Prostate carcinoma is one of the most commonly diagnosed solid tumours in males worldwide. Selection of the treatment method is strictly dependent upon disease stage and the patient’s age. Availability of diagnostic tests is constantly increasing in clinical practice, allowing early diagnosis and better chances for complete and permanent recovery. In the case of locally advanced prostate carcinoma, radical surgery or radiotherapy is considered as the most effective therapeutic approach, whereas in metastatic prostate carcinoma, hormone therapy or androgen deprivation therapy (ADT) is the primary therapeutic option. Moreover, increased use of chemotherapy with docetaxel and cabazitaxel in clinical practice has resulted in better prognosis for patients in this advanced stage of the disease. The biggest challenge for doctors and patients remains the treatment of hormone-resistant carcinoma (which very often is also metastatic). Concerns of today’s medicine regarding effective therapies for this type of disease have recently led to a significant increase in the number of papers/studies on new-generation biological treatments.

1. Prostate cancer:
current approach
and future perspective
in castration-resistant
cancer treatment
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Author:
Bozena Sikora-Kupis, MD
Oncology, Medical Affairs
KCR
Prostate carcinoma is one of the most commonly diagnosed solid tumors in males worldwide. Selection of the
treatment method is strictly dependent upon disease stage and the patient’s age. Availability of diagnostic
tests is constantly increasing in clinical practice, allowing early diagnosis and better chances for complete
and permanent recovery. In the case of locally advanced prostate carcinoma radical surgery or radiotherapy
is considered as the most effective therapeutic approach, whereas in metastatic prostate carcinoma hormone
therapy or Androgen Deprivation Therapy (ADT) is the primary therapeutic option. Moreover, increased use
of chemotherapy with docetaxel and cabazitaxel in clinical practice has resulted in better prognosis for patients
in this advanced stage of the disease.
The biggest challenge for doctors and patients remains the treatment of hormone-resistant carcinoma (which
very often is also metastatic). Concerns of today’s medicine regarding effective therapies for this type of disease
have recently led to a significant increase in the number of papers/studies on new generation biological
treatments.
Keywords:
prostate carcinoma, CRPC, castration-resistant, chemotherapy
ABSTRACT

3. www.kcrcro.com 3
Prostate cancer is one of the most common types
of cancer among men of all races and usually begins
without symptoms. The prevalence of prostate cancer
in Europe was estimated at 416,700 cases in 2012[1].
Prostate cancer has been recognized as the third
leading cause of death in Europe. According to the
International Agency for Research on Cancer, the
biggest incidence of prostate cancer in 2012 was
reported in northern European countries (Norway,
Sweden, Ireland, Iceland and Switzerland). Reported
mortality was also the highest in Scandinavian
countries. Based on data analyzed by the American
Cancer Society, it is estimated that in the U.S. about
220,800newcasesofprostatecancerwillbediagnosed
in 2015, and the number of deaths will reach 27,540.
One of the primary risk factors is age. Prostate
carcinoma is usually diagnosed in patients aged over
65. According to the American Cancer Society, about
6 in 10 cases of prostate cancer are diagnosed in men
over 65. Other risk factors include genetic burden and
race (prostate cancer prevalence is highest among
African and Caucasian men).
Early prostate cancer may not cause any symptoms
for years, therefore screening for prostate cancer
is recommended, especially in high risk populations.
Recently, due to better availability of diagnostic
tests, particularly determination of serum prostate
specific antigen (PSA), the detection rate of prostate
carcinoma has significantly improved. Blood PSA
levels above 4 ng/ml may suggest the presence
of carcinoma cells and indicate the need for further
diagnostics. However, studies have indicated that
PSA levels below 4 ng/ml are not definitely predictive
of the absence of prostate carcinoma.
Most cases of prostate carcinoma (90%) are
adenocarcinomas, malignant tumors of the epithelial
tissue. Histopathologic differentiation is based
on Gleason score [3], a combined total of 2 most
prevalent patterns in the biopsy material (Table 1).
Prostate carcinoma is the most commonly located
in the peripheral zone and typically multifocal.
The term advanced prostate carcinoma is used
to describe the stage of the disease in which the
tumor has already spread beyond the organ and
infiltrated the surrounding tissues and organs (locally
advanced carcinoma) or has metastasized to bones
or distant organs (disseminated, metastatic cancer).
Early detection significantly increases the chances
of survival. In the United States, where screening tests
are commonly used, over 90% of prostate cancer
cases are diagnosed in the organ-limited or locally
advanced stage, and 5-year survival rate at this stage
is nearly 100% [2].
According to the most recent data analyzed
by the American Cancer Society (including all stages
of prostate cancer) the survival rates are as follows:
• The relative 5-year survival rate is almost 100%
• The relative 10-year survival rate is 99%
• The relative 15-year survival rate is 94%
Background
Table 1. 15-year risk of death due to prostate carcinoma, depending on the differentiation pattern based
on Gleason score
Gleason score Histopathological characteristics
15-year risk of death
due to prostate carcinoma
2-4 Well differentiated 4-7%
5 Well differentiated 6-11%
6 Well differentiated 18-30%
7 Moderately differentiated 42-70%
8-10 Poorly differentiated 60-87%

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Prostate cancer growth is androgen-dependent,
therefore androgen blockade is an effective anti-
cancer therapy. It can be achieved with surgical
castration, radiation therapy, or medical castration
(hormone therapy).
The choice of the therapy course largely depends
on the stage of the disease. General therapeutic
approaches in prostate carcinoma are outlined
in Table 2.
Radical surgery is indicated only in patients with
prostate-limited carcinoma (cT1-2 N0 M0) whose life
expectancy is above 10 years.
Radical irradiation – teletherapy and/or
brachytherapy is also indicated in patients with
prostate-limited carcinoma (stage cT1-T3 N0 M0)
and some cases of locally advanced carcinoma
(T4 and N(+)).
Hormonal therapy (HTH) or Androgen Deprivation
Therapy (ADT) is the primary therapy for advanced
disease. The treatment eliminates the endogenous
androgens in patients who are not eligible for radical
therapy. Hormonal therapy is the first line treatment
for advanced prostate cancer.This course of treatment
allows slowing down the cancer growth but it does
not cure the disease itself.
Traditional ADT (Table 3) includes a variety
of approaches:
• Surgical castration – removal of the testes, thus
blocking the secretion of androgens.
• Pharmacological castration – blocking the
secretion of androgens at the pituitary level.
• Intracellular pharmacologic castration –
blocking the effect of androgens on prostate
cells with androgen receptor blocking drugs
(so-called anti-androgens).
Combination of surgical and pharmacologic
castration is known as total or maximal androgen
blockade (MAB). Ablation therapy results in reducing
testosterone levels to castration values, i.e. <50 ng/ml.
Therapy – general principles
Table 2. Prostate carcinoma treatment options
Table 3. Hormonal therapies in prostate carcinoma
Organ-limited prostate
carcinoma
Locally advanced prostate
carcinoma
Metastatic prostate
carcinoma
• radical prostatectomy
• radical radiotherapy
• radical brachytherapy
• radical radiotherapy
• hormone therapy
• palliative hormone therapy
• palliative radiotherapy
• palliative brachytherapy
• chemotherapy
• novel drugs
Gonadoliberin analogues Gonadoliberin antagonists Antiandrogens
• Goserelin
• Leuprorelin
• Triptorelin
• Degarelix • Flutamide
• Bicalutamide

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Unfortunately, in many cases, the prostate carcinoma
progresses despite castration and very low blood
testosterone levels. Despite the high efficacy
of hormonal therapy, cancer cells become adapted
to low (castrate) androgen levels after some time and
castration-resistant prostate cancer (CRPC) develops
[4,5]. Definition of CRPC is presented in Table 4.
Typically the skeletal system is the first area of
metastasis for prostate carcinoma. Bone metastases
are observed in 90% of patients with metastatic
castration-resistant prostate carcinoma (mCRPC).
This patient population requires particular
and thorough therapy due to severe disease
symptoms, dramatically affecting the quality of life.
The objective of therapy is to improve quality of life,
but also prolong time to progression and total survival.
Further efforts are being made to modify early stage
treatment to obtain maximum improvement of time
to development of hormone-resistance and
metastases. How to proceed, if an aggressive type
of disease is suspected, particularly in young patients
with high histologic grade (Gleason 8 or above),
remains one of the most challenging questions.
Despite insufficient knowledge of the precise
mechanisms involved in the development of CRPC,
difficulties and challenges related to CRPC therapy
have led to development and launch of several
new drugs, improving patients’ prognosis. These
new medicines include: abirateron, enzalutamide,
sipuleucel, docetaxel (new in this indication),
and cabazitaxel (Diagram 1).
hormone resistance
Diagram 1. Therapeutic options for patients after biochemical progression (increase of PSA level) used
in combination with hormonal therapy
Table 4. Definition of castration-resistant prostate
carcinoma. PSA – prostate specific antigen, RECIST
- Response Evaluation Criteria in Solid Tumors
Biochemical
progression
Radiographic
progression
Castrate level of blood
testosterone
(< 50 ng/dl or 1.7 nmol/l)
+
Three consecutive PSA
increments within
1 week by 50% from
the lowest PSA level
Castrate level of blood
testosterone
(< 50 ng/dl or 1.7 nmol/l)
+
• development of min.
2 bone lesions
• or development
or growth of metastatic
lesions in soft tissues,
according to RECIST
Performance
status 0 or 1
Asymptomatic
disease
Symptomatic
disease
Performance
status 2
Symptomatic
disease bone
Alpharadin
Follow-up
Asymptomatic
patients
Docetaxel or
Alpharadin
Docetaxel
Moderate symptoms without
metastases to soft tissues:
1. Abiraterone or
2. Sipuleucel T or
3. Enzalutamide or
4. Docetaxel or
5. Cabazitaxel
mCRPC
Metastases
to soft tissues
No metastases
to soft tissues

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For many years prostate cancer has been believed
to be cytostatic-resistant. A significant step forward
was made in 2004, with the publication of two large
studies comparing the efficacy of docetaxel and
mitoxantrone plus prednisone chemotherapy, which
was the standard therapy at that time. Docetaxel
is an anticancer drug that works by binding
to microtubules and stabilizing them, which
eventually leads to cell death. The safety and efficacy
of docetaxel in combination with prednisone and
prednisolone in patients with hormone-independent
prostate carcinoma has been studied also
in a multicenter phase 3 randomized trial TAX 327.
This study recruited 1006 patients. The median
(mean) survival time was 18.9 months compared
to 16.6 months in the mitoxantrone group
(HR=0.7695%, CI: 17.0-21.2) [9-12].
The only drug which has shown an improvement
oftotalsurvivalinpatientswithprogressionfollowing
docetaxel-based chemotherapy was cabazitaxel.
This semi-synthetic taxoid belongs to new
generation antineoplastic drugs and is characterized
by partial lack of cross-resistance to docetaxel.
The TROPIC study comparing treatment with
cabazitaxel and prednisone vs. mitoxantrone and
prednisone has shown improvement of median
survival time by more than 2 months (15.1 vs. 12.7
months, respectively) and a doubled median time
to progression (2.8 vs. 1.4 months) [13,14].
Chemotherapy
Clinical trial Regression of
PSA level > 50%
Pain
regression
Survival
(months)
Time to
progression
TAX 327
Mitoxantrone
12 mg/m2 body surface area
every 3 weeks for 10 cycles
32.00% 22.00% 16.5
Docetaxel
75 mg/m2 body surface area
every 3 weeks for 10 cycles
45.00% 35.00% 18.91
Docetaxel
30 mg/m2 body surface area
every week for the first
5 weeks, in a 6-week cycle, for
5 cycles
48.00% 31.00% 17.4
SWOG 99-16
Mitoxantrone
12 mg/m2 body surface area
every 3 weeks for 10 cycles
50.00% 15.6 3.2 months
Docetaxel / EMP every
3 weeks 60 mg/m2; EMP
3 x 280 mg/dose
27.00% 17.52 6.3 months
CALGB 9182
Hydrocortisone 38.00% 12.3 2.3 months
Mitoxantrone / HC
every 3 weeks 12 mg/m2
22.00% 12.6 3.7 months
Table 5. Selected phase 3 clinical trials in patients with known castration-resistant prostate carcinoma:
PSA regression rate, pain, total survival, time to progression. EMP=estramustine; HC=hydrocortisone;
1p<0.000 compared to mitoxantrone; 2p=0.001 compared to mitoxantrone

7. www.kcrcro.com 7
Clinical trial Regression of
PSA level > 50%
Pain
regression
Survival
(months)
Time to
progression
Tannock et al.
Prednisone 22.00% 12.00% 18 weeks
Mitoxantrone
every 3 weeks 12 mg/m2 /
Prednisone
33.00% 29.00% 43 weeks
TROPIC
Cabazitaxel + prednisone 15.1 2.8 months
Mitoxantrone + prednisone 12.7 1.4 months
Recently, two novel hormone therapies have been
introduced based on abiraterone and enzalutamide.
They act by blocking androgen receptor activation
pathways, but their mechanism of action is different
than in therapies used so far.
Therapeuticbenefitsofabirateroneandenzalutamide
have been evaluated following docetaxel
chemotherapy, as well as prior to docetaxel therapy,
as a first line therapy in patients diagnosed with
CRPC. Results of selected phase 3 clinical trials are
presented in Table 6.
Abiraterone selectively inhibits CYP17 activity
(17α-hydroxylase and C17,20-lipase activity).
This enzyme is responsible for the biosynthesis
of androgens in the testes, adrenal glands
and prostate cancer tissue. Blocking its activity
results in stopping testosterone production.
In a prospective, placebo-controlled phase
3 randomized clinical trial (COU-AA-301) abiraterone
was used in combination with prednisone in patients
with known castration-resistant prostate cancer,
following a failure of docetaxel therapy. A statistically
significant therapeutic benefit was shown – mean
total survival in the non-abiraterone group was 11.2
months (95% CI 10.4-13.1 months) vs 15.8 months
(95% CI 14.8-17.0 months) in the abiraterone arm.
Median follow-up time was 20.2 months. The study
also demonstrated increased median time to PSA
progression of 8.5 months (95% CI 8.3-11.1) vs 6.6
months (95% CI 5.6-8.3); HR 0.63; p< 0.0001.
Current hormonal therapy in advanced
prostate carcinoma
Author Year Study drug
(sample size)
Time to progression
(months)
Total survival
Abiraterone
Ryan 2013
Abiraterone + Prednisone (546)
vs Placebo + Prednisone (542)
16.5
vs 8.5
Median not reached
vs 27.2 months
Fizazi 2012
Abiraterone + Prednisone (797)
vs Placebo + Prednisone (398)
5.6
vs 3.6
15.8
vs 11.2 months (p<0.001)
Enzalutamide
Scher 2012
Enzalutamide (800)
vs Placebo (399)
8.3
vs 2.9
18.4
vs 13.8 months (p< .001)
Table 6. Selected randomized phase 3 clinical trials in patients with known castration-resistant prostate cancer

8. www.kcrcro.com 8
In another prospective phase 3 randomized
clinical trial (COU-AA-302) abiraterone was used
in combination with prednisone in docetaxel-naive
patients with known castration-resistant prostate
carcinoma. The study demonstrated an increased
median of total survival by 4.8 months (35.3
vs 30.1 months; HR 0.79, p=0.0151). Abiraterone also
reduced the risk of radiographic progression (rPFS,
radiographic progression free survival) or death
by 47% compared to placebo (HR=0.530; 95% CI:
0.451; 0.623; p<0.0001) [6-8].
Enzalutamide is indicated for the treatment
of metastatic castration-resistant prostate cancer
in patients with disease progression during
or following docetaxel treatment. It is a potent
inhibitor of the androgen receptor signaling pathway.
It blocks several stages of the androgen receptor
signaling pathway. The efficacy and safety of this
drug have been evaluated e.g. in a randomized,
placebo-controlled, multicenter phase 3 clinical trial
in patients with metastatic castration-resistant
prostate carcinoma, following earlier docetaxel
therapy. The patients received a concomitant
gonadotropin-releasing hormone (GnRH) analogue
or underwent surgical castration (orchyectomy).
Progression free survival confirmed by radiologic
evaluation determined with RECIST (Response
Evaluation Criteria In Solid Tumors) v. 1.1 criteria
was 8.3 months in the enzalutamide group and 2.9
months in the placebo group (HR = 0.404, 95% CI:
[0.350; 0.466]); p < 0.0001).
Combination therapies including both products
(enzalutamide and abiraterone) are currently
under investigations in mCRPC. These medicinal
products with different targets given in parallel may
demonstrate significantly higher efficacy than used
alone.
The purpose of immunotherapy is to induce and
stimulate immunologic mechanisms in order
to destroy cancer cells. A breakthrough strategy
in the treatment of CRPC turned out to be the
use of autologous dendritic cells, professional
antigen presenting cells. Sipuleucel-T is a vaccine
for personalized treatment based on patient’s own
cells obtained during leukapheresis. Immunotherapy
and therapies targeting the receptors and
signaling pathways in prostate carcinoma cells
and endothelium provide a true opportunity
for improving future prognosis in patients with CRPC.
Further studies, both in the field of immunology and
cancer molecular biology, should allow to identify
currently unknown therapeutic targets, and design
new, promising systemic treatment strategies of early
and advanced prostate cancer. Results of selected
clinical trials are presented in Table 7.
Sipuleucel-T was approved by the FDA in 2010 and
shortlyafterthemarketingauthorizationtheNational
Comprehensive Cancer Network added Sipuleucel-T
as a category 1 recommendation for patients with
castration-resistant prostate cancer.
Immunotherapy for prostate carcinoma
Author Year Study drug
(sample size)
Time to progression
(months)
Total survival
Sipuleucel-T
Kantoff 2010
Sipuleucel-T (341)
vs placebo (171)
3.7 vs. 3.6 25.8 vs 21.7 months (p.03)
Small 2006
Sipuleucel-T (82)
vs Placebo (45)
11.7 vs. 10 25.9 vs 21.4 months (p.03)
Table 7. Selected clinical trials of Sipuleucel-T

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Prostate cancer is one of the most common types
of cancer and one of the leading causes of cancer
death worldwide. The most difficult type of prostate
cancer for effective therapy is metastatic castration-
resistant prostate cancer. CRPC remains an incurable
disease usually associated with poor prognosis
and short survival time. Multidisciplinary approach
is advised in the treatment of patients with a known
castration-resistant stage of prostate carcinoma, but
patient care remains a tremendous challenge for
today’s medicine. Very high incidence of prostate
cancer and lack of fully effective treatment methods
of its advanced, castration-resistant forms have
resultedinadynamicprogressofclinicaltrialsofnovel
therapies. The primary purpose of novel therapies,
including chemotherapies, is to reduce the patient’s
pain, improve quality of life and above all improve
survival rates. Positive and promising study results
have been obtained for abiraterone, enzalutamide
as well as for Sipuleucel-T. During the last years these
products were granted marketing authorization both
in the United States (FDA) as well as throughout the
European Union (EMA), however because of the high
cost of novel therapies, patient’s access to advanced
treatment is still limited in many countries.
Currently, the potential use of these hormonal drugs
is also being studied in other clinical indications,
e.g. the use of enzalutamide prior to radical
prostatectomy. Therapies targeting the receptors
and signaling pathways in prostate carcinoma cells
and endothelium provide a true opportunity for
improving future prognosis in patients with CRPC.
Further studies both in the field of immunology
and cancer molecular biology should allow the
identification of currently unknown therapeutic
targets, and design new, promising systemic
treatment strategies of both early and advanced
prostate cancer.
Summary and conclusions
Bożena Sikora-Kupis is an experienced oncologist with over 10 years of practice in the clinical research
area. She supports KCR Medical AffairsTeam with her extensive hands-on experience and broad knowledge
in managing clinical studies in complex indications.
KCR is a Contract Research Organization (CRO) operating across 19 countries in Europe as well as the U.S.
The company is a strategic solutions provider for pharmaceutical and biotechnology firms who are looking for
a reliable alternative to top tier CROs. Over 300 professionals offer full service capabilities in three main product
lines: Trial Execution, Functional Service Provision (FSP) and Late Phase, across a wide range of therapeutic
areas. Focusing on knowledge, quality and innovation, KCR with its services supports 12 of the Top 20 Global
Pharma companies, as well as biotech firms from Europe, Israel and the U.S. on long standing contracts.
For more information please visit: www.kcrcro.com or contact us at info@kcrcro.com.
About KCR
KCR: We see human behind every number

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