Metastatic Castrate-Resistant Prostate Cancer …...Reprinted from Clin Cancer Res, 2013, 19(6):1335–9, Hoffman-Censits J, Kelly WK, Enzalutamide: a novel antiandrogen for patients

METASTATIC CASTRATE-RESISTANT PROSTATE CANCER TREATMENT (MCRPC)

Fabricio Racca

GU, CNS and Sarcoma Programme, Oncology Department

Vall d’Hebron University Hospital, Barcelona, Spain

First-line treatment in mCRPC patients: Standard of Care

Androgen Biosynthesis Inhibitors (ABIs)

Second generation antiandrogens

Docetaxel

Radium 223

Novel hormonal therapies

Immunotherapy

Targeted therapies

Failed trials

Conclusions

AGENDA

Siegel RL, et al., CA Cancer J Clin 2017;67:7–30. © 2017 American Cancer Society. With permission from John Wiley and Sons.

SINCE 2010 A PLETHORA OF NEW

TRIALS HAVE SHOWN BENEFIT

IN MCRPC

Trial / agent approved Disease state Comparator Hazard ratio P value

IMPACT (Provenge vaccine) 2010

Chemo-näive CRPC Placebo 0.77 0.032

COU-AA-302 (Abiraterone acetate) 2012

Chemo-naïve CRPCPlacebo

PrednisoneUK UK

ALSYPMCA (Radium 223) 2013Pre-docetaxel

CRPCBSC 0.74 <0.00046

PREVAIL (Enzalutamide) 2014 Chemo-naïve CRPC Placebo 0.71 <0.0001

TAX327 (Docetaxel) 2004 Chemo-naïve CRPC MitoxantronePrednisone

0.76 0.009

TROPIC (Cabazitaxel) 2010 Post-docetaxel CRPCMitoxantronePrednisone

0.70 <0.0001

COU-AA-301(Abiraterone acetate) 2010

Post-docetaxelCRPC

PlaceboPrednisone

0.65 <0.0001

ALSYPMCA (Radium 223) 2013Post-docetaxel

CRPCBSC 0.71 <0.00046

AFFIRM (Enzalutamide) 2012Post-docetaxel

CRPCBSC 0.63 <0.0001

ANDROGEN BIOSYNTHESISINHIBITORS (ABIS)

ABIRATERONE ACETATE +

PREDNISONE

Cholesterol

Pregnenolone Progesterone Corticosterone

17α-OH-

pregnenolone

DHEA Androstenedione Testosterone

17α –OH-

progesteroneCortisol

CYP17

C17,20-lyase

CYP17

17α-hydroxylase

AldosteroneDeoxy-

corticosterone

DHT

5α-reductase

11-Deoxy-

cortisol

11β-Hydroxylase

CYP19: aromatase

Estradiol

Desmolase

X

X

Renin

ACTH

Adapted from Attard G, et al., J Clin Oncol 26(28), 2008: 4563-71. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved.

ABIRATERONE:

PHASE III (COU-AA-301)

Phase 3, multinational, multicentre, randomised, double-blind, placebo-controlled study

(147 sites in 13 countries; USA, Europe, Australia, Canada)

Stratification according to:

ECOG performance status (0-1 vs. 2)

Worst pain over previous 24 hours (BPI short form; 0-3 [absent] vs. 4-10 [present])

Prior chemotherapy (1 vs. 2)

Type of progression (PSA only vs. radiographic progression with or without PSA progression)

Efficacy endpoints (ITT)

Primary endpoint:

OS (25% improvement;

HR 0.8)

Secondary endpoints (ITT):

TTPP

rPFS

PSA response

Abiraterone 1000 mg daily

Prednisone 5 mg BID

N=797

Placebo daily

Prednisone 5 mg BID

n=398

RANDOMISED

2:1

1195 patients with

progressive, mCRPC

Failed 1 or

2 chemotherapy

regimens, one of

which contained

docetaxel

de Bono JS, et al., N Eng J Med 2011;364 21:1995-2005.

UPDATED ANALYSIS (775 EVENTS):

OS BENEFIT OF A AA INCREASED

FROM 3.9 TO 4.6 MONTHS

Median duration of follow-up: 20.2 months

Median duration of treatment: 8 months with AA vs. 4 months with placebo

HR (95% CI): 0.74 (0.64-0.86)

p < 0.0001

AA median OS (95% CI):

15.8 months (14.8-17.0)

Placebo median OS (95% CI):

11.2 months (10.4-13.1)

100

80

60

40

20

00

Sur

viva

l (%

)

6 12 18 24

797

398

657

306

473

183

273

100

15

6

Time to death (months)30

0

0

AA

Placebo

AA

Placebo

Reprinted from The Lancet Oncology 2012; 13 (10), Fizazi K, et al., Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival

analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study, 983–92. Copyright 2012, with permission from Elsevier.

ABIRATERONE:

PHASE III (COU-AA-302)

Phase 3 multicentre, randomised, 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

(n = 546)

Efficacy endpoints

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

Placebo daily

Prednisone 5 mg BID

(n = 542)

RANDOMISED

1:1

Patients

Progressive chemo-naïve

mCRPC patients

(n = 1088)

Asymptomatic or mildly

symptomatic

Ryan C, et al., N Engl J Med 2013;368(2)138-148.

STATISTICALLY SIGNIFICANT

IMPROVEMENT IN RPFS PRIMARY

ENDPOINT

Reprinted from Eur Urol, 66(5), Rathkopf D, et al., Updated interim efficacy analysis and long-term safety of abiraterone acetate in metastatic castration-resistant prostate

cancer patients without prior chemotherapy (COU-AA-302), 815–25. Copyright 2014 with permission from the European Association of Urology.

COU-AA-302: OVERALL SURVIVAL

Reprinted from The Lancet Oncology 2015; 16(2), Ryan C, et al., Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men

with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study;

152–60. Copyright 2015, with permission from Elsevier.

SAFETY OF LONG TERM

TREATMENT OF CHEMO-NAÏVE MCRPC

PATIENTS WITH AA + P FOR ≥4 YEARS

12

Conclusion

41 of 546 patients in COU-AA-302 continued AA + P treatment for ≥4 years

As expected, efficacy measures were improved for AA + P ≥4 years vs. AA + P <4 years group

There were no new safety signals or signs of cumulative toxicity over time with AA + P

AEs in COU-AA-302 patients who received AA + P for ≥4 years

vs. <4 years

AA + P ≥4 years

(n=41)

AA + P <4 years

(n=505)

Any grade, n (%) 41(100) 500 (99.8)

Grade 3/4, n (%) 23 (56) 267 (53)

Any

grade*

Grade

3-4

Any

grade

Grade

3-4

Fatigue 27 (66) 1 (2) 217 (43) 15 93)

Diarrhoea 21 (51) 1 (2) 116 (23) 7 (1)

Arthralgia 20 (49) 2 (5) 153 (31) 9 (2)

Back pain 20 (49) 1 (2) 180 (36) 17 (3)

Peripheral

oedema17 (42) 0 132 (26) 3 (<1)

*>40% cut-off.

AEs in COU-AA-302 patients who received AA + P for ≥4 years

either early (0-12 Months) or late (36-48 months)

During 0-12 months of

treatment (n=41)

During 36-48 months

of treatment (n=41)

Any grade, n (%) 41(100) 39 (95)

Grade 3/4, n (%) 9 (22) 6 (15)

Any

gradea Grade 3b Any

gradeGrade 3b

Fatigue 11 (27) 0 8 (20) 0

Diarrhoea 6 (15) 0 7 (17) 0

Arthralgia 7 (17) 1 (2) 5 (12) 0

Back pain 7 (17) 1 (2) 5 (12) 0

Peripheral

oedema10 (24) 0 4 (10) 0

Carles J, et al., Ann Oncol 2016;27(6):243–65. 740P.

a. >15% cut-off; b.There were no grade 4 or 5 AEs.

SECOND GENERATION ANTIANDROGENS

ENZALUTAMIDE

Reprinted from Clin Cancer Res, 2013, 19(6):1335–9, Hoffman-Censits J, Kelly WK, Enzalutamide: a novel antiandrogen for patients with castrate-resistant prostate

cancer, with permission from AACR.

AFFIRM

A phase 3 trial of Enzalutamide vs. placebo in post-chemotherapy

treated castration-resistant prostate cancer (CRPC)

RANDOMISED

2:1

Primary endpoint:

Overall Survival

Patient population:

1199 patients with progressive

CRPC

*Failed docetaxel

chemotherapy

*Glucocorticoids were not required but allowed.

Scher HI, et al., N Engl J Med 2012;367(13):1187-97.

Enzalutamide

160 mg daily

n = 800

Placebo

n = 399

OVERALL SURVIVAL

From N Engl J Med, Scher HI, et al., Increased survival with enzalutamide in prostate cancer after chemotherapy, 367(13):1187–97. Copyright © 2012 Massachusetts

Medical Society. Reprinted with permission from Massachusetts Medical Society.

TIME TO PSA PROGRESSION AND

RADIOGRAPHIC PROGRESSION-

FREE SURVIVAL

From N Engl J Med, Scher HI, et al., Increased survival with enzalutamide in prostate cancer after chemotherapy, 367(13):1187–97. Copyright © 2012 Massachusetts


Time to PSA progression Radiographic progression-free survival

PREVAIL

A phase 3 trial of Enzalutamide vs. placebo in chemotherapy-naïve

metastatic castration-resistant prostate cancer (mCRPC)

RANDOMISED

1:1

Co-Primary endpoints:

Overall Survival

rPFS

Enzalutamide

160 mg daily

n = 872

Placebo

n = 845

Patient population:

1717 patients with

progressive mCRPC

Asymptomatic

Chemotherapy naïve

Beer TM, et al., N Engl J Med 2014;371(5),424–33.

PREVAIL:

CO-PRIMARY ENDPOINTS

Rate of rPFS: 65% (Enza) vs.14% (Placebo) - HR 0.19 (95% CI, 0.15 to 0.23; P<0.001)

Median OS: 32.4 months (Enza) vs. 30.2 (Placebo) HR 0.71 (95% CI, 0.60 to 0.84; P<0.001)

From N Engl J Med, Beer TM, et al., Enzalutamide in metastatic prostate cancer before chemotherapy, 371 (5), 424–433. Copyright © 2014 Massachusetts


DOCETAXEL

DOCETAXEL IS STANDARD IN

FIRST-LINE CPRC

Docetaxel plus prednisone or mitoxantrone

plus prednisone for advanced PC1

Docetaxel and estramustine compared

with mitoxantrone and prednisone for

advanced refractory prostate cancer2

1. From N Engl J Med, Tannock IF, et al., Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate Cancer, 351:1502–12. Copyright © 2004

Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society; 2. From N Engl J Med, Petrylak DP, et al. Docetaxel and Estramustine

Compared with Mitoxantrone and Prednisone for Advanced Refractory Prostate Cancer, 351:1513–20. Copyright © 2004 Massachusetts Medical Society. Reprinted with

permission from Massachusetts Medical Society.

Median survival (mos) HR P-value

Combination 0.83 0.04

Docetaxel q3w 18.9 0.76 0.009

Docetaxcel qw 17.4 0.91 0.36

Mitoxantrone 16.5 n/a n/aHR: 0.80

(95% CI 0.67, 0.97)

PHASE III CLINICAL TRIALS

SHOWING DOCETAXEL

IMPACT ON SURVIVAL

Study Regimen ORRPSA

response

% with

paliative

response

Time to

progression

(months)

Survival

SWOG Docetaxel + Estramustine 17 50 17 6 18

Mitoxantrone + PDN 10 27 11 3 16

TAX 327 Docetaxel (3w) + PDN 12 45 35 7.9 18.9

Docetaxel (w) + PDN 8 48 31 8.2 17.4

Mitoxantrone + PDN 7 32 22 7.8 16.5

Sternberg C, et al., Progress in the treatment of advanced prostate cancer. Educational Book ASCO 2014.

Docetaxel-based phase III trials

RADIUM 223

RADIUM-223 TARGETS BONE

METASTASES

Alpha-particles induce double-strand DNA breaks in adjacent tumour cells1

Short penetration of alpha emitters (2–10 cell diameters) = highly localised

tumour cell killing and minimal damage to surrounding normal tissue

1. Halperin EC, et al., 2007:103 Perez and Brady’s Principles and Practice of Radiation Oncology. 5th ed. Lippincott Williams & Wilkins;

2. Parker C, et al., EMCC 2011:abstr E16-2669; Image from Shore ND. Radium-223 Dichloride for Metastatic Castration-resistant Prostate Cancer: The Urologist's

Perspective. Urology 2015;85(4):717–24.Available at: https://doi.org/10.1016/j.urology.2014.11.031 under the terms of the Creative Commons Attribution-NonCommercial-

No Derivatives License (CC BY NC ND) https://creativecommons.org/licenses/by-nc-nd/4.0

Radium-223

TREATMENT

6 injections at 4-week intervals

Radium-223 (50 kBq/kg) + best

standard of care

Placebo (saline)

+ best standard of care

R

A

N

D

O

M

I

S

E

D

2:1

N = 922

Patients

Confirmed

symptomatic

CRPC

≥ 2 bone

metastases

No known visceral

metastases

Post-docetaxel or

unfit for docetaxel

ALSYMPCA: PHASE III STUDY

DESIGN

Clinicaltrials.gov identifier: NCT00699751.

Total ALP:

< 220 U/L vs. ≥ 220 U/L

Bisphosphonate use:

Yes vs. no

Prior docetaxel:

Yes vs. no

Stratification

Planned follow-up is 3 years

Parker C, et al., N Engl J Med 2013;369:213–23.

Month 0 3 6 9 12 15 18 21 24 27

Radium-223 541 450 330 213 120 72 30 15 3 0

Placebo 268 218 147 89 49 28 15 7 3 0

ALSYMPCA: OVERALL SURVIVAL

0

10

20

30

40

50

60

70

80

90

100

Su

rviv

al (

%)

Radium-223, n=541

Median OS: 14.0 months

Placebo, n=268

Median OS: 11.2 months

HR 0.695; 95% CI, 0.552-–0.875

p=0.00185

From N Engl J Med, Parker C, et al., Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer, 369:213–23. Copyright © 2013

Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

ALSYMPCA: OVERALL SURVIVAL

BENEFIT ACROSS EACH PATIENT

SUBGROUPS

From N Engl J Med, Parker C, et al., Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer, 369:213–23. Copyright © 2013

Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

RADIUM-223 COMBINATION

CLINICAL TRIALS

NCT Identifier Ra-223Drug

associatedPrimary endpoint Secondary endpoints

NCT02034552 Ra-223Enza or

AbirateroneBone scan response

rPFS, SSE-FS, time to first SSE,

OS…

NCT02463799 Ra-223 Sipuleucel-T

Immune response

(peripheral PA2024 T-

cell proliferation)

Antigen-specific antibody

response to sipuleucel, Time to

PSA PD…

NCT02043678

(ERA223)Ra-223 Enzalutamide SSE-free survival OS, rPFS…

NCT02194842

(mCRPC-

PEACEIII)

Ra-223 Enzalutamide rPFS OS, First SSE…

NCT02396368 Ra-223 TasquinimodSafety of the

combination

Bone ALP response, time to first

symptomatic SRE…

FIRST LINE CHEMOTHERAPY

NEGATIVE TRIAL

FIRSTANA TRIAL

Cabazitaxel 20 mg/m2

vs.

Cabazitaxel 25 mg/m2

vs.

Docetaxel 75 mg/m2

FIRSTANA: STUDY DESIGN

Endpoints

Primary: Overall Survival

Secondary: Safety, PFS (based on tumour, PSA, or pain progression or death), tumour

response, PSA response, pain response, time to skeletal-related events, HRQoL,

pharmacokinetics/pharmacogenomics

Exploratory: cfDNA

Oudard S, et al., J Clin Oncol 2017;35(28):3189-3197.

159 centres worldwide

mCRPC and no prior

chemotherapy

N = 1,168 pts

R

A

N

D

O

M

I

S

E

CBZ 20 + PRED

Cabazitaxel 20 mg/m² Q3W

+ prednisone 10 mg/d

n = 389

CBZ 25 + PRED

Cabazitaxel 25 mg/m² Q3W


n = 388

DOC + PRED

Docetaxel 75 mg/m² Q3W


n = 391

FIRSTANA: SURVIVAL

C20, cabazitaxel 20 mg/m2 plus prednisone

C25, cabazitaxel 25 mg/m2 plus prednisone

D75, docetaxel 75 mg/m2 plus prednisone

Primary endpoint:

Overall survival

Secondary endpoint:

Progression-free survival

Oudard S, et al., J Clin Oncol 35(28), 2017: 3189–97. Reprinted with permission. Copyright © 2017 American Society of Clinical Oncology. All rights reserved.

Median OS, months (95% CI)

C20 24.5 (21.75, 27.20)

C25 25.2 (22.90, 26.97)

D75 24.3 (22.18, 27.60)

Median PFS, months (95% CI)

C20 4.4 (3.91, 5.09)

C25 5.1 (4.60, 5.72)

D75 5.3 (4.86. 5.78)

Sartor O, et al., J Clin Oncol 34, 2016 (suppl; abstr 5006)

FIRSTANA: TREATMENT-EMERGENT

ADVERSE EVENTS

NOVEL HORMONAL THERAPIES

CYP 17 inhibition and AR antagonist:

ODM-204

VT-464

Second Generation antiandrogens:

ODM-201

N-terminus AR Selective blocker

EPI-506

NEW HORMONAL DRUGS

UNDER DEVELOPMENT

ODM-204: NON-STEROIDAL

INHIBITOR AND AR ANTAGONIST

Its dual CYP17 plus AR antagonist

Activity against: T877A, F876L, W741L

Oksala R, et al., Poster presented at 2015 Genitourinary Cancers Symposium, February 26–28, 2015; Orlando, FL. Abstract 221. With permission from Dr Oksala.

Its dual CYP17 plus AR antagonist

Activity against: T877A, F876L

VT-464: NON-STEROIDAL

INHIBITOR AND AR ANTAGONIST

Maity SN, et al., Sci Rep 2016;6:35354. Available under CC BY 4.0 licence. https://creativecommons.org/licenses/by/4.0/

VT-464 IN MCRPC:

ONGOING TRIALS

NCT Identifier Year Status Population Arms

NCT02445976 2015Phase 2

Active recruiting

mCRPC with progressive

disease to enzalutamide

or abiraterone

Single arm VT-464

(Seviteronel)

NCT02361086 2015 - 2017Phase 1 / 2

Completed recruitingmCRPC

Single arm VT-464

(Seviteronel)

NCT02012920 2013Phase 1 / 2

Active recruitingmCRPC

Single arm VT-464

(Seviteronel)

NCT02130700 2014Phase 2

Active recruiting

mCRPC patients

previously treated with

enzalutamide

Single arm VT-464

(Seviteronel)

ODM-201 IN MCRPC:

ARADES TRIAL


NCT01317641

ARADES Trial

2011 Phase 1-2

Completed

recruiting

mCRPC with

progressive

disease

Single arm ODM-

201

Dose-escalation

Phase n: 24

Multiple dose

escalation

n 38: 200 mg, n 37:

400 mg, or n 35:

1400 mg

Primary endpoint in phase 1 was safety and tolerability

Primary endpoint in phase 2 was the proportion of patients with a PSA response ≥ 50% at week 12

Secondary endpoint in phase 1 was the pharmacokinetics of ODM-201

Secondary endpoint in phase 1 were ORR by RECIST and by PCWG2, time to PSA progression

and time to radiographic disease progression by RECIST and PCWG2 criteria

Fizazi K, et al., Lancet Oncol 2014;15:975–85.

ODM-201 IN MCRPC:

ARADES TRIAL

Reprinted from The Lancet Oncology, 15, Fizazi K, et al., Activity and safety of ODM-201 in patients with progressive metastatic castration-resistant

prostate cancer (ARADES): an open-label phase 1 dose-escalation and randomised phase 2 dose expansion trial, 975–85. Copyright 2014, with

permission from Elsevier.

ODM-201: ONGOING TRIALS

NCT Identifier Status Population N / Dose

ARAFOR

NCT01784757

Phase 1 trial

OngoingmCRPC chemo naïve

n: 30

1200 mg

ARAMIS

NCT02200614

Phase 3 trial

OngoingCRPC M0

n: 1500

2x300 mg BID

ARASENS

NCT02799602

Phase 3 trial

OngoingmHSPC chemo naïve

Docetaxel 75 mg/m2 + ADT + ODM-201

600 mg BID

EPI-506 (NCT02606123)

Phase I-II Trial (2016) with oral prodrug of EPI-002, capable of targeting AR N-terminal domain B1

EPI-

5062

1. ClinicalTrials.gov. Safety and Anti-Tumor Study of Oral EPI-506 for Patients With Metastatic Castration-Resistant Prostate Cancer. ClinicalTrials.gov Identifier:

NCT02606123 Available at: https://clinicaltrials.gov/ct2/show/NCT02606123;

2. Pakula H, et al., Cancers 2017;9(2):14. Available under CC BY 4.0. license. http://creativecommons.org/licenses/by/4.0/).

https://clinicaltrials.gov/ct2/show/NCT02606123

First-line treatment in mCRPC patients: Standard of Care

Androgen Biosynthesis Inhibitors (ABIs)

Second generation antiandrogens

Docetaxel

Radium 223

Novel hormonal therapies

Immunotherapy

Targeted therapies

Failed trials

Conclusions

AGENDA

IMMUNOTHERAPY

Active immunotherapy

Tumour 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

Prostate Specific Membrane Antigen (PSMA)

Immune Checkpoint Inhibitors

Strategies to maintain activated tumour specific T-cells by neutralising co-inhibitory receptors

Anti-cytotoxic T lymphocyte protein 4 (CTLA 4)

Ipilimumab, Tremelimumab

Anti- program death 1 (PD-1)

Nivolumab, Pembrolizumab

IMMUNOTHERAPY APPROACHES

Active immunotherapy

Tumour 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

Prostate Specific Membrane Antigen (PSMA)

Immune Checkpoint Inhibitors


Anti-cytotoxic T lymphocyte protein 4 (CTLA 4)

Ipilimumab, Tremelimumab

Anti- program death 1 (PD-1)

Nivolumab, Pembrolizumab

IMMUNOTHERAPY APPROACHES

Phase I/II results published show safety and a clear dose-related biologic activity

SIPULEUCEL-T: VACCINE THERAPY

WITH PULSED DENDRITIC CELLS

Reprinted by permission from Macmillan Publishers Ltd: Nat Rev Immunol, Drake CG, et al., Nat Rev Immunol 2010;10:580–93, copyright 2010

RANDOMISED PHASE 3

IMPACT TRIAL

Immunotherapy Prostate Adeno Carcinoma Treatment

Asymptomatic or

minimally symptomatic

metastatic castration

resistant prostate

cancer (N=512)

Sipuleucel-TQ2 weeks x3

PlaceboQ2 weeks x3

2:1

Treated at physician discretion

Treated at physician discretion and/or salvage protocol

S

U

R

V

I

V

A

L

P

R

O

G

R

E

S

S

I

O

N

Primary endpoint: Overall survival

Secondary endpoint: Objective disease progression

Kantoff PW, et al., N Engl J Med 2010;363:411–22.

IMPACT TRIAL: OVERALL

SURVIVAL ADDITIONAL ANALYSIS

(349 EVENTS)

From N Engl J Med, Kantoff PW, et al., Sipuleucel-T Immunotherapy for Castration-Resistant Prostate Cancer, 363:411–22, Copyright © 2010 Massachusetts


Risk of death HR: 0.78 (95% CI 0.61, 0.98)

p=0.03 (Cox model)

Median survival benefit = 4.1 months

N=171

Median survival 21.7 mo

36-mo survival: 23.0%

N=341

Median survival 25.8 mo

36-mo survival: 31.7%

PROSTVAC-VF

1. Rotow J, et al., Vaccines as monotherapy and in combination therapy for prostate cancer. Clin Transl Sci 2010;3(3):116–22. © 2010 Wiley Periodicals, Inc., with

permission from John Wiley and Sons; 2. Reprinted by permission from Springer Customer Service Centre GmbH: Springer Nature, Nat Rev Urol, Metastatic

Castrate-Resistant Prostate Cancer Treatment (mCRPC), Geary SM, et al. Copyright 2013; Gerritsen WR, et al. Ann Oncol 2012;23, Suppl 8:viii22–7.

PHASE II TRIAL

Of Vaccinia-PSA-Tricom and Fowlpox-PSA-Tricom compared to placebo

in metastatic castration-resistant prostate cancer

Recombinant Vaccinia and Fowlpox-based vaccine containing a PSA transgene with a

modified HLA-A2 epitope to increase immunogenicity

Also contains Tricom (lymphocyte function-associated antigen LFA-3, ICAM-1, and T-

cell receptor costimulatory molecule B7.1) to increase immune response

Eligibility:

Asymptomatic or minimally

symptomatic metastatic

castration-resistant prostate

cancer

Gleason ≤ 7

No liver, lung, or brain mets

No prior chemotherapy

N=125

Vaccinia-PSA-Tricom/Fowlpox-PSA-

Tricom + GM-CSF

Empty vector + placebo

(n = 84)

(n = 41)

R

2:1

Crossover allowed upon

disease progression

Kantoff PW, et al., J Clin Oncol 2010;28:1099–105.

Overall survival

Kantoff PW, et al., J Clin Oncol 28(7), 2010; 1099–105. Reprinted with permission. © 2010 American Society of Clinical Oncology. All rights reserved.

Primary endpoint is

progression-free survival

RANDOMISED PHASE 3

PROSPECT TRIAL

PROSTVAC+/- GM-CSF in mCRPC

Asymptomatic or

minimally

symptomatic

metastatic

castration resistant

prostate cancer

(N=1298)

PROSTVAC-VF +

TRICOM + low dose

adjuvant GM-CSF

PROSTVAC-VF + TRICOM + adjuvant

Placebo

S

U

R

V

I

V

A

L

STANDARD

OF CARE

Vector Placebo +

adjuvant Placebo


Secondary endpoint: Progression-free survival

1:1:1

ClinicalTrial.gov. NCT01322490

PASSIVE IMMUNOTHERAPY

Prostate Specific Membrane Antigen (PSMA)*

A type II non-secreted integral cell-surface protein

Expressed on virtually all prostate cancer cells

Expression increases (by logs) with higher grade, stage, and

androgen deprivation

Expressed (too much lower degree) on prostate epithelial cells, brush border of small

intestine, luminal surfaces of renal tubules and salivary glands, nervous system

For practical purposes, sites that are not exposed to circulating mAb

Also expressed on endothelium of the neovasculature of nearly all solid

tumours (but NOT normal vasculature)

*AKA folate hydrolase 1, glutamate carboxypeptidase II

Israeli RS, et al., Cancer Res 1994;15(54):6306–12; Silver DA, et al., Clin Cancer Res 1997;3:81–5; Bostwick JS, et al., Cancer 1998;82(11);2256–61; Wright

GL, et al., Urol Oncol 1995;1(1):18–28; Wright DL, et al., Urology 1996;48(2):326–34.

THERANOSTICS PHASE II TRIAL

Efficacy, safety and QoL in mCRPC patients treated with LuPSMA

177Lu-PSMA617 was administered every 6 weeks for up to 4 cycles to 30 enrolled

patients with PSMA-avid mCRPC who progressed after standard therapies

Hofman MS, et al., Lutetium-177 PSMA (LuPSMA) Theranostics Phase II trial: Efficacy, safety and QoL in patients with castrate-resistant prostate cancer

treated with LuPSMA. Presented at ESMO 2017 Congress. Abstract 7850.


IMMUNE CHECKPOINT INHIBITORS

CTLA4 antibodies: Ipilimumab - Tremelimumab

PD-1 antibody: Nivolumab - Pembrolizumab

Reprinted by permission from Macmillan Publishers Ltd: Nat Rev Cancer, Pardoll DM, Nat Rev Cancer 2012;12(4):252–64. Copyright 2012.

PD-L1 ANTIBODIES

MM: S. Keefe

Stats: L. Pang

CS: A. Gipson

Cin Ops: K. rt

Response assessment tumour assessments by CT and Tc-99 bone scan every 12 weeks and serum PSA

every 3 weeks during active treatment with pembrolizumab and every 6 weeks in active follow-up

Primary endpoints: PSA response ≥50%

Secondary endpoints: ORR by radiographs, PSA PFS and OS

PHASE 2 SINGLE-ARM STUDY

OF PEMBROLIZUMAB

In treating patients with previously treated with enzalutamide

(NCT02312557)

Continue enzalutamide

plus pembrolizumab

(200 mg IV every 3w for

four doses

Patients

mCRPC

ECOG PS 0 or 1

PSA response to

enzalutamide

Not prior CT for

mCRCP

No prior CTLA-4, PD-

1 or PD-L1 blockade

Biopsy if there is a

metastatic deposit that

can be biopsied at

baseline

Response

Assessment

after 4 cycles

Response or SD

Retreat with Pembro

until PD

PD STOP Pembro

Enrolment

PD on

enzalutamide by

PCWG2 (not

clinical PD)

Graff J, et al., Oncotarget 2016;7(33):52810–7.

MM: S. Keefe

Stats: L. Pang

CS: A. Gipson

Clin Ops: K. Kort

RESPONDING PATIENTS


ADVERSE EVENTS: GRADE ≥ 3 OR

IMMUNE-RELATED (IR)


Event Grade (number of subjects)

Urinary tract infection 2 (1)

Myelitis 3 (1)

Diarrhea 1 (2), 2 (1), 3 (1)

ir-Myositis 2 (4) High dose steroid taper one time. Resolved, and pembrolizumab

discontinued

ir-Hypothyroidism 3 (6) Thyroid replacement and high dose steroid taper three times, as the

symptoms quickly returned after taper. Currently on third taper with improvement

of symptoms. Pembrolizumab discontinued.

MM: S. Keefe

Stats: L. Pang

CS: A. Gipson

Clin Ops: K. Kort

‡Response assessment: Every 8 weeks for the first 6 months; every 12 weeks thereafter

Primary end points: ORR per RECIST v1.1 and safety

Secondary end points: PFS, OS, duration of response

KEYNOTE-028 (NCT02054806)

Phase 1b multicohort study of pembrolizumab in PD-L1–positive

advanced solid tumours

Pembrolizumab

10 mg/kg IV Q2W

Complete response,

partial response, or

stable disease

Treat for 24 months, or

until progression§ or

intolerable toxicity

Confirmed progressive

disease§ or

unacceptable toxicity

Discontinue

pembrolizumab

Patients

Unresectable or

metastatic prostate

cancer

Failure of or inability to

receive standard therapy

ECOG PS 0 or 1

Measurable disease

(RECIST v1.1)

PD-L1 positive†

†Membranous PD-L1 expression in ≥1% of tumour or stromal cells using a prototype immunohistochemistry assay and 22C3 antibody (Merck). §Clinically stable patients were allowed to remain on pembrolizumab until progressive disease was confirmed on a second scan performed ≥4

weeks later. Patients who experienced progression after discontinuing pembrolizumab were eligible for up to 1 year of additional treatment

if no other anticancer therapy was received.

Response

Assessment‡

Hansen A, et al., Ann Oncol 2016;27(Suppl_6);725PD.

BEST OVERALL RESPONSE

Per RECIST v1.1, Investigator Review

N=23 n % (95% CI)

Overall response rate† 3 13 (3-34)

Partial response 3 13 (3-34)

Stable disease 9 39 (20-62)

Progressive disease 8 35 (16-57)

Non-evaluable 1 4 (0.1-22)

No assessment 2 9 (1-28)

Only confirmed responses are included. 3 patients were non-evaluable or had no assessment. Data cutoff date: February 17, 2016†There were no complete responses.


TREATMENT-RELATED

ADVERSE EVENTS

Any-grade treatment-related AEs observed in ≥2 patients, and all grade 3-4 treatment-related AEs, are shown.

Data cutoff date: February 17, 2016

N=23Any Grade

n (%)

Grade 3-4

n (%)

Nausea 3 (13) 0

Asthenia 2 (9) 1 (4)

Decreased appetite 2 (9) 0

Decreased weight 2 (9) 0

Diarrhea 2 (9) 0

Hyperthyroidism 2 (9) 0

Increased lipase 2 (9) 1 (4)

Maculopapular rash 2 (9) 0

Pruritus 2 (9) 0

Fatigue 1 (4) 1 (4)

Peripheral neuropathy 1 (4) 1 (4)

There were no deaths or

discontinuations due to

treatment-related AEs


TARGETED THERAPIES

N-mycAR-V7

ATMWNT

BRCA2

PTEN

PIK3CA/B

AKT

ERG-FUSION

Molecular alteration in mCRPC Current or Potential Therapies

PARP

inh

Taxanes

PI3K Inh

Anti-

PD1 /

PD-L1

Tankirase-Inh

Purcupine-Inh

CDK4/6 Inh

Cell cycle

pathways

Adapted from Beltran H, et al., Emerging Molecular Biomarkers in Advanced Prostate Cancer: Translation to the Clinic. Presented at ASCO Annual Meeting 2016

mCRPC

1 or 2 QMT lines

ECOG 0-2

No prior CDDP, cyclophosphamide, mitoxantrone, or PARP inhib

PCWG2 progression

Phase II

Olaparib 400 mg twice a day

Primary endpoint: Response Rate

Results

33% response rate

25.5% received treatment >6 m

TOPARP-A PHASE II TRIAL

OLAPARIB IN MCRPC

Mateo J, et al., N Engl J Med 2015;373:1697–708.

Characteristic Value

Received prior regimens for CRPC — no. (%)

2 3 (6)

3 7 (14)

≥4 40 (80)

Received prior treatments — no. (%)

Radical prostatectomy or radiotherapy 25 (50)

Castration (chemical or surgical) 5 (100)

Abiraterone acetate 48 (96)

Enzalutamide 14 (28)

Docetaxel 50 (100)

Cabazitaxel 29 (58)

Radium-223 1 (2)

Baseline Characteristics of the 50 Study Patients

TOPARP-A PHASE II TRIAL

OLAPARIB IN MCRPC

From N Engl J Med, Mateo J, et al., DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer, 373:1697–708. Copyright © 2015 Massachusetts Medical

Society. Reprinted with permission from Massachusetts Medical Society.

Radiologic progression-free survival Overall survival

January 2016:

FDA approved Olaparib for BRCA 1/2 and ATM mutated CRPC

ABIRATERONE + PREDNISONE +/–

VELIPARIB IN mCRPC

*PSA CR: PSA ≤0.2 ng/mL; PSA PR ≥50% decrease

Hussain M, et al. J Clin Oncol 2017 Dec 20. [Epub ahead of print]

Registration

Metastatic tissue biopsy

adequate for ETS fusion

status evaluation

ETS

stratificiation

(+/–)

Metastatic tissue biopsy

inadequate for ETS

fusion status evaluation

Off protocol

Key inclusion criteria

Progressive mCRPC by at

least 1 criteria:

– PSA progression

– Measurable disease

– Bone disease

No prior abiraterone

Prior ketoconazole and

chemo allowed

Agree to undergo biopsy of

metastatic site with adequate

tissue (adequate metastatic

archival tissue allowed)

Arm A

AA + pred

Arm B

AA/pred + veliparib

200(300) PO bid

Objectives Primary: To evaluate in patients with mCRPC

• Whether the combination of AA/pred + veliparib is superior to AA/pred alone as reflected by

PSA response rate (CR + PR)*

• Whether ETS gene fusion is a predicative biomarker for response to AA/pred +/– veliparib

Secondary: Measurable disease response rate, PFS, toxicities

Translational: Identify predictive biomarkers of response in tumour tissue and CTC

ABIRATERONE + PREDNISONE +/-

VELIPARIB IN mCRPC

CR, complete response; PR, partial response; PSA, prostate-specific antigen; RECIST, Response Evaluation Criteria in Solid Tumours

Hussain M, et al., J Clin Oncol 2017 Dec 20. [Epub ahead of print]. Reprinted with permission. © 2017 American Society of Clinical Oncology. All rights reserved.

PFS and OS

• No difference in PFS by ETS status

Median OS (95% CI)

AA: 30.6 mo (28.4, NR)

AA+V: 32.3 mo (28.4, NR)

PFS

Overall ETS(+) ETS(–)

AA

(n=72)

AA+V

(n=76)

AA

(n=25)

AA+V

(n=27)

AA

(n=47)

AA+V

(n=49)

Best overall PSA outcomes (%)

PSA response

(CR/PR)64.0 72.4 60.0 70.4 66.0 73.5

Stable disease 26.4 19.7 28.0 25.9 25.5 16.3

Measurable

disease (n=86) (n=40) (n=46) (n=15) (n=19) (n=25) (n=27)

RECIST

response

(CR/PR)

45.0 52.2 40.0 52.6 48.0 51.9

Best overall PSA and measurable

disease response rate (Evaluable patients: N=148)

ABIRATERONE + PREDNISONE +/-

VELIPARIB IN mCRPC

PFS by DRD status overall and by arm

PFS by DRD status (n=80)Arm A: Abiraterone (n=31)

Arm B: Abiraterone + Veliparib (n=47)

DRD, DNA-damage repair defect; WT, wild type

Hussain M, et al.,J Clin Oncol 2017 Dec 20. [Epub ahead of print]. Reprinted with permission. © 2017 American Society of Clinical Oncology. All rights reserved.

ONGOING TRIALS MCRPC AND

PI3K PATHWAY


NCT01385293 2011 Phase II Trial

Study was stopped at the

first stage due to futility

Post chemo; prior sipuleucel-T,

abiraterone (Abi), or

enzalutamide (Enza) allowed.

BKM120

NCT01884285 2013 Phase I Trial

Active recruiting

TNBC/NSCLC or CRPC known

PTEN-deficient/PI3 mutated

disease

AZD8186 (PI3Kβ and PI3Kδ)

+/− Abi or AZD2014 (dual

mTORC1/2 inhibitor)

NCT02215096 2014 Phase I Trial

Active recruiting

n: 44

PTEN-deficient mCRPC and

recently PD EnzaEnza + GSK2636771 (PI3K-

beta inhibitor)

NCT02407054 2015 Phase II Trial

Active recruiting

n: 144

mCRPC post PD Abi; no prior

chemo, immunotherapy or

Ra223

Enza+/- LY3023414 (PI3

Kinase/mTOR Inhibitor)

NCT02525068

(RE-AKT)

2015 Phase II Trial

Active recruiting

N: 136

PD 1 or 2 Taxanes and PD >12

weeks treatment to AbiEnza + AZD5363 (AKT

inhibitor)

PI3K / AKT Inh

mTORC-Inh

Olaparib

Immuno-

therapy

Abiraterone

Enza

Novel anti-AR

Reprinted from Cell, 161(5), Robinson D, et al., Integrative Clinical Genomics of Advanced Prostate Cancer, 1215–28, Copyright 2015, with permission from Elsevier.

FAILED TRIALS

Docetaxel combinations

Tasquinimod

Orteronel

Ipilimumab

DOCETAXEL COMBINATION IN

PHASE III TRIALS

Docetaxel Drug associated Primary endpoint (os) Secondary endpoints

Docetaxel Bevacizumab Negative Positive

Docetaxel Aflibercept Negative UK

Docetaxel Atrasentan Negative Negative

Docetaxel Calcitriol Negative Negative

Docetaxel Dasatinib Negative Negative

Docetaxel Gvax Negative Negative

Docetaxel Lenolidamide Negative Negative

Docetaxel Custirsen (OGX-011) Negative -

Docetaxel Pelareorep (Reolysin) Negative Negative

Docetaxel Prostvac Ongoing Ongoing

Docetaxel DCVAC Ongoing Ongoing

Docetaxel Ribociclib Ongoing Ongoing

PHASE III TASQUINIMOD IN MCRPC

Sternberg C, et al., J Clin Oncol, 34(22), 2016: 2636–43. Reprinted with permission. © 2016 American Society of Clinical Oncology. All rights reserved.

ELM-PC 5 TRIAL

Fizazi K, et al., J Clin Oncol 2015;33(7):723–31. Reprinted with permission © 2015 American Society of Clinical Oncology. All rights reserved.

ELM-PC 5 TRIAL


Fizazi K, et al., J Clin Oncol 33(7), 2015: 723–31. Reprinted with permission © 2015 American Society of Clinical Oncology. All rights reserved.

Median follow-up time: 10.7 mo (range 0.2–29.5)

ELM-PC 4 TRIAL

Saad F, et al., Lancet Oncol. 2015;16(3):338-48.

• Recruitment in 324 centres from 43 countries across 6 continents, October 2010 through

June 2012

ELM-PC 4 TRIAL

Reprinted from Lancet Oncol, Saad F, et al, 16(3), Orteronel plus prednisone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer

(ELM-PC 4): a double-blind, multicentre, phase 3, randomised, placebo-controlled trial, 338-48. Copyright 2015, with permission from Elsevier.

Median: Orteronel plus prednisone 31.4 mo vs. placebo plus prednisone 29.5 mo

Events: Orteronel plus prednisone 294 vs. placebo plus prednisone 317

Post-

docetaxel

mCRPC

(n=799)

Radio

Therapy

to bone

(8Gy)

Placebo

every 12 w

Placebo

Week 1, 4, 7, 10

Ipilimumab

(10 mg/kg

every 12 w

Ipilimumab

(10 mg/kg)

Week 1, 4, 7, 10

N=399

N=400

Stratification: centre, Alk Ph, Hb and ECOG.

Treatment till unacceptable toxicity

or disease progression

CTLA-4 IN MCRPC

CA 184-043 PHASE III STUDY


Kwon ED, et al., Lancet Oncol 2014;15:700–12.

Ipilimumab

(n=399)

Placebo

(n=400)

Median OS in months (95% CI) 11.2 (9.5-12.7) 10.0 (8.3-11.0)

HR (95% CI): 0.85 (0.72-1.00)

Stratified log-rank: P=0.0530

Ipilimumab

Placebo

Overall Survival


IPILIMUMAB

Reprinted from Lancet Oncol, 15(7), Kwon ED, et al., Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate

cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. 700–12. Copyright 2014, with

permission from Elsevier.

Placebo

every 12 w

Placebo

Week 1, 4, 7, 10

Ipilimumab

(10 mg/kg

Every 12 w

Ipilimumab

(10 mg/kg)

Week 1, 4, 7, 10

No visceral mets.

For 3 years

mCRPC

asymptomatic or

middle symptomatic

(n=600)


IPILIMUMAB


Beer TM, et al., J Clin Oncol 35(1), 2017:40-47.

Overall Survival

Median OS: 28.7 months ipilimumab arm vs. 29.7 months placebo arm

Hazard ratio, 1.11; 95.87% CI, 0.88 to 1.39; P = 0.3667)


IPILIMUMAB

Beer TM, et al., J Clin Oncol 35(1), 2017: 40–7. Reprinted with permission. © 2017 American Society of Clinical Oncology. All rights reserved.

Identifying the best treatment for each patient is an unmet clinical objective in

patients with mCRPC

We need further studies that allow us to develop biomarkers of response to different

therapies

Precision medicine may be the future for prostate cancer treatment algorithms if we

are able to integrate all the epigenetic changes

We should not forget that tumour stroma (IO) appears to have an important role in

the evolution of prostatic cancer

CONCLUSIONS

THANK YOU!

Documents

Metastatic Castrate-Resistant Prostate Cancer …...Reprinted from Clin Cancer Res, 2013, 19(6):1335–9, Hoffman-Censits J, Kelly WK, Enzalutamide: a novel antiandrogen for patients