ESMO E-Learning Metastatic Castrate-Resistant Prostate Cancer

METASTATIC CASTRATE- RESISTANT PROSTATE CANCER TREATMENT (MCRPC)

Fabricio Racca GU, CNS and Sarcoma Programme, Oncology Department Vall d’Hebron University Hospital, Barcelona, Spain AGENDA

 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 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 Chemo-näive CRPC Placebo 0.77 0.032 (Provenge vaccine) 2010 COU-AA-302 Placebo Chemo-naïve CRPC UK UK (Abiraterone acetate) 2012 Prednisone Pre-docetaxel ALSYPMCA (Radium 223) 2013 BSC 0.74 <0.00046 CRPC

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

Mitoxantrone TAX327 (Docetaxel) 2004 Chemo-naïve CRPC 0.76 0.009 Prednisone Mitoxantrone TROPIC (Cabazitaxel) 2010 Post-docetaxel CRPC 0.70 <0.0001 Prednisone COU-AA-301 Post-docetaxel Placebo 0.65 <0.0001 (Abiraterone acetate) 2010 CRPC Prednisone Post-docetaxel ALSYPMCA (Radium 223) 2013 BSC 0.71 <0.00046 CRPC Post-docetaxel AFFIRM (Enzalutamide) 2012 BSC 0.63 <0.0001 CRPC ANDROGEN BIOSYNTHESIS INHIBITORS (ABIS) ABIRATERONE ACETATE + PREDNISONE

Cholesterol Desmolase Renin Deoxy- Pregnenolone Progesterone Corticosterone Aldosterone corticosterone

CYP17 17α-hydroxylaseX 11β-Hydroxylase

ACTH 17α-OH- 17α –OH- 11-Deoxy- Cortisol pregnenolone progesterone cortisol

CYP17 C17,20X-lyase 5α-reductase DHEA Androstenedione Testosterone DHT CYP19: aromatase

Estradiol

 1195 patients with R Efficacy endpoints (ITT) Abiraterone 1000 mg daily progressive, mCRPC A N Prednisone 5 mg BID  Primary endpoint:  Failed 1 or D N=797  OS (25% improvement; 2 chemotherapy O HR 0.8) regimens, one of M  Secondary endpoints (ITT): which contained I docetaxel S Placebo daily  TTPP E Prednisone 5 mg BID  rPFS D n=398 2:1  PSA response

 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) 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

AA 100 Placebo HR (95% CI): 0.74 (0.64-0.86) 80 p < 0.0001 AA median OS (95% CI): 60 15.8 months (14.8-17.0)

40 Survival(%) Placebo median OS (95% CI): 20 11.2 months (10.4-13.1)

0 0 6 12 18 24 30 Time to death (months) AA 797 657 473 273 15 0 Placebo 398 306 183 100 6 0

 Median duration of follow-up: 20.2 months

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

Efficacy endpoints Patients R A  Primary:  Progressive chemo-naïve N AA 1000 mg daily  rPFS by central review mCRPC patients D Prednisone 5 mg BID  OS (n = 1088) O (n = 546) M  Secondary:  Asymptomatic or mildly I symptomatic S  Time to opiate use (cancer- E Placebo daily related pain) D Prednisone 5 mg BID  Time to initiation of (n = 542) chemotherapy 1:1  Time to ECOG-PS deterioration

 TTPP

 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

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

AEs in COU-AA-302 patients who received AA + P for ≥4 years AEs in COU-AA-302 patients who received AA + P for ≥4 years vs. <4 years either early (0-12 Months) or late (36-48 months) AA + P ≥4 years AA + P <4 years During 0-12 months of During 36-48 months (n=41) (n=505) treatment (n=41) of treatment (n=41) Any grade, n (%) 41(100) 500 (99.8) Any grade, n (%) 41(100) 39 (95) Grade 3/4, n (%) 23 (56) 267 (53) Grade 3/4, n (%) 9 (22) 6 (15) Any Grade Any Grade Any Any Grade 3b Grade 3b grade* 3-4 grade 3-4 gradea grade Fatigue 27 (66) 1 (2) 217 (43) 15 93) Fatigue 11 (27) 0 8 (20) 0 Diarrhoea 21 (51) 1 (2) 116 (23) 7 (1) Diarrhoea 6 (15) 0 7 (17) 0 Arthralgia 20 (49) 2 (5) 153 (31) 9 (2) Arthralgia 7 (17) 1 (2) 5 (12) 0 Back pain 20 (49) 1 (2) 180 (36) 17 (3) Back pain 7 (17) 1 (2) 5 (12) 0 Peripheral Peripheral 17 (42) 0 132 (26) 3 (<1) 10 (24) 0 4 (10) 0 oedema oedema *>40% cut-off. a. >15% cut-off; b.There were no grade 4 or 5 AEs.

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

Carles J, et al., Ann Oncol 2016;27(6):243–65. 740P. 12 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)

Patient population: R Primary endpoint: A Enzalutamide  1199 patients with progressive N  Overall Survival CRPC D 160 mg daily O n = 800  *Failed docetaxel M chemotherapy I S E Placebo D n = 399 2:1

*Glucocorticoids were not required but allowed. Scher HI, et al., N Engl J Med 2012;367(13):1187-97. 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

Time to PSA progression Radiographic progression-free survival

A phase 3 trial of Enzalutamide vs. placebo in chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC)

Patient population: R A Enzalutamide  1717 patients with N Co-Primary endpoints: progressive mCRPC D 160 mg daily O n = 872  Overall Survival  Asymptomatic M I  rPFS  Chemotherapy naïve S E Placebo D n = 845

1:1

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 Medical Society. Reprinted with permission from Massachusetts Medical Society. DOCETAXEL DOCETAXEL IS STANDARD IN FIRST-LINE CPRC

Docetaxel plus prednisone or mitoxantrone Docetaxel and estramustine compared plus prednisone for advanced PC1 with mitoxantrone and prednisone for Median survival (mos) HR P-value advanced refractory prostate cancer2 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/a HR: 0.80 (95% CI 0.67, 0.97)

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. PHASE III CLINICAL TRIALS SHOWING DOCETAXEL IMPACT ON SURVIVAL

Docetaxel-based phase III trials

% with Time to PSA Study Regimen ORR paliative progression Survival response response (months) 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. RADIUM 223 RADIUM-223 TARGETS BONE METASTASES

Radium-223

1  Alpha-particles induce double-strand DNA breaks in adjacent tumour cells

 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 ALSYMPCA: PHASE III STUDY DESIGN

TREATMENT

6 injections at Patients 4-week intervals R  Confirmed Stratification symptomatic A Radium-223 (50 kBq/kg) + best CRPC  Total ALP: N < 220 U/L vs. ≥ 220 U/L standard of care  ≥ 2 bone D metastases  Bisphosphonate use: O Yes vs. no  No known visceral M metastases  Prior docetaxel: I Yes vs. no S Placebo (saline)  Post-docetaxel or + best standard of care unfit for docetaxel E D

2:1

N = 922 Planned follow-up is 3 years

Parker C, et al., N Engl J Med 2013;369:213–23. Clinicaltrials.gov identifier: NCT00699751. ALSYMPCA: OVERALL SURVIVAL

100 HR 0.695; 95% CI, 0.552-–0.875 90 p=0.00185 80 70 Radium-223, n=541 60 Median OS: 14.0 months

40 Survival Survival (%) 30 Placebo, n=268 20 Median OS: 11.2 months 10 0 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

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

Drug NCT Identifier Ra-223 Primary endpoint Secondary endpoints associated Enza or rPFS, SSE-FS, time to first SSE, NCT02034552 Ra-223 Bone scan response Abiraterone OS… Immune response Antigen-specific antibody NCT02463799 Ra-223 Sipuleucel-T (peripheral PA2024 T- response to sipuleucel, Time to cell proliferation) PSA PD… NCT02043678 Ra-223 Enzalutamide SSE-free survival OS, rPFS… (ERA223) NCT02194842 (mCRPC- Ra-223 Enzalutamide rPFS OS, First SSE… PEACEIII) Safety of the Bone ALP response, time to first NCT02396368 Ra-223 Tasquinimod combination 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

CBZ 20 + PRED Cabazitaxel 20 mg/m² Q3W R + prednisone 10 mg/d A n = 389 N CBZ 25 + PRED  mCRPC and no prior D Cabazitaxel 25 mg/m² Q3W chemotherapy O + prednisone 10 mg/d  N = 1,168 pts M n = 388 I 159 centres worldwide S DOC + PRED E Docetaxel 75 mg/m² Q3W + prednisone 10 mg/d n = 391 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. FIRSTANA: SURVIVAL

Primary endpoint: Secondary endpoint: Overall survival Progression-free survival Median OS, months (95% CI) Median PFS, months (95% CI) C20 24.5 (21.75, 27.20) C20 4.4 (3.91, 5.09) C25 25.2 (22.90, 26.97) C25 5.1 (4.60, 5.72) D75 24.3 (22.18, 27.60) D75 5.3 (4.86. 5.78)

C20, cabazitaxel 20 mg/m2 plus prednisone C25, cabazitaxel 25 mg/m2 plus prednisone D75, docetaxel 75 mg/m2 plus prednisone

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. FIRSTANA: TREATMENT-EMERGENT ADVERSE EVENTS

Sartor O, et al., J Clin Oncol 34, 2016 (suppl; abstr 5006) NOVEL HORMONAL THERAPIES NEW HORMONAL DRUGS UNDER DEVELOPMENT

 CYP 17 inhibition and AR antagonist:

 ODM-204

 VT-464

 Second Generation antiandrogens:

 ODM-201

 N-terminus AR Selective blocker

 EPI-506 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. VT-464: NON-STEROIDAL INHIBITOR AND AR ANTAGONIST

Its dual CYP17 plus AR antagonist Activity against: T877A, F876L

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 mCRPC with progressive Phase 2 Single arm VT-464 NCT02445976 2015 disease to enzalutamide Active recruiting (Seviteronel) or abiraterone Phase 1 / 2 Single arm VT-464 NCT02361086 2015 - 2017 mCRPC Completed recruiting (Seviteronel) Phase 1 / 2 Single arm VT-464 NCT02012920 2013 mCRPC Active recruiting (Seviteronel) mCRPC patients Phase 2 Single arm VT-464 NCT02130700 2014 previously treated with Active recruiting (Seviteronel) enzalutamide ODM-201 IN MCRPC: ARADES TRIAL

NCT Identifier Year Status Population Arms NCT01317641 2011 Phase 1-2 mCRPC with Single arm ODM- ARADES Trial Completed progressive 201 recruiting disease 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 Phase 1 trial n: 30 mCRPC chemo naïve NCT01784757 Ongoing 1200 mg ARAMIS Phase 3 trial n: 1500 CRPC M0 NCT02200614 Ongoing 2x300 mg BID ARASENS Phase 3 trial Docetaxel 75 mg/m2 + ADT + ODM-201 mHSPC chemo naïve NCT02799602 Ongoing 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- 2 506

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/). AGENDA

 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 IMMUNOTHERAPY 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

 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

 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 SIPULEUCEL-T: VACCINE THERAPY WITH PULSED DENDRITIC CELLS

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

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

P R S Asymptomatic or Sipuleucel-T O Treated at physician minimally symptomatic U Q2 weeks x3 G discretion metastatic castration R R resistant prostate V 2:1 E cancer (N=512) I S Treated at physician V Placebo S discretion and/or A Q2 weeks x3 I salvage protocol L 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)

Risk of death HR: 0.78 (95% CI 0.61, 0.98) p=0.03 (Cox model) Median survival benefit = 4.1 months

N=341 Median survival 25.8 mo 36-mo survival: 31.7%

N=171 Median survival 21.7 mo 36-mo survival: 23.0%

From N Engl J Med, Kantoff PW, et al., Sipuleucel-T Immunotherapy for Castration-Resistant Prostate Cancer, 363:411–22, Copyright © 2010 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. 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: Vaccinia-PSA-Tricom/Fowlpox-PSA-  Asymptomatic or minimally symptomatic metastatic 2:1 Tricom + GM-CSF castration-resistant prostate cancer R (n = 84)

 Gleason ≤ 7

 No liver, lung, or brain mets Empty vector + placebo

 No prior chemotherapy (n = 41)  N=125 Crossover allowed upon disease progression

Kantoff PW, et al., J Clin Oncol 2010;28:1099–105. Primary endpoint is progression-free survival 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. RANDOMISED PHASE 3 PROSPECT TRIAL PROSTVAC+/- GM-CSF in mCRPC

PROSTVAC-VF + TRICOM + low dose Asymptomatic or adjuvant GM-CSF S minimally U symptomatic R PROSTVAC-VF + metastatic STANDARD V 1:1:1 TRICOM + adjuvant castration resistant OF CARE I prostate cancer Placebo V (N=1298) A Vector Placebo + L adjuvant Placebo

Primary endpoint: Overall survival Secondary endpoint: Progression-free survival

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

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

CTLA4 antibodies: Ipilimumab - Tremelimumab PD-1 antibody: Nivolumab - Pembrolizumab

In treating patients with previously treated with enzalutamide MM: S. Keefe Stats: L. Pang (NCT02312557) CS: A. Gipson Cin Ops: K. rt

Patients

 mCRPC

 ECOG PS 0 or 1

 PSA response to Response or SD  enzalutamide Enrolment Retreat with Pembro Continue enzalutamide  Not prior CT for  PD on until PD mCRCP enzalutamide by plus pembrolizumab (200 mg IV every 3w for  No prior CTLA-4, PD- PCWG2 (not four doses 1 or PD-L1 blockade clinical PD) PD STOP Pembro  Biopsy if there is a metastatic deposit that can be biopsied at Response baseline Assessment after 4 cycles

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

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

MM: S. Keefe Stats: L. Pang CS: A. Gipson Clin Ops: K. Kort

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

Graff J, et al., Oncotarget 2016;7(33):52810–7. KEYNOTE-028 (NCT02054806)

MM: S. Keefe Phase 1b multicohort study of pembrolizumab in PD-L1–positive Stats: L. Pang CS: A. Gipson advanced solid tumours Clin Ops: K. Kort

Patients Complete response, Treat for 24 months, or  Unresectable or § metastatic prostate partial response, or until progression or cancer stable disease intolerable toxicity

 Failure of or inability to Pembrolizumab receive standard therapy 10 mg/kg IV Q2W  ECOG PS 0 or 1

 Measurable disease Confirmed progressive Discontinue (RECIST v1.1) disease§ or † Response pembrolizumab  PD-L1 positive Assessment‡ unacceptable toxicity

‡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 †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.

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.

Hansen A, et al., Ann Oncol 2016;27(Suppl_6);725PD. TREATMENT-RELATED ADVERSE EVENTS

Any Grade Grade 3-4 N=23  There were no deaths or n (%) n (%) discontinuations due to Nausea 3 (13) 0 treatment-related AEs 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)

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

Hansen A, et al., Ann Oncol 2016;27(Suppl_6);725PD. TARGETED THERAPIES Molecular alteration in mCRPC Current or Potential Therapies

AR-V7 N-myc PARP inh Anti- PD1 / ATM BRCA2 WNT PD-L1 Taxanes PIK3CA/B PTEN AKT PI3K Inh CDK4/6 Inh ERG-FUSION Tankirase-Inh Purcupine-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 TOPARP-A PHASE II TRIAL OLAPARIB IN MCRPC

mCRPC

 1 or 2 QMT lines Phase II  ECOG 0-2

 No prior CDDP, cyclophosphamide, mitoxantrone, or PARP inhib Olaparib 400 mg twice a day

 PCWG2 progression Primary endpoint: Response Rate Baseline Characteristics of the 50 Study Patients Characteristic Value Received prior regimens for CRPC — no. (%) 2 3 (6) 3 7 (14) ≥4 40 (80) Results Received prior treatments — no. (%)  33% response rate Radical prostatectomy or radiotherapy 25 (50)  25.5% received treatment >6 m Castration (chemical or surgical) 5 (100) Abiraterone acetate 48 (96) Enzalutamide 14 (28) Docetaxel 50 (100) Cabazitaxel 29 (58) Radium-223 1 (2)

Mateo J, et al., N Engl J Med 2015;373:1697–708. TOPARP-A PHASE II TRIAL OLAPARIB IN MCRPC

Radiologic progression-free survival Overall survival

January 2016: FDA approved Olaparib for BRCA 1/2 and ATM mutated CRPC

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. ABIRATERONE + PREDNISONE +/– VELIPARIB IN mCRPC

Key inclusion criteria Arm A  Progressive mCRPC by at Metastatic tissue biopsy ETS AA + pred least 1 criteria: adequate for ETS fusion stratificiation – PSA progression status evaluation (+/–) Arm B – Measurable disease AA/pred + veliparib – Bone disease Registration 200(300) PO bid  No prior abiraterone

 Prior ketoconazole and Metastatic tissue biopsy chemo allowed inadequate for ETS Off protocol  Agree to undergo biopsy of fusion status evaluation metastatic site with adequate tissue (adequate metastatic archival tissue allowed)

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

*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] ABIRATERONE + PREDNISONE +/- VELIPARIB IN mCRPC

Best overall PSA and measurable PFS and OS disease response rate (Evaluable patients: N=148) Median OS (95% CI) AA: 30.6 mo (28.4, NR) Overall ETS(+) ETS(–) AA+V: 32.3 mo (28.4, NR) AA AA+V AA AA+V AA AA+V (n=72) (n=76) (n=25) (n=27) (n=47) (n=49) PFS Best overall PSA outcomes (%) PSA response 64.0 72.4 60.0 70.4 66.0 73.5 (CR/PR) 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 45.0 52.2 40.0 52.6 48.0 51.9 (CR/PR)

• No difference in PFS by ETS status

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. ABIRATERONE + PREDNISONE +/- VELIPARIB IN mCRPC PFS by DRD status overall and by arm Arm A: Abiraterone (n=31) PFS by DRD status (n=80)

Arm B: Abiraterone + Veliparib (n=47)

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

NCT Identifier Year Status Population Arms NCT01385293 2011 Phase II Trial Post chemo; prior sipuleucel-T, BKM120 Study was stopped at the abiraterone (Abi), or first stage due to futility enzalutamide (Enza) allowed. NCT01884285 2013 Phase I Trial TNBC/NSCLC or CRPC known AZD8186 (PI3Kβ and PI3Kδ) Active recruiting PTEN-deficient/PI3 mutated +/− Abi or AZD2014 (dual disease mTORC1/2 inhibitor) NCT02215096 2014 Phase I Trial PTEN-deficient mCRPC and Enza + GSK2636771 (PI3K- Active recruiting recently PD Enza beta inhibitor) n: 44 NCT02407054 2015 Phase II Trial mCRPC post PD Abi; no prior Enza+/- LY3023414 (PI3 Active recruiting chemo, immunotherapy or Kinase/mTOR Inhibitor) n: 144 Ra223 NCT02525068 2015 Phase II Trial PD 1 or 2 Taxanes and PD >12 Enza + AZD5363 (AKT (RE-AKT) Active recruiting weeks treatment to Abi inhibitor) N: 136 Abiraterone Enza Novel anti-AR

Olaparib PI3K / AKT Inh Immuno- mTORC-Inh therapy

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

Primary endpoint: Overall survival

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

• Recruitment in 324 centres from 43 countries across 6 continents, October 2010 through June 2012

Saad F, et al., Lancet Oncol. 2015;16(3):338-48. ELM-PC 4 TRIAL

Median: Orteronel plus prednisone 31.4 mo vs. placebo plus prednisone 29.5 mo Events: Orteronel plus prednisone 294 vs. placebo plus prednisone 317

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. CTLA-4 IN MCRPC CA 184-043 PHASE III STUDY

Ipilimumab Ipilimumab (10 mg/kg) (10 mg/kg Week 1, 4, 7, 10 every 12 w N=399 Post- Radio docetaxel Therapy Treatment till unacceptable toxicity mCRPC to bone or disease progression (n=799) (8Gy) N=400

Placebo Placebo Week 1, 4, 7, 10 every 12 w

Primary endpoint: Overall survival

Stratification: centre, Alk Ph, Hb and ECOG.

Kwon ED, et al., Lancet Oncol 2014;15:700–12. CA 184-043 PHASE III STUDY IPILIMUMAB

Overall Survival

Ipilimumab Placebo (n=399) (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

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. CA 184-095 PHASE III STUDY IPILIMUMAB

Ipilimumab Ipilimumab (10 mg/kg) (10 mg/kg Week 1, 4, 7, 10 Every 12 w mCRPC asymptomatic or For 3 years middle symptomatic (n=600) Placebo Placebo No visceral mets. Week 1, 4, 7, 10 every 12 w

Primary endpoint: Overall survival

Beer TM, et al., J Clin Oncol 35(1), 2017:40-47. CA 184-095 PHASE III STUDY IPILIMUMAB

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)

 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 THANK YOU!