Immunotherapy and new agents in CRPC. Karim Fizazi, MD, PhD Institut Gustave Roussy Villejuif, France

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1 Immunotherapy and new agents in CRPC Karim Fizazi, MD, PhD Institut Gustave Roussy Villejuif, France

2 Disclosure Participation to advisory boards/honorarium for: Amgen, Astellas, Astrazeneca, Bayer, Clovis, Curevac, Janssen, Orion, Sanofi

Initiation of Immune Response: Key Components

Tissue Antigen Antigen fragments Naive T-cell

Ready to rapidly respond to same antigen again

T-cell interaction T-cell activation Replication

3 Initiation of Immune Response: Key Components Peripheral Tissue Lymphoid Organs Peripheral Tissue Antigen Antigen fragments Naive T-cell Antigen presenting cell (APC) Activated T-cell Antigen receptors Effector cells: 1. Activate other immune cells 2. Kill target cells Memory cells: 1. Circulate for months years 2. Ready to rapidly respond to same antigen again Antigen recognition Activation Activated APC T-cell interaction T-cell activation Replication of antigen-specific T-cells T-cells become specialized Adapted from: Abbas AK, Lichtman AH. Basic Immunology. 3rd ed. 2011

4 Immunotherapy modalities in Oncology Cellular immunotherapy Therapeutic vaccines Checkpoint inhibitors (Cytokines) (Monoclonal antibodies)

5 PSA/Tumor Burden A Theoretical Mathematical Model of Differential Effects of Immunotherapy vs Chemotherapy Changes in PSA values might not reflect treatment response to immunotherapy Immunotherapy Cytotoxic Therapy Initiation of treatment Time Madan RA, et al. Oncologist 2010:15:969 75

6 Immunotherapy with demonstrated activity in CRPC - Sipuleucel-T

7 Autologous Cellular Immunotherapy With Sipuleucel-T PAP-GM-CSF combines with resting antigen presenting cell (APC) APC takes up the recombinant protein PAP-GM-CSF is processed and presented on surface of the APC PAP-GM-CSF loaded APCs are the active component of sipuleucel-t T cells proliferate and attack prostate cancer cells The precise mechanism of action of sipuleucel-t is not known Sipuleucel-T activates T cells in the body PAP-GM-CSF, Prostatic acid phosphatase-granulocyte-macrophage-colony-stimulating factor

8 A first «negative-positive» trial Small EJ, J Clin Oncol 2009; 24:

PROGRESSION Treated at Physician Discretion SURVIVAL IMPACT: Phase III

CRPC (N=512) 2:1 Sipuleucel-T Q2 weeks x 3 CONTROL* Q2 weeks x 3 Treated

Immunotherapy (n=62) Primary endpoint: Overall survival Secondary

control group, following progression, crossed over to receive autologous

9 PROGRESSION Treated at Physician Discretion SURVIVAL IMPACT: Phase III Trial of Sipuleucel-T 9 Asymptomatic or Minimally Symptomatic Metastatic CRPC (N=512) 2:1 Sipuleucel-T Q2 weeks x 3 CONTROL* Q2 weeks x 3 Treated at Physician Discretion (N=341) Cryopreserved Immunotherapy (n=109) No Immunotherapy (n=62) Primary endpoint: Overall survival Secondary endpoint: Time to objective disease progression 64% of patients in the control group, following progression, crossed over to receive autologous immunotherapy made from cryopreserved cells. Kantoff PW et al. N Engl J Med 2010; 363:

10 Survival, % Sipuleucel-T: Impact Phase 3 trial months Sipuleucel-T (n=341) Control (n=171) 25.8 months Sipuleucel-T: Time Since Randomization, Months 4.1 month survival benefit Reduction in risk of death: 22.5% HR = (95% CI: 0.614, P=0.032 not available in Europe NS, not statistically significant Kantoff PW, et al. N Engl J Med 2010;363:411 22

11 Checkpoint inhibitors in CRPC - CTLA-4 - PD1/PD-L1

13 Immune checkpoints Activating receptor Inhibitory receptor

14 Ipilimumab Blocks Negative Signaling of CTLA- 4 Dendritic cell MHC B7 B7 TCR CD28 CTLA-4 anti-ctla T cell Fong et al., J Clin Oncol 2008;26:

15 Ipilimumab Phase III development Phase III pre-docetaxel («95» trial): Ipilimumab vs placebo (/3w then /3 m) Phase III post-docetaxel («43» trial): RXT + Ipilimumab/placebo (/3w then /3m)

16 Ipilimumab phase III trial 043 : Study Design Screening Postdocetaxel CRPC (N=799) 1:1 Singledose, bonedirected RT (8 GY) N=399 Ipilimumab (10 mg/kg) Wks 1, 4, 7, 10 N=400 Placebo Wks 1, 4, 7, 10 Ipilimumab (10 mg/kg) Every 12 wks Placebo Every 12 wks Patients stratified by investigator site, alkaline phosphatase, hemoglobin, and ECOG PS Treatment until disease progression or intolerable toxicity Primary endpoint: overall survival (OS) Secondary endpoints: progression-free survival, safety Exploratory endpoint: PSA response rate

17 Proportion Alive Ipilimumab + RXT to bone: Overall Survival Patients at Risk Ipilimumab Placebo Ipilimumab (N=399) Placebo (N=400) Median OS (95% CI) 11.2 ( ) 10.0 ( ) HR (95% CI): 0.85 ( ) Stratified log-rank P= yr OS rate 47% 40% 2-yr OS rate 26% 15% Months Ipilimumab Censored Placebo Censored Kwon E, Lancet Oncol 2014; 15:

18 Proportion Alive Results: Updated OS n=799 Primary endpoint= OS Ipilimumab post-docetaxel phase III trial Ipi (n=399) Pbo (n=400) Median OS, mo (95% CI) 11.2 ( ) 10.0 ( ) HR (95% CI) 0.84 ( ) Stratified log-rank* P= yr OS rate 47% 41% 2-yr OS rate 25% 17% 3-yr OS rate** 12% 6% Ipi Censored Pbo Censored Months Fizazi K et al., ESMO September 2014, Madrid, Spain esmo.org

19 Long-lasting complete response after Ipilimumab in CRPC 2011: mcrpc progressing post-docetaxel Pain requiring opioids Ipilimumab + RXT to 1 bone lesion PSA 2017: No detectable disease at 6 years Cabel L, J Immunother Cancer 2017; 5: 31

20 Ipilimumab in CRPC (docetaxel-naïve) PFS OS Beer T, J Clin Oncol 2016

21 Immune checkpoint blockade Limited activity of PD-1/PD-L1 inhibitors in CRPC? (mutations are rare)

22 5% of prostate cancers with MMR mutations?

23 CRPC progressing after Enzalutamide Lymph node biopsy shows: - MYC amplification - TMPRSS2-ERG - MSH2, MSH6 mutations 05/27/16 07/11/16 Stop enzalutamide Atezolizumab Courtesy of Christophe Massard

24 Baseline 6/18/16 Post-Atezolizumab 8/16/16 : -40% Courtesy of Christophe Massard

25 Pembrolizumab + continuous Enzalutamide in Enzalutamide-progressing CRPC Responder Cycle 1 PSA (ng/ml) every 3-weeks and nadir Measurable Disease at Baseline Best Radiologic Response 1 April Yes (lymph) PR present 2 October No n/a n/a 3 January <0.01 Yes (liver) PR absent 4 March No n/a n/a 5 June * Yes (liver) PR pending MSI Graff JN, ESMO 2016

26 Pembrolizumab in CRPC: Keynote 0-28 Best Change From Baseline in Tumor Size Per RECIST v1.1, Investigator Review Hansen A, ESMO 2016

27 Turn a cold tumor into a hot one (Generate neo-antigens) Increasing PD-1 inhibition efficacy by: Radiation or other local treatments (cryo?) Systemic pression (Enzalutamide, etc) Selection of a subgroup (AR V7+?, DRD?) Anti-PD-1/PD-L1 + anti-ctla4 combination Checkpoint inhibition + vaccine?

PROGRESSION SURVIVAL Prostvac in Patients with mcrpc (Randomized Phase 2 study) Asymptomatic or Minimally Symptomatic Metastatic Castration Resistant Prostate Cancer

Endpoint: Progression Free Survival Secondary Endpoint: Overall Survival Prostvac: Recombinant viral vaccine:» Prime: recombinant vaccinia virus expressing PSA in

28 PROGRESSION SURVIVAL Prostvac in Patients with mcrpc (Randomized Phase 2 study) Asymptomatic or Minimally Symptomatic Metastatic Castration Resistant Prostate Cancer N=125 PSA-TRICOM + GM-CSF n=84 Treated at physician discretion 2:1 Treated at physician Empty Vector + Placebo n=41 discretion and/or salvage protocol Primary Endpoint: Progression Free Survival Secondary Endpoint: Overall Survival Prostvac: Recombinant viral vaccine:» Prime: recombinant vaccinia virus expressing PSA in combination with B7.1, ICAM and LFA-3» Boost: recombinant fowlpox virus expressing PSA in combination with B7.1, ICAM and LFA-3 Kantoff PW, et al. J Clin Oncol 2010;28:

29 Overall survival (% patients) Prostvac in Patients with mcrpc Phase 2: Efficacy N Deaths Median Control PROSTVAC month survival benefit Reduction in risk of death: 44% HR: 0.56 (95% CI: ) P= Control PROSTVAC Months NS, not statistically significant Kantoff PW, et al. J Clin Oncol 2010;28:

30 Prospect Trial: Design (SPA) Phase 3 Global (US-CAN-AUS/WE/EE/Latin America) Non/Minimally symptomatic Metastatic Castration Resistant Prostate Cancer PROSTVAC-(V)(F) TRICOM + low dose adjuvant GM-CSF PROSTVAC-(V)(F) TRICOM Adjuvant placebo No cross Over Standard of Care S U R V I V A L Vector Placebo Adjuvant placebo

31 Conclusion: Immunotherapy Immunotherapy has demonstrated effect on overall survival in prostate cancer (Sipuleucel-T: not available in Europe) New approaches ongoing: CTLA4 (Ipilimumab): PFS met, not OS PD-1/PD-L1: Preliminary activity Prostvac: Phase 3 data expected

32 «Other» drugs

33 Genomics and new targets in CRPC Robinson, Cell 2015

34 DNA damage repair defect

35 PARP and DNA repair: Summary description DNA damage initiates repair PARP binds to DNA PARP enzyme modifies itself with polyadp ribose Recruitment of repair enzymes Repair and dissociation Bender et al. PARP inhibitors on trial. Turning Point 2011

36 Synthetic lethality

37 BRCA-related synthetic lethality with PARP inhibition Sonnenblick et al. Nature Reviews Clinical Oncology 2015; 12: 27 41

general population Somatic DNA repair mutations: - 10% in men with

38 DNA repair and prostate cancer Germline DNA repair mutations: - 12% in men with M1 prostate cancer - 5% in men with localized CaP - 3% general population Somatic DNA repair mutations: - 10% in men with mcrpc? Pritchard CC, NEJM 2016: 375: Robinson D, Cell 2015; 162: 454

39 Cumulative Survival Cumulative Survival Time from ADT initiation to mcrpc by germline DDR status CI-95% Median PFS Noncarriers months 28.2 Carriers 18.6 months ( ) ( ) Log-rank p= 0.04 CI-95% Median PFS Non BRCA2 months BRCA months ( ) ( ) Log-rank p= 0.05 n=419 mcrpc pts DDR+= 9.1% Months Months esmo.org Castro E, ESMO 2017

40 DNA repair defects and CRPC Not only young men Not only those with a family history Worse prognosis Likely maintained sensitivity to current drugs, although of less duration: Taxanes AR targeted drugs

41 Olaparib: activity is predicted by DRD gene mutations Mateo, N Engl J Med 2015;373:

42 PARP inhibitors in CRPC 4 compounds currently in trials (P2-3): Olaparib Niraparib Rucaparib Talazoparib Patient selection: Tumor sample vs ctdna? Monoallelic vs Biallelic? Are all gene mutations the same? Germline vs somatic mutations?

43 PARP inhibitors in CRPC What is needed for approval? OS? Efficacy vs Carboplatin? Post-carboplatin? Use earlier?

44 Targeting the Akt and the AR pathways Abiraterone androgen precursors synthesis adrenal testicular tumor androgens Ipatasertib AR target genes

45 200 mg Ipatasertib 400 mg Ipatasertib Abiraterone +/- Ipatasertib (Akt inhibitor): PFS PTEN loss PTEN non-loss HR, a 0.39 ( ) 400 mg Ipat + Abi Median 11.5 mo Pbo + Abi Median 4.6 mo HR, a 0.84 ( ) 400 mg Ipat + Abi Median 7.5 mo Pbo + Abi Median 5.6 mo HR, a 0.46 ( ) 200 mg Ipat + Abi Median 11.1 mo 200 mg Ipat + Abi Median 4.6 mo HR, a 1.13 ( ) Pbo + Abi Median 4.6 mo Pbo + Abi Median 5.6 mo a Unstratified HR; 90% CI. de Bono et al, Ipatasertib, ESMO 2016

submandibular +++ Type II transmembrane glycoprotein (FOLH1) 68 Ga-PSMA-11 177 Lu-PSMA- 617 liver+ spleen+ Highly

46 Image from Maurer T et al. Nat Rev Urol, 2016 Apr;13(4): HOFMAN Prostate specific membrane antigen (PSMA) lacrimal +++ suv parotid +++ submandibular +++ Type II transmembrane glycoprotein (FOLH1) 68 Ga-PSMA Lu-PSMA- 617 liver+ spleen+ Highly over-expressed in prostate cancer castrate-resistant metastatic disease kidney+++ small bowel+ (duodenum++) 111 In-capromab Prostascint radioactive urine PSMA PET normal biodistribution LuPSMA Theranostic Hofman et al

47 HOFMAN THERANOSTICS TARGETED THERAPEUTIC + DIAGNOSTIC COMPANION 177 Lu-PSMA Ga-PSMA-11 PET/CT Posttherapy SPECT/CT Pretherapy PET/CT LuPSMA Theranostic Hofman et al

48 HOFMAN 177 LU-PSMA-617: 1º ENDPOINT: PSA RESPONSE PSA 12 Weeks from 1 st dose Best PSA Response (PCWG2 criteria) >50% in 50% >50% in 57% >80% in 27% >80% in 43% LuPSMA Theranostic Hofman et al Hofman MS, ESMO 2017

49 Finally, can we improve outcomes with simple, old treatments?

50 PEACE-4: European Phase III Trial of Aspirin and Statin in CRPC Funded! Standard of care (SOC) Patients with early CRPC Stratification on M0 vs M patients planned R A N D O M I Z E D SOC + Aspirin 100 mg SOC + Statin Primary endpoint: OS (HR: 0.77) SOC + Aspirin + Statin Study sponsor: Gustave Roussy Courtesy of K Fizazi

51 Conclusion: Targeted treatments AR targeting remains key (major oncogenic driver) DNA damage repair defect clearly emerging PSMA targeting clearly emerging PI3K/Akt/Pten targeting clinically relevant? Immunotherapy as a player Role of non-anticancer drugs? (Metformin, Aspirin, Statins)

PROSTATE CANCER HORMONE THERAPY AND BEYOND. Przemyslaw Twardowski MD Professor of Oncology Department of Urologic Oncology John Wayne Cancer Institute

PROSTATE CANCER HORMONE THERAPY AND BEYOND Przemyslaw Twardowski MD Professor of Oncology Department of Urologic Oncology John Wayne Cancer Institute Disclosures I am a Consultant for Bayer and Sanofi-Aventis