1. Castrate-resistant prostate cancer (CRPC)

2. Castrate-resistant prostate cancer (CRPC)
disease progression despite androgen depletion therapy (ADT)
present as :
continuous rise in PSA
progression of pre-existing disease
appearance of new metastases

4. "Castrate resistant"
growing despite the hormone therapy with testosterone at "castrate" levels.
Still helped by other forms of hormone therapy

5. "hormone refractory"
no response to any type of hormone therapy, including the newer medicines.

6. Combined androgen blockade (CAB)
orchiectomy
LHRH agonist anti-androgen
LHRH antagonist
Superior tomonotherapy

7. CRPC mechanism

8. Management of CRPC

9. Secondary hormonal manipulations
In relatively asymptomatic CRPC:
First Line

10. Monotherapy treated (LHRH agonist or orchidectomy):
Total androgen blockade (TAB) with testosterone antagonists, such as bicalutamide , …
( PSA responses in 30% to 35% )
First Line

11. TAB patients First Line
First discontinue the antiandrogen : exclude an antiandrogen withdrawal response (AAWD).
Not response?
Second line hormonetherapy (adrenal)
First Line

12. ketoconazole First Line 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

13. First-line systemic chemotherapy
In CRPC with detectable macroscopic metastatic disease
improve survival for CRPC
1996, mitoxantrone was the first chemotherapy
second Line

14. Mitoxantrone second Line 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

15. late 1990 s, the microtubulestabilizing taxane agents showed promise
second Line

16. Docetaxel
a 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.
second Line

17. 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

18. second Line approved by FDA in 2004 and EMA in 2005
Side effect: myelosuppression, fatigue, edema, neurotoxicity, hyperlacrimation, and changes in liver function.
second Line

19. Second-line systemic chemotherapy
docetaxel (again): for no definitive evidence of resistance to docetaxel
Cabazitaxel
Third Line

20. Cabazitaxel Third Line 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

21. Abiraterone Third Line
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

22. Third Line The mechanism of action similar to ketoconazole
marked palliative and skeletal related benefits.
FDA approved for treatment
Third Line

23. Sipuleucel-T Third Line 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

24. Third Line All three have an FDA indication in mCRPC
Docetaxel and sipuleucel-T immunotherapy: survival advantage
Abiraterone + prednisone: radiographic progression-free survival benefits
Third Line

25. AUA Guideline