Advanced Prostate Cancer

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Myles Justin Barrett
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1 Advanced Prostate Cancer January 13, 2017 Sindu Kanjeekal MD FRCPC Medical Oncology and Hematology Regional Systemic Quality Lead Erie St Clair Adjunct Professor Schulich School of Medicine and University of Windsor

2 Disclosures Honoraria from Janssen, Astellas, Sanofi

3 Objectives 1. Review natural history of advanced prostate cancer 2. Metastatic disease in castrate sensitive setting 1. Early Chemotherapy 3. Metastatic disease in castrate resistant setting 1. Androgen inhibitors 2. Chemotherapy 3. Bone directed therapy 4. Future directions

4 Background In Canada, Prostate Cancer is the most common cancer among men 3 rd most common cause of cancer death in men prostate cancer that recurs after local treatment usually responds at least temporarily to androgen deprivation therapy (ADT) Most patients experience disease progression on ADT within 18-24m

6 PSA

7 Androgen drives PC growth Androgen can come from testicular (90%) non-testicular (10%) Extra-testicular androgen production plays an important role in resistance of PC cells to medical or surgical castration ADT orchiectomy LHRH agonists/antagonists Androgen receptor antagonists

Castrate Resistance NEW Definitions Hormone Resistance Castrate sensitive prostate cancer (CSPC) disease progression in the setting of normal testosterone levels Castrate resistant prostate cancer

8 Castrate Resistance NEW Definitions Hormone Resistance Castrate sensitive prostate cancer (CSPC) disease progression in the setting of normal testosterone levels Castrate resistant prostate cancer (CRPC) Disease progression despite castrate levels of testosterone: rising PSA, progression of pre-existing disease or new metastases Extra-testicular androgen production plays significant role in resistance of PC cells to medical castration Castrate=testosterone level <1.7nmol/L (8-28) or <50ng/dL Androgen receptor remains active in CRPC so ADT is continued indefinitely

9 Prostate Cancer Progression Primary localized disease PSA-only relapse Metastatic disease Castrate Sensitive Castrate Resistant

Case 1: (Metastatic Castrate Sensitive) 50 yo man previously well Had PSA in 2012 was normal In the fall 2013 was a little tired, had some hip pain and shoulder pain

11 Case 1: (Metastatic Castrate Sensitive) 50 yo man previously well Had PSA in 2012 was normal In the fall 2013 was a little tired, had some hip pain and shoulder pain PSA=100 then PSA=125 Rectal exam:hard nodular prostate gland TRUS biopsy:gleason score 9 in 10/12 cores Bone scan showed extensive bone mets CT normal except bone mets

12 Case 1 (metastatic castrate sensitive) Started on ADT by urologist with improvement in bone pain PSA down to 13 in couple of months Referred to Medical Oncology What next?

13 Metastatic Prostate Cancer

14 Early Chemo+ADT: A debate in one slide a need for randomized phase 3 trial Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

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

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

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

18 Other studies GET-UG (France) n=385 OS HR=1.01 Chaarted (US) n=790 OS HR=0.61 Stampede (UK) n=1817 OS HR=0.76 Gravis G, et al. Lancet Oncol. 2013;14: Sweeney CJ, et al. N Engl J Med. 2015;373: James ND, et al. Lancet. 2016;387:

19 Case 1A (Metastatic castrate sensitive ) Pt had high burden of metastatic disease Good PS once ADT started and bone pain controlled Recommended 6 cycles docetaxel chemotherapy then continue with ADT until PSA rises or progression of metastases (castrate resistance)

20 Case 1B 12m later:rising PSA (metastatic castrate resistant-crpc) Still on ADT PSA was 2 now rising PSA=15 then 40 Testosterone=0.1nmol/dL Secondary hormonal treatment did not affect PSA addition of casodex or withdrawl/ketoconozole/prednisone: no survival advantage-transient PSA response in ~30% of patients

21 Case 1B 12m later: Rising PSA (metastatic castrate resistant-crpc) Restaging bone scan and shows progression of bone mets Treatment Options?

22 Metastatic Prostate Cancer

Androgen Receptor signaling inhibit androgen biosynthesis block androgen receptor activation Abiraterone Acetate (Zytiga) Potent irreversible inhibitor of CYP- 17 critical enzyme in androgen

23 Androgen Receptor signaling inhibit androgen biosynthesis block androgen receptor activation Abiraterone Acetate (Zytiga) Potent irreversible inhibitor of CYP- 17 critical enzyme in androgen biosynthesis Enzalutamide (Xtandi) Potent multi-targeted androgen signaling pathway inhibitor Abiraterone or enzalutamide are recommended as first line for minimally symptomatic met CRPC or if progressing after docetaxel based chemotherapy (Level 1,grade A)

24 Abiraterone Acetate Cholesterol + Prednisone Desmolase Renin Pregnenolone Progesterone Deoxy- Corticosterone corticosterone X CYP17 17α-hydroxylase 11β- Hydroxylase Aldosterone 17α-OHpregnenolone X CYP17 C17,20-lyase 17α OHprogesterone 11-Deoxycortisol DHEA Androstenedione Testosterone 5α-reductase Cortisol DHT CYP19: aromatase ACTH Autocrine and paracrine (adrenal) pathways Attard G, et al. JCO. 2008;26: Estradiol

25 Abiraterone Acetate in Chemo-Naive mcrpc OS 30.3 mos (PBO) 34.7 mos (ABI); HR 0.81; P =.0033 Ryan CJ, et al. Lancet Oncol. 2015;16: Ryan CJ, et al. N Engl J Med. 2013;368:

26 Abiraterone Acetate: Safety Profile Ryan CJ, et al. Lancet Oncol. 2015;16:

27 PREVAIL: Enzalutamide in Chemo-Naive CRPC Overall Survival rpfs N = 1717; randomized 1:1 ENZ vs PBO Asymptomatic minimally symptomatic rpfs reduced by 81% Risk of death reduced by 29% Significantly delayed time to opiate initiation Beer TM, et al. N Engl J Med. 2014;371: Beer TM, et al. ASCO Abstract Loriot Y, et al. Lancet Oncol. 2015;16:

28 PREVAIL: Enzalutamide Safety Beer TM, et al. N Engl J Med. 2014;371:

29 Differences in drug characteristics Abiraterone Enzalutamide Oral yes yes Prednisone required yes no Drug interactions (CYP) yes yes Lowers seizure threshold no yes Potential liver toxicity yes less Risk for hypertension yes yes Risk for CV events, atrial fib Dose 250 mg x 4 40 mg tablets x 4 Empty stomach yes no yes yes

30 Timing and Selection of Secondary AR- Directed Therapies Similar OS, PFS from cross-trial comparisons Both are category 1 recommendations in NCCN guidelines Therefore choice is based on differential toxicity Abiraterone acetate for seizure-prone men and those more frail, elderly (> 75 years old) men at high risk for falls Enzalutamide for men with significant CV risk factors, contraindications to prednisone, brittle diabetes, and metabolic syndrome Significant cross-resistance, so initial choice is likely most important one

31 Bone targeted therapy Denosumab (Xgeva) or Zoledronic Acid (Zometa) inhibits osteoclast activity prevents SREs (Level 1,Grade A) Does not improve OS Watch for ONJ ~2%(appears time dependent) Only if bone mets present Castrate resistant PC Radium-223 (XOFIGO) recommended in patients with pain due to bone metastases and no visceral mets (Level 1,Grade A) Improves OS

a calcium mimetic 2-10 cell diameter range of alpha-particle Radium-223 Perez et al.

32 Mechanism of Action of and Administration of Radium-223 Radium-223 is a short-range but high-energy alpha-emitting particle It targets osteoblastic bone metastases by acting as a calcium mimetic 2-10 cell diameter range of alpha-particle Radium-223 Perez et al. Principles and Practice of Radiation Oncology. 5th ed. Lippincott Williams & Wilkins; 2007.

33 Phase III ALSYMPCA Trial Eligibility (n = 921) Confirmed symptomatic CRPC 2 bone metastases 2:1 R Radium Best supportive care (n = 614) No visceral metastases Post docetaxel/unfit for docetaxel Placebo + Best supportive care (n = 307) Median overall survival: 14.9 versus 11.3 months Time to first skeletal-related event: 15.6 versus 9.8 months Bone pain Grade >3: 18% versus 23% Parker C et al. Proc ESMO 2012;Abstract 898PD.

34 Parker C, et al. New Engl J Med. 2013;369: ALSYMPCA: Predictors of Radium-223 Benefit?

35 ALSYMPCA Updated Analysis: Select Adverse Events All Grades Grades 3 or 4 Patients with AEs n, (%) Radium-223 n = 600 Placebo n = 301 Radium-223 n = 600 Placebo n= 301 Hematologic Anemia 187 (31) 92 (31) 77 (13) 39 (13) Neutropenia 30 (5) 3 (1) 13 (2) 2 (1) Thrombocytopenia 69 (12) 17 (6) 38 (6) 6 (2) Non-Hematologic Bone pain 300 (50) 187 (62) 125 (21) 77 (26) Diarrhea 151 (25) 45 (15) 9 (2) 5 (2) Nausea 213 (36) 104 (35) 10 (2) 5 (2) Vomiting 111 (18) 41 (14) 10 (2) 7 (2) Constipation 108 (18) 64 (21) 6 (1) 4 (1) Safety of taxane chemotherapy following radium-223 not well characterized Parker C, et al. New Engl J Med. 2013;369: Parker et al NEJM 2013

36 Radium-223: Summary Administration: Once every 4 wks for 6 infusions 60-second IV infusion Given by radiation oncologist or nuclear medicine radiologist Enteric excretion No pre-medication, no post-medication CBC check before each treatment Clinical Benefit: Primary endpoint of improvement in symptomatic SRE 3.6-mo benefit in OS Should be considered in symptomatic men with bone-predominant mcrpc Consider spinal imaging for epidural disease in men with high burden of disease and rapid progression; palliative EBRT should be used if high risk for spinal cord compression

37 Case 1C 12m later (metastatic CRPC progression on 1 st line) Pt doing well on AI and monthly denosumab minimal S/E but new hip pain Restaging bone scan and CT shows progression of bone mets Options? Radium 223-bone only disease docetaxel Cabazitaxel (post docetaxel) Palliative RT

38 Metastatic Prostate Cancer

39 Metastatic CRPC Phase III Trials Agent Setting Comparator Arm in Trial OS Benefit, Months (HR) Docetaxel Mitoxantrone 2.4 (0.76) Abiraterone Chemotherapy- Naïve Prednisone 4.4 (0.81) Enzalutamide Placebo 2 (0.70) Cabazitaxel Mitoxantrone 2.4 (0.70) Abiraterone Post-Docetaxel Prednisone 4.6 (0.74) Enzalutamide Placebo 4.8 (0.63) Radium-223 Placebo 3.6 (0.70) +/- Chemotherapy Sipuleucel-T Placebo 4.1 (0.78) 39

Chemotherapy Docetaxel 75mg/m2 q3weeks with prednisone for met CRPC (Level 1, grade A) Cabazitaxel is recommended for mcrpc patients progressing on or following docetaxel (Level 1, Grade A) For

40 Chemotherapy Docetaxel 75mg/m2 q3weeks with prednisone for met CRPC (Level 1, grade A) Cabazitaxel is recommended for mcrpc patients progressing on or following docetaxel (Level 1, Grade A) For patients who have had a good response to first-line docetaxel re-treatment with docetaxel can be considered (Expert Opinion) Mitoxantrone has not shown any survival advantage, but may give symptomatic relief. Of note in the second-line setting, mitoxantrone has limited activity and increased toxicity (Grade C).

41 Case 1D 12 months later (metastatic CRPC progressing on 2 nd line) Was doing OK after receiving radium 223 then was started on cabazitaxel chemotherapy but CT shows new adenopathy and liver lesion To recap: 1. Continuous ADT 2. Early docetaxel chemotherapy 3. AI therapy 4. Bone protective therapy 5. Bone targeted therapy 6. 2 nd line chemotherapy Wants something else

Immuno-Oncology Atezolizumab Inhibits the Binding of PD-L1 to PD-1 and B7.1 can restore antitumor T-cell activity and enhance T-cell priming [1] 1. Petrylak DP, et al. ASCO 2015. Abstract 4501. 2. Akbari O, et al.

42 Immuno-Oncology Atezolizumab Inhibits the Binding of PD-L1 to PD-1 and B7.1 can restore antitumor T-cell activity and enhance T-cell priming [1] 1. Petrylak DP, et al. ASCO Abstract Akbari O, et al. Mucosal Immunol. 2010;3: Matsumoto et al. Biochem Biophys Res Commun. 2008;365: Brown JA, et al. J Immunol. 2003;170: Latchman Y, et al. Nat Immunol. 2001;2: Slide credit: clinicaloptions.com

43 Genomic targeted therapy

44 Genomics to classify based on actionable mutation

45 Target Matched to Drug

46 Approach to Metastatic PC 1. Maintain castrate levels testosterone 2. Bone-directed therapy 3. Androgen Receptor Inhibition 4. Chemotherapy 5. Palliative RT if indicated 6. Clinical trials

Advanced Prostate Cancer

Advanced Prostate Cancer SAMO Masterclass 4 th March 2016 Aurelius Omlin Conflicts of interest Advisory Rolle: Astra Zeneca, Astellas, Bayer, Janssen, Pfizer, Sanofi Aventis Research support: TEVA, Janssen