This document discusses treatment options for metastatic prostate cancer. It begins by outlining first line hormonal therapies like androgen deprivation therapy using LHRH agonists or antagonists. It then discusses secondary hormonal manipulations for castration-resistant prostate cancer, including antiandrogens, CYP17A inhibitors, and estrogens. Novel agents targeting the androgen axis like abiraterone and MDV3100 are also reviewed. Chemotherapy options for metastatic CRPC including docetaxel and cabazitaxel are summarized. The timing of chemotherapy and immunotherapy agents like sipuleucel-T are also addressed.

1. Treatment of Metastatic Prostate
cancer: How Urologists Should
Sequence Available Agents

2. INTRODUCTION :Prostate cancer is the most
commonlly diagnosed non-cutaneous malignancy
among men in the United State. Represented the
second leading cause of cancer death in men and
nearly 10% of cancer deaths in the U.S. With the
advent of PSA. based screening the overwhelming
majority of patients are diagnosed with clinically
localized disease amenable to defenitive surgery or
radiation with curative intent.We discuss the practical
considerations of the treatment of advanced
Pca.While hormonal ablation remains the cornerstone
of therapy. We focus on treatment that address
survival end points and not the agents that modulate
bone health or quality of life.

3. FIRST LINE HORMONAL THERAPY FOR
METASTATIC PCA
with ADT, thereby suppressing its transactivation
potential and preventing androgen driven disease
progression Strategies include surgical
casration‘chemical castration via gonadotropin
releasing hormone agonists or antagonists. combined
androgen blockadeThe biochemical goal of
ADT(androgen deprivation therapy) is to deprive the
androgen receptor of its legand and /or blok legand
mediated interactions of AR with the use of
antiandrogens and lnrermittent androgen
suppression.

4. LHRH agonists vs antagonists:
The mainstay of hormonal therapy is suppression of testicular
androgen production via depot administration of agents
inhibiting the pituitary/luteinizing hormone signaling axis.
LH releasing hormone agonists are peptidg analogues of LHRH
which initially stimulate pituitary secretion of LH, resulting in
a brief surge in testosterone (T) production(the so called'flare
response “).Under continued stimulation, pituitary expression
of LHRH receptors is down-regulated, leading to loss of'LH-
secretion and a decline in testicular androgen production by
14 to 21days. LHRH antagonists, which directly inhibit
pituitary LH secretion, have been developed to more rapidly
suppress androgen levels without inducing the flare
phenomenon.

5. Currently approved LHRH agonists include
1- buserelin (Suprefact, Suprecor)
2-leuprolide (Lupron, Eligard)
3-nafarelin (Synarel)
4-histrelin (Supprelin LA, Vantas)
5-goserelin (Zoladex)
6-deslorelin (Suprelorin, Ovuplant)
7-Triptorelin (Pamorelin LA).
These medications can be administered intranasally, by injection, or by implant.
Injectables have been formulated for daily, monthly, and quarterly use; and implants
can last from 1 to 12 months.
Currently approved LHRH antagonists include
1-Cetrorelix
2-Ganirelix
3-Abarelix
4-Degarelix
GnRH antagonists are administered by either intramuscular injection (abarelix)
or subcutaneous injection (cetrorelix, degarelix and ganirelix).

6. With the withdrawal of abarelix due to a 1% incidence of
anaphylaxis,the introduction of degarelix a minimal histamine
response. has spured re evaluation of this question. The
phase III noninferiority study of degarelix vs leuprolide in -600
patients ,demonstrated more rapid suppression of LH, follicle-
stimulating hormone T and PSA levels, without evidence of T
surge (>95% of patients reaching castrate T levels by day 3
and >80% within 24 hours in other studies). Degarelix was
associated with a lower risk"of-PSA failure and a more
sustained reduction in levels of serume alkaline phosphatase
(a marker of bone turnover in patients with skeletal
metastases) in the subset of patients with baseline PSA >50
ngldl or metastatic disease.

7. These findings are hypothesis generating regarding a
superior clinical benefit of LHRH antagonists
particularly as patients with metastatic PCs today
have less extensive disease compared to the era when
LHRH agonists were introduced. Interestingly ,LHRH
antagonist have been reported to induce durable
androgen suppression in patients in whom LHRH
agonists did not maintain castrate (<50 ng/dl) serum T
levels and may be of value in this setting.

8. Monitoring of serum testosterone levels for LHRH
analogue resistance
Failure to maintain T levels <50 ng/dl has been reported in
l2% to 25% of men receiving LHRH agonist therapy, with more
than 30% failing to achieve T levels <20ng /dl which
approximates surgical castration. The etiology of resistance is
unclear but may be related to granulomatous injection site
reactions disrupting sustained drug release or to upregulated
expression of pituitary LHRH receptors in men with metastatic
cancer the risk of death was correlated with serum T level >50
ng/dl at 6 months. These data suggest that maintenance of
serum T levels <50 ng/dl should be periodiqally ascertained
and verified at disease progression before macking a
desgnation of CRPC.

9. Combined androgen blockade
ADT can be administered as monotherapy with LHRH
analogues or in combination with antiandrogens The
rationale for CAB (combined androgen blockade). intended to
inhibit testicular and adrenal anderogen activity, is the well
substantiated hypothesis that despite testicular androgen
ablation, tumoral uptake of circulating adrenal androgens can
lead to generation of T and DHT, resulting in continued AR
signaling .To date, randomized studies of CAB have been
inconclusive and the therapeutic advantage of CAB for
advanced PCa remains debated. A central problem is lack of
data on target activiry. In particular, the currently available
nonsteroidal AAs are relatively poor competitive AR
antagonists, with affinities for AR that are 50 to 100times
lower than the affinity of DHT for AR.

10. Given the relativelly, small-OS (overall survival),benefit,
coupled with increased costs and potential side effect
associated with AA. CAB is generally reserved for the early
flare period or at the time of disease progression on ADT
monotherapy.
Multitargeted androgen blockade
The poor affinity and potential agonist activity of
nonsteroidal AAs strongly suggest that failure of CAB to
demonsrate substantial clinical benefit is due to lack of
effective agent targeting the AR-axis rather than failure of the
concept. The efficacy of CAB may be improved by multitarget
androgen blockade incorporating an LHRH analogue and a
nonsteroidal AA with aSRD5A inhibitor to inhibit intratumoral
conversion of T to DHT. The reduction of intraprostaticDHT levelsby
SRD5A inhibitor alone (75% by fenasteride and >90% by dutasteride)
approaches or exceed the 75%reduction achieved with testicular

11. intermittent androgen suppression:(IAS)
Cyclic administration of ADT has been evaluated with the goal
of delaying progression to CRPC, and mitigating costs and
toxicities of continuous androgen deprivation. Patients
treated with IAS had reduced hot flashes but otherwise no
differences in adverse events including myocardial events or
osteoporotic fractures. This trial was the first to report that
IAS is not inferior to CAD with respect to OS in men with PSA
recurrence after radical therapy. In general, induction consists
of 6 to 9 months of LHRH monotherapy or CAB, with
discontinuation at PSA nadir <4 ng/ml . Reinitiation is generally
considered at PSA10 to 15 ng/ml (4 ro 6 ng/ml in patienrs with relapse
afrer radicaltherapy) if the PSA doubling time decreases to 4 to 6
months or at clinical progression. It is not yet recommended as standard
of care by organizations such as the American Society of Clinical
Oncology or the National Comprehensive Cancer Network.

12. Timing of ADTfor metastatic PCa:
A subset analysis revealed patients with baseline PSA >50
ng/ml had a 3.5-fold increased risk of death from PCa vs
those with baseline PSA<8 ng/ml. Of patients with PSA 8 to
50 ng/m1 those with PSADT(PSA doubling time) greater vs
less than 12 months had 47.6% vs 11.4% risk of
PCSM(prostate cancer specific mortality), at 7 years,
respectively. These data suggest that patients with serum
PSA>50 ng/ml or PSADT <12 months present a significantly
increased risk of dying from PCa and should be considered for
early initiation of ADT, while trearment (and toxicity) may be
reasonably delayed in men with lower risk disease.

13. SECONDARY HORMONAL MANIPULATION
A substantial body of evidence suggests that castration
resistant tumors are not, in fact, androgen independent but
occur in a setting of continued AR mediated signaling driven
by residual tumoral or adrenal androgens.
The initial therapy of CRPC includes AA withdrawal, high dose
bicalutamide, alternative AAs such as flutamide or nilutamide
(after progression on bicalutamide), SRD5A inhibitors such as
finasteride or dutasteride, the nonspecific CYP17A inhibitor
and adrenolytic agent, ketoconazole, estrogenic agents such
as DES or transdermal estradiol, the synthetic progestin
megestrol acetate and palliative glucocorticoids. Therefore,
the choice of agent and sequence is largely empiric and
physician dependent, and often driven by side effect profiles
of each agent.

14. Practical treatment considerattons in secondary-
hormonal manipulation
Important considerations include the management of known
toxicities,which primarily include hepatotoxicity with
nonsteroidal AAs and ketoconazole, the necessity for steroid
replacement when using ketoconazole and significant risks of
thrombosis in patients taking oral estrogens. Liver enzymes
should be measured before therapy, monthly for 3 to 4
months and periodically thereafter. Ketoconazole is
associated with nausea and hepatotoxicity (especially at the
higher doses used for impending cord compression and/or
urinary obstruction), and must be given with replacement
steroids (typically 20 mg and 10 mg hydrocortisone in the
morning and evening, respectively). DES increases in risk of
cardiovascular events, including myocardial infarction, stroke

15. Predictors of response to secondary hormonal
suppression
Circulating adrenal androgen and T levels have been
identified as potential predictors of response to secondary
hormonal suppression and PSA response. These observations
suggest that androgen levels may be useful for stratifying
patients likely to sustain durable benefit from second line
therapies from those who should be considered for earlier
initiation of chemotherapy or enrollment in clinical trials.
NOVEL HORMONAL AGENTS TARGETING THE
ANDROGEN AXIS IN CRPC
Accumulating evidence suggests that CRPC remains a ligand
and AR driven disease, and that residual tumor androgens
play a prominent role in mediating CRPC progression. AR
pathway, such as abiraterone and MDV3100.

16. Abiraterone:
generally suppressed serum DHEA(dihydroepiandrosterone),
levels by approximately 75%, and DHEA-S,
AED(androstenedione), and T to essentially undetectable.It
demonstrate a transient increase in bone scan intensity at
3 months after starting_abiraterone, with improvement or
stability of findings at 6 months. These were generally mild
(grade 1 to 2 hypertension, hypokalemia, edema and fatigue)
and responded to eplerenone or low dose glucocorticoids
(spironolactone should be avoided due to potential AR
agonist activity). Decreases in cortisol (twofold) with
elevations in ACTH (fivefold) were also observed so addition
of steroid to decrease ACTH

17. MDV3I00:
MDV3100 is a competitive AR antagonist that binds rhe
AR with fivelold to eightfold greater affinity than bicaluramide
and only two to threefold lower affinity than DHT. The mosr
common adverse events were fatigue, nausea, dyspnea,
anorexia and back pain.
CHEMOTHERAPY FOR METASTATIC. CRPC
Significant gairs have been made in the use of chemotherapy
for metastatic CRPC for which estramustine, mitoxantrone,
docetaxel and cabazitaxel are now approved. Although clinical
benefit with agents such as ixabepalone and satraplatin has
not been realized.

18. Docetaxel:
every 3 weeks was approved for first line chemotherapy in
men with CRPC in 2004 based on 2 phase III studies
demonstrating improvements in OS. docetaxel every 3 weeks
or mitoxantrone every 3 weeks, all in combination with twice
daily oral prednisone for. Significant improvements in OS were
demonstrated in men receiving docetaxel every 3 weeks vs
mitoxantrone 10 cycle.
Cabazitaxel:
Cabazitaxel is thought to be effective for docetaxel resistant
tumors via decreased sensitivity to p-glycoprotein mediated
drug resistance.

19. Predictors of survival of men undergoing
chemotherapy for CRPC:
Prognostic factors in men initiating first line chemotherapy
include visceral metastases, pain, anemia, progression on
bone scan or prior use of estramustine. Post-chemotherapy
predictors included duration of first line therapy, number of
progression factors (pain, PSA or radiographic progression)
and whether progression occurred during or- after
completing chemotherapy. The number-of progression factors
was highly associated with survival, with median survivals of
15.9, 13.2 or 8.0 months for patients with disease progression
based on 1,2 or 3 factors, respectively.

20. Timing of chemotherapy for metastatic CRPC:
Although rapidly progressive or symptomatic disease is a clear
indication for initiating chemotherapy, the optimal timing of
therapy in men with asymptomatic disease remains debated.
While the indication for mitoxantrone plus prednisone for
CRPC is symptomatic bone pain. Importantly, the magnitude
of benefit associated with docetaxel treatment for CRPC was
independent of age, performance status, baseline PSA
(median 114 ng/ml in TAX-327 and 84 ng/mt in SWOG
9916)or presence of symptomatic disease, suggesting that
delaying chemotherapy until symptomatic progression does
not decrease clinical benefit. Therefore, initiation of
chemotherapy in asymptomatic men may be reasonably
delayed until parameters such as high PSA levels, PSADT <4 to
6 months and radiographic progression suggest onset of
symptomatic disease is likely.

21. Increasing PSA or pain flares within the first few months of
therapy should not be criteria for discontinuation, and a
minimum of 9 to 12 months of therapy is recommended to
maximize recognition of response.
IMMUNOTHERAPY FOR METASTATIC CRPC
A number of immunological based strategies for PCa have
been studied,including the sipuleucel-T (APC 8015),
PROSTVAC-VF and GVAX vaccines.

22. Sipuleucel-T: Sipuleucel-T is an autologous dendritic cell
vaccine derived via leukopheresis, ex vivo activation and then
re-infusion of a patient's peripheral blood mononuclear cells.
Activation is accomplished by incubating blood cells with
granulocyte macrophage colony stimulating factor (an
immune cell activator) and PAP(prostatic acid phosphatase),
expressed by -95% of PCa. Uptake and processing of PAP by
dendritic cells activate them so that once re-infused, they
stimulate the immune system, generating activated T cells
that proliferate and attack tumor cells expressing PAP.
Patients undergo'pheresis 3 times at 2-week intervals, with
reinfusion of the activated dendritic cells within 2 to 3 days.
The primary side effects were minor flu-likesymptoms including grade 1
to 2 chills, fever, headache and myalgias,which resolved by day 2
following the infusion and were slightly morecommon after the second
and third infusions.

23. Timing of immunotherapy for CRPC
An important consideration is the potential to exploit
interactions with chemotherapy and/or ADT,both of which
alter the exposure and interaction with tumor antigens of the
immune system. At present, therefore, sipuleucel-T may be
considered for patients with CRPC and asymptomatic or
minimally symptomatic metastatic disease. This agent
represents a particularly attractive option compared to early
chemotherapy as it is rapidly delivered with minimal side
effects. In addition, 18% of patienrs in the IMPACT study had
received docetaxel, and sipuleucel-T may represent a viable
option for minimally post-chemotherapy symptomatic
patients with life expectancies greater than 6 months.
Conversely, patients with large tumor burdens, those with
multiple prior chemotherapy regimens and those without
indolent disease are less likely to respond to immunotherapy.