Prostate cancer and management

Nicholas James School of Cancer Sciences University of Birmingham

Prostate cancer
Most common cancer in men Occurs in later life Occult disease common
80% of 80 year olds have prostate cancer at post mortem, 30% of 50 year olds

Clinical prevalence in 60 year old men around 4% Aetiological factors unknown

New cases prostate cancer by age

Screening & diagnosis

Diagnostic triad for early detection of prostate cancer

PSA testing
PSA is a protein produced in the epithelial cells of the prostate1 Blood levels of PSA can be used for screening or monitoring of patient with diagnosed prostate cancer1 Consistent elevated PSA level should be further investigated, e.g. with prostate biopsy2 PSA >4 ng/mL does not necessarily indicate prostate cancer as PSA level is a continuous parameter2
The higher the value the more likely the existence of prostate cancer

BPH=benign prostatic hyperplasia; PSA=prostate-specific antigen; WHO=World Health Organization. 1. NCI. PSA Test Fact Sheet. Available from: http://www.cancer.gov/cancertopics/factsheet/Detection/PSA. Last accessed January 2013. 2. Heidenreich A, et al. Eur Urol 2011;59:6171.

Characterising the tumour

Gleason grading system

The Gleason grading system is based on glandular architecture, divided into five patterns of growth with different levels of differentiation The Gleason score is the sum of the two most common patterns
e.g. 4 (most prevalent pattern) + 3 (secondary pattern) = 7

Histological appearance and Gleason pattern

Gleason score
2,3,4

5,6

7,8,9,10

SEER training modules: Morphology & grade. Available at: http://training.seer.cancer.gov/prostate/abstract-code-stage/morphology.html. Last accessed January 2013.

Imaging techniques
Transrectal ultrasound Scintigram Computed tomography MRI Radionuclide bone scan

Classification and staging: TNM system

Primary tumour (T)
TX T0 T1 Primary tumour cannot be assessed No evidence of primary tumour Clinically unapparent tumour neither palpable nor visible by imaging
T1a: Tumour incidental histological finding in 5% of tissue resected T1b: Tumour incidental histological finding in >5% of tissue resected T1c: Tumour identified by needle biopsy (e.g. because of elevated PSA)

Regional Nodes (N)

NX N0 N1 Regional lymph nodes were not assessed No regional lymph node metastases Metastasis in regional lymph node(s)

T2

Tumour confined within prostate*

T2a: Tumour involves 50% of one lobe T2b: Tumour involves >50% of one lobe but not both lobes T2c: Tumour involves both lobes

Distant Metastases (M)

M0 M1 No distant metastases Distant metastases
M1a: Non-regional lymph node(s) M1b: Bone(s) M1c: Other site(s) with or without bone disease

T3

Tumour extends through the prostate capsule

T3a: Extracapsular extension (unilateral or bilateral) T3b: Tumour involves seminal vesicle(s)

T4

Tumour is fixed or invades adjacent structures other than seminal vesicles, such as external sphincter, rectum, bladder, levator muscles, and/or pelvic wall

*Tumour found in one or both lobes by needle biopsy, but not palpable or reliably visible by imaging is classified as T1c. Invasion into the prostatic apex or into (but not beyond) the prostatic capsule is classified not as T3 but as T2. AJCC: Prostate. In: Edge SB, eds. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, p45768.

10

Clinical practice: Staging and risk assessment

Category of localised prostate cancer1 Low risk Risk assessment criteria All of T12a Gleason <7 PSA <10 ng/mL T2b2c Gleason = 7 PSA 10 and <20 ng/mL Recommended follow-up Imaging tests are not routinely recommended

Intermediate risk

Bone scintigraphy considered if bone metastases are suspected clinically, if Gleason is 4 + 3 or serum PSA 15 ng/mL CT/MRI of the pelvis should be considered and bone scintigraphy performed

High risk

Any of T34 Gleason >7 PSA 20 ng/mL

CT=computed tomography; DRE=digital rectal examination; MRI=magnetic resonance imaging; PSA=prostate-specific antigen. 1. Horwich A, et al. Ann Oncol 2010:21(Suppl. 5);v12933. 2. Heidenreich A, et al. Eur Urol 2011:59;6171.

11

Initial treatment of prostate cancer

Prostate cancer treatment paradigms

T1/2
Low risk

T3/4
High risk

N+

M+

HRPC

Clinically Localized

Relapsed
and

Newly diagnosed M+

Hormone/Castrate Refractory

Local treatment

Hormonal

Chemotherapy, new hormone therapies, Radium-223, etc

Options for initial treatment

Active monitoring Watch and wait Treatments of curative intent
Surgery Radiotherapy
External beam Brachytherapy

New modalities
Cryotherapy High-intensity focused ultrasound (HIFU)

Treatment of localised prostate cancer

Increasing risk
Active monitoring Brachytherapy/ HIFU/Cryo Surgery

Radiotherapy + short course ADT Radiotherapy + long course ADT Hormone therapy alone

Active monitoring vs. watch and wait

AM
No immediate treatment Low risk cases only Early intervention for progression

W&W
Any category patient No intervention for PSA progression TURP for obstructive symptoms Hormones for distant spread

Brachytherapy: Insertion of needles

10-15

Brachytherapy: Side effects

Symptoms (% G3/4) Frequency Dysuria Nocturia Urgency Incontinence 3 months 36/2 18/4 28/10 10/2 3/0 6 months 12/0 5/0 3/0 6/6 0/0 12 months 0/0 0/0 6/0 0/0 0/0

Proctitis
Perineal pain

6/0
2/0

4/0
0/0

2/0
0/0

AL Booz et al BJU International 82 53-56

External beam radiotherapy (EBRT)

Neoadjuvant hormone therapy RTOG 8610 disease-specific survival

Disease-specific mortality. Failure is defined as death resulting from prostate cancer. Time to a disease-specific mortality is measured from the date of random assignment to the date of death or to the date of the most recent follow-up.
ADT, androgen deprivation therapy; EBRT, external-beam radiotherapy. Roach M, III et al. J Clin Oncol 2008;26:58591.

Neoadjuvant hormone therapy RTOG 8610 overall survival

Overall survival. Failure is defined as death resulting from any cause. Survival time is measured from the date of random assignment to the date of death or last follow-up.
ADT, androgen deprivation therapy; MST, median survival time; EBRT, external-beam radiotherapy. Roach M, III et al. J Clin Oncol 2008;26:58591.

EORTC 22863 trial: study design

T1T4, N0, M0 (n=415)

Randomized RT + goserelin 3.6 mg (n=205)

RT alone (n=198) Hormonal therapy at progression

Bolla M et al. N Engl J Med 1997;337:295300; Bolla M et al. Eur J Cancer 1999;35(Suppl 4):S82 (Abstr 266).

EORTC 22863
Disease-free survival

Percentage of patients

100 90 80 70 60 50 40 30 20

RT+LHRH (n=203)

RT (n=198)

10
0

p<0.001
0 1 2 3 4 5 6 7 8 9 10

Time (years)
LHRH, luteinizing hormone-releasing hormone. Bolla M et al. N Engl J Med 1997;337:295300.

EORTC 22863
Overall survival

Percentage of patients

100 90 80 70 60 50 40 30 20

RT+LHRH (n=203)

10
0

p<0.001
0 1 2 3 4 5 6 7

RT (n=198)
8 9 10

Time (years)
LHRH, luteinizing hormone-releasing hormone. Bolla M et al. N Engl J Med 1997;337:295300.

Hormone therapy pus radiotherapy

Hormone therapy pre-RT improves overall survival Hormone therapy post-RT improves overall survival
Benefit probably biggest in highest-risk cases

Do we need the RT at all?

SPCG-7
Locally advanced CaP PSA up to 70 (n=880) Randomised

Initial androgen ablation RT 70Gy to Prostate + pelvis Adjuvant oral anti-androgen

Initial androgen ablation Switch to Adjuvant oral anti-androgen

Initial results with 10 year follow up reported ASTRO 2008

SPCG-7 results

Widmark et al The Lancet 2009 373, 301-308

Intergroup Randomized Phase III Study of Androgen Deprivation Therapy + Radiation Therapy in Locally Advanced Prostate Cancer
NCIC CTG PR.3/ MRC PR07/ SWOG JPR3
(NCT00002633, ISRCTN24991896)

M. D. Mason, P.R. Warde, M. R. Sydes, M. K. Gospodarowicz, G. P. Swanson, P. Kirkbride, E. Kostashuk, J. Hetherington, K. Ding, W. R. Parulekar
On behalf of all trial collaborators

PR07 PR3 disease specific survival

100
7 yr DSS 90% ADT

80
7 yr DSS 79% ADT+RT

60 Percentage

40

140 Deaths from Prostate Cancer 89 ADT alone, 51 RT+ADT

HR=0.57 (95% C.I. 0.37-0.78) p=0.001

20

0
# at Risk

0
602
603

3
509
512

9
51
60

ADT ADT+RT

Time (Years)

213
232

Surgery
Open Laparoscopic Robotic No trials of surgery vs. radiotherapy

Surgery vs WW for low risk disease

Bill-Axelson et al NEJM 352 1977-84 2005.

PIVOT trial
Radical prostatectomy versus observation for localized prostate cancer

N Engl J Med 2012; 367:203-213

Pre-op PSA velocity and risk of prostate cancer death

DAmico et al NEJM 351 125-35 2004.

Da Vinci Robots

Early disease
Huge overtreatment Many options Low risk of death Little data on relative outcomes Significant morbidity

Hormone therapy

37

Hormone therapy strategies

Block synthesis
At level of regulation At level of synthetic pathways

Block binding to receptor

Block post-receptor effects Add alternative hormones to alter environment

Hormone therapy strategies

Block synthesis
At level of regulation LHRH analogues At level of synthetic pathways CYP17 inhibitors

Block binding to receptor bicalutamide, enzalutamide

Block post-receptor effects enzalutamide Add alternative hormones to alter environment diethylstilboestrol, dexamethasone

Androgen pathways in human prostate

LHRH Agonists LH Anterior Pituitary ACTH

Testis Leydig cells

Adrenal cortex

Testosterone DHT
Prostate

DHEA

Antiandrogens

Effect of castration on androgen levels

Labrie F. Nature Reviews Urology 2011

Androgen deprivation therapy (ADT)

ADT is the standard of care for advanced prostate cancer 1,2 Current approaches to ADT focus on inhibiting testicular production of androgens via surgical or medical castration3 Surgical castration (orchidectomy) Chemical castration
LHRH analogues (agonists and antagonists) Anti-androgens Combined androgen blockade Oestrogens

ADT=androgen deprivation therapy; LHRH=luteinising hormone-releasing hormone. 1. Heidenreich A, et al. Guidelines on Prostate Cancer. Available from: http://www.uroweb.org/gls/pdf/08%20Prostate%20Cancer_LR%20March%2013th%202012.pdf. Last accessed February 2013. 2. Horwich A, et al. Ann Oncol 2010;21:v12933. 3. Hou X, Flaig TW. Adv Urol 2012 doi:10.1155/2012/978531. 4. Ryan CJ, Tindall DJ. J Clin Oncol 2011;29:365158.

42

Side effects: ADT

Endocrine
Hot flushes, gynaecomastia, mastalgia, testicular atrophy, impotence, and/or libido decrease

Haematological: anaemia Central nervous system

Insomnia, dizziness, headache

General
Fatigue, hypertriglyceridemia Weight gain, loss of muscle bulk, gain in body fat Osteoporosis

Anti-androgens
Anti-androgens bind to androgen receptors in the target cell Compete with exogenous or endogenous androgens

44

Older anti-androgen drugs

Steroidal
Cyproterone

Non-steroidal
Bicalutamide Flutamide Nilutamide

Limitations of anti-androgens
Low binding affinity to androgen receptor
Bicalutamide has an approximately 30-fold lower affinity to the AR than DHT Relatively high doses are required to suppress AR signalling in the presence of androgens

May act as a partial agonist which often manifests when AR signalling is already aberrant;
AR overexpression AR mutations

A clinically significant consequence of the partial agonist activity is the anti-androgen withdrawal syndrome

46

Stilboestrol
Very first drug licenced for cancer therapy Still used as palliative therapy after failure of first line therapy Often used with dexamethasone and aspirin or warfarin (risk of DVT)

Disease course

48

Natural history for locally advanced patients

Death PSA SRE

Initial Diagnosis & Therapy

ADT

Bone Mets

CRPC (PSA relapse under ADT)

~2 yr

~1.5 yr

Course of Disease

Natural history for metastatic patients

Initial diagnosis & ADT PSA Second line hormone therapy Death Chemotherapy SRE

CRPC (PSA relapse under ADT)

~2 yr

~1.5 yr

Development of CRPC
Intraprostatic androgen synthesis
Increased expression of enzymes converting DHEA to testosterone and DHT in tumour tissue Increased androgen synthesis

Androgen receptor (AR) abnormalities

Increased AR expression Mutation of AR ligand binding domain Constitutively active AR mutants (truncated AR)

Abiraterone

AFFIRM phase 3 trial of Enzalutamide (MDV3100) post-chemotherapy

Phase 3 randomized, double-blind, placebo-controlled trial

N = 1199 mCRPC 12 prior chemothera py regimens*

R 2:1

MDV3100 160 mg qd Placebo qd

Primary endpoint: Overall survival Secondary endpoints: radiographic PFS, time to first SRE, time to PSA progression

* 1 docetaxel

http://clinicaltrials.gov/ct2/show/NCT00974311 http://www.astellas.com/en/corporate/news/pdf/111104_Eg.p

AFFIRM trial: Summary of adverse events

Total events MDV3100 (n = 800) Adverse events Serious adverse events Discontinuations due to adverse events Adverse events leading to death Adverse events of interest Cardiac disorders Myocardial infarction LFT abnormalities* Seizure 6.1% 0.3% 1.0% 0.6% 7.5% 0.5% 1.5% 0.0% 0.9% 0.3% 0.4% 0.6% 2.0% 0.5% 0.8% 0.0% 98.1% 33.5% 7.6% 2.9% Placebo (n = 399) 97.7% 38.6% 9.8% 3.5% Grade 3 events MDV3100 (n = 800) 45.3% 28.4% 4.6% 2.9% Placebo (n = 399) 53.1% 33.6% 7.0% 3.5%

*Includes terms hyperbilirubinemia, AST increased, ALT increased, LFT abnormal, transaminases increased, and blood bilirubin increased The adverse event reporting period was on average more than twice as long for MDV3100 compared with placebo Data are percent of patients

Scher HI et al. J Clin Oncol 2012;30 (suppl 5; abstr LBA1).

MDV3100 trial results

37% improvement in survival times More side effects reported in placebo arm
Minimal drug related side effects

Control arm patients had longer survival times than in the abiraterone trial due to exposure abiraterone and cabazitaxel
Suggests different drugs can be added to each other for further benefit

Clinical presentation of CRPC

In CRPC, prostate cancer progresses despite castrate serum levels of testosterone (<50 ng/dL)1 The median time to symptomatic progression after a rise in PSA level of >4 ng/mL is ~68 months in patients with mCRPC, this may be evidenced by:2
Appearance of local disease-related symptoms, e.g. obstructive voiding symptoms, or
Documented metastatic disease progression, e.g. from bone scan or CT/MRI, and bone pain

Huge variation with case-mix

mCRPC=metastatic castration-resistant prostate cancer; EAU=European Association of Urology; CT=computed tomography; MRI-magnetic resonance imaging; PSA=prostate-specific antigen. 1. Ryan CJ, Tindall DJ. J Clin Oncol 2011;29:36518. 2. Chodak GW. Prostate Cancer Treatment and Management 2013 Available at: http://emedicine.medscape.com/article/1967731-treatment. Last accessed February 2013.

57

Metastatic disease

58

CRPC: Sites of metastases

Prostate cancer more commonly metastasises to the bone but other sites include distant organs such as the liver, lungs and brain1
90% of men develop bone metastases2 10% of men develop lung metastases3

3% of men develop liver metastases3

~40% of men develop a combination of both osseous and soft tissue lesions3

CPRC=castration-resistant prostate cancer. 1. Jin JK, et al. Int J Cancer 2011;128:254561; 2. Beltran H, et al. Eur Urol 2011;60:27990; 3. Heidenreich A, et al. Urol Int 2010;85:110.

59

Steps in metastasis
Primary malignant neoplasm New vessel formation Invasion Embolism

Multi cell aggregates (Lymphocytes, platelets) Bone metastases Extravasation

Tumor cell Proliferation Response to Microenvironment

Arrest in distant capillary bed in bone

Adherence

Endothelial cell

Bone metastasis in prostate cancer

Bone: most frequent site of prostate cancer metastasis
Favorable microenvironment for prostate tumor cells Lesions first appear in axial skeleton, then appendicular skeleton

Main source of prostate cancerassociated morbidity

The vicious cycle of bone metastases and tumor cell growth in the bone marrow microenvironment1

PTHrP IL-6 PGE2 TNF M-CSF

RANKL

BMP PDGF FGFs IGFs TGF-

1. Roodman GD, et al. N Engl J Med. 2004;15:1655-1664.

Chemotherapy

62

Docetaxel: Overall survival SWOG 9916

100%

80%
60% 40% 20%

D+E M+P

# at Risk 338 336

# of Median Deaths in Months 217 18 235 16

HR: 0.80 (95% CI 0.67, 0.97), p = 0.01

0%
0 12

Months

24

36

48

Docetaxel: TAX 327 overall survival

1.0 0.9 Docetaxel 3 wkly Docetaxel wkly Mitoxantrone

Probability of Surviving

0.8
0.7 0.6

0.5
0.4 0.3 0.2 0.1 0.0 0 6 12 18 24 30 Combined: D 3 wkly: D wkly: Mitoxantrone 18.2 18.9 17.3 16.4 0.83 0.76 0.91 0.03 0.009 0.3 Median survival (mos)

Hazard ratio

P-value

Months

Cabazitaxel: TROPIC overall survival (ITT analysis) 100

80 Proportion of OS (%) Median OS (months) Hazard Ratio MP 12.7 CBZP 15.1

60

95% CI P-value

0.70 0.590.83 <.0001

40

20

0 0 months Number at risk MP CBZP 377 378

6 months 300 321

12 months 188 231

18 months 67 90

24 months 11 28

30 months 1 4

Bone targeted therapies

Bone metastases
The burden of bone metastases Pain Disability Hospitalizations Cost SREs are clinically important endpoints

Orthopaedic Surgery

Radiation to Bone

Pathologic Fracture

Spinal Cord compression

Denosumab versus zoledronic acid in CRPC type of SREs

30 Percent of Subjects With First SRE All subjects 20.0 20

25

14.7
15 10 5 0 Radiation to Bone Fracture Spinal Cord Compression Surgery to Bone 3.3 0.3

Denosumab Versus Zoledronic Acid in CRPC Time to First On-Study SRE

Proportion of Subjects Without SRE
1.00

HR 0.82 (95% CI: 0.71, 0.95) P = 0.0002 (Non-inferiority) P = 0.008 (Superiority)

0.75

0.50

0.25

KM Estimate of Median Months Denosumab Zoledronic acid 20.7 17.1

0 0
Subjects at risk:
Zoledronic Acid Denosumab 951 950 733 758 544 582 407 472

12
299 361

15
207 259

18
140 168

21
93 115

24
64 70

27
47 39

Study Month

Denosumab versus zoledronic acid in CRPC cumulative number of SREs

2.0

Cumulative Mean Number of SREs per Patient

1.8 1.6 1.4 1.2 1.0 0.8

Rate Ratio = 0.82 (95% CI: 0.71, 0.94) P = 0.008

0.6
0.4 0.2 0.0

Events Denosumab Zoledronic acid

0 3 6 9 12 15 18 21 24 27 30

494 584
33 36

Study Month

*Events occurring at least 21 days apart

SRE frequency in trial of Ra223 vs placebo

30 25

20

15

Ra-223 Placebo

10

0 Pathologic Bone Fracture Spinal Cord Compression External beam RT Surgical intervention

Radium-223 chloride (Alpharadin) impact on overall survival and skeletal-related events in patients with castrationresistant prostate cancer with bone metastases: A phase III randomized trial (ALSYMPCA). Sartor et al AUA 2012

71

Phase III Study treatments

A
B C D

Docetaxel 75mg/m2 every 3 weeks + prednisolone 10mg od

(cycles 1-10)

docetaxel + prednisolone + ZA 4mg iv

(cycles 1-10)

docetaxel + prednisolone
(cycles 1-6)

Sr89 150 MBq

(day 28 cycle 6)

+ 28

Days*

docetaxel + prednisolone
(cycles 7-10)

* At least 28 days

docetaxel + prednisolone + ZA
(cycles 1-6)

Sr89
(day 28 cycle 6)

+ 28 Days*

docetaxel + prednisolone + ZA
(cycles 7-10)

ARMS B & D : Post chemotherapy, ZA will be administered at 4-weekly intervals until protocol defined disease progression.
Presented by: Nick James

SRE Free Interval: ZA comparison

Presented by: Nick James

Total Skeletal Related Events by type

Sr89 comparison No Sr89 Sr89
N (%) Symptomatic pathological fractures Spinal cord or nerve root compression Cancer related surgery to bone Radiation therapy to bone Change in antineoplastic therapy to treat bone pain Hypercalcaemia Other Total
Presented by: Nick James

ZA comparison No ZA ZA
N (%)

N (%)

N(%)

16 39 10 317 16 0 1 399

18 45 13 258 12 2 1 349

23 52 18 337 17 2 0 449

11 32 5 238 11 0 2 299

Skeletal Related Events per patient

Sr89 comparison No Sr89 Sr89
N(%) 0 1 2 3 4 5 or more Number of patients with at least one SRE 196 (52) 92 (25) 32 (8) 28 (7) 11 (3) 19 (5) 182 (48) N(%) 201 (53) 96 (25) 38 (10) 20 (5) 11 (3) 12 (4) 177 (47)

ZA comparison No ZA ZA
N(%) 185 (49) 91 (24) 33 (9) 38 (10) 13 (3) 21 (5) 196 (51) N(%) 213 (56) 97 (26) 37 (10) 10 (3) 9 (2) 10 (3) 163 (44)

Presented by: Nick James

Radio-isotopes

Alpharadin
Radium 223 calcium mimetic agent High uptake in bone metastases Alpha-particle emitter Phase III licencing trial completed

Alsympca overall survival

Parker et al ESMO 2011.

Current EU CRPC treatment

Note: Added abiraterone here

Clinical trial 2nd-line hormone Rx* Docetaxel Observation Mitoxantrone Abiraterone 2nd-line hormone Rx* Clinical trial Clinical trial

Cabazitaxel Docetaxel rechallenge Abiraterone Mitoxantrone 2nd-line hormone Rx*

No metastases Asymptomatic

Metastases Symptomatic

*Options: anti-androgen ( anti-androgen withdrawal), corticosteroids, estrogen or ketoconazole

Mottet et al. Eur Urol 2011;59:57283. Horwich et al. Ann Oncol 2010;21(Suppl. 5):v12933. NICE. Prostate Cancer Diagnosis and Treatment (NICE Clinical Guideline 58) 2008. de Reijke et al. Ned Tijdschr Geneeskd. 2008;152:17715. NCCN clinical practice guidelines in oncology: prostate cancer, v.4.2011. http://www.nccn.org. Miller et al. Aktuelle Urologie. 2006;37:2014.

Future CRPC treatment

Clinical trial Observation 2nd-line hormone Rx*

Abiraterone Docetaxel

Docetaxel Radium 223

Cabazitaxel Docetaxel Abiraterone Enzalutamide

No metastases Asymptomatic

Metastases Symptomatic

Conclusions
Prostate cancer is a spectrum from trivial to very serious disease Treatment options are rapidly changing across the whole spectrum Many new drugs being licenced for advanced disease Management of bone metastases a substantial burden and some treatments controversial

81