Patients Living Longer: The Promise of Newer Therapies

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1 Patients Living Longer: The Promise of Newer Therapies David M. Nanus, MD! Chief, Division of Hematology and Medical Oncology! Weill Cornell Medicine! New York Presbyterian Hospital!!

2 Demographics 180,890 estimated new cases in 2016! % of all cancers in males! - most common cancer in men! - Lifetime risk: 16% (1 in 6)!! 26,120 estimated deaths! - 8.3% of cancer deaths in males! - second to lung cancer in men! - decreased by 3.5% per year 2003 to 2012!

3 Death from other causes! Death from! Prostate cancer! Clinically! Localized! Disease! Rising! PSA! Clinical! Metastases! Non-Castrate! Castrate! Rising! PSA! Castrate! Metastatic! Disease! Adapted from Scher et al.!

4 Prostate Cancer Clinical States Model Scher HI, Am Soc Clin Oncol Educ Book. 2014:e

Androgen Deprivation Therapy (ADT) = Testosterone Lowering Therapy = Hormonal Therapy! Charles Huggins recognized as an androgen -sensitive disease in 1941!

5 Androgen Deprivation Therapy (ADT) = Testosterone Lowering Therapy = Hormonal Therapy! Charles Huggins recognized as an androgen -sensitive disease in 1941!! 21 patients metastatic prostate cancer orchiectomy or administration of phenolic estrogens (stibestrol) resulted in regression in prostate cancer, extended life span, and decreased man-pain hours! Huggins et al, Cancer Res 1941 Huggins et al, Arch Surg 1941

6 Prostate Cancer Clinical States Model Scher HI, Am Soc Clin Oncol Educ Book. 2014:e

Probability E3805 CHAARTED: ChemoHormonal Therapy versus Androgen Abla?on Randomized Trial for Extensive Disease in Prostate Cancer 1.0 0.

12 months R A N D O M IZ E ARM A: ADT + Docetaxel 75mg/m2 every 21 days for maximum 6 cycles ARM B: ADT (androgen deprivation therapy alone) 0.8 0.7 0.6 0.5 0.

7 Probability E3805 CHAARTED: ChemoHormonal Therapy versus Androgen Abla?on Randomized Trial for Extensive Disease in Prostate Cancer STRATIFICATION Extent of Mets - High vs Low Age 70 vs < 70yo ECOG PS vs 2 CAB> 30 days - Yes vs No SRE PrevenLon - Yes vs No Prior Adjuvant ADT 12 vs > 12 months R A N D O M IZ E ARM A: ADT + Docetaxel 75mg/m2 every 21 days for maximum 6 cycles ARM B: ADT (androgen deprivation therapy alone) OS (Months) HR=0.61 ( ) p= Median OS: ADT + Docetaxel: 57.6 months ADT alone: 44.0 months Presented by: Christopher Sweeney ASCO 2014

8 What s new in prostate cancer therapy? Targeting the androgen axis! Immunotherapy! Chemotherapy (what and when)! Bone targeted therapies! Molecular genetics! Circulating Biomarkers! - prostate cancer tumor cells! - ctdna!

Volume and AcLvity Local Therapy CastraLon Hormone Therapy AsymptomaLc Sipuleucel- T Abiraterone or Enzalutamide

9 Mul?ple Treatment Op?ons Are Now Available for Men With Metasta?c Prostate Cancer Natural History of Lethal Prostate Cancer and Treatment OpLons NonmetastaLc MetastaLc Tumor Volume and AcLvity Local Therapy CastraLon Hormone Therapy AsymptomaLc Sipuleucel- T Abiraterone or Enzalutamide Docetaxel Cabazitaxel Enzalutamide Radium- 223 SymptomaLc NONMETASTATIC Time Higano CS. Springer Science+Business Media, LLC; 2010: ; NCCN Guidelines. Version

10 Adapted from Harris et al. Nature Reviews Clin Onc 2009!

Enzalutamide (Xtandi) Oral drug rationally designed

cytoplasm T AR Enzalutamide 2 Inhibits Nuclear

11 Enzalutamide (Xtandi) Oral drug rationally designed to target AR signaling, impacting multiple steps in AR signaling pathway. No demonstrated agonist effects in preclinical models. 1 T Inhibits Binding of Androgens to AR Cell cytoplasm T AR Enzalutamide 2 Inhibits Nuclear TranslocaLon of AR Cell nucleus AR Tran et al. Science 2009;324: Charles Sawyers & Michael Jung 3 Inhibits AssociaLon Of AR with DNA

12 Simplified view of cholesterol à testosterone synthesis! cholesterol Occurs in: Testes,! Adrenal Gland,! Prostate cancer cells! pregnenolone CYP17! CYP17! 17α- hydroxy- pregnenolone DHEA androstenedione Mineralocor?coids Cor?sol Testosterone DHT Montgomery et al. Cancer Res 2008! Locke et al. Cancer Res!

13 Abiraterone! Acetate! (Zytiga)! cholesterol n n Oral irreversible inhibitor of CYP17!!- 17α hydroxylase!!- C 17,20 -lyase! Inhibits testosterone production in testis, adrenal, and prostate! pregnenolone CYP17! CYP17! 17α- hydroxy- pregnenolone DHEA androstenedione Mineralocor?coids Cor?sol Testosterone DHT Montgomery et al. Cancer Res 2008! Locke et al. Cancer Res!

mcrpc Post-chemotherapy COU-AA-302 PREVAIL Co-Primary

14 Abiraterone and Enzalutamide: Four Positive Studies! mcrpc Pre-chemotherapy mcrpc 1 st Line Chemotherapy mcrpc Post-chemotherapy COU-AA-302 PREVAIL Co-Primary Endpoints: OS, rpfs COU-AA-301 AFFIRM Primary Endpoint: OS

15 Immunotherapy Cancer vaccines Modulation of immune regulatory mechanisms - Blocking CTLA-4 - Blocking PD-1 or PDL-1 Monoclonal antibody targeting of tumour growth

Sipuleucel-T: Autologous APC Cultured with

Prostatic Acid Phosphatase (PAP) antigen

cell (APC) APC takes up the antigen Antigen

the APC Active T-cell Fully activated, the

T-cells in the body The precise mechanism

16 Sipuleucel-T: Autologous APC Cultured with PAP-cytokine Fusion Protein Recombinant Prostatic Acid Phosphatase (PAP) antigen combines with resting antigen presenting cell (APC) APC takes up the antigen Antigen is processed and presented on surface of the APC Active T-cell Fully activated, the APC is now sipuleucel-t INFUSE PATIENT Inactive T-cell T-cells proliferate and attack cancer cells Sipuleucel-T activates T-cells in the body The precise mechanism of sipuleucel-t in prostate cancer has not been established.

17 IMPACT Trial! HR=0.759 (95% CI: 0.606, 0.951) P=.017 (Cox model) Median Survival Benefit: 4.1 months Sipuleucel- T (n=341) Median Survival: 25.8 months 36- months survival: 32.1% Control (n=171) Median Survival: 21.7 months 36- months survival: 23.0% Kantoff et al, ASCO GU 2010

18 PROSTVAC: Overall Survival Hazard Ratio = 0.56 (95% CI 0.37 to 0.85) P = (stratified logrank) N Control 40 PROSTVAC 82 Deaths Median Months Kantoff, ASCO 2009 J Clin Oncol, in press

Nature Reviews Cancer 12, 252-264 (April 2012) Cancer Immunotherapy: Checkpoint Inhibitors Mutations make tumors recognizable by the immune system Oncogenic signaling in tumor cells can stimulate

19 Nature Reviews Cancer 12, (April 2012) Cancer Immunotherapy: Checkpoint Inhibitors Mutations make tumors recognizable by the immune system Oncogenic signaling in tumor cells can stimulate PD-L1 expression to help evade immune surveillance Inhibiting the PD-L1/PD-1 interaction (Checkpoint Inhibitors) can restore anti-tumor T-cell activity, potentially leading to long-lasting responses

Second Generation Anti-PSMA Abs: J591 2nd

20 Second Generation Anti-PSMA Abs: J591 2nd generation mabs Bind extracellular domain Bind viable PSMA + cells Rapidly internalized Capromab binding site J591 binding site Liu H et al. Cancer Res 1997; 57: 3629 Liu H et al. Cancer Res 1998; 58: 4055

21 100% 50% Individual best PSA changes 0% -50% -100% Low dose = 14.6 mo RP2D = 27.7 mo P = 0.004* At optimal dose: 87.5% with PSA decline Median survival 48.3 months 40 mci/m 2 x2 = 19.6 mo 45 mci/m 2 x2 = 48.3 mo P = Fractionated 177 Lu-J591 Presented by: Scott T. Tagawa

22 J591 PSMA- Targeted PET Scan SubstanLal improvement over convenlonal imaging (bone, CT, MR, FDG) Confirms ability of J591 to target PC wherever it is in body Allows quanltalve imaging

Pt with no known soft tissue disease until 89 Zr-J591

Zr89-J591 PET (avid) Pathology Diagnosis: Aortocaval node

23 Pt with no known soft tissue disease until 89 Zr-J591 detected this LN met CT (not detected) FDG PET (non avid) Zr89-J591 PET (avid) Pathology Diagnosis: Aortocaval node biopsy: Prostatic adenocarcinoma. Positive for PSA and PSAP by IHC. Patient with rising PSA, suspicious LN on MRI, but CT and FDG negative. 89 Zr-J591 avid; biopsy-proven as the first metastatic site in the patient. CT (not detected) FDG PET (non avid) Morris et al, 2013 Genitourinary Cancers Symposium Zr89-J591 PET (avid)

24 Molecular Markers Beyond the microscope! May be diagnostic, prognostic, and/or predictive! Gene fusions! Expression of abnormal proteins! Circulating Tumor Cells (CTCs)! Circulating Tumor DNA!

25 Molecular Classification of Prostate Cancer * Discoveries led by NYP- Weill Cornell Medical College

27 January 2016: olaparib granted FDA Breakthrough DesignaLon for BRCA1/2 and ATM mutated CRPC Mateo et al, NEJM 2015

28 Detec?on of BRCA2 loss in tumor in circula?ng tumor DNA Chedgy et al, Clin Genitourin Ca, 2015

30% Switch to docetaxel Cycle 1 Cycle 5 Screening Day 1 Day 8 Day 1 Day 8 Progression CTC CTC CTC CTC CTC CTC

29 TAXYNERGY: Study Design Docetaxel 75 mg/m 2 30% < 30% Continue docetaxel Switch to cabazitaxel Patients with mcrpc (N = 63) Randomized 2:1 PSA reduction after 4 cycles Follow-up Cabazitaxel 25 mg/m 2 30% Continue cabazitaxel < 30% Switch to docetaxel Cycle 1 Cycle 5 Screening Day 1 Day 8 Day 1 Day 8 Progression CTC CTC CTC CTC CTC CTC Primary Endpoint: PSA response rate ( 50% reduction from baseline) Co-primary Endpoint: DTE Presented by: Scott T. Tagawa

30 CRPC Therapeutic Options Abiraterone/P vs. placebo/p! Enzalutamide vs. placebo!! Docetaxel(q3w)/P vs. Mitoxantrone/P! Cabazitaxel/P vs. mitoxantrone/p! Sipuleucel T vs. placebo!! Alpharadin vs. placebo! Increase in median survival! Relative reduction in risk of death! Hazard ratio! (95% CI; P-value)!! 3. 9 mos! 35%! 0.65! ( ; P<0.001)! 4.8 mos! 37%! 0.63! (P<0.0001)! 2.4 mos! 24%! 0.76! ( ; P=0.009)! 2.8 mos! 30%! 0.70! ( ; P<0.0001)! 4.1 mos! 22%! 0.78! ( ;! P:0.03)!! 2.8 mos! 31%! 0.70! ( ; P: )!

SESSIONE PLATINUM SERIES (Best Papers Poster o Abstract on Prostate Cancer) In Oncologia

SESSIONE PLATINUM SERIES (Best Papers Poster o Abstract on Prostate Cancer) In Oncologia Divisione di Oncologia Medica Unità Tumori Genitourinari SESSIONE PLATINUM SERIES (Best Papers Poster o Abstract