Castrate-resistant prostate cancer (CRPC)

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

12. 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

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 • 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 microtubulestabilizingtaxane 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. 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 • 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 • oral selective irreversibleinhibitor 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. The mechanism of action similar to ketoconazole • marked palliative and skeletal related benefits. • FDA approved for treatment Third Line

23. 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

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

25. AUA Guideline