Management overview of High Risk, Metastatic and castration resistant prostate carcinoma

1. Carcinoma Prostate
Management of advanced disease
Dr Animesh Agrawal
28.03.2017
Dr Ram Manohar Institute of Medical Sciences, Lucknow

2. Risk Stratification
Very Low risk Low Intermediate High
D’Amico PSA < 10
GS < 7
cT1
PSA 10-20
GS = 7
cT2a-2b
PSA > 20
GS > 7
cT2c-3a
NCCN cT1c, GS < 7, PSA
< 10 ng/mL, PSAD
< 0.15, < 3 positive
biopsy cores
PSA < 10
GS < 7
cT1-2a
PSA 10-20
GS 7
cT2b-2c
PSA > 20
GS > 7
cT3a
cT3b-4
EAU PSA < 10
GS < 7
cT1-2a
PSA 10-20
GS 7
cT2b-2c
PSA > 20
GS > 7
> cT3a
RTOG T1-T2
GS2-6
T1T2, GS7
T3, GS2-6
T1-T2,
GS8-10
T3, GS7
T3,
GS8-10

3. Management of High Risk Disease
• PSA > 20 or GS > 7 or cT3a
• Management options
• Radiotherapy (RT)
- External Beam RT (EBRT)
- Brachytherapy (BT)
• Androgen Deprivation Therapy (ADT)
- Neoadjuvant/concurrent/adjuvant
• Surgery (Radical Prostatectomy + Pelvic LN Dissection)
• Management approaches:
- EBRT + ADT
- RT (EBRT + BT) + ADT
- RP + PLND + adjuvant treatment

4. Surgery
• Radical Prostatectomy
- A large number of patients may need adjuvant RT
- Nodal dissection indicated routinely for High risk patients.
• Adjuvant RT
- Indicated in pT3 and/or +ve margins
- 60-64 Gy, single or 2 phase treatment
- NCCN 2017 suggests doses of 64-72 Gy in this setting.
• Retrospective data suggests that salvage RT may reduce
overtreatment without compromising disease control.1
- RADICALS trial: ongoing; for immediate adjuvant RT vs salvage RT on
BCR (> 4200 patients; recruitment closed Dec 2016).
1. Briganti et al. Eur Urol 2012

5. Trials demonstrating benefit with adjuvant RT in
patients with high risk features
n FU FF BCR LC DFS DMFS OS
SWOG
8794
RT: 214
Obs: 211
12.5
51*
25
92*
78
70*
49
71*
61
74*
66
EORTC
22911
RT: 502
Obs: 503
10.6
61*
41
93*
83
70
65
90
89
77
81
ARO
9602
RT: 148
Obs: 159
9.4
72*
54
NR NR NR 97
95
FU: Median follow up in years; FF BCR: Freedom from Biochemical relapse; LC: Local control;
DFS: Disease Free Survival; DMFS: Distant Metastasis free survival; OS: Overall Survival; NR:
Not reported
* Statistically significant difference
In Red: Study primary end point
1. Thompson et al. J Urol 2009
2. Bolla et al. Lancet 2012
3. Wiegel et al. Eur Urol 2014

6. Radiotherapy
• Conventional doses:
- 66-70 Gy to Prostate
- 45-50 Gy to whole pelvis followed by 18-20 Gy boost to the
prostate.
• Nodal irradiation
- In cN0, benefit uncertain
- In cN1, benefit in RFS; OS benefit uncertain.

7. EBRT Dose escalation (DE-EBRT)
n RT dose
LR/IR/
HR
DFS
(%)
OS
(%)
GU Tox
(%)
GI Tox
(%)
Kuban (MDACC)
20111, 8 yrs
301
78 (151)
70 (150)
20/46/
34
78*
59
78
79
13
8
26*
13
RTOG 95-09**
20102, 10 yrs
393
79.2 (195)
70.2 (196)
58/37/5
83*
68
83
78
29
25
24
13
GETUG 063
20113, 5 yrs
306
80 (153)
70 (153)
0/72/28
72*
61
NR
18*
10
20
14
MRC RT014
20144, 10 yrs
843
74 (422)
64 (421)
19/37/
44
71*
60
71
71
11
8
33*
24
Dutch Trial5
20145, 9 yrs
664
78 (333)
68 (331)
18/27/
55
49*
42
69
69
40
41
35*
25
* Statistically significant difference; ** allowed protons
• Several studies have now shown that DE-EBRT improves DFS.
1. Kuban et al. IJROBP 2011
2. Zietman et al. JCO 2010
3. Beckendorf et al. IJROBP 2011
4. Dearnaley et al. Lancet Oncol, 2014
5. Heemsbergen et al. Radiother Oncol, 2014

8. Hypofractionation: Modest
Trial characteristics
BED
α/β = 1.5
Primary end
point
FU
(yrs)
CHHiP1
n = 3216
LR 15%
IR 73%
HR 12%
1. 74Gy/37# (1065)
2. 60Gy/20# (1074)
3. 57Gy/19# (1077)
173
180
171
Time to
Biochemical failure
5.2
HYPRO2
n = 800
IR 26%
HR 74%
1. 78 Gy/ 39# (397)
2. 64.6Gy/19# (407)
182
211
Relapse free
survival
5
PROFIT3
n = 1204
IR
1. 78Gy/39# (598)
2. 60Gy/20# (608)
182
180
Biochemical-
clinical failure
6
NRG 4154
n = 1067
LR
1. 73.8Gy/41# (542)
2. 70 Gy/ 28# (550)
162
186
Disease free
survival
5.8
1. Dearnaley et al. Lancet Oncol, 2016
2. Incrocci et al. Lancet Oncol, 2016
3. Catton et al. JCO 2017
4. Robert Lee et al. JCO 2016

9. Arm 5 year outcomes
Late Toxicity (%)
GU GI
CHHiP1 1. 74Gy/37# (1065)
2. 60Gy/20# (1074)
3. 57Gy/19# (1077)
88.3% [Failure free rate]
90.6% (non inferior)
85.9% (not non-inferior)
9.1
11.7
6.6
13.7
11.9
11.3
HYPRO2 1. 78 Gy/ 39# (397)
2. 64.6Gy/19# (407)
77.1% [RFS]
80.5% (not superior)
39
41*
17.7
21.9
PROFIT3 1. 78Gy/39# (598)
2. 60Gy/20# (608)
79% [Failure Free Rate]
79% (non inferior)
22.4
22.4
13.9
8.2*
NRG
04154
1. 73.8Gy/41# (542)
2. 70 Gy/ 28# (550)
85.3% [DFS]
86.3% (non inferior)
20.5
26.2*
11.4
18.3*
Gr2+
Gr2+
Gr2
Gr2+
1. Dearnaley et al. Lancet Oncol, 2016
2. Incrocci et al. Lancet Oncol, 2016
3. Catton et al. JCO 2017
4. Robert Lee et al. JCO 2016
Modest Hypofractionation: contd

10. Hypofractionation: Extreme
N Dose
EQD2 BED Late effects
(%) α/β = 3
Outcome
α/β = 1.5
Madsen et al1
2.5y (2007)
40
33.5 Gy/
5#/6.7Gy
78 183
Gr 2+
GI 7.5, GU 20
DFS 90%
King et al2
2.7y (2012)
67
LR
36.25 Gy/
5#/7.25Gy
90.6 211
Gr 2+
GI: 2, GU: 8.5
RFS 94%
pHART33
4.5y (2013)
84
LR
35 Gy / 5#
7 Gy
85.1 198
Gr 2+
GI 8, GU 5
FFS 98%
Katz et al4
> 6y (2013)
254
70% LR
36.25 Gy/
5#/7.25Gy
90.6 211
Gr 2+
GI 2.9, GU 11
RFS: 97%
LR, 91% IR
RTOG 09385
12m (2016*)
240
LR
36.25Gy/ 5#
51.6Gy/ 12#
90.6
85.5
211
199
Gr 3+
0.8 vs 1.7
NR
* Abstract only; NR: Not reported
• Swedish HYPO-RT-PC has randomized >1200 patients with IR disease to either
78Gy/39# or 42.7Gy/7#
- Early toxicity results comparable (ASTRO 2016); outcome results awaited.

11. Hypofractionation: Summary
• Modest hypofractionation:
• Short follow up (5-6 years).
- Collectively these trials show that in over 6000 patients, 2 shorter
courses of RT lasting 4 or 5 weeks (70Gy/28# and 60Gy/20#) led to
similar disease control and late effects as longer RT courses lasting 7
or 8 weeks.
- Reasonable approach; may be discussed with patients as a treatment
option1.
• Extreme hypofractionation
• Phase II data only, mostly for LR and IR disease; outcomes good
• Role in HR disease yet to be evaluated
1. NCCN Guidelines 2017

12. EBRT or EBRT + BT or BT alone?
• In high risk disease, role of BT restricted to boosting the dose to
prostate during definitive RT.
- Typical dose: 6-10 Gy x 2-4 fractions HDR, boost to 100-110 Gy LDR
• BT as monotherapy is not recommended1,2
, though Phase II
studies have shown good outcomes3,4.
• ASCENDE-RT5 study with mostly HR (70%) patients (EBRT
[200] to Pelvic RT + BT boost [198]) was reported with a
median FU of 6.5 years.
- HR for failure: 2.04 (p = 0.004, favoring Brachytherapy arm)
- No difference in OS, DMFS.
1. ABS Guidelines. Brachytherapy 2012
2. GEC-ESTRO Guidelines. Radiother Oncol, 2013
3. Patel et al. Brachytherapy, 2017
3. Mason et al. Brachytherapy, 2014
4. James Morris et al. Brachytherapy, 2017

13. RT in HR disease: Summary
• Dose escalation to > 76 Gy should be the norm.
• Modest hypofractionation is a reasonable alternative; future
directions may include extreme hypofractionation.
• May be delivered as a combination of EBRT + BT.

14. Androgen Deprivation Therapy (ADT)
• Surgical or Medical
• Drugs used:
• HP Axis suppression
- GnRH agonists: Leuprolide, Goserelin, Triptorelin, Histrelin
- GnRH antagonists: Degarelix, abarelix1
• Antiandrogens
- Steroidal: Cyproterone acetate
- Non-steroidal
- 1st Gen: Flutamide, Bicalutamide, Nilutamide
- 2nd Gen: Enzalutamide
• Novel antiandrogens (inhibitors of synthesis)
- 17-20 lyase inhibitor: Abiraterone acetate, Orteronel2, Galeterone3
1. Abarelix approval has been withdrawn
2. Orteronel no longer being developed
3. Galeterone Phase II/III trial has been closed because of unfavourable results.

15. ADT: General Principles
• Surgical Castration is the gold standard of ADT, with mean
testosterone levels < 15 ng/ml.1
• LHRH analogues are now the standard of care because of the
potential for reversibility.
• Non steroidal anti androgens (NSAA)
- Generally used in combination with Castration (surgical or medical)
with a small survival benefit (upto 5%) over castration alone.2,3
- Monotherapy is less effective than either of above two strategies.4
1. Oefelein et al. Urology 2000
2. Schmitt et al. Cochrane Database Stst
Rev 2000
1. Akaza et al. Cancer 2009
2. Kunath et al. Cochrane Database Syst
Rev 2014

16. Androgen synthesis inhibitors
GnRH agonists, antagonists
and estrogens
Antiandrogens

17. • Several trials have shown that the addition of ADT to EBRT
improves outcomes.
Androgen Deprivation Therapy
Treatment LR/IR/HR
(%)
Outcome
RTOG 85-311
11y (2005)
70Gy + ADT (cont)
468 v 477
15/50/35*
Better DFS, DMFS,
CSS, OS**
EORTC 228632
9.1y (2010)
70Gy + ADT (3y)
208 v 207
HR > 90*
Better DFS, DMFS,
CSS, OS
RTOG 86-103
>12y (2008)
70Gy + ADT (6m)
232 v 224
HR > 70*
Similar OS
Better DFS DMFS
RTOG 94-084
9.1y (2011)
66.6Gy + ADT (4m)
992 v 987
35/54/11
Better DFS, DMFS,
CSS, OS
TROG 96015
10.6y (2011)
66Gy + ADT (3m or 6m)
270 v 265 v 267
0/16/84
Better DFS, DMFS,
CSS, OS for 6m ADT
* Not reported; ** All were study end points, primary end point not specified
In red: Primary end point

18. Duration of ADT
• Studies have shown that
1. Long term ADT (> 2 years) is superior to short term ADT for high
risk disease.
2. Reduction in duration of LT-ADT may be considered.
HR % Study Arms CSS OS
RTOG 92-021
(19.6y, 2017#)
> 50
70 Gy + ADT 28m (753)
70 Gy + ADT 4m (761)
84*
78
30*
27
EORTC 229612
(6.4y, 2009)
~ 50
70 Gy + ADT 3y (487)
70 Gy + ADT 6m (483)
96.8*
95.3
84.7*
81
Canadian PCS
IV (6y, 2013**)
100
70 Gy + ADT 18m (320)
70 Gy + ADT 36m (310)
96.6
95.3
91.1
86.1
# Primary end point was DFS * Statistically significant; ** abstract only; in red: Primary end point

19. Dose escalated RT with ADT
• Appears reasonable to offer ADT to patients receiving DE-EBRT.
• Optimal duration of ADT in this setting is uncertain.
LR/IR/HR % Study arms DFS % OS %
EORTC 229911
(7.2y, 2016) 0/75/25
RT + ADT 6m; 408
RT (70-78Gy); 409
82.6*
69.8
91.3
88.4
DART01/05
GICOR2 (5y, 2015)
0/46/54
78Gy + ADT 24m; 178
78Gy + ADT 4m; 177
90*
81
95*
86
MRC-RT013
(10y, 2014) 19/37/44
74Gy + ADT 6m; 422
64Gy + ADT 6m; 421
55*
43
71
71
* Statistically significant; in red: Primary end point
1. Bolla et al. JCO 2016
2. Zapatero et al. Lancet Oncol 2015 3. Dearnaley et al. Lancet Oncol 2014

20. Drugs and their doses
Name Dose
GnRHanalogs
Leuprolide
Goserelin
Triptorelin
Histrelin
Degarelix
7.5mg monthly, 22.5mg 3 monthly
3.6mg monthly, 10.8mg 3 monthly
3.75mg monthly, 11.25 mg 3 monthly
50mg implanted for 12 months
240mg loading fb 80mg monthly
Antiandrogens
Flutamide
Bicalutamide
Nilutamide
250mg TDS
50mg OD (combination), 150mg (monotherapy)
300mg OD x 1 month fb 150 mg OD
Abiraterone
Enzalutamide
1000 mg (250mg x 4) OD
160 mg OD
Androgen Deprivation Therapy
* FDA approved dosages

21. Toxicities of ADT
Androgen deprivation syndrome:
(LH-RH analogues)
• Hot flushes
• Decrease in libido, Erectile dysfunction
• Fatigue, Anaemia
• Alteration in fat metabolism, weight gain, loss of muscle mass
• Cardiovascular complications, increased risk of T2DM
• Bone loss (osteopenia and osteoporosis)
• Memory loss, depression, insomnia, personality changes

22. Toxicities (Anti-androgen)
• Elevation in hepatic enzymes
• Stomach upset and diarrhoea
• Pulmonary complications (fibrosis)
• Gynecomastia/ breast tenderness
- Generally seen to have lower risk of decreased libido and
erectile dysfunction as compared to GnRH analogues.

24. Recurrent, non-metastatic disease
• Both groups of patients may receive adjuvant ADT, duration uncertain.
• For select RT failures, brachytherapy may be a salvage option.
- Only small phase I/II studies.
• After Surgery
- Imaging recommended if:
• At least IR disease at diagnosis
• PSA doubling time < 6m
• Symptomatic patients
Salvage RT
Retrospective studies
suggest SRT may be as
good as adjuvant RT.
• After RT
- Biopsy recommended to document failure
• Multiparametric MRI modality of choice
• PET-CT not routinely recommended.
Salvage RP
Disease that was initially
LR or IR; life expectancy
> 10y
EAU – ESTRO – SIOG Consensus guidelines, 2016

25. High Risk Disease: Summary
• Local Treatment
• Radical Prostatectomy + Adjuvant RT
• Radical RT (EBRT + BT)
• EBRT only
- > 76 Gy, preferably IMRT or other newer techniques
- May consider modest hypofractionation (60Gy / 20#)
• EBRT + BT: 45-50 Gy Pelvic RT + BT Boost (LDR, HDR)
• Systemic Treatment
• Androgen Deprivation: 2-3 years; GnRH analogue + Antiandrogen.
• ADT to start with EBRT or 1-2 months before starting RT.
• Recurrent disease: May salvage with RT or RP, depending on
prior local treatment.

26. Castration Resistant Prostate Carcinoma
&
Metastatic disease

27. Overview
• Rising PSA and clinical metastases (symptomatic or otherwise)
- Noncastrate
- Castrate
• Principles of treatment
- ADT
• Deplete androgens
• Inhibit signaling through the androgen receptor (AR).
- Cytotoxic chemotherapy
- Newer approaches
- Palliation

28. History
Treatment Year
Orchidectomy or exogenous estrogen 1940
The palliative role of surgical adrenalectomy 1945
aminoglutethimide and Ketoconazole 1980s
LHRH agonist, Nonsteroidal antiandrogens 1980s
“combined androgen blockade” era 1986
First cytotoxic drug, Mitoxantrone 1996
Docetaxel 2004
Cabazitaxel 2010
Abiraterone acetate 2011
Enzalutamide 2012

29. A significant
initial rise in
PSA
A slow rise
following an
initial decline.
Scher et al. JCO 2011

30. Noncastrate metastatic prostate cancer

31. • ADT forms the cornerstone of treatment.
• ADT should be given as a combination of LHRH analogue
+ antiandrogen (non steroidal).
• Initiate therapy and monitor the disease with serial PSA
and imaging as appropriate until disease progression.
Management: Basic Principles

32. • Prognostic Factors:
- Gleason’s Score
- Gleason’s Grade
- PSA kinetics (doubling time <3m)
- PSA nadir (absolute value, and time taken to reach)
- Extent of disease when hormone therapy was started.
- Low performance status
- Low haemoglobin
- High alkaline phosphatase
- Site and number of metastases
- Percentage of the skeleton involved

33. Complete androgen suppression or Monotherapy?
• PCTCG summarized 27 randomized trials with 8,275 patients, and
found a 2% difference in mortality at 5 years:1
- 72.4% for monotherapy
- 70.4% for CAS.
• Another meta-analysis limited to trials of a nonsteroidal
antiandrogen noted a mortality of 72.4% vs 75.3% at 5 years
favouring CAS.2
• While survival benefit is small, it is consistent; monotherapy is not
recommended.
1. PCTCG. Lancet 1995
2. Bennett et al. Prostate Cancer Prostatic Dis 1999

34. Agent of choice for ADT monotherapy?
• No one form of androgen deprivation monotherapy is clearly
superior to the others.
• An EORTC study showed similar outcomes between DES 1
mg & orchiectomy1.
• In a meta-analysis of 10 randomized controlled trials that
included LHRH agonists/antagonists, orchiectomy, DES, or
choice of DES or orchiectomy, outcomes were similar.2
- Anti androgens alone, however, had an inferior survival.
1. Sidenfield et al. Ann Intern Med 2000
2. Robinson et al. Eur Urol, 1995

35. Timing: Early versus late
• Early hormone therapy delays the time to metastases and
symptoms, but the effect on overall survival is less clear.
• MRC PR03 trial (n = 998)
- Locally advanced or asymptomatic metastatic prostate cancer
- Immediate treatment (orchiectomy or LHRH analog) vs deferred
treatment
- Early therapy were less likely to require a TURP or develop ureteral
obstruction, progress from M0 to M1 disease, or to develop pain.
• Decision to be made on basis of risk factors for individual
patients.
MRC PCWPIG. Br J Urol 1997

36. Role of Intermittent ADT
•Attractions of the intermittent approach:
- Minimizing the exposure to a castrate environment may help
retain sensitivity to ADT for subsequent therapy.
- Potential for a better QoL
•Several trials and reviews but no evidence of non
inferiority in terms of survival outcomes.
•General consensus:
- May be offered to patients who respond well to ADT (nadir < 4ng/ml)
- Some improvement in QoL noted (hot flushes, impotence).
- Outcome differences not yet clear.

37. Chemohormonal treatment
Patients
included
Study arms OS*
GETUG AFU15
83m, 20161 M1
ADT + D (192)
ADT (193)
61
46.5
CHAARTED
29m, 20152
M1; High burden
~50%
ADT + D (397)
ADT (393)
57.6**
44
STAMPEDE
43m, 20163
N+ relapse
and/or M1
ADT (1184)#
ADT+Z (593)
ADT+D (592)
ADT+Z+D (593)
55
57
63**
60**
* OS was primary end point for all 3 studies; ** Statistically significant; # Reference arm
1. Gravis et al. Eur Urol 2016
2. Sweeney et al. NEJM 2015 3. James et al. Lancet 2016

38. ADT: Summary
• Relapse after local treatment:
- May be withheld till symptoms occur
- May offer intermittent therapy to good responders (nadir < 4ng/ml
within 6m), especially to those with asymptomatic metastatic disease.
• First diagnosis with metastatic disease:
- Start with orchiectomy / LHRH analogs.
- Chemohormonal treatment better than ADT alone
- In asymptomatic, may consider either ADT alone
- Watchful waiting may be considered.
- Antiandrogen monotherapy not to be offered.

39. ADT: Follow up
• Evaluate patients at 3–6 months after the initiation of treatment
• Tests should include serum PSA measurement, physical
examination, serum testosterone, and careful evaluation of
symptoms to assess the treatment response and side effects
• In patients with PSA progression, assess the testosterone levels
• In patients with suspicion of progression, imaging as per
symptoms.

40. Castration Resistant Prostate Cancer

41. • A rising PSA / progressive disease, despite castrate levels of
testosterone (< 50 ng/dl)
• Clinically disease may be:
- Nonmetastatic that includes a rising PSA and/or disease limited
to the prostate or prostate bed (uncommon)
- Metastatic which includes:
• The patterns of osseous disease and no soft tissue disease
• Nodal spread and no bone or visceral spread
• Visceral spread with or without osseous disease.

42. Management of CRPC: Principles
• Aim of therapy is to prolong survival while maintaining QoL.
• For non metastatic disease, enrolment in clinical trials
recommended.
• Anti-androgens may be withdrawn after CRPC has been
documented. However, LHRH analogues may be continued
(small survival benefit)1,2.
• Treatment options:
- First Line: Docetaxel
- Alternatives: Abiraterone, enzalutamide
- Second/3rd Line: Cabazitaxel, Sipuleucel T, Ra 223
1. Taylor et al. JCO 1993
2. Hussain et al. JCO 1994

43. Docetaxel
Study Arms OS (PEP)
TAX 327
21m, 20041
DP 3 wkly (335)
DP wkly (334)
MP 3 wkly (337)
50%*
43%*
40%
SWOG 99-16
32m, 20042
E + D (386)
M + P (384)
36%*
30%
PEP: Primary end point; * statistically significant
1. Tannock et al. NEJM 2004
2. Petrylak et al. NEJM 2004
• Given the improvement shown by docetaxel over mitoxantrone, it
is considered the first line cytotoxic agent in patients with mCRPC.
• Regimen: 75mg/m2 3 weekly with daily oral prednisolone (10mg).

44. Docetaxel
3 wkly
Docetaxel
wkly
Mitoxantrone
Pain Response Rate*
n, evaluable 153 154 157
Response rate (%) 35 31 22
P-value (vs. mitoxantrone) 0.01 0.07 -
PSA Response Rate*
n, evaluable 291 282 300
PSA response rate (%) 45 48 32
P-value (vs. mitoxantrone) 0.0005 <0.0001 -
Tumor Response Rate*
n, evaluable 141 134 137
Response rate (%) 12 8 7
P-value (vs. mitoxantrone) 0.1 0.5 -
TAX 327: Secondary Objectives
Response Rates
* Determined only for patients with pain or PSA ≥20 or measurable disease at baseline, respectively

45. Cabazitaxel
• Semi synthetic taxane; developed in docetaxel-resistant prostate
cancer cell lines
• In the Phase III TROPIC* study, 755 patients who had
progressed on or after docetaxel were randomized to either
Cabazitaxel (C, 378) or Mitoxantrone (M, 377) chemotherapy.
- Median survival for the C and M cohorts was 15.1m v 12.7m (HR =0.70;
95% CI = 0.59 - 0.83; p <0.0001)
- Median PFS 2.8 months and 1.4 months (HR = 0.74; 95% CI = 0.64 to
0.86; p <0.0001)
• In 2010, the FDA approved Cabazitaxel plus prednisone for the
treatment of metastatic CRPC previously treated with a
Docetaxel-containing regimen.
• Regimen: 25 mg/m2 3 wkly with daily oral prednisolone (10mg)
* de Bono et al. Lancet, 2010

46. • COU-AA-3011: 1195 patients with mCRPC that had progressed after
docetaxel were randomised 2:1 to abiraterone or placebo.
- The primary end point was OS and median FU was 20.2m
- Median survival with abiraterone was 15.8m v 11.2m with placebo (HR:
0.74; p < 0.0001).
- All secondary objectives were in favour of abiraterone (PSA, radiologic
tissue response, time to PSA or objective progression).
• COU-AA-3022: 1088 patients with mCRPC who were chemotherapy
naïve were randomized to abiraterone or placebo.
- Median FU was 49.2m, and OS was 34.7m vs 30.3m favouring
abiraterone, p = 0.0033).
• FDA approved for mCRPC as both 1st line and after failure on
docetaxel.
Abiraterone acetate
1. Fizazi et al. Lancet Oncol 2012 2. Ryan et al. Lancet Oncol 2015

47. • The AFFIRM1 study randomised 1199 patients with mCRPC who had
progressed after docetaxel in a 2:1 fashion to enzalutamide or placebo.
- The primary end point was OS and median FU was 14.4m.
- Median survival was 18.4m with enzalutamide vs 13.6m in the placebo
arm (HR: 0.63; p < 0.001).
- All secondary objectives were in favour of enzalutamide (PSA, soft
tissue response, QoL, time to PSA or objective progression).
• PREVAIL study2 reported similarly encouraging results – at a median FU of
22 months, OS was 72% v 63% favouring enzalutamide (p < 0.001); both
trials were halted after interim analyses given the magnitude of the benefit.
• FDA approved for mCRPC: both 1st line and as salvage after failure on
docetaxel. Also approved as a part of combination ADT for mCRPC based on
outcomes from the TERRAIN3 study.
1. Scher et al. NEJM, 2012
2. Beer et al. NEJM 2014 3. Shore et al. Lancet 2016
Enzalutamide

48. Immunotherapy Approaches in PC
• Active immunotherapy
- Tumor associated antigen is directly targeted by loading in that antigen in APC
or into vaccine vector at protein or DNA level.
- Antigen specific immunotherapy
• Sipuleucel-T
• Poxvirus-based vectors
• DNA based vaccines
• Passive immunotherapy
- Antibodies to specific receptors/antigens, eg. PSMA.
• Immune Checkpoint Inhibitors
- Strategies to maintain activated tumor specific T-cells by neutralizing co-
inhibitory receptors
- Anti-CTLA 4, eg. Ipilumimab and tremelimumab
- Anti-programmed death 1 (PD-1)
• MDX-1106

49. Sipuleucel-T
• An autologous active cellular immunotherapy that includes an acid
phosphatase specific, replication-competent adenovirus.
• Kantoff et al (IMPACT Study Group)
• 512 patients with asymptomatic mCRPC; Primary end point OS
• All had failed after local therapy and ADT, and surviving patients on failure
went on to receive docetaxel.
• Median FU: 34 months
• In the study arm risk of death was 25.8% vs 21.7% in placebo arm (HR 078,
95% CI, 0.61 to 0.98, p = 0.03)
• No improvement in time to progression.
• Based on this trial, approved by the FDA for
asymptomatic/minimally symptomatic patients with mCRPC.
Kantoff et al. NEJM 2010

50. Palliation

51. Bone Events Defined
• Skeletal Related Event (SRE)
• Radiation to bone
• Pathologic fracture
• Surgery to bone
• Spinal cord compression
• Hypercalcemia of malignancy
• Symptomatic Skeletal Event (SSE)
• EBRT to relieve skeletal symptoms
• New symptomatic pathologic bone fracture
• Occurrence of spinal cord compression
• Tumor-related orthopedic surgical intervention

52. Bisphosphonates
• Reduce the risk of SREs and osteoporosis.
• MoA: Inhibit osteoclast activity to reduce bone turnover.
• Drugs in this group are:
- Zoledronate (4mg iv, 4 weekly)
- Ibandronate (150mg PO monthly or 3mg iv 3 monthly)
- Pamidronate (90mg iv 4 weekly)
- Etidronate (not approved for bone mets; 5-20mg/kg OD)
- Alendronate (not approved for bone mets; 10-40 mg OD)
• Caution:
- Nephrotoxic; dose adjustments needed in renal dysfunction.
- Cause hypocalcemia; monitor serum levels
- ADR: Bone pain, nausea, fatigue, hypersensitivity; jaw osteonecrosis
Saad et al. JNCI 2002

53. Denosumab
• Monoclonal antibody that binds RANKL, inhibiting
osteoclast mediated bone resorption.
• Denosumab 120 mg every 4 weeks
• Adverse effects
- Back and extremity pain (muscuskeletal)
- Osteonecrosis (< 5%)
- Hypersensitivity reactions

54. Pain palliation
• EBRT
• Radiopharmaceuticals:

55. Palliative EBRT
• For one or more painful lesions that can be encompassed by a
single or regional radiation port, EBRT offers excellent
palliation.
• A variety of dose fractionation schemes:
• 30 Gy in 10 fractions
• 20 Gy in 5 fractions
• 8 Gy in 1 fraction
• No clear evidence of superiority of one over the other
• Studies suggest similar pain relief, which is maintained for longer
duration with longer schedules.

56. • To control more diffuse pain
• Directed at the tumor/bone interface; maximal deposition at the
site of maximal bone turnover.
• Directed at specific cytokines produced by tumor cells and the
host that contribute to disease progression within the bone.
• Directed at the tumor itself.
• Options
- Radium-223: α emitter with t1/2 11.4 days.
- Samarium (153 Sm) lexidronam: β + γ emitter with t1/2 2.9 days
- Strontium 89: β emitter with t1/2 50 days
Radiopharmaceuticals

57. Samarium (153Sm) lexidronam
• T1/2 2.9 days
• Relies on the diphosphonate moiety for targeting,
• Simultaneously emits gamma rays that can be imaged Beta rays
that penetrate ~ 2.5mm that can be therapeutic.
• Shown to provide good pain relief by week 2.
Radium - 223
• α emitter (> 95%), very short range (< 0.1mm) penetration
• Only radiopharmaceutical shown to have a survival benefit
• ALSYMPCA study randomized 921 patients with symptomatic
mCRPC to receive Ra 223 (614) or placebo (307)
- Median OS was improved by 3.6m with Ra-223 (14.9 vs 11.3m, HR 0.7,
95% CI, 0.58 - 0.83, p < 0.001)
- Rates of SRE, ALP and PSA progression were also improved.

58. Strontium 89 and Phosphorous 32:
• Low-energy β emitters
• T1/2 14.3 days for P-32, 50 days for Sr 89
• Penetration up to 2.4 mm in bone.
• Generally superseded by Ra 223 and Sm 153.