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Prostate Cancer: Current Approach and Future
Perspective in Castration-resistant Cancer Treatment
Abstract
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.
Background
Prostate cancer is one of the most common types of cancer
among men of all races and usually begins without symptoms.
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 six 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 tumours of the epithelial tissue.
Histopathologic differentiation is based on the Gleason
score3, a combined total of the two most prevalent patterns
in the biopsy material (Table 1).
Table 1.
on Gleason score
Gleason score
Histopathological characteristics
15-year risk of death
due to prostate carcinoma
2-4
4-7%
5
6-11%
6
18-30%
7
42-70%
8-10
60-87%
The prevalence of prostate cancer in Europe was estimated at
416,700 cases in 20121. Prostate cancer has been recognised
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 analysed by the
American Cancer Society, it is estimated that in the US about
220,800 new cases of prostate cancer will be diagnosed in
46 Journal for Clinical Studies
Prostate carcinoma is 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 tumour has already spread beyond the
organ and infiltrated the surrounding tissues and organs
(locally advanced carcinoma) or has metastasised to bones or
distant organs (disseminated, metastatic cancer).
Early detection significantly increases the chances of
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Therapeutics
Table 2. Prostate carcinoma treatment options
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
Table 3. Hormonal therapies in prostate carcinoma
Gonadoliberin analogues
Gonadoliberin antagonists
Antiandrogens
• Goserelin
• Leuprorelin
• Triptorelin
• Degarelix
• Flutamide
• Bicalutamide
•
Table 4.
- Response Evaluation Criteria in Solid Tumors
Biochemical
progression
Radiographic
progression
Castrate level of blood
Castrate level of blood
testosterone
testosterone
(< 50 ng/dl or 1.7 nmol/l) (< 50 ng/dl or 1.7 nmol/l)
+
+
Three consecutive PSA
increments within
1 week by 50% from
the lowest PSA level
• development of min.
2 bone lesions
• or development
or growth of metastatic
lesions in soft tissues,
according to RECIST
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
five-year survival rate at this stage is nearly 100%2.
According to the most recent data analysed by the
American Cancer Society (including all stages of prostate
cancer) the survival rates are as follows:
•
•
The relative five-year survival rate is almost 100%
The relative 10-year survival rate is 99%
www.jforcs.com
The relative 15-year survival rate is 94%
Therapy – General Principles
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 prostatelimited 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
Journal for Clinical Studies 47
Therapeutics
effect of androgens on prostate cells with androgen
receptor blocking drugs (so-called anti-androgens).
Diagram 1. Therapeutic options for patients after biochemical progression (increase of PSA level) used
in combination with hormonal therapy
Asymptomatic
disease
Moderate symptoms without
metastases to soft tissues:
1. Abiraterone
or
2. Sipuleucel T
or
3. Enzalutamide
or
4. Docetaxel
or
5. Cabazitaxel
Performance
status 0 or 1
No metastases
to soft tissues
Docetaxel or
Alpharadin
Metastases
to soft tissues
Docetaxel
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.
Symptomatic
disease
mCRPC
Symptomatic
disease bone
Alpharadin
Asymptomatic
patients
Follow-up
Hormone Resistance
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)
develops4,5. The definition of CRPC is presented in Table 4.
Performance
status 2
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 hormoneresistance 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.
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
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
48.00%
31.00%
17.4
Docetaxel
30 mg/m2 body surface area
5 weeks, in a 6-week cycle, for
5 cycles
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
Despite insufficient knowledge of the precise mechanisms
involved in the development of CRPC, difficulties and
challenges related to CRPC therapy have led to the
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).
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
Prednisone
22.00%
12.00%
18 weeks
Mitoxantrone
every 3 weeks 12 mg/m2 /
Prednisone
33.00%
29.00%
43 weeks
TANNOCK ET AL.
Chemotherapy
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
TROPIC
Cabazitaxel + prednisone
15.1
2.8 months
Mitoxantrone + prednisone
12.7
1.4 months
Table 6. Selected randomized phase 3 clinical trials in patients with known castration-resistant prostate cancer
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
48 Journal for Clinical Studies
Enzalutamide (800)
8.3
18.4
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Therapeutics
Table 7. Selected clinical trials of Sipuleucel-T
Author
Year
Study drug
(sample size)
Time to progression
(months)
Total survival
Sipuleucel-T
Small
2010
Sipuleucel-T (341)
vs placebo (171)
3.7 vs. 3.6
25.8 vs 21.7 months (p.03)
2006
Sipuleucel-T (82)
vs Placebo (45)
11.7 vs. 10
25.9 vs 21.4 months (p.03)
the efficacy of docetaxel and mitoxantrone plus prednisone
chemotherapy, which was the standard therapy at that
time. Docetaxel is an anti-cancer drug that works by binding
to microtubules and stabilising 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 also
been studied in a multi-centre Phase III randomised 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 of total
survival in patients with progression following docetaxelbased chemotherapy was cabazitaxel. This semi-synthetic
taxoid belongs to new generation antineoplastic drugs and is
characterised 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 two
months (15.1 vs. 12.7 months, respectively) and a doubled
median time to progression (2.8 vs. 1.4 months)13,14.
Current Hormonal Therapy in Advanced Prostate Carcinoma
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.
Therapeutic benefits of abiraterone and enzalutamide
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 III
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 III randomised 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 14.817.0 months) in the abiraterone arm. Median follow-up time
was 20.2 months. The study also demonstrated increased
www.jforcs.com
median time to PSA progression of 8.5 months (95% CI 8.311.1) vs 6.6 months (95% CI 5.6-8.3); HR 0.63; p< 0.0001.
In another prospective Phase III randomised clinical trial
(COU-AA-302) abiraterone was used in combination with
prednisone in docetaxel-naive patients with known castrationresistant 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 signalling pathway.
It blocks several stages of the androgen receptor signalling
pathway. The efficacy and safety of this drug have been
evaluated e.g. in a randomised, placebo-controlled, multicentre Phase III 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
investigation in mCRPC. These medicinal products with
different targets given in parallel may demonstrate
significantly higher efficacy than when used alone.
Immunotherapy for Prostate Carcinoma
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 personalised
treatment based on patient’s own cells obtained during
leukapheresis. Immunotherapy and therapies targeting the
receptors and signalling pathways in prostate carcinoma cells
and endothelium provide a true opportunity for improving
Journal for Clinical Studies 49
Therapeutics
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 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
shortly after the marketing authorization, the National
Comprehensive Cancer Network added Sipuleucel-T as a
category 1 recommendation for patients with castrationresistant prostate cancer.
Summary and Conclusions
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. A multidisciplinary approach is
advised in the treatment of patients with a known castrationresistant 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 resulted in a dynamic progress of clinical trials
of novel 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
authorisation both in the United States (FDA) and throughout
the European Union (EMA), however because of the high cost
of novel therapies, patients’ access to advanced treatment is
still limited in many countries.
5.
6.
7.
8.
9.
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Ryan CJ, Smith MR, de Bono JS, et al. COU-AA-302 Investigators.
Abiraterone in metastatic prostate cancer without previous
chemotherapy. N Engl J Med 2013 Jan;368(2):138Fizazi K, Scher HI, Molina A, et al. COU-AA-301 Investigators.
Abiraterone acetate for treatment of metastatic castrationresistant prostate cancer: final overall survival analysis of the
COU-AA-301 randomised, double-blind, placebo-controlled phase 3
study. Lancet Oncol 2012 Oct;13(10):983-92.http://www.ncbi.nlm.
nih.gov/pubmed/22995653
de Bono JS, Logothetis CJ, Molina A, et al. COU-AA-301 Investigators.
Abiraterone and increased survival in metastatic prostate cancer. N
Engl J Med 2011 May;364(21):1995-2005.http://www.ncbi.nlm.nih.
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Tannock IF, de Wit R, Berry WR, et al. TAX 327 Investigators.
Docetaxel plus prednisone ormitoxantrone plus prednisone for
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Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and
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for advanced refractory prostate cancer. New Engl J Med
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Kantoff PW, Halabi S, Conaway M, et al. Hydrocortisone with or
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Tannock IF, Osoba D, Stockler MR, et al. Chemotherapy with
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gov/pubmed/208889
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 signalling 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.
13.
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Bożena Sikora-Kupis is an experienced oncologist with
over 10 years of practice in the clinical research area as an
investigator and medical monitor. With the broad scientific
background and high-level education gained with the medical
doctor degree and additional postgraduate diploma of
specialty of oncology she has comprehensive knowledge of
the industry. She practiced in the department of diagnostic
oncology in the Institute of Oncology, Warsaw, Poland, with
a focus on prostate cancer. At KCR she currently supports
Medical Affairs Team with her extensive hands-on experience
in managing clinical studies in complex indications.
Email: [email protected]
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cancer: from new pathophysiology to new treatment targets.
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pubmed/19560857
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