Prostate cancer: Role of systemic therapy in high risk and locally advanced disease

Robert Dreicer, M.D., M.S., FACPChair Dept of Solid Tumor OncologyTaussig Cancer InstituteCleveland ClinicProfessor of Medicine Cleveland Clinic Lerner College of Medicine

LocallyAdvancedDisease

Rising PSAHormone

Naive

Rising PSACastrate

MetastasesCastrateResistant

Asymptomatic

Metastases

CastrateResistant

Symptomatic

OrganConfined

Metastatic Disease

(De novo)

Clinical States In Prostate Cancer

MetastasesCastrateResistant

Post Docetaxel

MetastasesCastrateResistant

Post Cabazitaxel

Sipuleucel-T

Abiraterone

CabazitaxelDenosumab

Modified from Scher HI, et al. Urology 2000 55:323-7

Alpharadin, MDV- 3100 ?

Definitions

Locally Advanced prostate cancer: Gleason 8-10 PSA ≥ 15 T3 disease

High risk(for this presentation) - biochemical failure PSA DT < 12 months

“Is cure possible?

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

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

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

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

Bolla et al. Lancet. 2005 ;366):572-8, Thompson et al.

J Urol. 2009;181:956-62

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)

HR 0.73 (95% CI 0.55, 0.97) p=0.031

90%

74%

50%

39%

66%

89%

0%

20%

40%

60%

80%

100%

0 5 10 15 20Years from Registration

Adjuvant RTObservation

At Risk214211

Death87108

Medianin Years

15.213.5

Survival By Treatment ArmSurvival By Treatment Arm

Thompson et al. J Urol. 2009;181:956-62

High-risk localized

CAP

RP

ADT + docetaxel followed by RP RA

ND

OM

IZE

Primary EPC = 5-year bPFS

bPFS = biochemical progression-free survival.Eastham et al, 2003.

CALGB 90203: Phase III Study of Radical CALGB 90203: Phase III Study of Radical Prostatectomy Alone +/- Docetaxel in High-Risk Prostatectomy Alone +/- Docetaxel in High-Risk

Localized Prostate Cancer (PUNCH)Localized Prostate Cancer (PUNCH)

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

First Rise in PSA

RP

Bone scan (+)

Death

8 yrs 5 yrs

Pound JAMA 1999Pound CR, et al. JAMA 1999; 281:1591

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

Patients with a Rising PSA-Importance of PSADT

Freedland SJ, et al. JAMA. 2005;294(4):433-439.

Patients with a Rising PSA-Importance of PSADT

PSADT Median Time to Median Survival

(months) Metastases (years) (years)

3 2 6

6 4 8

9 6 10

12 8 12

D'Amico AV, et al. J Natl Cancer Inst. 2004;96(7):509-515.

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

Androgen Deprivation TherapySide 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

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

John Randolph, Representative of Virginia(1773-1833)