Prostate carcinoma- Castrate Resistant Prostate Cancer (crpc)

Prostate carcinoma- Castrate Resistant Prostate Cancer (crpc)

1. CASTRATE RESISTANT
PROSTATE CANCER
DEPT OF UROLOGY
GOVT ROYAPETTAH HOSPITAL AND KILPAUK MEDICAL COLLEGE
CHENNAI

1

2. MODERATORS:
Professors:
Prof. Dr. G. Sivasankar, M.S., M.Ch.,
Prof. Dr. A. Senthilvel, M.S., M.Ch.,

Asst Professors:
Dr. J. Sivabalan, M.S., M.Ch.,
Dr. R. Bhargavi, M.S., M.Ch.,
Dr. S. Raju, M.S., M.Ch.,
Dr. K. Muthurathinam, M.S., M.Ch.,
Dr. D. Tamilselvan, M.S., M.Ch.,
Dr. K. Senthilkumar, M.S., M.Ch.
DEPT OF UROLOGY, GRH AND KMC, CHENNAI. 2

3. DEFINITION
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
b) Radiological progression:
The appearance of new lesions: either two or more new bone
lesions on bone scan or a soft tissue lesion
3 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

4. TERMINOLOGY
In the past
Hormone Refractory
Androgen Independent
Androgen Resistant
Now … Castrate Resistant Prostate Cancer (CRPC) – Why?
Even though patients have castrate levels of serum testosterone, AR signaling is
still happening
They are resistant to castration, but these tumors are still responding to AR
signaling
4 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

5. CLINICAL STATES OF PROSTATE CANCER
5 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

6. ANTIANDROGEN WITHDRAWL
Carefully observed discontinuation of antiandrogen in patients
progressing while on antiandrogens
Serial monitoring of PSA level for 4-8 weeks
Approximately 15% to 30% of men will exhibit a greater than
50% decline in serum PSA level.
When the PSA level begins to rise
Initiate treatment with a second-line antiandrogen 6 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

7. MOLECULAR BIOLOGY OF ANDROGEN AXIS
AR – member of nuclear receptor superfamily
Cause transcription of target genes within specific cells after ligands bind
to them
All forms of ADT act by reducing the ability of androgen to activate the
androgen receptors
By lowering levels of androgen
By blocking androgen AR binding
7 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

8. ANDROGEN RECEPTOR
8 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

9. 9 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

10. MECHANISMS
OF
CASTRATION
RESISTANCE
AR hypersensitivity
Prosmiscuity of AR
AR outlaw model
Bypass AR model
Lurker Cell model
10 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

11. HYPERSENSITIVITY PATHWAY
Increase in sensitivity to available low androgen levels by

Increasing AR synthesis

and/or

Increasing AR sensitivity

11 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

12. AR GENE AMPLIFICATION
Stanbrough and colleagues - genomic segment of chromosome X encoding the AR
is amplified, up to 60-fold

Seen in 28-30%

Abundance of AR increases the total AR content of the tumor that is available for
ligand binding and allows seemingly androgen-independent cancer cells to
proliferate in an androgen depleted environment

12 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

13. PROMISCUITY OF AR
Ligands other than androgen activate AR
Non androgenic steroids
Antiandrogens

Mechanism
Mutations in the LBD
Through alterations in the coregulator profile

13 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

14. OUTLAW AR MODEL
Increase transcriptional activity in the absence of androgens by non steroidal
molecules
Growth factor peptides such as EGF, KGF and IGF-1
Cytokines – IL-6
Protein kinase A & C

Increased expression of AR coregulators – autonomous activation of AR pathway

14 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

15. BYPASS AR MODEL
Activation of parallel or alternative survival pathways independent of AR
transactivation

INHIBITING APOPTOSIS
Upregulate the antiapoptotic protein, Bcell lymphoma 2 (Bcl-2)
Inactivating the proapoptotic tumor suppressor gene Phosphatase and Tensin
Homologue (PTEN).
NEUROENDOCRINE DIFFERENTIATION
Neuroendocrine cells secrete neuropeptides, such as serotonin and bombesin
OVEREXPRESSION OF ER ALPHA

15 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

16. LURKER CELL MODEL
Outgrowth of castration resistant cells
Proliferates under the selective pressure of Androgen deprivation
Tumorigenic
Preexistent epithelial stem cells
16 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

17. 17 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

18. TREATMENT OPTIONS
18 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

19. TREATMENT
OPTIONS
Androgen Receptor Directed Approaches
•CYP 17 inhibition
•AR modulation
Cytotoxic chemotherapy
Immunotherapy
Targetted treatments
•PI3K/Akt/mTOR pathway
•Angiogenesis
•MET signaling
•Apoptosis pathway
19 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

20. AR DIRECTED APPROACHES – CYP 17 INHIBITION
Suppresses extragonadal androgen synthesis
Abiraterone – oral selective CYP17 inhibitor – inhibits both 17,20 lyase and 17 alpha
hydroxylase
Approved for all patients with mCRPC even in patients who have not received
docetaxel chemotherapy
Not currently approved for non metastatic CRPC
Other agents
High dose Ketaconazole – weak inhibitor
Orteronel, Seviteronel (17,20 lyase inhibitor), – not FDA approved

20 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

21. AR DIRECTED APPROACHES – CYP 17 INHIBITION
Improved PFS, OS
57% reduction in risk of radiographic progression
Significantly delayed initiation of cytotoxic chemotherapy
In predocetaxel setting – improved patient reported quality of life outcomes

21 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

22. AR DIRECTED APPROACHES – CYP 17 INHIBITION
22 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

23. AR DIRECTED APPROACHES – AR MODULATION


Enzalutamide
Apalutamide
Darolutamide



23 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

24. 24 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

25. AR MODULATION - ENZALUTAMIDE
AFFIRM TRIAL – mCRPC in docetaxel pretreated patients – survival benefit in
good performance status
PREVAIL TRAIL – mCRPC in Prechemotherapy setting – improved PFS, OS
Approved for all mCRPC irrespective of prior docetaxel therapy
PROSPER TRIAL – non-metastatic CRPC – significant 71% lower risk of
metastases, delay in the time to first use of antineoplastic therapy, no difference
in quality of life
Advantage: No concurrent steroid administration
25 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

26. FDA approval
- nm CRPC
(2018)
SPARTAN
TRIAL

APALUTAMIDE
26 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

27. CYTOTOXIC CHEMOTHERAPY

Mitoxantrone
Docetaxel
Cabazitaxel

Other cytotoxic agents are no longer used as they have not been associated with either
symptomatic improvements or extension of survival

27 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

28. MITOXANTRONE

Semisynthetic anthracycline - 12mg/m2 iv every 21 days
Modest symptomatic benefits with minimal objective antitumor activity
Maximal palliative effect in combination with low dose corticosteroids
Survival was not significantly improved
FDA approved (1997) – symptomatic CRPC
Still useful for patients
With docetaxel and cabzitaxel refractory disease
Marginal performance status where toxic taxane agents may not be well tolerated


28 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

29. DOCETAXEL
Taxane family – 75 mg/m2 iv every 21 days
Acts in cancer cells through TP53
independent mechanism
By inhibition of microtubule
depolymerization
Blocakade of antiapoptotic signaling
By inducing apoptosis by BCL
phosphorylation
29 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

30. As of 2004, docetaxel has become the
agent of choice for treatment of
metastatic CRPC
TAX 327
30 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

31. THE SOUTHWEST ONCOLOGY
GROUP (SWOG) 9916 STUDY
31 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

32. DOCETAXEL TOXICITY
Myleosuppression
Fatigue
Peripheral edema
Neurotoxicity
Hyperlacrimation
Nail dystrophy
32 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

33. CABAZITAXEL
FDA approved in 2010 - 25mg/m2 every 21 days – docetaxel refractory mCRPC
Novel tubulin binding taxane – poor affinity for P-glycoprotein, the ATP dependent
drug efflux pump
Active in both docetaxel-sensitive and primary or acquired docetaxel resistant CRPC
Principal dose limiting toxicity – neutropenia  administered along with G-CSF
33 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

34. TROPIC TRIAL
mCRPC progressed after docetaxel
based chemotherapy
Mitoxantone vs Cabazitaxel
Improved PFS, extended time to PSA
progression, OS
34 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

35. IMMUNOTHERAPY
Activating immune responses against malignant cells
Overcoming tumor induced tolerance

35 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

36. IMMUNOTHERAPY IN PROSTATE CANCER
Prostate cancer – IDEAL TARGET
Slow growing
Allowing stimulated immune system the time to generate an anti-tumor response
Produces several tissue specific proteins – serve as tumor antigens
PSA, prostatic acid phosphatase, PSMA
36 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

37. IMMUNOTHERAPY IN PROSTATE CANCER
Dendritic cell based therapies
Adjuvants such as granulocyte macrophage colony stimulating factor
Viral carriers
Single antigen or whole cell vaccines
Genetically modified tumor cell vaccine
DNA plasmid vaccine
Incorporating costimulatory molecules, cytotoxic T lymphocyte antigen 4 (CTLA4)
blockade, PD1 blockade
Intracellular viral or bacterial mediators

37 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

38. IMMUNOTHERAPY IN PROSTATE CANCER
Sipuleucel T
ProstVac VF
Immunecheck point inhibitior – Ipilimumab, Pembrolizumab
GVAC – allogeneic recombinant whole cell vaccine

38 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

39. SIPULEUCEL - T - PROVENGE
Personalised vaccine
Derived from autologous CD54+ dendritic cells – apheresed from individuals
Processed with recombinant fusion proteins composed of PAP & GM-CSF
PAP – prostate cell membrane localization  prostate specific immune responses

39 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

40. 40 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

41. SIPULEUCEL - T - PROVENGE
FDA approval in 2010 – asymptomatic / minimally
symptomatic CRPC
Statistically significant improvement in overall survival
Largest impact in prechemotherapy setting & early disease
Preparation & production in large quantities – challenging
Well tolerated & Minimal infusion related fevers and
rigors
Not recommended in – visceral disease or in severely
symptomatic mCRPC
Ongoing trials - for use in nm BCR, combination with AR
directed Rx

IMPACT
41 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

42. PROSTVAC - VF
PSA targeted poxviral based vaccine
Incorporates a DNA plasmid containing the PSA gene + 3 costimulatory molecules
Increase PSA specific immune responses
Not a personalized product
Relatively inexpensive to synthesize
Administration – subcutaneous injection through several months
Improved overall survival in mCRPC
Currently in phase III testing
42 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

43. IMMUNE CHECKPOINT INHIBITION
CTLA 4 Inhibitor – Ipilimumab
PD 1 inhibitor – Nivolumab,
Pembrolizumab
PDL 1 inhibitor – Atezolizumab,
Durvalumab
43 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

44. IMMUNE CHECKPOINT INHIBITION
Prevents normal attenuation of antitumor T
cell responses
Ipilimumab – monoclonal anti CTLA4
antibody
Not currently FDA approved
Greatest benefit in pts without visceral
disease, normal hemoglobin and ALP levels
Immunological toxicity from unchecked
immune response
Colitis, hepatitis, adrenal insufficiency,
endocrinopathies, dermatitis, hypophysitis
44 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

45. PARP
INHIBITORS
•Poly ADP Ribose Polymerase
Inhibitors
•Agents – Olaparib, Niraparib,
Veliparib, Telazoparib,
Rucaparib
•BRCA mutated metastatic
CRPC
45 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

46. TARGETED TREATMENTS – NON AR PATHWAYS
Phospahtidylinositol 3 kinase (PI3K)/Akt/mTOR pathway
EGFR signaling
Mitogen activated protein kinase (MAPK) signaling
IGF1R singaling
Endothelin, Hedgehog, Src kinase signaling and several others

46 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

47. PI3K/AKT/MTOR PATHWAY
Bidirectional talk between PI3K and AR
mTOR inhibitors – failed to demonstrate significant
clinical activity in mCRPC ; Can reverse
chemotherapy resistance in PTEN deficient CaP
Combined blockade – PI3K/mTOR: BEZ235 +
Enzalutamide/abiraterone
Akt inhibitor – MK2206, perifosine
PI3K inhibitors – BKM120, PX866
47 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

48. ANGIOGENESIS INHIBITORS
Bevacizumab – humanized monoclonal antibody to VEGF : 15mg/kd IV every 21 days
PFS improved but not approved by FDA – toxicities and treatment related mortality
Afilbercept – decoy receptor that binds VEGF - No significant differences in PFS/OS + higher
toxicity rate
Sunitinib – promiscuous TKI inhibitor (blocks VEGFR2 & PDGbeta) - PFS ^; no ^ in OS; not
approved
Tasquinimod – in Phase III trial - Second generation quinolone-3-carboxamide analogue
Prevents upregulation of HIFalpha
Induces endogenous antiangiogenesis factor, thrombospondin 1
Inhibits S100A9 – protein involved in differentiation and cell cycle progression
48 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

49. APOPTOSIS PATHWAY
Clusterin – stress induced antiapoptotic chaperone protein expressed in CaP after
androgen ablation/chemotherapy
CUSTIRSEN – intravenous antisense oligonucleotide moiety that inhibits clusterin
at mRNA level, increasing sensitivity to androgen deprivation and chemotherapy
May reverse chemotherapy resistance
SYNERGY & AFFINITY – ongoing trials
49 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

50. EPIGENETIC MODIFICATION
50 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

51. PALLIATION
Pain Management
Epidural cord compression
Management
Bone tagetted treatments
51 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

52. PAIN MANAGEMENT
CAUSES
Focal & diffuse bone involvement
Epidural metastasis & cord
compression
Neuralgia, neuropathies & nerve
plexopathies
Extensive skull metastasis with cranial
nerve/skull base involvement
Extensive painful liver metastasis
Pelvic masses

MANAGEMENT OPTIONS
RT & Surgical stabilization of pathological fractures
Pharmacological pain management – Amitriptyline,
Gabapentin, pregabalin
Neurolytic procedures & Physical therapy for neurologic
functions
Discontinuation of neurotoxic drugs – docetaxel
Coritosteroids – cranial nerve involvement, diffuse bone
pain, epidural metastasis
Intrathecal chemotherapy – meningeal involvement
52 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

53. EPIDURAL CORD COMPRESSION
First therapeutic intervention – High dose IV glucocorticoids - Dexamethosone
Loading dose - 10mg followed by 4-10mg every 6 hours
 Maintenance -16-100 mg/day
Radiation therapy
Decompression surgery
Progressive signs and symptoms during radiation therapy
Unstable pathologic fractures that require stabilisation
Experience recurrence after RT
53 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

54. BONE TARGETED APPROACHES
Bisphosphonates
RANK L inhibitor
Radiopharmaceuticals
54 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

55. BISPHOSPHONATES
Reduce bone resorption by inhibiting osteoclastic activity and proliferation
Agents shown clinical benefit in patients with prostate cancer with bone metastasis
Zoledronate & Pamidronate
Other agents - – benefit in Prostate Cancer not established
Alendronate, Etidronate, Ibandronate, Clodronate
55 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

56. ZOLEDRONIC ACID
First approved for treatment of hypercalcemia and decreased bone mineral density in
postmenopausal women
Progressive CRPC with bone metastasis – 4mg iv repeated at 4 weeks interval
Side effects – fatigue, myalgia, fever, anemia, Sr. Creatinine elevation
Hypocalcemia – concomitant administration of oral calcium (1000mg/day) + Vitamin
D (800units/day)
Unusual complication – osteonecrosis of mandible – most frequently seen in patients
undergoing dental work/poor dentition / chronic dental disease

56 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

57. RANK L INHIBITORS
RANK L binds and activates RANK in osteoclasts  osteoclastic activation
RANKL inhibitors
Recombinant osteoprotegerin – natural decoy receptor
Denosumab – monoclonal antibody against RANK L
Improved time to first skeletal related event but no difference in OS
DENOSUMAB - FDA approval (2010) – for prevention of skeletal related events in bone
metastases
Toxicities – hypophosphatemia, hypocalcemia, fatigue, nausea
Does not require dose adjustment or monitoring of renal impairment
Dose: 120 mg SC every 4 weeks
57 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

58. RADIOPHARMACEUTICALS
Beta emitters
Strontium 89
Samarium 153
Alpha emitters
Radium 223
Not only palliate but also improve OS
FDA approved for palliation of mCRPC
No improvement in overall survial
58 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

59. BONE TARGETING
Calcium-mimetic in the human body
Deposit in osteoblastic bone metastatic sites
Bone targeting occurs via hydroxyapatite Ca5(PO4)3(OH) binding
Hydroxyapatite is an essential portion of the inorganic matrix of bone and is inter-
mixed with cancer cells in lesions with an osteoblastic phenotype.
59 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

60. RADIUM 223
Alpha particles - 7000 times heavier than beta paritcles
Very short path length - <100 micrometer
50 KBq/kg iv every 4 weeks – 6 doses
FDA approval - Symptomatic bone metastatic CRPC
without visceral or bulky nodal metastases
Docetaxel refractory and/or ineligible or uninterested in
chemotherapy
Only radiopharmaceutical agent with improved OS &
quality of life
60 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

61. RADIUM 223
61 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

62. CHOOSING THE RIGHT
TREATMENT…
62 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

63. EVALUATING THE PATIENTS WITH CRPC

PSA 2ng/mL  bone scan, CT chest,
Abdomen & Pelvis

PSA @ every 3 months for
asymptomatic patients
Repeat bone scan & CT @ 5ng/mL

Again after every PSA doubling

Symptomatic  Relevant investigations
regardless of PSA
Negative for metastasis
Negative for metastasis
NON METASTATIC VS METASTATIC CRPC
PSMA PET/ wb MRI  early mCRPC
63 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

64. CRPC
1. NON
METASTATIC
METASTATIC
PRE
DOCETAXEL
2.
ASYMPTOMATIC /
MILDLY
SYMPTOMATIC
SYMPTOMATIC
3. GOOD
PERFORMANCE
4. POOR
PERFORMANCE
POST
DOCETAXEL
5. GOOD
PERFORMANCE
6. POOR
PERFORMANCE
INDEX PATIENTS IN CRPC
64 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

65. INDEX PATIENT - 1
65 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

66. INDEX PATIENT 1 – NON METASTATIC CRPC
STANDARD
Apalutamide or enzalutamide with continued androgen
deprivation (Grade A)
RECOMMENDATION
Observation with continued androgen deprivation
(Grade C)
OPTION
Second-generation androgen synthesis inhibitor
(abiraterone + prednisone) who do not want or cannot
have one of the standard therapies and are unwilling to
accept observation (Grade C)
66 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

67. INDEX PATIENT 1 – NON METASTATIC CRPC
RECOMMENDATION AGAINST
Systemic chemotherapy or immunotherapy outside the context of a clinical trial
(Evidence Level Grade C)
67 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

68. INDEX PATIENT - 2
68 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

69. INDEX PATIENT 2 – METASTATIC CRPC
STANDARD
Abiraterone + prednisone (Grade A)
Enzalutamide(Grade A)
Docetaxel (Grade B)
Sipuleucel-T (Grade B)
Asymptomatic / minimally symptomatic with no prior docetaxel therapy
69 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

70. INDEX PATIENT 2 – METASTATIC CRPC
OPTION (Evidence Level Grade C)
First- generation anti-androgen therapy
Ketoconazole + steroid
Observation to patients who do not want or cannot have one of the standard
therapies
Asymptomatic / minimally symptomatic with no prior docetaxel therapy
70 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

71. INDEX PATIENT - 3
71 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

72. INDEX PATIENT 3 – METASTATIC CRPC
STANDARD
Abiraterone + prednisone (Grade A)
Enzalutamide (Grade A)
Docetaxel (Grade B)
Radium-223 to patients with symptoms from bony metastases from mCRPC without
known visceral disease (Evidence Level Grade B)
Symptomatic good performance status with no prior docetaxel therapy
72 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

73. INDEX PATIENT 3 – METASTATIC CRPC
OPTION
Ketoconazole + steroid (Grade C)
Mitoxantrone (Grade B)
radionuclide therapy to patients who do not want or cannot have one of the standard
therapies (Evidence Level Grade C)
Symptomatic good performance status with no prior docetaxel therapy
73 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

74. INDEX PATIENT 3 – METASTATIC CRPC
RECOMMENDATION AGAINST
Estramustine or sipuleucel-T (Evidence Level Grade C)
Symptomatic good performance status with no prior docetaxel therapy
74 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

75. INDEX PATIENT - 4
75 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

76. INDEX PATIENT 4 – METASTATIC CRPC
OPTION (Evidence Level Grade C)
Abiraterone + prednisone
Enzalutamide
Ketoconazole+ steroid
Radionuclide therapy
Symptomatic poor performance status with no prior docetaxel therapy
To patients who are unable or unwilling to receive
abiraterone + prednisone or enzalutamide
76 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

77. INDEX PATIENT 4 – METASTATIC CRPC
EXPERT OPINION
Docetaxel or mitoxantrone chemotherapy
In select cases, specifically when the performance status is directly related to the cancer
Radium-223
To patients with symptoms from bony metastases from mCRPC without known visceral
disease in select cases, specifically when the performance status is directly related to
symptoms related to bone metastases
Symptomatic poor performance status with no prior docetaxel therapy
77 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

78. INDEX PATIENT 4 – METASTATIC CRPC
RECOMMENDATION AGAINST
Sipuleucel-T (Evidence Level Grade C)
Symptomatic poor performance status with no prior docetaxel therapy
78 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

79. INDEX PATIENT - 5
79 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

80. INDEX PATIENT 5 – METASTATIC CRPC
STANDARD
Abiraterone + prednisone (Grade A)
Cabazitaxel (Grade B)
Enzalutamide (Grade A)
If the patient received abiraterone + prednisone prior to docetaxel chemotherapy, he
should be offered cabazitaxel or enzalutamide
Radium-223 to patients with symptoms from bony metastases from mCRPC and
without known visceral disease (Evidence Level Grade B)
With prior docetaxel therapy & good performance status
80 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

81. INDEX PATIENT 5 – METASTATIC CRPC
OPTION
Ketoconazole + steroid if abiraterone + prednisone, cabazitaxel or enzalutamide is
unavailable (Evidence Level Grade C)
Retreatment with docetaxel to patients who were benefitting at the time of
discontinuation (due to reversible side effects) of docetaxel chemotherapy (Evidence
Level Grade C)
With prior docetaxel therapy & good performance status
81 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

82. INDEX PATIENT - 6
82 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

83. INDEX PATIENT 6 – METASTATIC CRPC
EXPERT OPINION
Palliative care;
Alternatively, for selected patients, clinicians may offer treatment with abiraterone +
prednisone, enzalutamide, ketoconazole + steroid or radionuclide therapy

EXPERT OPINION AGAINST
Systemic chemotherapy or immunotherapy
With prior docetaxel therapy & poor performance status
83 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

84. BONE HEALTH
RECOMMENDATION
Preventative treatment (e.g. supplemental calcium, vitamin D) for fractures and
skeletal related events (Evidence Level Grade C)
OPTION
Choose either denosumab or zoledronic acid when selecting a preventative
treatment for skeletal related events for mCRPC patients with bony metastases
(Evidence Level Grade C)
84 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

85. SUMMARY
NM CRPC FIRST LINE SECOND
LINE
THIRD LINE
Apalutamide
Enzalutamide

Abiraterone
Enzalutamide
Docetaxel
Radium 223
Cabazitaxel
Pembrolizumab
Observation Docetaxel Cabazitaxel Abiraterone
Enzalutamide
Docetaxel
rechallenge
Mitoxantrone
Abiraterone
Enzalutamide
Radium 223
Cabazitaxel
Radium 223

Cabazitaxel
Abiraterone
Enzalutamide
Abiraterone Radium 223 Pembrolizumab
PARP inhibitors
Sipuleucel T
85 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

86. MONITORING
PSA
RFT
LFT
ALP
BONE SCAN
CT chest, abdomen & pelvis
Repeat Blood profile every 2-3 months
& Bone scan + CT – every 6 months
even in the absence of clinical indication

STOP TREATMENT if two out of
three criteria present
PSA PROGRESSION
RADIOLOGICAL PROGRESSION
CLINICAL DETERIORATION
86 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

87. THANK YOU
87 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

88. ANTIANDROGEN WITHDRAWL PHENOMENON
Decline in PSA and even objective responses with
withdrawal of antiandrogen
Rapid PSA responses following androgen ablation –
higher rates of antiandrogen withdrawal phenomenon
88 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

89. 89 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

90. 90 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

91. NEUROENDOCRINE DIFFERENTIATION

91 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

92. CABOZATINIB

92 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

93. 93 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.

94. 94 DEPT OF UROLOGY, GRH AND KMC, CHENNAI.