metastatic prostate cancer

1. Molecular biology of Prostate cancer.
Three major pathways of prostate cancer .
(1) Androgen receptor pathway
(2) PI3K/Akt Pathway
(3) Rb pathway
Others
(4) Fusion of TMPRSS2-ETS
(5)TGF-b1- Associated with higher histologic grade
and malignant phenotype and greater
metastatic potential.
.

2. • TMPRSS2-ETS fusion is associated with high
chances of disease recurrence after surgery
and radiotherapy.
• PTEN /MMAC1-its loss is associated with more
aggressive prostate cancer and progression of
castration sensitive to castration resistant
prostate cancer.

3. • E-cadherin-Aberrant E-cadherin expression is
associated with high histologic grade and
more aggressive behaviour.

4. Risk factors-
(1)Age
(2) Ethnicity
(3) Genetic factors-
• BRCA2 and BRCA1 — The presence of BRCA1
or BRCA2 mutations increases the risk of
developing prostate cancer.
• HOXB13-Early onset and familial disease.

5. • Diet
• Hormone Levels And Obesity
• Physical activity
• Cadmium exposure.

6. Metastatic prostate cancer

7. • Although most cases of prostate cancer are
diagnosed and treated while disease is
localized,
• some men have evidence of metastatic
prostate cancer at presentation and others
develop disseminated disease after their
definitive treatment

8. • In many cases, the only manifestation of
disseminated disease is an elevated or rising
serum prostate specific antigen (PSA) following
definitive local radiation therapy (RT or surgery).
• However, some men with prostate cancer have
overt metastases either at presentation or as
their first sign of recurrence following definitive
therapy.
• In the vast majority of cases, such metastases are
predominantly osteoblastic lesions in the axial
skeleton.

9. • Metastasis typically bone and nodes
• Wide variation in natural history
– Depends on extent of osseous mets
– Presence of visceral mets
– Grade of tumor
– PSADT

10. Investigations-
(1)DRE
(2)PSA
(3) BIOPSY
(4)MRI/CT
(5)Bone scan

11. (A)Kallikrein markers-(1)4K Sscore test
(2) phi
(B)Urinary molecular biomarkers-
(1)PCA-3 - FDA approved

15. HORMONE-SENSITIVE PC
• The androgen receptor (AR) is the most important target in
prostate cancer
– Initial lowering of testosterone targets AR and is effective
> 90% time.
– Cells that are “sensitive”, ie require normal levels of
testosterone will die.
– PSA always declines (often to undetectable)
– Clinical response is seen (tumor shrinkage, pain improves)
– Side-effects develop from lowering of testosterone

16. ADT
Androgen deprivation therapy- can be
accomplished either with
• (1) Bilateral orchiectomy (surgical castration)
• (2)Medical orchiectomy.

17. Bilateral orchiectomy-
• Simple, cost-effective procedure,irreversible.
• Useful when an immediate decrease in
testosterone is necessary (eg, impending
spinal cord compression, urinary tract outlet
obstruction)
• when cost or adherence to medical therapy
are an issue.

18. Medical orchiectomy
• It decreases testicular production of testosterone
by its effects on the hypothalamic pituitary axis.
• The most widely used approach is continuous
treatment with a gonadotropin releasing
hormone (GnRH) agonist,
• which suppresses luteinizing hormone production
and therefore the synthesis of testicular
androgens.

19. GnRH agonists available are
• leuprolide, goserelin, buserelin, triptorelin
• Depot formulations are frequently used to
permit less frequent treatment
administration.

20. The GnRH antagonist- degarelix
• It binds to the GnRH receptors on pituitary
gonadotropin-producing cells but does not cause
an initial release of luteinizing hormone.
• Degarelix suppresses testosterone production
and avoids the flare phenomenon observed with
GnRH agonists
• a GnRH antagonist may be a useful alternative to
a GnRH agonist when an immediate decrease in
testosterone levels is required.

21. Flare phenomenon
• With the initiation of treatment with GnRH
agonists, there is a transient surge of luteinizing
hormone before the luteinizing hormone levels
fall
• This surge can cause an increase in serum
testosterone, which may result in a worsening of
disease. This "flare phenomenon" may be of
particular concern in clinical settings such as
impending epidural spinal cord compression or
urinary tract outflow obstruction.

22. Combined androgen blockade
• Antiandrogens bind to androgen receptors
and competitively inhibit their interaction
with testosterone and dihydrotestosterone.
• The use of antiandrogens with a GnRH agonist
thus produces a combined androgen
blockade.

23. • Combined androgen blockade is widely used for
two to four weeks during the initiation of
treatment with a GnRH agonist in order to
prevent a disease flare due to the transient
increase in testosterone levels.
• Combined androgen blockade is sometimes
considered for long-term therapy to improve on
the efficacy of a GnRH alone, although its long-
term use is limited by costs and increased toxicity.

24. Continuous versus intermittent ADT
• Many of the side effects of ADT are due to castrate
levels of serum testosterone. When treatment is
withdrawn, serum testosterone levels gradually return
toward normal; discontinuation of long-acting GnRH
agonists may be associated with a very slow
testosterone recovery.
• Intermittent ADT has been proposed as a way to
minimize the side effects of medical castration by
withholding active therapy once patients have
responded to treatment.
• ADT can then be reinstituted when there is evidence
of progression. The time when men are off therapy
may be associated with decreased side effects, thereby
improving quality of life.

25. ●Metastatic disease − intermittent ADT is not indicated in
patients with metastatic prostate cancer unless
survival is considered secondary to quality of life.
• A phase III intergroup trial found that intermittent ADT
could not be considered noninferior compared with
continuous ADT in terms of overall survival
●Rising or elevated PSA only − Intermittent ADT may be
appropriate for a subset of men whose only
manifestation of disseminated prostate cancer is an
elevated or rising serum PSA.

26. Antiandrogens
• Antiandrogens block the effects of circulating
androgens with fewer adverse effects (hot
flashes, loss of libido, impotence) than are
associated with surgical or medical castration.
• Antiandrogens may be useful in patients
whose initial ADT included either medical
orchiectomy with a GnRH agonist alone or
surgical orchiectomy.

27. • Nonsteroidal antiandrogens – bicalutamide
,flutamide, and nilutamide.
• Steroidal antiandrogen -cyproterone
acetate,megestrol acetate.

28. • Ketoconazole — Ketoconazol is an antifungal
agent that inhibits adrenal androgen
synthesis.
• Ketoconazole also has a direct cytotoxic effect
on prostate cancer cells.
• Serum testosterone levels decline to castrate
levels within 24 hours and antitumor efficacy
is rapid.
• Adverse effects and drug interactions may
limit the use of ketoconazole in some patients.

29. • Glucocorticoids — Prednisone, dexamethasone
,hydrocortisone reduce pituitary production of
ACTH
• Resulting in suppression of adrenal
steroidogenesis, including adrenal androgens.
• Several studies have shown significant subjective
and objective improvement in men with
castration resistant prostate cancer who receive
glucocorticoids.

30. • Estrogens and progesterones — Estrogens
inhibit the release of GnRH from the
hypothalamus, thus suppressing pituitary
luteinizing hormone release and thereby
reducing testicular production of testosterone.
• Diethylstilbestrol (DES) . DES at a dose of 1
mg/day is useful in some patients . no longer
used at a dose of 5 mg/day in men with
prostate cancer because of the increased risk
of cardiovascular disease.

31. Antiandrogen withdrawal
• The so-called "antiandrogen withdrawal
syndrome" refers to a decline in serum PSA that is
sometimes observed following the withdrawal of
an antiandrogen in men who had progressed
while being managed with complete androgen
blockade.
• Approximately 20 percent of men progressing
after complete androgen blockade have a PSA or
"biochemical" response when antiandrogens are
withdrawn, and some experience symptomatic or
objective improvement.

32. • For men who have progressed while on
complete androgen blockade, the first
therapeutic maneuver is the discontinuation
of the antiandrogen.
• Other therapy generally should not be
initiated until adequate time has elapsed to
assess for a possible withdrawal response

33. Side effects of ADT
●Loss of lean body mass, increased body fat,
and decreased muscle strength.
●Sexual dysfunction − Loss of libido in men
receiving GnRH agonists usually develops
within the first several months and is followed
by erectile dysfunction.
●Loss of bone mineral density, which can result
in bone fracture due to osteoporosis.

34. ●Vasomotor instability, which is manifested by
hot flashes.
●Gynecomastia, decreased body hair, and
smaller penile and/or testicular size.
●Fatigue or lack of energy.
●Behavioral and neurologic effects.
●Cardiovascular and metabolic abnormalities.

35. Chemohormonal therapy
• CHARTERED AND STEMPEDE trials has shown
that the combination of ADT plus docetaxel
offers a clinically meaningful and statistically
significant benefit for men with castration
sensitive disease and high volume disease.
• Sequential therapy with ADT alone and the
later addition of Docetaxel to ADT remains the
standard of care in most settings

36. CASTRATION RESISTANT DISEASE
• Patients who have evidence of disease
progression (eg, increase in serum prostate
specific antigen [PSA],
• New clinical metastases
• Progression of existing metastases ,while
being managed with androgen deprivation
therapy (ADT) are considered to have
castration resistant disease

37. • The presence of castration resistant disease
does not imply that disease is totally
independent of androgens and resistant to
further therapies directed at the androgen
stimulation of tumor growth.
• For patients whose initial ADT was a medical
orchiectomy (gonadotropin releasing
hormone [GnRH] agonist or antagonist), such
treatment should be continued even when
additional systemic treatment is initiated.

38. PROGNOSTIC FACTORS
(1)site of metastatic involvement.
Overall survival was best for those with lymph-
node-only disease and decreased progressively
for those with bone, lung, or liver metastases .
(2)performance status
(3)serum LDH
(4)serum PSA
(5)serum alkaline phosphatase
(6) serum albumin,
●These factors were combined into a nomogram to
classify patients as being at low, intermediate, or
high risk

39. Prognostic biomarkers
• Circulating tumor cells
• Markers of bone metabolism
• Gene expression panels
• Ki-67 Index

40. • CTCs can be detected in the systemic circulation of men
with prostate cancer, and the presence of increasing
numbers of CTCs assessed using the CellSearch assay has
been associated with shorter overall survival in two large
trials:
●In the phase III trial comparing abiraterone plus
prednisone with placebo plus prednisone in men with
castration resistant metastatic prostate cancer who had
progressed on docetaxel chemotherapy, CTCs were
measured in 972 of 1195 patients at baseline and/or
serially thereafter . Median overall survival was significantly
longer in those with baseline CTCs <5 per 7.5 mL compared
with those with CTCs ≥5 per 7.5 mL (22.1 versus 10.9
months in those assigned to abiraterone and 19.7 versus
8.2 months in those assigned to placebo).

47. Mitoxantrone
• It was the first chemotherapy agent approved for
use in men with castration resistant prostate
cancer.
• Mitoxantrone was approved based upon
improvement in symptoms, and not a
prolongation of survival.
• Its use now is generally limited to patients
requiring chemotherapy who have progressed on
or are not candidates for taxane chemotherapy.

48. Docetaxel
• Docetaxel (75 mg/m2) given every three
weeks in combination with daily prednisone (5
mg twice a day) significantly prolonged overall
survival compared with mitoxantrone plus
prednisone in the TAX 327 phase III trial .

51. Cabazitaxel
• Synthetic taxane derivative developed to have
activity in patients who progressed after
treatment with docetaxel.
• In a phase III trial, cabazitaxel plus prednisone
significantly increased survival compared with
mitoxantrone plus prednisone in men whose
disease had progressed on docetaxel .

52. • Cabazitaxel can cause significant
myelosuppression and requires premedication
to minimize the risk of infusion reactions.
• Therapy with prednisone is also required in
combination with cabazitaxel.
Contraindications - underlying hepatic
dysfunction or compromised bone marrow
function

57. Abiraterone
• Androgens produced in the testis can cause
"autocrine/paracrine" signaling that results in
tumor progression.
• orally administered small molecule that
irreversibly inhibits the products of the CYP17
gene (including both 17,20-lyase and 17-
alpha-hydroxylase).
• abiraterone blocks the synthesis of androgens
in the tumor as well as in the testis and
adrenal glands.

58. • Patients treated with abiraterone are at risk
for adrenal insufficiency and require
concurrent steroid replacement therapy.
• In two phase III trials, abiraterone plus
prednisone prolonged overall survival
compared with prednisone alone in men who
had previously been treated with docetaxel ,
and in those who were chemotherapy naïve

59. Abiraterone is generally well tolerated.
side effects are
• Fluid retention,
• Hypokalemia,
• Hypertension

67. Enzalutamide
• orally administered agent that acts at
multiple sites in the androgen receptor
signalling pathway,
• (1)Blocking the binding of androgen to the
androgen receptor.
• (2)Inhibition of nuclear translocation of the
androgen receptor,
• (3) Inhibition of the association of the
androgen receptor with nuclear DNA.

68. • Enzalutamide has been compared with
placebo in two phase III trials, one in men who
had previously been treated with docetaxel
and the other in those who were
chemotherapy naïve .
• Overall survival was significantly prolonged in
both trials.

69. • Treatment with enzalutamide has been
associated with seizures in rare cases,
• its use is contraindicated in patients with a
seizure disorder.

73. Orteronel (TAK-700).
• Other agents that inhibit CYP17 are in clinical trials.
• The most advanced of these is orteronel (TAK-700).
• In two large phase III trials, orteronel plus prednisone
was compared with placebo plus prednisone, one in
chemotherapy-naïve patients [24,25] and the other in
patients who had previously received docetaxel .
• Both trials showed an improvement in progression-
free survival, but no statistically significant difference in
overall survival.
• A third phase III trial comparing ADT plus orteronel
with ADT plus bicalutamide is in progress
(NCT01809691).

76. Sipuleucel-T
• Dendritic cell vaccine that is prepared from peripheral
blood mononuclear cells .
• These cells are exposed ex vivo to a novel recombinant
protein immunogen, which consists of prostatic acid
phosphatase (PAP) fused to human granulocyte
macrophage colony-stimulating factor.
• In randomized trials in men with minimally
symptomatic, metastatic prostate cancer, sipuleucel-T
prolonged overall survival compared with placebo.
• Treatment is contraindicated in patients who are on
steroids or opioids for cancer-related pain, and should
be used with caution in patients with liver metastases.

83. Bone directed therapy
• (1) Zoledronic acid
• (2) Denosumab
• (3)EBRT
• (4) Radioisotopes.
Phase III trial showed delay in first SRE with
denosumab compare to zoledronic acid
(20.7mv/s17.1m)

84. • Denosumab arm had a slightly higher
frequency of serious adverse events.
• Overall survival and progression free survival
not different significantly

85. EBRT
• Indicated for men with either a single or a few
focally symptomatic bone metastases, when pain
cannot be controlled with moderate analgesics.
• Local field RT provides some benefit in 80 to 90
percent of cases, and 50 to 60 percent have
complete relief of symptoms.
• Repeated use of palliative RT, especially when
given to areas encompassing much of the active
marrow, can cause bone marrow suppression,
which may impair quality of life and limit the use
of palliative chemotherapy.

86. • Advanced prostate cancer can cause pelvic symptoms
that significantly impair quality of life. These include
lower urinary tract symptoms, pelvic pain, hematuria,
and obstructive rectal symptoms. Systemic therapy is
the primary approach for the control of such
symptoms.
• Although there are no prospective clinical studies in
patients with castration resistant prostate cancer,
retrospective series indicate that radiation therapy (RT)
may be useful for symptom palliation .
• As an example, in one series, 58 men were treated with
20 Gy in five fractions . Four months after RT, 31 of 35
patients (89 percent) had complete resolution of
symptoms.

88. • The beta-particle emitting radioisotopes
samarium-153 and strontium-89 have been
used for palliative treatment of patients with
multifocal, painful osteoblastic bone
metastases.
• Used in persistent or recurrent pain despite
receiving external beam RT to maximal normal
tissue tolerance.

90. Radium-223
• alpha particle emitting radiopharmaceutical.
• Radium is a bone-seeking element, and
radium-223’s radioactive decay allows the
deposition of high energy radiation over a
much shorter distance than with beta-
emitting radioisotopes,
• thus minimizing toxicity to normal bone
marrow and to other organs.

91. • Because of its mechanism of action, its use is
limited to patients who have bone metastases
without other clinically significant sites of
disease
• In a phase III trial, treatment with radium-223
was well tolerated and increased both overall
survival and time to first symptomatic skeletal-
related event in patients with symptomatic
bone metastases and no known visceral
metastases

100. Checkpoint Inhibitors
• By blocking inhibitory molecules or, alternatively, activating stimulatory molecules, these
treatments are designed to unleash and/or enhance pre-existing anti-cancer immune
responses.
• A phase II trial testing ipilimumab (Yervoy®), an anti-CTLA-4 antibody made by Bristol-Myers
Squibb, following sipuleucel-T (Provenge) for patients with chemotherapy-naïve metastatic
castration-resistant prostate cancer (CRPC) (NCT01804465).
• A phase II trial testing ipilimumab in patients currently receiving hormone therapy in
metastatic CRPC (NCT02113657).
• A phase II study of ipilimumab plus androgen suppression therapy in patients with an
incomplete response to androgen suppression therapy alone for metastatic prostate cancer
(NCT01498978).
• A phase II study combining ipilimumab, the hormone therapy degarelix, and radical
prostatectomy in men with newly diagnosed metastatic castration sensitive prostate cancer
or ipilimumab and degarelix in men with biochemically recurrent castration sensitive prostate
cancer after radical prostatectomy (NCT02020070).
• A phase II study of pembrolizumab (Keytruda®), an anti-PD-1 antibody made by Merck, in
patients with metastatic CRPC previously treated with enzalutamide (NCT02312557).
• A phase II trial testing atezolizumab (MPDL3280A), an anti-PD-L1 antibody made by
Genentech/Roche, in patients with solid tumors, including prostate cancer (NCT02458638).
• A phase II study of sipuleucel-T, CT-011 (anti-PD-1 antibody; CureTech), and
cyclophosphamide for advanced prostate cancer (NCT01420965).

101. Therapeutic Vaccines
• Therapeutic vaccines in phase II or phase III clinical trials
include:
• PROSTVAC (rilimogene galvacirepvac) is a therapeutic
cancer vaccine .
• PROSTVAC uses viruses (vaccinia and fowlpox) as vectors to
deliver the PSA antigen along with three costimulatory
molecules directly to cancer cells.
• The virus vectors stimulate an immune response against
the PSA antigen, which directs the immune system to
attack cancer in the prostate. Based on promising results
from a randomized phase II trial involving 122 patients with
metastatic castrate-resistant prostate cancer that showed
an 8.5 month improvement in median overall survival,
• a large phase III trial of PROSTVAC-VF (PROSPECT
trial; NCT01322490 was initiated in November 2011 and
enrollment is now complete. They expect the results by late
2016 or early 2017.

102. Oncolytic virus therapy
• It uses a modified virus that can cause tumor cells
to self-destruct, in the process generating a
greater immune response against the cancer.
• ProstAtak uses a disabled virus as a vector to
deliver a gene directly to tumor cells, and is
followed by the oral anti-herpes drug valacyclovir
which kills the cancer cells containing the gene.
• ProsAtak is currently being tested along with
radiation in a phase III trial for patients with
localized prostate cancer (NCT01436968).

103. Targeted therapy
(1) cMET/VEGF inhibitors-Cabozantinib.
(2) src/abl inhibitor-Dasatinib
(3) Anti clustrin- Custirsen
(4) PARP inhibitors-Olaparib
(5) Tasquinimod