2. Prostate Cancer
• Epidemiology
• Diagnosis
• Risk factors
• Endocrine pathogenesis
• Hormonal therapies for Locally advanced or metastatic Prostate Ca
• Castrate Resistant Prostate Cancer
• mCRPC: Clinical unmet needs
3. • Gland found only in men
• Sits below the urinary bladder in front of the rectum
• Normal size of gland is same as a walnut
• Cells of the prostate make fluid contained in the seminal fluid which nourishes sperm
Prostate Gland
4. Prostate Cancer
• Major health threat and considerable
challenge to healthcare systems
throughout the World
• Second most frequently diagnosed
cancer in men worldwide, with more
than 900,000 cases each year
• Second leading cause of male cancer-
related deaths
Symptoms
• Decreased urinary stream, Urinary frequency,
Hematuria
• Bone pain (advanced disease)
• LE (lower extremity) numbness or weakness
• Bladder/bowel incontinence
Prognosis is poor
– Local disease: 15 yr survival rate is 76%
– Metastatic disease: 1 to 3 yrs
5. Prostate Cancer
..growing presence !
Incidence Mortality
Lung Ca 18.7% 22.3%
Prostate Ca 4.1% 2.5%
Incidence Mortality
Lung Ca 10.9% 13%
Prostate Ca 3.4% 3.2%
ASIA
INDIA
GLOBOCAN 2008 (IARC) Section of Cancer Information (29/8/2013)
6. Prostate Ca: Endocrine Pathogenesis
Androgens circulating in the testes can promote the growth of majority of
prostate cancer tumors during the early stages of the disease
7. Risk Factors for Prostate Cancer
• Age – Rare before 40; 65% over the age of 65
• Race - More common in African-American men; more likely diagnosed at advanced stage; 2x more
likely to die of the disease; less common in Asian-American and Hispanic-American men than non-
Hispanic whites.
• Family History - 1st degree relatives, father, brother
• Nationality - North America and NW Europe vs Asia, Africa, Central and South America
• Genetics – BRCA1 and BRCA2 increase risk, but account for very small percentage of prostate
cancer
• Obesity, Diet, Exercise, prostatitis, STDs, Vasectomy – not much effect, BUT…….
8. Risk Factors for Prostate Cancer Claimed by some studies
• Diet
Red meat, high fat dairy products
Fruits, vegetables, grains
• Exercise and maintaining healthy weight may decrease the risk
10. Staging Prostate Ca
• Stage I - T1a and grade 1 (Incidental,
early)
• Stage II -
– T1a and Grade 2-4; T1b,c (By biopsy
only)
– T2 (Confined to Prostate)
• Stage III - T3 (Through prostate capsule)
• Stage IV - T4 (Invades adjacent
structures), N1-3, M1
Surgical Orchiectomy*/
Medical castration
(Androgen Deprivation
Therapy*) followed by
Hormonal /
Chemotherapy
Surgical therapy /
Prostatectomy
Orchiectomy - a surgical procedure to remove one or both testicles (testes).
LHRH agonist - leuprolide, goserelin,
LHRH antagonist - flutamide, bicalutamide
11. Prostate Specific Antigen (PSA)
• Secreted protein as product of prostate gland–Secreted in semen
– Normal tissue: low levels in blood
– Increased PSA indicative of abnormalities in prostate gland architecture/vascularisation
• Non-invasive, inexpensive for
– Disease detection;
– monitoring progression/recurrence
12. PSA & Prostate Cancer Risk
• When prostate cancer develops, the PSA level usually goes above 4
• Still, a level below 4 does not mean that cancer isn't present -- about 15% of men
with a PSA below 4 will have prostate cancer on biopsy
• Men with a PSA level in the borderline range between 4 and 10, have about a 1 in
4 chance of having prostate cancer
• If the PSA is more than 10, the chance of having prostate cancer is over 50%
14. Recurrence Risk for Clinically Localized Prostate Cancer
Low Risk:
– T1-T2a and Gleason score 2-6 and PSA < 10 ng/ml
Intermediate Risk:
– T2b-T2c or Gleason score 7 or PSA 10-20
High Risk:
– T3a or Gleason score 8-10 or PSA > 20
Very High Risk:
– T3b-T4(locally advanced)
15. Prostate Ca - Goals of Therapy
• Primary Therapy
– T1a - Except in very young (< 60), follow with no therapy
– T1b, T1c, T2 - radical prostatectomy or high dose radiation therapy. (May also observe
if low-grade)
– T3 (Stage III) - Usually treated with radiation therapy
– Locally advanced (High-risk) or Metastatic disease
1. Orchiectomy (Surgical Castration)
2. LHRH analogs +/- anti-androgens (Medical Castration)
Orchiectomy - a surgical procedure to remove one or both testicles (testes).
LHRH analogs- leuprolide, goserelin,
Antiadrogens- flutamide, bicalutamide
17. Hormonal or ADT: Unmet Clinical need
• All hormonal therapies can cause sexual dysfunction and decreased libido; less with
finasteride and anti-androgen
• Current therapies did not fully ablate androgens
Medical/surgical castration with ADT does not inhibit
Adrenal axis pathway supplying Androgens (Testosterone) to Prostate gland
Prostate gland synthesis of Testosterone due to New mutated Androgen Receptors on prostate gland
Nearly 80 – 90% patients eventually develop progressive disease in the next 18 to 36
months
Referred to as castrate-resistant prostate cancer
18. mCRPC..driven by Androgen (Adrenal & Prostrate gland)
…leading to further Disease Progression or Metastases
Prostate
Gland
19. Castrate-resistant prostate cancer (CRPC)
• “Disease progression despite ADT and may present as one or any combination of
a continuous rise in serum levels of PSA, progression of pre-existing disease, or
appearance of new metastases”
• Castrate Range defined as Sr. testosterone level < 50 ng/dl
• The resulting clinical-states model can be used to classify patients as
– Asymptomatic with rising PSA levels without further metastases or symptoms
– Symptomatic with metastases especially to bone
Prostate-specific antigen: PSA
21. Timing of Disease Progression in Prostate Cancer
•
Castration-Resistant Prostate Cancer
M0 M1 Asymptomatic M1 Symptomatic
M0 M1 M1+
A continuum, but not equal in time
25-30 10-12 10-15
months
23. 1984-1989
Treatment Options for Prostate Cancer Have Snowballed After
a 6-Yr Hiatus
However, this rapid change has left many unanswered
questions, including the optimal selection and sequence
of therapy
1. The Leuprolide Study Group. N Engl J Med. 1984;311:1281-1286. 2. Crawford ED, et al. N Engl J Med. 1989;321:419-424. 3. Tannock IF, et al. J Clin Oncol. 1996;14:1756-1764. 4. Saad F, et al. J Natl Cancer
Inst. 2002;94:1458-1468. 5. Petrylak DP, et al. N Engl J Med. 2004;351:1513-1520. 6. Tannock IF, et al. N Engl J Med. 2004;351:1502-1512. 7. de Bono JS, et al. Lancet. 2010;376:1147-1154. 8. Kantoff PW, et al.
N Engl J Med. 2010;363:411-422. 9. Fizazi K, et al. Lancet. 2011;377:813-822. 10. de Bono JS, et al. N Engl J Med. 2011;364:1995-2005. 11. Scher HI, et al. ASCO GU 2012. Abstract LBA1.
12. Parker C, et al. ASCO GU 2012. Abstract 8.
1996 2002 2004 .... 2010 2011
Mitoxantrone[3] Docetaxel*[5,6]
Sipuleucel-T*[8]
LHRH agonists*[1,2]
Abiraterone*[10]
Reversible AR
blockers[1,2]
Cabazitaxel*[7]
Denosumab[9]
Zoledronic Acid[4]
MDV3100[11]
Radium-223[12]
* Approved agent for PCa
24. Drugs Indication Route Steroids Cis/ Caution
PSA
response
to
treatment
PSA
Decline
≥50%
Median OS
results
Abiraterone
acetate
Chemo-naïve mCRPC
Post-chemo mCRPC
Oral daily Yes
Caution with regular
monitoring in Liver
dysfunction;
Hypokalemia; Heart
failure; MI; Vent.
arrhythmias
Yes
62% vs 24%
29% vs 6%
Chemo-naïve
mCRPC: 34.7 mo
Post-chemo
mCRPC: 15.8
Enzalutamide
Chemo-naïve mCRPC
Post-chemo mCRPC
Oral daily No Seizures Yes
78% vs 3%
54% vs 2%
Chemo-naïve
mCRPC: 32.4 mo
Post-chemo
mCRPC: 18.4 mo
Docetaxel Chemo-naïve mCRPC
IV, every 3
wks
Yes
Moderate liver
dysfunction; cytopenia
Yes 53.8% mCRPC: 18.9 mo
Cabazitaxel Post-chemo mCRPC
IV, every 3
wks
Yes
Moderate liver
dysfunction; cytopenia
Yes 39.2%
mCRPC: 15.1 mo
Comparison of drugs used in mcrpc:
25. Prostate Cancer
• Risk factors are age, family history, race, and possibly diet and exercise
• Overall survival excellent (many years)
• Early detection can find localized cancer, but survival benefits still uncertain
• Treatment depends on grade, extent and location of disease
• Surgery and radiation are equivalent therapeutic tools for localized prostate cancer
• Hormonal therapy is effective for metastatic prostate cancer
• Symptomatic Hormone refractory prostate cancer pts on chemotherapy (Docetaxel)
show progression with limited options
– Mitoxantrone: for Chemotherapy intolerant pts shows limited efficacy
– Cabazitaxel: Docetaxel refractory pts that shows systemic S/E (Neuropathy, Febrile Neutropenia)
