Prostate Cancer - Current Approach and Future Perspective in Castration-Resistant Cancer Treatment

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

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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

220,800 new cases of prostate cancer will be diagnosed

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 deathdue 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 within1 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

Symptomaticdisease

Performance status 2

Symptomatic disease bone

Alpharadin

Follow-upAsymptomatic patients

Docetaxel or Alpharadin

Docetaxel

Moderate symptoms without metastases to soft tissues:1. Abiraterone or2. Sipuleucel T or3. Enzalutamide or4. Docetaxel or5. Cabazitaxel

mCRPCMetastases to soft tissues

No metastasesto 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

of total survival in patients with progression following

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

Mitoxantrone12 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

Mitoxantrone12 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

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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.

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 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)

16.5vs 8.5

Median not reachedvs 27.2 months

Fizazi 2012 Abiraterone + Prednisone (797)vs Placebo + Prednisone (398)

5.6vs 3.6

15.8vs 11.2 months (p<0.001)

Enzalutamide

Scher 2012 Enzalutamide (800)vs Placebo (399)

8.3vs 2.9

18.4vs 13.8 months (p< .001)

Table 6. Selected randomized phase 3 clinical trials in patients with known castration-resistant prostate cancer

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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

shortly after the marketing authorization the National

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

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 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 Affairs Team 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 [email protected].

About KCR

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References

Health & Medicine

Prostate Cancer - Current Approach and Future Perspective in Castration-Resistant Cancer Treatment