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

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- 3100 ? Abiraterone Modified from Scher HI, et al. Urology 2000 55:323-7

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 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

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

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

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. 2005 ;366):572-8, Thompson et al. J Urol. 2009;181:956-62

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

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

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

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. 15

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 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

"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)