This document discusses optimal sequencing in metastatic castration-resistant prostate cancer (mCRPC). It presents several case studies and discusses the role of radiation, surgery, nuclear medicine, and systemic therapies. It then addresses questions about standard of care options for mCRPC, including chemotherapy, chemotherapy plus androgen deprivation therapy, chemotherapy plus antiandrogen therapy, and PARP inhibitors. Clinical trials evaluating treatments like cabazitaxel, abiraterone, and enzalutamide in mCRPC are also summarized.

1. DR. RAJKUMAR , R. D.M
CONSULTANT MEDICAL ONCOLOGIST
VELAMMAL MEDICAL COLLEGE HOSPITAL
MADURAI
OPTIMAL SEQUENCING IN mCRPC

2. CASE PRESENTATIONS
75y M 09/2017
GRADE IV GROSS PROSTATOMEGALY
IPP: 1.6 CM
BOO

3. CASE PRESENTATIONS

4. CASE PRESENTATIONS

5. CASE PRESENTATIONS

6. CASE PRESENTATIONS
MULTIDISCIPLINARY TUMOR BOARD
1. ROLE OF RADIATION
2. ROLE OF SURGERY
3. ROLE OF NUCLEAR MEDICINE
4. ROLE OF SYSTEMIC THERAPY

7. Newly Diagnosed Metastatic Prostate Cancer
Which systemic therapy for which patient?
7

8. QUESTIONS?
mHSPC- WHAT IS THE STANDARD OF CARE ?
1. CHEMO
2. ADT
3. CHEMO+ ADT
4. CHEMO+ CYP17A1 INHIBITORS
4. AR INHIBITORS
5. CHEMO+TAB

9. Dynamic Progression Model: Patient Flow Between Distinct Clinical States
9
PLoS One. 2015;10(10): e0139440

10. Metastatic Hormone Sensitive Prostate Cancer: mHSPC
10
 Androgen Deprivation Therapy (ADT) has been mainstay of treatment
for advanced prostate cancer for > 60 years
 We know that essentially all men will have rising PSA &/or develop new
metastases despite castrate levels of testosterone i.e. castration-
resistant prostate cancer (CRPC)
 Does more potent upfront treatment of mHSPC improve outcomes?
o Non-AR mechanisms (docetaxel)
o AR driven (abiraterone, enzalutamide)

11. Spectrum of Patients
11
Spectrum of patients starting testosterone suppression for “metastatic”
disease
 Some present de novo vs some present after prior prostatectomy or
radiation
 Some are fit & young, some are frail & elderly
o & every iteration in between
 Some have minimal disease on conventional scans and some
widespread disease
 Some prior adjuvant testosterone suppression with radiation,
prostatectomy
o (+/- abiraterone; +/- docetaxel)

12. How to Decide on Treatment?
12
Treatment Considerations of mHSPC
De novo vs recurrent disease at presentation
Volume of disease
Co-morbidities
Side effect profiles
Patient preference
Cost
Availability of drug

13. Which Systemic Therapy for which Patient: Patient Profiles?
13
Docetaxel Abiraterone Enzalutamide
 Chemo-fit , High volume
disease
 Not chemo-fit, high volume
 Not chemo-fit/ chemo-fit with
low volume denovo-METs
 Not chemo-fit/ chemo-fit with
low volume prior therapy
 Not chemo-fit, high volume
 Not chemo-fit/ chemo-fit with
low volume denovo METs
 Not chemo-fit/ chemo-fit
with low volume prior therapy
 Denovo METs  Skeletal METs  Visceral METs (pre docetaxel )
 Difficulty in swallowing
medicines
 Poor diabetic control
 Other contraindication with
prednisone
 Heart failure or hypervolemia
 Mild base line pain
 Steroids may help
 Significant baseline fatigue
 Falls, gaits or neurological
disorder
 Pre existing neuropathy
 Fragile diabetes
 Baseline edema
 Hypokalemia
 Pre existing neuropathy
 Remote living

14. How we decide risk category of patient?
14
 ADT + docetaxel
 ADT + enzalutamide
 ADT + abiraterone
What would be
your treatment plan?
Definition
CHAARTED
(Volume)
High
Visceral metastases AND/OR
≥4 Bone metastases (≥1 outside vertebral column or pelvis)
LATITUDE
(Risk)
High
≥2 high risk features
 ≥3 bone metastases
 Visceral metastases
 ≥Gleason 8

15. Clinical evidences to direct treatment selection?
15
There are numerous Phase III studies supporting various therapeutic
combinations in metastatic hormone-sensitive prostate cancer:
TRIALS TREATMENT ARMS
CHAARTRED, STAMPEDE-C ADT VS ADT + DOCETAXEL
STAMPEDE-G , LATITUDE ADT VS ADT + ABIRATERONE
ARCHES, ENZAMET
ADT + DOCE VS ADT + (DOCE 17.9, 65%) +
ENZALUTAMIDE
TITAN
ADT (+ DOCE 10%) VS ADT (+ DOCE 10%) +
APALUTAMIDE

16. What are learnings from long term follow-up of CHAARTED?
16
Test for Heterogeneity
With long term
follow-up low
volume & high
volume had
differential effect
with early docetaxel

17. CHAARTED FACT-P: Quality of Life
17
Low-volume High-volume
 ADT alone in low volume had no change in QOL over 12 months in low volume but
decline in high volume (progression of disease – symptoms and progression)
 ADT plus docetaxel) decline in QOL in low vol on chemo But no decline and better 12
month QOL in high volume

18. 18

19. Current Outcome with Docetaxel by Volume of Disease
 Direct overall survival benefit for high volume patients in 2 studies
documented improvement in QOL
 Two studies provide DIRECT evidence of no clear OS benefit in low
volume disease
 Await retrospective volume analysis of STAMPEDE-docetaxel arm
o Will this translate into routine care (benefit less, toxicity including
treatment related deaths worse than in trials)
 Volume is prognostic for outcome on ADT & predictive for docetaxel
benefit
o Does this mean there are different biological diseases in “mHSPC"?
19

20. STAMPEDE-docetaxel: Test for heterogeneity – M0 vs M1
20
 M0 combines
o High risk localized treated with ADT +
XRT
o Rising PSA post local therapy
 M1 combines
o Low & High Volume
 LV benefit based on inference because
no difference on test of heterogeneity
between M0 & M1

21. Current mHSPC OS with Abiraterone by Volume of Disease
21

22. STAMPEDE-Abiraterone: Outcome by Volume of Disease
22

23. Current Outcome with Abiraterone by Volume of Disease
 3 year absolute OS point estimates to help patient counselling
o Relative risks are less ”intuitive” for patients
o High volume: ~ 20% absolute benefit.
o Very similar to docetaxel
o Low volume ~ 5% absolute OS.
 Need longer term OS data to see if OS benefit is greater with early
use abiraterone
o Or are the indolent patients able to be salvaged with addition of
abiraterone at CRPC?
 LATITUDE are all de novo & < 5% STAMPEDE relapsed after prior local
therapy
23

24. Current mHSPC OS with “Amides” by Volume of Disease
24
ENZAMET Primary Endpoint: Overall Survival
A Mixed Bag
 High & Low Volume
 De novo vs Metach
Mets
 Concurrent Docetaxel
 Many Permutations

25. Trial[1] Comparator Arm Control Arm N
HR for PFS (or Other
Endpoint)
HR for OS
Docetaxel
 CHAARTED[2] ADT + Doc ADT 513 0.58 (time to CRPC) 0.63
 GETUG-15[3] ADT + Doc ADT 183 NA 0.78
 STAMPEDE Arm C[4] ADT + Doc ADT 148 NA 0.81
AR Pathway Inhibitors
 LATITUDE[5] ADT + ABI + Pred ADT 955 NA 0.62
 STAMPEDE Arm G[6] ADT + ABI + Pred ADT 473 0.31 (FFS) 0.54
 ENZAMET[7] ADT + ENZA (± Doc) ADT + NSAA (± Doc) 588 0.45 0.80
 ARCHES[8] ADT + ENZA* ADT* 727 0.43 (rPFS) TBD
 TITAN[9] ADT + APA* ADT* 660 0.53 0.68
RT
 STAMPEDE Arm H[10] ADT + RT to prostate ADT (+ DOC possible) 1120 NA 1.07
 HORRAD[11] ADT + RT to prostate ADT 272 NA 1.06
Reported RCTs in mHSPC: High-Volume/High-Risk Disease
*Prior DOC allowed.

26. Local Treatment in Metastatic Prostate Cancer
 HORRAD (N = 425)[1]
‒ ADT vs ADT + EBRT, ≥ M1a disease on conventional imaging
‒ At a median FU of 47 months no significant difference in median OS (43 vs 45 months)
 STAMPEDE arm H (N = 2061)[2]
‒ ADT vs ADT + EBRT, ≥ M1a disease on conventional imaging
‒ For low volume disease OS HR = 0.68 (P = .007) vs 1.07 (P = .420) for high volume
disease
‒ At median FU of 37 months no OS improvement from local RT
 Trials in progress: SWOG 1802 (NCT03678025), PEACE-1 (NCT01957436)
1. Boevé. Eur Urol. 2019;75:410-8. 2. Parker. Lancet. 2018;392:2353.

27. NCT01957436.
PEACE1: ADT vs ADT + Abiraterone, Local RT, or Both in
Newly Diagnosed Metastatic Prostate Cancer
 Prospective, randomized
phase III multicenter trial
 Primary endpoints:
OS and PFS (HR: 0.75)
 Secondary endpoints: PSA
RR, safety, radiologic PFS
Patients with newly
diagnosed metastatic,
hormone-naive prostate
cancer; ECOG PS 0/1
(N = 1173)
ADT*
ADT* + Abiraterone 1000 mg/day PO +
Prednisone 5 mg BID
ADT* + Local RT (74 Gy in 37 fractions)
ADT* + Local RT (74 Gy in 37 fractions) +
Abiraterone 1000 mg/day PO +
Prednisone 5 mg BID
Upon
reaching
CRPC,
treatment
can include
abiraterone
if previously
received in
this trial
*Either LHRH agonist, LHRH antagonist, or surgical castration,
plus docetaxel 75 mg/m2/cycle x six 3-wk cycles

28. CASE PRESENTATIONS

29. CASE PRESENTATIONS

30. Hormone-Sensitive Metastatic Prostate Cancer: Big
Picture Issues
 mHSPC is a heterogeneous disease state
‒ de novo vs recurrent metastatic disease
 Compelling evidence that ADT + “X” is the standard of care (polymetastatic disease)
‒ Rare case indeed for ADT only therapy in 2020 and beyond but …
‒ A recent study found that 43% of patients with mHSPC receive ADT alone[1]
 Role of local therapy in metastatic disease
 Decision re: what is the optimal “X” therapy is not based on comparative trial
evidence, but requires consideration of multiple disease and non-disease factors
 Germline testing is now standard of care for all metastatic patients
1. Ke. ASCO 2020. Abstr. e19131.

31. CASE PRESENTATIONS

32. CASE PRESENTATIONS

33. CASE PRESENTATIONS
mCRPC- what is the standard of care ?
1. CHEMO
2. CHEMO+ ADT
3. CHEMO+AR
4. PARPi

34. CASE PRESENTATIONS

35. 21
Chemotherapy for mCRPC: OS With Docetaxel
SWOG 99-16 TAX-327
1. Petrylak. NEJM. 2004;351:1513. 2. Tannock. NEJM. 2004;351:1502.
HR: 0.83; P = .04
Mos
OS
(%)
100
80
60
40
20
0
48
0 12 24 36
P = .02
Docetaxel + estramustine
(217 deaths; median OS: 17.5 mos)
Mitoxantrone + prednisone
(235 deaths; median OS: 15.6 mos)
Mos
OS
(%)
100
80
60
40
20
0
33
0 24
Weekly
docetaxel
Docetaxel
every 3 wks
Mitoxantrone
3 6 9 12 15 18 27 30

36. THERAPEUTIC OPTIONS IN M1 CRPC

38. CASE PRESENTATIONS

39. CARD Trial: Phase IV Trial of Cabazitaxel vs Abiraterone
or Enzalutamide in Previously Treated mCRPC
 Primary endpoint: imaging-based PFS
 Secondary endpoint: OS, PFS, PSA response, tumor response, time to SSE,
pain response, and safety
Patients with mCRPC
previously treated with
≥ 3 cycles of docetaxel and
disease progression after
≤ 12 mos on abiraterone or
enzalutamide (before or
after docetaxel)
(N = 255)
Until PD
Cabazitaxel 25 mg/m2 Q3W
+ Prednisone + G-CSF
(n = 129)
Enzalutamide 160 mg QD or
Abiraterone 1000 mg QD + Prednisone 5 mg BID
(n = 126)
Stratified by ECOG PS (0/1 vs 2), time to progression of prior
alternative ARTA (≤ 6 mos vs > 6-12 mos), timing of prior
AR-targeted therapy (before vs after docetaxel)
de Wit. NEJM. 2019;381:2506.

40. 50
Patients at Risk, n
Cabazitaxel
AR inhibitor
CARD: OS
de Wit. NEJM. 2019;381:2506.
Cabazitaxel
(n = 129)
AR Inhibitor
(n = 126)
Median OS, mos (95% CI) 13.6 (11.5-17.5) 11.0 (9.2-12.9)
HR 0.64 (95% CI: 0.46-0.89; P = .008)
Months
Cabazitaxel
AR Inhibitor
OS
(%)
Mos
100
90
80
70
60
40
30
20
10
0
30
0 3 6 9 12 18 24
129
126
122
116
96
88
77
64
51
39
21
11
8
3
2
0

41.  23% of metastatic castration-resistant prostate
cancers have DNA repair alterations[1]
 Frequency of DNA repair alterations increases
with disease progression
DNA Repair Gene Alterations Are Common in Metastatic
Prostate Cancer
 11.8% of 692 men with metastatic
prostate cancer had germline DNA repair
defects[2]
 Not all men with germline mutations had
a family history of cancer
1. Robinson. Cell. 2015;161:1215. 2. Pritchard. NEJM. 2016;375:443.
Distribution of Presumed Pathogenic
Germline Mutations[2]
PALB2, 4%
RAD51D, 4%
ATR, 2%
NBN, 2%
PMS2, 2%
GEN1, 2%
MSH2, 1%
MSH6, 1%
RAD51C, 1%
MRE11A, 1%
BRIP1, 1%
FAM175A, 1%
BRCA2, 44%
ATM, 13%
CHEK2,
12%
BRCA1, 7%

42. Phase III PROfound: Olaparib vs Physician’s Choice in
Progressing mCRPC
*Enzalutamide 160 mg QD or abiraterone acetate 1000 mg QD plus prednisone 5 mg BID.
†BRCA1/2, ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RA51D, or RAD54L.
 Primary endpoint: radiographic PFS in cohort A by BICR using RECIST 1.1 and PCWG3
 Secondary endpoints: radiographic PFS in both cohorts, confirmed radiographic ORR in cohort A,
time to pain progression in cohort A, OS in cohort A
de Bono. NEJM. 2020;382:2091.
Patients with mCRPC
and progression on
prior NHA; harboring
gene alterations with
a role in HRR†
(N = 387)
Olaparib 300 mg BID
(n = 162)
Physician’s Choice*
(n = 83)
2:1
Olaparib 300 mg BID
(n = 94)
Physician’s Choice*
(n = 48)
Cohort A: BRCA1,
BRCA2, or ATM
alterations
(n = 245)
Cohort B: Other
alterations
(n = 142)
2:1
Stratified by previous taxane (yes vs no) and
measurable disease (yes vs no)
PD
by BICR
PD
by BICR
Crossover allowed upon
progression on physician’s
choice therapy

43. PROfound: Final OS in Cohort A
Hussain. NEJM. 2020;[Epub].
Patients at Risk, n
Olaparib
Control
Mos
OS
(%)
Olaparib
(n = 162)
Control
(n = 83)
Median OS, mos 19.1 14.7
HR 0.69 (95% CI: 0.50-0.97; P = .02)
Cohort A: BRCA1, BRCA2, or ATM mutations
162
83
155
79
150
74
142
69
136
64
124
58
107
50
101
43
91
37
71
27
56
18
44
15
30
11
18
9
6
6
2
3
1
1
0
0
34
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32
100
90
80
70
60
50
40
30
20
10
0
91%
84%
73%
61%
54%
42%
Olaparib
Control

44. TRITON2: Rucaparib in Metastatic CRPC With HRR Gene
Alterations
 International, multicenter, open-label phase II study
Abida. ESMO 2018. Abstr 793PD. Abida. JCO. 2020;[Epub].
Patients with mCRPC and deleterious
somatic or germline alteration in HRR
genes*; progression on AR-directed tx†
for PC and 1 prior line of taxane-based
CT for CRPC; no prior PARPi,
mitoxantrone, cyclophosphamide, or
platinum-based CT; ECOG PS 0/1
(N = 190‡)
Until radiographic
progression or
discontinuation for
other reason
Rucaparib 600 mg BID
in 28-d cycles§
 Primary endpoints
‒ Among patients with measurable disease at BL: centrally assessed, confirmed ORR per modified
RECISTǁ/PCWG3
‒ Among patients without measurable disease at BL: locally assessed, confirmed PSA response
(≥ 50% decrease) rate
*Local or central testing of blood or tumor samples for alterations in HRR genes: BRCA1, BRCA2,
ATM, BARD1, BRIP1, CDK12, CHEK2, FANCA, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D,
RAD54L.†Abiraterone, enzalutamide, or apalutamide. ‡Enrollment cutoff: February 28, 2019.
§Assessments: tumor Q8W for 24 wks, then Q12W; PSA Q4W.

45. PROpel Trial: First-line Olaparib + Abiraterone
 Primary endpoints: radiographic PFS (rPFS) by investigator
 Key secondary endpoints: OS, time to subsequent therapy or death; time to pain
progression
 Randomized, double-blind, international, phase III study
Patients with progressing mCRPC;
no prior therapy for mCRPC;
docetaxel for mHSPC allowed;
ECOG PS 0/1; no prior
abiraterone
(planned N = 720)
Until radiographic progression or
unacceptable toxicity
Crossover from placebo to
olaparib not permitted
Olaparib 300 mg BID +
Abiraterone* 1000 mg qd
(n = 360)
Placebo +
Abiraterone* 1000 mg qd
(n = 360)
Stratified by metastatic disease (bone only vs
visceral vs other); docetaxel for mHSPC (yes vs
no)
* Prednisone/prednisolone (5 mg) given with abiraterone.
NCT03732820.

46. New Therapies in the Pipeline

47.  Theranostics: use of a compound for both diagnostics and therapeutics
Therapy:
Lu-177
Y-90
PSMA-I&T
Imaging:
Ga-68
Theranostics and PSMA Targeting
Schottelius. EJNMMI Res. 2015;5:68.

48. Theranostics - LuPSMA
ESMO 2016

49.  Primary endpoint: OS
 Secondary endpoints: rPFS, RECIST response, time to first symptomatic skeletal event
 Median follow-up: 12-14 mo (minimum: 15 mo)
 Phase I/II PRINCE trial planned: Lu-PSMA + immunotherapy in mCRPC (NCT03658447)
VISION: Lu-PSMA vs Best Supportive Care in
Progressive, Metastatic CRPC
 Randomized, ongoing phase III study at 9 sites in North America and Europe
ClinicalTrials.gov. NCT03511664.
Patients with
progressive CRPC; PSMA
positive; previous
treatment with taxane
and novel androgen
axis-targeted therapy
(N = > 750 recruited)
177Lu-PSMA-617
7.4 GBq IV Q6w
x 6 cycles + BSC/BSOC
Best Supportive Care /
Best Standard of Care
2:1
BSC/
BSOC

50. GSK2636771, a PI3Kβ inhibitor, in Pts with PTEN-
Deficient Tumors
Arkenau HT, et al. ASCO 2014. Abstract
2514.

51. 2. CASE PRESENTATIONS
• 75 Y /M 11/2016
• GRADE III PROSTATOMEGALY
• 2017- PSA – 22.2

52. 2. CASE PRESENTATIONS

53. 2. CASE PRESENTATIONS

54. 2. CASE PRESENTATIONS

55. 2. CASE PRESENTATIONS

56. 2. CASE PRESENTATIONS

57. QUESTIONS?

58. Thank you