Cytoreductive Radical Prostatectomy for de Novo Metastatic Prostate Cancer

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2 Cytoreductive Radical Prostatectomy for de Novo Metastatic Prostate Cancer Timothy G. Wilson, MD Professor and Chair of Urology John Wayne Cancer Institute Santa Monica, California

3 Disclosures I am on the Speakers Bureau for Intuitive Surgical and Stock/Shareholder in HaimaChek.

4 Theoretical Advantage of Cytoreductive RARP Prevent continued metastatic seeding Relieve Local Progression Retention, Upper tract obstruction, urinary and pelvic pain, hematuria Quality of life Delay time to castrate resistance Survival

5 Prevent Continued Metastatic Seeding

6 Prospective phase II trial. (n = 40) 30 had RP and 2 had CxPx - 4 decided against surgery, 2 progressed, 2 unresectable High probability of LN mets. No visceral or bone mets. All required at least one follow up biopsy-proven lymph node met. Primary cancer GS = 8 or higher. Primary stage T3 or T4 deemed resectable after neoadjuvant therapy. Excluded non adenocarcinoma and severe comordidities. All received 3 cycles of docetaxel and leuprolide for one year RP Histology and markers (n = 29) compared to untreated archived specimens.

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9 No correlation between biomarker levels and stage or tumor volume. NS differences in expression of proliferation, apoptosis or NE differentiation. IGF-I increased after Tx. AR nuclear expression high in both groups. Increased expression of steroid-synthetic enzymes (CYP17, SRD5A1) in treated compared to untreated. Epithelial and stromal Hh signaling upregulated in treated specimens. Angiogenesis marker VEGF downregulated with treatment.

10 Journal of Urology 193:832,2015

11 N = 23 all had RP after ADT Surgically resectable local disease 3 or less bone mets Absence of gross RP lymph node mets Absence of bulky pelvic lymph nodes (> 3cm) No visceral mets Compared to 38 men treated only with ADT followed until: Progression Development of castration resistance Death Follow-up: Q 3mo for 2 yrs; Q 6mo for 2 yrs, then annually. BCR = PSA increase to 0.2ng/ml validated by 2 consecutive increases at 2 week intervals. No routine imaging unless PSA > 5ng/ml. J Urol. 193:832, 2015

12 Heidenreich et al. J Urol 193:832,2015

13 J Urol. 193:832, 2015

14 Group 1 3 (13%)had intervention for lymphoceles 2 (8.6%) had postop DVT 1 PE A third DVT at 2 years postop 56% zero pads 91.3% zero to one pad Group % required surgical or perc intervention for local progression 23.7% TURP, 5.2% PCN 10.4% received transfusions Mean time to intervention = 23mo No GS <8 required an intervention J Urol. 193:832, 2015

15 J Urol. 193:832, 2015

16 J Urol. 193:832, 2015

17 EUROPEAN UROLOGY 65 (2014)

18 Culp et al. EUROPEAN UROLOGY 65 (2014) Surveillance Epidemiology and End Results (SEER) Database Identified 8185 men with Stage IV (M1a c), received no local therapy 245 underwent RP 129 underwent Brachytherapy

19 EUROPEAN UROLOGY 65 (2014)

20 EUROPEAN UROLOGY 65 (2014)

21 EUROPEAN UROLOGY 65 (2014)

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23 MULTIMODAL SYSTEMIC THERAPY WITH DEFINITIVE PROSTATECTOMY IN DE NOVO METASTATIC PROSTATE CANCER Ramkishen Narayanan, MD, Jennifer A. Linehan, MD, Nicholas J. Vogelzang, MD, Chikako Matsuba, PhD, Przemyslaw Twardowski, MD, Timothy G. Wilson, MD John Wayne Cancer Institute at Providence Saint John s Health Center, Santa Monica, CA; Comprehensive Cancer Centers of Nevada, Las Vegas, NV Table 1. Preoperative characteristics (N=20) Median PSA (ng/ml) at dx 27 ( ) Biopsy Gleason score (%): 6 5% 7: % 5% 8 (all 4+4) 25% 9: % 5% 10 15% ct stage (%): T1c T2 T3 T4 cn stage (%): N0 N1 cm stage (%): M1a M1b 25% 10% 55% 10% 45% 55% 10% 90% Median # extrapelvic nodes 2 (1-5) (incident in 40% of pts) Median # osseous lesions 5 (1-13)

24 MULTIMODAL SYSTEMIC THERAPY WITH DEFINITIVE PROSTATECTOMY IN DE NOVO METASTATIC PROSTATE CANCER Ramkishen Narayanan, MD, Jennifer A. Linehan, MD, Nicholas J. Vogelzang, MD, Chikako Matsuba, PhD, Przemyslaw Twardowski, MD, Timothy G. Wilson, MD John Wayne Cancer Institute at Providence Saint John s Health Center, Santa Monica, CA; Comprehensive Cancer Centers of Nevada, Las Vegas, NV Table 2. Peri-operative findings (N=20) Median age (yrs) at surgery 66 (39-78) Preop invasive tx for bladder outlet obstruction (BOO) N = 4 [Foley (1); SPT (1); TUR (2)] Median ECOG score at time of surgery 0 (0-1) Surgical procedure (%): RARP + PLND RARP only Open RP + PLND Robotic cystoprostatectomy + PLND 75% (N=15) 10% (N=2) 10% (N=2) 5% (N=1) Pathologic (yp and N) stage (%): T0 T2 T3a T3b T4 Nx N0 N1 Positive surgical margin rate (%) 25% 20% 5% 40% 10% 10% 45% 45% 30% (all ypt3) Extraprostatic extension (%) 55%

25 MULTIMODAL SYSTEMIC THERAPY WITH DEFINITIVE PROSTATECTOMY IN DE NOVO METASTATIC PROSTATE CANCER Ramkishen Narayanan, MD, Jennifer A. Linehan, MD, Nicholas J. Vogelzang, MD, Chikako Matsuba, PhD, Przemyslaw Twardowski, MD, Timothy G. Wilson, MD John Wayne Cancer Institute at Providence Saint John s Health Center, Santa Monica, CA; Comprehensive Cancer Centers of Nevada, Las Vegas, NV Median EBL RARP and PLND Table 4. Operative complications and continence outcomes 150 (50-900cc) Complications grade 3 or greater and 1 (5%) pelvic abscess 1 (5%) urine leak Patient reported continence Continent 37% Mild incontinence 25% Severe incontinence 16% Not specified 21%

26 MULTIMODAL SYSTEMIC THERAPY WITH DEFINITIVE PROSTATECTOMY IN DE NOVO METASTATIC PROSTATE CANCER Ramkishen Narayanan, MD, Jennifer A. Linehan, MD, Nicholas J. Vogelzang, MD, Chikako Matsuba, PhD, Przemyslaw Twardowski, MD, Timothy G. Wilson, MD John Wayne Cancer Institute at Providence Saint John s Health Center, Santa Monica, CA; Comprehensive Cancer Centers of Nevada, Las Vegas, NV ID *MST pre- RP Clinicopathologic data per patient PSA just prior to RP Start of systemic tx to RP (mos) % Ca in gland F/U since RARP (mos) 1 ABO ABC BCD BDC ABC < ; +NE BDC ABDEF < ABCDF < BDCFE BCF < ABCD < ABCF < BAC AB BCEDF ABCD nr; +NE ABCDF ABCD nr BC ABCD < Preop PSA: < ng/ml 90% < 0.2ng/ml Systemic Therapy: 6.0 to 39.8 months Average Time: 16.1 months 85% received ADT and Chemo *MST Legend: A = 1 st generation anti-androgen B = GNRH agonist/antagonist C = chemotherapy D = abiraterone or enzalutamide; E = Provenge F = Radium 223 O = ipilimumab

27 Cytoreductive Radical Prostatectomy for de Novo Metastatic Prostate Cancer Summary and Conclusions Cancer cells with metastatic potential remain in primary despite systemic therapy and low PSA s. Roughly 1/3 of patients with the prostate left in place will need a surgical or radiographic intervention to treat local symptoms and problems - especially in GS > 7. CRP (open or robotic) can be done safely with acceptable complications. CRP may decrease time to castrate resistance and improve cancer specific and overall survival.

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