Download new alternatives for the management of patients with hormone

REVIEW
NEW ALTERNATIVES FOR THE MANAGEMENT OF PATIENTS WITH
HORMONE-REFRACTORY PROSTATE CANCER
—
Joel B. Nelson, MD,* Philip W. Kantoff, MD,† A. Oliver Sartor, MD,‡ and Daniel P. Petrylak, MD§
ABSTRACT
Nearly all men receiving androgen deprivation therapy for metastatic prostate cancer will
ultimately manifest evidence of disease progression, thus requiring a re-evaluation of treatment
strategy. Treatment alternatives for men with hormone-refractory prostate cancer (HRPC) have
been limited to palliative care in the absence of a
survival advantage associated with chemotherapy. In 2004, docetaxel-based chemotherapeutic
regimens, now the standard for HRPC, were
shown to confer a significant survival advantage
in 2 large, randomized, controlled phase III trials. Bone-targeted therapies, specifically
endothelin-A receptor antagonists (eg, atrasentan), bone-targeted radiopharmaceuticals, and
bisphosphonates (eg, zoledronic acid), directly
address the bone-stromal interactions underlying
painful bone metastases. Atrasentan potentially
reduces the incidence of and delays time to the
onset of bone pain, may delay time to disease
progression, and may improve the quality of life
in patients with HRPC. Zoledronic acid was
shown, in a phase III trial, to decrease the incidence of skeletal-related events and prolong the
*Professor and Chairman of Urology, University of
Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
†Director, The Lank Center for Genitourinary Oncology;
Chief, Division of Solid Tumor Oncology, Dana-Farber
Cancer Institute; Professor of Medicine, Harvard University
Medical School, Boston, Massachusetts.
‡Director, Stanley S. Scott Cancer Center; Chief,
Hematology/Oncology, Louisiana State University Health
Sciences Center New Orleans, New Orleans, Louisiana.
§Associate
Professor of Medicine, New York
Presbyterian Hospital, Columbia University Medical Center,
New York, New York.
Address correspondence to: Joel B. Nelson, MD, Professor
and Chairman of Urology, University of Pittsburgh School of
Medicine, 5200 Center Avenue, Pittsburgh, PA 15232.
Email: [email protected].
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time to a first skeletal-related event in men with
HRPC. Bone-targeted radiopharmaceuticals have
been shown in phase III trials to decrease bone
pain and decrease opioid utilization in patients
with bony metastatic disease. Clinical trials are in
progress to identify novel agents, in addition to
optimize the combination of chemotherapeutic,
bone-targeted agents and immunologic approaches. A wide variety of novel approaches, including
immunologic therapies, are being tested.
(Adv Stud Med. 2006;6(4C):S300-S312)
HORMONE-REFRACTORY PROSTATE CANCER:
A CLINICAL DEFINITION
Hormone-refractory prostate cancer (HRPC), also
referred to as androgen-independent prostate cancer
(AIPC) or postcastration progressive prostate cancer, is
typically characterized by successive rises in prostate-specific antigen (PSA) levels within the setting of serum castrate testosterone levels (<50 ng/mL). The European
Association of Urology Guidelines define HRPC biochemical progression as 3 consecutive rises in PSA levels,
2 weeks apart, resulting in two 50% increases over nadir
or baseline (whichever is higher); antiandrogen withdrawal for at least 4 weeks; and progression of osseous or
soft-tissue lesions.1 Clinically, radiographic evidence of
progression in the absence of PSA progression is rare and
can be characteristic of unusual histologic conditions,
such as small-cell cancer. By this definition, even small
increases in PSA (ie, successive elevations as low as 0.1
ng/mL) are sufficient to consider the patient for the category of hormone-refractory disease.
As the nature of the disease changes in the era of
chemotherapy and bone-targeted therapies, the term
HRPC is being redefined to encompass patients with
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metastatic and nonmetastatic disease, in addition to
patients with and without symptomatic disease.
Although the level of testosterone required to declare a
patient castrate remains open to debate, it is important
to realize that some patients will respond to secondary
hormonal manipulation (ie, antiandrogen withdrawal,
antiandrogen administration, ketoconazole, estrogens,
and corticosteroids), despite having failed initial hormonal therapy.1
In the recently issued position statement of the
Society of Urologic Oncology, a multidisciplinary panel
recognized 3 broad categories of tumors based on hormone sensitivity: hormone-naïve/hormone-sensitive
tumors that respond to initial hormonal manipulation;
androgen-independent/hormone-sensitive tumors that
may respond to secondary or tertiary hormonal manipulation; and androgen-independent/hormone-insensitive tumors that have failed to respond (or progress) after
secondary hormonal manipulation in a castrate setting.2
Clinically, tumors may also be classified based on
hormonal status (castrate vs noncastrate levels of testosterone), extent and location of radiographically
detectable disease, and the presence or absence of symptoms. Therefore, patients may have biochemical disease
recurrence only, clinically evident local (nonmetastatic)
or distant (metastatic) disease progression, or both.2
Increasingly, more men are seen with biochemical evidence of HRPC (ie, rising PSA alone) without radiographic evidence of disease and without any symptoms.
Even in HRPC, despite low or undetectable testosterone levels, the androgen receptor pathway retains its
ability to signal and thereby comprises a potential target for drug therapy. Therefore, clinicians must adapt
therapy to an individual patient’s clinical status in light
of the heterogeneous nature and shifting definitions of
HRPC. In general, the broadest definition of HRPC
includes all patients who experience PSA and/or clinical
disease progression in the context of castrate levels of
testosterone.2 Overall, the prognosis for patients with
HRPC is improving, in part because of the advent of
novel therapeutic approaches and earlier institution of
therapies. However, given that HRPC is now diagnosed
earlier than in the past, a component of the improvement is likely because of lead-time biases.
CHEMOTHERAPY IN THE MANAGEMENT OF
HORMONE-REFRACTORY DISEASE
Traditionally, the management of HRPC was
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directed toward palliating symptoms with secondary
and tertiary hormonal therapy, focal external beam
radiation to symptomatic lesions, and systemic radiopharmaceuticals. Until recently, many urologists and
oncologists viewed chemotherapy as toxic and ineffective for HRPC because no single or combination
approach had demonstrated a survival benefit. In the
1990s, results from 2 trials showed that mitoxantronebased regimens conferred a palliative benefit, although
no overall survival advantage, and slightly delayed time
to treatment failure for men with HRPC.3,4 However,
in 2004, the publication of results from 2 large,
prospective, randomized, controlled phase III studies
using docetaxel-based regimens set a new standard for
chemotherapeutic treatment for patients with
HRPC.5,6 Studies by Petrylak et al and Tannock et al
indicated that a docetaxel-based regimen reduced the
risk of death by 20% to 24%, and increased the median survival time by 1.9 to 2.4 months.5,6 These
improvements in survival are similar to the results of
patients with metastatic prostate cancer treated with
chemotherapy for lung or breast cancer.7 To date, docetaxel-based treatment is the only chemotherapeutic
approach to demonstrate a survival advantage in phase
III trials of patients with HRPC.
DOCETAXEL/PREDNISONE
In a pivotal phase III trial (TAX 327), Tannock et
al compared 2 schedules of docetaxel plus daily prednisone versus standard chemotherapy with mitoxantrone plus prednisone.6 Patients with HRPC
(n = 1006) were randomized to 1 of 3 groups: docetaxel 75 mg/m2 every 3 weeks for 10 cycles (group 1);
docetaxel 30 mg/m2 weekly for 5 cycles (group 2); or
mitoxantrone 12 mg/m2 every 3 weeks for 10 cycles
(group 3). Prednisone (5 mg daily) was added to each
regimen.8 The primary endpoint was overall survival.
The study had a 90% power to detect a hazard ratio of
0.75 for death. Secondary endpoints were pain, PSA
levels, and quality of life (QOL).6
Patients were recruited from centers in 24 countries and all had progressive disease, defined as increasing serum levels of PSA from 3 consecutive
measurements obtained at least 1 week apart, or findings on physical examination or imaging studies.6
Importantly, the characteristics of this mostly elderly
patient population reflected those typically seen in
oncology practices. Approximately 25% of patients
received 2 or more prior hormonal regimens, with more
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Probability of overall survival, %
than 80% of patients with metastases to bone.
Figure 1. Kaplan-Meier Estimates of Probability of Overall
Overall, almost 50% of treated patients had substanSurvival in 3 Treatment Groups: Docetaxel (every 3
tial pain. Pain was defined by a score of 2 or more on
weeks)/Prednisone, Docetaxel (weekly)/Prednisone, and
the Present Pain Intensity scale (range 0–5, with highMitoxantrone (every 3 weeks)/Prednisone
er scores indicating greater pain) or an analgesic score
of at least 10. A standard dose of a narcotic analgesic
(eg, 10 mg morphine) was assigned a score of 4; a
standard dose of a nonnarcotic analgesic was assigned
a score of 1.6
Even in this advanced-stage population, the results
Docetaxel
showed clear superiority of docetaxel/prednisone every
every 3 weeks
3 weeks versus mitoxantrone/prednisone in lengthening median survival time by approximately 2.5
months (18.9 months vs 16.4 months, respectively;
P = .009; Figure 1).6 In addition, the study showed a
24% reduction in the risk of death in patients treated
with docetaxel/prednisone every 3 weeks.8 Notably,
No. at risk
Docetaxel every
the survival advantage of docetaxel every 3 weeks was
3 weeks
maintained regardless of patient age, Karnofsky perWeekly Docetaxel
Mitoxantrone
formance score, and presence or absence of pain.6 By
contrast, no significant survival benefit was observed
Reprinted with permission from Tannock et al. N Engl J Med. 2004;351:1502-1512.
Copyright (©) 2004 Massachusetts Medical Society. All rights reserved.
between docetaxel/prednisone given once weekly versus mitoxantrone/prednisone given every 3 weeks
(17.4 months vs 16.5 months; P = NS).6 Table 1 summarizes the major findings of TAX 327.8
In secondary endpoints, significantly more men
in the docetaxel-treated arms had at least a 50%
decline in PSA (P <.001). Additionally,
more men had met the criteria for a predefined reduction in pain (P <.01 and P
<.08) versus the mitoxantrone-treated
Table 1. Summary of Results of TAX 327: Docetaxel/Prednisone Versus
arm.6 QOL was evaluated in 815
Mitoxantrone/Prednisone
patients using the Functional
Assessment of Cancer Therapy-Prostate
Group 1
Group 2
Group 3
questionnaire.6 A significantly higher
percentage of patients in the docetaxel
Docetaxel 75 mg/m2 Docetaxel 30 mg/m2 Mitoxantrone
Chemotherapy
every 3 weeks for 10 weekly for
12 mg/m2 every
schedule
groups (22%, docetaxel every 3 weeks
cycles
+
prednisone
5
cycles
+
pred3
weeks for 10
[P = .009]; 23%, docetaxel weekly
5 mg daily
nisone
cycles +
[P = .005]) reported improvement in
5 mg daily
prednisone
QOL compared with the mitoxantrone
5 mg daily
group (13%).6 The greatest improve18.9 months
17.3 months
16.4 months
Median survival
ments in QOL occurred in prostate-spe(P = .009 vs group 3) (P = .3 vs group 3)
cific domains (ie, weight loss, appetite,
22%
Pain response rate
35%
31%
pain, physical comfort, bowel function,
(P = .01 vs group 3)
(P = .07 vs group 3)
and genitourinary function).
32%
Prostate-specific anti- 45%
48%
Safety. Although adverse events were
gen response rate
(P <.001 vs group 3)
(P <.001 vs group 3)
more common in the docetaxel groups,
Adapted with permission from Petrylak and Kelly. Chemotherapeutic options in prostate cancer. Chapter
they were not life threatening (eg, senso5. Report to the Nation on Prostate Cancer 2004. Prostate Cancer Foundation. Available at:
ry neuropathy).6 Serious adverse events
http://www.prostatecancerfoundation.org. Accessed June 6, 2005.
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Overall survival, %
DOCETAXEL/ESTRAMUSTINE
In the phase III Southwest Oncology Group
(SWOG) Intergroup Protocol 9916 study,
Petrylak et al randomized 770 patients with progressive HRPC to receive estramustine (280 mg, 3
times daily, on days 1 through 5) plus docetaxel
(60 mg/m2 every 3 weeks) plus dexamethasone
(60 mg in 3 divided doses before docetaxel) versus
standard chemotherapy with mitoxantrone (12
mg/m2 every 3 weeks) plus prednisone (5 mg
twice daily).5 Progressive disease was defined
according to recommended criteria as: a bidimensionally measurable lesion assessed within 28 days
before study registration; progression of disease
that could be evaluated but not measured (eg, by
bone scanning) as assessed within 42 days before
registration; or an increase in serum PSA level over
the baseline level in at least 2 consecutive samples,
obtained at least 7 days apart.5
Treatment continued until disease progression, unacceptable adverse events occurred, or
until a maximum of 12 cycles of docetaxel and
estramustine or 144 mg/m2 mitoxantrone had
been administered.5 The primary endpoint of
the study was overall survival. The study had an
80% statistical power to detect a 33% improvement in median survival.5 Secondary endpoints
included progression-free survival, objective
response rates, and post-treatment declines of at
least 50% in serum PSA.5
Study results showed a 20% reduction in mortality in the docetaxel/estramustine group compared with the mitoxantrone/prednisone group
(95% confidence interval, 3%–33%).5 Median
overall survival time was approximately 2 months
longer in the docetaxel/estramustine group (17.5
months) than in the mitoxantrone/prednisone
group (15.6 months; P = .02 by the log rank test;
Figure 2).5 Additionally, median time to disease
progression was significantly superior in the
Figure 2. Kaplan-Meier Estimates of Overall Survival Among Men
with Androgen-Independent Prostate Cancer Treated with
Mitoxantrone and Prednisone or Docetaxel and Estramustine
P = .02
Docetaxel + estramustine
(217 deaths; median, 17.5 mo)
MItoxantrone + prednisone
(235 deaths; median, 15.6 mo)
Months after enrollment
No. at risk
Docetaxel +
estramustine
Mitoxantrone +
prednisone
Reprinted with permission from Petrylak et al. N Engl J Med. 2004;351:1513-1520.5
Copyright © 2004 Massachusetts Medical Society. All rights reserved.
Figure 3. Kaplan-Meier Estimates of Progression-Free Survival
Among Men with Androgen-Independent Prostate Cancer
Treated with Mitoxantrone and Prednisone or Docetaxel and
Estramustine
Progression-free survival, %
occurred among 26% of patients in the group
receiving docetaxel every 3 weeks and 29% in the
group receiving weekly docetaxel compared with
20% in the group receiving mitoxantrone.
Although grade 3 or 4 neutropenia was most common in the group receiving docetaxel every 3
weeks, febrile neutropenia was rare (3%), as was
treatment-related death (0.3%).6
Docetaxel + estramustine
(311 events; median, 6.3 mo)
< .001
PP<.001
MItoxantrone + prednisone
(312 deaths; median, 3.2 mo)
No. at risk
Docetaxel +
estramustine
Mitoxantrone +
prednisone
Reprinted with permission from Petrylak et al. N Engl J Med. 2004;351:1513-1520.5
Copyright © 2004 Massachusetts Medical Society. All rights reserved.
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docetaxel/estramustine group versus the mitoxpatterns, in addition to minor differences in study
antrone/prednisone group (6.3 months vs 3.2 months,
entry criteria. The only valid method to evaluate the
respectively; P <.001; Figure 3).5 PSA declines of at
contribution of estramustine is with adequately powleast 50% occurred in 50% of docetaxel/estramustineered randomized trials comparing estramustine comtreated patients compared with 27% of mitoxbined with docetaxel to docetaxel alone. The toxicities
antrone/prednisone-treated patients (P <.001). The
of estramustine and the small postulated improvement
proportion of patients with a partial response in meain survival make it unlikely that such a trial will ever
surable disease (17% vs 11%) did not differ signifibe implemented. Given toxicity considerations, both
5
cantly between the 2 groups. Table 2 summarizes the
SWOG and the Cancer and Leukemia Group B
major findings of this study.8
(CALGB) use docetaxel/prednisone as the standard
Safety. Although docetaxel/estramustine therapy
treatment arm for phase III studies.
was generally well tolerated, a higher incidence of
grade 3/4 toxicity, particularly cardiovascular events
INVESTIGATIONAL DOCETAXEL-BASED
COMBINATION REGIMENS: A TO Z
and neutropenia, was reported in the docetaxel/estramustine arm of the study.5,8 No difference in deaths
caused by toxicity or study discontinuation was
Phase II trials of docetaxel in combination with vari5,8
observed between the 2 arms.
ous agents, including atrasentan, bevacizumab, calcitriol,
The SWOG 9916 study team concluded that
thalidomide, and zoledronic acid, have been completed.
although treatment with estramustine and docetaxel
The impact of these combination regimens on survival
moderately prolongs survival, it is at the cost of an
and PSA response awaits confirmation in appropriately
increased rate of adverse events. Physicians and
designed, large-scale, randomized phase III trials. The
patients must weigh both the benefits and risks when
investigational goal is to identify multiagent chemotherconsidering the use of docetaxel and estramustine as
apeutic regimens with a docetaxel backbone that further
first-line therapy for men with metastatic HRPC.5
extend the survival benefits of docetaxel, while avoiding
Based on the results from TAX 327, the US Food
redundant toxicities.
and Drug Administration (FDA) approved docetaxel/prednisone for the treatment of AIPC. Because the
DOCETAXEL PLUS ATRASENTAN
Atrasentan, a selective endothelin receptor antagoexperimental combination of estramustine and docnist, is a novel agent that, in part, targets tumor-stromal
etaxel also demonstrated a survival benefit, one must
question whether estramustine should
be included in the treatment of
HRPC. Despite the known toxicities
of estramustine, improved time to
Table 2. Summary of Results of SWOG 9916: Docetaxel/Estramustine
progression and the proportion of
Versus Mitoxantrone/Prednisone
patients with a PSA decline of 50% or
more can be demonstrated when it is
Experimental Arm
Control Arm
P
(21-Day Cycle)
(21-Day Cycle)
Value
combined with paclitaxel,9 vinblastine,10 or epothilone-B11 compared
Mitoxantrone
Chemotherapy
Docetaxel 60 mg/m2
with these agents administered alone.
schedule
every 21 days +
12 mg/m2
Although underpowered, when comestramustine 280 mg
every 21 days +
pared with the respective single agent
TID, days 1–5
prednisone 5 mg BID
alone, significant survival differences
Median survival
18 months
16 months
.01
were seen when estramustine was comTime to progression
6 months
3 months
<.0001
bined with vinblastine or paclitaxel.
Prostate-specific
antigen response
50%
27%
<.0001
Direct comparisons of the results of
SWOG 9916 and TAX 327 to answer
Partial response rate
17%
11%
NS
the question of estramustine adminisBID = twice daily; TID = three times daily.
Adapted with permission from Petrylak and Kelly. Chemotherapeutic options in prostate cancer. Chapter
tration cannot be made because of dif5. Report to the Nation on Prostate Cancer 2004. Prostate Cancer Foundation. Available at:
ferent post-treatment crossover
http://www.prostatecancerfoundation.org. Accessed June 6, 2005.
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interactions, and is discussed in more detail later in this
article. In a planned phase III SWOG study (SO421) of
docetaxel plus placebo versus docetaxel plus atrasentan
(n = 706), patients with HRPC will be randomized to
receive docetaxel 75 mg/m2 every 3 weeks plus placebo
or docetaxel 75 mg/m2 every 3 weeks plus atrasentan 10
mg. The trial is designed to detect a 30% increase in
median survival with 85% power, and the primary and
secondary endpoints are being finalized.
DOCETAXEL PLUS BEVACIZUMAB
Bevacizumab is a monoclonal antibody that exerts
its effects by binding to the vascular endothelial
growth factor (VEGF). In 2004, bevacizumab became
the first antiangiogenesis agent to receive US FDA
approval based on data in patients with metastatic colorectal cancer.12 In HRPC xenograft models, this agent
appears to slow the growth of prostate cancer, an effect
that is enhanced with the addition of chemotherapy.13
Plasma and urine levels of VEGF are prognostic in
men with HRPC. Plasma VEGF levels are significantly elevated in patients with metastatic prostate cancer
versus localized prostate cancer (P = .003) and are
inversely correlated with survival time (P = .002).14,15
Additionally, patients with a baseline urine VEGF of
28 pg/mL or less had an average survival time of 17
months, whereas those with a level above 28 pg/mL
had a survival time of 10 months (P = .024).16
On the basis of these data, Picus et al investigated
the use of bevacizumab in combination with docetaxel/estramustine in 79 patients with HRPC enrolled in
the phase II CALGB 90006 trial.17 Patients received
estramustine 280-mg thrice-daily dosing on days 1 to
5, docetaxel 70 mg/m2 on day 2, and bevacizumab 15
mg/kg over 30 minutes on day 2. Dexamethasone 8mg twice-daily dosing was administered on days 1 to
3, and warfarin 2 mg daily was encouraged but not
required to reduce estramustine-associated thromboembolic complications. Results showed a post-therapy PSA decline of greater than 50% in 58 of 72
patients (81%), a median time to objective disease
progression of 9.7 months, and an overall median survival time of 21 months.12
A randomized, double-blind, placebo-controlled
phase III trial of more than 1000 patients (CALGB
9040) is under way, comparing docetaxel/prednisone
with and without bevacizumab in patients with HRPC.
The primary endpoint of the study will be overall survival, with the secondary endpoints of PSA, relative risk,
Johns Hopkins Advanced Studies in Medicine
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and progression-free survival. The study is designed to
show a median survival time improvement from 19 to
24 months, with a 2-sided alpha of 0.05. Patients will be
stratified based on a validated nomogram.18,19
DOCETAXEL PLUS CALCITRIOL
Calcitriol, a biologically active form of vitamin D,
has been found to inhibit angiogenesis and induce
apoptosis in vitro and in vivo.20 A phase II study found
that the regimen of calcitriol 0.5 µg/kg on day 1, followed by docetaxel 32 mg/m2 on day 2, and repeated
weekly for 6 of 8 weeks, was associated with a median
survival advantage of 19.5 months and a PSA reduction rate of greater than 75% for 59% of study participants.21 To evaluate whether a high-dose preparation
of calcitriol, DN101, combined with weekly docetaxel had a superior PSA decline rate when compared
with weekly docetaxel alone, randomized phase II trials enrolled 250 patients. Although the PSA decline
rates at 6 months were not significantly different
between the DN101/docetaxel (58%) and docetaxel
arms (49%), an adjusted survival analysis demonstrated an improved survival with DN101/docetaxel. The
DN101/docetaxel-treated patients had a lower rate of
significant adverse events compared with docetaxeltreated patients alone. The reduction in significant
adverse events was primarily because of lower rates of
thrombotic and gastrointestinal events in the combination arm. Based on these study results, a phase III
study of weekly docetaxel combined with DN101 is
being compared with administration of docetaxel/
prednisone every 3 weeks.
DOCETAXEL PLUS THALIDOMIDE
Thalidomide, another angiogenesis inhibitor, has
also shown promise in combination with docetaxel. In
a randomized phase II trial, 75 chemotherapy-naive
patients with metastatic HRPC were randomized to
receive docetaxel monotherapy or docetaxel in combination with thalidomide (200 mg daily).22 Fifty-three
percent of patients treated with the combination regimen showed a post-therapy PSA decline of at least
50% compared with 37% of patients in the docetaxel
monotherapy group. The median progression-free survival time was higher in the docetaxel/thalidomide
group (5.9 vs 3.7 months), although the difference did
not reach statistical significance. At 18 months, overall
survival was higher in the docetaxel/thalidomide group
(68.2% vs 42.9%).22 Although underpowered to detect
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a survival difference, further follow-up demonstrated a
significant difference in median survival time (25.9 vs
14.7 months; P = .04) in favor of the docetaxel/
thalidomide regimen.23
DOCETAXEL PLUS ZOLEDRONIC ACID
Zoledronic acid is a potent intravenous bisphosphonate with proven utility in the management of
skeletal complications of HRPC. It has been reported
that the bisphosphonates may have a synergistic antitumoral effect when combined with taxanes.
In a recent study, 54 patients with HRPC
received zoledronic acid along with a
docetaxel/estramustine treatment regimen.24 Every 2
weeks, patients received docetaxel 45 mg/m2 and
estramustine 140 mg (administered orally every 8
hours for 9 doses). Zoledronic acid 4 mg was administered every 28 days. All patients had received at
least 2 previous regimens of hormonal therapy, and
43% had also undergone estramustine therapy. Of
the 54 patients in the study, 27 (50%) had only bone
metastases, and 17 (31%) had disease in the
prostate. At the end of the study, 45% (22/49) of
assessable patients had a PSA response, defined as a
decrease of more than 50% from baseline with no
objective progression; 38% (9/24) with measurable
disease had a response to therapy (1 complete, 8 partial); and 37% (14/38) of the patients who had been
using analgesics had discontinued use. Overall survival time was 13.3 months. Results of this study
indicate that docetaxel/estramustine plus zoledronic
acid is a well-tolerated regimen that results in symptomatic improvement in a significant proportion of
patients with HRPC.24 Whether this combination
warrants further study is debatable.
Osteonecrosis of the jaw has been reported in
patients receiving treatment regimens including bisphosphonates. A dental examination should be considered prior to treatment with bisphosphonates in
patients with concomitant risk factors (eg, chemotherapy, corticosteroids, or poor oral hygiene) and these
patients should avoid invasive dental procedures during treatment, if possible. It is also recommended that
the bisphosphonate dose be adjusted based on the
patient’s baseline creatinine clearance.
DOCETAXEL PLUS RADIOPHARMACEUTICALS
A variety of studies have suggested potential synergy
between taxanes and radiation, thus examination of doc-
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etaxel and radiopharmaceuticals represents a reasonable
clinical approach. Docetaxel has been used in combination with the radiopharmaceutical samarium-153
EDTMP (ethylene diamine tetramethylene phosphonate) in small European trials that have been published
to date only in abstract form.25 These data indicate that
combinations of these agents may be used safely. Efficacy
data are limited. Additional studies are now ongoing in
several centers in the United States and these trials
should begin to mature in the next year.
TIMING AND SEQUENCING OF CHEMOTHERAPY
For patients who have failed androgen deprivation
therapy, the optimal time to initiate chemotherapy
remains unresolved. In the absence of data, a stepwise
approach, in which potentially toxic chemotherapy is
deferred until symptoms progress, seems reasonable.
Secondary or tertiary hormonal manipulation is
appropriate for asymptomatic patients with slowly
progressive disease. Chemotherapy should be reserved
for patients with a rapidly rising PSA and/or metastatic disease. Patients generally prefer a stepwise
approach that starts with the least toxic agent and progresses to more toxic agents as their therapeutic
options narrow or their symptoms increase.
In the recently issued position statement of the
Society of Urologic Oncology, a multidisciplinary panel
outlined a logical progression of treatment choices and
determined that management strategies must consider
individual patient status.2 Because of the heterogeneous
nature of the disease process, treatment options must be
based on the nature and degree of the patient’s cancer.2
Using this approach, chemotherapy may be an option
for patients with symptomatic disease or asymptomatic
disease with bone metastases.2 However, what steps to
take after chemotherapy treatment with a taxane fails
remains a major question for physicians and patients.
There are no drugs approved by the US FDA in this setting, and only 1 large, randomized clinical trial is currently addressing the issue. In that trial, a novel oral
platinum (satraplatin) plus prednisone is being compared with prednisone alone. This trial has completed its
accrual of more than 900 patients. Endpoints include
time to progression and overall survival. Results are
anticipated in the next year.
Clinical trials are needed to assess the value of
chemotherapy earlier in the disease course, before or
after radical prostatectomy or radiation, in hormone-
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naïve patients with a rising PSA, particularly those
with a rapid doubling time or other adverse prognostic features.
A normal ejaculatory protein, ET-1 concentrations
are highest in seminal fluid, reaching levels almost 500
times greater than those found in plasma (Figure 5).29,30
Of the 2 endothelin receptors found in the normal
prostate, endothelin-B (ETB) predominates in epithelium, whereas underlying stromal cells express ETA.31
In prostate cancer, ETB expression is lost, whereas
ETA expression increases with the stage of prostate
cancer.31-33 As with serum PSA, studies confirm that
levels of ET-1 are higher in some men with metastatic
prostate cancer.30-33 Finally, the pain associated with the
bony metastatic lesions of advanced prostate cancer
may be induced by ET-1.34
Bone pain is often associated with advanced
prostate cancer and is the cause of significant morbidity. As a mediator of pain, ET-1, acting through the
ETA receptor, has a direct effect on nerves and as a
potentiator of other noxious stimuli.35 The endothelin
axis, including ET-1 and the endothelin receptors,
promotes a variety of other tumorigenic cellular
events, including proliferation, apoptosis inhibition,
abnormal osteogenesis, and altered nociceptive stim-
SELECTIVE ENDOTHELIN RECEPTOR ANTAGONISTS:
POTENTIAL OPTIONS FOR THE TREATMENT OF BONY
METASTATIC PROSTATE CANCER
Because docetaxel-based chemotherapeutic regimens have been shown to confer a small but significant survival advantage in 2 large phase III trials,
subsequent research efforts have focused on identifying novel agents. Agents targeting signaling pathways
that are potentially important in HRPC growth represent an area of particular focus. Recent research has generated significant interest in compounds termed
selective endothelin-A (ETA) receptor antagonists.
These compounds were originally investigated for
hypertension and congestive heart failure because of
endothelin’s role in vasoconstriction. Research showed
that prostate cancer cells secrete endothelin; therefore,
compounds that block this excess secretion may play a
role in the metastases of prostate cancer in bones
and elsewhere.26 These agents may offer another
treatment alternative for patients who choose not
to undergo chemotherapy, in addition to those
Figure 4. Endothelin-1 Activity in Bone Remodeling
patients with concomitant medical conditions
that do not permit the use of cytotoxic agents or
for taxane-resistant populations.
Some of the more important advances in this
area have been the bone-targeting strategies.
One such target is endothelin-1 (ET-1), a potent
vasoconstrictor that modulates cell growth and
proliferation, inhibits apoptosis, and stimulates
osteoblast activity by selectively binding to the
ETA receptor.27 The bony metastases in prostate
cancer are primarily osteoblastic in nature,
rather than osteolytic, and are mediated in part
by ET-1 stimulation of growth factor and cell
signaling pathways (Figure 4).27,28 Therefore, an
ETA receptor antagonist would inhibit the deleThe proliferative effects of ET-1 on osteoblasts are enhanced by 1,25-dihydroxyvitamin D3,
teriously prolific effects of ET-1 on the
enhancing ETA receptor expression and by a direct stimulatory effect. Parathyroid hormone
(PTH) inhibits Ca2+-dependent signaling and downregulates ET-receptor expression; ETA
osteoblasts that contribute to the painful bone
receptor antagonists block the effects of ET-1 on osteoblasts. Conversely, osteoclastic funcmetastatic lesions of prostate cancer. Atrasentan,
tion is inhibited by ET-1 as resorptive activity and osteoclast motility are dose-dependently
a novel agent that targets tumor-stromal interreduced in the presence of ET-1. A host of factors that are abundantly found in bone, such
as transforming growth factor-β (TGF-β), interleukin-1B (IL-1B), and bone morphogenetic
actions, is an ETA receptor antagonist that is
protein-7 (BPM7), are potent inducers of ET-1 expression.
being evaluated for use in patients with bony
ET = endothelin.
metastatic HRPC to delay tumor progression in
Reprinted with permission of the publisher from Nelson et al. Nat Rev Cancer. 2003;3:110116. Copyright © 2003 Macmillan Magazines Ltd.
bone.
27
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REVIEW
uli. Atrasentan effectively targets this pathway to several of these phenomena.36 In the phase III clinical setting, atrasentan has been shown to suppress the
markers of biochemical and clinical prostate cancer
progression in bone.36
Blockade of the endothelin axis (ETA/ET-1 receptor binding) is an intriguing therapeutic approach
because it may disrupt osteoblastic metastasis, modulate cancer-induced bone pain, and inhibit tumor progression. Atrasentan, the first agent in its class to enter
late-phase clinical trials for prostate cancer, is orally
bioavailable. It is a potent competitive inhibitor of ET1 binding, with an 1800-fold superior selectivity for
ETA compared with ETB.31,36
S308
Figure 5. Increased Concentration of Plasma Immunoreactive
ET-1 in Prostate Cancer
Plasma immunoreactive endothelin (pg/mL)
PHASE II TRIALS
Two large, randomized, double-blind, multicenter phase II trials assessed atrasentan in men
with HRPC.37-39 In the initial 12-week study
(M96-500), Carducci et al randomized 131 men
with metastatic HRPC to 1 of 3 groups to
receive placebo, atrasentan 2.5 mg, or atrasentan
10 mg.38 Study participants had pain severe
enough to require opioid analgesics. There were
no statistically significant differences in response
rates for the primary endpoint (pain relief at
week 12).34,38 However, a trend toward improvement in pain without increased analgesic consumption was noted in the atrasentan 10-mg
group.
In the second phase II study (M96-594),
Carducci et al randomized 288 asymptomatic
patients with metastatic HRPC to 1 of 3 groups to
receive placebo, atrasentan 2.5 mg, or atrasentan
10 mg.39 All groups had metastatic disease as indicated by elevated serum markers of PSA, alkaline
phosphatase, acid phosphatase, and lactate dehydrogenase (LDH).40 The primary endpoint was
time to disease progression, and results from the
intention-to-treat (ITT) analysis showed that
median time to disease progression was 183 days
in the atrasentan 10-mg group compared with 137
days for the placebo-treated group (P = .13). In the
evaluable subset of 244 patients, there was a significant (P = .021) delay in disease progression
from 129 days (placebo group) to 196 days
(atrasentan 10-mg group).35
These phase II trials also studied bone deposition and bone resorption markers based on
preclinical data connecting ETA to osteoblastic activity. Although LDH and acid phosphatase, markers of
overall disease burden, continued to increase from
baseline in the placebo group, both markers were
attenuated in the atrasentan treatment groups in the
ITT and evaluable populations compared with placebo.38,40 These phase II findings provided the first indication that atrasentan may be most active in men with
bony metastatic HRPC and provided the impetus for
phase III trials.41 The phase II trials suggested that
atrasentan showed a beneficial effect and that further
studies were needed.
Hormone-Refractory
Metastatic Disease
Clinically
Localized
Normal
Reprinted with permission from Nelson et al. Nat Med. 1995;1:944-949.30
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PHASE III TRIALS
With the phase II data indicating a significant delay
in disease progression in the evaluable subset, 2 phase III
trials were designed. One of these studies (M00-211)
was designed to duplicate the time to disease progression
phase II trial (M96-594); however, with only 2 treatment arms, a placebo and an atrasentan 10-mg arm. In
addition, the M00-211 trial required bone scans and
axial imaging every 3 months. In this phase III study,
Carducci et al randomized 809 men with asymptomatic
metastatic HRPC to receive atrasentan 10 mg (n = 408)
or placebo (n = 401).41
The primary endpoint, time to disease progression defined as clinical events, pain, or progression
on bone scan, did not meet clinical significance.41
Nonetheless, atrasentan showed significantly smaller
increases in other clinical parameters, including
bone alkaline phosphatase, total alkaline phosphatase, and PSA.41 In a subset of 671 patients identified before the study was unblinded (n = 329,
placebo; n = 342, atrasentan), atrasentan significantly delayed time to disease progression and time to
bone alkaline phosphatase progression. 41 In 681
patients with at least 3 on-treatment bone alkaline
phosphatase values, atrasentan 10 mg extended bone
alkaline phosphatase doubling time 4-fold longer
compared with placebo. A bone alkaline phosphatase
doubling time of less than 12 months is a marker of
rapid disease progression and shortened survival.42
Another phase III trial of atrasentan (M00-244) in
men with nonmetastatic HRPC is in progress to evaluate time to disease progression as defined by the appearance of first metastasis. These patients are earlier in the
disease continuum and have no clinical or radiographic
evidence of metastatic disease. Accrual was completed in
May 2003 with 942 men enrolled.35
Another recent study found that ETA antagonists
improved blood flow into tumors.43 These results suggest that ETA antagonists may potentiate the effects of
radiation and chemotherapy, modalities that depend
on well-oxygenated blood flow for efficacy.
RECOMMENDATIONS FOR PHARMACOLOGIC
MANAGEMENT OF BONE PAIN IN HRPC
Traditional modalities, including radiation and
radioisotopes, will continue to play an important role in
alleviating pain from single and widespread osseous
lesions. Although effective, chemotherapy does not
Johns Hopkins Advanced Studies in Medicine
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directly address the underlying mechanisms responsible
for the bone pain and skeletal complications associated
with metastatic disease. Bone-targeted agents, such as
atrasentan and zoledronic acid, may also play a role.
Zoledronic acid, a potent intravenous bisphosphonate, has shown promise in the management of skeletal-related events in patients with prostate cancer with
bone metastases. However, no evidence to date suggests that these agents decrease pain. Results from a
phase III double-blind, placebo-controlled, randomized trial established that zoledronic acid (4 mg)
decreased the incidence of and prolonged the time to a
first skeletal-related event in men with metastatic
HRPC.44 Skeletal-related events were defined as pathologic bone fractures (vertebral or nonvertebral), spinal
cord compression, bone surgery, radiation therapy to
bone, or change of antineoplastic therapy to treat bone
pain.44 In this trial, zoledronic acid did not appear to significantly decrease pain compared with placebo; however, patients in the trial had increasing pain compared
with the baseline.44 Nonetheless, although patients in
the zoledronic acid group and the placebo group experienced pain, those treated with zoledronic acid had less
of an increase in pain than placebo-treated patients.44
Combination bone-targeted therapy with atrasentan and zoledronic acid is intriguing because the
agents may interact synergistically to help restore bone
homeostasis in men with metastatic HRPC. Because
metastasis disrupts the balance between osteoblastmediated bone formation and osteoclast-mediated
bone resorption, it has been postulated that the dual
combination of an osteoclast inhibitor (zoledronic
acid) with an osteoblast inhibitor (atrasentan) may further reduce skeletal complications and bone pain in
men with HRPC.27 A phase I/II clinical trial is completed but results are not compelling.35
APC8015
APC8015 is an autologous CD54-positive dendritic cell vaccine loaded with a recombinant granulocyte
macrophage colony-stimulating factor and a prostatic
acid phosphatase fusion protein. In a phase III randomized, placebo-controlled trial of 127 men with
asymptomatic AIPC, patients received APC8015 or
placebo. The primary endpoint was time to disease
progression. Secondary endpoints included time to
onset of disease-related pain and overall survival.
Although treatment with APC8015 did not result in
a statistically significant delay in time to disease pro-
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gression, it did result in a statistically significant
(P = .01) survival advantage of 4.5 months in an
ITT analysis of patients with AIPC.45 In a subset
analysis, treatment with APC8015 resulted in a 6
4-month survival advantage (P = .047) in patients
with a Gleason score of 7 or less, forming the basis
for an ongoing phase III trial.45 The combination of
APC8015 with bevacizumab is also being evaluated
in a phase II trial in men with hormone-sensitive
prostate cancer.46
metastatic HRPC typically requires further collaboration with a radiation oncologist.
As the management of prostate cancer evolves, the
integration of medical therapies, such as chemotherapy, bone-targeted therapies, and other targeted therapies, earlier in the disease course will become the
driving force involving not only urologists but also
medical oncologists in the management of prostate
cancer from its onset.
CONCLUSIONS
GVAX VACCINE
GVAX (Cell Genesys, San Francisco, CA) promotes granulocyte macrophage colony-stimulating
factor secretion through genetic modification of
allogeneic prostate cancer cell lines.12 In a small
phase II trial of men with metastatic HRPC (n =
34), Simons et al found that GVAX immunization
was well tolerated.47 In a larger phase II trial (n = 80),
Small et al found that GVAX immunization stabilized or decreased levels of a biomarker of osteoclast
activity in the majority of patients with metastatic
disease.48
Two phase III trials are in progress with symptomatic
and asymptomatic men with metastatic prostate cancer,
regardless of Gleason score: one to evaluate GVAX in
combination with docetaxel/prednisone, and the second
to evaluate whether GVAX plus chemotherapy is more
effective than chemotherapy alone.12
COLLABORATION IN THE MANAGEMENT
PATIENTS WITH PROSTATE CANCER
OF
As the value of adjuvant and neoadjuvant therapies
for prostate cancer becomes realized, greater partnership will be needed among the members of a patient’s
cancer care team, including the urologist, the medical
oncologist, and the radiation oncologist. Optimal
patient management will require these specialists to
collaborate in a multidisciplinary team approach
throughout all stages of the disease and all phases of
care. For example, a collaborative relationship between
the urologist and the medical oncologist is important
for the early recognition and management of ureteral
complications, such as urinary obstruction, urinary
retention, chronic irritative voiding symptoms, and
persistent hematuria, in addition to painful bony
metastases, while the patient is undergoing cytotoxic
chemotherapy. The management of painful bony
S310
With continued aging of the general population,
an increased number of men are being diagnosed
with prostate cancer in the United States and
throughout the world. Given the morbidity and
mortality associated with advanced disease, continued development of therapeutic alternatives is a top
priority for physicians and patients alike. Today,
more treatment options exist for men with HRPC
than ever before. The establishment of docetaxelbased chemotherapy as therapy associated with survival benefit has been a critical step in the
management of these patients. Bone-targeted therapies, such as atrasentan, bisphosphonates, and radiopharmaceuticals, may inhibit the bone-stromal
interactions that underlie the metastatic process.
The biologic activity of atrasentan is evident in
clinical trials showing a delay in time to disease progression versus placebo, especially in patients with
bone metastatic disease, in addition to a trend toward
improving the pain that compromises QOL for men
with metastatic disease. Aggressive new treatment
alternatives, including chemotherapy and bone-targeted therapy, need to be tested in randomized trials to
determine whether further improvements in the quantity of life and QOL can be achieved for men with
HRPC. Further research is warranted to identify novel
agents and optimize the use of existing agents in combination regimens that focus on lengthening and
improving QOL for men with HRPC.
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