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Castrate-resistant prostate cancer (CRPC). disease progression despite androgen depletion therapy (ADT) present as : 1. continuous rise in PSA 2. progression.

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Presentation on theme: "Castrate-resistant prostate cancer (CRPC). disease progression despite androgen depletion therapy (ADT) present as : 1. continuous rise in PSA 2. progression."— Presentation transcript:

1 Castrate-resistant prostate cancer (CRPC)

2 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

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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 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 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 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 irreversible inhibitor of the microsomal enzyme cytochrome P17 (17,20-lyase and 17 α -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 Docetaxel and sipuleucel-T immunotherapy: survival advantage Abiraterone + prednisone: radiographic progression-free survival benefits Third Line

25 AUA Guideline

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