Prostate Cancer Teaching Session Dr Anthony Joshua Kinghorn Cancer - PowerPoint PPT Presentation

Prostate Cancer Teaching Session Dr Anthony Joshua Kinghorn Cancer Centre St Vincents Hospital, Sydney

Natural History of Prostate Cancer Hormone-Sensitive Castrate-Resistant Tumor Volume & Activity Androgen Deprivation Chemotherapy Death Therapies After LHRH Surgery and Agonists Radiation and Antiandrogens Postchemotherapy Immunotherapy Radiographically Metastatic Premetastatic 7-15 years Asymptomatic Symptomatic 3-5 years NOTE: This diagram represents typical disease progression. Note that some patients are metastatic at diagnoses, and are thus still hormone-sensitive. 1. Chen Y, et al. Lancet Oncol. 2009;10:981-991. 2. Hofland J, et al. Cancer Res. 2010;70:1256-1264. 2

Question 1

Gleason Score Small Uniform Glands More Space Between Glands Infiltration of cells from glands at margins Irregular masses of cells few glands Lack of glands, sheets of cells More Aggressive

Question 2

The patient-based meta-analysis showed no significant benefit of MAB after 8000+ pts and 27 trials MAB is expensive, has increased toxicity, and should not be used Presentation to Medical Residents

Presentation to Medical Residents

Median survival was 5.8 years in the continuous-therapy group and 5.1 years in the intermittent-therapy group (HR for death with intermittent therapy, 1.10; 90% confidence interval, 0.99 to 1.23). Intermittent therapy was associated with better erectile function and mental health (P<0.001 and P=0.003, respectively) at month 3 but not thereafter.

Minimal disease was disease confined to the spine, pelvic bones, or lymph nodes, and extensive disease was disease present in the ribs, long bones, or visceral organs.

The median survival after randomization among patients with extensive disease was 4.9 years in the intermittent-therapy group, as compared with 4.4 years in the continuous-therapy group (hazard ratio for death with intermittent therapy, 1.02; 95% CI, 0.85 to 1.22). The median survival after randomization among patients with minimal disease was 5.4 years in the intermittent- therapy group, as compared with 6.9 years in the continuous-therapy group (hazard ratio for death with intermittent therapy, 1.19; 95% CI, 0.98 to 1.43).

Question 3

The CHAARTED Hypothesis Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

E3805 – CHAARTED Treatment Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

Primary endpoint: Overall survival Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

Causes of Death Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

OS by extent of metastatic disease at start of ADT Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

ADT + Docetaxel benefited all subgroups Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

Secondary Endpoints Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

Question 4

Secondary hormonal therapy  Mr Rodrigues is prescribed the anti- androgen bicalutamide in addition to his goserelin injections.  His PSA decreases and his pain improves, but about 6 months later he again has a rising PSA and pain.  The bicalutamide is stopped and he again has a transient response for about 3 months Presentation to Medical Residents

Secondary hormonal therapy  About 80% of men respond to orchiectomy or LHRH agonist for a median of 1-2 years.  About 30% respond to the subsequent addition of an anti-androgen for a few months  About 20-30% of those who responded to addition of an anti-androgen will respond to its withdrawal (Antiandrogens start to stimulate prostate cancer cells instead of killing them!) Presentation to Medical Residents

Prednisone  Low dose steroid  5 mg in morning and 5mg in afternoon  Improves energy, appetite, weight  Minimal side effects  ~30% PSA response rate

Ketoconazole  Antifungal agent suppresses adrenal androgens  Given concurrently with Hydrocortisone  Some patients show PSA response  Side effects: Decreased energy, Nausea, Liver toxicity

New Hormonal agents  Abiraterone  Enzalutamide  TAK700  Galeterone

Question 5

Abiraterone Acetate • 250mg tablet formulation • Irreversible and specific steroidal inhibitor of CYP17 (P450c17) 1 • Abiraterone acetate is a novel inhibitor of androgen synthesis uniquely blocking testosterone production in the testes, adrenal glands, 3β -Acetoxy-17- and intra-tumoral prostatic (3-pyridyl) tissue. androsta-5,16-diene MW = 391.55 1. Shah et al Expert Opin. Investig Drugs 2010 28

The Suppression of Testosterone By Abiraterone Acetate ’ s Inhibition Of CYP17 In Men With Castration-Resistant Prostate Cancer Hypokalemia Hypertension Fluid overload ACTH Renin-angiotensin- x5 aldosterone loop Positive drive Negative feedback Pregnenolone Deoxycorticosterone Corticosterone Aldosterone x10 x40 x1.5 17 α -hydroxylase x2 x2 x2 17OH-Pregnenolone 11-deoxycorticol Cortisol C17,20-lyase < 1 nmol/dl Testosterone < 0.34 x3 Androstenedione DHEA nmol/L Estradiol < 3 pmol/l 1. Cougar Biotechnology Investigator ’ s Brochure Sept 2010

Selective androgen biosynthesis inhibitor Low-dose steroid replacement minimizes Mineralocorticoid-related toxicty ACTH Pregnenolone Deoxycorticosterone Corticosterone Aldosterone 17 α -hydroxylase 17OH-Pregnenolone 11-deoxycorticol Cortisol C17,20-lyase Testosterone Androstenedione DHEA Estradiol Attard G et al. J Clin Oncol 2008; 26(28): 4563-4571

COU302 pre-chemo

COU302

COU302

Question 6

MDV-3100 Enzalutamide Scher et al, NEJM epub Aug 15, 2012

PREVAIL: A Multinational Phase 3, Randomized, Double-Blind, Placebo- Controlled Efficacy and Safety Study of Oral MDV3100 in Chemotherapy- Naïve Patients with Progressive Metastatic Prostate Cancer Who Have Failed Androgen Deprivation Therapy  Co-primary endpoints OS and PFS  Planned evaluations – OS/radiographic PFS – Time to first SRE – Initiation of cytotoxic chemotherapy – QoL • FACT-P, EQ-5D n=1717 mCRPC Enzalutamide – PSA progression Asymptomatic or 160 mg qd* – Pain palliation R mildly symptomatic • BPI-SF 1:1 Progresion – Safety Placebo qd* after ADT • AEs, vital signs, physical exam, lab evaluations, ECG – * Patients required to be on continuous ADT (castration or Pharmacokinetics GnRH analogue) with study drug or placebo – Subgroups CONFIDENTIAL – FOR INTERNAL, NON-PROMOTIONAL USE ONLY. PROPRIETARY INFORMATION OF ASTELLAS. DO NOT COPY OR DISTRIBUTE.

Enzalutamide Reduced Risk of Death by 29% 100 Hazard Ratio: 0.706 (95% CI: 0.60,0.84) 90 P <0.0001 80 70 Survival (%) 60 50 40 30 20 Enzalutamide Patients still alive at data cut off 10 Placebo Enzalutamide: 72%; Placebo: 63% 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Duration of Overall Survival (Months ) Patients at Risk Enzalutamide 872 850 824 797 745 566 395 244 128 33 2 0 863 835 213 102 27 2 0 Placebo 845 781 744 701 644 484 328 Estimated median OS, months (95% CI): Enzalutamide: 32.4 (30.1, NYR); Placebo: 30.2 (28.0, NYR) NYR = Not Yet Reached 3 7

Enzalutamide Prolonged Radiographic Progression-Free Survival 100 Radiographic Progression-Free Survival (%) Hazard Ratio: 0.186 90 (95% CI: 0.15, 0.23) P <0.0001 80 70 60 50 40 30 20 Enzalutamide 10 Placebo 0 0 3 6 9 12 15 18 21 Time from Randomization (Months ) Patients at Risk Enzalutamide 832 514 256 128 34 5 1 0 Placebo 801 305 79 20 5 0 0 0 Estimated median rPFS, months (95% CI): Enzalutamide: NYR (13.8, NYR); Placebo: 3.9 (3.7, 5.4) NYR = Not Yet Reached 38

Subsequent Therapies Were Used More Commonly in the Placebo Group Enzalutamide Placebo (n=872) (n=845) Patients with at least one 40.3% 70.3% subsequent life-extending therapy Percentage of Patients Receiving Subsequent Therapies Docetaxel 32.8% 56.7% Abiraterone 20.5% 45.6% Cabazitaxel 5.8% 13.0% Enzalutamide 1.0% 4.4% Sipuleucel-T 1.4% 1.2% 39

Enzalutamide Delayed Median Time to Chemotherapy by 17 Months 100 Hazard Ratio: 0.35 Cytotoxic Chemotherapy Free (%) 90 (95% CI: 0.30, 0.40) P <0.0001 80 70 60 50 40 30 20 Median Enzalutamide 28.0 months 10 Enzalutamide Placebo Placebo 10.8 months 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Time to Initiation of Cytotoxic Chemotherapy (Months) Patients at Risk Enzalutamide 872 854 799 751 665 575 388 252 158 78 21 2 0 Placebo 845 734 518 415 324 257 165 103 64 25 9 0 0 4 0

Mr Rodrigues tries ketoconazole and hydrocortisone for 3 months, but his pain gets worse and his PSA continues to rise He now has castrate resistant prostate cancer Mr Rodrigues has severe pain in his right hip. He is fatigued and has several other painful areas What treatment should be given? Presentation to Medical Residents

Hormone Refractory Prostate Cancer (HRPC/CRPC)  Progression despite hormonal therapy  Disease progression  PSA progression  Clinical Progression  Radiologic Progression