1. Prostate cancer: Role of systemic therapy in high risk and locally advanced disease
Robert Dreicer, M.D., M.S., FACP
Chair Dept of Solid Tumor Oncology
Taussig Cancer Institute
Cleveland Clinic
Professor of Medicine
Cleveland Clinic Lerner College of Medicine

2. Clinical States In Prostate Cancer
Sipuleucel-T
Metastatic
Disease
(De novo)
Denosumab
Organ
Confined
Cabazitaxel
Metastases
Castrate
Resistant
Asymptomatic
Metastases
Castrate
Resistant
Symptomatic
Metastases
Castrate
Resistant
Post Docetaxel
Metastases
Castrate
Resistant
Post
Cabazitaxel
Rising PSA
Hormone
Naive
Locally
Advanced
Disease
Rising PSA
Castrate
Alpharadin, MDV ?
Abiraterone
Modified from Scher HI, et al. Urology :323-7

3. Definitions Locally Advanced prostate cancer:
Gleason 8-10
PSA ≥ 15
T3 disease
High risk(for this presentation) - biochemical failure PSA DT < 12 months

4. Is cure possible only when it is not necessary ?”
Is cure necessary?
Is cure possible only when it is not necessary ?”
Willet Whitmore, Jr.,M.D.
Distinguished Chair of Urology at Memorial Sloan Kettering

5. Issues: High systemic failure rate
Locally Advanced Prostate Cancer: A clinical dilemma that has not gone away
Issues:
High systemic failure rate
Poorly controlled by unimodality therapy
Clearly a group at risk of dying from prostate cancer

6. Locally Advanced Prostate Cancer: A clinical dilemma that has not gone away
What we know:
Multimodality therapy is the standard of care for these patients
Surgery/adjuvant radiotherapy
EBRT/ADT
Neoadjuvant hormonal therapy prior to RRP- NOPE

7. Locally Advanced Prostate Cancer: A clinical dilemma that has not gone away
What we dont know:
Is adjuvant and salvage radiotherapy equal?
Does brachytherapy/ADT = EBRT/ADT
Is there a role for perioperative systemic therapy
i.e. does earlier use of docetaxel improve outcomes

8. Adjuvant Radiotherapy
EORTC 22911: 1005 pts
Adj xrt PFS advantage with early radiotherapy: 74.8% versus 52.6% (p < 0.001)
SWOG 8794: 410 pts
Adj xrt PFS advantage with early radiotherapy: 67% versus 48% (p < 0.001)
metastatic-free survival was 84% vs 69% at 5 yrs, 68% vs 49% at 10 years with an (HR of 0.62  p = 0.001)
Improved OS (median 15.2 yr compared with 13.5 yr, p = 0.031)
Bolla et al. Lancet ;366):572-8, Thompson et al. J Urol. 2009;181:956-62

9. Thompson et al. J Urol. 2009;181:956-62
Survival By Treatment Arm 0%
20%
40%
60%
80%
100% 5 10 15 20
Years from Registration
90%
HR 0.73 (95% CI 0.55, 0.97)
p=0.031
74%
89%
50%
66%
39%
Median
At Risk
Death
in Years
Adjuvant RT
214 87
15.2
Observation
211
108
13.5
Thompson et al. J Urol. 2009;181:956-62

11. High-risk localized CAP
CALGB 90203: Phase III Study of Radical Prostatectomy Alone +/- Docetaxel in High-Risk Localized Prostate Cancer (PUNCH)
RANDOMIZE RP
High-risk localized CAP
Primary EPC = 5-year bPFS
ADT + docetaxel followed by RP
bPFS = biochemical progression-free survival.
Eastham et al, 2003. 11

13. What is the Natural History Of Patients Who Relapse After Local Therapy
304 men relapsed after surgery
No hormones until (+) bone scan
Time to PSA rise, Gleason, PSADT were predictors of survival RP
8 yrs
5 yrs
First Rise in PSA
Bone scan
(+)
Death
Pound CR, et al. JAMA 1999; 281:1591
Pound JAMA 1999

14. Biochemical Failure: Sorting out the relatively good and bad actors
Differences in biochemical failure between surgical and radiotherapy patients
PSA bounce
Remember to consider the biology
Role of salvage therapies
For RRP failure
For EBRT/Brachy failure

15. Patients with a Rising PSA-Importance of PSADT
Freedland SJ, et al. JAMA. 2005;294(4): 15

16. Patients with a Rising PSA-Importance of PSADT
PSADT Median Time to Median Survival
(months) Metastases (years) (years)
D'Amico AV, et al. J Natl Cancer Inst. 2004;96(7):

17. Challenges in Managing Patients with PSA only Disease
Moving the patient ( and some of his docs) away from a curative mind set
Recognition of limitations of therapy
“really early ADT”
Using PSA DT to inform timing of evaluation/intervention

18. Androgen Deprivation Therapy Side Effects, Toxicities
Loss of libido
Muscle mass loss
Osteoporosis, osteoporotic related fx
Weight gain- increase in abdominal girth
Cognitive dysfunction
Diabetes/metabolic syndrome
Increase in coronary artery disease

20. "He is a man of splendid abilities, but utterly corrupt.
Like rotten mackerel by moonlight, he shines and stinks."
John Randolph, Representative of Virginia
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