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ARTICLE IN PRESS
Critical Reviews in Oncology/Hematology xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Critical Reviews in Oncology/Hematology
journal homepage: www.elsevier.com/locate/critrevonc
Expert opinion on first-line therapy in the treatment of castration-resistant
prostate cancer
Pablo Maroto a,∗ , Eduardo Solsona b , Enrique Gallardo c , Begoña Mellado d , Juan Morote e ,
José Ángel Arranz f , Francisco Gómez-Veiga g , Miguel Unda h , Miguel Ángel Climent i , Antonio Alcaraz j
a
Department of Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Department of Urology, Instituto Valenciano de Oncología, Valencia, Spain
c
Department of Oncology, Parc Taulí Sabadell Hospital Universitari, Sabadell, Barcelona, Spain
d
Department of Medical Oncology, Hospital Clínic, Barcelona, Spain
e
Department of Urology, Hospital Vall dı́Hebrón, Barcelona, Spain
f
Department of Oncology, Hospital General Universitario Gregorio Marañón, Madrid, Spain
g
Department of Urology, Hospital Universitario de Salamanca, Salamanca, Spain
h
Department of Urology, Hospital de Basurto, Bilbao, Spain
i
Department of Urology, Instituto Valenciano de Oncología, Valencia, Spain
j
Department of Urology, Hospital Clínic, Barcelona, Spain
b
Contents
1.
2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Classification of patients for first-line therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.1.
Definition of patients ineligible for docetaxel treatment: UNFIT patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.2.
Definition of asymptomatic or minimally symptomatic patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.3.
Risk factors for a rapid symptomatic progression in patients with minimally symptomatic disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.3.1.
Gleason score . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.3.2.
Absolute PSA level and PSA doubling time . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.3.3.
Hemoglobin, alkaline phosphatase, and lactate dehydrogenase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.3.4.
Neutrophil/lymphocyte ratio . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.3.5.
Tumor burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.3.6.
Testosterone levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.3.7.
Radiological progression-free survival . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.3.8.
Poor response to prior hormone therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.3.9.
Prior ketoconazole therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.4.
Symptomatic patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.5.
Patients with visceral metastases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.6.
Molecular biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.
Cross-resistance between abiraterone and docetaxel and between abiraterone and enzalutamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.
When to finalize first-line therapy? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.
Discussion and algorithm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Authors contribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
a r t i c l e
i n f o
Article history:
Received 27 August 2014
Received in revised form 26 June 2015
Accepted 28 July 2015
a b s t r a c t
Treatment of metastatic castration-resistant prostate cancer (mCRPC) has been revolutionized in recent
years. It is well known that androgen receptor is still active in most patients with disease progression and
serum testosterone levels <50 ng/dL. Moreover, further hormonal maneuvers, either through decreasing
androgen levels (abiraterone) or by targeting the androgen receptor (AR) pathway (enzalutamide), prolong survival. In addition, a new cytostatic able to overcome docetaxel resistance, cabazitaxel, and the
radioisotope radium 223 have been incorporated to the armamentarium of mCRPC.
∗ Corresponding author at: Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Mas Casanovas s/n, 08025 Barcelona, Spain. Fax: +34 935565769.
E-mail address: [email protected] (P. Maroto).
http://dx.doi.org/10.1016/j.critrevonc.2015.07.011
1040-8428/© 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Maroto, P., et al., Expert opinion on first-line therapy in the treatment of castration-resistant prostate
cancer. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.07.011
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2
Keywords:
Castration-resistant prostate cancer
Hormone therapy
Cabazitaxel
Prognostic factors
Consensus
Algorithm
mCRPC is not only a heterogeneous tumor, it changes over time developing neuroendocrine features or
selection of clones resistant to hormonal maneuvers. In addition, the multiplicity of current treatments,
make it necessary to design algorithms that help the specialist to choose the most appropriate treatment
for a particular patient. The lack of randomized trials comparing face to face the different available options
limit the scope of this review. In this article, the authors describe the prognostic factors for first line therapy
in patients with mCRPC, and propose a treatment algorithm for mCRPC based on the levels of scientific
evidence available and, if not available, on the consensus between medical professionals. Finally, the panel
discuss how to define progressive disease in the setting of mCRPC and treatment with targeted therapies.
© 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
The management of metastatic castration-resistant prostate
cancer (mCRPC) has undergone a radical change in recent years
with the development of new therapies targeting AR—abiraterone
(AA) and enzalutamide (ENZ)—a new taxane able to overcome docetaxel resistance—cabazitaxel (CBZ)—and a radioisotope, radium
223. They have all shown to prolong overall survival (OS) in patients
with mCRPC progressing after docetaxel-based chemotherapy
[1–4]. In addition, AA and ENZ have also achieved OS benefits
in chemo-naïve minimally symptomatic patients, in which only
one immunotherapy—sipuleucel-T—had previously done so [5–7].
Still, 10 to 20% of patients are primarily refractory to either AA or
ENZ [5,6]. Adequate characterization of those patients would avoid
undesirable delays of potentially more successful therapies.
In 2004, the combination of docetaxel and prednisone was first
able to demonstrate a survival benefit in mCRPC patients and it is
considered the standard of care (SOC) [8,9], although there is no a
clear consensus for the optimum timing to be initiated [10–13].
Besides docetaxel, in first line therapy, physicians in charge of
patients with mCRPC have available three treatments for which
there is strong evidence of survival as well as QoL benefit, with a
favorable benefit-risk profile: AA, ENZ, and radium 223 (for patients
with predominantly bone metastases). Because of this, the classification of pre-docetaxel and post-docetaxel setting is old fashion
nowadays. Guidelines should contemplate therapy with a first line
therapy, either docetaxel, radium-223, AA or ENZ, and subsequent
second and third-line therapies. Discussion with the patient and
into multidisciplinary teams about the best therapy for patients
progressing under castrate levels of testosterone is imperative,
incorporating a more modern classification between asymptomatic
and symptomatic patients [14].
In order to perform clinical trials in more homogeneous groups
of patients, the Prostate Cancer Trials Working Group (PCWG2)
established 5 clinical subgroups ranging from a patient with local
progression (subtype 1) to a metastatic patient with visceral
involvement (subtype 5) [15]. The PCWG2 recognizes the absence
or presence of symptoms as a prognostic factor, but not as a stage
of progression of the disease itself [15]. The classificationı́s final
aim is to define patient groups in which treatment intervention
should have low toxicity —because of excellent prognosis and
asymptomatic disease—or groups where a higher level of toxicity
could be acceptable due to symptomatic disease and poor prognosis. The pivotal studies of AA and ENZ in chemo-naïve patients
included asymptomatic patients where a low toxicity profile seems
a prerequisite to establish a new therapy [5,6]. Otherwise, a new
concept emerges from the ALSYMPCA study, where radium 223 was
compared to placebo in symptomatic patients with only or predominantly bone metastases that had received chemotherapy, refused
chemotherapy or were considered “not suitable for chemotherapy”,
a term that should be better defined [4].
The importance of including chemotherapy in the management of mCRPC despite the number of new therapeutic
options is enhanced after the publication of the results from
the CHAARTED—ECOG 3805 study, wherein patients with high
tumor burden, early introduction of docetaxel still in the hormonesensitive disease setting, provided a benefit in survival. In this trial,
patients defined as with high tumor burden (defined by present
of visceral metastases, or presence of extra-axial bone metastases) receiving docetaxel plus androgen deprivation therapy had
a median survival of 49.2 months vs 32.2 in patients receiving only
androgen deprivation therapy. Although a similar trial previously
published was negative, the GETUG trial, there are subtle differences between the CHAARTED and GETUG trials in terms of trial
design and patient population recruited that may lead to different
clinical outcomes, including the CHAARTED trial patients with far
advanced disease [16,17].
A third trial, STAMPEDE (Systemic Therapy in Advancing or
Metastatic Prostate Cancer: Evaluation of Drug Efficacy), have communicated evidence of the benefit in terms of overall survival
of adding docetaxel in the hormone-sensitive setting for patients
either with advanced locoregional or metastatic disease [18]. Since
2005, more than 6500 men with prostate cancer were recruited
making STAMPEDE the largest randomized study to date. The addition of new therapies as well as a change in the standard of care
for this growing cancer population can be expected from this study
that is still ongoing in the UK.
Four were the therapies analyzed in the study and 2962 the
hormone-naïve prostate cancer patients assigned to either of the
following groups: SOC with androgen deprivation therapy for at
least three years and radiation therapy for eligible patients; SOC
with six cycles of docetaxel; SOC with zoledronic acid for two years;
and SOC with both docetaxel and zoledronic acid. The addition of
zoledronic acid to hormonal therapy, either alone or with docetaxel,
did not improved survival in comparison to SOC with docetaxel
alone. On the other hand, the addition of docetaxel showed an
improvement in survival from 43 months to 65 months in men
with detectable metastatic disease (61% of the 2962 men included
in the analysis). The overall survival in the docetaxel arm (after a
median follow-up of 42 months) was 77 months (24% improvement) in comparison to 67 months of the standard of care arm. The
time to relapse of the docetaxel arm also showed an increase by
38% in all the patients.
These results will lead to a change in the current metastatic
prostate cancer therapy towards the early introduction of docetaxel to patients with hormone sensitive disease. Moreover, the
meaning of these results may also influence the management of
hormone-refractory disease since the benefit of the early introduction of chemotherapy surpasses the benefit of chemotherapy
in more advanced disease.
The objective of the panel when elaborating this guideline was
to help define the optimum first-line therapy for each individual
patient. As there is no randomized information, this objective can
Please cite this article in press as: Maroto, P., et al., Expert opinion on first-line therapy in the treatment of castration-resistant prostate
cancer. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.07.011
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only be reached through a rigorous review of the available evidence
and through the consensus of the specialists involved in mCRPC
management. Medical oncologists and urologists have collaborated
in the elaboration of the present manuscript. Finally, definition of
progressive disease as well as a short review of modern predictive
molecular factors are included.
2. Classification of patients for first-line therapy
Patients with CRPC can be included into two groups: those eligible and those ineligible for docetaxel chemotherapy. Patients
ineligible for chemotherapy might follow hormonal therapy
(although there is no information of the risk/benefit ratio or quality
of life in this population from specifically designed clinical trials)
or radioisotopes if they had predominantly bone metastatic disease and are symptomatic. Patients eligible for chemotherapy are
classified according to the presence or absence of symptoms. In
addition, a special consideration is made for patients with visceral
metastases.
2.1. Definition of patients ineligible for docetaxel treatment:
UNFIT patients
Docetaxel-based chemotherapy has a number of contraindications. Absolute contraindications may include poor general
condition (ECOG 3 and most ECOG 2 patients), poor bone marrow
reserve (baseline neutrophil count <1500/mm3 ), hypersensitivity
to the active substance or any of its excipients and poor organ
function (serum bilirubin > normal range and/or SGOT y SGPT values > 3.5 times the upper limit of the normal range) [19]. Relative
contraindications—with a recommendation of special precaution
of use—include age-related comorbidities not related to prostate
cancer, and persisting frailty after an appropriate geriatric assessment according to the International Society of Geriatric Oncology
(SIOG) criteria since the adverse events of chemotherapy may be
exacerbated in such patients [19,20]. Finally, patients may refuse
chemotherapy. These patients could have been included in the
ALSYMPCA trial if they were symptomatic and had predominantly
bone disease [4].
2.2. Definition of asymptomatic or minimally symptomatic
patients
The pivotal trial for docetaxel, TAX327, included both symptomatic and asymptomatic patients. However, in a time when there
were no other therapeutic options, treatment with docetaxel was
delayed in most of the patients until symptoms developed. In addition, it is well known that the presence of symptoms, specifically
pain, is an adverse prognostic factor in mCRPC [21–23]. The definition of minimally symptomatic patients according to the PCWG2
is intended to identify patients in whom the benefit of docetaxel
treatment can be doubtful or not cost-effective, considering its
associated toxicity [15]. There is no a single standard definition
of minimally symptomatic patients. As this group of patients has
been the object of different randomized trials in the last few years,
to build a definition of minimally symptomatic patients, the panel
considered the inclusion and exclusion criteria in these trials.
The IMPACT trial (sipuleucel-T vs placebo) initially included
asymptomatic patients with a Gleason score ≤ 7, although subsequently allowed the inclusion of patients with any Gleason
score and mild symptoms [7]. Patients with a performance status (PS) > 2, visceral metastases, bone events (long bone fractures,
spinal cord compression, prior radiotherapy or surgery) or who
had received more than 2 previous lines of chemotherapy were
excluded; therefore, this was not a first-line treatment only trial [7].
3
Table 1
Criteria to define asymptomatic or minimally symptomatic patients with mCRPC
[5–7,22–25].
Inclusion criteria
PS 0-1 or Karnofsky index > 70%
No pain or pain does not interfere with daily activities of patient and does not
require treatment with opioids
No skeleton-related event during the castration-resistance period
No need for corticosteroid therapy to control symptoms
The COU-AA-302 trial (AA plus prednisone vs. placebo plus prednisone) recruited patients with an Eastern Cooperative Oncology
Group (ECOG) PS of 0 or 1, and with no or minimal symptoms as
assessed by the score of the Brief Pain Inventory–Short Form (BPISF) [5,24]. Patients were considered asymptomatic if they had a
score of 0 or 1, and minimally symptomatic if they had a score
of 2 or 3 on any of the questions [5]. The PREVAIL trial (ENZ vs
placebo) recruited patients with PS 0-2, BPI-SF < 4, and analgesia
below the third step [6]. The C2144 trial (orteronel vs placebo)
included patients with PS 0-1 and no pain or pain not requiring
opioids and excluded those with a history of spinal cord compression, hydronephrosis or urinary obstruction, prior radioisotopes or
radiotherapy and patients requiring continued steroid therapy [25].
The 10TASQ10 trial (tasquinimod vs placebo) recruited patients
with Karnofsky index ≥ 70% who did not require opioids or steroids
for symptom control and who had not previously received palliative
radiotherapy [26]. Finally, ipilimumab was compared to placebo in
patients with PS 0-1 not requiring opioids [27]. The criteria from
the different trials used to define minimally symptomatic disease
are summarized in Table 1.
2.3. Risk factors for a rapid symptomatic progression in patients
with minimally symptomatic disease
Factors of poor prognosis and subsequent risk of rapid disease
progression are classified as histological (Gleason score), biochemical (absolute prostate specific antigen (PSA) level, PSA doubling
time (PSA-DT), hemoglobin (Hb), alkaline phosphatase (AP), albumin, lactate dehydrogenase (LDH), neutrophil/lymphocyte ratio
(NLR) and testosterone levels), and clinical factors (radiological
progression-free survival (rPFS) and type of progression) [1].
2.3.1. Gleason score
In the setting of localized disease, Gleason score is one of the
criteria included in the D’Amico risk classification [28]. A Gleason
score > 8 has been related to an unfavorable course for the development of metastases and mortality in cohorts of patients previously
undergoing radical prostatectomy and/or radiotherapy [28,29]. For
advanced disease, a post-hoc analysis of patients included in the
TAX327 trial showed a benefit in survival for those patients receiving docetaxel with a Gleason score ≥ 7 (HR 0.69, 95% CI 0.52–0.91;
p = 0.009) [30]. These data support those previously reported in a
model used to predict the probability of OS in patients with mCRPC
[22]. The prognostic value of the Gleason scale is, nevertheless, limited by itself due to the fact that tumors with Gleason score < 7 are
almost never represented in randomized trials. In addition, we do
not know what the appropriate cut-off point is. In patients treated
with AA as first or second-line, the Gleason score was not a predictor
of response either in first-line or second-line therapy.
2.3.2. Absolute PSA level and PSA doubling time
In the non-metastatic biochemical failure setting in patients that
underwent radical prostatectomy, PSA-DT is a predictor of survival
[31]. As stratified by different cut-off points (<3.0 vs. 3.0–8.9 vs.
9.0–14.9 vs. ≥15 months), a PSA-DT value < 3 months was associated with mortality attributable to prostate cancer (HR 54.90,
Please cite this article in press as: Maroto, P., et al., Expert opinion on first-line therapy in the treatment of castration-resistant prostate
cancer. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.07.011
G Model
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P. Maroto et al. / Critical Reviews in Oncology/Hematology xxx (2015) xxx–xxx
4
95% CI 16.70-180) [32]. In mCRPC, a short PSA-DT constituted a
poor-risk factor for survival (HR 0.79; p < 0.001) [33]. Nevertheless, there is not an established cut-off point for PSA-DT. One study
showed that a PSA-DT ≤ 70 days (HR 1.79; p < 0.0001) was significantly associated with a shorter survival time than a PSA-DT > 70
days, whereas another study reported mean survival times of 16.5
and 26.4 months for patients with a PSA-DT < 45 and ≥ 45 days
respectively [34,35]. The TAX 327 study set a cut-off point PSA-DT
value > to 55 days as the prognostic value for survival [23].
The absolute PSA level has prognostic value in patients with
mCRPC both in the pre-chemotherapy and post-chemotherapy setting, but it is less consistent than PSA-DT. Two placebo-controlled
studies of atrasentan and zoledronate for prevention of bone metastases showed that absolute PSA levels ranging from 10 and 13
ng/mL were associated with a shorter time to occurrence of the
first bone metastases; however, PSA-DT was a better predictor of
survival [36,37]. A retrospective analysis of the denosumab trial
on prevention of bone metastases showed that the maximum benefit in metastasis prevention was achieved in high-risk patients,
defined by a short PSA-DT [38]. Nonetheless, the update of the Halabi nomogram only included the absolute value of PSA and not
PSA-DT [39].
2.3.3. Hemoglobin, alkaline phosphatase, and lactate
dehydrogenase
Anemia is a well-known adverse prognostic factor in both
symptomatic and asymptomatic mCRPC [22,40]. A subanalysis of
patients treated with docetaxel provided further support for this
finding (HR 1.11, CI 1.03–1.19; p = 0.004) [22].
Bone metastases in mCRPC are characterized by an imbalance
between osteogenesis and osteolysis [41]. AP levels are associated with bone disease and are a predictor of survival in patients
with mCRPC [33,42]. Thereby, in the TAX327 study, AP elevation
above the median was an adverse predictor of survival (HR 1.27; CI
1.15–1.39; p < 0.001) [23]. In the same way, the COU-AA-302 study
showed mean survival times of 23.6 and 27.5 months for AP values
below and above the mean respectively [5]. In a post-hoc analysis of
COU-AA-302, high AP and PSA above the third quartile at baseline
and during treatment represented an added risk of adverse clinical
outcomes in chemo-naïve patients [43]. In patients treated with
radium 223, AP normalization was a favorable factor for survival
[44].
LDH is a marker of tumor burden. Both LDH and circulating
tumor cells (CTC) were prognostic factors for survival in the COUAA-302 trial, patients with LDH levels higher than the median value
had poorer OS [45]. In a study for development and validation of a
model for predicting OS in patients with mCRPC, LDH was identified as an OS predictor (HR 1.37; 95% CI 1.21–1.55; p < 0.001) [22].
These data were supported by a subsequent study on 1296 patients
treated with chemotherapy [46].
Any of these factors individually define a poor prognosis for a
specific patient or predict the results of a therapy, while coexistence of some of them define clearly a group of patients with poor
prognosis. Final analyses of the COU-AA-301 showed anemia, plus
elevation of AP, ECOG, albumin, time from initiation of hormonetherapy to AA and presence of visceral metastases as prognostic
factors for survival, considering as poor prognosis the coexistence
of four to six of these factors in the same patient, showing this subgroup of patients an OS of less than six months [1]. These factors
have also been validated in the pre-docetaxel setting [47].
2.3.4. Neutrophil/lymphocyte ratio
The NLR has been found to be prognostic in many solid tumors,
with high NLR associated with worse OS and higher recurrence
rates [48]. The biological basis of this remains unclear, but is likely
related to altered tumor-inflammatory cell interactions. In men
with mCRPC treated with AA, NLR ≥5 was associated with lower
PSA response rates and shorter survival [49].
2.3.5. Tumor burden
A high tumor burden, evaluated as limited to bone vs bone plus
lymph nodes or visceral metastases, combined with NLR and LDH
levels, was prognostic of survival in patients with mCRPC receiving
AA [49]. The prognostic and therapeutic implications of tumor burden were proved with the communication of the results from the
CHAARTED study, where docetaxel improved survival in patients
with a high tumor burden in the setting of hormone sensitive
metastatic disease[16].
2.3.6. Testosterone levels
Serum testosterone levels, although under castration, are a
prognostic factor for survival. Testosterone escapes in the course
of treatment with hormone blockade are associated with poorer
survival [50]. A small Japanese study of patients progressing on a
LHRH agonist suggests that serum testosterone level is a predictor
of survival and response to bicalutamide rescue therapy [51]. A retrospective analysis of patients with mCRPC enrolled into different
chemotherapy clinical trials suggested better survival in patients
with testosterone even at the highest castration level [51].
A correlation has also been suggested between the probability
of response to salvage hormonal therapy and testosterone level.
Univariate analyses of androgen levels (testosterone and adrenal)
by Ryan et al. was prognostic of survival in patients receiving AA
or placebo, although it was not preserved in the multivariate analyses and was not predictive of response to therapy [52]. Gomez de
Liaño et al. analyzed the prognostic value of testosterone levels in
patients going to first-line chemotherapy [53]. Survival was significantly better for patients with testosterone levels above median
[53]. In addition, preliminary data suggest that testosterone levels
were predictive of response to second-line hormonal maneuvers
[53]. Post-hoc analyses of TAX327 also showed testosterone level
as prognostic of survival, but they were not predictive of the efficacy
of docetaxel [54].
2.3.7. Radiological progression-free survival
Biochemical progression is a prelude to radiological progression, being diagnosed in some trials after a median of 5.7 months
[55]. As a consequence, radiological progression is a further step
in advanced disease. In fact, rPFS is one of the prognostic factors
proposed by the PCWG2 [15,46,56]. Analyses based on patients
enrolled into the TAX 327 trial suggest that the type of progression
has an impact on OS (HR 1.37 for measurable disease progression
and 1.29 for bone progression measured by bone scan, p = 0.005
and 0.01, respectively) [23,56].
2.3.8. Poor response to prior hormone therapy
The quality of the response to prior hormone therapy can be
estimated by the time to PSA nadir, absolute PSA nadir value and
time to castration resistance. Time to PSA nadir more or less than 7
months is a predictive factor for survival in patients with metastatic
hormone sensitive prostate cancer treated with androgen deprivation therapy [57]. Failure to achieve an absolute nadir value
below 4 ng/mL at 6 months is associated with younger age, higher
prestudy PSA, worse performance status, weight change, bone pain,
higher Gleason score (≥8), presence of visceral metastases, and
distant lymphadenopathy [58]. Finally, time to castration resistance is a prognostic factor of survival, and it may constitute a
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predictive factor of response to further hormonal maneuvers. In
patients submitted to second-line hormonal maneuvers with AA,
ketoconazole-hydrocortisone, diethylstilbestrol, and bicalutamide
in five clinical trials, time to castration progression (≥16 vs <16
months) significantly predicted the biochemical response rate (58%
vs 18%) and the progression-free period (5 vs 3 months) [59]. Unfortunately, there is not a clear cut point. It has been published ranging
from 12 months to 24 months [60,61]. In the post-docetaxel study
comparing ENZ with placebo, duration of prior hormone therapy
was a predictor of survival [2]. Time to initiation of AA shorter
than 36 months was one of the prognostic factors included in the
nomogram predictive of survival or the COU-AA-301 [1].
On the other hand, time to castration resistance does not appear
to affect PSA response with docetaxel or cabazitaxel [60].
2.3.9. Prior ketoconazole therapy
The only study in which sensitivity to AA was analyzed in
patients who had received ketoconazole was a phase I trial on
33 patients with mCRPC who had not received chemotherapy, of
whom 19 (58%) had previously been treated with ketoconazole
[60]. In this study, a ≥50% reduction in serum PSA was evaluated
as a treatment response criterion [62]. The results, without providing a high level of evidence, showed that prior treatment with
ketoconazole in the pre-docetaxel phase should not be an exclusion
criterion for treatment with AA, but did suggest a lower efficacy of
the drug in chemo-naïve patients [62].
2.4. Symptomatic patients
In patients with symptoms clearly secondary to the disease,
such as pain from bone metastases (even if it has been controlled
with palliative radiotherapy), lower limb edema (due to growth of
pelvic or retroperitoneal lymphadenopathies), presence of visceral
metastases (even if asymptomatic), or impaired general condition
due to disease progression, chemotherapy with docetaxel continues to be the standard treatment because it has shown a clear
benefit in OS of these patients as compared to mitoxantrone [8,9].
2.5. Patients with visceral metastases
Visceral metastases are uncommon in prostate cancer, but they
are associated to a poor disease course [63]. They are included
as an adverse prognostic factor in both the Halabi and Armstrong
nomograms and in the two pivotal trials of docetaxel [22–24]. In
post-docetaxel randomized studies with CBZ, AA and ENZ, approximately 25% of patients recruited had visceral metastases [1–3]. In
all three studies, presence of visceral metastases was only a prognostic, not predictive factor of response [1–3].
In the scenario of patients with pre-docetaxel mCRPC, no data
are available about use of AA in patients with visceral metastases. In the COU-AA-302 study, comparing AA to placebo, presence
of symptoms or visceral involvement were exclusion criteria due
to the risk of rapid progression [5,64]. On the other hand, 12%
of patients included in the PREVAIL trial had visceral metastases
(lung and/or liver) [65]. Treatment with ENZ still provided a benefit compared to placebo (HR 0.69 and 0.82) [65]. The presence of
visceral metastases was an inclusion criterion in the CHAARTED
study, where patients still with hormone-sensitive disease benefit
in disease survival from docetaxel [16].
Within visceral metastases, hepatic metastases appear to be
specifically correlated with a poorer prognosis. In the randomized
trial of docetaxel and prednisone plus bevacizumab or placebo on
1050 patients with mCRPC, 5.6% had hepatic metastases. Although
presence of these metastases was not significantly associated with
poorer results in the biochemical remission rate or time to pro-
5
gression, poorer overall survival was reported (22 vs 14.4 months;
p < 0.019) [66]. In the subanalysis of patients with visceral metastases in the AFFIRM study, the presence of hepatic metastases
resulted in lower median survival as compared to pulmonary
metastases (9.0 vs 16.5 months in the ENZ arm and 5.7 vs 10.4
months in the placebo arm) [67].
According to the above, the presence of significant visceral or
hepatic metastases is associated with shorter survival in mCRPC.
Taking into account that it is a factor of poor prognosis and the
scarcity of data on the first-line hormonal approach, treatment with
docetaxel seems recommendable in this group of patients [12].
An update of the data from TAX327 by Halabi, et al., showed that
hepatic metastases were the most adverse prognostic for survival
among the visceral ones [39]. In patients with visceral metastases in
other locations, the decision should be individualized based on the
presence of other characteristics of the disease (Gleason, PSA-DT or
tumor volume) (Table 2).
2.6. Molecular biomarkers
In patients with mCRPC, the number of CTC constitutes a
dynamic biomarker. Baseline CTC are prognostic of OS while the
reduction in the number of circulating cells is a surrogate marker
of response to therapy [68,69]; it is accepted that fewer than 5CTC is
a good prognosis parameter, and it probably should be considered
for stratification in clinical trials. Although FDA has approved its use
as a biomarker, the results of ongoing analyses to finally state the
predictive value of early changes in therapy according to number of
circulating cells are still pending. The results of the Olmos study add
to the data already existing on the expression of microRNA profiles
capable of defining prognostic groups [70]. Recently, the androgen
receptor splice variant AR-V7, has been associated to resistance to
ENZ and AA in men with mCRPC [71]. No patient with this splice
variant, showed response to either salvage maneuver [71]. On the
other hand, responses to docetaxel or cabazitaxel do not seem to
be affected by the presence of AR-V7, supporting chemotherapy as
the first-line option for these patients expressing AR-V7 [72].
Automated quantitative determination of bone metastases
using the bone scan index may have diagnostic, prognostic and
predictive value in patients with mCRPC, but it is still subject to
validation [73]. Markers of tumor activity in bone as N-telopeptide
and bone AP (reflecting osteolytic and osteoblastic activity) have
been shown to be prognostic and survival markers [74–77].
Still, there is not one single factor predictive of response either
to hormonal maneuvers or chemotherapy. Different prognostic factors are well established. In nomograms, the combination of those
factors define subgroups of patients with poor prognosis and risk
of rapidly growing disease that might benefit from more aggressive first or second-line therapies. In addition, data coming from
the “West Coast Dream Team” suggest the importance of re-biopsy
to define therapy. Analyses of 124 biopsies in patients resistant to
AA or ENZ found 13% of patients with small cell carcinoma, and
additional 28% with an intermediate-type carcinoma [78]. These
findings have prognostic value and they can have therapeutic implications.
3. Cross-resistance between abiraterone and docetaxel and
between abiraterone and enzalutamide
The data available on sequencing of AA, ENZ, and docetaxel are
even more limited, and no definitive conclusion applicable to clinical practice may therefore be drawn at this time. In a retrospective
analysis conducted on 35 patients who had received AA in phase I/II
studies before receiving docetaxel, patients who had not reduced
their PSA levels by more than 50% were seen to be refractory to docetaxel, and only 26% had a biochemical response [53]. Time to PSA
Please cite this article in press as: Maroto, P., et al., Expert opinion on first-line therapy in the treatment of castration-resistant prostate
cancer. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.07.011
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6
Table 2
Phase III trials in first-line therapy for metastatic castration-resistant prostate cancer.
Agent
Control arm
OS
(months)
Specific differential characteristics
HR
p value
Docetaxel [9]
Orteronel [76]
Abiraterone [1]
Enzalutamide
[2]
Radium 223
[4]
Mitoxantrone
Placebo
Placebo
Placebo
18.9 vs 16.5
15.1 vs 12.7
15.8 vs 11.2
18.4 vs 13.6
Symptomatic and asymptomatic patients
Placebo patients received modern prolonging life therapies
Visceral metastases excluded
Visceral metastases included
0.76
0.70
0.74
0.63
0.009
n.s.
<0.0001
<0.0001
Placebo
14.9 vs 11.3
Patients unfit for docetaxel, refusing chemotherapy or
progressing after docetaxel. Only predominantly bone
mets allowed
0.695
progression was 4.6 months, and OS was 12.5 months [79]. These
results, clearly inferior to those observed in the pivotal docetaxel
trials, could suggest the existence of cross resistance between AA
and docetaxel or simply a more advanced stage of the disease.
On the other hand, the few retrospective studies conducted of
treatment with ENZ after AA and vice versa also suggest a worse efficacy of these drugs as compared to when they are used in patients
without prior second-line treatment [65,80–83]. CBZ might not
have a cross-resistance effect as a result of its dual mechanism of
action, which is less dependent on the androgen receptor [84,85].
4. When to finalize first-line therapy?
Historically, post-treatment changes in PSA have not demonstrated robust associations with survival and not qualified as an
endpoint to support regulatory approval. In addition, the limited
degree of nodal and visceral disease in mCRPC has reduced the
utility of standard imaging outcome measures, which also fail to
accurately assess bone disease, the most common site of spread.
As mentioned above, PCWG2 defined radiological criteria for progressive disease considering patients with either RECIST evaluable
disease or bone only disease. PCWG2 emphasized the need to
maintain men on effective therapies and reduce this misclassification of progression, and these guidelines were incorporated into
nearly every phase II and III trial in CRPC since their development.
Radiological progression-free survival was a surrogate marker of
0.00007
overall survival in the COU-AA-302 trial [86]. Patients and investigators accepted these designs and also accepted that early signs
of progression (for example, increasing PSA) did not necessarily
represent the end of treatment benefit. On the other hand, avoiding exposure to expensive and also ineffective drugs is mandatory,
especially when there are available potential salvage therapies that
may prolong life. The orteronel trial shows that this rule for stopping therapy is adequate, and that salvage therapy avoided any
benefit in survival for orteronel compared to placebo but it implies
that salvage therapy should be delivered at the right time. Confirmed symptomatic disease due to tumor progression should lead
to a salvage therapy. Shortening of PSA-DT might advance a salvage
therapy.
CTC have been considered a possible surrogate marker. Data
from the cabozantinib trial rise doubts: despite a benefit in terms of
response in number of CTC, no differences in survival were observed
between patients receiving orteronel and those receiving placebo.
When several effective therapies are available in clinical practice,
as for mCRPC, multiple parameters should be considered in public
health decisions as long as the novel agents display favorable safety
profiles.
5. Discussion and algorithm
The panel tried to summarize the previous data in an algorithm. First, dividing patients into fit or unfit for docetaxel, then
Fig. 1. Algorithm for first-line treatment in patients with mCRPC.
Please cite this article in press as: Maroto, P., et al., Expert opinion on first-line therapy in the treatment of castration-resistant prostate
cancer. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.07.011
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in symptomatic vs aymptomatic or minimally symptomatic. An
adequate definition of asymptomatic or minimally symptomatic
patients would identify patients with mCRPC at low risk of rapid
progression and, therefore, candidates for a treatment with a low
toxicity profile. As there is no randomized trials, this definition can
only be established by consensus. Some characteristics that define
these patients are summarized in Table 1. In clear opposition, it
would be the symptomatic patient, at risk of rapid progression,
and in a need for the right choice of therapy and rapid respose, for
whom docetaxel is the treatment of choice, as those patients have
not been included in randomized trials and no drug or combination of drugs has been superior to docetaxel in a randomized trial.
In the modern scenario, the introduction of new effective therapies
in chemo-naïve patients, although great news for patients, include
in itself a risk that some patients may not receive docetaxel therapy
at all because their performance status has deteriorated too rapidly
through an unsuccessful treatment by AR-targeted agents. Therefore, evidence may support that the choice of first-line treatment
may have therapeutic implications as well as the delay to salvage
therapy for a patient already progressing [87].
Castration-resistant disease has classically been defined, relative to treatment with docetaxel, as pre- and post-docetaxel. The
definition of a patient in a pre- and post-docetaxel situation, which
is purely artificial, will gradually be replaced by others, such as a
patient resistant or not to treatment to AR targeted agents, as new
definitions of the concept of hormone resistance are incorporated.
For example, the NCCN guidelines, 2015 version, classify patients
for a first-line therapy with docetaxel and patients for a first-line
therapy with AR targeted therapies. With the incorporation of at
least four new effective therapies for castration-resistant patients,
both pre- and post-docetaxel (ENZ, AA, radium 223 and CBZ), the
argument to delay docetaxel administration to reserve the only
effective therapy available disappears. In any case, the availability
of effective therapies in mCRPC with different mechanisms of action
requires to discriminate, by means of clinical or biological markers,
the most adequate sequence of therapies for a specific patient, in
order to optimize the risk-benefit ratio and to avoid undesirable
cross resistance phenomena as a potential consequence of starting
an inadequate treatment.
Pending validation of genetic footprints that correctly classify
patients, we do not currently have predictors of response to a
hormonal or cytostatic treatment. However, we do have prognostic factors which, when taken together, as reflected in numerous
nomograms, allow for defining a population of patients with poor
prognosis and, therefore, at risk of rapid development of symptoms
derived from the disease. Grouping different prognostic factors permits to increase the accuracy of prognostic classifications [88]. The
algorithm proposed by the panel in Fig. 1, in which different prognostic factors are added, defines minimally symptomatic disease
and patients not eligible for treatment with docetaxel, and may
help us with decision-making in patients with mCRPC.
Authors contribution
Dr. Maroto: Honoraria from Astellas, Bayer and Janssen. Participation in clinical trials involving cabazitaxel and enzalutamide.
Dr. Arranz: Participation in clinical trials involving cabazitaxel
and abiraterone.
Dr. Gallardo: Honoraria from Sanofi and Janssen. Participation in
clinical trials involving cabazitaxel, abiraterone and enzalutamide.
Dr. Climent: Honoraria from Sanofi, Janssen, Bayer and Astellas.
Participation in clinical trials involving cabazitaxel and abiraterone.
Dr. Alcaraz: Advisory and speaker from Sanofi, Janssen, Astellas
and GSK.
The authors have received a grant from Sanofi, but without any
influence in the development of this article.
7
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Biographies
Dr. Pablo Maroto graduated in Medicine and Surgery from the University of
Santiago de Compostela, Spain, in 1990; Medical oncology training at Hospital Sant
Pau, Barcelona from March 1992 until March 1996; Ph.D. from Barcelona University
(UAB) in 1997: mobilization of peripheral stem cells: Predictive factors of harvesting; and Uro-Oncology: Member of staff of the Medical Oncology Department of
Hospital Sant Pau since 1999. Clinical Research activity in more than 30 international clinical trials on: bladder cancer; hormone-refractory prostate cancer; germ
cell tumors; and advanced renal cell cancer. Vast experience as a Principal Investigator in different clinical trials, being one of the top Spanish recruiting hospitals.
Participation in phase III clinical trials involving bevacizumab, everolimus, temsirolimus. Participation in expanded access programs of everolimus and sunitinib;
active participation in combination studies involving sorafenib, temsirolimus and
everolimus. The medical and scientific associations related to his career are the
following: Associated Professor of Sant Pau Hospital Nursing School since 2003;
Associated Professor of Barcelona University of Medicine (UAB) since 2006; from
2000 to 2002, executive member of the Catalonian Academy of Medicine; chairman
of the Germ Cell Group specialized in research and treatment of testicular germ cell
tumors since 2012; member of the European Organization for Research and Treatment of Cancer (EORTC);member of the SOGUG (group for the research in the field
of urologic tumors in Spain) since 2000; executive member from 2005 until 2009;
and member of the American Society of Clinical Oncology (ASCO).
Dr. Eduardo Solsona is Chief of the Urology Department. Instituto Valenciano de
Oncología. Valencia. Spain. He graduated from the University of Valencia. Observer
to Cleveland Clinic Foundation. Academic Activities: MD and PhMD from the University of Valencia, Ex-Professor collaborator at Medicine High School of Valencia,
Honorary Professor of Universidad Ricardo Palma of Lima, Peru, Numerary member
of Royal Academy of Medicine of Valencia. Professional Activities: Former Chairman
and member of European Guidelines of Penile Carcinoma Ex-member of Non-Muscle
Invasive Bladder Cancer Team. Guidelines of Bladder Cancer EAU Member of International Consultation on Prostate Cancer 2003 and 2005 Member of International
Consultation on Bladder Cancer 2006, 2011 Member of International Consultation on
Penile Carcinoma 2008 President of Society of Urology of Comunidad Valenciana Coordinator of CUETO group Ex National Co-ordinator of Grupo de Urología Oncológica.
Member of International Societies: European Association of Urology: -Ex member of
Scientific Committee -Member of European Board, Societe d’ Urologie International,
9
Sociedad Española de Urología, Sociedad Valenciana de Urología, Honorary member of Sociedad Peruana de Urología, Honorary member of Sociedad Colombiana de
Urología, Honorary member of Sociedad Bonaerense de Urología, Honorary member
of Romanian Association of Urology. Publications: more than 150 publications, 80
in international journals and 15 chapters of International Books.
Dr. Enrique Gallardo earned his degree in Medicine and Surgery from the University of Seville in 1990. A specialist in Medical Oncology since 1996, after training
at Hospital General Vall d’Hebron in Barcelona between 1992 and 1995. He was
Attending Physician at the Oncology Department of Hospital Vall d’Hebron in 1996
and Clinical Trials Coordinator in the same department between 1996 and 1999, later
becoming Attending Physician at the Oncology Department of Hospital Terrassa in
Barcelona until 2002. He is currently Senior Attending Physician at the Oncology
Department of Corporació Parc Taulí in Sabadell, Barcelona, and responsible for the
Uro-Oncology Unit. He is a member of the Spanish Group for Treatment of GenitoUrinary Tumors (SOGUG) where he is actively involved in Kidney Cancer and Bladder
Cancer Working Groups. He is an active member of the SEOM (Spanish Society of
Medical Oncology), ESMO (European Society of Medical Oncology), ASCO (American Society of Clinical Oncology), IASLC (International Association for the Study of
Lung Cancer) and EORTC (European Organisation for the Research and Treatment
of Cancer), Genito-Urinary Cancer Group. He has participated as a researcher and
designer in many clinical trials in various areas of oncology, especially in urological
tumors, including phase I, II, II and IV trials. He has participated in the development
of Prostate Cancer OncoGuide in Catalonia and SOGUG Kidney Cancer and Bladder
Cancer Guides. He has published around 100 articles, book chapters and communications at national and international meetings. His areas of expertise include the
treatment of urological tumors (kidney, urothelial carcinomas, prostate and germcell tumors) and central nervous system neoplasms. He is also interested in other
cancer-related areas, such as cancer-related thrombosis and supportive care.
Dr. Begoña Mellado is a Consultant Medical Oncologist and Co-chair of the
Urology Cancer Unit at Hospital Clinic I Provincial de Barcelona, Barcelona, Spain.
She graduated in Medicine from the University of Barcelona in 1989, completed her
specialist training in Medical Oncology at Hospital Clinic I Provincial de Barcelona in
1993 and was awarded her PhD by the University of Barcelona in 2002. She has also
held research fellowship positions at the Hospital Clinic I Provincial de Barcelona
(1994) and the Memorial Sloan-Kettering Cancer Center (1995–1996). Since January
2014 she has been Assistant Professor in Medicine at the University of Barcelona. She
is the Leader of the Prostate Cancer Group at the Translational Oncology Research
Laboratory, IDIBAPS, Hospital Clinic, University of Barcelona, and an active member
of the Prostate Cancer Group of the Spanish Genitourinary Oncology Group (SOGUG).
Her research focuses on urological cancer and translational research, particularly
the detection and characterization of circulating tumor cells in prostate cancer, and
molecular mechanisms of resistance to chemotherapy in castrate-resistant prostate
cancer. She has authored or co-authored more than 50 peer-reviewed articles in
these fields.
Dr. Juan Morote is Professor and Chairman of Urology at the Autonomous University of Barcelona and Hospital Vall dı́Hebron. He trained in Urology at Hospital
Vall dı́Hebron in Barcelona, Peter Bent Brigham Hospital in Boston, Lahey Clinic in
Burlington and the Institute of Urology in London. He obtained his PhD in 1986 with
magna cum laude with the thesis: “Prostate specific antigen in human clinic” and
the FEBU in 1992. His area of interest has been prostate cancer since 1984. He directs
the Vall dı́Hebron Prostate Cancer Translational Research Program. He has authored
262 articles in peer review journals and 4 patents. He has served in different positions in a variety of urologic societies, editorial committees of different journals.
From 2006 he has chaired the Board of Urology of the Spanish Ministry of Health.
Dr. José Ángel Arranz, graduated in Medicine from the University of Valladolid,
Spain, in 1985. Certification in Medical Oncology in 1991 after their training in Medical Oncology at Hospital General Universitario Gregorio Marañón, Madrid, Spain,
between 1987 and 1991. Degree in Statistics for Health Sciences in 1994. From 2009
to date he is Chief of Section of Urologic and Gynaecologic Tumors at Hospital General Universitario Gregorio Marañón, Madrid, Spain. Membership of ASCO, ESMO,
SEOM, SOGUG. Author or contributor of many articles and abstracts at international
meetings. Local PI in many clinical trials in Gynaecologic and Urologic Oncology.
Dr. Francisco Gómez-Veiga studied Medicine at the University of Santiago de
Compostela (Spain), where he obtained his degree in Medicine. In 1987–1992, he
completed internship training in Urology at Hospital Universitaria de A Coruña,
where he earned his PhD. His main activities have concentrated on Kidney Transplant and Uro-Oncology. He was the Head of the Uro-Oncology/Prostate Cancer Unit
at Hospital Universitario de A Coruña. Now Head of Urology Department and Kidney Transplant at Hospital Universitario de Salamanca and Associate Professor of
Medicine. He received training at different European and US hospitals on different
techniques and aspects of kidney transplant and oncology. He has been coordinator and member of the steering committee in different clinical trials (CT) and has
vast experience in more than 30 of them. These studies are mainly focused on urooncology. Nowadays, he is the main investigator in 10 running CT, Phase II- III, on
prostate cancer; from local to castrate-resistant prostate cancer, bladder cancer,
kidney tumors and BPH. We are also running different lines on basic research of
Please cite this article in press as: Maroto, P., et al., Expert opinion on first-line therapy in the treatment of castration-resistant prostate
cancer. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.07.011
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prostate and bladder cancer, “Micro-rna and CTC”. He is the co-author of more than
100 published national and international articles. He has contributed to 30 published
books related to kidney transplant and uro-oncology. He is a peer reviewer for the
Urological Journals Actas Españolas de Urología, Archivos Españoles de Urología,
Urology International, Canadian Urological Association Journal among others. He
is an active member of the Scientific Committee of Spanish Guidelines for prostate
cancer, Spanish Urological Association European Board Urology “EBU sub-specialty”
and member in the Scientific Committee of European Urological Association, and as
an international reviewer for the French National Cancer Institute. He has received
awards from the Spanish and European Urological Associations and Société Internationale dı́Urologie in recognition for outstanding publications and presentations.
He is an active member of the Spanish Urological Association AEU, the European
Urological Association EAU -EBU Sub-specialty and Scientific Committee, and the
American Urological Association AUA.
Miguel Unda is head of the Urology Department, Hospital Universitario de
Basurto. Bilbao. Spain (Since 2005). Associate professor of the Basque Country University. Faculty of Medicine. Bilbao. Spain (Since 2001). Director of the Continuous
Medical Education Office of the Spanish Urol. Assoc. (2007–2012). President of the
Urologic Tumors Committees of University Hospital Basurto and Member of the
Committee of Infections and use of Antimicrobials (Since 1999 and 1995). Director
of the Oncological Group of the Spanish Urological Association (Since 2012). He graduated in Medicine and Surgery from the Basque Country University. Bilbao. Spain
(1977). Head of Urology Section, University Hospital Basurto. (Since 1991–2005)
President of the Basque Country Urological Society. (Since 1988–2002). Staff member of Urology Department (Since 1981–1991). Certificated in GPC in 2008 and 2009.
Principal Investigator or Co-Investigator in more than 30 multicenter Clinical Trials
Phase II and III (both national and international). Author or Co-Author of over 250
publications in national and international specialty journals, conferences, meetings.
Member of Basque Country Urological Society, Spanish Urological Association, European Urological Association, American Urological Association, Societe internationale
dı́Urologie.
Dr. Miguel Ángel Climent graduated in Medicine and Surgery from Universidad
Literaria (now the University of Valencia) in Valencia, Spain, in 1987. Medical Oncology training at Hospital de la Santa Creu I Sant Pau in Barcelona from 1988 to 1992.
Master in Statistics for Health Sciences at the Autonomous University of Barcelona
in 1994.PhD in 1996 from the Autonomous University of Barcelona with the Thesis: Prognostic value of p53 and c-erbB2 in node-positive breast cancer patients.
Staff member of Medical Oncology Department of Instituto Valenciano de Oncología
since 1992. Currently Chief of Section of Genitourinary Oncology. He is a member
of the Spanish Group for Treatment of Genito-Urinary Tumors (SOGUG) where he
is a member of the executive committee and responsible for the Prostate Cancer
Working Group. He has participated as a researcher and designer in many clinical
trials in various areas of oncology, especially in urological tumors, including phase
I, II, II and IV trials.
Dr. Antonio Acaraz is Professor of Surgery at the University of Barcelona, Spain.
He received his medical degree in 1983, and his PhD in 1987, both from the University of Barcelona. After a 5 year residency in urology at the University Hospital Clinic
in Barcelona, he became a member of the Spanish Board of Urology in 1988. He completed a research fellowship at the Mayo Clinic in Rochester, USA between 1993 and
1994. He was Head of the Transplant and Oncology Unit of the Department of Urology at Fundacio Puigvert between 2002 and 2005. Since February 2005, he has been
Chair of the Department of Urology at the University Hospital Clinic of Barcelona,
and was Chair of the Transplant Section (2004–2008) and then Secretary General
of the Spanish Association of Urology (2008–2012). Professor Alcaraz’s research
interests include major uro-oncological, laparoscopic and transplant surgery, being
pioneer in single port surgery and transvaginal nephrectomy. Most of his translational research has been done on cancer genetics. He has authored more than 210
international and Spanish publications. He has been a member of the board of the
European School of Urology, and presently member of the Scientific Committee of
the European Association of Urology.
Please cite this article in press as: Maroto, P., et al., Expert opinion on first-line therapy in the treatment of castration-resistant prostate
cancer. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.07.011