Stage IV prostate cancer :
is defined by the American Joint Committee on Cancer's TNM
T4, N0, M0, any prostate-specific antigen (PSA),
Any T, N1, M0, any PSA, any Gleason.
Any T, any N, M1, any PSA, any Gleason
Approximately 10-20% of newly diagnosed
prostate cancer cases involve locally advanced
Advanced disease is comparably less common,
because more early stage cancer is being
discovered d.t. PSA screening.
Presentation Median survival
~18 to 24 months
~9 to 16 months
Manifestations of metastatic and advanced disease
may include the following:
• Bone marrow suppression
• Weight loss
• Pathologic fractures
• Spinal cord compression
• Ureteral and/or bladder outlet
• Urinary retention
• Chronic renal failure
• Urinary incontinence
• Symptoms related to bony or
Mainstay: “androgen suppression”.
It is a palliative tool, no cure.
Results of treatment:
• median progression-free survival = 18-20 ms
• overall survival = 24-36 ms.
All patients develop hormone-refractory disease.
Put in consideration the toxic effects of treatment.
Any T, N1: Treatment includes ADT or radiation therapy (doses of 78-80+ Gy)
with 3D-CRT/IMRT with IGRT plus long-term neoadjuvant/concomitant/adjuvant
ADT for 2-3y
Any T, any N, M1: Treatment includes only ADT for patients with M1
Metas. prostate ca.
Initial therapy CRPC
2 nd line
Patients who do not show an adequate suppression of
serum testosterone (< 50 ng/dL) may be considered for CAB
Monotherapy of nonsteroidal antiandrogens are less
effective but are associated with fewer hot flashes and fatigue
and do not impair libido
If hormone therapy fails, that therapy should be continued
into and through the next hormone manipulation.
Recent data showed that CAB is not superior to LHRH-
agonists alone in treatment of metas PC.
Gonadotropin-releasing hormone agonists:
• Therapy with GnRH analogs may induce medical castration by suppressing
• These agonists can potentially cause a transient surge of LH when therapy
is initiated before the LH levels fall (flare phenomenon)
• GnRH agonists are offered in 1mo, 3mo, and once-yearly depots; it is
necessary to premedicate with antiandrogen to prevent flare phenomenon
• Leuprolide: 7.5 mg IM monthly or 22.5 mg IM every 3ms or 30 mg IM every
4ms or 45 mg IV every 6ms.
• Histrelin: one 50mg implant SC every 12ms ; continue therapy until disease
• Goserelin: 3.6 mg implant SC monthly or a 10.8 mg implant SC every 3ms.
• Triptorelin: 3.75 mg IM monthly or 11.25 mg IM every 3mo or 22.5 mg IM every
• Pure GnRH antagonists suppress testosterone and avoid
the flare phenomenon associated with GnRH agonists.
• Degarelix: 120 mg SC x 2 doses (ie, 2 separate injections
totaling 240 mg), and then, after 28 days, begin monthly
maintenance dose of 80mg SC.
• Antiandrogens bind to androgen receptors and competitively
inhibit their interaction with testosterone and dihydrotestosterone
• These agents do not decrease LH levels and androgen
• Antiandrogens are usually used in combination with a GnRH
agonist in order to prevent a disease flare caused by the transient
increase in testosterone levels.
Flutamide 250 mg PO TID.
Bicalutamide 50 mg PO daily; patients refractory to other antiandrogen
agents may start with 150 mg PO daily.
Nilutamide 300 mg PO daily for 30 days, and then 150 mg PO daily.
SWOG trial, NEGM 2013
7 ms induction
PSA ≤ 4
Survival results are inconclusive
According to NCCN guidelines:
You can consider intermittent ADT when the adverse effects of
ADT is a matter
Calcium + Vit-D
Denusomab / 6ms
Dexa scan / 1y
hormone-refractory prostate cancer is defined as
2-3 consecutive rises in prostate-specific antigen (PSA)
levels obtained at intervals of > 2 weeks
Documented disease progression based on:
Findings from CT scan and/or bone scan.
Obstructive voiding symptoms.
With castration levels of Testosterone: ( < 50 ng/dl)
Maintain the castration
Docetaxel / 3ws
Prednisone 5mg x 2 daily
Imaging studies +ve
PSA DT < 10 ms
Secondary hormone therapy
Denosumab or Zomita / month
4 tabs once daily, on empty stomach.
Androgen synthesis inhibitor
To be taken with prednisone tab (5mg 1 x 2).
FDA approval as first line therapy in asympt CRPC and as
second line therapy after failure of Docetaxel.
Monitor Bld pressure / month.
Most common S.E:
Fatigue, back+joint pain, periphr edema., HTN
Serious S.E: hepatic, cardiac and electrolytes.
• Monitor liver functions, K+, Phosphorus / month.
• Monitor Bld pressure / month.
De Bono et al, NEGM, 2011
~ 1200 pts.
Progression on Docetaxel.
PS ≤ 2.
Testosterone ≤ 2nmol/liter
•Liver enz ≥ 2.5 times norm.
•Chr liver dis.
•Signif cardiac dis.
Zytiga + prednisone
15 ms VS 11 ms
(P < 0.001)
More SE :
HTN, edema, K+
Phase III trial by Ryan CJ et al, NEGM, 2013
Aberaterone acetate as first line in asymptomatic CRPC
~ 1080 pts.
Asympt or minimal sympt.
Zytiga + prednisone
Placebo + Prednisone
Improvement of radiograph PFS: 16.5 ms VS 8 ms (P<0.001)
Inhibit signaling of androgen receptor at multiple levels.
Dose: 4 caps once daily, +/- food.
Not necessary to take prednisone with it.
Could be used in pts with poor PS.
Less S.E than Abiraterone.
Given with GnRH agonists.
Seroius S.E: Seizures. (0.6 %)
~ 1200 pts.
Progression on chemo.
13.5 ms VS 18.5 ms
(P < 0.001)
SE mild :
Ongoing PREVAIL trial to asses the role
of Enzalutamide in pre-docetaxel settings
IV over 60 min / 2 weeks x 3 cycles.
Autologous cancer vaccine.
1) Collect bld from pt.
2) Separate APC (Ag-presenting cells)
3) Exposure to (PAP-GM-CSF
recombinant fusion gene) ;
“prostatic acid phosphatase”
4) Re-infuse in the same pt.
• Metas CRPC.
• First line in asympt or minimal sympt pts.
• Good PS.
• Life expectancy > 6 ms.
• No visceral metas.
It was resulted in 22% reduction in mortality when
compared to placebo in a phase III trial, which was
published by Kantoff PW et al, NEGM 2010.
Common S.E: chills. pyrexia and headache.
25 mg/m2 over 1 hr / 3weeks.
After failure of Docetaxel.
TROPIC trial, Lancet 2010.
Updated Ann Oncol, 2013
755 pts. CRPC
Cabazitaxel + prednisone
Mitoxantrone + prednisone.
alpha particle-emitting radioactive
therapeutic agent (half life~11 day)
I.V injection over 1 min.
Every 4 weeks X 6 cycles.
Dose: 1.35 micro-curie / Kg.
Symptomatic CRPC + Bone metas – no visceral metas
The most common adverse drug reactions (≥ 10%) were nausea,diarrhea,
vomiting, and peripheral edema.
The most common hematologic laboratory abnormalities (≥ 10%) were
anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia
ADT associated with 20-50% relative increase of fracture risk.
ADT decrease bone menial density.
Longer treatment duration greater fracture risk.
Fracture risk can be assessed using algorithm FRAX®
NCCN recommendations: (with ADT)
Supplemental Calcium (1200 mg daily) + vit-D (1000 IU daily).
Base line DEXA scan then annually.
Denosumab: 60 mg / 6ms : phase III trial in non-metas PC
showed that Denosumab increase bone menial density by 6.7%
and reduces the risk of fracture ( from 3.9% to 1.5%); Smith MR et
al, NEGM 2009; 361(8):745-55.
Or Zoledronic acid (5mg/12 ms).
Bone health in metas PC:
Updated in 2004
Or minimal sympt.
Increase median time
No effect on OS.
Phase III trial, Lancet 2011.
(Good PS + no previous bisphosphonates + life expectancy > 6ms. )
Denosumab: 120 mg / month
Zoledronic acid : 4 mg / 4 weeks.
Hypocalcaemia more with Denosumab: (13% VS 6%)
SREs were similar
Median time to first SRE increase with Denosumab:
(21 ms VS 17 ms)
Considering the possible minimal survival benefit together with
the cost and toxicity of the additional anti-androgen, first-line
hormonal management of metastatic prostate cancer should be
based on chemical or surgical castration only [I, B].
Patients who develop castration-resistant prostate cancer
(CRPC) should continue androgen suppression and be
considered for further hormone therapies;
• Chemotherapy might be preferable in those with poor initial
hormone response or severe symptoms.
• In patients progressing following docetaxel, treatment with
abiraterone, or enzalutamide, should be discussed if not used
previously [II, A].
Docetaxel using a 3-weekly schedule should be considered for
symptomatic, castration-resistant disease [I, A].
Cabazitaxel is more effective than mitoxantrone in patients previously
treated with docetaxel [I, B].
External beam RT should be offered for patients with a moderate number
of painful bone metastases (1×8 Gy has equal pain-reducing efficacy to
multifraction schedules) [I, A].
Bone targeted therapy with one of the beta particle emitting radionuclides
(strontium-89 and samarium-153) should be considered for patients with
painful bone metastases [II, B].
In patients with bone metastases from CRPC at high risk for clinically
relevant SREs, denosumab or zoledronic acid can be recommended,
and a large trial found that denosumab delayed SREs for longer than
zoledronic acid. Neither agent has been shown to prolong survival [I, B].
MRI of the spine to detect subclinical cord compression should be
considered in men with CRPC with vertebral metastases and back pain [III,