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The optimal sequence and combinations
of drugs to manage metastatic
castration-resistant prostate cancer
remain to be defined.
Michele R. Sassi. Early Morning, South Egremont, Massachusetts. Photograph.
Sequencing Systemic Therapies in
Metastatic Castration-Resistant Prostate Cancer
Jane Jijun Liu, MD, and Jingsong Zhang, MD, PhD
Background: Men with prostate cancer will not die of the disease until it progresses to the metastatic castrationresistant stage. At that stage, the median survival is 9 to 30 months.
Methods: Recently approved and emerging treatments for metastatic castration-resistant prostate cancer
(mCRPC) were reviewed based on their mechanisms of action, as well as sequencing and combining these
treatments with existing options.
Results: Advances in androgen deprivation therapy, immunotherapy, bone-targeted therapy, and
chemotherapy have led to approvals of abiraterone acetate, sipuleucel-T, denosumab, and cabazitaxel for the
treatment of mCRPC. Despite improvements in patient survival and quality of life, mCRPC remains incurable.
Conclusions: With the emerging new therapies, this is an unprecedented time in treating mCRPC. A better
understanding of their mechanisms of action, the genetic makeup of each mCRPC, and the development of new
prognostic and predictive biomarkers will help determine sequencing or different combination treatments for
each individual patient.
Prostate cancer is the most common cancer among
North American men, with approximately 238,590
new cases diagnosed and 29,720 deaths expected in
From the Division of Hematology and Oncology (JJL) and the Genitourinary Oncology Program (JZ) at the H. Lee Moffitt Cancer
Center & Research Institute, Tampa, Florida.
Submitted January 21, 2012; accepted August 17, 2012.
Address correspondence to Jingsong Zhang, MD, PhD, Genitourinary Oncology Program, Moffitt Cancer Center, 12902 Magnolia
Drive, MCC-GME, Tampa, FL 33612. E-mail: [email protected]
No significant relationship exists between the authors and the
companies/organizations whose products or services may be referenced in this article.
The authors have disclosed that this article discusses unlabeled/
unapproved use of the products enzalutamide, orteronel, ipilimumab, PROSTVAC-VF, dasatinib, and radium-223 for the treatment of prostate cancer.
July 2013, Vol. 20, No. 3
2013 in the United States.1 Prostate cancer is not
deadly until it progresses to the metastatic castrationresistant stage, defined as progressive prostate cancer
despite a castrate level of serum testosterone (< 50
ng/dL). Patients with metastatic castration-resistant
prostate cancer (mCRPC) have a progressive and morbid disease process, with a median survival of 9 to 30
months.2 Although the survival period will likely be
improved with newly approved and emerging therapies, mCRPC remains an incurable disease. Based on
the palliative nature of systemic therapies, the goals
of treatment are to improve survival and to maintain
patient quality of life with minimum toxicities. In
this article, we review newly approved and emerging therapies for mCRPC, dividing them into four
strategies: antiandrogen therapy, immunotherapy,
cytotoxic chemotherapy, and bone-targeted therapy.
Cancer Control 181
We also discuss how to sequence these treatments to
maximize survival benefits.
Antiandrogen Therapy
Second-line androgen deprivation therapies with antiandrogens, estrogen, or ketoconazole in combination
with hydrocortisone have been widely used in patients
with mCRPC, but with limited response rates and duration of response. Furthermore, these therapies do not
improve survival for mCRPC.3 Over the last 3 years, a
paradigm shift in mCRPC treatment occurred with the
clinical confirmation that a significant proportion of
mCRPCs are dependent on the androgen axis despite
the castrate level of testosterone in the serum.4 Several
new agents were developed to more potently block
androgen synthesis or inhibit androgen binding to the
androgen receptor. Among them, abiraterone acetate
and enzalutamide improve survival rates of patients
with mCRPC in the post-docetaxel setting.5,6
Abiraterone acetate is a selective inhibitor of androgen biosynthesis that potently blocks cytochrome
P450c17 (CYP17, 17-α-hydroxylase and C17, 20-lyase), a critical enzyme in testosterone synthesis in the
adrenal glands, in the testes, and within the prostate
tumor.7-10 It is more potent and less toxic than ketoconazole.7 A phase III trial comparing abiraterone
plus prednisone with placebo plus prednisone studied 1,195 patients with mCRPC who had progressive disease after docetaxel chemotherapy.5 This trial
excluded patients who were previously treated with
ketoconazole. Based on a 4-month improvement in
the rates of overall survival (OS) during the interim
analysis (14.8 vs 10.9 months; hazard ratio [HR] =
0.65; P < .001), the US Food and Drug Administration (FDA) approved abiraterone in April 2011 for
mCRPC following docetaxel treatment. All secondary
and exploratory end points were met and favored
the abiraterone treatment group, including time to
prostate-specific antigen (PSA) progression (10.2 vs
6.6 months; P < .001), rate of progression-free survival (PFS; 5.6 vs 3.6 months; P < .001), PSA response
rate (29% vs 6%; P < .001), time to skeletal event
(9.9 vs 4.9 months), and rate of pain palliation (44%
vs 27%; P = .002).5 Adverse events associated with
elevated mineralocorticoid levels due to CYP17 blockade were fluid retention, edema, hypokalemia, and
hypertension. Abnormal liver function test results
were more common in the abiraterone group than
in the placebo group.
The approval of abiraterone marked the beginning of a new era of antiandrogen therapy, with a
wide array of agents undergoing phase III clinical trials for mCRPC. The second preplanned interim analysis of the phase III COU-AA-302 trial was recently
reported at the 2012 American Society of Clinical Oncology annual meeting. The trial tested the safety and
182 Cancer Control
efficacy of abiraterone in combination with prednisone chemotherapy-naive mCRPC patients who were
asymptomatic or mildly symptomatic.11 Compared
with the prednisone arm, abiraterone significantly
improved OS and radiographic PFS, co-primary end
points of this phase III study. TAK-700 (Orteronel) is a
selective nonsteroidal inhibitor of C17,20-lyase. After
encouraging data from a phase I/II trial,12 TAK-700
plus prednisone vs placebo plus prednisone is being
tested in two phase III studies for men with mCRPC in
both the chemotherapy-naive setting (NCT01193244)
and the post-docetaxel setting (NCT01193257).
MDV3100 is a potent antiandrogen that inhibits
androgen binding to androgen receptor, translocation
of androgen receptor to the nucleus, and the subsequent DNA binding.13 The results from an interim
analysis of the phase III AFFIRM trial were reported at
the 2012 ASCO annual meeting.6 The trial evaluated
MDV3100 (formerly enzalutamide) vs placebo in 1,199
men with advanced prostate cancer who were previously treated with docetaxel-based chemotherapy. It
demonstrated a clinically meaningful and statistically
significant improvement in OS compared with placebo
(18.4 vs 13.6 months, HR = 0.63; P < .001). Fatigue
(34% vs 29%), diarrhea (21% vs 18%), and hot flush
(20% vs 10%) were the most common events in the
MDV3100 arm, with an incidence higher than that reported in the placebo arm. Of note, 5 patients (0.6%)
in the MDV3100 arm developed seizure vs 0% in the
placebo arm. The ongoing phase III PREVAIL trial is
testing MDV3100 in the chemotherapy-naive mCRPC
patients (NCT01212991).
Prostate cancer cells express a number of tumor-associated antigens that can serve as targets for immunotherapy. The limited immune response to prostate
cancer in vivo has been attributed to impaired immune
system recognition by decreased immunogenicity of
surface antigens or blunted effectiveness of the immune response. Sipuleucel-T is an active cellular immunotherapy14,15 designed to stimulate an immune response to a widely expressed prostate cancer antigen,
prostatic acid phosphatase fused with granulocytemacrophage colony-stimulating factor (GM-CSF).16
The phase III IMPACT trial, in which sipuleucel-T
was compared with placebo, showed a 4.1-month
median survival benefit (25.8 vs 21.7 months) and a
22% reduction in the risk for death compared with
placebo (HR = 0.775; P = .03) in patients with asymptomatic or minimally symptomatic mCRPC.17 Similar
improvements in OS were supported by two smaller
previous phase III trials with similar design (D9901
and D9902A).18 However, improvement in OS was
not associated with improvements in PFS. In the
IMPACT trial, no significant difference occurred in
July 2013, Vol. 20, No. 3
time to objective response (3.7 vs 3.6 months; P =
.63), time to clinical progression (P = .4), or PSA
response (2.6% vs 1.3%; P > .05) in the sipuleucelT group vs the placebo group. Patients with poor
performance status (ECOG 2 or above) or visceral
metastasis were excluded, and 25% of patients in the
IMPACT trial had Gleason sum of 8 or more. The most
common adverse events reported were chills, fatigue,
fever, back pain, nausea, joint ache, and headache.17
The FDA approved sipuleucel-T for the treatment of
asymptomatic or minimally symptomatic men with
mCRPC in April 2010.
Other immunotherapies such as anti-CTLA immunotherapy and therapies using gene transfer approaches for mCRPC are also being evaluated in phase III
studies. Ipilimumab is a human monoclonal antibody
that blocks CTLA-4, a negative regulator of T cells.19-22
It was recently approved by FDA for treating metastatic melanoma.23 In a randomized phase II trial, 108
patients with advanced prostate cancer treated with
ipilimumab plus androgen ablation were more likely
to have undetectable PSA levels by 3 months compared with those treated with androgen ablation alone
(55% vs 38%), and significant clinical responses were
also seen.24 Ipilimumab is now being investigated in
two phase III clinical trials targeting chemotherapynaive and docetaxel-treated patients (NCT01057810
and NCT00861614, respectively). Another emerging
immunotherapy approach uses PSA-targeted poxviral
vaccines (PROSTVAC-VF). In a randomized phase II
trial, 125 men with mCRPC who were minimally symptomatic were randomly assigned to a PROSTVAC-VF
plus GM-CSF or to an empty vector with a GM-CSF
placebo for 24 weeks.25 PROSTVAC-VF immunotherapy
was associated with a 44% reduction in the death
rate and an 8.5-month improvement in median OS.5
A phase III trial (PROSPECT) to reevaluate these results has been open for accrual since November 2011
Cytotoxic Chemotherapy:
Beyond Single-Agent Docetaxel
Since the publications of the TAX 327 and SWOG-9916
phase III studies,26,27 docetaxel in combination with
prednisone has become the standard first-line chemotherapy for mCRPC on the basis of improvement in
survival compared with mitoxantrone plus prednisone.
Several agents have been studied in combination with
docetaxel and prednisone to improve the efficacy and
survival. The phase III Cancer and Leukemia Group B
study (CALGB 90401) evaluated docetaxel plus prednisone with or without bevacizumab.28 Regardless of the
significant improvement in PFS (9.9 vs 7.5 months; P
< .0001) and response rate (53.2% vs 42.1%; P = .01),
the trial was negative for the primary end point of OS
(22.6 vs 21.5 months; P = .91). Another phase III cliniJuly 2013, Vol. 20, No. 3
cal trial, MAINSAI, evaluating docetaxel combinations
with lenalidomide was halted at interim analysis due to
lack of efficacy.29 Despite these early disappointments,
combination strategy continues to be tested. Dasatinib, a potent inhibitor of the Src (sarcoma) family
of kinases that targets stromal-epithelial interactions,
was tested in the phase III READY trial. Despite its
promising phase II results, the addition of dasatinib to
docetaxel failed to improve survival of patients with
mCRPC compared to docetaxel alone when the results
of the READY trial were presented at the genitourinary
symposium in February 2013 (NCT00744497).30 In
summary, no combination to date has been shown to
triumph docetaxel and prednisone in phase III evaluation to enhance the activity of docetaxel and prednisone as first-line chemotherapy for men with mCRPC.
By contrast, the effort of developing second-line
chemotherapy after docetaxel has led to the FDA approval of cabazitaxel in 2010. Compared with mitoxantrone plus prednisone, cabazitaxel and prednisone
led to a 30% reduction in risk of death (HR = 0.70; P
< .0001) and a 2.4-month improvement in median OS
(15.1 vs 12.7 months) in the phase III TROPIC trial.31
Grade 3/4 toxicities included neutropenia (81.7%), febrile neutropenia (7.5%), infections (10.2%), vomiting
(1.9%), and diarrhea (6.2%). Deaths resulting from
adverse events were 4.9% with cabazitaxel (primarily
because of neutropenic infections) compared with
1.9% with mitoxantrone. Of note, the dose of cabazitaxel in the TROPIC trial was higher than what was
recommended from phase I evaluation (25 vs 20 mg/
m2), and a follow-up phase III trial (PROSELICA) is
now planned to directly compare cabazitaxel 25 and
20 mg/m2 (NCT01308580). Another phase III trial
(FIRSTANA) will compare cabazitaxel with docetaxel
in the first-line setting (NCT01308567).
Bone-Targeted Therapy
Skeletal complications are major causes of morbidity
in patients with mCRPC. Bisphosphonates, which
inhibit the bone resorbing activity of osteoclasts by
binding to the mineralized bone surface,32 are an established treatment for patients with mCRPC. Based
on the results of three randomized controlled trials,
intravenous zoledronic acid was approved in 2002
to treat patients with bone metastases from multiple
myeloma and solid tumors like prostate cancer.33-35
The prostate cancer-specific trial was in the setting
of mCRPC and showed that the zoledronic acid arm
had significant reduction in the frequency of skeletal
related events (33% vs 44%; P = .021) and prolongation of the median time to develop skeletal-related
events (16 vs 11 months).35 Pain and analgesic scores
were significantly lower in the group treated with
zoledronic acid, but there were no differences in disease progression or OS.
Cancer Control 183
In addition to bisphosphonates, osteoclast inhibition can be achieved by targeting the receptor activator of nuclear factor kappa B (RANK) ligand, a key
component in the pathway for osteoclast formation
and activation.36 Denosumab is a human monoclonal
antibody against the RANK ligand; it inhibits osteoclast-mediated bone destruction. When compared
against zoledronic acid in a phase III trial of 1,904
men with mCRPC, denosumab improved median time
to first on-study skeletal-related event by 3.6 months
(HR = 0.82; P = .008 for superiority).37 The two groups
were similar with regard to OS and time to disease
progression. Rates of adverse events were similar,
except an increased incidence of hypocalcemia (13%
in the denosumab group vs 6% in the zoledronic acid
group; P < .0001). The incidence of osteonecrosis of
the jaw was 2% in the denosumab group and 1% in
the zoledronic acid group. Denosumab was approved
for the treatment of mCRPC patients with bone metastases in November 2010.
The role of denosumab in preventing bone metastasis or death in nonmetastatic CRPC has been
examined. In a study protocol that randomized 1,432
men with CRPC at high risk for bone metastases (PSA
≥ 8 μg/L, PSA doubling time ≤ 10 months, or both)
to denosumab or placebo, denosumab significantly
increased median bone-metastasis–free survival by 4.2
months compared with placebo (29.5 vs 25.2 months;
HR = 0.85; P = .028).38 Denosumab also significantly
delayed time to first bone metastasis (33.2 vs 29.5
months; HR = 0.84; P = .032). However, OS did not
differ between the two groups (denosumab 43.9 vs
placebo 44.8 months; P = .91). Of note, 33 patients
(5%) on denosumab developed osteonecrosis of the
jaw compared with none on placebo. Hypocalcemia
occurred in 12 patients (2%) on denosumab and in 2
patients (< 1%) on placebo. The rates of other adverse
events and serious adverse events were similar in both
groups. Denosumab is not approved by the FDA for
preventing bone metastasis in nonmetastatic CRPC.
Men with multifocal painful bone metastases
and those with persistent or recurrent pain despite
receiving external palliative radiation therapy may
achieve palliation of their symptoms by treatment with
bone-targeted radioisotopes such as samarium-153
and strontium-89.39 Among the bone-targeted radioisotopes, radium-223, an alpha emitter, was the only
one that has been shown to improve survival by a
phase III trial. In the ALSYMPCA phase III trial, 922
men with symptomatic bone metastases from CRPC
were randomly assigned to radium-223 or placebo.40
The majority of the 922 subjects had previously been
treated with docetaxel. A planned interim analysis
observed a statistically significant reduction in the
risk of death with radium-223 compared with placebo
(median survival 14 vs 11.2 months; HR = 0.695; P =
184 Cancer Control
.002). There was also a significant delay in the time to
first skeletal event by 5.2 months (13.6 vs 8.4 months;
HR = 0.61; P = .00046). The incidence of bone pain
was numerically lower compared with placebo (43%
vs 58%), and the incidence of toxicities was similar
in both groups except increased mild hematologic
toxicity in the group treated with radium-223.
Treatment Sequencing and
Combination Strategy
Significant advances have been made in prostate cancer drug development in the past decade (Tables 1
and 2). Several new challenges now confront physicians treating mCRPC. These challenges include identifying the best sequencing of the approved agents for
individual patients and determining how to combine
these agents in a rational way to maximize survival
and minimize toxicity.
The division of patients with mCRPC into chemotherapy-naive and docetaxel-treated populations for
evaluation of androgen-targeting agents has been driven mostly by the motivation to select a trial population
that will minimize the time for obtaining regulatory
approval for a novel agent. With its convenient oral administration, efficacy in disease and symptom control,
survival benefit, and acceptable tolerability, androgen
pathway inhibition with abiraterone acetate and the
upcoming enzalutamide can be a desirable option at
any point in the continuum of mCRPC treatment. Both
agents, as well as TAK-700, have activity in chemotherapy-naive mCRPC based on early phase clinical
trials and are being tested in the phase III setting. The
combination of agents with different mechanisms of
action, namely androgen synthesis inhibition and androgen receptor blockade, for maximal antiandrogen
effect is an area to be explored. Antiandrogen therapy
combined with immunotherapy or chemotherapy and
continuous maximal androgen deprivation beyond
disease progression are potentially beneficial strategies
to be tested. Most importantly, these strategies need
to be tailored to the biology of the patient’s cancer.
Of note, a significant portion of mCRPC patients did
not respond to newer androgen-targeting agents, and
none of these agents are curative. Developing predictive biomarkers and investigating the mechanisms of
resistance are areas of active research.
As the first approved immunotherapy, sipuleucelT is indicated for minimally symptomatic or asymptomatic patients with mCRPC. It is currently the only
FDA-approved treatment that can be given in the prechemotherapy setting and has been shown to improve
survival of mCRPC patients. Given the fact that immunotherapy requires time to work and will likely
work the best with low disease burden, sipuleucel-T
is probably a superior choice as a frontline treatment
when cancer has progressed to the mCRPC stage and
July 2013, Vol. 20, No. 3
remains asymptomatic or minimally symptomatic.
Due to the immunosuppressive nature of corticosteroids and the fact that prednisone is a component
of approved combinations with abiraterone, docetaxel,
and cabazitaxel, the option to use sipuleucel-T requires reviewing immediate prior therapy and estimating the time to next therapy.
As the first agent approved for mCRPC with survival benefit, docetaxel has the longest track record
for symptom control and survival prolongation. It remains the treatment of choice for symptomatic mCRPC
in the chemotherapy-naive setting. For progression
after docetaxel, theoretically, patients now have three
options: sipuleucel-T, abiraterone, and cabazitaxel.
Enzalutamide could be another option after its approval by the FDA. For patients with mCRPC that
progresses on docetaxel within the first 3 months,
abiraterone is a more acceptable choice due to its
suggested taxane resistance. For those who have
poor performance status or residual bone marrow
suppression from prior chemotherapy, abiraterone is
currently the best option based on its proven efficacy
and favorable safety profile. For patients who have
responded to docetaxel before and have progressive
mCRPC while on chemotherapy break, we favor utilizing cabazitaxel rather than reintroducing docetaxel.
When managing mCRPC in patients with newly
approved agents such as abiraterone, it is important
to know that criteria developed by the Prostate Cancer
Working Group 2 (PCWG2) were used to define disease progression in recent phase III clinical trials. In
terms of progression of measurable soft-tissue lesions
by RECIST, the PCWG2 recommends a confirmation
second scan 6 or more weeks later. For prostate
cancer biological therapies or immunotherapy, a target lesion may increase in size before it decreases.
Bone metastasis, which occurred in ≥ 90% of mCRPC
cases,41 is not measurable by RECIST. Bone progression is defined as ≥ 2 new lesions by bone scan. If ≥
2 new lesions are present at the first reassessment, a
confirmatory scan performed 6 or more weeks later
that shows a minimum of 2 or more additional new
lesions is recommended by the PCWG2 to define disease progression in the bone. In terms of symptoms,
the PCWG2 recommends ignoring early changes (≤ 12
weeks) in pain or health-related quality of life in the
absence of compelling evidence of disease progression. These recommendations by the PCWG2 aim
Table 1. — Selected Phase III Trials of Overall Survival Prolongation in Metastatic Castration-Resistant Prostate Cancer
of Action
Control Arm
Clinical Setting
Improvement in
Overall Survival (m)
Abiraterone +
Placebo +
3.9 (14.8 vs 10.9)
4.8 (18.4 vs 13.6)
80.4% chemotherapy-naive
19.6% post-chemotherapy
4.1 (25.8 vs 21.7)
TAX 32726
Docetaxel +
Mitoxantrone +
2.4 (18.9 vs 16.5)
Docetaxel +
Mitoxantrone +
1.9 (17.5 vs 15.6)
Cabazitaxel +
Mitoxantrone +
2.4 (15.1 vs 12.7)
Post-docetaxel or
unfit for docetaxel
2.8 (14 vs 11.2)
Androgen blockade
Bone-targeted therapy
Table 2. — Selected Studies of Advanced Phase III Development for Metastatic Castration-Resistant Prostate Cancer
Mechanism of Action
Androgen blockade
Clinical Setting
Trial ID
Orteronel + prednisone
Placebo + prednisone
Orteronel + prednisone
Placebo + prednisone
Cabazitaxel + prednisone
Docetaxel + prednisone
Dasatinib + docetaxel + prednisone
Docetaxel + prednisone
July 2013, Vol. 20, No. 3
Cancer Control 185
Metastatic castration-resistant prostate cancer (mCRPC)
Metastatic, asymptomatic,
Metastatic, symptomatic,
Metastatic, post-docetaxel
Abiraterone, Enzalutamide
Cabazitaxel, Mitoxantrone
Bone-directed therapy
- Zoledronic acid, denosumab for all bone metastases
- Samarium for symptomatic bone metastases
- Radium-223 prolongs survival
Prostate cancer treatment continuum
Figure. — Current treatment paradigm for metastatic castration-resistant prostate cancer. From Higano CS. New treatment options for patients with metastatic castration-resistant prostate cancer. Cancer Treat Rev. 2012;38(5):340-345. Reprinted with permission from Elsevier.
to ensure a sufficient window of drug exposure and
reduce the reliance on early changes in PSA.
In general, the toxicity profiles of the newly developed antiandrogen therapies — immunotherapy
and bone-targeted therapy — are superior compared
to taxane-based chemotherapy. This advantage allows testing of the combination of different treatment
modalities to improve the outcome of mCRPC. One
example is a phase II randomized, open-label trial of
sipuleucel-T with concurrent compared with sequential
administration of abiraterone acetate plus prednisone
in men with mCRPC (NCT01487863). This trial aims to
study how concurrent vs sequential use of abiraterone
would affect the immune response to sipuleucel-T, and
the primary objective is to evaluate cumulative sipuleucel-T CD54 upregulation. Another approach would be
combining effective treatments earlier in the disease
stage to improve the margin of benefits. The STAMPEDE trial is one example, and the hormone therapy
plus abiraterone combination arm was recently added
to version 8 of the STAMPEDE protocol.
In addition to the underlying tumor biology and
the mechanisms of action for different agents, patient
comorbidities, performance status, and life expectancy
are other important factors in determining how to
sequence or combine different treatment modalities
for mCRPC. Based on the average wholesale price,
the cost of sipuleucel-T for 5 weeks (3 treatments) is
$93,000, 12 weeks of abiraterone is $18,000, 12 weeks
186 Cancer Control
of denosumab (3 injections) is $5,940, and 12 weeks
of docetaxel (4 cycles) is $12,000. Therefore, the decision-making process should incorporate cost-benefit
analyses to determine whether a combination treatment approach is justified for patients with mCRPC.
This is an unprecedented time in the history of clinical
development for patients with metastatic castrationresistant prostate cancer. In the last 2 years, several
large phase III trials demonstrated improvements in
survival rates using novel therapeutic agents with
diverse mechanisms of action (Table 1, Figure). As
our understanding of this heterogeneous disease improves, defining effective combination and sequencing strategies for these active agents will further improve patient outcomes.
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