The document provides a comprehensive overview of prostate cancer, including its risk factors, clinical workup, and treatment strategies for various stages of the disease, particularly focusing on castration-resistant prostate cancer (CRPC). It emphasizes the importance of advanced imaging and molecular prognostic tests in managing prostate cancer and highlights recent developments in treatment options, including combination therapies and emerging investigational agents. The document also discusses active surveillance strategies and addresses the unmet needs within prostate cancer management, especially concerning precision medicine and biomarkers.

1. Prostate
Cancer
2018: A Brief Overview.

2. TOCObjective
Overview
Known risk factors
Initial clinical
workup
Molecular
prognostic tests
Treatment
Management of
CRPC
Chemotherapy of
CRPC
Investigational
agents & unmet
needs
Follow-up

3. Addressing challenges in prostate cancer management
Advances in risk assessment,
differential diagnosis between
aggressive and non-aggressive tumors,
and the development of
novel/optimized treatment for
advanced disease are discussed.

4. Overview
Prostate cancer is the second most common cancer after skin cancer in US men and tends to strike after the
age of 50. However, African-Americans have a higher incidence of this treatable cancer and a higher rate of
disease-specific mortality compared with non-Hispanic whites. Because of the location of this walnut-shaped
gland (below the bladder in front of the rectum and surrounding the upper part of the urethra), a tumor can
also affect the bladder and sexual function. Fortunately, prostate cancer is treatable, with relative 5-year
survival rates ranging from almost 100% for localized disease to 29.8% for distant disease. However, most
patients are typically diagnosed with localized disease, when the tumor is confined to the gland. When the
cancer spreads, it can reach the seminal vesicals, lymph nodes in the pelvis, and bones.

5. Known risk factors
Risk factors can be grouped into categories of triggers that can be
changed eg, smoking and factors that cannot be changed e.g. age or
hereditary predisposition. Having one or more risk factors does not
mean the inevitable onset of the disease.
01 | Age
02 | Race/Ethnicity /Geography
03 | Family History
04 | Gene Changes e.g., BRCA1, BRCA2, Lynch syndrome
05 | Diet/Obesity/Smoking/Prostate Inflammation
>Prevalent in
Men of African/
Caribbean descent
than in other races.

6. Initial clinical workup
Staging
Digital rectal examination to assess extent of disease,
pretreatment PSA level, Gleason score/grade group in the
initial biopsy, number of biopsy cores involved by cancer
Imaging Radionuclide bone scan, computed tomography (CT) scan, and
multiparametric magnetic resonance imaging, are used to
assess extraprostatic disease

7. AJCC anatomic staging/groups (2017)
When either PSA/Gleason is not available, grouping should be determined by T stage and/or either PSA or Gleason as available;G, Gleason grade;
PSA, prostate-specific antigen; X, Gleason or PSA scores could not be processed

8. When newly diagnosed, key factors of
concern are:
1
Anatomic extent of the disease1 The eighth
edition (2017) of the AJCC/UICC staging system
uses anatomic (TNM) information along with
pretreatment serum PSA and the histologic
grade group to define prognostic groups for
adenocarcinoma and squamous carcinoma of
the prostate.
2
Estimated outcome with different treatment
options
3
Potential complications with different
treatment options.
4
Person’s general age, medical condition,
general comorbidities, and individual
preferences

9. Molecular
prognostic
tests

10. Cell proliferation
tests
Evaluation by immunohistochemistry of Ki-67, and the cell cycle
progression scored by a RT-PCR, which incorporates information
from 31 cell-cycle related genes and 15 housekeeping genes.
Implications: Among populations typically undergoing definitive
treatment, use of proliferation indices might be able to provide
valuable information that could influence the extent of therapy
(short versus long courses of androgen deprivation combined
with radiation therapy, for instance, or the use of adjuvant
radiation therapy after surgery)

11. Molecular characteristics
Loss of the PTEN tumor suppressor appears to be clinical
prognostic marker for untreated, localized disease. Two
commercial tests can be used to assess the presence of adverse
pathology. Decipher appears useful in predicting risk of
metastasis and death following a prostatectomy.
Implications:
In mouse models, PTEN deletion is predictive of rapid
progression to metastasis. Other multimarker tests are available
that are predictive of adverse parhology.

12. Proteomic biomarkers
An eight-biomarker assay further improves the accuracy of the
Gleason biopsy score in assessing favorable or unfavorable
pathology from the prostatectomy specimen.
Implications
Additional studies are required to understand the role of this
proteomic assay compared with other molecular prognostic tests.

13. Treatment
0
1
Mgmt. of castration-sensitive PC
Initial treatment may involve ADT +
medical/surgical orchiectomy as a component to
suppress testosterone levels in patients needing
systemic therapy.
0
2
Localized-, intermediate, and very
high risk PC
Treatment recommendations are based on risk
stratification in accordance with guidelines from
the American Urological Association and the
NCCN, as well as patient preferences.
0
3
Mgmt. of castration-resistant PC
(CRPC)
Patients who have evidence of disease
progression while being managed with ADT, are
said to have castration-resistant diseases.
Multiple treatments are available for CRPC.

14. Clinically localized, NCCN,
Very low risk
Disease detected by biopsy based on serum PSA only, without
detectable disease on DRE and imaging. Such patients must have
a tumor that is in histologic grade group 1 (Gleason score ≤6) on
biopsy and a serum PSA <10 ng/mL. Extent of disease within the
prostate must be limited (ie, fewer than three positive biopsy
cores with less than 50 percent involvement in any one core and
a PSA density less than 0.15 ng/mL/gram).
Treatment approach:
Active surveillance is usually recommended for men with very
low-risk disease and a life expectancy less than 20 years.
Prostate-specific antigen (PSA)
is a protein made by the fluid-
making cells that line small glands
inside the prostate. The larger the
prostate, the more PSA is made.
PSA levels could indicate
cancer/health conditions associated
with the prostate.
Active surveillance/close
Monitoring of cancer typically
involves a doctor’s visit with a
DRE and PSA test every
6 months. Prostate
biopsies may also be done
every year.
Gleason scores between
2 and 10 refer to how
closely cells resemble
normal cells under the
microscope. The higher the
number, the greater the
chance that the cancer will
spread.

15. Clinically localized, NCCN,
Low risk
No apparent tumor in the prostate (ie, diagnosis based upon a
biopsy only, with no abnormal findings on imaging or palpation)
or limited disease in one lobe of the prostate gland, a serum PSA
<10 ng/mL, and a histologic grade group 1 (Gleason score ≤6).
Treatment approach:
Treatment is tailored taking into account patient consent after
assessment of advantages/disadvantages associated with each
modality. Active surveillance, radiation therapy, and radical
prostatectomy are standard treatment options.
Radiation therapy (RT) may be
delivered by an external source or by
brachytherapy. Conformal
techniques, particularly intensity-
modulated RT (IMRT) and image-
guided RT (IGRT) form part of
Standard RT.
Approach
informed
by results from the
Prostate
Testing for Cancer and
Treatment (ProtecT) trial.
No significant differences
among treatment
modalities in terms
of 10-year cancer-
specific survival
and overall
survival
rates.
Radical
prostatectomy
may be carried
out
either by an
open /minimally invasive
approach. Surgical
pathology specimen may
result in a change in staging
that suggests additional
postoperative
therapy may improve
the chance for cure.

16. Clinically localized, NCCN,
Intermediate risk
Can have more extensive tumor in the prostate (ie, involving
more than one-half of one lobe of the prostate [T2b] or with
bilateral disease [T2c] on initial examination or imaging), but
without detectable extraprostatic extension or seminal vesicle
involvement. patients with T1 or T2a disease also are classified as
having intermediate-risk disease based upon a serum PSA ≥10
and <20 ng/mL, or a biopsy histologic grade group 2 or 3
(Gleason score of 7).
Treatment approach:
May involve RT/ADT/radical prostatectomy

17. Clinically localized, NCCN,
High risk
Patients with high-risk, clinically localized prostate cancer have
more extensive disease, based upon the presence of presumed
extraprostatic extension on digital rectal examination (T3a), or
are classified as being at high risk because of a serum PSA ≥20
ng/mL or a grade group 4 or 5 (Gleason score of 8 to 10)
Treatment approach:
May involve RT/ADT/radical prostatectomy

18. Clinically locally advanced
or NCCN very high risk
Patients whose initial evaluation suggests locally advanced disease
(T3b or T4) with seminal vesicle involvement, tumor fixation, or
invasion of adjacent organs are classified as being very high risk for
progression or recurrence. In addition, patients with a primary
Gleason pattern 5, or with four or more cores with Gleason score 8
to 10 (grade group 4 or 5) are classified as very high risk. Imaging of
the pelvis (CT, MRI) may be considered for those at significant risk of
pelvic lymph node involvement.
Treatment approach:
May involve RT/ADT/radical prostatectomy. Serum PSA will provide
information on whether or not disease has been resected/further
therapy is indicated.
Clinical lymph node involvement
Patients with lymph node involvement are
classified as having stage IV (metastatic) disease
in the American Joint Committee on Cancer
(AJCC)/Union for International Cancer Control
(UICC) staging system.
Disseminated metastasis
The initial approach to the management of disseminated
metastases (M1) and for a detectable or rising serum PSA
following treatment in those who are not candidates for
definitive locoregional therapy generally focuses on ADT,
with either a so-called medical orchiectomy (using a
gonadotropin releasing hormone) or bilateral orchiectomy.
In some cases, ADT may be combined with docetaxel
chemotherapy.

19. Management of
Castration-resistant
Prostate Cancer
(CRPC)

20. Rationale/Types of ADT Treatment
Androgen-based pathways have a clinically significant role in the progression of castration-resistant prostate cancer. In addition to
androgen production by the adrenal gland and testis, several of the enzymes involved in the synthesis of testosterone and
dihydrotestosterone, including cytochrome P450 17-alpha-hydroxysteroid dehydrogenase (CYP17), are highly expressed in tumor
tissue.
Androgen
receptor
antagonists
e.g.,
enzalutamide
Androgen synthesis
inhibitors e.g.,
Abiraterone and
ketoconazole
Despite high response rates to
androgen deprivation therapy
(ADT) in men with advanced
prostate cancer, nearly all
eventually develop
progressive, castration-
resistant disease.
Abiraterone and enzalutamide have not been compared with each other or with other agents that
can prolong survival in the context of castration-resistant disease.

21. Abiraterone and enzalutamide were combined in a prospective phase I/II study in 60 men
with metastatic castration-resistant prostate cancer. Preliminary results found that the
combination was well tolerated, and there were no unanticipated toxicities or
pharmacokinetic interactions. The combination was able to block the adaptive increase of
testosterone in the serum seen with enzalutamide. A randomized trial is comparing the
combination with abiraterone alone to provide additional information about whether this
approach may have clinical utility (NCT01946165).
ADT
Combination

22. Chemotherapy of CRPC
Progressed on
docetaxel+prednisone
2nd-line therapy may include
cabizataxel, mitoxantrone, or
platinum-based agents,
depending on patient needs.
Without neuroendocrine
features
Docetaxel (75 mg/m2 every
three weeks) plus oral
prednisone (5 mg twice a
day) is one treatment
option.
Low PSA and visceral rather than
Bone metastasis
Docetaxel+prednisone if non-neuroendocrine
features or similar treatment to small cell lung
cancer if tumor has neuroendocrine features.
*Gonadal androgen suppression should be continued during chemotherapy.
Taxane-based regimens have
been associated with higher
rates of objective tumor
regression and biochemical
(PSA) response, as well as
longer overall survival.

23. Side effects/caveats
An important component of
follow-up in men with advanced
prostate cancer is monitoring for the
adverse effects of androgen
ablation, including gynecomastia,
loss of bone, and lean muscle loss.
Not all prostate cancers make
significant amounts of PSA. Some
of these are neuroendocrine
tumors that may respond to
cisplatin-based chemotherapy
rather than hormonal
manipulation. Others lack
neuroendocrine features but are
poorly differentiated prostatic
adenocarcinomas with a serum
PSA <10 ng/mL.

24. Bone Health
ADT-treated patients with prostate cancer may experience increase bone
fracture risk due to elevated bone turnover or loss of bone mineral density.
This risk is measureable with the FRAX tool. The NCCN and National
Osteoporosis Foundation have recommendations regarding pharmacologic
and non-pharmacologic treatment options for at-risk patients. Additional
treatment for bone loss is recommended when the 10-year probability of
hip fracture is ≥ 3% or the 10-year probability of a major osteoporosis-
related fracture is ≥ 20%. Medical therapy with bone-modifying agents
including zoledronic acid, alendronate, or denosumab for those developing
reduced BMD should be initiated in select patients.

25. Active Surveillance
“For men undergoing active surveillance, follow-up should also include repeat
prostate biopsies, usually within one year following the original diagnosis and
then at selected intervals (eg, every two to four years) to monitor for evidence
of progression.”

26. Investigational
Agents & Unmet
Needs

27. Emerging near-term therapies
About one-third of patients with metastatic disease
have mutations in DNA damage repair (DDR) genes
and may be candidates for PARP inhibitors. These
drugs are not approved for prostate cancer, but
several candidates are being evaluated in phase 3
trials. In the case of the rilimogene galvacirepvec
vaccine, results from a phase 2 trial demonstrated a
median overall survival improvement of 8.5 months
in patients with advanced disease.
met,consecteturadipiscingelit.Duis
bibendumluctus.
PARP inhibitors include olaparib, rucabarib ,
and niraparib . DDR genes include BRCA1 and
BRCA2. About 10% of men with metastatic
disease have mutations in DDR genes.There
may be a need to test family members for
related cancers involving DDR genes e.g.,
breast, colon, ovarian, and pancreatic cancer.
An ongoing phase 3 trial is
assessing rilimogene
galvacirepvec/rilimogene
glafolivec with and without an
immune-stimulating agent
known as GM-CSF for the
treatment of metastatic
hormone-refractory prostate
cancer.

28. Future landscape of precision medicine
1 2 3
Investigational agents targeting
PTEN-loss, PIK3C, AKT, RAF,
WNT, CDK, IDH1, RB, and others
are also in development.

29. Unmet needs
Validated biomarker to complement PSA for screening; molecular stratification
and predictive biomarkers; adjuvant cure rates to increase cure rates in higher-
risk locally advanced PC; imaging of bone metastasis for staging and response
measures; surrogate biomarkers for overall survival benefit of treatment.
.
Consecteturneclabore
45K
Molecular differentiation
betweenslow-growingand
moreaggressivedisease.
Adipiscingelitsed
690K
Morevalidatedbiomarkersfor
diagnosisand prognosis.
Sedeiusmod
100K
Moreeffective treatment
optionsfor metastatic disease.

30. Follow-up
Active surveillance/watchdul waiting/assessment of the
complications or side effects of treatment are important
components of tailored follow-up evaluations. Non-cancer
related complications that may require added treatment
include psychological distress, cardiovascular disease, GI
or urinary tract toxicities, erectile dysfunction,
hypogonadism, and impaired bone health.
CEO
Berry Books
Prostate Cancer
Survivors
Prostate Cancer
Survivors

31. Thank you.