Given this patient's advanced age and comorbidities, I would recommend abiraterone acetate as the second line treatment option post enzalutamide progression. Abiraterone has shown survival benefit with good tolerability in older patients with comorbidities in the COU-AA-301 trial. Cabazitaxel could be considered but may have higher toxicity risks in this patient. Close monitoring would be needed.

1. Confidential and proprietary
Any use of this material without specific permission of Global Health Pvt. Ltd. is strictly prohibited
Advances in Management of
Metastatic Castration Resistant
Prostate Cancer
Dr Alok Gupta
MD, DM,
Associate Director & Head
Medical and Hemato Oncology
Medanta Lucknow
Ex-Asst. Professor, AIIMS, New Delhi

2. Therapies With Survival Benefit for mCRPC
Agent Indication
Route
Schedule
Cortico-
steroids
Symptoms
Contra-
indications
PSA
Response
Median OS
Benefit,
Mos
Sipuleucel-T
pre/post
docetaxel
IV every 2
wk x 3
no
asymptomatic,
minimally sx
narcotics for
pain, liver
mets
no 4.1
Abiraterone pre/post
docetaxel
oral, empty
stomach
yes* not specified
severe liver
dysfx, low K,
heart failure
yes
Post-doc:
4.6
Pre-doc: 4.4
Enzalutamide pre/post
docetaxel
oral no not specified seizures yes
Post-doc:
4.8
Pre-doc: 4.0
Docetaxel mCRPC
IV every 3
wk
yes* not specified
moderate
liver dysfx,
cytopenias
yes 2.4
Cabazitaxel
post
docetaxel
IV every 3
wk
yes* not specified
moderate
liver dysfx,
cytopenias
yes 2.4
Radium-223
post
docetaxel
or not fit
for doc
IV, every 4
wks for 6
doses
not
required
symptomatic
bone
metastases
visceral
mets
NR 3.6
* In clinical trials and on FDA label.

3. Available Treatment Options for mCRPC
FDA Approved
 Docetaxel
 Cabazitaxel
 Abiraterone
 Enzalutamide
 Sipuleucel T
 Radium223
 Pembrolizumab(MSIhigh)
Non FDA approved
 Lu177 PSMA therapy
 Olaparib
 Platinum chemotherapy
 Fosfesterol

4. Survival in Metastatic Prostate Cancer in
2014

5. Outline
1. Selecting First Line Treatment for mCRPC
2. Selecting Second Line Treatment for mCRPC
3. Sequencing of various agents
4. Emerging role of Targeted Therapy

6. Selecting First Line Treatment for mCRPC
ADT alone in mHSPC ADT + Docetaxel or
ADT + Abiraterone in
mHSPC
 Docetaxel
 Abiraterone
 Enzalutamide
 Docetaxel
 Abiraterone
 Enzalutamide
 Cabazitaxel
No
Phase III
data

7. Case1 : Mr BK 62 yrs old male, non-diabetic, hypertensive
mHSPC
• Diagnosed Carcinoma Prostate in Mar 2018
• Gleason Score- 9, PSA-545
• Extensive Bone & nodal mets
Treatment
• Started on ADT alone (April 2018)
• Nadir PSA- 1.94 ng/ml (July 2018)
Selecting First Line Treatment for mCRPC
(ADT alone in mHSPC)
Became symptomatic for bone pain and Progressed to mCRPC
in Nov 2018, PSA - 93.927 ng/ml

8. Selecting First Line Treatment for mCRPC
(ADT alone in mHSPC)
 Docetaxel vs Abiraterone vs Enzalutamide?

9. Docetaxel: TAX327 and SWOG 9916

10. Median
survival Hazard
(mos) ratio P-value
Combined: 18.2 0.83 0.03
D 3 wkly: 18.9 0.76 0.009
D wkly: 17.3 0.91 0.3
Mitoxantrone 16.4 – –
Months
ProbabilityofSurviving
0 6 12 18 24 30
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Docetaxel 3 wkly
Docetaxel wkly
Mitoxantrone
Eisenberger M, et al. ASCO Annual Meeting Proceedings. June 2004. Abstract 4.
Docetaxel – CRPC
Overall Survival—TAX 327

11.  Case 2 - Mr SC, 88 year, diagnosed mCa prostate in July 2017.
 Base line PSA 2794. Gleason 4+4= 8
 Node + Bone mets on PSMA PET CT scan.
 Started on Firmagon in July 2017. Nadir PSA = 33.18 in May 2018.
 CRPC - PSA rising since then - 82.27 (14.08.18), 133 (12.9.18)
 PSMA PET CT scan (20.9.18): Increase in extent of prostate lesion,
left external iliac node, skeletal lesions.
 PS- 2 for age with T2DM, HTN and CAD (Post CABG), EF 40%,
NYHA grade 2
Selecting First Line Treatment for mCRPC
(ADT alone in mHSPC)

12.  Docetaxel vs Abiraterone vs Enzalutamide?
Selecting First Line Treatment for mCRPC
(ADT alone in mHSPC)

13. PREVAIL Phase III Trial: Enzalutamide
After Progression in mCRPC
Beer T, et al. ASCO GU 2014. Abstract 1. ClinicalTrials.gov. NCT01212991.
Patients with
progressive mCRPC,
asymptomatic/mildly
symptomatic,
chemotherapy naive,
steroids allowed
(N = 1717)
Enzalutamide
160 mg/day
(n = 872)
Placebo
(n = 845)
 Primary endpoints: OS, radiographic PFS

14. PREVAIL Study of Enzalutamide in
mCRPC: OS and Radiographic PFS
Beer T, et al. ASCO GU 2014. Abstract 1.
Median Radiographic PFS,
Mos (95% CI)
Median OS,
Mos (95% CI)
Enzalutamide Placebo Enzalutamide Placebo
NR
(13.8-NR)
3.9
(3.7-5.4)
32.4
(30.1-NR)
30.2
(28.0-NR)
HR: 0.706 (0.60-0.84; P < .0001) HR: 0.186 (0.15-0.23; P < .0001)
 Risk of death reduced 29% with enzalutamide
 Consistent survival benefit across subgroups
 Trial halted and unblinded after data and safety monitoring committee
reported statistically significant benefits in OS and radiographic PFS
with enzalutamide

15. Overall Study Design of COU-AA-302
• Phase 3 multicenter, randomized, double-blind, placebo-controlled study conducted
at 151 sites in 12 countries; USA, Europe, Australia, Canada
• Stratification by ECOG performance status 0 vs 1
AA 1000 mg daily
Prednisone 5 mg BID
(Actual n = 546)
Co-Primary:
• rPFS by central review
• OS
Secondary:
• Time to opiate use
(cancer-related pain)
• Time to initiation of
chemotherapy
• Time to ECOG-PS
deterioration
• TTPP
Efficacy end points
Placebo daily
Prednisone 5 mg BID
(Actual n = 542)
R
A
N
D
O
M
I
Z
E
D
1:1
• Progressive chemo-
naïve mCRPC
patients
(Planned N = 1088)
• Asymptomatic or
mildly symptomatic
Patients
Ryan et al. ASCO 2012

16. Strong Trend in OS Primary End Point
546
542
538
534
482
465
452
437
27
25
0
0
524
509
503
493
0
2
120
106
258
237
412
387
100
80
60
40
20
0
0
Survival(%)
3 12 15 27
Time to Death (Months)
33
AA + P
PL + P
6 9 30242118
AA
PL
AA + P (median, mos): NR
PL + P (median, mos): 27.2
HR (95% CI): 0.75 (0.61-0.93)
P value: 0.0097
Updated GU ASCO 2013: Rathkopf et al. Abstract # 5
-r PFS 16.5 vs. 8.3 mo. HR 0.53 (0.45-0.62) p = <0.0001
- OS 35.3 vs. 30.1 mo. HR 0.79 (0.66-0.96) p= 0.0151

17. Outline
1. Selecting First Line Treatment for mCRPC
2. Selecting Second Line Treatment for mCRPC
3. Sequencing of various agents

18. Case 1
CRPC
• 1st line treatment – Docetaxel (Nov 2018), received 4
cycles
• Bone Pain persisted.
• PSMA PET Scan(Jan 2019)-Extensive Skeletal Mets
with disease progression
• PSA (Jan 2019)-466.97 ng/ml
Selecting Second Line Treatment for mCRPC
(Post Docetaxel progression)

19. Selecting Second Line Treatment for mCRPC
(Post Docetaxel progression)
 Cabazitaxel vs Abiraterone vs Enzalutamide?

20. TROPIC – Cabazitaxel vs Mitoxantrone
• CRPC
• PD during or
after
docetaxel
RANDOMIZE
Cabazitaxel 25 mg/m2 Q 21 d
Prednisone 10 mg daily
N=755
Mitoxantrone
Prednisone 10 mg daily
146 Sites /
26 Countries
Abbreviation: PD=progressive disease.
Source: deBono et al. Lancet. 2010;376:1147-1154.

21. TROPIC Primary Endpoint – OS
(ITT Analysis)
MP 377 300 188 67 11 1
CBZP 378 321 231 90 28 4
Number
at Risk
80
60
40
20
0
100
0 months 6 months 12 months 18 months 24 months 30 months
15.112.7Median OS (months)
0.59–0.8395% CI
<.0001P Value
0.70Hazard Ratio
CBZPMP
Abbreviation: ITT=intent-to-treat.
Source: deBono et al. Lancet. 2010;376:1147-1154.
ProportionofOS(%)

22. COU-AA-301: Phase III Study of
Abiraterone Acetate in mCRPC
 Primary endpoint: OS
 Abiraterone acetate: selective inhibitor of androgen
biosynthesis that blocks CYP17 activity
Patients with mCRPC
progressing after 1-2
chemotherapy regimens,
1 of which contained
docetaxel
(N = 1195)
Abiraterone acetate 1000 mg/day +
Prednisone 5 mg BID
(n = 797)
Placebo +
Prednisone 5 mg BID
(n = 398)
Stratified by ECOG PS, worst pain over previous
24 hrs, previous chemotherapy, type of progression
Scher HI, et al. ASCO GU 2011. Abstract 4.
Randomized 2:1
Study stopped at planned interim analysis at 534 events because
OS improvement crossed predetermined stopping boundary

23. COU-AA-301: Overall Survival
 Abiraterone acetate significantly improved OS vs placebo
– Survival benefit consistent across nearly all patient subgroups
Group n HR (95% CI)
Baseline ECOG 0-1 1068 0.64 (0.53-0.78)
BPI
 < 4 659 0.64 (0.50-0.82)
 ≥ 4 536 0.68 (0.53-0.85)
Prior chemotherapy
 1 regimen 833 0.63 (0.51-0.78)
 2 regimens 362 0.74 (0.55-0.99)
Progression type
 PSA only 363 0.59 (0.42-0.82)
 Radiographic 832 0.69 (0.56-0.84)
Visceral disease 363 0.70 (0.52-0.94)
Scher HI, et al. ASCO GU 2011. Abstract 4.
AA Placebo
HR: 0.646 (95% CI: 0.54-0.77; P < .0001)
Survival(%)
100
80
60
40
20
0
0 3 6 9 12 15 18 21
Mos to Death
Placebo:
10.9 mos (95% CI: 10.2-12.0)
Abiraterone acetate:
14.8 mos (95% CI: 14.1-15.4)
AA
Placebo
797
398
736
355
657
306
520
210
282
105
68
30
2
3
0
0

24. Scher HI, et al. ASCO GU 2012. Abstract LBA1.
Patients with progressive
CRPC who failed docetaxel
chemotherapy
(N = 1199)
 Primary endpoint: OS
 Secondary endpoints:
– Response: PSA response, STOR, QoL, pain palliation, CTC
– Progression: radiographic PFS, time to PSA progression, time to first SRE
Randomized 2:1
Stratified by ECOG PS and Mean Brief
Pain Inventory question 3 score
MDV3100 160 mg/day
(n = 800)
Placebo
(n = 399)
Study stopped at planned interim analysis at
520 events with observation of statistically
significant, clinically meaningful OS benefit
AFFIRM: Phase III Trial of MDV3100 in
Post-Docetaxel CRPC

25. Scher HI, et al. ASCO GU 2012. Abstract LBA1.
 OS improved with MDV3100 vs placebo
 Median follow-up: 14.4 mos
AFFIRM Trial of MDV3100 in Post-
Docetaxel CRPC: OS
HR: 0.631 (95% CI: 0.529-0.752; P < .0001)
37% reduction in risk of death
Placebo: 13.6 mos
(95% CI: 11.3-15.8)
MDV3100: 18.4 mos
(95% CI: 17.3-NR)
Duration of OS (Mos)
0 3 6 9 12 15 18 21 24
Survival(%)
0
10
20
30
40
50
60
70
80
90
100
MOV3100
Placebo
800
399
775
376
701
317
627
263
400
167
211
81
72
33
7
3
0
0

26.  Case 2 - Mr SC, 88 year, diagnosed mCa prostate in July 2017.
 Base line PSA 2794. Gleason 4+4= 8
 Node + Bone mets on PSMA PET CT scan.
 Started on Firmagon in July 2017. Nadir PSA = 33.18 in May 2018.
 CRPC - PSA rising since then - 82.27 (14.08.18), 133 (12.9.18)
 PSMA PET CT scan (20.9.18): Increase in extent of prostate lesion, left external iliac
node, few skeletal lesions.
 PS- 2 for age with T2DM, HTN and CAD (Post CABG), EF 40%, NYHA grade 2
 Received Enzalutamide. Disease progression after 6
months.
 PSMA PET on 27.3.19: Increase in Bone mets. Disease
Progression. PSA- 1763 (March 2019).
Selecting Second Line Treatment for mCRPC
(Post Abiraterone/Enzalutamide progression)

27. Selecting Second Line Treatment for mCRPC
(Post Abiraterone/Enzalutamide progression)
 Chemotherapy vs ART?

28. Outline
1. Selecting First Line Treatment for mCRPC
2. Selecting Second Line Treatment for mCRPC
3. Sequencing of various agents
Is there an optimal sequence of life-extending
therapies?

29. Patients progressing with an AR-targeted
agent poorly respond to a another one
Author Year
publishe
d
N pts Duration of
2
nd
treatment

PSA
≥ 50%
Median PFS
ENZ  A B I
Loriot et al. 2013 38 3 mo 8% 2.7 mo
Noonan et al. 2013 30 13 wks 3% 3.6 mo
ABI  ENZ
Schrader et al. 2013 35 4.9 mo 29% -
Badrising et al. 2014 61 3 mo 21% -
Bianchini et al. 2014 39 2.9 mo 23% -
Schmid et al. 2014 35 2.8 mo 10% -
Brasso et al. 2014 137 3.2 mo 18% -
Retrospective trials based on a small number of patients
Zhang T et al, Expert Opin Pharmacotherap
2014;16:1-9

30. • mPFS: 5.7 months in the combination
group vs 5.6 months in the control
group (HR: 0.83; P = 0.22).
• Secondary end points:
no difference.
• Tolerability: Grade 3 hypertension
(10% v 2%) and increased ALT (6% v
2%) or AST (2% v 0%) more frequent
in the combination than the control
group.
Attard G et al, JCO 2018; Sep 1;36(25):2639-
2646

31. VENICE1
DOC/P
bo
n=612
De
Bono2
ABI→D
OC
n=35
Schweizer3
Azad4
ABI→D
OC
n=86
DeBono5
(COU-AA-
302)
ABI→DOC
n=261
DO
C
n=
95
ABI→D
OC
n=24
DOCtherapyline 1 2 1 2 2 2
Visceralmets YES YES YES YES YES NO
 PSA≥50% 63.5%* 25.7%* 63.0%* 38.0%* 35.0%* 27%*
Median PSA-
PFS(mths)
8.1 4.6 6.7 4.1 4.0 (TTP7.6**)
OS,median(mths) 21.2 12.5 - - 11.7 NA
[2-5] = retrospective analyses; *confirmed PSA responses; **TTPP: time to PSA progression (not PSA- PFS) was obtained in only
100 patients
1. Tannock et al, Lancet Oncol 2013; 14:760-8; 2. Mezynski H et al, Ann Oncol 2012. 23:
2943–2947;
3. Schweizer MT et al, Eur Urol 2014; 66:646-52; 4. Azad et al, The Prostate 2014; 74:1544-1550; 5. De Bono et al. Eur Urol 2016 (epub
ahead of print)
Impaired activity of docetaxel Post ABI?

32. ABI or ENZA Prior to CABA – No impact?
Author
Year
Publish
ed
N pts
Viscer
al
Mets,
%
 PSA
≥50%
Medi
an
PF
S
No prior ABI or ENZA
De Bono1
2010 378 25% 39.2% 2.8 mo
ABI or ENZA  CABA
Pezaro2
2012 37 35% 41% 5.5 mo
Al Nakouzi3
2014 79 14% 35% 4.4 mo
Sella4
2014 24 29% 31.5% -
Wissing5
2014
Prior ABI, 69
No ABI, 63
-
-
31.9%
49.2%
6.5 mo
8.1 mo
1is a prospective randomized study of CABA/P vs Mito/P in mCRPC (post-DOC); [2 and 5] trials are retrospective
studies in mCRPC pts (post-DOC)
ABI: abiraterone acetate; ENZA: enzalutamide; CABA: cabazitaxel;P: prednisone; Mito: mitoxantrone
1. De Bono JS et al, Lancet. 2010;376:1147-54; 2. Pezaro CJ et al.,Eur Urol.2014;66:459-65; 3. Al Nakouzi N et al.,Eur Urol.
2015;68: 228-35; 4. Sella A et al.,Clin GU Cancer. 2014;12:428-32; 5. Wissing MD et al, Int J Cancer. 2015;136:E760-72.

33. Systematic review of 13 published
retrospective studies in mCRPC
(n=1016)
ART: Androgen receptor targeted agents; CABA:
cabazitaxel
A R T  A R T (n=469)
C A B A  A R T (n=229)
A R T  C A B A (n=318)
Survival%
20
10
0
30
50
40
60
70
80
100
90
0 1 2 3 4 5 6
Months
7 8 9 10 11 12
12-month OS rate by sequence in post-Docetaxel
Poor outcome when ART are prescribed in sequence
Mayne F et al, Crit Rev Hematol Oncol 2015; 96: 498-
506

34. FLAC International database (HEGP)
• Records of 387 consecutive mCRPC patients treated with cabazitaxel after
docetaxel in 5 countries (France, Greece, Spain, Turkey)
DOC ART* CAB
DOC ART*CAB
*ART: Enzalutamide or
Abiraterone
DOC CAB
• Retrospective data collection:
– Disease history (duration and response to 1st ADT), treatment sequences received, clinical
characteristics at initiation of the next life-extending therapy post-docetaxel (ie cabazitaxel or ART)
– Efficacy of cabazitaxel (PSA response, radiological and/or clinical PFS)
– Overall survival
Angelergues A et al, Clin Genitourin Cancer 2018
Aug;16(4):e777-e784

35. FLAC study - OS from diagnosis of mCRPC
Angelergues A et al, Clin Genitourin Cancer 2018 Aug;16(4):e777-
e784

36. 669 mCRPC
pts treated
with DOC, CABA
and ART
• Retrospective analysis of 669 consecutive patients treated with DOC,
CABA and one ART in 34 centers in 8 countries (France, Austria, Greece,
Italy, Israel, Denmark,Spain, UK)
CATS International Database
DOC  CABA  A R T (N=158)
DOC  ART  CABA (N=456)
ART  DOC  CABA (N=55)
Delanoy N et al. Eur Urol Oncol 2018 (In
press)
Doc: docetaxel; CABA: Cabazitaxel; ART: Androgen Receptor–Targeted agent

37. Overall Survival by treatment sequence in
the CATS study
Delanoy N et al, Eur Urol Oncol 2018 (epub ahead of
print)
mOS was longer in DOC
starting sequence compared
to ART (p= 0.007).
CABA seemed to retain its
activity regardless of
treatment sequence.

38. Emerging Role of Targeted Therapy
 DNA Damage Response Pathways
 Genomic alterations in mCRPC
 Therapeutic implications of Genomic alterations in
mCRPC
 HRD - PARP inhibitors and synthetic lethality
 MMR defects and immune checkpoint inhibitors

39. DNA repair gene mutations
• Evolution of next-generation sequencing has allowed germline DNA
repair gene mutations to be linked to PCa
Single strand DNA
repair pathways
Double strand DNA repair
pathways
Mismatch repair (MMR) Homologous recombination (HR)
Base excision repair Non-homologous end joining (NHEJ)
Nucleotide excision repair
DNA damage response (DDR)

40. Germline DNA repair gene mutations & Prostate
Cancer
Higher risk of developing PCa
Mutated gene Increased risk of PCa Reference
BRCA2 Up to 8.6 fold Br J Cancer. 2011;105(8):1230-4
BRCA1 3.75 fold Br J Cancer. 2012;106(10):1697
ATM 2.2 fold Nat Genet. 2015;47(8):906
CHEK2 1.6 fold J Clin Oncol. 2016;34(11):1208
NBN 3.9 fold Cancer Res. 2004;64(4):1215
PALB2 ???
0.4% of metastatic PCa
N Engl J Med. 2016;375(5):443-53
MMR/Lynch 4.9 fold Genet Med. 2014;16(7):553

41. More aggressive PCa (vs. non-carriers)
• BRCA2
• Younger onset, higher T stage, higher Gleason, more LN
involvement, shorter PCa-specific survival and OS1,2
• BRCA2 or BRCA1 or ATM :
• 4-fold higher risk lethal PCa, shorter OS3
• BRCA1 :
• Higher recurrence rates, shorter PCa-specific survival4
1J Natl Cancer Inst.
2007;99(12):929
2J Clin Oncol. 2013;31(14):1748
3Eur Urol. 2017;71(5):740
4Clin Cancer Res.
2010;16(7):2115
Germline DNA repair gene mutations & Prostate
Cancer

42.  11.8% (82/692) of men with
metastatic prostate cancer
inherited a germline DNA repair
mutation vs 4.6% of
499 men with localized disease
Germline Mutations in Prostate
Cancer: 1 in 10
Pritchard CC, et al. N Engl J Med. 2016;375:443-
453.
Distribution of Presumed
Pathogenic Germline
Mutations
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%
Gene No. of
Mutations
% of Men
BRCA2 37 5.35
ATM 11 1.59
CHEK2* 10 1.87
BRCA1 6 0.87
Presumed Pathogenic Germline
Mutations
in Metastatic Cases (N = 692)
*n = 534; data censored for metastatic cases with
inadequate sequencing.

43. DNA Repair Defects in Localized
Prostate Cancer
 Sequence analysis of localized, nonindolent
prostate tumors with similar risk profiles (N = 477)
– 200 whole-genome sequences, 277 whole-exome
sequences
 47/477 (9.9%) tumors had DNA repair mutations
– FANCA (n = 9)
– ATM (n = 8)
– RAD51 (n = 7)
– CDK12 (n = 6)
– BRCA2 (n = 5)
Fraser M, et al. Nature. 2017;541:359-364.

44. DNA Repair Defects in mCRPC
 34/150 (22.7%) mCRPC pts had DNA repair
alterations, many of which were biallelic
– 19/150 (12.7%) with loss of BRCA2
– ~ 90% were biallelic, with 8/150 (5.3%) resulting
from a pathogenic germline BRCA2 mutation + a
somatic event
– Recurrent biallelic loss of ATM also observed,
including some arising from pathogenic germline
alterations
– Mutation events also observed in BRCA1,
CDK12, FANCA, RAD51B, and RAD51C
Robinson D, et al. Cell. 2015;5:1215-1228.

45. Therapeutic Implications of
DNA Repair Defects in Advanced
Prostate Cancer
PARP Biology

46. Repair,
Survival
Cell Death
Cancer cell
BRCA mutation carrier
(both alleles lost)
PARP function
BRCA function
PARP inhibitor
DNA damage
PARP function
BRCA function
Synthetic Lethality Hypothesis

47. TOPARP: Trial of Olaparib in mCRPC
30 patients 20 patientsTotal: 50 patients
(49 evaluable)
Eligibility: Histologically confirmed metastatic CRPC, ECOG 0-2, no previous PARPi or platinum
Mateo J, et al. N Engl J Med. 2015;373:1697-1708.
FIRST PART:
TREATED
UNSELECTED
mCRPC pts
Randomized
study in
unselected
mCRPC pts
Biomarker
guided patient
selection in next
part (Part B)
END OF TRIAL
High response rate:
≥ 50% Responding
Intermediate RR
(10-50% responding)
Putative biomarker
identified (RR > 50%)
Low antitumor
activity RR < 10%

48. 49evaluable pts-RR 33%
16/49ptshadDNA repair
defect
-RR 88%

49. Radiologic PFS by Presence
of Genomic Defects in DNA
Repair Genes
OS by Presence of Genomic
Defects in DNA Repair Genes
ProportionofPatients
ProportionofPatients
Mateo J, et al. N Engl J Med. 2015;373:1697-1708.
0
0.25
0.50
0.75
1.00
0 1 2 3 4 5 6 7 8 91011121314151617181920
Mos Since Trial Entry
Log-rank P < .001
Biomarker positive,
median: 9.8 mos
Biomarker negative,
median: 2.7 mos
0
0.25
0.50
0.75
1.00
0 1 2 3 4 5 6 7 8 91011121314151617181920
Mos Since Trial Entry
Log-rank P = .05
Biomarker positive,
median: 13.8 mos
Biomarker negative,
median: 7.5 mos
TOPARP-A: PFS and OS by Presence of
DNA Repair Defects
 All patients (N = 50) treated with olaparib 400 mg PO BID

50. De Felice F, et al. Drug Des Devel Ther. 2017;11:547-552.
Olaparib: Ongoing Studies in Prostate Cancer
Trial
Study
Design
Eligibility Study Arms Endpoint Results
TOPARP Phase II Advanced CRPC Oral olaparib ORR 33% ORR
Kaufman, et
al
Phase II
BRCA1/2-mut adv
solid tumors (PC n =
8)
Oral olaparib ORR
PFS: 9.8 vs 2.7
mos
OS: 13.8 vs 7.5
mos
ORR in PC: 50%
NCT0197221
7
Randomize
d phase II
mCRPC
Olaparib +
abiraterone
Safety
PFS: 7.2 mo
OS: 18.4 mo
(ongoing study)
NCT0248440
4
Phase I/II
Adv/recurrent solid
tumors
Anti-PD-L1 + olaparib Safety
Recommended
dose (ongoing)
KEYNOTE
365
Phase I/II mCRPC
Anti-PD-L1 + cediranib
± olaparib
Pembro + olaparib
Safety
AEs, ORR, OS
(ongoing)
NCT0289391
7
Randomize
d Phase II
mCRPC Olaparib + cediranib PFS
PFS, RR, OS
(ongoing)
NCT0232499
8
Phase I Int/high-risk PC Olaparib ± placebo
Degree of
PARPi
AEs (ongoing)

51. MMR Mutations in mCRPC
 3/150 (2%) had MMR mutations
 4/150 (2.7%) were MSI-high
Patient Cases With DNA Repair Defects
Reprinted from Robinson D, et al. Integrative clinical genomics of advanced
prostate cancer. Cell. 2015;161(5):1215-1228. Copyright © 2015 with permission
from Elsevier Inc.

52. KEYNOTE-016: Responses to Pembrolizumab
in MMR-Deficient Tumors
 Radiographic responses across 12 tumor types at 20
wks (N = 86)
Le DT, et al. Science. 2017;357:409-413.
Ampulla of Vater
Cholangiocarcinoma
Colorectal
Endometrial cancer
Gastroesophageal
Neuroendocrine
Osteosarcoma
Pancreas
Prostate
Small Intestine
Thyroid
Unknown primary
100
50
0
-50
-100
ChangeFrom
BaselineSLD(%)
Prost
ate
Prostate
(n = 1)

53. Take Home Message
 First Question – What treatment received in mHSPC?
 ADT alone in mHSPC
 Docetaxel for symptomatic pts / visceral mets
 Abiraterone/Enza for asymptomatic/mildly symptomatic.
 Avoid Enza for patients with seizure disorder
 Avoid Abira for patients with symptomatic Heart failure or
Uncontrolled diabetes.
 ADT + Doce in mHSPC – Consider Abiraterone/ cabazitaxel rather
than rechallenge with docetaxel
 ADT + Abira in mHSPC – Consider Docetaxel or Cabazitaxel
 Avoid ARTART sequencing.
 Exposure to Docetaxel, Cabazitaxel and ART – Best outcomes
 DoceARTCaba OR DoceCabaART sequence probably
gives best survival outcomes.

54.  Genomic /Molecular understanding of CRPC in
improving every year.
 PARP Inhibitors and Immunotherapy for select
group of patients.
 Lu - PSMA therapy also catching up..
Take Home Message

55. Thank You