Castrate-resistant prostate
cancer (CRPC)
Castrate-resistant prostate cancer
(CRPC)

disease progression despite androgen
depletion therapy (ADT)
present as :
1. continuous rise in PSA
2. progression of pre-existing disease
3. appearance of new metastases

"Castrate resistant"

growing despite the hormone therapy
with testosterone at "castrate" levels.

Still helped by other forms of hormone
therapy
"hormone refractory"

no response to any type of hormone
therapy, including the newer medicines.
Combined androgen blockade
(CAB)
orchiectomy
LHRH agonist
LHRH antagonist

+
Superior tomonotherapy
anti-androgen
CRPC mechanism
Management of CRPC
Secondary hormonal manipulations
First Line

In relatively asymptomatic CRPC:
First Line
Monotherapy treated
(LHRH agonist or orchidectomy):

Total androgen blockade (TAB) with
testosterone antagonists, such as
bicalutamide , …

( PSA responses in 30% to 35% )
TAB patients
First Line

First discontinue the antiandrogen :
exclude an antiandrogen withdrawal
response (AAWD).
Not response?
 Second line hormonetherapy (adrenal)

First Line
ketoconazole

weak inhibitor of CYP11A and CYP17A

suppresses the synthesis of adrenal and
tumor tissue androgens.

nausea and hepatotoxicity

must be given with replacement steroids

PSA response rates around 50%.
First-line systemic chemotherapy
second Line



In CRPC with detectable macroscopic
metastatic disease
improve survival for CRPC
1996, mitoxantrone was the first
chemotherapy
second Line
Mitoxantrone

a semi-synthetic anthracycline

first chemotherapy to be approved by
(FDA)

no survival benefit in two phase 3 trials

significant improvements of pain
second Line

late 1990 s, the microtubulestabilizing
taxane agents showed promise
second Line
Docetaxel

a taxane drug : polymerization of
microtubules and phosphorylation of bcl2 protein

docetaxel 75 mg/m2 intravenously every 3
weeks + 5 mg oral prednisone twice daily

the standard of care for men with CRPC
with detectable metastatic disease.
second Line

Improve overall survival, disease control,
symptom palliation and quality of life

27% increase in progression-free survival
(PFS), a 55% increase in objective
response rate (ORR), and 1.9-mo
improvement in median overall survival
(OS)
second Line

approved by FDA in 2004 and EMA in
2005

Side effect: myelosuppression, fatigue,
edema, neurotoxicity, hyperlacrimation,
and changes in liver function.
Third Line
Second-line systemic chemotherapy

docetaxel (again): for no definitive
evidence of resistance to docetaxel

Cabazitaxel
Third Line
Cabazitaxel

tubulin-binding taxane

most common serious adverse events
:hematological, including grade ≥3
neutropenia in 82% of patients, 8% febrile
neutropenia and 5% deaths

prophylactic neutrophil growth factor
support :older individuals and with significant
prior radiotherapy
Third Line
Abiraterone

oral selective irreversible inhibitor of the
microsomal enzyme cytochrome P17
(17,20-lyase and 17α-hydroxylase)

expected increases in mineralocorticoids
upstream of CYP17A

side effects: hypertension, hypokalemia,
edema and fatigue treat with low dose
glucocorticoids.
Third Line

The mechanism of action similar to
ketoconazole

marked palliative and skeletal related
benefits.

FDA approved for treatment
Third Line
Sipuleucel-T

Immunotherapy, FDA-approved agent

vaccine derived from CD54+ dendritic cells,
(major antigen-presenting cells)

less than 10% exhibit a clinical, serologic or
radiographic response

benefit patients with a lower disease burden
and better performance status
Third Line

All three have an FDA indication in mCRPC

Docetaxel and sipuleucel-T immunotherapy:
survival advantage

Abiraterone + prednisone: radiographic
progression-free survival benefits
AUA Guideline