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Cancer Biology & Therapy 13:11, 1001-1008; September 2012; © 2012 Landes Bioscience
REVIEW
REVIEW
Introduction
In Europe, prostate cancer is the most common cancer a mong men
with 382,000 new cases and 89,000 deaths annually.1 Androgen
deprivation therapy (ADT) is the cornerstone for recurrent or
metastatic prostate cancer, but almost all patients will develop
progressive castration-resistant disease in 12–18 months.2
*Correspondence to: Amelia Altavilla; Email: altamelia@libero.it
Submi tte d: 03/19/12; Accepted: 06/20/12
http://dx.doi.org/10.4161/cbt.21188
The current landscape of treatment of castration-resistant
prostate cancer (CRPC) has recently change d. Cabazitaxel, a new
taxane with potential antineoplastic a ctivity, has been approved
by Food and Drug Administration (FDA) after docetaxel failure.
In a phase III trial, cabazitaxel showed increased overall survival
(OS) compared with mitoxantrone (15.1 vs. 12.7 mo, HR 0.70,
95% CI 0.59–0.83, p < 0.0001). Furthermore, chemotherapy is
not the only strategy available: several studies have shown as
CRPC remains dependent on androgen receptor function for
growth. Abiraterone acetate, an irreversible inhibitor of CYP17,
has also been approved by the FDA after docetaxel failure.
In a phase III trial comparing abiraterone acetate to placebo,
abiraterone showed improvement in OS (14.8 vs. 10.4 mo, HR
0.65, 95% CI 0.54–0.77; p < 0.0001).
This review will discuss current options and the ongoing tri-
als for second-line treatm ent of CRPC including chemotherapy,
hormonal therapies, antiangiogenetic and immune strategies.
Medical strategies for treatment
of castration resistant prostate cancer (CRPC)
docetaxel resistant
Amelia Altavilla,1,†,* Roberto Iacovelli,1,† Giuseppe Procopio,2 Daniele Alesini,1 Emanuela Risi,1 Giuseppe Maria Campennì,1
Antonella Palazzo1 and Enrico Cortesi1
1Department of Radiology, Oncology and Human Pathology; “Sapienza” University of Rome; Rome, Italy; 2Department of Me dical Oncology; Ist ituto Nazionale dei Tumori;
Milan, Italy
†These autho rs contributed equall y to this work.
Keywords: CRPC, second-line therapy, antiangiogenic therapy, chemotherapy, hormone therapy, abiraterone acetate, cabazitaxel,
MDV3100, TAK 700, sipuleucel-T
Abbreviations: CRPC, castration-resistant prostate cancer; FDA, Food and Drug Administration; OS, overall survival; HR, hazard
ratio; ADT, androgen deprivation therapy; ASCO, American Society of Clinical Oncology; ESMO, European Society of Medical
Oncology; PSA, prostate-specific antigen; PR, partial response; PFS, progression-free survival; CI, confidence interval; TPP, time
to pain progression; PSA RR, PSA response rate; PRR, pain response rate; TRR, objective tumor response rate; TTPP, time to PSA
progression; TTP, time to tumor progression; AR, androgen-receptor; RECIST, Response Evaluation Criteria In Solid Tumors;
rPFS, radiographic progression-free survival; LHRHa, luteinizing hormone-releasing hormone agonist; CTC, circulating tumor
cells; BID, bis in die; QD, quaque die; VEGF, vascular endothelial growth factor; PDGF, platelet derived growth factor; TGF,
transforming growth factor; MVD, microvessel density; ECOG, Eastern Cooperative Oncology Group
Mitoxantrone, estramustine and docetaxel are currently
approved for first-line treatment of CRPC. Until 2004, mitoxan-
trone was the only therapy available because it showed improve-
ment in quality of life, pain control and palliation of symptoms
in two randomized trials, although not any benefit in OS over
prednisone alone was reported.3,4
In 2004, two landmark phase III studies have established that
docetaxel plus prednisone is the standard first-line therapy in
CRPC. In TAX327 trial, docetaxel every three weeks demon-
strated a survival benefit over mitoxantrone and weekly docetaxel
(18.9 vs. 16.5 vs. 17.4 mo, respectively).5 An update analysis at
three years confirmed an increased OS for docetaxel compared
with mitoxantrone (19.2 vs. 16.3 mo, p = 0.004).6
The Southwest Oncology Group 99-16 study, comparing
docetaxel plus estramustine to mitoxantrone plus prednisone,
confirmed the increased OS for docetaxel arm (17.5 vs. 15.6 mo,
p = 0.02).7 Furthermore, the addition of estramustine to docetaxel
and prednisone did not provide any clinical advantage and more
digestive and cardiovascular toxicities were reported.8
According to these data, docetaxel plus prednisone is con-
sidered the gold standard first-line chemotherapy for CRPC.
Unfortunately, median OS for patients affected by metastatic
prostate cancer is less than 20 months.
Recently, the FDA approved cabazitaxel and abiraterone ace-
tate as second-line therapies after docetaxel failure. Furthermore,
other agents have been tested in this setting and interesting
results have recently been published. In this article, we review the
current options and the ongoing trials for second-line treatment
of CRPC.
©2012 Landes Bioscience. Do not distribute
1002 Cancer Biology & Therapy Volume 13 Issue 11
quality-of-life assessment was not part of the trial, but satraplatin
showed a positive effect on pain control.
Treatment was well tolerated: hematologic and gastrointestinal
toxicities were more frequent adverse events in satraplatin group,
but in contrast to other platinum analogs, no significant worsen-
ing of renal function or neuropathy occurred with satraplatin.
Because of the lack of survival benefit, the sponsor decided to
not pursue on the drug’s development in prostate cancer.
Cabazitaxel. Cabazitaxel is a novel tubulin-binding taxane
that showed antitumor activity in models resistant to docetaxel
and paclitaxel. Cabazitaxel binds to and stabilizes tubulin and
unlike other taxane compounds, this agent has decreased pro-
pensity for P-glycoprotein-mediated drug resistance. Cabazitaxel
side effect profile is similar to that reported for other taxanes,
with neuropathy and neutropenia being the most commonly
reported toxicities.
A phase I trial evaluated cabazitaxel in 25 patients affected
by advanced solid tumors refractory to conventional therapies.13
Patients were treated with a 3-weekly schedule at four dose levels
(from 10 to 25 mg/mq). Neutropenia was the principal dose-lim-
iting toxicity and the recommended dose for further studies was
20 mg/mq. PR was documented in two patients, both affected by
metastatic prostate cancer and in one case after docetaxel failure.
The lack of effective second-line therapies for CRPC and the
encouraging results of the phase I trial conducted directly to a
phase III study.
The TROPIC is a randomized, multicenter, open-label, phase
III trial undertaken in 26 countries comparing cabazitaxel with
mitoxantrone as second-line therapy in CRPC.14 In this trial
755 men affected by metastatic prostate cancer after progres-
sion with taxane-based chemotherapy were enrolled. Although
the recommended dose was 20 mg/mq in the phase I study,
25 mg/mq of cabazitaxel was used in the phase III trial based
on a previous phase II study conducted in younger women with
metastatic breast cancer.15
Patients were randomly assigned to treatment groups: 378
received cabazitaxel 25 mg/mq every 3 weeks and 377 received
mitoxantrone 12 mg/mq every 3 weeks, both plus prednisone
10 mg daily. Premedication consisting of corticosteroids, his-
tamine H2-antagonist and antihistamine was administered
30 min before cabazitaxel. The primary endpoint of the study
was OS, the secondary endpoints were PFS, PSA RR, time to
PSA progression (TTPP), TRR, PRR, TPP, time to tumor pro-
gression (TTP) and safety. After a median follow-up of 12.8 mo,
cabazitaxel showed an improvement in OS (15.1 vs. 12.7 mo)
with a 30% reduction in relative risk of death (HR 0.70, 95%
CI 0.59–0.83, p < 0.0001). PFS (2.8 vs. 1.4 mo, p < 0.0001),
PSA RR (39.2 vs. 17.8%, p = 0.0002), TRR (14.4 vs. 4.4%, p =
0.0005), TTP (8.8 vs. 5.4 mo, p < 0.0001) and TTPP (6.4 vs. 3.1
mo, p = 0.001) were all in favor of cabazitaxel arm. PRR (9.2 vs.
7.7%, p = 0.63) and TPP were similar in the two groups.
Grade 3– 4 related adverse events were: anemia, neutropenia
(82% for cabazitaxel vs. 58% for mitoxantrone, febrile 8% vs.
1% respectively) and diarrhea (23% vs. < 1%). Death within
30 days from the last infusion was reported in 5% of patients
treated with cabazitaxel and 2% treated with mitoxantrone,
Methods
We performed a review of publications identified through
searches of Medline/PubMed from 2000 to the present, with
particular focus on phase II/III trials. Abstracts from annual
oncology meeting [e.g., American Society of Clinical Oncology
(ASCO) and European Society of Medical Oncology (ESMO)]
were taken into account. The ongoing phase II/III trials were
searched from www.clinicaltrials.gov. Studies evaluating radio-
therapy and systemic isotope therapy were not considered.
Chemotherapy
Satraplatin. Satraplatin is an oral platinum compound that
forms platinum-DNA adducts and cross links but is not suscep-
tible to some cisplatin resistance mechanisms. Phase I trials have
tested satraplatin in different types of tumors and have explored
several different dosing schedules, from daily dose for 5 days to
a single dose every 3 weeks. Because of myelosuppression, the
recommended dose and schedule is 100 and 120 mg/mq, for pre-
viously treated and untreated patients, for 5 days repeated every
4–5 weeks.9
A phase II trial evaluated safety and antitumor activity of satra-
platin in 39 patients affected by CRPC.10 Satraplatin was admin-
istered at 120 mg/mq for 5 days every 4 weeks. Twenty-six percent
of patients had prostate-specific antigen (PSA) decline > 50% and
10% of patients with measurable disease had partial response
(PR). Most frequent grade 3 –4 toxicities were hematologic (54%
thrombocytopenia, 52% neutropenia, 24% anemia) and gastroin-
testinal (28% diarrhea, 16% vomiting and 13% nausea).
The important side effects reported in the phase II led to two
phase III studies based on different dose and schedule. The first
one was prematurely closed to further accrual by the sponsoring
company.11 In this trial, satraplatin at dose of 100 mg/mq for 5 d
every 5 weeks plus prednisone was compared with prednisone
alone as first-line chemotherapy in CRPC. The ad hoc analy-
sis of 50 enrolled patients showed improvement in progression
free survival (PFS; 5.2 vs. 2.5 mo; HR 0.50, 95% CI 0.28– 0.92,
p = 0.02) and OS (14.9 vs. 11.9 mo) for satraplatin arm but the
advantage in OS was not statistically significant due to the small
sample size. These data led to the SPARC trial where satraplatin
was compared with placebo on 950 patients affected by CRPC
progressing after one prior chemotherapy. They were randomly
assigned (2:1) to receive satraplatin 80 mg/mq for 5 days every
35 days or placebo, both plus prednisone 10 mg daily.12 Crossover
between treatment arms was not allowed. Primary endpoints of
the study were OS and PFS, secondary endpoint was time to pain
progression (TPP), exploratory endpoints were PSA response
rate (PSA RR), pain response rate (PRR) and objective tumor
response rate (TRR). PFS was 11.1 vs. 9.7 weeks, p < 0.001, HR
0.67 (95% CI 0.57–0.77, p < 0.001) and median TPP was 66.1
vs. 22.3 weeks, p < 0.001, both higher in satraplatin arm. PSA
RR (25.4% vs. 12.2%, p < 0.001), PRR (24.2% vs. 13.8%,
p = 0.005) and TRR (8 vs. 0.7%, p = 0.002) were all in favor
of satraplatin. Median OS was 61.3 weeks for satraplatin and
61.4 weeks for placebo (HR 0.98, 95% CI 0.84–1.15, p = 0.80). A
©2012 Landes Bioscience. Do not distribute
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activated by other endogenous steroids as those produced by
adrenal gland.18,19
Several molecules with antiandrogen activity are currently
under investigation in CRPC patients who have received or not
docetaxel: abiraterone acetate, MDV3100 and TAK-700.
Abiraterone acetate. Abiraterone acetate is an orally active
acetate salt of the steroidal compound abiraterone with anti-
androgen activity (Fig. 1). Abiraterone inhibits the enzymatic
activity of steroid 17alpha-monooxygenase (17alpha-hydrolase /
C17,20 lyase complex), a member of the cytochrome P450 family
that catalyzes the 17alpha-hydroxylation of steroid intermediates
involved in testosterone synthesis. Administration of this agent
may suppress testosterone production from testes and adrenal
glands to castrate-range levels.
Preclinica l data revealed a s 17-(3 -pyridyl)androst a-5,16-dien-3
β-ol (CB7598) is a potent steroidal inhibitors of cytochrome
P450 (17) α, a key enzyme for androgen biosynthesis.20
Two phase I studies demonstrated safety and activity of abi-
raterone acetate in patients with CRPC.21, 22 A total of 54 patients
were enrolled and received once daily orally escalating dose of
abiraterone: from 250 to 1,000 mg in patients previously treated
with ketoconazole and from 250 to 2,000 mg in ketoconazole-
naïve patients. The most common adverse events were fatigue,
hypertension, headache, nausea and diarrhea, which were pre-
dominantly grade 1–2. The most frequent treatment-related
grade 3–4 toxicities were hypertension, hypokalemia, constipa-
tion, diarrhea, muscular weakness and arthralgia.
The pharmacokinetics analysis showed as abiraterone acetate
was rapidly converted to abiraterone, confirming the intrapatient
variability of metabolism and the influence of food. Particularly,
the absorption was significantly extended after food intake
and drug exposure was significantly increased (by 4.4-fold) by
high-fat content food, compared with fasting administration.
These studies did not show any cross-resistance between keto-
conazole and abiraterone acetate and the recommended dose for
respectively. The most frequent cause of death in the cabazitaxel
group was neutropenia and its clinical consequences. The higher
risk of death within 1 month from the last drug dose and high
rates of neutropenia and diarrhea suggest that cabazitaxel treat-
ment requires careful monitoring. Prophylactic use of granulo-
cyte colony-stimulating growth factors and dose modifications
can be considered correct strategies to manage side effects. To
assess whether a lower dose of cabazitaxel has a better safety pro-
file with the same efficacy, a phase III trial has been designed.
The PROSELICA trial (NCT01308580) compares cabazitaxel
at 25 mg/mq vs. cabazitaxel at 20 mg/mq, both every 3 weeks
in combination with prednisone. The primary endpoint of the
study is OS and the secondary endpoint is PFS.
Considering the improvement in OS and the manageable tox-
icity profile, cabazitaxel has been approved by the FDA as second-
line treatment for CRPC.
Hormonal Strategies
After an initial response to ADT, about 90% of patients with
metastatic prostate cancer register an increase of serum PSA con-
centrations, with or without radiological progression of disease,
and develop site-related symptoms which indicate the androgen-
receptor (AR) reactivation after a time variable of length from
months to several years.16 These events characterize a different
phase of disease, referred as CRPC, with the development of a
clone of cells insensible to the ADT.17
Over the past decade, several studies have shown that CRPC
remains dependent on AR function for growth. The molecular
basis for AR reactivation remains unclear, but some possible
mechanisms include increased AR expression, AR mutations
that enhance activation by weak androgens and AR antagonists,
increased expression of transcriptional coactivator proteins and
activation of signal transduction pathways that can enhance
AR responses to low levels of androgens. Moreover AR may be
Figure 1. Mechanism of action of Abiraterone acetate.52
©2012 Landes Bioscience. Do not distribute
1004 Cancer Biology & Therapy Volume 13 Issue 11
whose metastatic CRPC had previously been treated with one or
two chemotherapeutic agents, included docetaxel. Patients were
randomized 2:1 to receive abiraterone acetate 1,000 mg once
daily or placebo, each with prednisone 5 mg twice daily continu-
ously. OS was the primary endpoint of the study and the second-
ary were TTPP, PSA RR, radiographic progression-free survival
(rPFS) and TRR.
The 797 patients in the abiraterone acetate arm reported a
median OS of 14.8 months compared with 10.4 months of the
398 patients who received placebo (HR 0.65, 95% CI 0.54–0.77,
p < 0.0001). Moreover, significant differences emerged between
placebo and treatment groups for all secondary endpoints, includ-
ing TTPP (10.2 vs. 6.6 mo, p < 0.0001), rPFS (5.6 vs. 3.6 mo, p <
0.0001), PSA RR (29% vs. 6%, p < 0.0001) and TRR (14 vs. 3%,
p < 0.001).26 The most severe abiraterone-related adverse events
were fluid retention (31 vs. 22% in placebo arm), hypokalemia
(17 vs. 8%) and cardiac disorders (13 vs. 11%). Patients receiving
placebo were permitted to cross over to the abiraterone arm. On
the basis of these results, abiraterone acetate has been approved
by the FDA for CRPC after docetaxel failure on April 2011.
Given its efficacy and manageable toxicities, ongoing tri-
als explore the effects of abiraterone in different setting. A sec-
ond large phase III trial is ongoing involving comparison of
abiraterone acetate 1,000 mg with placebo, both with predni-
sone, in CRPC patients who have not yet received docetaxel
(NCT00887198). A phase II trial is evaluating the role of abi-
raterone and prednisone with an LHRHa agonist as neoadjuvant
and concurrent therapy with external beam radiation in patients
with intermediate-risk or high-risk localized prostate cancer
(NCT01023061). The effect on androgen deprivation by LHRH
and abiraterone combination is currently under investigation in
patients with intermediate-risk or high-risk prostate cancer suit-
able for prostatectomy in a nonrandomized (NCT00924469)
and in a randomized (NCT01088529) phase II trial, comparing
the combined therapy with the LHRHa alone.
Considering the feasibility and safety of combination with
LHRH agonists, future combinations with new-generation
subsequent phase II trials was 1,000 mg daily, supporting the
once daily administration based on the pharmacodinamics and
pharmacokinetics data.
Three phase II studies have been conducted in CRPC patients.
In a first study conducted in patients who did not receive first-
line docetaxel chemotherapy, abiraterone acetate showed a sig-
nificant clinical activity, with a ≥ 50% PSA reduction in 67%
of patients and PR according to Response Evaluation Criteria In
Solid Tumors (RECIST) in 37.5% of patients. Furthermore, the
addition of dexamethasone at disease progression reversed resis-
tance in 33% of patients.23
The other two studies tested the activity of abiraterone acetate
in 105 patients with docetaxel-treated CRPC.24,25 The first trial
reported a ≥ 50% PSA decline from baseline in 51% of patients.
Moreover, ≥ 30% or ≥ 90% PSA decline was reported in 68%
and 15% of patients respectively; 27% of patients with measur-
able disease had PR defined by RECIST criteria.24
The second trial, evaluating the activity of abiraterone ace-
tate plus prednisone, reported a ≥ 50% PSA decline in 36% of
patients and a ≥ 30% or ≥ 90% PSA decline in 47% and 16% of
patients, respectively; PR was observed in 18% of patients with
soft tissue measurable lesions. Both studies showed a period of
169 days TTPP.25
The aforementioned trials demonstrated that treatment with
abiraterone is well tolerated and toxicities could be influenced by
the concomitant administration of steroids. Abiraterone acetate
alone caused hypokalemia, hypertension and fluid retention in
55, 17 and 15% of patients, respectively; on the contrary, the
combined modality caused hypokalemia and fluid retention in
5 and 7% of patients, respectively. Other reported toxicities in
both studies such as fatigue, nausea, anorexia, headache and AST
increase were not influenced by concomitant administration of
steroids.
Recently the results from a pre-specified interim analysis of
the phase III study have been published.26 The COU-AA-301
is a multinational, randomized, double blind, placebo-controlled
trial conducted in 13 countries. The trial enrolled 1,195 patients
Figure 2. Possible algorithm for treatment of docetaxel progressed CRPC.52 PD, progression of disease; CRPC, castration resistant prostate cancer;
ECOG PS, Eastern Cooperative Oncology Group. Performance status; RR, response rate. *Unlike other drugs approved for CRPC patients progressing
during or after docetaxel-based chemotherapy, Sipuleucel-T has been approved for patients with metastatic, asymptomatic or minimally symptom-
atic, hormone-refractory prostate cancer.
©2012 Landes Bioscience. Do not distribute
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was OS, and secondary endpoints included PSA RR, Soft tissues
objective response rate, circulating tumor cells (CTC) count con-
version rate, rPFS, TTPP and time to first skeletal-related event.
Recently, a planned interim analysis revealed that estimated
median OS is 18.4 months for men in the MDV3100 arm com-
pared with 13.6 months for men treated with placebo, with a
reduction of the risk of death by 37% (p < 0.0001, HR 0.631).
PSA RR (54 vs. 1.5%, p < 0.0001), TTPP (8.3 vs. 3.0 mo, p <
0.0001), soft tissue response rate (28.9 vs. 3.8%, p < 0.0001),
rPFS (8.3 vs. 2.9 mo, p < 0.0001) were all in favor of MDV3100.
MDV3100 was also well tolerated and the most frequent adverse
events were fatigue (33.6 vs. 29.1% in the placebo arm), cardiac
disorders (6.1 vs. 7.5%), liver function tests abnormalities (1 vs.
1.5%) and seizure (0.6% vs. 0%)
As a result, the trial’s Independent Data Monitoring
Committee recommended that AFFIRM trial be stopped early
and that men who were receiving placebo be offered MDV3100.31
Further ongoing trials evaluate MDV3100 in different setting.
An ongoing trial will determine the effect of MDV3100 on the
androgen-signaling pathway in order to identify potential pre-
dictors of response or resistance to therapy in patients affected
by prostate cancer with bone metastasis, already treated with
ADT (NCT01091103). MDV3100 is compared with placebo in
patients with metastatic CRPC who have failed ADT but not
yet received chemotherapy (PREVAIL trial, NCT01212991).
Furthermore, a phase II trial is testing the efficacy and safety
of MDV3100 in patients with prostate cancer for whom ADT
is indicated (except when indicated in a neoadjuvant/adjuvant
therapy), with non-castrate level of testosterone (≥ 8 nmol/L)
and PSA ≥ 2 ng/mL (NCT01302041). Another phase II trial
evaluates MDV3100 vs. bicalutamide in men with metastatic
prostate cancer who have failed medical or surgical castration
(NCT01288911).
TAK-700. TAK-700 is an orally bioavailable non-steroidal
androgen synthesis inhibitor of steroid 17alpha-monooxygenase
(17,20 lyase) with potential antiandrogen activity. TAK-700
antiandrogen molecules (MDV3100, TAK-700, etc.) may be fea-
sible as well as the possible combination with chemotherapy.27, 28
MDV310 0. MDV3100 is an orally bioavailable, organic, non-
steroidal small molecule targeting the androgen receptor with
potential antineoplastic activity. MDV3100 inhibits the activity
of prostate cancer cell ARs, which may result in prostate cancer
cell proliferation reduction and, correspondingly, in PSA levels
decline. This compound has been demonstrated to bind ARs in
castration resistant xenograft prostate cancer cells with five to
8-fold greater affinity than bicalutamide, did not show agonist
activity and antagonized the induction of PSA and other genes
regulated by ARs, impairing DNA binding.29
A multicenter phase I–II trial enrolled patients with histologi-
cally proven prostate cancer and progressive castration-resistant
disease, defined by the combination of castrate levels of testoster-
one (< 1.7 nmol/L), and a rising PSA with or without detectable
metastases.30
A total of 140 patients were enrolled, with a median age of
68 years and radiological evidence of metastasis in the major-
ity of patients. Both chemotherapy-naïve and previously treated
patients were enrolled.
MDV3100 was associated with tumor regression and stable
disease in 22 and 49% of patients with soft tissue disease, while
stable disease was shown in 56% of patients with bone metasta-
ses. Median TTPP was 27 weeks and median TTP was 47 weeks.
PSA decline ≥ 50% was observed in 62% of chemotherapy-naïve
patients and in 51% of post-chemotherapy patients.
The most common adverse events were fatigue, nausea, con-
stipation, diarrhea and anorexia. Considering that only 1% of
patients treated at 240 mg or below discontinued treatment for
an adverse event, it was chosen as maximum tolerated dose.
The AFFIRM trial is a randomized, double-blind, multina-
tional phase III trial comparing MDV3100 (160 mg orally per
day) vs. placebo in 1,199 patients with CRPC previously treated
with at least one docetaxel-based chemotherapy.31 Corticosteroids
were not required but allowed. The primary endpoint of the study
Tab le 1. Clinical trials in CRPC after docetaxel progression
Class of drug Molecule Phase
study Patients Comparator PSA-RR (%) ORR (%) PFS
(months)
OS
(months) HR
Chemotherapy
Satraplatin +
prednisoneaIII 950 (2:1) Placebo +
prednisone
25.4 vs 12.4
p < 0.001
8.0 vs. 0.7
p = 0.002
11.1 vs 9.7
weeks
p = 0.001
66.1 vs. 62.9
weeks p = 0.8
0.91 (95% CI,
0.72–1.14)
Cabazitaxel
+ prednisone III 755 (1:1) Mitoxantrone
+ prednisone
39.2 vs. 17.8
p = 0.0002
14.4 vs. 4.4
p = 0.0005
2.8 vs. 1.4
p = 0.0001
15.1 vs. 12.17
p < 0·0001
0.70 (95% CI,
0.59 –0.83)
Immunotherapy SipuleucelbIII 512 ( 2:1) Placebo 2.6 vs. 1.3 N.A. 3.7 vs. 3.6
p = 0.63
25.8 vs. 21.7
p = 0.02
0.76 (95% CI,
0.61–0.95)
Hormonal
Abiraterone
+ prednisone III 1195 (2 :1) Placebo +
prednisone
29.0 vs. 6.0
p < 0.001
14.0 vs. 3.0
p < 0.001
5.6 vs. 3.6
p < 0.001
14.8 vs. 10.9
p < 0.001
0.67, (95% CI,
0.58–0.78)
MDV3100 ±
prednisone III 1199 (2:1) Placebo ±
prednisone
54.0 vs. 1.5
P < 0.0001
28.9 vs. 3.8
p < 0.0001
8.3 vs. 2.9
p < 0.0001
18.4 vs. 13.6
p < 0.0001
0.63 (95% CI, 0.53-
0.75)
Abbreviations: CRPC, castration resistant prostate cancer; PSA-RR, PSA response rate (≥ 50%); ORR, overall response rate; PFS, progression free sur-
vival; OS, overall sur vival; HR, hazard ratio (for OS); CI, confidence inter val. aOnly 51% of patients have received docetaxel; bonly 14.4% of patients have
received docetaxel.
©2012 Landes Bioscience. Do not distribute
1006 Cancer Biology & Therapy Volume 13 Issue 11
tumor measurements increasing > 50% or increase of PSA.
Results showed reduction of bone lesions despite PSA raising,
reporting manageable side effects. In the study’s conclusions, it
is hypothesized an activity only in patients presenting primar-
ily with metastatic bone lesions whereas PSA seems to be a poor
marker of disease progression.
Sunitinib is a tyrosine kinase inhibitor with potential anti-
neoplastic activity in prostate cancer. It acts blocking the tyro-
sine kinase activity of VEGFR2, PDGFR-b and c-kit, thereby
inhibiting angiogenesis and cell proliferation. Sunitinib is cur-
rently considered the best therapeutic approach for patient with
advanced renal cell carcinoma and for the treatment of gastroin-
testinal stromal tumors after disease progression or intolerance to
imatinib mesylate.
Preclinical evidence of sunitinib activity in prostate cancer
cells41,42 leaded to a phase II trial in patients with CRPC after a
docetaxel-based chemotherapy.
The primary end-point of the study was reached, with a PFS
at 12 weeks of 75.8% and a median PFS of 19.4 weeks. Twelve
percent of patients had a ≥ 50% PSA decline and 21% had a
≥ 30% PSA decline compared with baseline; decrease of mea-
surable disease and of pain score were also reported. A favorable
safety profile characterized by fatigue, anemia, nausea, anorexia
and neutropenia as the most common toxic effects was also dem-
onstrated.43 Despite these encouraging results, the subsequent
phase III trial was prematurely closed due to lack of any advan-
tage compared with placebo.
Bevacizumab, a recombinant humanized monoclonal anti-
body directed against VEGF, was also tested in CRPC patients.
Particularly, at the 2010 ASCO Annual Meeting was reported
that bevacizumab plus docetaxel/prednisone prolongs PFS as
first-line therapy but is unable to prolong OS compared with
docetaxel/prednisone in a phase III trial.44
Moreover, a combined therapy with docetaxel and bevaci-
zumab was administered to a group of highly pretreated patients
with CRPC in a non randomized phase II trial.45 The combina-
tion showed a favorable safety profile with grade 4 toxicity lim-
ited to neutropenia and thrombocytopenia and a ≥ 50% PSA
decline in 55% of patients. Objective responses were observed in
37.5% of patients with measurable disease.
In conclusion, angiogenesis remains an attractive target in
prostate cancer although clinical trials did not show any encour-
aging result. Current data are extremely confused due to hetero-
geneity of studied populations and of endpoints used. Probably,
deeper insights in prostate cancer biology and a better under-
standing of the optimal timing of the angiogenic switch may
improve the clinical activity of these therapeutic strategies in
CRPC patients.
Immune strategies. The IMPACT study showed first as ther-
apy with the autologous vaccine sipuleucel-T yielded an improve-
ment in OS compared with placebo in CRPC patients.
Sipuleucel-T is an active cellular immunotherapy, a type of
therapeutic cancer vaccine, consisting of autologous peripheral-
blood mononuclear cells, including antigen-presenting cells, that
have been activated ex vivo with a recombinant fusion protein
(PA2024). PA2024 consists of a prostate antigen, prostatic acid
binds to and inhibits the steroid 17alpha-monooxygenase in
both the testes and adrenal glands, thereby inhibiting androgen
production.
TAK-700 has shown impressive activity in a phase I/II
study.32,33 In the first portion of the study,32 26 patients affected
by metastatic CRPC received TAK-700 at five doses levels (from
100 to 600 mg BID, plus prednisone 10 mg daily). All patients
receiving at least 300 mg BID had a PSA decrease. The most
common adverse events were fatigue, nausea, constipation,
anorexia and vomiting.
The second portion of the study33 is a open-label, multicenter,
phase II trial evaluating four additional dose cohorts (300 mg
BID, 400 and 600 mg BID plus prednisone 10 mg daily, 600 mg
QD). Patients enrolled have not received prior chemotherapy,
have baseline testosterone < 50 ng/dL and PSA ≥ 5 ng/ml. TAK-
700 appears well tolerated and active in all groups. PSA decline
≥ 50% at 12 weeks was observed in 63, 50, 41 and 60% of
patients in the 300 mg BID, 400 and 600 mg BID plus pred-
nisone and 600 mg QD groups. At 12 weeks, median dehydro-
epiandrosterone sulfate, testosterone levels and CTC numbers
decreased from baseline in all groups.
An ongoing phase III trial (NCT01193257) evaluates TAK-
700 vs. placebo, both with prednisone, in patients with CRPC
who have progressed following taxanes-based therapy.
Antiangiogenic and Immune Strategies
Antiangiogenic therapies. Tumor angiogenesis is a well-known,
crucial target in many solid tumors such as colon, lung, breast
and renal cancer. Antiangiogenic therapy represents as well a
fashionable approach in advanced prostate cancer treatment.
Main markers of angiogenesis such as vascular endothelial
growth factor (VEGF), platelet derived growth factor (PDGF),
and transforming growth factor (TGF) are highly expressed in
prostate carcinoma compared with nonmalignant prostate cells.34
Moreover, angiogenesis (measured as microvessel density, MVD)
seems to be correlated with tumor stage, grade and clinical course
in prostate cancer.35,36
Some antiangiogenic strategies have been studied and are
currently under investigation in patients with CRPC. Tyrosine
kinases inhibitors including sorafenib, sunitinib and cediranib
or monoclonal antibodies against circulating VEGF have been
tested in phase II-III trials.
Sorafenib is a synthetic compound targeting RAF kinase, a
critical component of the RAF/MEK/ERK signaling pathway
that controls cell division and proliferation. In addition, sorafenib
inhibits vascular endothelial growth factor receptor 2/platelet
derived growth factor receptor β (VEGFR-2/PDGFR-β) signal-
ing cascade, thereby blocking tumor angiogenesis. In prostate
cancer cell lines, sorafenib inhibits ERK phosphorylation and
induces apoptosis.37
Three phase II38-40 tested sorafenib at the dose of 400 mg orally
twice daily in CRPC patients, but only one included patients that
have received a previous line of chemotherapy.38 In this trial the
primary endpoint was disease progression, defined as either the
appearance of new lesions or unidimensional or bidimensional
©2012 Landes Bioscience. Do not distribute
www.landesbioscience.com Cancer Biology & Therapy 1007
(14.4% for cabazitaxel and 14% for abiraterone). Patients with
an ECOG performance status of 2 represent only a small part
(about 10%) of the study population of the main phase III trials.
For them, best supportive care is still a feasible option. Recent
data have demonstrated that a previous duration of prostate can-
cer sensitivity to ADT ≥ 16 months is a predictive factor for
efficacy of subsequent endocrine manipulations in patients with
CRPC.48
Furthermore, new biomarkers predictive of efficacy have to be
evaluated. Until now, PSA has been the most studied biomarker
of disease evolution for prostate cancer, but some data suggest
that it is not a surrogate of survival in all phases of disease.49
Recently, there is a strong interest for CTC and it has been dem-
onstrated that pre-treatment CTC count is an independent pre-
dictor of OS in CRPC.50 The role of CTC count in second-line
setting is still under investigation, but it appears promising.51
Further trials have to be designed to better understand how
to use the new agents in sequence or in combination for treating
CRPC. Results of the ongoing trials evaluating hormonal treat-
ments after ADT failure (NCT00887198 for abiraterone and
PREVAIL trial for MDV3100) are awaited to better define the
role of docetaxel in CRPC.
Nowadays we have more opportunities than in the past, so
next challenge should be to find out the best sequential ther-
apy after docetaxel failure and a possible third-line for selected
patients.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
phosphatase, that is fused to granulocyte-macrophage colony-
stimulating factor, an immune cell activator.
Although the IMPACT study was designated to assess
Sipuleucel-T in first-line setting, the trial enrolled patients who
had received docetaxel (15%). The results confirmed an improve-
ment in OS (25.8 vs. 21.7 mo, HR 0.78, 95% CI 0.61–0-98,
p = 0.03) for the whole group.46
Conclusions
All these data show the traditional approach to CRPC progressed
after docetaxel in first-line therapy is changing. Cabazitaxel, abi-
raterone acetate, Sipuleucel-T and MDV3100 have demonstrated
improvement in OS in second-line setting (Table 1).
Although new drugs are available, many questions should be
resolved as the best sequence after docetaxel failure or the selec-
tion of appropriate predictive factors of response to second-line
therapies.
Further clinical trials are needed to better understand which
patients will most benefit from a second-line cytotoxic chemo-
therapy rather than hormonal approaches. Probably patient’s
conditions, response and toxicities reported with previous thera-
pies and the history of disease may be the most useful parameters
in clinical practice before that new guidelines will be published.
In asymptomatic patients, timing of treatment is not clear and it
should be tailored individually (Fig. 2).47 Symptomatic patients
need a rapid response rate to improve pain and disease related
symptoms. For them, both cabazitaxel and abiraterone should be
considered an appropriate treatment, reporting the same TRR
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