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Enzalutamide is a next-generation antiandrogen that directly binds to androgen with high affinity, impairs nuclear translocation, coactivator peptide recruitment, and DNA binding of the androgen receptor (AR) by inducing a conformational change in the AR distinct from bicalutamide.
Enzalutamide: Future Directions -Prevail: Phase III mCRPC (pre docetaxel) enzalutamide vs placebo endpoints PFS/OS enrolled 1680 pts -Terrain: Randomized phase II ( bicalutamide) mCRPC (pre docetaxel), endpoint PFS (370 pts) -Strive: Randomized phase II ( bicalutamide) CRPC (M0 or MI1 (pre docetaxel), endpoint PFS (400 pts)
Ca prostate presentation parth
Treatment of metastatic ca.
Prostate & CRPC
Dr. Parth Patel
Surgical oncology resident,
• The core principle of treatment of advanced
– to deplete androgens or inhibit signaling through the
androgen receptor (AR).
– Huggins and Hodges- close relationship of androgens
with prostate tumor growth. 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.
• The palliative role of surgical adrenalectomy - 1945,
later replaced by the first-generation enzymatic
inhibitors of adrenal steroid biosynthesis
(aminoglutethimide and ketoconazole).
• LHRH agonists - 1980s
• Nonsteroidal antiandrogens were introduced in the
• All these agents lower androgen levels, with the
exception of the nonsteroidal antiandrogens that block
the binding of androgens to the AR.
• Initial responses to castration therapy are
quite favourable, with a significant clinical
regression and rapid biochemical responses,
as assessed by decline in S.PSA in 80–90% of
patients with metastatic disease.
• Despite a good initial response, remissions last
on average 2-3 years, with eventual
progression occurring despite castration.
• In these cases prostate cancer will progress to a castration-
insensitive phase of disease (Castration-Resistant Prostate
Cancer—CRPC) which carries a worse prognosis and
translates into a survival time of 16–18 months in average
from the beginning of progression.
• Systemic therapies have also been an option in the
management to these patients. However, chemotherapy is
not well tolerated by all CRPC patients, who were often
elderly men with limited bone marrow reserve and
concurrent medical conditions
• a biologic agent (Sipuleucel-T),
• a cytotoxic (Cabazitaxel),
• a bone-seeking alpha-emitting radionuclide (Radium-223),
• 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
• Denosumab, a monoclonal antibody that binds the cytokine
RANKL (receptor activator of nuclear factor-κB ligand)
• Current methods of castration (or ADT)
– LHRH agonists
– LHRH antagonists
– Nonsteroidal antiandrogens
• 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
• 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
• 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
– Higher rate of injection site reactions
• 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 non steroidal 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
• 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.
Toxicity of ADT
• “androgen deprivation syndrome”
• hot flashes,
• a decrease in libido,
• erectile dysfunction,
• 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
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
CASTRATION RESISTANT CA. PROSTATE
• Definition – disease progression despite androgen deplation
therapy and may present as either a continues rise in S.PSA ,
progression of pre existing disease, and/or appearance of new
• The development of hormone resistance 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
Castrate Resistant Prostate Cancer
• In the past, we used terms like
– Hormone Refractory
– Androgen Independent
– Androgen Resistant
• Now … Castrate Resistant Prostate Cancer
• 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.
Mechanism of development of CRPC
Resistance mechanisms can be divided into 6 groups:
(i) Increased Expression of Enzymes Involved in Steroid genesis. -
- in CRPC patients, even castrate serum levels of androgen are
still sufficient for AR activation and able to maintain cancer
- the intra tumoral levels of testosterone in CRPC patients are
equal of those found in non castrate patients.
The source of these androgens is thought to be derived from
the synthesis of androgens directly in prostate cancer cells
due to an up regulation of the enzymes.
(ii) Increased Expression of AR.
- The activated AR pathways has been postulated
as a result of genetic phenomena that promotes
increased sensitivity of AR.
(iii) AR Gene Mutations and Altered Ligand
- While the androgens are the main factors of
tumor growth and AR signaling, the presence of
AR mutations leads to its activation by
nonandrogenic steroid molecules and
(iv) Downstream Signaling Receptor for
- One of the most important mechanisms.
(v) Bypass Pathways.
- The induction of bypass pathways
independent of AR, is an important
mechanism of castration resistance, that can
overcame apoptosis induced by androgen-
(vi) Stem Cells.
- Prostatic cancer stem cells are rare and
undifferentiated cells that do not express AR
on their surface, being independent of
androgens to survive.
- These cells can be responsible for maintaining
tumor growth and development, because they
are able to survive under androgen-
• 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 PSA level alone, new bone
metastasis, visceral and nodal metastasis)
– Presence or absence of symptoms
– Response and compliance to prior endocrine treatment.
• 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).
• The current treatment options for patients with
CRPC can be divided in different groups such as
A) Discontinuation of antiandrogens
B) Secondary hormonal therapies,
C) Bone-Targeted Therapy: Bisphosphonates and
D) Chemotherapy agents,
E) Vaccine-based immune therapy,
F) Radiotherapy and
G) Novel targets.
• 1st step ,A)Discontinuation of antiandrogens (both steroidal
and non steroidal) 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.
• serial monitoring of PSA levels for a period of 4 to 8 weeks
before embarking on the next therapeutic maneuver.
• 30% of the patients have a drop in PSA after discontinuing
• 2nd step : B) second-line hormonal manipulation or cytotoxic
• Agents that have been reported to produce some benefit in this
– Corticosteroids- oral glucocorticoids at lower doses (10 mg/day) can
result in temporary PSA responses for 25% of the patients, presumably
due to adrenal androgen suppression
– Diethylstilbestrol- Diethylstilboestrol (DES), a synthetic estrogen, as
well as the other estrogens, suppresses the HPA and it reduces ≥50%
the total PSA in 26% to 66% of patients with CRPC. However, the
thromboembolic toxicity limited is use
– Ketoconazole– in CRPC patients after antiandrogen withdrawal
because it inhibits cytochrome P-450 enzyme-mediated
steroidogenesis in testes and adrenal glands and when given at high-
dose (1200 mg/day). it resulted in ≥50% PSA reduction in 27% to 63%.
– Abiraterone acetate
– MDV3100 (Enzalutamide)
• Abiraterone acetate –
- a prodrug of abiraterone, is potent and highly
selective inhibitor of androgen biosynthesis that
blocks cytochrome P450 c17 (CYP 17), a critical
enzyme in testosterone synthesis, thereby blocking
androgen synthesis by the adrenal glands and testes
and within prostate tumor.
Abiraterone Phase III Trials:
COU-AA-301 and COU-AA-302
301 eligibility criteria:
• Progressive mCRPC pts who
failed a docetaxel regimen ±
302 eligibility criteria:
• Progressive chemo-naïve
mCRPC, asymptomatic or
Abiraterone 1000mg qd+ prednisone bidR
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.
Primary endpoint: OS
Median OS Adverse Events
Abiraterone Placebo Abiraterone
14.8 mo 10.9 mo Fluid retention and
cardiac disorders(P < 0.0001)
Not reached 27.2 mo Mineralocorticoid-related
+ abnormalities on liver-
function testing(P = 0.01)
• 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 .
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
• CRPC pts who progressed during
or after treatment with a
Enzalutamide 160 mg qdR
Primary endpoint: OS
Scher HI et al. N Engl J Med. 2012;367:1187-97.
mOS=median overall survival.
• 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).
C) Bone-Targeted Therapy: Bisphosphonates
• Reduce bone resorption by inhibiting osteoclastic activity and
• 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
• 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
• OTHER: Alendronate, Etidronate, Ibandronate and Clodronate
• Monoclonal antibodies to RANKL significantly inhibit
osteoclastic function in vitro and in vivo.
• Denosumab, a fully human monoclonal antibody against
• Common toxicities of denosumab include fatigue, nausea,
hypophosphatemia, hypocalcemia and osteonecrosis of the
• Prophylactic calcium and vitamin D supplementation is
-In a phase III study denosumab, a human
monoclonal antibody against RANKL, was
compared with zoledronic acid for prevention
of skeletal-related events. The results showed
advantage to denosumab, representing
another treatment opportunity for CRPC
• 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.
• A first step forward in the chemotherapeutic management of CRPC
came with mitoxantrone, 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.
- Docetaxel is the only approved chemotherapy that has been shown
to prolong survival among men with metastatic CRPC.
– docetaxel 75 mg/m2 every 3 weeksfor up to 10 cycles
– docetaxel 30 mg/m2 weekly for 5 cycles (group 2),
– mitoxantrone 12 mg/m2 every 3 weeks for 10cycles (group
– Prednisone (10 mg daily) was added to all regimens.
• The primary end point was overall survival;
• secondary end points included changes in pain, PSA,
tumor response rate and overall QOL.
• Median survival 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-
• 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 standard.
• 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
SWOG 9916 STUDY
• 770 patients to
– Estramustine (280 mg orally 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
• 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.
• Till 2010 the treatment for docetaxel resistant CRPC was
lacking until FDA approved 2nd drug, CABAZITAXEL
• Cabazitaxel, a novel tubulin-binding taxane, is the first
chemotherapy shown to improve survival in patients with
docetaxel-refractory metastatic castration resistant prostatic
• Cabazitaxel was shown to be active in both docetaxel-
sensitive tumors as well as those with primary or acquired
The TROPIC trial
• a randomized phase III study compared
cabazitaxel plus prednisone
mitoxantrone plus prednisolone,
in patients with docetaxel-refractory prostate cancer.
• The cabazitaxel arm showed an improvement in
median PFS (2.8 months versus 1.4 months) (P <
0.0001), median OS (15.1 months versus 12.7 months),
and lower risk of death (hazard ratio 0.70) (P < 0.0001)
• Administered by intravenous infusion every 3 weeks at
escalating doses of 10 to 25 mg/m2
• The principal dose-limiting toxicity was neutropenia.
E) External Beam Radiotherapy, Hemibody RT, and Radioisotope
- Radioisotope pharmaceuticals which may be associated with less toxicity
and are more appropriated for patients with multiple painful lesions.
- These radioisotopes are used in men with advanced prostate cancer with
osteoblastic bone metastasis.
- These patients are often characterized by a high ratio of bone to soft
- In order for these patients to be treated with radioisotopes the presence
of uptake on bone scan due to metastatic disease at sites that correlate
with pain is necessary.
• MC : strontium-89 (89Sr) and samarium-153
• Radium-223 is an alpha-emitting
pharmaceutical agent that showed to improve
survival in a phase III study . Compared
with placebo, Radium-223 was associated
with improved overall survival
-Sipuleucel-T (Provenge, APC8015) is an autologous
dendritic cell vaccine, consisting of autologous
peripheral blood mononuclear cells (PBMCs).
-In the first two randomized trials, sipuleucelT, the
primary endpoint was not accomplished since these
studies did not show a significant effect on the time to
disease progression comparing with placebo. Despite
this, the hazard ratios were in favour of sipuleucel-T.
- IMPACT trial
- a phase III, randomized trial,
- asymptomatic or minimally symptomatic metastatic CRPC.
- Result: 4.1-month improvement in median overall survival
and an improvement in the rate of 3-year survival (31%
versus 23%) in sipuleucel-T arm, with limited toxicity.
- No effect on time to progression which was the primary
MONITOR THE RESPONSE
• PSA doubling time (PSADT) predicts for the rapidity of bone
scan 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.
• PROSTVAC- is a cancer vaccine consisting of a
recombinant vaccinia vector as a priming
immunization with subsequent multiple booster
vaccinations, using a recombinant fowlpox vector.