castrate-resistant prostate cancer (crpc). disease progression despite androgen depletion therapy...

Castrate-resistant prostate cancer (CRPC)

Castrate-resistant prostate cancer (CRPC)

disease progression despite androgen depletion therapy (ADT)

present as :1. continuous rise in PSA2. progression of pre-existing

disease3. 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 + anti-androgenLHRH antagonist

Superior tomonotherapy

CRPC mechanism

Management of CRPC

Secondary hormonal manipulations

In relatively asymptomatic CRPC:

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Monotherapy treated (LHRH agonist or orchidectomy):

Total androgen blockade (TAB) with testosterone antagonists, such as bicalutamide , …

( PSA responses in 30% to 35% )Fir

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TAB patients

First discontinue the antiandrogen : exclude an antiandrogen withdrawal response (AAWD).

Not response?Second line hormonetherapy

(adrenal)

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ketoconazoleweak 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%.

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First-line systemic chemotherapy In CRPC with detectable

macroscopic metastatic disease

improve survival for CRPC

1996, mitoxantrone was the first chemotherapy

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Mitoxantronea semi-synthetic anthracycline

first chemotherapy to be approved by (FDA)

no survival benefit in two phase 3 trials

significant improvements of pain

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late 1990 s, the microtubulestabilizing taxane agents showed promise

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Docetaxela taxane drug : polymerization of

microtubules and phosphorylation of bcl-2 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.

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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)

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approved by FDA in 2004 and EMA in 2005

Side effect: myelosuppression, fatigue, edema, neurotoxicity, hyperlacrimation, and changes in liver function.s

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Second-line systemic chemotherapy

docetaxel (again): for no definitive evidence of resistance to docetaxel

Cabazitaxel

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Cabazitaxeltubulin-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

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Abirateroneoral 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.

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The mechanism of action similar to ketoconazole

marked palliative and skeletal related benefits.

FDA approved for treatment

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Sipuleucel-TImmunotherapy, 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

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All three have an FDA indication in mCRPC

Docetaxel and sipuleucel-T immunotherapy: survival advantage

Abiraterone + prednisone: radiographic progression-free survival benefits

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AUA Guideline