Non-metastatic CRPC and Asymptomatic Metastatic CRPCWhich treatment for which patient Michael A. Carducci, M.D., FASCO AEGON Professor in Prostate Cancer Research Johns Hopkins Kimmel Cancer Center Baltimore, MD
May 4, 2012
1
Disclosures
• Consultant
Amgen Bayer Sanofi Data Safety Monitoring Medivation/Astellas
Educational Objectives • Discuss the clinical state “non-metastatic castration resistant prostate cancer” • Review treatment options and controversies for this patient population • Examine differences between “non-metastatic” to “asymptomatic” CRPC and the treatment landscape
July 11, 2013
3
Definition of Castration-resistant Prostate Cancer (CRPC) • CRPC defined as disease progression on androgen deprivation therapy • Criteria defining CRPC vary – Presence of progressive metastatic measurable disease (by RECIST) – Progression of bone metastases (by bone scan) – Biochemical progression: 2 consecutive increases in PSA – Castrate testosterone levels ( 18.8 mos
0.8
0.6
0.4
0.2
0 0 0.5 1.0 1.5 2.0 2.5 3.0 Yrs Since Random Assignment Smith MR, et al. J Clin Oncol. 2005;23:2918-2925. Reprinted with permission. © 2005 American Society of Clinical Oncology. All rights reserved.
Denosumab to Prevent Metastases
Patients with CRPC and no bone metastases; PSA > 8 or PSADT < 10 mos
Denosumab 120 mg monthly
Placebo monthly (N = 1435)
Primary endpoint: bone metastasis–free survival
Smith MR, et al. Lancet. 2012.
Proportion of Patients With Bone Metastasis–Free Survival
Primary Endpoint: Bone Metastasis-Free Survival 1.0
HR: 0.85 (95% CI: 0.73-0.98; P = .028)
0.8 0.6 0.4 Median Mos Placebo 25.2 Denosumab 29.5
0.2 0
39
42
Patients at Risk, n Placebo 716 691 569 500 421 375 345 300 259 215 168 137 99 60 Denosumab 716 695 605 521 456 400 368 324 279 228 185 153 111 59
36 35
0
3
Smith MR, et al. Lancet. 2012.
6
9
12
15 18 21 24 Study Mo
27
30 33
36
Metastasis-Free Survival What is meaningful? • ODAC meeting to discuss 11/2011 – Meaningful > 1 year, and based on toxicity profile
• ARN-509 / Enzalutamide / Orteroneleach will launch Phase III studies to delay metastasis • Can immunotherapy be moved to this setting, when no improved PFS noted in more advanced disease July 11, 2013
25
Androgen Pathways Still Active • Maintenance of castrate level of testosterone life long • Second line hormonal therapy most commonly used – Anti-androgens- bicalutamide, nilutamide, flutamide – Androgen synthesis inhibitors- ketoconazole – Estrogens – Newer agents (not yet approved but available) July 11, 2013
26
Sipuleucel-T Ketoconazole Estrogens Abiraterone Orteronel Enzalutamide Tasquinimod Ipilumimab Radium-223 11ststline line
M0
M1
Low-volume metastases, no/minimal symptoms
Docetaxel Curtisen Cabazitaxel Mitoxantrone
1st line Cytotoxic Progressive metastases, symptomatic
Mitoxantrone Abiraterone Cabazitaxel Enzaluatmide Radium 223 Cabozantinib
2nd line
High-volume or symptomatic metastases
Death
Sipuleucel-T Ketoconazole Estrogens Abiraterone Orteronel Enzalutamide Tasquinimod Ipilumimab
Improve survival QoL Docetaxel Curtisen Cabazitaxel Mitoxantrone Extend time Delay symptoms Defer chemotherapy
1st line 11ststline line
M0
M1
Low-volume metastases, no/minimal symptoms
Chemotherapy Based Progressive metastases, symptomatic
High-volume or symptomatic metastases
Death
FDA-Approved Agents for Prevention of SREs in Metastatic Prostate Cancer Agent Zoledronic acid Denosumab
Drug Class
Recommended Dose and Schedule
Bisphosphonate
4 mg IV q3-4w
RANKL-targeted MAb
120 mg SQ q4w
NCCN recommends either zoledronic acid or denosumab for prevention/delay of SREs in men with metastatic CRPC[1] Choice between agents may be guided by – Underlying comorbidities – Adverse events: renal insufficiency, ONJ, hypocalcemia – Logistics - Differences in administration (SQ vs IV) – Cost considerations 1. NCCN. Clinical practice guidelines in oncology: prostate cancer. v.4.2011.
Summary • In 2013, “Non-metastatic” CRPC remains a clinical state • Management remains conservative – Reliance on traditional agents – Bone health – Attention to metabolic issues
• Asymptomatic metastatic CRPC in the midst of changing treatment landscape, with limited data on sequence /timing July 11, 2013
30
