This document discusses treatment options for castration-resistant prostate cancer (CRPC). It describes how CRPC is defined and various treatment approaches. Key points: - CRPC is defined as disease progression despite castrate levels of testosterone (<50 ng/dL) through rising PSA levels, new bone lesions, or soft tissue metastases. - Common treatments include secondary hormonal therapies like abiraterone or enzalutamide, cytotoxic chemotherapies like docetaxel or cabazitaxel, immunotherapy like sipuleucel-T, and novel targeted agents. - Choice of treatment depends on factors like metastasis status, symptoms, performance status, and prior docetax

1. (CRPC)
Castration Resistant Ca Prostate .
Dr Shankar Ram HS
Dept of GenitoUrinary Surgery
TD MCH – Alleppy –Kerala- INDIA

2. A rise in serum PSA level precedes evidence of advancing disease on the bone scan, and
during this time patients may remain relatively asymptomatic

3. ADT
• Suppression of gonadal testosterone is the
central principle of androgen deprivation therapy
• Basic strategy for the systemic control of prostate
cancer.
• The baseline PSA level (>10 ng/mL) and the PSA
velocity independently predicted time to bone
metastasis and survival
• The castrate level is < 50 ng/dL /
15 -20

4. Options
• b/l Orchidectomy
• Estrogens (DES)
• Luteinising-hormone-releasing hormone
agonists –(Lupride)
• Luteinising-hormone-releasing hormone
antagonists(Abarelix S/c Degarelix)

5. AntiAndrogens (ReceptorLevel)
• steroidal, e.g. cyproterone acetate (CPA),
megestrol acetate and medroxyprogesterone
acetate;
• non-steroidal or pure, e.g. nilutamide,
flutamide and bicalutamide

6. PCWG2
• defining CRPC as prostate cancer progressed
despite castrate levels of testosterone (<0.5
ng/ml);
• this progression may be biochemical,
radiological or symptomatic.

7. CRPC
• Castrate serum testosterone < 50 ng/dL or 1.7
nmol/L plus either;
• a) Biochemical progression: Three consecutive
rises in PSA 1 week apart resulting in two 50%
increases over the nadir, and a PSA > 2 ng/mL or,
• b) Radiological progression: The appearance of
new lesions: either two or more new bone
lesions on bone scan or a soft tissue lesion using
RECIST

8. Clinical considerations
• Understand that the presentation of mCRPC is
heterogeneous
• secondary hormonal manipulations before
initiation of cytotoxic chemotherapy,
especially
• in men with nonmetastatic CRPC or in those
who are asymptomatic.

9. • despite castrate levels of androgens, the
androgen receptor (AR) remains active and
continues to drive prostate cancer
progression.
• also many other biologic pathways that
function independent of androgen signaling

10. • CRPC itself may produce intratumoral
androgens autonomously
• overexpression of CYP17
• Standard hormonal therapies such as LHRH
agonists/antagonists inhibit gonadal
androgenesis but do not
• affect androgen synthesis from adrenal or
other extragonadal sources

12. Novel Androgen Receptor–Directed
Approaches
• Abiraterone and Other Agents
• oral selective inhibitor of cytochrome P450
isoform 17 (CYP17),
• an enzyme that has both 17,20-lyase and 17α-
hydroxylase activity, and is a key regulator of
extragonadal androgen synthesis
• suppressing its synthesis at the adrenal level
and inside the cancer cells (intracrine
mechanism).

13. Androgen Receptor Modulation:
• Enzalutamide and other agents
• potent oral nonsteroidal AR antagonist
• prevents nuclear translocation and DNA
binding. blocks AR transfer
• CYP17-targeting agents (e.g., orteronel) and
AR-targeting agents (e.g., ARN-509) are in
clinical development.

14. Cytotoxic chemotherapy
• Docetaxel - standard first-line
• Cabazitaxel
• Mitoxantrone - approved to palliate symptoms

15. Immunotherapy
• Sipuleucel-T (Provenge)
• ProstVac-VF
• Ipilimumab- monoclonal anti–CTLA-4 antibody
inhibit immunologic evasion by tumor cells is
through the blockade of the immune
checkpoint molecule

16. • Phosphatidylinositol 3-Kinase/Akt/Mammalian
Target of Rapamycin Pathway
(everolimus and temsirolimus)
• Angiogenesis - Bevacizumab
• MET Signaling - Cabozantinib
• Apoptosis Pathway (Anti Clusterin m RNA ) -
Custirsen
Targeted Agents….

18. Indexing
• Metastatic or nonmetastatic
• Symptoms +/-
• Prior Docitaxel
• Performance status

19. • Asymptomatic non-metastatic CRPC
• Asymptomatic or minimally-symptomatic,
mCRPC without prior docetaxel chemotherapy
• Symptomatic, mCRPC with good performance
status and no prior docetaxel chemotherapy
• Symptomatic, mCRPC with poor performance
status and no prior docetaxel chemotherapy
• Symptomatic, mCRPC with good performance
status and prior docetaxel chemotherapy
• Symptomatic, mCRPC with poor performance
status and prior docetaxel chemotherapy

20. S +

21. M -CAP
M +
DT
-
DT
+
S -
S +
GPS
PPS
GPS
PPS
1
2
3
4
5
6
•BLT, NIL, FLT
• KTZ+STD
•No ImmRx/CRx
•Abi+Pred
•ENZ
•DCT
•SIPU
First gen Ant andr
KTZ+STD
•Abi+Pred
•ENZ
•DCT
•KTZ+STD
•Ra 223
•mitoxantrone
NO
Estramustine
or
sipuleucel-T
Abi+Pred
Enz
Ktz+Std
Ra223
No SIPU
Abi+Pred
Enz
Cabazitaxel
Ktz +stz
DCT
Ra223
•Palliative care
•Enz/Abi+std/Ra
•KTZ+Std
•No ImmRx/CRx

22. M -CAP
M +
D-
DT
+
S -
S +
GPS
PPS
GPS
PPS
1
2
3
4
5
6
•BLT, NIL, FLT
• KTZ+STD
•No ImmRx/CRx
•Abi+Pred
•ENZ
•DCT
•SIPU
First gen Ant andr
KTZ+STD
•Abi+Pred
•ENZ
•DCT
•KTZ+STD
•Ra 223
•mitoxantrone
NO
Estramustine
or
sipuleucel-T
Abi+Pred
Enz
Ktz+Std
Ra223
No SIPU
Abi+Pred
Enz
Cabazitaxel
Ktz +stz
DCT
Ra223
•Palliative care
•Enz/Abi+std/Ra
•KTZ+Std
•No ImmRx/CRx

23. MD4-S2P
1. M- D-S-P-
2. M+D-S-P-
3. M+D-S+P-
4. M+D-S+P+
5. M+D+S+P-
6. M+D+S+P+
Ab Pred Enz, in all mets pts
Ket Stx in all
D2D3D5 (2+3=5)
Sipu 2 (s2)
Mit-4
D4- up to Cat 1,2,3,4,- Not Received Docetaxel)
-S2 up to Cat 1,2 (no symptoms.Rest have)
Cat 1 (No mets.all others have )
P-46 (cat,4 and 6 have poor performance status
PRAY For (4) 6 )
Categories increase form severity from 1 to 6 MD-SP