This document discusses recent advances in prostate cancer, including updated screening guidelines, diagnostic tools, biomarkers, staging, and treatments. It provides an overview of prostate cancer epidemiology and risk factors. Screening involves PSA testing and digital rectal exams for men aged 55-69. Multiparametric MRI and MRI-ultrasound fusion biopsies have improved detection of aggressive cancers. Staging involves bone scans, PET scans, and the TNM system. Biomarkers like PSMA and PCA3 are also discussed.

2. Carcinoma Prostate – Recent
Advances
Dr. Robal Lacoul
Junior Resident (2nd year)
B. P. Koirala Institute oh Health Sciences, Nepal

3. Introduction
• Prostate cancer (PC) is the second-most frequently diagnosed
cancer in men worldwide, with 1.1 million new cases
estimated to have occurred in 2012 and incidence rate: 168.3
cases per 100,000 men.
• The estimated lifetime risk of disease is 16.72%, with a
lifetime risk of death at 2.57%.
• There are significant differences in occurrence between
regions and country development (70% of accounted cases
are in developed countries).
*Torre LA, Siegel RL, Ward EM, Jemal A. Global Cancer Incidence and Mortality Rates and TrendsÐAn
Update. Cancer Epidemiol Biom

4. Age-adjusted cancer incidence rates
for men, United States, 1975-2005.
INCIDENCE* MORTALITY*
White 161.4 25.6
African-American 255.5 62.3
Hispanic/Latino 140.8 21.2
Asian-American and Pacific Islander 96.5 11.3
American Indian and Alaska Native 68.2 21.5
*Per 100,000, age adjusted to the 2000 U.S. standard population.
Source: CAMPBELL-WALSH Urology, Tenth Edition

5. PROSTATIC INTRAEPITHELIAL NEOPLASIA
• Prostatic intraepithelial neoplasia (PIN) consists of architecturally benign
prostatic acini or ducts lined by cytologically atypical cells and is classified
as low-grade and high-grade neoplasia.
• High-grade PIN is a precursor lesion to many peripheral intermediate- to
high-grade adenocarcinomas of the prostate.
• The most frequent sites of metastatic prostate carcinoma are lymph
nodes, bones, and lung, followed by bladder, liver, and adrenal gland.
• In general, the size of a prostate cancer correlates with its stage.
Extraprostatic extension is uncommon in tumors of less than 0.5 cm3, and
tumors that are less than 4 cm3 uncommonly reveal lymph node
metastases or seminal vesicle invasion

6. Fig: Cellular and molecular model of early prostate neoplasia progression.

7. Risk Factors
• Both genetics and environment play a role in the origin and evolution of
this disease.
(A) Familial and Genetic Influences
- Relative risk increases according to the number of affected family
members, their degree of relatedness, and the age at which they were
affected.
- Linkage studies have identified a number of prostate cancer susceptibility
genes, including RNaseL (hereditary prostate cancer-1 [HPC1] region,
1q23-25), ELAC2 (HPC2 region, 17p) and MSR1 (8p22-23).
- However, sporadic cancers account for about 85% of all prostate cancers
and about 15% are familial and/or hereditary.

8. (B) Inflammation, Infection, and Genetic Susceptibility
- Preclinical studies support a potential role of chronic inflammation in the
development and progression of PC.
- A number of stimuli might activate different molecular pathways and lead
to intraprostatic inflammation with consequent architectural modification
of prostatic tissue and alterations of epithelial cells and prostatic stroma.
- Inflammation heralds microenvironmental changes that might contribute
to genotoxicity and, ultimately, the development of a niche that promotes
malignant transformation.

9. Disease Screening
• Goal
– To detect potentially lethal cancer at an early, treatable
stage and to intervene with intent to cure.
• Recommendations are for screening in men aged 55 to 69
years to be a joint decision between the physician and the
patient and a routine screening interval to occur every 2
years.
• Use a combination of DRE and PSA

10. Guidelines on Prostate Cancer Screening
• American Cancer Society (ACS)
• National Comprehensive Cancer Network (NCCN)
• American Urological Association (AUA)
• U.S. Preventive Services Task Force (USPSTF)
• European Society for Medical Oncology (ESMO)
• European Association of Urology/European Society for
Radiotherapy and Oncology/International Society of Geriatric
Oncology (EAU/ESTRO/SIOG)

11. American Cancer Society (ACS)
• Asymptomatic men with at least a 10-year life expectancy should be given
an opportunity to make an informed decision with their health care
provider after receiving information on the uncertainties, risks and
benefits of screening.
• Men should receive the information starting at the following ages:
– Age 50 for those at average risk of developing prostate cancer
– Age 45 for those at high risk, including African Americans and men
with a first-degree relative (father, brother, son) diagnosed with
prostate cancer before age 65
– Age 40 for those at higher risk (more than one first-degree relative
diagnosed with prostate cancer at an early age)

12. NCCN Screening guidelines
• The NCCN recommends performing a baseline evaluation, with a history
and physical examination that includes the following:
– Family history
– Medications
– History of prostate disease and screening, including prior PSA and/or
isoforms, exams, and biopsies
– Race
– Family or personal history of BRC1/2 mutations
• In patients 45-75 years of age, subsequent evaluation is based on the
results of those tests, as follows
– PSA 1-3 ng/mL, DRE normal (if done): Repeat testing at 1–2 year
intervals
– PSA >3 ng/mL or very suspicous DRE result: Evaluate for biopsy

13. AUA screening guidelines
• The guidelines do not recommend routine screening for the following
groups:
– Any man with a life expectancy less than 10-15 years
– Men under 40 years
– Men between ages 40 to 54 years at average risk
– Men over age 70
• For men 55 to 69 years of age, the decision to undergo PSA screening
involves weighing the benefits and risks and strongly recommend shared
decision-making and proceeding based on patients’ values and
preferences.
• A routine screening interval of two years or more in those men who have
participated in shared decision-making and decided on screening.

14. DRE
• DRE (digital rectal exam) has a 50% positive predictive value
• DRE alone is not a good screening tool
• BUT it is an important part of screening

15. PSA
• A Serine protease (enzyme) found in the prostate
• Secreted by prostate epithelial cells
• Found in ejaculate
• As diagnostic tool for:
– Screening
– Staging
– Prognostic indicator
– Surveillance

16. Causes of an elevated PSA
1. Prostate cancer
2. Age
3. BPH
4. Infection/inflammation
5. Recent instrumentation (biopsy, catheterization, etc)
6. Physiological variation
• Recent ejaculation

17. • No clear cut-point between normal and abnormal PSA levels.
Even PSA cut-off of 1.1 ng/ml misses up to 15% of prostate
cancer (The Cancer Prevention Trial – 2003)
• Positive predictive value for PSA > 4ng/ml = 30% (i.e. About 1
in 3 men with elevated PSA have prostate cancer detected at
time of biopsy
• PPV increases to 45-60% for PSA > 10ng/ml
• Nearly 75% of cancers detected in the grey zone (PSA: 4-10)
are organ confined; potentially curable.
• <50% of prostate cancers organ confined if PSA >10.

18. • Free/Total PSA Ratio:
– Prostate cancer may be associated with more protein-
bound PSA (less free PSA) than in BPH
– F/T ratio is lower in patients with prostate cancer
– Can improve test specificity
– Useful when total PSA in 4-10 ng/ml range
• PSA Density - Normalized to prostate volume
• PSA Velocity - Change in PSA over time (e.g., more than 15%
per year)

19. Other Biomarkers:
• Heparan sulfate proteoglycan glypican-1 (GPC-1)
– GPC-1 is a prostate cancer biomarker as it is present on the cell
surface and also shed by the cells.
– Circulating GPC-1 levels can differentiate non-cancer (normal and
benign prostatic hyperplasia) patients from prostate cancer
patients, as well as benign prostatic hyperplasia patients alone
from prostate cancer patients.
– Future studies are underway to develop a MIL-38 based GPC-1
ELISA to assess the levels of GPC-1 in normal, BPH and prostate
cancer patients to determine whether secreted GPC-1 may
represent a clinically relevant biomarker for prostate cancer
diagnosis.

20. Glutathione-S-Transferase Pi (GSTP1)
• GSTP1 belongs to a family of detoxifying enzymes that are
involved in metabolic reduction of electrophilic carcinogens.
• These enzymes are thought to be involved in the development of
prostate cancer.
• Elevated levels of GSTP1 CpG hypermethylation have been
detected in tissues from precancerous lesions (atypia and
prostatic intraepithelial neoplasia [PIN]) and within ejaculates,
urine, and plasma from men with prostate cancer. (Nakayama et al, 2003)

21. Prostate-Specific Membrane Antigen
• The glycoprotein prostate-specific membrane antigen (PSMA) is a
folate hydrolase and is found embedded within the cell membrane of
all prostatic epithelial cells.
• PSMA mRNA expression among prostate cancers is highest in the
hormone-deprived state. (Henttu et al, 1992; Israeli et al, 1994)
• PSMA/PSM ratio is upregulated three- to sixfold in prostate cancer
compared with BPH (0.76 to 1.6) and normal (0.075 to 0.45) tissue. Su
and colleagues (1995)
• The clinical usefulness of PSMA for diagnosis, monitoring, and
imaging continues to be promising and remains under investigation in
many laboratories.

22. • Gene Susceptibility Loci:
– Polymorphic variants in genes encoding the androgen
receptor (AR), CYP17, and 5α- reductase type 2 (SRD5A2)
have been evaluated and suggest a role for infection and
inflammation in the development of prostate cancer.
(DeMarzo et al, 2003)
• α-Methylacyl Coenzyme A Racemase:
– α-methylacyl coenzyme A racemase (AMACR) gene, located
on chromosome 5, is upregulated in prostate cancer tissues.
(Luo et al, 2001; Rubin et al, 2002)

23. Investigations:
• TRUS
– The prostate is divided into distinct anatomical zones and
these can be depicted by TRUS. The peripheral zone (PZ) is
echogenic relative to the central zone (CZ) and the
transition zone (TZ), which are echopoor.
– Inspection of the gland should focus on identifying
asymmetry, areas of increased vascularity,
hypoechogenicity and the presence of focal bulges,
irregularity or breaches of the capsule, which are
associated with the presence of cancer.

24. Transrectal ultrasound appearances suspicious for cancer

25. TRUS guided biopsy
• Standard biopsy template involves 12 cores with a spring-loaded biopsy
instrument; tissue obtained from the base, mid and apex regions, medially and
laterally from left and right sides.
• Indications for prostate biopsy
– Elevated total PSA
– Free PSA <20%
– PSA velocity >0.75 ng ml−1 per year
– Abnormal digital rectal examination
– Previous negative biopsies, but continuing high suspicion for prostate cancer
• Absolute contraindications
– Surgical absence of rectum
– Ilio-anal pouch
– Inflammatory bowel disease (especially Crohn’s disease)
– Severe bleeding diatheses.

27. MRI/Ultrasound Fusion Guided
Biopsy
• precisely target the area of the prostate that needs to be
biopsied and guide the needle to the precise spot.
– PSA between 4 and 10.
– men who have had several biopsies with PSA >15 and have a
high risk for metastatic prostate cancer in the near future.
– men who have undergone multiple biopsies, but we can’t find
their cancer.
– help detect aggressive cancers in patients who have not had a
previous biopsy.

28. Multiparametric Magnetic Resonance
Imaging
• NCCN multiparametric magnetic resonance imaging (mpMRI) can be used
in the staging and characterization of prostate cancer.
• NCCN guidelines recommend considering mpMRI in patients undergoing
active surveillance if anterior and/or aggressive cancer is suspected when
PSA increases and systematic prostate biopsies are negative.
• The 2016 EAU/ESTR/SIOG guidelines recommend mpMRI prior to
performing a repeat biopsy when clinical suspicion of prostate cancer
persists inspite of negative biopsies.
• The guidelines recommend performing mpMRI for local staging and
metastatic screening in predominantly Gleason pattern 4 intermediate risk
patients and for local staging in high-risk localised prostate cancer.

29. PI-RADS v2
• PI-RADS (Prostate Imaging Reporting and Data System) refers to a structured
reporting scheme for evaluating the prostate for prostate cancer. It is designed
to be used in a pre-therapy patient.
• The score is calculated from evaluation of a prostate specific MRI. Images are
obtained using a multiparametric technique including T2 weighted images, a
dynamic contrast study (DCE), and Diffusion-weighted imaging (DWI).

30. Bone Scan
• Gleason grade of greater than 6 are candidates for a bone scan, irrespective
of their PSA level.
• A bone scan may be performed as a baseline for treatment response in
patients with recurrent metastatic disease at high risk of having bony
metastatic disease.
• Bone scan is indicated in patients with prostate cancer who have symptoms
suggesting bony metastases.
• Activity in the bone scan may not be observed until 5 years after
micrometastasis has occurred; therefore, negative bone scan results do not
rule out metastasis.
• In biochemical failure, a follow-up bone scan usually has no value until the
PSA level exceeds 30ng/mL.

31. PET Scan
• Fluciclovine F 18 (Axumin) was approved in May 2016 for PET
imaging in men with suspected prostate cancer recurrence.
• The diagnostic performance of fluciclovine PET/CT in
recurrent prostate cancer was superior to that of CT, and
fluciclovine PET/CT provided better delineation of prostatic
from extraprostatic recurrence.

32. Prostate elastography
• Krouskop et altheorized that cell density is greater in neoplastic tissue,
causing a change in tissue elasticity.
• Elastrography is an ultrasound tool that is capable of mapping tissue
stiffness of the prostate.
• It involves the analysis of prostate tissue deformation before and after
compression by the ultrasound transducer. This difference in deformation
is used to estimate the tissue stiffness, and reduced deformation typically
indicates neoplastic tissue; additionally, if this tissue appears hypoechoic,
it is likely a malignancy.
• In Miyanaga’s 2006 study, of 29 patients with untreated prostate cancer,
the sensitivity of elastography, TRUS, and DRE were 93%, 59%, and 55%,
respectively and has been shown to have a negative predictive value of up
to 99%.

33. Staging of Prostate Cancer
AJCC Cancer Staging Manual, 7th Edition (2010)
Primary tumor
Tx - Primary tumor cannot be assessed
T0 - No evidence of primary tumor
T1 - Clinically inapparent tumor not palpable or visible by imaging
T1a - Tumor incidental histologic finding in less than or equal to 5% of tissue resected
T1b - Tumor incidental histologic finding in greater than 5% of tissue resected
T1c - Tumor identified by needle biopsy (because of elevated PSA level); tumors
found in 1 or both lobes by needle biopsy but not palpable or reliably visible by imaging
T2 - Tumor confined within prostate
T2a - Tumor involves up to half of one lobe
T2b - Tumor involves more than half of one lobe but not both lobes
T2c - Tumor involves both lobes
T3 - Tumor extending through the prostatic capsule; no invasion into the prostatic
apex or into, but not beyond, the prostatic capsule
T3a - Extracapsular extension (unilateral or bilateral)
T3b - Tumor invading seminal vesicle(s)
T4 - Tumor fixed or invading adjacent structures other than seminal vesicles (eg,
bladder neck, external sphincter, rectum, levator muscles, pelvic wall)

34. Regional lymph nodes
NX - Regional lymph nodes not assessed
N0 - No regional lymph node metastasis
N1 - Metastasis in one or more regional lymph nodes
Distant metastasis
M0 - No distant metastasis
M1 - Distant metastasis
M1a - Non-regional lymph node(s)
M1b - Bone(s)
M1c - Other site(s), with or without bone disease

35. Stage groupings
The TNM system for prostate cancer is based on the following five key pieces
of information:
• The extent of the primary tumor (T category)
• Whether the cancer has spread to nearby lymph nodes (N category)
• The absence or presence of distant metastasis (M category)
• The PSA level at the time of diagnosis
• The Gleason score, based on prostate biopsy (or surgery)

36. Stage I - Cancer found in the prostate only:
• T1, N0, M0, Gleason score 6 or less, PSA less than 10 or
• T2a, N0, M0, Gleason score 6 or less, PSA less than 10
Stage II (IIa and IIb)- Cancer is more advanced than stage I, but has not spread
outside the prostate:
Stage IIa - One of the following applies:
• T1, N0, M0, Gleason score of 7, PSA less than 20 or
• T1, N0, M0, Gleason score of 6 or less, PSA at least 10 but less than 20 or
• T2a or T2b, N0, M0, Gleason score of 7 or less, PSA less than 20
Stage IIb - One of the following applies:
• T2c, N0, M0, any Gleason score, any PSA or
• T1 or T2, N0, M0, any Gleason score, PSA of 20 or more or
• T1 or T2, N0, M0, Gleason score of 8 or higher, any PSA

37. Stage III - Cancer has spread outside the prostate and may have invaded the
seminal vesicles:
• T3, N0, M0, any Gleason score, any PSA
Stage IV - Cancer has spread outside the prostate, into surrounding pelvic
organs, lymph nodes, or distant metastasis outside the pelvis:
• T4, N0, M0, any Gleason score, any PSA or
• Any T, N1, M0, any Gleason score, any PSA or
• Any T, any N, M1, any Gleason score, any PSA

38. GLEASON GRADING SYSTEM
• The Gleason system is based on the glandular pattern of the tumor as
identified at relatively low magnification.
• The Gleason system is based on the glandular pattern of the tumor as
identified at relatively low magnification.

39. Risk stratification for men with
localised prostate cancer
Level of risk PSA Gleason score Clinical stage
Low risk <10ng/ml and ≤6 and T1-T2a
Intermediate
risk
10–20ng/ml or 7 or T2b
High Risk >20ng/ml or 8-10 or ≥T2c

40. Management
• Most prostate cancers are now either localised or locally
advanced at diagnosis, with no evidence of spread beyond the
pelvis.
• A number of treatments are available for localised disease,
including:
– Active surveillance
– Radical prostatectomy
– External beam radiotherapy and brachytherapy
– Hormone therapy (androgen deprivation or anti-androgens)
is the usual primary treatment for metastatic prostate
cancer, but is also increasingly being used for men with
locally advanced, non-metastatic disease.

41. Active Surveillance
Timing Tests
At enrolment in active
surveillance
Multiparametric MRI if not previously performed
Year 1 of active surveillance •Every 3–4 months: measure PSA
•Throughout active surveillance: monitor PSA kinetics
•Every 6–12 months: DRE
•At 12 months: prostate rebiopsy
Years 2–4 of active
surveillance
•Every 3–6 months: measure PSA
•Throughout active surveillance: monitor PSA kinetics
•Every 6–12 months: DRE
Year 5 and every year
thereafter until active
surveillance ends
•Every 6 months: measure PSA
•Throughout active surveillance: monitor PSA kinetics
•Every 12 months: DRE
•Intervention is recommended if Gleason pattern 4 or 5 is present, more than two biopsy cores
are involved, or more than 50% of a biopsy core is involved.
•In most studies of active surveillance, approximately 25% to 50% of patients, depending on
their individual risk factors, develop objective evidence of tumor progression within 5 years
(Neulander et al, 2000; Patel et al, 2004; Warlick et al, 2006).

42. Radical Prostatectomy
• Localised prostate cancer who had chosen an active surveillance
regimen but have evidence of disease progression.
• Intermediate and high-risk localised prostate cancer.
• The main advantage of radical prostatectomy is that when
skillfully performed, it offers the possibility of cure with minimal
collateral damage to surrounding tissues (Han et al, 2001b; Hull et al, 2002)

44. Surgical Approaches to Radical
Prostatectomy
• Perineal
• Retropubic
• Laparoscopic
• Robotic

45. Perineal
• It is usually associated with less blood loss and a shorter
operative time than the retropubic approach.
• The disadvantages are that
– does not provide access for a pelvic lymph node
dissection,
– higher rate of rectal injury, and
– occasional postoperative fecal incontinence (Bishoff et al, 1998)
– difficult to spare the cavernous nerves through the
perineal approach.

46. Retropubic
• Familiar surgical anatomy
• lower risk for rectal injury
• lower risk of postoperative fecal incontinence
• wide exposure and ready access provided for pelvic
lymphadenectomy and prostate excision with preservation of
the neurovascular bundles
• lower risk for positive surgical margins.

48. Laparoscopic
• Laparoscopic prostatectomy can be performed through a
transperitoneal or extraperitoneal approach.
• Less bleeding, better visualization, less postoperative pain,
and shorter convalescence than the standard open approach.
• Rectal, ureteral, and vascular injuries and anastomotic leaks
have also been more common with laparoscopic
prostatectomy (Rassweiler et al, 2003).

49. Robotic
• The availability of three-dimensional visualization is an advantage over
standard laparoscopic techniques.
• Greater technical ease for the surgeon, especially for tying sutures and
performing the vesicourethral anastomosis.
The Da Vinci Robot

50. Selection of Patients for
Radical Prostatectomy
• An ideal candidate for radical prostatectomy is healthy and free of
comorbidities.
• Life expectancy of at least 10 years.
• Tumor should be deemed to be biologically significant and
completely resectable.
• The generally accepted upper age limit for radical prostatectomy
is about 75 years.

51. RADIATION THERAPY
External Beam Radiotherapy
• External beam radiotherapy involves the use of beams of gamma
radiation, usually photons, directed at the prostate and
surrounding tissues through multiple fields.

52. Brachytherapy
• Brachytherapy using permanent or temporary radioactive
implants within the prostate alone or combined with IMRT.
• Most commonly used radioisotopes for permanent seed
brachytherapy are iodine-125 (125I) and palladium-103 (103Pd)

53. Intensity-Modulated Radiation Therapy (IMRT)
• can provide localization of the radiation dose to geometrically
complex fields (Burren et al, 1999; Zelefsky et al, 2006)

54. 3D Conformal Radiation Therapy
• Conformal radiation therapy uses the targeting information to
focus precisely on the tumor, while avoiding the healthy
surrounding tissue.
• This exact targeting makes it possible to use higher levels of
radiation in treatment. More radiation is more effective in
shrinking and killing tumors.

55. HIFU
• High-intensity focused ultrasound (HIFU) procedure is a new
technique approved by the FDA to remove prostate tissue.
• It hasn't been approved for the treatment of prostate cancer
in the U.S., it is being used in clinical trials to treat it.
• Men with cancer that hasn't spread beyond the prostate, and
can also be done if the cancer comes back to your prostate.
• HIFU uses sound waves that points through the wall of
rectum to the target site.

57. Androgen Deprivation Therapy (ADT)
ADT is used as adjuvant therapy
• Improve local eradication of locally advanced tumors by reducing tumor
size.
• Eliminate tumor clonogens inherently resistant to radiotherapy by
impairing DNA repair pathways.
• Reducing prostate volumes by 30% to 40%, which improves the ability to
deliver maximal radiation dose levels without exceeding the tolerance for
the surrounding normal tissue.
• Hormone therapy also has a favorable effect on micrometastatic disease
that may be present at the time of diagnosis in men with high-risk tumors.

58. Hormone Therapy
Four therapeutic approaches for androgen axis blockade in
current clinical use:
(1) ablation of androgen sources,
(2) inhibiting androgen synthesis,
(3) antiandrogens, and
(4) inhibition of LH-RH and/or LH release

59. Ablation of Androgen Sources:
• Bilateral orchidectomy quickly reduces circulating
testosterone levels to less than 50 ng/dL, which, based on this
procedure, is considered the castrate range.
• Within 24 hours of surgical castration, testosterone levels are
reduced by greater than 90% (Maatman et al, 1985).

60. Steroidal Antiandrogens
• Cyproterone Acetate
Nonsteroidal Antiandrogens
• Flutamide
• Bicalutamide
• Nilutamide
Inhibitors
• Ketoconazole
• Corticosteroids
• Aminoglutethimide
Estrogens
• Diethylstilbesterol
• Estradiol
• Polyestradiol phosphate
LHRH Agonist
• Leuprolide
• Goserelin
• Triptorelin
• Histrelin
LHRH Antagonists
• Degarelix

61. Chemotherapy
• Docetaxel
• Cabazitaxel
• Mitoxantrone
• Estramustine
• Is combined with the steroid drug prednisone.
• Used if prostate cancer has spread outside the prostate gland
and hormone therapy isn’t working.
• Chemo is not a standard treatment for early prostate cancer,
but some studies are looking to see if it could be helpful if
given for a short time after surgery.

62. Novel Agents Recently Approved or
Under Investigation for Treatment of
Metastatic Castrate-resistant Prostate Cancer
Hormonal Therapies Bone-targeting Agents
Abiraterone (Zytiga)
Enzalutamide (Xtandi)
TAK 700
ARN-509
Denosumab (Xgeva)
Rad 223 Chloride (Alpharadin)
(XL-184) Cabozantinib
Immunotherapies Clusterin Inhibition
Sipuleucal-T (Provenge)
PROSTVAC
Ipilimumab (Yervoy)
OGX-011 (Custirsen)
Chemotherapy
Cabazitaxel (Jevtana)

63. Immune checkpoint inhibitors
• newer drugs such as Pembrolizumab (Keytruda) and
Nivolumab (Opdivo) target the immune checkpoint protein
PD-1.
• Ipilimumab (Yervoy), which targets a checkpoint protein
called CTLA-4 on certain immune cells.
• These types of drugs have been shown to treat some other
cancers. Studies are now being done to see how well they
might work against prostate cancer.

64. Isoliquiritigenin
• Isoliquiritigenin, a chalcone compound belonging to the
flavonoid family, in relation to its treatment of castration-
resistant prostate cancer patients.
• It arrests the G2/M cell cycle and induces apoptosis in
prostate cancer cell lines.
• Isoliquiritigenin was able to suppress the growth of prostate
cancer cells both in vitro and in vivo.
Zhang et al 2017; Antineoplastic activity of isoliquiritigenin, a chalcone compound, in androgen-independent
human prostate cancer cells linked to G2/M cell cycle arrest and cell apoptosis.

65. Denosumab
• Denosumab is a fully human monoclonal antibody that
specifically binds to the receptor activator of nuclear factor-κB
ligand, a key mediator of osteoclast formation, function, and
survival.
• Denosumab is associated with increased bone mineral density
at all sites and a reduction in the incidence of new vertebral
fractures among men receiving androgen-deprivation therapy
for nonmetastatic prostate cancer.
Matthew R. Smith et al., N Engl J Med 2009;Denosumab in Men Receiving Androgen-Deprivation Therapy for
Prostate Cancer; DOI: 10.1056/NEJMoa0809003

66. ADT Adjuvant to Radiation Therapy or
Prostatectomy
• Several phase 3 randomized trials have shown a benefit in overall survival
when comparing radiation therapy alone to radiation therapy plus ADT for
patients with locally advanced (ie, extracapsular or node-positive) disease.
• The European Organisation for Research and Treatment of Cancer conducted
a phase 3 trial in 412 patients with locally advanced disease, randomizing the
patients to GnRH-A plus radiation therapy vs radiation therapy alone.
• In the combination arm, ADT was started on the first day of radiation and
continued for 3 years. Overall survival at 5 years was 78% for combined
treatment and 62% (P<.001) for radiation therapy alone.
• Among surviving patients, 74% and 40% were free of disease at 5 years in the
combined treatment and radiation-only groups, respectively (P<.001).
Androgen Deprivation Therapy for Prostate Cancer Nima Sharifi,; James L. Gulley,; William L. Dahut

67. Management of Advanced and
Metastatic Disease
The 2017 NCCN guideline and the 2011 European Association
of Urology (EAU) guideline provide recommendations for
treating patients with advanced prostate cancer which
include:
• LHRH agonists - Available in 1-month, 3-month, 6-month, and
once-yearly depots
• LHRH antagonist - Available in a 1-month depot
• Complete androgen blockade - LHRH agonist or antagonist
with an oral antiandrogen
• Nonsteroidal antiandrogen monotherapy
• Bilateral orchidectomy

68. Systemic Therapy in Advancing or Metastatic
Prostate Cancer: Evaluation of Drug Efficacy
(STAMPEDE)
• STAMPEDE (also known as MRC PR08) is a multi-arm multi-
stage (MAMS) randomised controlled trial recruiting in the UK
and Switzerland.
• It aims to evaluate multiple therapeutic strategies in the
management of high-risk locally advanced and metastatic
hormone-naïve prostate cancer.
• Standard of care was hormone therapy for at least 2 years;
radiotherapy was encouraged for men with N0M0 disease to
November, 2011, then mandated; radiotherapy was optional
for men with node-positive nonmetastatic (N+M0) disease.

69. • Stratified randomisation allocated men 2:1:1:1 to standard of
care only (SOC-only; control), standard of care plus zoledronic
acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc),
or standard of care with both zoledronic acid and docetaxel
(SOC + ZA + Doc).
• Zoledronic acid showed no evidence of survival improvement
and should not be part of standard of care for this population.
Docetaxel chemotherapy, given at the time of long-term
hormone therapy initiation, showed evidence of improved
survival accompanied by an increase in adverse events.

70. Prostate Cancer Intervention Versus
Observation Trial (PIVOT)
• Among men with clinically localized prostate cancer that had
been diagnosed after PSA testing came into practice, the
study showed that radical prostatectomy did not reduce all-
cause or prostate-cancer mortality, as compared with
observation, through at least 12 years of follow-up.
• But there were clear indications that RP reduced the risk of
dying of cancer in the subset of men who had aggressive
cancers, including
– Those whose PSA was >10.0 ng/ml and
– Those with high-risk cancers

71. POTEN-C trial
• Patients in the study will be treated with a highly precise form
of radiation called stereotactic ablative radiotherapy (SAbR),
and a spacer gel (SpaceOAR) will be placed between the
rectum and prostate, which may help reduce the radiation
dose to nerve bundles involved in sexual function.
• SpaceOAR hydrogel provides up to 1.2 cm of space between
the rectum and the prostate, reducing high dose radiation to
the rectum.
• SpaceOAR hydrogel is clinically proven to minimize urinary,
sexual, bowel side effects and protect quality of life for
prostate cancer patients undergoing radiation therapy.

72. A Little Space Makes A BIG Difference