Locally advanced and metastatic prostate cancer can be treated with surgery, radiation therapy, hormone therapy, chemotherapy, or a combination. For locally advanced disease, short-term and long-term hormone therapy combined with radiation therapy improves outcomes. Adjuvant radiation after prostatectomy improves survival for high-risk patients. Advanced disease is treated by depleting androgens through surgical or medical castration. Newer agents like abiraterone, enzalutamide, radium-223, cabazitaxel, and sipuleucel-T provide additional treatment options.

1. Treatment of locally advanced
and metastatic ca. Prostate
Dr. Tanay N. Shah
Surgical oncology resident,
BMCHRC, Jaipur

2. Locally advanced ca. prostate
• cT3a, cT3b or cT4 (T3-4,N+/N-,M0)
• D'Amico and associates (1998) defined
patients at low, intermediate, and high risk for
biochemical failure, still based on
pretreatment disease characteristics (clinical
stage, PSA value, Gleason score).

3. T-STAGE PSA VALUE(NG/ML) GLEASON’S SCORE
LOW T1-T2A <10 <=6
INTERMEDIATE T2B T2C 10-20 7
HIGH T3A >20 8-10
VERY HIGH T3B – T4 >20 8-10 IN >4 CORE
BIOPSIES OR
PRIMARY GLEASON
PATTERN 5

5. Surgery for Clinical Stage T3 Prostate
Cancer
• Overall survival ranges from 64% to 96% at 5
years, 12.5% to 72% at 10 years, and 20% to
51% at 15 years after treatment.
• Cancer-specific survival rates are 85% to 92%
and 79% to 82% at 5 and 10 years,
respectively, regardless of adjuvant therapy.

7. Androgen Deprivation and Radiation Therapy
• Routinely recommended for patients with locally advanced
prostate cancer.
• ADT can improve local eradication of the locally advanced
tumors by reducing the size of the mass or the concurrent
elimination of tumor clonogens inherently resistant to
radiotherapy, or both.
• ADT can effectively reduce the size of larger prostate volumes
by 30% to 40%, thereby improving the ability to deliver
maximal radiation dose levels without exceeding the
tolerance of the surrounding normal tissues.

8. • Various trials have demonstrated improved outcomes when ADT is
combined with EBRT delivered at dose levels of 70 Gy.
• RTOG 85-31 randomized patients with clinical stage T3 as well as
patients with T1-T2 disease with lymphadenopathy. In this trial,
ADT was administered during the last week of radiotherapy and
continued indefinitely. With a median follow-up of 7.6 years, a
survival benefit was noted for patients treated with long-term ADT
compared with radiotherapy alone.
• the intent in the ADT cohort was for the therapy to continue
indefinitely, the median duration of ADT usage was 2.2 years (range,
1 day to 13.5 years).
• Patients who remained on ADT for 5 or more years experienced
improved overall survival and disease-free survival outcomes
compared with those patients with shorter ADT duration times.

9. • European Organisation for Research and Treatment of
Cancer (EORTC) 22863, assessed the role of adjuvant ADT
among node-negative patients with clinical stage T3
disease or T1-T2 patients with high-grade disease.
• Adjuvant ADT was initiated on the first day of
radiotherapy and continued for 3 years. In an update of
the outcome, with a median follow-up of 66 months,
improved outcomes in all parameters, including absolute
survival, were observed.

10. • Neoadjuvant and concurrent ADT in conjunction with EBRT
has been shown to improve outcomes in RTOG 86-10. In that
study, patients with bulky, locally advanced tumors were
randomized to 2 months of ADT prior to radiotherapy and 2
months during treatment compared with radiotherapy alone.
The 10-year long-term outcomes including cause-specific
mortality, distant-metastases-free survival, and biochemical
failure outcomes were significantly improved with ADT.
• The use of short-term ADT appeared to effectively delay the
onset of distant metastases in these high-risk patients.

11. • The optimal duration of adjuvant ADT was evaluated in RTOG 92-02,
the first ADT trial performed with baseline PSA information
available.
• In this study, patients with clinical T2-T4 with PSA baseline levels
less than 150 ng/mL were randomized to neoadjuvant and
concurrent ADT (4 months) and the same therapy in addition to 24
months of adjuvant ADT.
• With a median follow-up of 5.8 years, patients treated with the
longer course of ADT experienced improvement for all end points
compared with overall survival.
• However, in a subset analysis, a 10% overall survival advantage was
observed for those patients with Gleason scores 8 to 10 treated
with longer-course ADT compared with short-course neoadjuvant
and concurrent ADT.

12. • D'Amico et al. reported the results of a randomized trial
comparing 70 Gy of 3D-CRT alone or similar radiotherapy in
combination with 6 months of ADT in which androgen
deprivation was initiated 2 months prior to radiotherapy.
• Patients included in this study were mostly those with
intermediate-risk disease, namely pretreatment PSA 10
to 40 ng/mL or Gleason scores more than 7 with T1-T2
disease. With a median follow-up of 4.5 years, an overall
5-year survival advantage was demonstrated for the
combination-therapy regimen compared with
radiotherapy alone (88% vs. 78%; P = .04).

13. Randomized Trials Involving Hormone Therapy (Ht) and
Radiation Therapy (Rt) for Locally Advanced Prostate Cancer
Trial Eligibility Arms LF (%) DM (%) bNED (%) DFS (%) OS (%)
RTOG
85-31
T3 (15%)
or T1-2,
N+ or
path T3
and (+)
margin
or (+) SV
RT (HT @
failure)
vs. RT +
AHT
indefinit
e
10-y 38
vs. 23 (P
<.0001)
10-y 39
vs.24 (P
<.0001)
10-y 9
vs. 31 (P
<.0001)
10-y 23
vs. 37 (P
<.0001)
10-y 39
vs. 49 (P
= .002)
EORTC
22863
T3-4
(89%) or
T1-2
WHO 3
RT vs. RT
+ CAHT 3
y
5-y 16.4
vs. 1.7
(P
<.0001)
5-y 29.2
vs. 9.8
(P
<.0001)
5-y 45
vs. 76 (P
<.0001)
5-y 40
vs. 74 (P
<.0001)
5-y 62
vs.78 (P
= .0002)
RTOG
86-10
Bulky
T2b, T3-
4, N+
allowed
RT vs. RT
+ NHT
(TAB) 3.7
mo
8-y 42
vs. 30 (P
= .016)
8-y 45
vs. 34 (P
= .04)
8-y 3 vs.
16 (P
<.0001)
8-y 69
vs. 77 (P
= .05)
8-y 44
vs. 53 (P
= .10)

14. Trial Eligibility Arms LF (%) DM (%) bNED (%) DFS (%) OS (%)
RTOG 92-
02
T2c-4
w/PSA
<150, N+
allowed
RT + NHT
(TAB) 4 mo
vs. RT +
NHT + AHT
× 28 mo
5-y 12.3 vs.
6.4 (P =
.0001)
5-y 17 vs.
11.5 (P =
.0035)
5-y 45.5 vs.
72 (P
<.0001)
5-y 28.1 vs.
46.4 (P
<.0001)
5-y 78.5 vs.
80 (P = .73)
RTOG 94-
13
T2c-4
w/Gleason
≥6, or >15%
risk of N+
WP + NHT
WP + AHT
PO + NHT
PO + AHT
4-y 9.1 WP
vs. 8.0 PO
(P = .78)
4-y 8.2 WP
vs. 6.6 PO
(P = .54)
4-y 69.7
63.3 57.2
63.5 (P =
.048)
4-y 59.6
48.9 44.3
49.8 (P =
.008)
4-y 84.7
vs.84.3 (P =
.94)
Brigham
and
Women's
Hospital
PSA ≥10
Gleason ≥7
T1-T2B
RT 70 Gy
30-CRT vs.
RT + 6
months
NS NS 5-y 82% vs.
57% (P =
.002)
5-y 88%
vs.78% (P =
.04)
LF, local failure; DM, distant metastasis; bNED, biochemical failure-free survival; DFS, disease-free survival; OS, overall
survival; RTOG, Radiation Therapy Oncology Group; SV, seminal vesicle; AHT, adjuvant HT; EORTC, European Organisation
for Research and Treatment of Cancer; WHO, World Health Organization; CAHT, concurrent adjuvant HT; NHT, neoadjuvant
HT; PSA, prostate-specific antigen; TAB, total androgen blockade; WP, whole pelvis; PO, prostate only; CRT, conformal RT.

15. Adjuvant Radiation Therapy for High-Risk Patients
After Radical Prostatectomy
• The long-term results of Southwest Oncology Group (SWOG)
trial 8794 have demonstrated a survival benefit for the use of
adjuvant radiotherapy in high-risk patients after RP. This study
included 425 patients with high-risk localized disease who
were randomized to receive 60 to 64 Gy to the prostatic fossa
versus only observation.
• Among patients treated with adjuvant radiotherapy, the 10-
year distant-metastases-free survival outcomes and overall
survival outcomes were 71% and 74% compared with 61%
and 66% for the observation arm (P = .01; hazard ratio, 0.71
and 0.72, respectively).

16. • The EORTC Trial 22911 included 1,005 patients with positive
surgical margins or pT3 (ECE and SVI) disease and randomized
them to adjuvant EBRT (50 Gy to the prostatic fossa and
periprostatic tissue plus a 10- to 14-Gy boost to the prostatic
fossa only) versus no immediate treatment.
• With the use of adjuvant irradiation, 5-year biochemical
progression-free survival improved from 52.6% to 74% (P
<.0001). Clinical progression-free survival was also
significantly improved from 78% to 85% (P = .0009). The
cumulative rate of locoregional failure was significantly lower
in the irradiated group (P <.0001).

17. • These trials provide evidence that adjuvant
postprostatectomy irradiation reduces the risk of tumor
recurrence and distant metastases, and in one trial improved
survival was demonstrated.

18. Role of ADT in Combination with Adjuvant
Radiotherapy
• In study RTOG 85-31, a subset analysis of postprostatectomy
patients revealed a better biochemical failure-free survival for
patients treated with immediate LHRH analogue, without,
however, an impact on survival.
• RTOG-0534 is currently accruing patients with a rising PSA
after prostatectomy to radiotherapy alone to the prostate
bed, radiotherapy to the prostate bed plus 4 to 6 months of
ADT, and radiotherapy to the pelvis and prostate bed in
combination with 6 months of ADT.

19. Advanced Prostate Cancer: Rising Prostate-
Specific Antigen and Clinical Metastases—
Noncastrate and Castrate
• The core principle of treatment of advanced prostate cancer
– to deplete androgens or inhibit signaling through the androgen receptor
(AR).Huggins and Hodges,
– who showed that surgical removal of the testes or the administration of
exogenous estrogen could induce
• tumor regressions,
• reduce the level of acid phosphatase
• palliate symptoms of the disease.
• (LHRH) agonists - 1980s
• The palliative role of surgical adrenalectomy - 1945, later replaced by the
first-generation enzymatic inhibitors of adrenal steroid biosynthesis
(aminoglutethimide and ketoconazole).
• Nonsteroidal antiandrogens were introduced in the 1980s.
• All these agents lower androgen levels, with the exception of the
nonsteroidal antiandrogens that block the binding of androgens to the AR.

20. • a biologic agent (sipuleucel-T),
• a cytotoxic (cabazitaxel),
• a bone-seeking alpha-emitting radionuclide (radium-223),
• two hormonal agents, the CYP17 inhibitor abiraterone
acetate that inhibits androgen biosynthesis in combination
with prednisone and
• a next generation antiandrogen, enzalutamide, which is
mechanistically unique from the first-generation
compounds.
• denosumab, a monoclonal antibody that binds the cytokine
RANKL (receptor activator of nuclear factor-κB ligand)

22. LHRH AGONISTS
• LHRH agonists produce an initial rise in LH that increases
testosterone levels, followed 1 to 2 weeks later by
downregulation of LH receptors that results in a medical
castration.
• The initial rise in testosterone can flare the disease,
precipitating or exacerbating symptoms such as pain,
obstructive uropathies, and spinal cord compromise.
• compared with oral estrogens,
– Reduction in edema, thrombosis and thromboembolism,
myocardial infarction, and stroke.
• Leuprolide, goserelin, triptorelin, historelin- available in
daily or monthly injection dosages or 3,4 ,6 or 12 monthly
depot prepes.

23. LHRH ANTAGONISTS
• castrate levels of testosterone in 48 hours
without the initial rise making
• At present, degarelix, available as monthly
subcutaneous injections, is the only LHRH
antagonist that is approved in the United
States.
• DISADVANTAGE:
– requirement of monthly injections
– Higher rate of injection site reactions

24. ANTIANDROGENS
• block the binding of testosterone to the AR.
– the steroidal type I agents such as cyproterone
acetate have progestational properties that
suppress LH levels and lower serum testosterone;
these are not widely used.
– The nonsteroidal type II agents bind to the AR and
act as competitive antagonists for ligands that
might otherwise bind and activate the ligand-
dependent transcriptional activity of the receptor

25. • FLUTAMIDE: shorter t1/2- used along with
LHRH agonists to prevent initial flare
• Bicalutamide(50mg/day) and Nilutamide- T1/2
in weeks, so effective in once daily doses.
• Do not reduce the LHRH secretions-
testosterone levels continue to rise.
• Not approved as monotherapy by US FDA.

26. Enzymatic Inhibitors of Androgen
Synthesis
• All steroidal hormones are derived from pregnenolone and
subsequently metabolized via several CYP450 class enzymes.
• Within the adrenal gland, CYP17 mediates the synthesis of weak
androgens dehydroepiandrosterone (DHEA) and androstenedione
whereas in the testes, the presence of 17-keto reductase generates
testosterone that can be further converted to DHT in peripheral
tissues by 5α-reductase.
• Ketoconazole is a nonspecific P450 inhibitor that, at a dose of 1,200
mg/d, produces castrate levels of testosterone in 24 hours through
inhibition of adrenal and testicular steroidogenesis.
• It was useful for patients who presented with acute spinal cord
compression or disseminated intravascular coagulation, when LHRH
analogs are contraindicated and the risk of hemorrhage from
surgery is significant

27. Toxicity of ADT
• “androgen deprivation syndrome”
• hot flashes,
• a decrease in libido,
• erectile dysfunction,
• impotence,
• fatigue, anemia,
• weight gain and alterations in fat metabolism,
• loss of muscle mass and weakness,
• bone loss,
• a decrease in mental acuity, mood swings, personality
changes, memory loss, depression, and insomnia

28. Toxicity of anti androgens
• Elevations in hepatic enzymes, stomach upset
and diarrhea, and pulmonary complications such
as fibrosis; these toxicities are a rare class effect
of the first-generation antiandrogens,which occur
most frequently with nilutamide.
• Gynecomastia and/or breast tenderness may also
develop, which, if severe, might require a
reduction mammoplasty.
• Prophylactic breast irradiation can reduce the
frequency and severity of these effects.

29. When should ADT be initiated – early
or late?
• Complete review of all trials suggest that
– Early ADT delays time to metastasis and symptoms but
effect on overall survival is unclear.
• Vetrans administration research service co-
operative urological rearch group trial
– 1900 npts staged by DRE received DES or
orchidectomy- delay in development of metastatic dz
in pts with locally advanced disease.
– Overall survival – worse due to cvs complications
– Also no overall survival benefit for pts with metastatic
dz.

30. • The MRC PR03 trial randomized 998 patients with locally advanced
or asymptomatic metastatic prostate cancer to
“immediate”treatment (orchiectomy or LHRH analog) or to the
same treatment deferred until there was an “indication.” The
trigger to initiate treatment was “clinically significant progression,”
which was as frequent locally as metastatic.
• Early therapy were less likely to require a TURP or develop ureteral
obstruction, progress from M0 to M1 disease to develop pain or to
die of prostate cancer relative to those in whom therapy was
“deferred.”
• Even so, survival times were similar between the two arms.

31. The Early Prostate Cancer Trials Group
trial
• (n = 985) randomized men with T0-4N0-2M0 prostate cancer who
were not candidates for local therapy to immediate or to deferred
treatment until symptomatic progression.
• Increased risk of death in the deferred arm which remained after
adjusting for baseline factors. Notable was that only 49.7% of men
in the deferred arm began anticancer therapy during the median
7.8-year followup period, suggesting that a significant proportion of
men on the immediate arm were overtreated.
• The median time to treatment for those who required it, however,
was 3.2 years.
• Deaths were equally balanced between prostate cancer (n = 193,
18.8% of the population) and cardiovascular disease (n = 185)

32. Rising PSA ( extrapelvic disease)
• One series that addressed this question included 1997 RP-treated
patients, of whom 315 (15%) developed a rising PSA and were followed
with annual imaging and PSA assessment until metastatic disease was
documented.
• Of these patients, metastatic disease was subsequently documented in
103 at a median actuarial time of 8 years, of whom 44 (44%, or 2% of the
1997) died of disease.
• Factors associated with the development of metastasis included the grade
of the primary tumor, the time interval between the start of the treatment
to the date of first recurrence, the absolute PSA value, and the rate that it
was rising, typically expressed in terms of the PSADT.
• In a separate study, virtually all cancer related deaths occurred in men
who had PSADT ≤6 months, independent of whether the patient received
radiation or surgery as primary treatment.
• In practice, many physicians consider treating patients when the PSADT is
≤12 months, although there remains no absolute PSA level mandating that
treatment be started.

33. Strategies to reduce the toxicity of ADT
• Antiandrogen monotherapy:
– Bicalutamide 50 mg OD was inferior to surgical
castration
– But dose of 150 mg OD was equivalent in M0 pts but
again inferior in c/o M1 pts.
• Another approach is to begin with the
antiandrogen alone and add a testosterone-
lowering therapy when PSA levels rise.
• Unfortunately, only 30% of patients treated in
this fashion respond to the addition of the LHRH
analog

34. Intermittent Androgen
Depletion/Blockade
• The central hypothesis, based on studies in murine
tumors, is that by minimizing the exposure time to a
castrate environment, the sensitivity to subsequent
androgen depletion would be retained.
• An additional advantage is the potential for an
improved QOL during the “off” intervals.
• The approach is considered for patients who respond
well to ADT, typically defined as a PSA nadir ≤4 ng/ml
for those with metastatic disease, and is restarted
when PSA levels return to a predetermined level
(typically 10 ng/ml to 20 ng/ml).

35. • In the largest trial reported to date, 3,040 men
with noncastrate metastatic disease were
enrolled, of whom 1,535 met the criteria for
discontinuation.
• No significant different in survival was observed
overall, but for the subset of men with disease
limited to the axial skeleton and no visceral
disease at presentation, the median survival was
7.1 years for continuous therapy and 5.1 years for
the intermittent group.

36. • 3 meta-analyses based on 8 trials enrolling a total
of 4,664 patients,9 trials of 5,508 patients,and 13
trials of 6,419 men.
• All showed no difference in overall survival,
• 2 showed no significant differences in disease-
specific survival,
• 1 showed more deaths with IAD.
• IAD was superior with respect to overall QOL and
sexual function with significantly reduced costs.

37. CASTRATION RESISTANT CA. PROSTATE
• The development of hormone resistance (i.e., cancer
progression despite castrate levels of serum testosterone) is
virtually a universal issue that affects all patients treated with
ADT.
• Criterias :
– Testosterone levels < 50 ng/ml
– Biochem progression
– Progressive metastasis
– Progression despite cessation of ADT

38. Castrate Resistant Prostate Cancer
• In the past, we used terms like
– Hormone Refractory
– Androgen Independent
– Androgen Resistant
• Now … Castrate Resistant Prostate Cancer
(CRPCa)
– Why?

39. CRPCa
• Even though patients have castrate levels of serum
testosterone (50ng/mL), AR signalling is still happening
– By our current methods of “castration”, they are resistant but these
tumors are still responding to AR signalling
• Current methods of castration (or ADT)
– LHRH agonists
– LHRH antagonists
– Orchiectomy
–  Nonsteroidal antiandrogens

40. Mechanism of development of CRPC
• Somatic alterations of the androgen receptor.
• Activation of AR by other hormones eg.Estrogens,
progestational agents, GH and Cytokines.
• The observation that the androgen receptor can still be
activated even after long-term gonadal ablation suggests that
it continues to play an important role in prostate cancer
growth and may indeed be a reasonable target for treatment
in patients with androgen-independent disease.

41. Mechanism of development of CRPC
• Androgen ablation primarily affects the cell death rate by
inducing a swift apoptotic cascade.
• As the tumor progresses the threshold of apoptosis
progressively rises to a point at which cell proliferation
exceeds cell death
Accumulation of endocrine-independent cells that eventually
dominate the biologic behavior of prostate cancer in late
stages

42. Clinical considerations
• A complete disease evaluation is required to estimate the
outcome and to make therapeutic decisions.
• Critical baseline components
– Extent of disease
– Mode and site of progression (rising prostatespecific antigen [PSA]
level alone, new bone metastasis, visceral and nodal metastasis)
– Presence or absence of symptoms
– Response to prior endocrine treatment.

43. Clinical considerations
• Regular monitoring with serial bone scintiscans and serum
PSA levels during hormone treatment provides important
information in patients demonstrating evidence of disease
progression
• Usually the first manifestation of disease progression after
hormone therapy is a rising serum PSA level.
• In patients with metastatic disease, a rise in serum PSA level
precedes evidence of advancing disease in the bone
scintiscan, and during this time patients may remain relatively
asymptomatic.

44. Disease Progression

45. Clinical considerations
• Routine evaluation of serum testosterone levels may provide
important information for the choice of treatment.
• To suspect treatment noncompliance or if the choice of prior
treatment involved regimens known not to result in a
sustained suppression of serum testosterone to castrate levels
(e.g., monotherapy with nonsteroidal antiandrogens, low-
dose estrogens, or 5α-reductase inhibitors).

46. Clinical considerations
• Discontinuation of antiandrogens (both steroidal and
nonsteroidal) can result in short term clinical responses
expressed by decreases in PSA levels, symptomatic benefits,
and, less frequently, objective improvements in soft tissue
and bone metastasis in a small proportion of patients.
• 1st step : The discontinuation of these agents and careful
observation including serial monitoring of PSA levels for a
period of 4 to 8 weeks before embarking on the next
therapeutic maneuver.

47. Clinical considerations
• 2nd step : second-line hormonal manipulation or cytotoxic
chemotherapy
• Agents that have been reported to produce some benefit in this
setting include,
– Diethylstilbestrol
– Aminoglutethimide
– Ketoconazole
– Corticosteroids
• Hormonal > cytotoxic chemotherapy for those patients with
relatively limited metastatic disease who remain asymptomatic at
the time of disease progression (eg. Rising serum PSA value without
other clinical manifestations).

48. MONITOR THE RESPONSE
• PSA doubling time (PSADT) predicts for the rapidity of bone
scintiscan progression and survival
• Patients with PSADTs shorter than 3 months have a
particularly rapid clinical course and should be considered for
more aggressive management approaches.

49. Nonmetastatic Castration-
Resistant Disease
• Patients picked up in early stage of their disease with first sign
of rising PSA, before clinical or radiological evidence of
metastasis seen
• Rx Options:
– 2nd line hormonal manipulations,
– bone targeted therapy eg: Biphosphonates zoledronate
– ?? Cytotoxic chemotherapy

50. Metastatic Castration-Resistant
Disease

51. Metastatic Castration-Resistant
Disease
• MC site to metastasis bone > soft tissue (LN) > visceral
• Presentation: a range of hematologic problems caused
primarily by the disease or by its treatment.
– Anemia (MC) anemia of chronic disease, bone marrow
invasion, blood loss, long-term androgen deprivation and
rarely secondary to DIC.
– Granulocytopenia
– Thrombocytopenia
– Pancytopenia

52. Metastatic Castration-Resistant
Disease
• Obstructive uropathy with pain, infection and impairment of
renal functions
– Mx may require stent / PCN placements

53. Cytotoxic Chemotherapy
• A first step forward in the chemotherapeutic management of
CRPC came with mitoxantrone, a semi-synthetic anthracycline,
had previously shown modest symptomatic benefits but with
minimal evidence of objective antitumor activity
• In addition, mitoxantrone appeared to have its maximal
palliative effect in combination with low-dose corticosteroids.
• The combination resulted in significant improvements of
various quality of life parameters, including pain, but survival
was not significantly improved in either trial.

54. Cytotoxic Chemotherapy
• Docetaxel, a member of the taxane family.
• M/A:
– Inducing apoptosis in cancer cells through TP53-independent
mechanisms that are thought to be due to inhibition of
microtubule depolymerization and blockade of antiapoptotic
signaling.
– The induction of microtubule stabilization intracellularly through
β-tubulin interactions causes guanosine triphosphate (GTP)-
independent polymerization and cell cycle arrest at G2M.
– Induce BCL2 phosphorylation in vitro, a process that has been
correlated with caspase-3 activation and loss of its normal
antiapoptotic activity.

55. TAX-327 TRIAL
• Compared
– docetaxel 75 mg/m2 every 3 weeksfor up to 10 cycles (group 1),
– docetaxel 30 mg/m2 weekly for 5 cycles (group 2),
– mitoxantrone 12 mg/m2 every 3 weeks for 10cycles (group 3).
– Prednisone (10 mg daily) was added to all regimens.
• The primary end point was overall survival;
• secondary end points included changes in pain, PSA, and overall QOL.
• Mediansurvival for the respective arms was 18.9 months, 17.4 months, and 16.5
months, respectively, which led to the approval of docetaxel plus prednisone for
“androgen-independent (hormone-refractory)”disease.
• The 2.4-month difference in median survival (18.9 months versus 16.5 months) for
the every-three-week docetaxel versus the mitoxantrone schedule established the
every-three-week regimen as the de facto standard.

57. TAX 327 study
• Toxicity in the 3-weekly versus weekly docetaxel groups was
notable for more hematologic toxicity in the every-3-week
group but slightly lower rates of nausea and vomiting, fatigue,
nail changes, hyperlacrimation, and diarrhea.
• Neuropathy was slightly more common in the every-3-week
group

58. SWOG 9916 STUDY
• 770 patients to
– Estramustine (280 mgorally three times daily on days 1 to 5), docetaxel (60
mg/m2every 3 weeks), and dexamethasone (60 mg every 3 weeks) versus
– Mitoxantrone and prednisone (5 mg twice a day) to a maximum of 12 cycles
with no crossover at progression.
• The primary end point was overall survival.
• PSA declines, soft tissue response, and PFS were secondary end points.
• 2-month difference in median survival was observed for
docetaxel/estramustine (17.5 months versus 15.6 months), representing a
20% reduction in mortality.
• A higher incidence of neutropenia and fever, nausea, vomiting, and
vascular events with docetaxel/estramustine was noted despite the lower
dose of docetaxel.
• The results further supported docetaxel 70 mg/m2 every 3 weeks as the
standard regimen.

59. Cabazitaxel
• Till 2010 the treatment for docetaxel resistant CRPC was
lacking until FDA approved 2nd drug, CABAZITAXEL
• A novel tubulin-binding taxane that differs from docetaxel and
paclitaxel due to its poor affinity for p-glycoprotein, the ATP-
dependent drug efflux pump.
• Cabazitaxel was shown to be active in both docetaxel-
sensitive tumors as well as those with primary or acquired
docetaxel resistance.

60. Cabazitaxel
• Administered by intravenous infusion every 3 weeks at
escalating doses of 10 to 25 mg/m2
• The principal dose-limiting toxicity was neutropenia.
• The study to prove the efficacy of cabazitaxel was TROPIC
randomized phase III trial; C 25mg/m2 IV every 3 wkly + P 10
mg PO vs M 12 mg/m2 IV + P 10 mg PO

61. cabazitaxel
• Results favouring cabazitaxel were,
– OS (15.1 vs 12.7)
– Lengthened PFS (2.8 months vs. 1.4 months; P < .0001)
– Extended time to PSA progression (6.4 months vs. 3.1 months;
P = .001)
– Increased radiographic tumor response rates (14.4% vs. 4.4%;
p = .0005)
– Increased PSA response rates (39.2% vs. 17.8%)

62. Cabazitaxel
• Adverse events related to cabazitaxel:
• Hematological, including grade ≥3 neutropenia in 82% of
patients (febrile neutropenia in 8%).
– Use of growth factor support should be strongly considered,
• Nonhematologic toxicities included grade ≥3 diarrhea (6%)
• Grade ≥3 fatigue (5%).
• Peripheral neuropathy (all grades)

63. The Neuroendocrine/Anaplastic
Subtype
• Serum chromogranin A and urine serotonin metabolites may
be detected.
• These tumors are invariably unresponsive to hormonal
manipulations but highly sensitive to radiation therapy and
platinum-etoposide combinations

64. Palliative Management
• Pain control:
– EBRT
– IV corticosteroids
– Biphosphonates
– Calcitonin
– TCA
– Chemotherapy
– Surgical intervention

65. Bone Targeted Approach
Biphosphonates
• Reduce bone resorption by inhibiting osteoclastic activity and
proliferation.
• Zoledronate is a potent intravenous bisphosphonate first
approved for the treatment of hypercalcemia and decreased
bone mineral density in postmenopausal women.
• In patients with progressive castration-refractory disease and
bone metastases zoledronate was shown to reduce the
incidence of skeletal-related events (eg. Pain, fractures)
• Standard dose: 4 mg iv 3-4 wks apart

66. Biphosphonates
• Side effects: fatigue, myalgias, fever, anemia, and mild
elevation of the serum creatinine concentration.
• Hypocalcemia has been described, and concomitant use of
oral calcium supplements (1500 mg/day) and vitamin D (400
units/ day) is often recommended.
• An unusual complication of zoledronate is the development of
severe jaw pain associated with osteonecrosis of the
mandibular bone
• OTHER: Alendronate, Etidronate, Ibandronate and Clodronate

67. RANKL Inhibitors
• Interactions between tumor cells and the bone marrow
microenvironment have been postulated as an additional important
mechanism in the pathogenesis of bone metastasis.
• Tumor-associated cytokines have been shown to induce the
expression of RANKL (the receptor activator of nuclear factor κB
ligand), which binds and activates RANK, which is found in
osteoclasts.
• Among the approaches employed are monoclonal antibodies to
RANKL and the use of recombinant osteoprotegerin (the natural
decoy receptor of RANKL), both of which significantly inhibit
osteoclastic function in vitro and in vivo

68. RANKL inhibitors
• Denosumab, a fully human monoclonal antibody against
RANKL
• Common toxicities of denosumab include fatigue, nausea,
hypophosphatemia, hypocalcemia and osteonecrosis of the
jaw (2%)
• Prophylactic calcium and vitamin D supplementation is
strongly encouraged.

69. RANKL inhibitors
• Denosumab is a reasonable alternative to zoledronate for the
prevention of skeletal-related events in patients with
metastatic crpc with the advantage that it does not require
dose adjustment or monitoring for renal impairment.
• The recommended dose of denosumab is 120 mg given by
subcutaneous injection every 4 weeks.

70. Radiopharmaceuticals
• The introduction of “bone-seeking” radiopharmaceuticals has
provided a useful resource for the management of diffuse
bone pain from widespread prostate cancer metastases.
• MC : strontium-89 (89Sr) and samarium-153 (153Sm).
• The pharmacokinetics of 89Sr vary considerably according to
the extent of bone involvement, but the half-life is generally 4
to 5 days.
• The retention of the isotope is significantly longer in patients
with diffuse osteoblastic metastases compared with those
with relatively limited bone involvement.

71. Radiopharmaceuticals
• It is important to recognize this factor because it will
undoubtedly affect the degree and duration of myelotoxicity
associated with this radioactive compound.
• 153Sm : shorter half life 1-2 days and less toxicity
• A study undergoing to prove synergistic effect of doxorubicin
with 89Sr

72. Vitamin D Analogues
• Vitamin D analogues may have differentiation,
antiproliferation and chemosensitizing properties
• an increased risk of prostate cancer in those with relative
vitamin D deficiency.
• A phase 2 trial of weekly docetaxel and highdose calcitriol
demonstrated PSA responses in 30 of 37 patients (80%) and
measurable responses in 8 of 15 (53%), with a median time to
progression of 11.4 months and median survival of 19.4
months

73. CYP17 System
• Overexpression of CYP17 has been demonstrated in tumors of
men with CRPC
• The novel agent abiraterone acetate is an oral selective
inhibitor of the microsomal enzyme cytochrome P17 (17,20-
lyase and 17α-hydroxylase) that is a key regulator of adrenal
androgen synthesis
• S/E: Hypokalemia, pedal edema, hypertension (due to
mineralocorticoid excess)
• Improved with use of MC antagonist Eplerenone

74. Abiraterone Phase III Trials:
COU-AA-301 and COU-AA-302
301 eligibility criteria:
• Progressive mCRPC pts who
failed a docetaxel regimen ±
another chemotherapy
302 eligibility criteria:
• Progressive chemo-naïve
mCRPC, asymptomatic or
mildly symptomatic
Abiraterone 1000mg qd+ prednisone bidR
A
N
D
O
M
I
Z
E
(N=1195)
2:1
Placebo qd+ prednisone bid
Co-primary endpoints: OS + rPFS
by central review
1. de Bono et al. N Engl J Med. 2011;364:1995-2005. 2. Ryan CJ, et al. N Engl J Med. 2013;368:138-48.
1:1
(N=1088)
Primary endpoint: OS
Median OS Adverse Events
Abiraterone Placebo Abiraterone
COU-AA-3011
14.8 mo 10.9 mo Fluid retention and
edema, hypokalemia,
cardiac disorders(P < 0.0001)
COU-AA-3022
Not reached 27.2 mo Mineralocorticoid-related
+ abnormalities on liver-
function testing(P = 0.01)

75. • COU-AA-301 : secondary end points-rPFS, PSA
response, time to PSA progression, overall
QOL.
• COU-AA-302: co primary end point was rPFS,
which was 8.3 months in placebo arm at a
median interval of 8.3 months and yet to9 be
reached in abiraterone arm.

76. Androgen Receptor Modulation
• (AR)-directed approach has focused on the development of
second-generation antiandrogens
• One such drug is MDV3100 (Enzalutamide), a potent oral
nonsteroidal AR antagonist.
• Importantly, MDV3100 remains a potent antagonist of the AR
in the castration-resistant state, even in the setting of
overexpressed or constitutively activated AR
• No partial agonistic action

77. Enzalutamide Phase III AFFIRM Trial
• Median OS: 18.4 mo enzalutamide, 13.6 mo placebo (P < 0.0001)
• Adverse events: Enzalutamide group reported 45% of patients with any
≥ grade 3 adverse event vs 53% with placebo
– 3% of enzalutamide group and 4% of placebo group had an adverse event that
led to death
– Highest reported ≥ grade 3 adverse event was fatigue, with 6% of the
enzalutamide group and 7% of placebo reporting
Eligibility criteria:
• CRPC pts who progressed during
or after treatment with a
docetaxel-based regimen
Enzalutamide 160 mg qdR
A
N
D
O
M
I
Z
E
(N=1199)
2:1
Placebo qd
Primary endpoint: OS
Scher HI et al. N Engl J Med. 2012;367:1187-97.
mOS=median overall survival.

78. Prevail trial
• PREVAIL randomized 1,717patients with prechemotherapy CRPC to
enzalutamide 160 mg daily or placebo using the coprimary end points of
rPFS and overall survival.
• This study was stopped by the data and safety monitoring board after 540
deaths based on the superiority of enzalutamide in delaying radiographic
progression or death and risk of death relative to placebo.
• The benefit of enzalutamide was consistent for all secondary end points
including
– rate of ≥50% PSA decline (78% versus 3%;),
– overall soft tissue response (59% versus 5%),
– time to PSA progression
– time to initiation of cytotoxic chemotherapy
– time to first SRE

79. IMMUNOTHERAPY
• Sipuleucel-T (Provenge)
• “Cancer vaccine”
– Autologous cancer vaccine – involvescollection of WBC fraction
containing antigen presenting cells from each patient, exposure of
these cells to
• Prostatic acid phosphatase
• GMCSF (an immune cell activator)
– Leukopharesis weeks 0, 2, 4 and infusion 3 days later
• Manufactured centrally

80. APC vaccine: sipuleucel-T (provenge).
*On day 1 leukapheresis is performed at a center.
*On day 2-3 sipuleucel-T is manufactured at
company.
*On day 3-4 the patient is infused at the doctor’s
office.

81. Sipuleucel-T Background
• RCT, placebo-controlled, double-blind, n = 512 metastatic
CRPCa patients; 2:1 randomization to receive sipuleucel-T or
placebo- IMPACT TRIAL
– Median Overall survival 2.8 months vs. 21.7 months
– 22% reduction in mortality risk
– Complications – mild to moderate chills, pyrexia, headache- transient
• No effect on time to progression which was the primary
endpoint.

82. 82
IMPACT: Randomized Phase 3 Trial
(IMmunotherapy Prostate AdenoCarcinoma Treatment)
Patients (342) will be treated with Sipuleucel-T (Q 2 weeks x 3).
Patients (170) will be treated with Placebo (Q2 weeks x 3).
The primary endpoint is overall survival and the secondary
endpoint it time to objective disease progression.

83. Sipuleucel-T: IMPACT Overall Survival:
Primary Endpoint Intent-to-Treat Population
0 6 12 18 24 30 36 42 48 54 60 66
0
25
50
75
100
PercentSurvival
Survival (Months)
P = 0.032 (Cox model)
HR = 0.775 [95% CI: 0.614, 0.979]
Median Survival Benefit = 4.1 Mos.
Sipuleucel-T (n = 341)
Median Survival: 25.8 Mos.
Placebo (n = 171)
Median Survival: 21.7 Mos.
Survival in months
Percentagesurvival

84. NEWER AGENTS
• PROSTVAC- a vaccine for fowlpox
immunization
• Ipilimumab:
– Fully humanised Ig to cytotoxic T-lymhocyte
antigen-4.
– T- cell co-inhibitory and immune checkpoint
molecule expressed by activated and regulatory T-
cells playing a critical role in immune homeostasis
and peripheral tolerance to self antigens. Also
useful in malignant melanoma and RCC.

85. • Cabozatinib:
– Orally bioavailable tyrosine kinase inhibitor with potent
activity against MET and VEGF2.
– Inhibits osteoclastic activity
• Transquinimod:
– A quinolone carboxyamide with antiangiogenic activity in
xenograft models through a VEGF independent
mechanism.
• New anti androgens:
– ARN-509 and Galeterone- currently under phase-3 trials,
galeterone- blocks and degrades AR, ARN-509 more potent
than Enzalutamide in phase 1 studies.

86. Summary
• Mx approach for CRPC
• Pre Docetaxel / Asymptomatic mCRPC
– Sipulecel-T
– Abiraterone / Enzaalutamide
• Post Docetaxel / symptomatic mCRPC
– Cabazitaxel
– Abiraterone / Enzalutamide
– Alpharadin
• Targeted therapy