPC (Bubley et al, 1999). These guidelines
were recently updated and now also provide a consensus on the
use of radiologic end points as well as clinical end points (e.g.,
pain) for the evaluation of men with CRPC (Scher et al, 2008). The
use of serum acid phosphatase and alkaline phosphatase has not
been proven beneficial. Undoubtedly, new biomarkers are needed
to enhance our ability to rapidly identify active treatments for
CRPC. Evolving noncytotoxic and targeted therapies may require
a new set of end points and identification of drug-specific intermediate biomarkers that reflect mechanism-specific biologic
activity.
Clinical Trials
Most of the chemotherapeutic agents available in oncologic practice have been employed in patients with CRPC, either as single
agents or in various combinations. Examples have included cyclophosphamide, 5-fluorouracil, estramustine, vinorelbine, etoposide, cisplatin, carboplatin, doxorubicin, mitoxantrone, paclitaxel,
and docetaxel (Eisenberger, 1988). With the exception of docetaxel
and perhaps mitoxantrone, most other cytotoxic agents are no
longer being used with frequency because they have not been
associated with either symptomatic improvements or extension of
survival. Evolving data with selected chemotherapy during the
new millennium suggest that the survival of patients with
advanced CRPC is now somewhere between 16 and 18 months
(Petrylak et al, 2004; Tannock et al, 2004) as opposed to 6 to 12
months as previously described (Eisenberger, 1988).
A first step forward in the chemotherapeutic management of
CRPC came with mitoxantrone. This agent, a semi-synthetic
anthracycline, had previously shown modest symptomatic benefits but with minimal evidence of objective antitumor activity
(Osborne et al, 1983; Rearden et al, 1995). In addition, mitoxantrone appeared to have its maximal palliative effect in combination with low-dose corticosteroids (Moore et al, 1994). In two
seminal prospective randomized trials of mitoxantrone plus prednisone versus prednisone alone (Tannock et al, 1996) or mitoxantrone plus hydrocortisone versus hydrocortisone alone (Kantoff
et al, 1999), the combination resulted in significant improvements
of various quality of life parameters, including pain, but survival
was not significantly improved in either trial. These studies provided the justification for the approval in 1997 by the U.S. Food
and Drug Administration (FDA) of the combination of mitoxantrone and prednisone for symptomatic metastatic prostate cancer.
The next significant advance in the use of chemotherapy for CRPC came with docetaxel, a member of the
taxane family. This agent acts by inducing apoptosis in
cancer cells through TP53-independent mechanisms that
are thought to be due to inhibition of microtubule depolymerization and blockade of antiapoptotic signaling.
The induction of microtubule stabilization intracellularly through β-tubulin interactions causes guanosine
triphosphate (GTP)-independent polymerization and
cell cycle arrest at G2M. In addition, docetaxel has been
found to induce BCL2 phosphorylation in vitro, a process
CHAPTER 110 ● Treatment of Castration-Resistant Prostate Cancer
Docetaxel 75 mg/m2 q3 wks +
prednisone 5 mg bid
Stratification:
Figure 110–3. TAX 327 study design. AS, analgesic score;
KPS, Karnofsky performance status score; PPI, present pain
intensity score.
Pain level
PPI 2 or AS 10
vs.
PPI < 2 or AS < 10
Docetaxel 30 mg/m2 wkly
5 of 6 wks +
prednisone 5 mg bid
Randomize
KPS
70 vs. 80
Mitoxantrone 12 mg/m2
q3 wks +
prednisone 5 mg bid
Treatment duration in
all 3 arms = 30 wks
Hazard ratio in favor of:
1.0
Docetaxel
0.9
Mitoxantrone
Intent to treat
Docetaxel 3 wkly
Docetaxel wkly
Mitoxantrone
0.8
Probability of surviving
2959
Age < 65
Age 65
Age 75
0.7
0.6
Pain no
Pain yes
0.5
KPS 80
KPS 70
0.4
Median
survival Hazard
(mos)
ratio
0.3
0.2
Combined:
D 3 wkly:
D wkly:
Mitoxantrone
0.1
18.2
18.9
17.3
16.4
0.83
0.76
0.91
−
0.2
P-value
0.4
0.6
0.8
1
1.2
1.4
Figure 110–5. Survival in subgroups, docetaxel every 3 weeks
versus mitoxantrone. KPS, Karnofsky performance status score.
.03
.009
.3
−
0.0
0
6
12
18
24
30
Months
Figure 110–4. Overall survival, TAX 327.
Table 110–3. TAX 327: Secondary Objectives (Response Rates)
that has been correlated with caspase-3 activation and
loss of its normal antiapoptotic activity. Unable to
inhibit the pro-apoptotic molecule BAX, phosphorylated
BCL2 may also induce apoptosis through this alternate
pathway. However, additional mechanisms may also be
important, such as CDKN1B (formerly p27) induction
and repression of BCL-XL. Data with docetaxel monotherapy previously suggested that this compound has
significant activity as a single agent (Friedland et al, 1999;
Picus and Schultz, 1999; Beer, 2004).
As of 2004, docetaxel has become the agent of choice
for treatment of metastatic CRPC on the basis of a large
phase 3 randomized trial, TAX 327 (Figs. 110–3 to 110–5 and
Tables 110–3 to 110–5), which demonstrated superiority
over the previous standard, mitoxantrone and prednisone (Tannock et al, 2004). TAX 327 enrolled 1006 patients with
no prior chemotherapy and stable pain scores to one of three
study arms (all with concomitant prednisone at 5 mg orally twice
daily): mitoxantrone, 12 mg/m2 intravenously every 21 days;
docetaxel, 75 mg/m2 intravenously every 21 days; or docetaxel,
30 mg/m2 intravenously every 7 days. Patients remained on
DOCETAXEL
(THREE TIMES DOCETAXEL
A WEEK)
(WEEKLY)
MITOXANTRONE
Pain Response Rate*
N, evaluable
PSA response rate
(%)
P value (vs.
mitoxantrone)
153
35
154
31
.01
157
22
.07
PSA Response Rate*
N, evaluable
Response rate (%)
P value (vs.
mitoxantrone)
291
45
.0005
282
48
<.0001
300
32
134
8
137
7
Tumor Response Rate*
N, evaluable
Response rate (%)
P value (vs.
mitoxantrone)
141
12
.10
.50
*Determined only for patients with pain or PSA ≥ 20 ng/mL or measurable disease
at baseline, respectively.
PSA, prostate-specific antigen.
2960
SECTION XVI ● Prostate
Table 110–4. D/E*
Docetaxel 60 mg/m2 IV D2 every 21 days
Estramustine 280 mg po TID, D1-5
TAX 327: Quality of Life Response (>16 Points FACT-P
Score Compared with Baseline)
DOCETAXEL
(THREE TIMES
A WEEK)
No. of evaluable
patients
Response (%)
95% CI
P value (vs.
mitoxantrone)
278
DOCETAXEL
(WEEKLY)
270
22
17-27
.009
R
MITOXANTRONE
M/P
Mitoxantrone 12 mg/m2 IV every 21 days
Prednisone 5 mg po BID continuously
267
23
18-28
.005
13
9-18
* Coumadin 2 mg PO daily + ASA 325 mg PO daily was added
Docetaxel and mitoxantrone doses could be increased to
70 mg/m2 and 14 mg/m2, respectively, if no grade 3 or 4
toxicities were seen in cycle 1
Figure 110–6. SWOG 9916 study design. D/E, docetaxel plus
estramustine; M/P, mitoxantrone plus prednisone.
Table 110–5. TAX 327: Grade 3-4 Hematologic Toxicity (%)
No. treated
Anemia
Neutropenia
Neutropenic
infection
Febrile neutropenia
Septic death
332
5%
32%
3%
3%
0%
330
5%
2%
0%
0%
0.3%
335
2%
22%
1%
2%
0.3%
gonadal suppression (e.g., LH-RH agonists) but had all other hormonal agents discontinued. Treatment duration was 30 weeks in
all study arms, or a maximum of 10 cycles in the every-3-week
study arms, with more patients completing treatment in the every3-week docetaxel group than in the mitoxantrone group, mostly
because of differences in disease progression (46% vs. 25%). After
a median follow-up of 20.7 months, overall survival in
the every-3-week docetaxel group was 18.9 months (with
a pain response rate of 35% and a PSA response of 45%),
contrasted to weekly docetaxel at 17.3 months (and 31%
and 48%), respectively. This translated into a 24% relative reduction in the risk of death (95% confidence interval [CI], 6% to 48%; P = .0005) with 3-weekly docetaxel
(see Fig. 110–4). Patients on the mitoxantrone arm had a
median survival of 16.4 months, a pain response of 22%,
and a PSA response of 32%.
Toxicity in the 3-weekly versus weekly docetaxel
groups was notable for more hematologic toxicity in the
every-3-week group (3% neutropenic fever vs. 0%; 32%
grade-3/4 neutropenia versus 1.5%) (see Table 110–5) but
slightly lower rates of nausea and vomiting, fatigue, nail
changes, hyperlacrimation, and diarrhea. Neuropathy
was slightly more common in the every-3-week group
(grade 3/4 in 1.8% vs. 0.9% in the weekly treated group).
Quality of life responses as measured by the FACT-P
scores did not differ significantly among the docetaxel
schedules but were more favorable than in the mitoxantrone group.
The Southwest Oncology Group (SWOG) 9916 study
was a second large phase 3 trial (Figs. 110–6 to 110–8) (Petrylak et al, 2004) in which 770 patients with progressive
CRPC were randomly assigned to oral estramustine
(280 mg three times daily) plus docetaxel (60 mg/m2
100%
# at risk
# of deaths
Median
months
338
336
217
235
18
16
D+E
M+P
80%
HR: 0.80 (95% Cl 0.67, 0.97), P = .01
60%
40%
20%
0%
0
12
24
Months
36
Figure 110–7. Overall survival, SWOG 9916. D+E, docetaxel plus
estramustine; M+P, mitoxantrone plus prednisone.
% of patients with a ≥ 50% decrease in PSA
DOCETAXEL
(THREE TIMES DOCETAXEL
A WEEK)
(WEEKLY)
MITOXANTRONE
50
40
P < .0001
30
50%
20
27%
10
0
Docetaxel/
estramustine
n = 303
Mitoxantrone/
prednisone
n = 303
Figure 110–8. SWOG 9916 prostate-specific antigen (PSA)
response rate.
48
CHAPTER 110 ● Treatment of Castration-Resistant Prostate Cancer
every 21 days) versus mitoxantrone (12 mg/m2 every 21
days) plus prednisone. In this study, median overall survival
was longer in the docetaxel-estramustine group than in the
mitoxantrone-prednisone group (17.5 vs. 15.6 months, P = .02),
with a corresponding hazard ratio (HR) for death of 0.80 (95% CI,
0.67 to 0.97). Because of the high rate of thromboembolic events
with estramustine, prophylactic low-dose warfarin and aspirin
were added to that study arm, which did not reduce the incidence
of thromboembolism. Similarly, 20% and 15%, respectively, of
patients in the docetaxel-estramustine arm had grade 3/4 gastrointestinal and cardiovascular toxicities. Although comparisons
between the docetaxel arms across these two seminal
trials may not be appropriate because of differences in
schedule, patient populations, and docetaxel dosing
(60 mg/m2 in SWOG 9916 and 75 mg/m2 in TAX 327), it
may be concluded that estramustine is unlikely to add
significantly to the activity of single-agent docetaxel.
Until recently, effective life-prolonging therapies for men with
docetaxel-refractory prostate cancer were lacking. This changed
in 2010, when the FDA approved a second chemotherapy agent,
cabazitaxel, for the treatment of metastatic CRPC. Cabazitaxel
(Jevtana, Sanofi-aventis, Paris, France) is a novel tubulin-binding
taxane that differs from docetaxel and paclitaxel due to its poor
affinity for P-glycoprotein, the ATP-dependent drug efflux pump
(Paller and Antonarakis, 2011). In preclinical studies using cancer
cell lines and mouse xenograft models, cabazitaxel was shown to
be active in both docetaxel-sensitive tumors as well as those with
primary or acquired docetaxel resistance (Attard et al, 2006).
The first hint of cabazitaxel’s safety and efficacy in men with
prostate cancer came during phase I testing, where cabazitaxel was
administered by intravenous infusion every 3 weeks at escalating
doses of 10 to 25 mg/m2 (Mita et al, 2009). In that study, the
principal dose-limiting toxicity was neutropenia. Given the lack
of cross-resistance to this agent with docetaxel, and early reports
of responses in men with CRPC from this phase 1 trial, a phase 3
trial was launched to evaluate efficacy.
The safety and efficacy of cabazitaxel in patients with advanced
prostate cancer was definitively evaluated in a pivotal randomized
phase III trial (TROPIC) conducted in 146 institutions across 26
countries, and recruited 755 men with metastatic CRPC who had
progressed during/after docetaxel-based chemotherapy (de Bono
et al, 2010). Of these, 377 patients were randomized to receive
mitoxantrone 12 mg/m2 intravenously every 3 weeks (with oral
prednisone 10 mg daily), and 378 patients were assigned to receive
cabazitaxel 25 mg/m2 intravenously every 3 weeks (plus prednisone). This study was the basis of the FDA’s approval of cabazitaxel
with prednisone for the second-line treatment of docetaxel-refractory metastatic CRPC in June 2010.
After a median follow-up of 12.8 months, overall survival in
men receiving cabazitaxel was 15.1 months compared to 12.7
months in men receiving mitoxantrone (HR, 0.70; P < .0001) (de
Bono et al, 2010). Compared to mitoxantrone, cabazitaxel also
significantly lengthened progression-free survival (2.8 months vs.
1.4 months; P < .0001), extended time to PSA progression (6.4
months vs. 3.1 months; P = .001), increased radiographic tumor
response rates (14.4% vs. 4.4%; P = .0005), and increased PSA
response rates (39.2% vs. 17.8%; P = .0002). There were no differences between the two treatment arms with respect to pain
responses, or time to pain progression.
In subset analyses, the survival advantage of cabazitaxel persisted regardless of whether patients had measurable disease or
pain, or whether progression had occurred while receiving
docetaxel or following a treatment holiday. In addition,
2961
cabazitaxel’s survival benefit was most pronounced for men with
ECOG performance status 0-1 (vs. 2), and for patients with disease
progression within <3 months of docetaxel initiation (vs. ≥3
months of docetaxel initiation) (de Bono et al, 2010). The last
observation implies that cabazitaxel may be effective even in men
with truly docetaxel-refractory disease.
The most common serious adverse events related to cabazitaxel
were hematological, including grade ≥3 neutropenia in 82% of
patients (febrile neutropenia in 8%) (de Bono et al, 2010). This
degree of myelosuppression begs the question of whether a lower
dose of cabazitaxel (e.g., 20 mg/m2) may have been more appropriate, and a randomized trial comparing the safety and efficacy of
these two doses (25 mg/m2 vs. 20 mg/m2) is now being conducted.
Use of growth factor support should be strongly considered, as
reflected in several national guidelines (Mohler et al, 2010). Other
nonhematologic toxicities included grade ≥3 diarrhea (6%) and
grade ≥3 fatigue (5%). Encouragingly, although peripheral neuropathy (all grades) was observed in 14% of patients receiving
cabazitaxel, only 1% developed grade 3 neuropathy.
Key Points: Cytotoxic Chemotherapy
l Docetaxel is the standard treatment for metastatic castration-
resistant prostate cancer. It prolongs progression-free and
overall survival, ameliorates pain, and improves quality of
life.
l Toxicity of docetaxel includes myelosuppression, fatigue,
edema, moderate to modest neurotoxicity, hyperlacrimation, and changes in liver function.
l No other chemotherapy regimen has shown a survival
advantage in CRPC, but mitoxantrone has been approved
to palliate symptoms associated with metastatic disease.
l Cabazitaxel has recently emerged as a treatment option for
patients with metastatic CRPC who have experienced progressive disease during or after docetaxel treatment.
The Neuroendocrine/
Anaplastic Subtype
Laboratory and clinical evidence indicates that alterations in the
differentiation pathway of prostate cancer can be seen in a small
proportion of patients with advanced disease, giving rise to a
neuroendocrine/anaplastic transformation (diSant’Agnese, 1995;
Nelson et al, 2007). The therapeutic implications of this finding
are of significance because tumors demonstrating this phenotype
usually represent an inherently endocrine-resistant subtype and,
in view of their different clinical and biologic properties compared
with the usual adenocarcinoma of the prostate, these tumors
usually require different treatment strategies.
Such tumors express a number of biologic characteristics unique to neuroendocrine tumors that can also
arise from other organs, most commonly the lung.
Among these are the expression of receptors to various
neuroendocrine peptide growth factors, such as somatostatin, chromogranin A, and serotonin, as well as parathyroid hormone–related protein (PTHrP) and TP53
mutations. These tumors have an uncharacteristic clinical behavior (compared with the usual metastatic prostate cancer), reflected by frequent visceral involvement
and rapidly growing soft tissue metastases. Patients
2962
SECTION XVI ● Prostate
Figure 110–9. Neuroendocrine/anaplastic carcinoma of the prostate. PSA, prostate-specific antigen.
frequently present with subacute and often dramatic
changes in their disease pattern characterized primarily
by a rapidly growing soft tissue mass (frequently involving the primary site but also with retroperitoneal
masses), rapid development of visceral (lung and liver)
infiltration, osteolytic (as opposed to osteoblastic) bone
metastasis, and a high incidence of parenchymal brain
involvement (Fig. 110–9). Histologic evaluation of areas
demonstrating rapid growth is strongly encouraged.
This frequently culminates with demonstration of a
small cell variant or a poorly differentiated neoplasm on
pathology and the presence of neuroendocrine markers
on immunostaining (diSant’Agnese, 1995; Nelson et al, 2007).
Interestingly, patients with this tumor phenotype either
stop expressing PSA in the presence of major tumor progression or even have undetectable PSA levels at the time
of this transformation.
Treatment is usually similar to that of patients with
other neuroendocrine tumors (e.g., small cell carcinoma
of the lung) and includes combinations of cisplatin
(or carboplatin) and etoposide (Frank, 1995), paclitaxel,
docetaxel, and topotecan. Doxorubicin-containing combinations have been reported to be moderately effective
by one group (Papandreou et al, 2002). Radiation therapy is
effective and should be considered in cases with bulky
disease, with brain metastasis, or when local disease
control in critical areas may have a positive impact on
quality of life (pain, potential pathologic fractures, and
bladder outlet obstruction). A combined chemotherapy
and radiation therapy approach is frequently necessary
to accomplish maximal disease control. Despite high
initial response rates with chemotherapy and radiation
treatment, the prognosis of these patients remains poor
and is dependent on various factors, including extent
and location of metastases.
Key Points: The Neuroendocrine/Anaplastic Subtype
l Rapidly
growing disease with the following clinical characteristics should prompt evaluation for the neuroendocrine/
anaplastic phenotype: pelvic masses, visceral involvement,
osteolytic metastasis with hypercalcemia (associated with
high serum PTHrP), and brain metastasis.
l PSA is most commonly undetectable (or levels are low/
declining) despite evidence of rapid disease progression.
Serum chromogranin A and urine serotonin metabolites
may be detected.
l These tumors are invariably unresponsive to hormonal
manipulations but highly sensitive to radiation therapy and
platinum-etoposide combinations.
PALLIATIVE MANAGEMENT
Pain and Epidural Cord Compression
As in other disseminated malignant neoplasms, palliation of
symptoms and maintenance of adequate levels of quality of life
represent the most important objectives in the management of
advanced prostate cancer.
Cancer-related pain is undoubtedly the most debilitating
symptom associated with metastatic prostatic carcinoma. Prompt
recognition of the various pain syndromes associated
with this disease is critical to accomplish effective
control of this devastating symptom. The most common
pain syndromes and their respective therapeutic considerations
are described in Table 110–6.
Focal bone pain in patients with castration-refractory disease
can be well controlled by external-beam localized radiation
therapy. In general, it is also recommended that painful areas
CHAPTER 110 ● Treatment of Castration-Resistant Prostate Cancer
2963
Table 110–6. Common Pain Syndromes in Metastatic Castration-Resistant Prostate Cancer
PAIN SYNDROME
INITIAL MANAGEMENT
OTHER THERAPEUTIC ALTERNATIVES
Localized bone pain
Pharmacologic pain management
Localized radiotherapy (special attention to
weight-bearing areas, lytic metastasis, and
extremities)
Diffuse bone pain
Pharmacologic pain management
“Multi-spot” or widefield radiotherapy
Radiopharmaceuticals
Epidural metastasis and cord
compression
High-dose corticosteroids
Radiation therapy
Surgical decompression and stabilization should be
indicated in high-grade epidural blocks, extensive
bone involvement, or recurrence after irradiation.
Pharmacologic pain management
Radiation therapy (if not previously employed)
Neurolytic procedures (nerve blocks)
Careful neurologic evaluation
Pharmacologic pain management
Discontinuation of neurotoxic drugs: paclitaxel,
docetaxel, Vinca alkaloids, platinum compounds
Radiation therapy
Pharmacologic pain management
Corticosteroids (cranial nerve involvement)
Surgical stabilization of pathologic fractures or
extensive bone erosions
Epidural metastasis and cord compression should
be evaluated in patients with focal back pain.
Radiopharmaceuticals should be considered if
local radiation therapy fails.
Corticosteroids
Bisphosphonates
Calcitonin
Chemotherapy
Pharmacologic pain management
Plexopathies caused by
direct tumor extension or
prior therapy (rare)
Miscellaneous neurogenic
causes: postherpetic
neuralgia, peripheral
neuropathies
Other uncommon pain
syndromes: extensive
skull metastasis with
cranial nerve involvement,
extensive painful liver
metastasis or pelvic
masses
shown to be abnormal on bone scintigraphy should be evaluated
with plain radiographs to exclude the presence of osteolytic lesions
or pathologic fractures. Such considerations become even more
important when the painful areas affect extremities and weightbearing sites.
Epidural metastasis is a fairly common and potentially devastating complication of systemic cancer. In
view of the propensity for prostate cancer to metastasize
to the vertebrae and paravertebral region, the incidence
of epidural cord compression is particularly high in this
disease. Early diagnosis and treatment of epidural metastasis is critical in preserving ambulation and bowel and
bladder function and aids in the management of back
pain (Grossman and Lossignol, 1990; Gabriel and Schiff, 2004).
Epidural cord compressions arising from vertebral bodies account
for the majority of spinal cord compression; only less frequently
is it associated with soft tissue masses involving the paravertebral
region. Most patients have abnormalities on bone scintiscans
and abnormal findings on radiography at the time of diagnosis.
However, an abnormality on neurologic examination may be the
only finding in patients who have soft tissue epidural metastasis
in the paravertebral region.
Spinal magnetic resonance imaging (MRI) is routinely used to
exclude the possibility of significant epidural disease, and it has
almost entirely replaced other methods such as computed tomographic myelography and conventional myelography. The first
therapeutic intervention should include the administration of
high doses of intravenous glucocorticoids. Dexamethasone at
doses ranging from 16 to 100 mg daily is most commonly
employed. Most frequently, patients are given an
Tricyclic antidepressants (amitriptyline)
Anticonvulsants
Tricyclic antidepressants (amitriptyline)
Anticonvulsants
Chemotherapy
Intrathecal chemotherapy may ameliorate
symptoms of meningeal involvement; regional
infusions may be considered.
intravenous “loading dose” of 10 mg of dexamethasone
followed by 4 to 10 mg every 6 hours; the optimal dose
remains relatively undefined. On improvement of symptoms, which can be accomplished promptly with corticosteroids,
the corticosteroid dose may be tapered during a 2- to 3-week
period.
Radiation therapy is often the main modality of definitive treatment. However, recent reports suggest that
surgery followed by radiation therapy may be superior
to radiation therapy alone (Patchell et al, 2005). Surgery
should be considered in patients who present with evidence of progressive signs and symptoms during radiation therapy, develop or present with unstable pathologic
fractures, or have recurrence after radiotherapy. Clearly,
the overall prognosis of the underlying disease should be
taken into consideration during treatment selection.
Chemotherapy is rarely used to treat epidural cord
compressions.
Bone-Targeted Approaches
The pathogenesis of bone metastases in prostate cancer remains a
subject of major study (Galasko, 1986). Alterations in the normal
process of bone absorption and formation, which usually follows
an orderly and sequential basis, appear to be a key determining
factor in the development of bone metastasis associated with most
malignant neoplasms (Roodman, 2004). Under normal physiologic conditions the process of bone remodeling is initiated by an
increase in osteoclastic activity followed by an increase in osteoblastic differentiation and maturation, which results in the
2964
SECTION XVI ● Prostate
formation of new bone and repair of the initial absorption caused
by osteoblasts. Bone loss associated with prostate cancer can result
from an enhanced osteoclastic activity associated with long-term
androgen suppression, which in turn will cause excessive resorption of bone mineral and organic matrix. Tumor cells may also
cause mineral release and matrix resorption in the areas involved
by metastatic disease (Galasko, 1986). In addition, various cytokines, growth factors, tumor necrosis factors, and bone morphogenic proteins have been shown in preclinical studies to play a
major role in the induction of both osteoclastic and osteoblastic
activity (Reddi and Cunningham, 1990). In prostate cancer, bone
metastases are predominantly blastic, which reflects a predominance of osteoblastic activity in the process of bone remodeling
(Roodman, 2004). This phenomenon may be due to specific
growth factor secretion that is responsible for the induction of
osteoblasts. Hypercalcemia is rare in metastatic prostate cancer. In
fact, a significantly elevated serum calcium concentration is most
frequently due to the neuroendocrine prostate cancer phenotype
and is mediated through PTHrP, as discussed earlier (diSant’Agnese,
1995; Nelson et al, 2007).
Bisphosphonates
Bisphosphonates have become an integral part of the
management of metastatic prostate cancer to the bones
(Van den Wyngaert et al, 2009). These compounds reduce bone
resorption by inhibiting osteoclastic activity and proliferation.
Zoledronate is a potent intravenous bisphosphonate first approved
for the treatment of hypercalcemia and decreased bone mineral
density in postmenopausal women (Green and Rogers, 2002). In
patients with progressive castration-refractory disease and bone
metastases zoledronate was shown to reduce the incidence of
skeletal-related events (e.g., pain, fractures) compared with placebo
in a prospective randomized trial of 422 patients (Saad et al, 2004).
In addition, zoledronate and pamidronate have also been shown
to increase mineral bone density in patients with nonmetastatic
prostate cancer receiving long-term androgen deprivation (Smith
et al, 2001, 2003). At present, zoledronate is indicated for the
treatment of patients with progressive prostate cancer with evidence of bone metastasis, and it is administered at a dose of 4 mg
intravenously repeated at intervals of 3 to 4 weeks for several
months. Side effects of this agent include fatigue, myalgias, fever,
anemia, and mild elevation of the serum creatinine concentration.
Hypocalcemia has been described, and concomitant use of oral
calcium supplements (1500 mg/day) and vitamin D (400 units/
day) is often recommended. An unusual complication of
zoledronate is the development of severe jaw pain associated with osteonecrosis of the mandibular bone. The etiology of this effect is not well understood. However, it is most
frequently seen in patients undergoing dental work or those with
a history of poor dentition and chronic dental disease. Zoledronate should not be administered to patients with these problems.
Other bisphosphonates have also been evaluated in prostate
cancer, including alendronate, etidronate, ibandronate, and clodronate; however, their benefit has not been conclusively established in prospective randomized clinical trials (Berry et al, 2006;
Van den Wyngaert et al, 2009).
RANKL Inhibitors
Interactions between tumor cells and the bone marrow microenvironment have been postulated as an additional important mechanism in the pathogenesis of bone metastasis. Tumor-associated
cytokines have been shown to induce the expression of RANKL
(the receptor activator of nuclear factor κB ligand), which binds
and activates RANK, which is found in osteoclasts (Brown et al,
2001). Inhibition of the RANKL system has recently been the focus
of much research and represents an evolving bone-targeted strategy. Among the approaches employed are monoclonal antibodies
to RANKL and the use of recombinant osteoprotegerin (the natural
decoy receptor of RANKL), both of which significantly inhibit
osteoclastic function in vitro and in vivo (Schwarz and Ritchlin,
2007). Denosumab, a fully human monoclonal antibody against
RANKL, has entered clinical trials in prostate and breast cancers.
In a phase 2 randomized study evaluating 50 patients with metastatic prostate cancer, denosumab (180 mg subcutaneously every
4 weeks) produced a reduction in bone resorption over that of
zoledronate, as indicated by a lowering of urinary N-telopeptide
levels, and also resulted in less skeletal-related events (Fizazi et al,
2009). Following from these encouraging results, a pivotal multicenter phase III double-blind randomized study was conducted
comparing denosumab against zoledronate for the prevention of
skeletal-related events in patients with bisphosphonate-naïve metastatic CRPC. In that trial of 1904 patients, compared to men
receiving zoledronate (n = 951), men receiving denosumab (n =
950) had an improved time to first skeletal-related events (20.7 vs.
17.1 months; P = .008) and longer time to first-and-subsequent
skeletal-related events (HR, 0.82; P = .004) (Fizazi et al, 2011).
Notably, there was no difference in overall survival or progressionfree survival between study arms. Based partially on the results of
this study (and partially on two other large randomized studies in
metastatic breast cancer and other solid metastatic tumors), the
FDA approved denosumab (Xgeva, Amgen, Thousand Oaks, CA)
in November 2010 for the prevention of skeletal-related events in
patients with bone metastases from solid tumors. Common toxicities of denosumab include fatigue, nausea, hypophosphatemia,
hypocalcemia (5% grade ≥3), and osteonecrosis of the jaw (2%),
and prophylactic calcium and vitamin D supplementation is
strongly encouraged. Therefore denosumab is a reasonable alternative to zoledronate for the prevention of skeletal-related events in
patients with metastatic CRPC, and also has the advantage that it
does not require dose adjustment or monitoring for renal impairment. The recommended dose of denosumab is 120 mg given by
subcutaneous injection every 4 weeks.
Radiopharmaceuticals
The introduction of “bone-seeking” radiopharmaceuticals has provided a useful resource for the management
of diffuse bone pain from widespread prostate cancer
metastases (Pandit-Taskar et al, 2004). Among the most commonly used compounds are strontium-89 (89Sr) (Porter et al, 1993)
and samarium-153 (153Sm) (Sartor et al, 2004). Rhenium-186 has
also been used (Kucuk et al, 2000). Initial studies with 89Sr have
shown palliation of bone pain in 25% to 65% of patients with
castration-refractory disease and diffuse pain (Jager et al, 2000).
The pharmacokinetics of 89Sr vary considerably according to the
extent of bone involvement, but the half-life is generally 4 to 5
days. The retention of the isotope is significantly longer in patients
with diffuse osteoblastic metastases compared with those with
relatively limited bone involvement. It is important to recognize
this factor because it will undoubtedly affect the degree and duration of myelotoxicity associated with this radioactive compound
(its most significant side effect). The clinical experience with
153
Sm suggests that this isotope is associated with a lower
incidence of severe myelotoxicity, probably because of
CHAPTER 110 ● Treatment of Castration-Resistant Prostate Cancer
its shorter half-life of 2 days. Encouraging results were
reported by Sartor and colleagues (2004) in a phase 3 trial comparing radioactive 153Sm and nonradioactive 152Sm, indicating that a
dose of 153Sm of 1 mCi/kg is both safe and effective palliation for
patients with castration-refractory disease and severe bone pain.
One study reported encouraging synergism with 89Sr and doxorubicin, a known and well-studied radiosensitizer (Tu et al, 2001).
Randomized studies evaluating the synergism of various chemotherapeutic agents, including taxanes, and radiopharmaceuticals
are being done.
Key Points: Palliative Management
l Patients
with back pain and a history of bone metastasis
should be aggressively evaluated for epidural cord compression. The clinical syndrome often has at least one of the
following signs and symptoms: back pain, focal neurologic
findings (leg weakness, sensory levels), or changes in bladder
or bowel control.
l Initial management of suspected cord compression includes
immediate magnetic resonance imaging of the spine and
high-dose intravenous corticosteroid therapy.
l Definitive therapy should include surgical decompression,
radiation therapy, or both.
l Zoledronic acid and denosumab are both reasonable treatment options for the prevention of skeletal-related events
in patients with castration-resistant bone metastases.
NOVEL APPROACHES
Rational Target Overview
An understanding of the basic biology involved of pathogenesis of prostate cancer provides the opportunity to
identify potential targets that predict the clinical
outcome of the disease. The first opportunity is the demonstration of a mutation or functional dysregulation of
the target. Simply targeting overexpressed proteins has
2965
been less efficient than the specific targeting of mutations that drive the bulk of the tumor growth. The
second goal is identifying target causality, indicating the
importance of the target alone or in combination with
other mutations in reproducing the phenotypic findings
of prostate cancer. Finally, there should be evidence from
preclinical models that inhibition of the target leads to
tumor regression or quiescence. In prostate cancer, the
androgen receptor is one potential target although there
are many others. Various molecular changes in the
androgen receptor have been shown to parallel disease
progression in castrate patients and in some situations
may provide the explanation for the responses associated with some therapeutic maneuvers (antiandrogen
withdrawal syndrome, responses to secondary endocrine
manipulations with compounds designed to bind to the
receptor). Despite this, a precise role of the androgen
receptor in the pathogenesis of disease progression
remains to be better elucidated. Given the molecular complexity of the prostate cancer cell pathways and relatively poor
understanding of the role of individual pathways in the process
of disease-specific progression, the simultaneous inhibition of
multiple pathways remains a common strategy to induce sustained and clinically meaningful responses in prostate cancer.
The major biologic processes under therapeutic investigation in
prostate cancer involve growth and survival, chemotherapy and
hormone therapy resistance, extragonadal androgen production,
modulation of the androgen receptor, angiogenesis, the bone
interface, epigenetic regulation, immune surveillance and escape,
and stem cell renewal. This section provides an overview of these
pathways as they pertain to prostate cancer rational targets and
the approaches that are currently being developed for therapeutic
purposes (Table 110–7).
Targeted Treatments
Although a prostate cancer stem cell has yet to be conclusively
demonstrated, prostate cancer clearly progresses from an androgendependent tumor with features similar to the luminal
Table 110–7. Targeted Therapies for Castration-Resistant Prostate Cancer (CRPC): Selected Ongoing Clinical Trials
TARGET
AGENT
PI3K/mTOR
EGFR/HER2
PDGFR
Vitamin D
HDAC
Everolimus
Lapatinib
Imatinib
Calcitriol
Vorinostat
Panobinostat
Atrasentan
Zibotentan
Denosumab
Bevacizumab
Sorafenib
Sunitinib
Vatalinib
Abiraterone
MDV3100
Sipuleucel-T (Provenge)
GVAX
Endothelin receptor
RANK ligand
VEGF
VEGF receptor
CYP17
Androgen receptor
Immunotherapy
CTLA-4
Ipilimumab
PHASE
2
2
2
3
2
2
3
3
3
3
2
2
2
3
1/2
3
3
3
SUMMARY OF TRIAL
Docetaxel + everolimus for first-line metastatic CRPC
Single-agent lapatinib for nonmetastatic CRPC
Docetaxel ± imatinib for first-line metastatic CRPC
Docetaxel ± calcitriol for first-line metastatic CRPC
Single-agent vorinostat for second-line metastatic CRPC
Single-agent panobinostat for second-line metastatic CRPC
Docetaxel ± atrasentan for first-line metastatic CRPC
Docetaxel ± zibotentan for first-line metastatic CRPC
Denosumab vs. zoledronate for palliation in metastatic CRPC
Docetaxel ± bevacizumab for first-line metastatic CRPC
Docetaxel + sorafenib for first-line metastatic CRPC
Docetaxel + sunitinib for first-line metastatic CRPC
Single-agent vatalinib for nonmetastatic CRPC
Single-agent abiraterone for second-line metastatic CRPC
Single-agent MDV3100 for nonmetastatic/metastatic CRPC
Sipuleucel-T vs. placebo for first-line metastatic CRPC
GVAX vs. docetaxel for first-line metastatic CRPC
Docetaxel ± GVAX for first-line metastatic CRPC
Ipilimumab vs. placebo for second-line metastatic CRPC
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SECTION XVI ● Prostate
differentiated glands of the prostate to a castration-refractory
tumor that has features of adult stem cells, including antiapoptotic
mechanisms, chemotherapy resistance, and reliance on nonhormonal signaling pathways. Candidate pathways currently
evaluated include hedgehog signaling, epidermal growth
factor receptor (EGFR) signaling, phosphatidylinositol
3-kinase (PI3K)/Akt signaling, mitogen-activated protein
kinase (MAPK) signaling, and others (see Table 110–7). Activation of the hedgehog developmental pathway has been demonstrated in prostate cancer metastases and in preclinical models,
and inhibition of this pathway has led to antitumor effects and
significant inhibition of prostatic epithelial regeneration after
androgen withdrawal. Inhibitors of this pathway, such as
cyclopamine analogues and other agents, are in preclinical
development.
PI3K/Akt/mTOR Pathway
In advanced prostate cancer, loss of the tumor suppressor PTEN (phosphatase and tensin homologue deleted on
chromosome 10) occurs in more than 50% of metastatic
lesions and in approximately 20% of locally advanced
lesions (McMenamin et al, 1999; Graff, 2002). Loss of PTEN
correlates with advanced Gleason sum, stage, chemotherapy resistance, and other features of advanced prostate cancers (McMenamin et al, 1999). PTEN is a negative
regulator of the PI3K/Akt survival pathway, and
advanced prostate cancers frequently have elevated
levels of phosphorylated (activated) Akt (Gera et al, 2004).
The Akt pathway is involved in signal transduction from multiple
cell surface receptors, including the insulin receptor, epidermal
growth factor receptor, insulin-like growth factor receptor, plateletderived growth factor receptor, and interleukin-6 receptor, and it
is likely to function as a cellular sensor for nutrient and growth
signals (Vivanco and Sawyers, 2002). In addition to promoting cell
survival through the inhibition of apoptosis, the Akt pathway
regulates cell growth, proliferation, and angiogenesis through the
mammalian target of rapamycin (mTOR) pathway and the facilitated translation of signals such as c-MYC, cyclin D, and vascular
endothelial growth factor (Gera et al, 2004). Restoration of functional PTEN activity or inhibition of mTOR activity can block the
growth of PTEN−/− prostate cancer xenografts and restore chemotherapy and possibly hormonal sensitivity (Neshat et al, 2001;
Podsypanina et al, 2001; Grunwald et al, 2002).
Rapamycin is a natural compound derived from soil samples
containing the bacterium Streptomyces hygroscopicus. It was initially
discarded as an antifungal agent because of its immunosuppressive
properties but later revived as a potent immunosuppressive agent
for use in solid organ transplantation. Its antiproliferative properties and antitumor activity in cell lines led to its clinical development in cardiology as a means of preventing stent restenosis and
in oncology, in which a wide variety of tumors were found to
exhibit sensitivity to this agent and its analogue temsirolimus
(Hidalgo and Rowinsky, 2000; Bjornsti and Houghton, 2004). Toxicities with rapamycin and its analogues have been predictable
and often not dose related; they include maculopapular rash,
hypertriglyceridemia, hyperglycemia, allergic reactions, pedal
edema, mucositis, and thrombocytopenia (Hidalgo and Rowinsky,
2000; Atkins et al, 2004; Raymond et al, 2004). The combination
of these agents with docetaxel is attractive, given their ability to
induce apoptosis when they are given in combination with chemotherapy in patients who have demonstrable activation of the
Akt pathway as a result of PTEN mutation or loss or other genetic
alterations. For example, a new mTOR inhibitor, everolimus
(RAD001), is being evaluated in combination with docetaxel as
first-line treatment for metastatic CRPC in a phase 1/2 trial (Ross
et al, 2008).
EGFR and PDGFR Pathways
The rapid development in the past several years of small molecules
that inhibit tyrosine kinases has yielded encouraging results in a
host of cancers. Demonstration of tumor response has usually
correlated with mutation in the target tyrosine kinase, such as
epidermal growth factor receptor (EGFR), BCR-ABL, and c-KIT. In
these cases the target mutation has played a central role in the
pathogenesis of these tumors. In prostate cancer, no such mutation has been identified, and early trials of tyrosine kinase inhibitors in prostate cancer have been disappointing.
EGFR is overexpressed in 40% to 80% of prostate
cancer cells, and overexpression may be more common
in African-American men with prostate cancer (Shuch
et al, 2004). Furthermore, preclinical data suggested a correlation
of EGFR expression with Gleason sum and androgen independence (Syed, 2003). In a phase 2 study of approximately 100
patients with castrate-resistant disease evaluating the EGFR tyrosine kinase inhibitor gefitinib, minimal activity and no PSA
responses were reported (Moore et al, 2002; Schroder and Wildhagen, 2004). Gefitinib resistance may be related to overactivity
of the PI3K/Akt pathway in prostate cancer, and thus combinations of agents that target multiple pathways may be more beneficial (She et al, 2003). Further trials of combination EGFR or dual
kinase inhibitors with chemotherapy or other novel agents are in
development.
Prostate cancer cells express high levels of plateletderived growth factor receptor (PDGFR), and this signaling pathway uses the PI3K/Akt pathway, which has been
implicated in prostate cancer progression. Single-agent
activity with imatinib has been disappointing; however,
encouraging results in combination with weekly doceta­
xel have been reported. A phase 2 randomized trial
of this combination compared with docetaxel alone is in
progress.
Another potential target in this family of receptors is the HER2/
neu tyrosine kinase, whose expression has been shown to increase
androgen receptor activation leading to prostate cancer growth
and survival (Gregory et al, 2005). However, phase 2 studies using
the anti-HER2 monoclonal antibody trastuzumab showed minimal
efficacy in CRPC, perhaps owing to a low frequency of HER2
overexpression (Ziada et al 2004). Studies using the dual EGFR/
HER2 small molecule inhibitor lapatinib for asymptomatic CRPC
are now being conducted.
Vitamin D Analogues
Vitamin D analogues may have differentiation, antiproliferation,
and chemosensitizing properties, and epidemiologic studies have
shown an increased risk of prostate cancer in those with relative
vitamin D deficiency. A phase 2 trial of weekly docetaxel and highdose calcitriol demonstrated PSA responses in 30 of 37 patients
(80%) and measurable responses in 8 of 15 (53%), with a median
time to progression of 11.4 months and median survival of 19.4
months (Beer et al, 2005). A randomized study with a total
of 250 patients (125 per study arm) comparing the combination with docetaxel alone resulted in more than
50% decline of PSA level in 63% of the patients receiving
the combination treatment compared with 52% with
docetaxel alone (P = .07). However, interestingly, the
authors reported a survival difference in favor of the
CHAPTER 110 ● Treatment of Castration-Resistant Prostate Cancer
combination (23.4 vs. 16.4 months; P = .03). These results
led to the design of a large phase 3 placebo-controlled trial in
metastatic CRPC evaluating docetaxel chemotherapy with or
without calcitriol, with power to detect a survival benefit as the
primary end point. However, early reports from this trial have
shown that the primary end point was not met and that mortality
was increased in the calcitriol groups, leading to premature closure
of the study (Novacea, Inc., 2007).
Bone Interface
Preclinical studies suggest that endothelin A receptors
are overexpressed in prostate cancer, and higher plasma
endothelin levels in patients with prostate cancer have
been shown to correlate with tumor stage, grade, and
metastases. Endothelin-1 is a potent vasoconstrictor, and antagonists have been developed for the treatment of pulmonary hypertension. In oncology, endothelin is likely to be involved in the
paracrine signals between osteoblasts and prostate cancer cells that
regulate the development of bone metastases and have been
shown to influence cell growth and proliferation, regulate osteoblast activity, and inhibit apoptosis. These preclinical observations
suggest that this pathway may be a rational target for the interference of tumor-stromal interactions (Nelson JB et al, 2003;
Carducci et al, 2002; Yin et al, 2003).
Atrasentan is a highly selective endothelin A receptor
antagonist and has been extensively tested in prostate
cancer. In preliminary phase 2 trials, a 10-mg dose of
atrasentan was found to prolong time to progression
compared with placebo in men with metastatic CRPC
(196 vs. 129 days, respectively; P = .02) (Carducci et al, 2003).
Adverse events with atrasentan were mild and related to
vasomotor reactions, including headache, rhinitis, flushing, and peripheral edema. In addition, favorable effects
were seen in markers of bone deposition and resorption.
However, in a placebo-controlled double-blind phase 3 trial
involving 809 patients with metastatic CRPC, oral atrasentan
(10 mg/day) did not reduce the risk of disease progression
(P = .14), despite evidence of biologic affects on PSA and bone
alkaline phosphatase (Carducci et al, 2007). A second phase 3 trial
in nonmetastatic CRPC that randomized 467 men to atrasentan
and 474 to placebo also failed to improve time to metastatic progression (P = .29) or overall survival (Nelson et al, 2008). A large
cooperative group phase 3 clinical trial evaluating docetaxel plus
or minus atrasentan as first-line therapy for metastatic CRPC is in
progress.
A novel small molecule endothelin receptor inhibitor, zibotentan (ZD4054), has shown initial promising results. In a phase 2
trial of zibotentan versus placebo in men with metastatic CRPC,
this agent did not improve time to disease progression (the primary
study end point; P = .55); however, overall survival was longer in
the zibotentan group (P = .01) (James et al, 2009). Although survival was a secondary end point, this has led to the design of
several ongoing placebo-controlled phase 3 clinical trials evaluating zibotentan either alone or in combination with docetaxel in
patients with metastatic CRPC.
Angiogenesis Targets
Tumor angiogenesis is likely to be an important biologic
component of prostate cancer metastasis, and elevated
levels of the potent angiogenic molecule vascular endothelial growth factor (VEGF) have been shown to correlate with advanced clinical stage and survival (Duque
et al, 1999; George et al, 2002).
2967
In a retrospective study of archived serum samples, VEGF levels
were independently associated with survival from prostate cancer
(George et al, 2001). Similarly, antibodies to VEGF have slowed
prostate xenograft growth rates, especially in combination with
chemotherapy (Fox et al, 2002; Sweeney et al, 2002). These findings led to the phase 2 CALGB 90006 trial, which added bevacizumab to docetaxel and estramustine in men with metastatic
CRPC. Among 79 treated patients in this study a decline of more
than 50% in PSA level was seen in 65% of men, median time to
progression was 9.7 months, and overall median survival was
21 months (Picus et al, 2003). Other phase 2 trials combining
docetaxel and bevacizumab have also shown promising results
(Ryan et al, 2006; Di Lorenzo et al, 2008). These favorable trials
have led to the design of a phase 3 randomized study (CALGB
90401) evaluating docetaxel 75 mg/m2 every 3 weeks and prednisone 10 mg daily plus either bevacizumab 15 mg/kg or placebo
given every 3 weeks. The primary end point of this trial is overall
survival, and accrual of 1020 patients with metastatic CRPC has
been completed.
Thalidomide was originally developed in the 1960s for treatment of morning sickness and subsequently linked to teratogenic
effects resulting in phocomelia and dysmelia. Whereas the exact
mechanism of teratogenesis is unproven, the metabolites of thalidomide have been shown to inhibit angiogenesis through multiple potential mechanisms, including inhibition of proangiogenic
signals such as VEGF, basic fibroblast growth factor (bFGF),
interleukin-6, and tumor necrosis factor-α (Bartlett et al, 2004;
Franks et al, 2004). Preclinical studies suggest that thalidomide has
T-cell costimulatory activity and immunomodulatory properties
as well. Phase 1/2 studies with high doses of thalidomide as a
single agent have yielded low response rates on the order of 20%
for PSA declines (Figg et al, 2001; Franks et al, 2004). However, in
a randomized phase 2 trial of weekly docetaxel and low-dose thalidomide versus docetaxel alone, PSA responses, time to disease
progression, and overall survival were greater in the combination
therapy group (Dahut et al, 2004). Although this trial was underpowered to detect a difference from the standard study arm, the
clinical activity and manageable toxicity of this agent have led to
the development of more potent thalidomide analogues for combination therapy, and these are currently undergoing clinical
evaluation. In a recent phase 2 trial using a three-drug combination of docetaxel, thalidomide, and bevacizumab, PSA responses
were seen in approximately 80% of patients (Ning et al, 2008).
However, neurotoxicity was a significant side effect with this
regimen.
Toxicities with thalidomide include deep venous thrombosis,
sedation, neuropathy, constipation, and fatigue. Newer thalidomide analogues with immunomodulatory features have been
developed that lack the neurotoxicity of thalidomide but retain
many of the T-cell modulatory functions, antiangiogenic properties, and even direct pro-apoptotic functions (Bartlett et al, 2004).
Lenalidomide and CC-4047 are second-generation compounds
with much more potent tumor necrosis factor-α inhibition than
the parent compound, and clinical testing with these agents has
begun. For example, several phase 1 and 2 studies have revealed
PSA responses and partial radiologic responses with lenalidomide,
both when used alone and when combined with ketoconazole or
docetaxel (Dreicer et al, 2007; Moss et al, 2007; Garcia et al, 2008).
Phase 3 trials using thalidomide or lenalidomide in CRPC have
not yet been conducted.
There has been a recent interest in the evaluation of tyrosine
kinase inhibitors (TKIs), agents that block angiogenic growth
factor targets such as the VEGF and PDGF receptors. The drug
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SECTION XVI ● Prostate
sorafenib is an oral inhibitor of RAF kinase, VEGFR, and PDGFR,
which has been approved for use in metastatic renal cell carcinoma. In phase 2 studies using sorafenib in men with metastatic
CRPC, this agent was shown to prevent radiologic progression and
cause regression of bone metastases in some patients, but without
affecting PSA levels (Dahut et al, 2006; Aragon-Ching et al, 2008).
To conclusively evaluate the efficacy and safety of abiraterone,
a pivotal multicenter placebo-controlled blinded randomized
phase III trial (COU-AA-301) was conducted in men with docetaxelpretreated ketoconazole-naïve metastatic CRPC (de Bono et al,
2011). This trial randomized men (2 : 1) to receive either abiraterone 1000 mg daily plus prednisone 10 mg daily (n = 797) or
placebo plus prednisone (n = 398). The trial met its primary endpoint, demonstrating a median overall survival of 14.8 months in
the abiraterone arm and 10.9 months in the placebo arm (HR,
0.65; P < .0001). In addition, when compared to placebo, abiraterone prolonged radiographic progression-free survival (5.6 vs.
3.6 months; P < .0001), improved time to PSA progression (10.2
vs. 6.6 months; P < .0001), and produced more PSA responses (38%
vs. 10%; P < .0001). Notably, the overall survival duration seen
here (14.8 months) is similar to that of cabazitaxel/prednisone
(15.1 months) in this second-line population with similar baseline
characteristics, while the survival of men treated with prednisone
alone was slightly inferior to that of mitoxantrone/prednisone in
the TROPIC trial (10.9 vs. 12.7 months). Based on the results of
the COU-AA-301 trial, the FDA approved abiraterone acetate
(Zytiga, Janssen Biotech, Horsham, PA) in April 2010 for the treatment of patients with metastatic CRPC who have received prior
docetaxel chemotherapy. The recommended dose of abiraterone
is 1000 mg daily by mouth. A second randomized phase III trial
(COU-AA-302) targeting men with docetaxel- and ketoconazolenaïve CRPC has completed accrual of over 1000 patients. Given
the comfort level and safety of using this and other hormonal
agents in prostate cancer patients prior to chemotherapy, it is very
likely that abiraterone will be used clinically in both the predocetaxel and postdocetaxel settings.
CYP17 System
It has recently been recognized that the androgen receptor and
ligand-dependent androgen receptor signaling commonly remain
active and upregulated in men with castrate levels of testosterone
(i.e., <50 ng/dL) (Debes and Tindall, 2004). Standard hormonal
therapies inhibit gonadal androgenesis but do not affect androgen
synthesis from adrenal or other extragonadal sources that may
account for 5% to 10% of total androgen production. It has also
been suggested that CRPC itself may produce intratumoral androgens autonomously (Mostaghel et al, 2007). In addition, overexpression of CYP17 has been demonstrated in tumors of men with
CRPC (Stigliano et al, 2007). The novel agent abiraterone acetate
is an oral selective inhibitor of the microsomal enzyme cytochrome P17 (17,20-lyase and 17α-hydroxylase) that is a key
regulator of adrenal androgen synthesis. Phase 1/2 studies using
abiraterone in men with CRPC (both before and after docetaxel)
have shown a substantial number of PSA responses (PSA declines
≥ 50%) and also some partial radiologic responses in men with
bony and visceral metastases (Attard et al, 2008; Danila et al,
2008). Common side effects of this agent include hypokalemia,
hypertension, and pedal edema. These effects are explained by a
syndrome of secondary mineralocorticoid excess, which improves
with use of the mineralocorticoid receptor antagonist eplerenone.
Phase 3 randomized studies of abiraterone plus docetaxel in firstline metastatic CRPC, and abiraterone used alone in the docetaxelrefractory setting, are being conducted.
Androgen Receptor Modulation
A slightly different androgen receptor (AR)-directed approach has
focused on the development of second-generation antiandrogens
that have advantages over the established agents in this class
(bicalutamide, nilutamide, flutamide). One such drug is MDV3100,
a potent oral nonsteroidal AR antagonist (Chen et al, 2009).
Importantly, MDV3100 remains a potent antagonist of the AR in
the castration-resistant state, even in the setting of overexpressed
or constitutively activated AR (Watson et al, 2010). In addition,
unlike other antiandrogens that may also function as partial AR
agonists, MDV3100 does not exhibit any measurable agonistic
activity and is able to prevent AR nuclear translocation with resultant tumoricidal (not cytostatic) activity (Tran et al, 2009). Notably,
recent studies have demonstrated the emergence of ligand-independent AR splice variants in CRPC, some of which may also be
inhibited by MDV3100.
A pivotal placebo-controlled double-blind phase III study
(AFFIRM), randomizing 1170 patients with docetaxel-pretreated
ketoconazole-naïve CRPC to MDV3100 160 mg daily (n = 780) or
placebo (n = 390), has now completed accrual. A second randomized phase III trial (PREVAIL) investigating the same treatment
arms in men with chemotherapy-naïve CRPC is currently underway. One advantage of MDV3100 over agents such as abiraterone
is the lack of requirement for concurrent corticosteroid administration. However, the optimal sequencing of this agent, if approved,
with immunotherapies and other emerging hormonal therapies
will need to be defined through future clinical trials.
A phase I/II study of oral MDV3100 in men with chemotherapynaïve (n = 65) or taxane-pretreated (n = 75) metastatic CRPC has
recently been published (Scher et al, 2010). In that trial, ≥50% PSA
declines were seen in 62% and 51% of chemotherapy-naïve and
taxane-pretreated patients, respectively; objective tumor responses
were observed in 36% and 12% of men, respectively. Radiographic
progression-free survival was 6.7 months in the docetaxel-pretreated patients and >17 months in chemotherapy-naïve patients.
Side effects of MDV3100 are generally mild and include fatigue
(27%) and nausea (9%). Rare seizures (3/140 patients) have also
been reported, perhaps mediated by a direct effect of AR antagonism on central nervous system GABA-A receptors.
Epigenetic Approaches
Histone deacetylases (HDACs) are key regulators of histone acetylation status, which is critical for AR-mediated transcriptional
activation of genes implicated in the regulation of cell survival,
proliferation, differentiation, and apoptosis. Vorinostat is a potent
oral HDAC inhibitor that has shown antitumor activity in prostate
cancer cell lines and animal models (Welsbie et al, 2009). This
agent has previously been approved for the treatment of cutaneous T-cell lymphoma. However, a phase 2 study of vorinostat in
the second-line treatment of men with CRPC that had progressed
on docetaxel did not show significant PSA or radiologic responses
and was associated with a high frequency of grade 3/4 adverse
events, which included fatigue, nausea, anorexia, vomiting, diarrhea, and weight loss (Bradley et al, 2008). A novel oral HDAC
inhibitor, panobinostat (LBH589), is currently in phase 1 development as an adjunct to docetaxel in first-line CRPC (Rathkopf et al,
2008).
Immunotherapy
Entraining the immune system to overcome tumor-induced tolerance is the goal of nearly every cancer vaccine program, and
CHAPTER 110 ● Treatment of Castration-Resistant Prostate Cancer
active immunotherapy with vaccination against tumor antigens
has been pursued in many different cancer models. A variety of
approaches have been employed, including dendritic cell-based
therapies; novel adjuvants such as bacille Calmette-Guérin (BCG),
granulocyte-monocyte colony-stimulating factor (GM-CSF), and
viral carriers; single-antigen or whole cell vaccines; and genetically
modified tumors. More recently, combination therapies using
costimulatory molecules, CTLA-4 blockade, Toll-like receptor
agonism, and intracellular viral or bacterial mediators have been
developed (Pardoll, 1992; Blattman et al, 2002; Mapara and Sykes,
2004; Harzstark and Small, 2009).
In prostate cancer, several immunologic strategies have been
under clinical development. The most important of these
include the sipuleucel-T (Provenge) autologous prostatic acid
phosphatase (PAP)-loaded dendritic cell vaccine, the GVAX allogeneic recombinant whole cell vaccine, and CTLA-4 inhibitory
approaches. Less successful strategies have included the Prostvac-VF
recombinant pox viral PSA vaccine and the BLP25 MUC1 liposomal vaccine, among many others. Each of these vaccines is
designed to stimulate the immune system to recognize a previously tolerance-inducing tumor in a cancer-specific way (Webster
et al, 2005).
Sipuleucel-T
Sipuleucel-T (Provenge) is a vaccine derived from CD54+ dendritic
cells, the major antigen-presenting cells, which are apheresed
from individuals and processed with the recombinant fusion
protein PAP and GM-CSF. PAP was chosen on the basis of its prostate cell membrane localization and the success of preclinical
models using it to generate prostate-specific immune responses
and autoimmune prostatitis. Modest activity was reported in
phase 2 trials in patients with CRPC. In a randomized phase 2/3
trial comparing sipuleucel-T against placebo in 127 asymptomatic
men with metastatic CRPC (PAP positive), the investigators
reported no significant differences in time to disease and pain
progression (P = .052), which corresponded to the main study end
point (Small et al, 2006). Patients randomized to placebo were
crossed over to receive the active vaccine at the time of progression, whereas those initially randomized to receive the active
vaccine were treated at their physician’s discretion at the time of
progression. This postprogression management period was not
part of the study and not prospectively controlled. Whereas the
study as designed was negative, a 3-year update suggested a statistically significant improvement in survival for those randomly
assigned to receive the active vaccine initially (P = .01). It is highly
probable that survival differences were due to postvaccine treatments. Post hoc analyses also suggested that the benefits of
sipuleucel-T may be limited to the subgroup of men with tumor
Gleason sums of 7 or lower. Although preparation and production
of large-scale quantities of individually tailored vaccine can be
challenging, this vaccine was well tolerated with minimal infusionrelated fevers and rigors being the predominant adverse events
(Small et al, 2006).
A second phase 2/3 trial that randomized 98 men with asymptomatic CRPC to either sipuleucel-T or placebo also failed to show
a statistically significant improvement in time to progression
(the primary end point) but, unlike the previous study, did not
demonstrate an overall survival advantage at 3 years (P = .33)
(Dendreon, Inc., 2005). A post-hoc pooled analyses of these two
trials (n = 225) did show an overall survival advantage, with
median survival being 18.9 months in the placebo group and
23.2 months in the sipuleucel-T group (HR, 1.5; P = .01) (Dendreon, Inc., 2005). However, because overall survival was not the
2969
primary end point in either trial, the FDA did not grant approval
of this treatment.
In an effort to satisfy FDA requirements, a pivotal multicenter
double-blind placebo-controlled randomized phase III trial
(IMPACT) was conducted in men with asymptomatic or minimally
symptomatic metastatic CRPC (Kantoff et al, 2010), leading to the
FDA-approval of this agent in April 2010. In this trial, 512 patients
were randomized (2 : 1) to sipuleucel-T or placebo and the study
was powered to detect an overall survival advantage. Notably, this
study did not enroll men with visceral metastases or those taking
narcotics for cancer pain, and most patients (85%) were chemotherapy-naïve. Impressively, median overall survival was 25.8
months in the sipuleucel-T group versus 21.7 months in the
placebo group (HR, 0.78; P = .03), despite 64% of patients on
placebo crossing over to receive salvage sipuleucel-T. In the subset
of patients with prior chemotherapy exposure, overall survival
trended in favor of sipuleucel-T, but this effect was not statistically
significant. Therefore, although this immunotherapy is approved
for all patients with asymptomatic or minimally symptomatic
CRPC, it will likely have its largest impact in the prechemotherapy
setting.
Similar to previous studies with sipuleucel-T, the IMPACT study
found no difference in progression-free survival or PSA/radiographic response rates between the two treatment arms. Some
investigators attribute the discordance between progression-free
and overall survival to a possible class effect of immunotherapy
agents, relating to their mechanism of action which is distinct
from cytotoxic therapies. Problematic endpoints such as progression-free survival in CRPC (which may be confounded by bone
scan flare or delayed-onset effects) may perhaps be better addressed
by revised guidelines using outcomes that are tailored to immunologic agents (Hoos et al, 2010).
GVAX
Prostate GVAX is based on the demonstration in mouse melanoma
models of improved tumor rejection when the irradiated tumor
vaccine expressed the cytokine GM-CSF compared with other
cytokine adjuvants (Dranoff et al, 1993; Dranoff, 2003). This form
of immunotherapy uses inactivated allogeneic prostate cancer cell
lines (PC3 and LNCaP) that have been modified through adenoviral transfer to secrete GM-CSF and irradiated to prevent further
cell division (Ward and McNeel, 2007). The advantage with this
approach is that the vaccine can be manufactured in large quantities and that multiple tumor antigens can be targeted simultaneously. However, because of the relative weakness of individual
antigens, repeated intradermal dosing is necessary.
Two uncontrolled single-arm phase 2 studies in men with
asymptomatic metastatic CRPC have shown antitumor effects of
prostate GVAX, one demonstrating an overall survival of 26.2
months (n = 34) and the other showing an overall survival ranging
from 20.0 to 29.1 months (n = 80) depending on dosing regimen
(Small et al, 2007; Higano et al, 2008). In both studies the proportion of patients who generated an antibody response to one or
both cell lines increased with the dose of vaccine given, and no
dose-limiting or autoimmune toxicities were seen. The most
common adverse events in both studies were injection-site erythema, fatigue, malaise, myalgias, and arthralgias.
Based on these promising findings, two large randomized
phase 3 studies of GVAX immunotherapy (VITAL-1 and VITAL-2)
were designed. VITAL-1 involved 626 men with asymptomatic
chemotherapy-naive CRPC and randomized them to GVAX or
docetaxel/prednisone, with the primary end point being overall
survival. VITAL-2 was planned initially to enroll 600 patients with
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SECTION XVI ● Prostate
symptomatic metastatic CRPC, randomizing them to docetaxel/
prednisone or docetaxel/GVAX. Both trials were terminated early
because of data observed at the time of interim analyses, suggesting that the survival improvements initially hypothesized were
unlikely to be observed if the trials were to be continued (Higano
et al, 2009). Moreover, in the VITAL-2 study, mortality was higher
in patients on the experimental arm receiving docetaxel/GVAX
(Small et al, 2009).
CTLA-4 Inhibition
Due to ongoing host immunologic pressures on evolving tumors,
cancers have developed mechanisms to escape immune surveillance, effectively inducing a state of immune tolerance (Drake
et al, 2006). One way to inhibit immunologic evasion by tumor
cells is through blockade of the immune checkpoint molecule
CTLA-4 (cytotoxic T lymphocyte-associated antigen-4), thus preventing the normal attenuation of antitumor T-cell responses
(Hodi, 2007). In murine prostate cancer models, CTLA-4 inhibition has been shown to potentiate T-cell effects and induce tumor
rejection.
Several clinical trials using the monoclonal anti-CTLA-4 antibody, ipilimumab, have been conducted in men with metastatic
CRPC. These include phase I and II studies of ipilimumab monotherapy or in combination with radiation (Small et al, 2007), as
well as a phase I study combining ipilimumab with GM-CSF (Fong
et al, 2009). Encouragingly, ≥50% PSA reductions have been
observed in about 20% of patients, and radiologic tumor responses
were seen in about 5% of men, which is particularly noteworthy
given that PSA and tumor responses were rarely reported in the
immunotherapy trials with sipuleucel-T or other therapeutic vaccines. Common side effects of ipilimumab include fatigue (42%),
nausea (35%), pruritus (24%), constipation (21%), and rash (19%).
In addition, because CTLA-4 normally serves to attenuate autoimmunity, immunologic toxicities resulting from an unchecked
immune response may occur. Such immune-related adverse events
include colitis (8%), adrenal insufficiency (2%), hepatitis (1%),
and even hypophysitis (1%) (Dillard et al, 2010). Ipilimumab is
now in placebo-controlled phase 3 testing in the postdocetaxel
setting in men with CRPC following a palliative and perhaps
immune-stimulatory dose of radiation to a metastatic site, with
the intent to demonstrate a survival advantage over radiation
alone. A second predocetaxel placebo-controlled study is also
underway.
Key Points: Novel Approaches
l Sipuleucel-T
is the first therapeutic vaccine to be FDAapproved for the treatment of any cancer and is indicated
for use in men with asymptomatic or minimally symptomatic metastatic CRPC.
l Abiraterone acetate is a novel androgen biosynthesis inhibitor that has gained FDA approval for the treatment of
patients with metastatic CRPC who have previously received
docetaxel chemotherapy.
CONCLUSIONS
With more drugs at our fingertips for the treatment of metastatic
CRPC than ever before, and an increasing number of novel therapeutic targets being discovered every day, we are still left with
several challenges and unanswered questions. First, we must determine how these approved and experimental therapies should
ideally be sequenced in individual patients with CRPC. For
example, should sipuleucel-T routinely be given prior to chemotherapy or abiraterone with prednisone? Should abiraterone be
reserved only for docetaxel-resistant patients? How should we
treat cabazitaxel-refractory patients? Second, we will need to
develop strategies to optimally combine these drugs in a rational
manner, taking advantage of our understanding of negative feedback loops and alternative pathway activation to overcome resistance to monotherapies. Ultimately, only prospective trials
incorporating biomarker-driven hypotheses will be able to address
these key clinical questions. Thus the collection of tumor specimens or correlative samples may be essential in identifying novel
targets or developing enrichment strategies for future study of
these agents. Third, we must design smarter trials with the goal of
quickly yet reliably identifying agents that do not hold promise,
while enabling those that do to move swiftly to registrational
studies. For example, in the clinical development of MDV3100
and cabazitaxel, pivotal phase III trials were designed directly following the initial phase I/II studies that demonstrated significant
drug activity in men with CRPC. Finally, we must select our
patients more carefully based on clinical or molecular characteristics, in order to identify the subset most likely to benefit from a
particular therapy. For example, in men with significant pain,
perhaps sipuleucel-T is not appropriate systemic therapy given the
prolonged onset of action and lack of palliative benefits; additionally, immune-based biomarkers may shed light on which men may
obtain a greater degree of benefit from immunotherapies. Several
active agents are currently in phase III development, and some of
these therapies are also likely to further expand our therapeutic
arsenal for men with metastatic CRPC in the near future.
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